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{"paper_id": "159350775", "_pdf_hash": "a1ffbcba5e3de3c43cdc9689264e54c42873d73d", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "159355391", "_pdf_hash": "8bba4d8c9df7a83e3d3bec8408e1868c54a80d41", "abstract": [{"section": "Abstract", "text": "The emergence and the dominance of African banks in Africa have been touted as one of the popular mechanisms for financial development leading to a concept termed as Pan-African cross-border banking. African Banks have become dominant in the African market as opposed to European colonial banks substantially increasing their geographic footprints on the continent. African banks have become economically significant beyond their home countries and of systematic importance in a number of jurisdictions. This systematically examined the influence of the political environment on Pan-African cross-border banking using Kenya Commercial bank as a case study.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Interpretive research paradigm guided the study seeking using qualitative data by interviewing employees, managers, and policymakers from the three subsidiaries of Kenya Commercial Bank; Uganda, Rwanda, and Burundi. This was further supported by secondary data collected from journal articles and reports from the Kenya Commercial Bank.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "The study established that political environment plays an important role in influencing Pan-African cross-border banking either through catalysing or inhibiting. Despite effort integration by African Union, regional unions like East African Community there still areas for improvement. In order to enhance Pan-African cross-border banking, there has to be systematically management of political environment which was distorted by history, ideologies, different political systems, different regulatory frameworks between the subsidiaries and home countries. This will further enhance the significance of Pan-African banks African cross-border banks enhancing economic development within Africa.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Host and home country regulatory environment diversely influences the cross-border strategy and competitiveness of cross-border bank. Multinational Enterprises jurisdiction and organisational structures are paramount in the development and implementation of the cross-border business strategy (Windsor, 2007) . Getz (2006) highlights that the political environment in different jurisdictions determines the strategy. MNEs are fragmented along global, regional, national, and sub-national regulatory dimensions (Windsor, 2007) . Bonardi, Hillman, and Keim (2005) argue that each regulatory arena becomes a political market where demand and supply depend on the prevailing regulatory in the jurisdiction. Svaleryd, Hakkala, and Norback (2005) argue that domestic firms are more effective than international firms because of their knowledge of and alignment to domestic policies. Managers responsible for the development of an international strategy will have to face many different types of political, legal, accounting, cultural, language, and payment systems (Diaconou, 2012) . According to Gooderham (2013) MNEs are confronted by political environments in both domestic and foreign countries. Lundan (2014) argues that diverse forms of governance structures make operations of MNEs across borders a bigger challenge than domestic operations. Gooderham (2012) opines that undertaking cross-border trade without incorporating firms' responses to national policies and actions results in failure because government interventions are central to cross-border trade. Governance structures together with policies of the home and subsidiary countries influence the strategies employed by MNCs (Lundan, 2014) . Cross-border involves following a regulatory discipline that encompasses a firm's business environment together with government policies (Camillo, 2015) . The political environment provides a critical context for MNEs at home and abroad (Shenkar and Luo, 2008: 184) . Governments are responsible for trade and investment policies, capital, and exchange controls and transfer pricing regulations (Diacanou, 2012) . Home and host countries regulatory environments significantly contribute to greater certainty with regard to predictability and consistency in implementation, a significant reduction in compliance costs across the region, and raising standards in more challenging environments and emergence of international and global strategy. Frameworks in the home and host country influence the strategy and competitiveness of cross-border banking (Becks et al., 2014) .", "cite_spans": [{"start": 1059, "end": 1075, "text": "(Diaconou, 2012)", "ref_id": "BIBREF7"}, {"start": 1091, "end": 1107, "text": "Gooderham (2013)", "ref_id": "BIBREF12"}, {"start": 1194, "end": 1207, "text": "Lundan (2014)", "ref_id": "BIBREF17"}, {"start": 1343, "end": 1359, "text": "Gooderham (2012)", "ref_id": "BIBREF11"}, {"start": 1686, "end": 1700, "text": "(Lundan, 2014)", "ref_id": "BIBREF17"}, {"start": 1840, "end": 1855, "text": "(Camillo, 2015)", "ref_id": "BIBREF4"}, {"start": 2553, "end": 2573, "text": "(Becks et al., 2014)", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Introduction", "text": "The study to undertake an assessment of pan-African cross-border competitiveness was assessed by assessing the different elements that influence the political environment in the subsidiary and home country. Different aspects of political environments were examined by use of qualitative statements. The political elements in the subsidiary and home country include; regulatory frameworks, monitoring, and supervision, a collaboration between regulators, political stability, political system, political ideology, political history, a judicial system, social norms, and cultural norms. Gooderham (2013) argues that MNEs have to deal with the political and socio-cultural environment in both domestic and foreign countries. The major emphasis was to understand the participant's point of view, interpretation and the rational approach, observations and measurements in natural settings, subjective and insider view and closeness to the data.", "cite_spans": [{"start": 585, "end": 601, "text": "Gooderham (2013)", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Methodology", "text": "The study used the case study research design based on interpretive research philosophy. Qualitative methodologies are popular in social sciences for validation of models as it provides the researchers with the ability to understand the experiences of the respondents (Strauss & Corbin, 1998; Ghauri&Gronhaug, 2003) . McGloin (2008:45) argued that qualitative research is concerned with the explanation of a social phenomenon focusing on people's behaviour being the effect of events on people, cultural influence, developments and differences in social groups. Qualitative study facilitated the expression of experiences which couldn't be expressed in numbers (Strauss & Corbin, 2003 , Berg, 1989 . It emphasized understanding from the participant's point of view, interpretation and the rational approach, observations and measurements in natural settings, subjective and insider view and closeness to the data in relation to the impact of political environment on competitiveness by a cross-border bank.", "cite_spans": [{"start": 268, "end": 292, "text": "(Strauss & Corbin, 1998;", "ref_id": "BIBREF19"}, {"start": 685, "end": 697, "text": ", Berg, 1989", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Methodology", "text": "IMF (2017) argues that despite the global financial crisis, Africa has witnessed a rapid expansion of cross-border banking, led by banking groups based in Africa that are spurring financial and economic integration and transforming the continent's financial landscape. Pan-African banks have become economically significant beyond their home countries and of systematic importance in a number of jurisdictions. Pan-African banks have become significant in the different regions; Nigerian Banks in West Africa, South African Banks in South African Development Community (SADC) countries and Morrocan Banks in North Africa. Kenya Commercial bank was used as a case for studying cross-border banking as the phenomenon was similar where regional banks had influence within the different regions. The approach enabled the researcher to explore operations of Kenya Commercial bank in the four countries covered by the scope of this research. This enlightened the researcher on the insights of the holistic behaviour and regulatory environments in Kenya, Uganda, Rwanda, and Burundi.", "cite_spans": [], "ref_spans": []}, {"section": "Methodology", "text": "The researcher interviewed employees, policymakers, and regulators of Kenya Commercial Bank form Uganda, Rwanda, and Burundi subsidiary branches. The studies focused on these are the major developers of strategy with an understanding of competitiveness in cross-border banking. This was further supported by secondary data collected from journal articles and reports from the Kenya Commercial Bank.", "cite_spans": [], "ref_spans": []}, {"section": "Findings", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Regulatory Framework Impact on Cross-border Strategy and Competitiveness", "text": "Regulatory framework constitutes requirements, restrictions, guidelines that are established by the central banks in different jurisdictions in order to maintain the integrity of the monetary system. The subsidiary and home regulators undertake the process of regulating the banking in the different jurisdictions. The quantitative part of the study provided insight that subsidiary and home regulatory frameworks are critical influence strategy and competitiveness. Most of the respondents interviewed argued that regulatory frameworks in the different jurisdictions are critical in influencing the actions of banks in different jurisdictions.", "cite_spans": [], "ref_spans": []}, {"section": "Regulatory Framework Impact on Cross-border Strategy and Competitiveness", "text": "Subsidiary regulatory frameworks are critical for the development of a strategy in cross-border banking. One of the employees opined that \"the regulatory framework shapes the business environment which the bank operates in the policies adopted by the Bank of Rwanda has an impact on the strategies adopted by the bank. The current policy adopted by the bank of Rwanda making its mandatory for all deposit-taking institutions to pay premium has increased the cost of doing business. This definitely influences the strategy and competitiveness.\" Gooderham (2012) opines that undertaking cross-border trade without incorporating firms' responses to national policies and actions results in failure because government interventions are central to cross-border trade. Governance structures together with policies of the subsidiary countries influence the strategies employed by MNCs (Lundan, 2014) . Peter one of the subsidiary manager in one of the countries submitted the regulatory mechanisms adopted are critical. In his argument said that \"the regulatory framework basically forms standards that all the players in the market have to use for playing. Failure to adhere to the regulations attracts penalties which are not good for business.\" Getz (2006) highlights that the political environment provides formal arrangements that determine the strategy. MNEs are fragmented along global, regional, national, and sub-national regulatory dimensions (Windsor, 2007) . Bonardi, Hillman, and Keim (2005) argue that each regulatory arena becomes a political market where demand and supply depend on the prevailing regulatory in the jurisdiction. Deficient contractual framework curtails the ability of financial institutions to enforce contracts and therefore undermining the cross-border contribution to the financial system influencing competitiveness and strategy (Beck et al., 2014) .", "cite_spans": [{"start": 544, "end": 560, "text": "Gooderham (2012)", "ref_id": "BIBREF11"}, {"start": 878, "end": 892, "text": "(Lundan, 2014)", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "Regulatory Framework Impact on Cross-border Strategy and Competitiveness", "text": "Qualitative findings also highlight that home-based regulatory frameworks are critical in the determination of the political environment of headquarters. The process of development of strategy and competitiveness of the cross-border bank is undertaken in the headquarters. The process of undertaking cross-border banking is provided for the circumstances in the political environment in the home country. Shenkar & Luo (2008:184) argue that \"regulatory environment at home and abroad as critical for cross-border banking strategy and competitiveness\". Political environments provide contexts for competitiveness and the ground for the firm to follow. Governments are responsible for trade and investment policies, capital, and exchange controls and transfer pricing regulations (Diaconou, 2012) . Home and host countries regulatory environments significantly contribute to greater certainty with regard to predictability and consistency in implementation, a significant reduction in compliance costs across the region, and raising standards in more challenging environments and emergence of international and global strategy. One of the employees interviewed argued that \"regulators in the different jurisdictions have different guidelines to be followed for successful competition. In the Republic of South Sudan, the regulator has conditions that the South Sudanese citizens can't be paid outside Sudan borders; the different jurisdictions also have different legal requirements for liquidity and cash ratios in the different countries. These strategies have different implications on strategy and competitiveness\". Frameworks in the home and host country influence the strategy and competitiveness of cross-border banking (Becks et al., 2014) . Another subsidiary manager in one jurisdiction explained the process of shaping the strategy by arguing that \"the bank mainly survives through commissions and the bank avoids incurring losses by payment of penalties to regulators that have negative consequences to the success, survival, and competitiveness of the bank\". The penalties charged by regulators have negative consequences on the bank success this shapes the strategy adopted by the bank as the employees are focused on meeting targets which have been set.", "cite_spans": [{"start": 778, "end": 794, "text": "(Diaconou, 2012)", "ref_id": "BIBREF7"}, {"start": 1725, "end": 1745, "text": "(Becks et al., 2014)", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Regulatory Framework Impact on Cross-border Strategy and Competitiveness", "text": "The cross-border seeking to gain competitiveness has to understand the regulatory frameworks in both subsidiary and home country jurisdictions. This facilitates in the process of developing an appropriate strategy mindful of regulatory frameworks in the different jurisdictions. Understanding of different frameworks supports both strategy and competitiveness in a cross-border bank.", "cite_spans": [], "ref_spans": []}, {"section": "Impact of Monitoring and Supervision on Cross-border Banking", "text": "The central banks undertake monitoring and supervision of financial institutions in the different jurisdictions in order to ensure adherence to the regulatory frameworks in respective countries. Cross-border bank operating in the different subsidiaries will be faced with different regulators undertaking supervision. The regulator establishes standards and guidelines on the different aspects of financial prudence; core principles of effective banking supervision, standards on capital adequacy. The study findings highlighted that monitoring and supervision undertaking by the subsidiary and home regulator influence the strategy adopted and competitiveness of the cross-border bank. Monitoring and supervision are critical in the execution of countries regulatory framework.", "cite_spans": [], "ref_spans": []}, {"section": "Impact of Monitoring and Supervision on Cross-border Banking", "text": "The process of ensuring that the players in the financial sector play by the rules and regulations stipulated critically determines the strategy adopted. One of the subsidiary managers argued that\"actions of the regulators determine the strategy and competitiveness of the bank. He argues the penalties and sanctions that come with monitoring and detrimental for the bank success, therefore pushing banks towards coming up with appropriate strategies which for success\". He said that the penalties erode the profitability of the bank and this pushes the subsidiary and headquarters to take due care of the strategies to be undertaken. Host countries regulatory framework drives the cross-border banking strategy; exchange rates, level of trade for the home country (Goldberg and Saunders, 1980) , regulations of in the host countries (Buch, 2003; Herrero and Per\u00ed a, 2007) , size of the bank, effective lending rate differentials, size of host banking market (Cho, 1986) , size of the home country, level of home country FDI (Fisher and Molyneux, 1996) , expected growth and degree of openness and diversification potential of host market, and efficiency of the subject bank (Focarelli and Pozzolo, 1999) .The subsidiary regulators usually play a traditional role of protecting and safeguarding their financial institutions and banking systems, taking into consideration the risks associated with the growth of cross-border activity in recent years (Becks, Fuchs, Singer and Makaio, 2014) . This forces them to put in place mechanisms for the prudent management of monetary policy within the jurisdiction.", "cite_spans": [{"start": 847, "end": 872, "text": "Herrero and Per\u00ed a, 2007)", "ref_id": "BIBREF13"}, {"start": 1175, "end": 1204, "text": "(Focarelli and Pozzolo, 1999)", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Impact of Monitoring and Supervision on Cross-border Banking", "text": "Qualitative data provides insight that home-based monitoring and supervision influence strategy and competitiveness. The regulatory framework together with supervision influence the strategy adopted. The legal requirements in the home country in terms of liquidity and other performance standards influence the strategy adopted in the headquarters. One of the headquarters respondents argued that \"the parent bank usually is influenced by the home regulator in terms of a strategy adopted to undertake operations in the home country. However, the process at home can have a bearing on the strategies adopted in the subsidiaries. This is because these mechanisms can free up capital for further investment in the subsidiaries. The practices learned in the home country, and the method of doing things usually are a template that will be first used in the subsidiaries.\" The depth of the home country banking system expands business opportunities which enable banks to offer more innovative products to exploit profit opportunities locally rather than expand abroad fully (Focarelli and Pozzolo (2005) . Schoenmaker and van Laecke (2007) argue that deeper banking systems provide banks with a steady income at home that enables them to finance cross-border operations and competitiveness. The regulators of the home will always work towards the establishment of home conditions which enhance banking growth at home and in foreign countries.", "cite_spans": [{"start": 1070, "end": 1099, "text": "(Focarelli and Pozzolo (2005)", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Impact of Monitoring and Supervision on Cross-border Banking", "text": "Monitoring and supervision in the subsidiary and home country influence the strategy and competitiveness in cross-border banking. However, subsidiary monitoring in the subsidiary is more critical for cross-border competitiveness. This implies that cross-border bank undertaking cross-border banking has to be mindful of both subsidiary and home regulatory supervision in the process of development of the cross-border strategy for competitiveness.", "cite_spans": [], "ref_spans": []}, {"section": "Impact of Regulators Collaboration on Cross-border Banking", "text": "Basel Committee on Banking Supervision (BCBS) established in 1974 provided a forum for regular cooperation between regulators (Gattani, 2014) . The Basel Committee provides a framework for cooperation establishes standards and guidelines for international standards on capital adequacy, core principles for effective banking supervision and concordat on cross-border banking supervision. The regulators released norms for regulation of the banking sectors using different standards; Basel 1-1988 , Basel II-2004 and Basel 3-2010 . The norms established to provide a framework for collaboration between the subsidiary and home-based regulators. Basel III established due to the failure of Basel II to adequately deal with the global financial crisis of 2008 (Gattani, 2014) .", "cite_spans": [{"start": 126, "end": 141, "text": "(Gattani, 2014)", "ref_id": "BIBREF10"}, {"start": 757, "end": 772, "text": "(Gattani, 2014)", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Impact of Regulators Collaboration on Cross-border Banking", "text": "Collaboration between the home and subsidiary regulators; the process of monitoring and supervision has become critical especially after the financial crisis in the USA that affected economies in different countries. Beck et al., (2014) argue that cross-border banks that are driven by regional integration provide potential channels of risks associated with the integration of financial systems as a result of increased linkage between the banking systems and financial markets these allows transmission of shocks across borders. Regulatory authorities in a subsidiary and home countries, therefore, have to develop appropriate frameworks for the management of risks from cross-border banking due to an emerging trend of interwoven financial systems as a result of cross-border banking. One of the regulators argued that \"the process of supervision of cross-border banks require collaboration as the home-based supervisors and subsidiary supervisors are usually guided by the same benchmarks of a stable monetary policy in the home country. She highlighted that whereas the home-based supervisors are concerned about the challenges in home economies but regional challenges can easily be transferred to the subsidiaries or home country. The process of collaboration facilitates the development of appropriate mitigation mechanism in advance\". However, the cross-border banks and regulators need to provide adequate risk management and mitigation mechanisms (Beck et al., 2014) . Management of risks as a result of cross-border banking calls for \"a greater commitment and adherence to common rules of the game, as embodied in internationally accepted standards and practices, in order to foster greater confidence in the financial sectors on the continent\" (Becks, Fuchs, Singer and Makaio, 2014) . Collaboration facilitates the process of building appropriate networks for appropriately dealing with risks across the borders. One of the respondents argued that \"the current economic crisis in Uganda and the East African regulators have to put in place mechanisms for dealing with contagion. The failure of banks in Uganda like Crane bank calls for the regulators in the different jurisdictions to focus on critical supervision and monitoring and being mindful of spillover effects or contagion to the different subsidiaries.\"", "cite_spans": [], "ref_spans": []}, {"section": "Impact of Regulators Collaboration on Cross-border Banking", "text": "Home regulators in the process of regulating the bank in the home country influence the strategies adopted by the bank both at home and in the subsidiaries. Becks et al. (2014) argues that in order to provide a competitive regulatory environment, authorities have to develop appropriate platforms and formats for regular information interchange with data providing for i) basic quantitative and qualitative characteristics of cross-border banks ii) supervisory data in relation to performance iii) regulatory frameworks with definitions underlying supervisory data and market intelligence. Regulatory harmonisation is a huge undertaking, and care needs to be taken to focus convergence efforts on key concerns, especially in environments with severe capacity constraints (Beck et al., 2014) . They advocate for upgrading of mechanisms by regulators by use of strategies like consolidated supervision of a bank's activities through all its affiliates, across sectors and jurisdictions; Memoranda of Understanding (MoU) between home and host supervisors; and Colleges of Supervisors (CoS) for individual cross-border financial institutions, are the basis for effective cross-border regulatory cooperation.", "cite_spans": [{"start": 157, "end": 176, "text": "Becks et al. (2014)", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Impact of Regulators Collaboration on Cross-border Banking", "text": "In order for Kenya Commercial Bank to be competitive, the bank has to respond to the subsidiary and domestic home regulators effectively. Collaboration facilitates the integration of the regulatory and supervisory responsibilities of the home and subsidiary regulators. The cross-border bank seeking to gain competitiveness has to appropriately understand the collaboration between the subsidiary and headquarters in order to appropriately respond to the requirements.", "cite_spans": [], "ref_spans": []}, {"section": "Influence of Political Stability on Cross-border Banking", "text": "Political stability determines the integrity and durability of a current government regime, measured by the amount of violence and other forms of instability in the nation. Subsidiary and home country political stability are critical in the determination of the atmosphere for banking. Political instability affects the level of economic activity in the jurisdictions.", "cite_spans": [], "ref_spans": []}, {"section": "Influence of Political Stability on Cross-border Banking", "text": "Qualitative findings agree with quantitative findings that cross-border strategy influences strategy and competitiveness in cross-border banking. Most of the respondents interviewed highlighted that the political stability is critical in determining the strategy which is adopted by the bank. One of the managers in the headquarters in his statement opined that \"the political instability in Kenya in 2007 greatly affected the operations within the country. He said that since the headquarters was the driver of most of the operations of the bank, it adversely affected the strategies and competitiveness of bank especially against those banks from other countries\". The headquarters are critical in the process of coming up with appropriate strategies and coordination of operations of the subsidiaries. Political instability in the home country substantially affects the strategy employed and competitiveness of the bank.", "cite_spans": [], "ref_spans": []}, {"section": "Influence of Political Stability on Cross-border Banking", "text": "Subsidiary political stability is equally important in the development of strategy and competitiveness of the bank. One of the regulators interviewed highlighted that currently there are two countries experiencing political instability; Southern Sudan and Burundi. He said that \"political instability South Sudan led the bank to close branches and repatriation of the staff from the Country\". It's imperative to highlight that political instability in the subsidiary influences cross-border strategy and competitiveness. This is in agreement with findings by KCB (2016) highlighting the poor performance of the bank in Burundi. Burundi's economy has experienced pressure as a result of the political crisis that engulfed the country resulting in poor economic performance, therefore, affecting the banking sector (KCB, 2016). The World Bank indicates that Burundi's economic growth contracted by 2.3% in 2015 compared to a GDP growth of 4.8% in 2014, coupled with an increase in inflation from 3.5% to 7.1% as a result of an increase in consumer goods. The treasury bills rates have doubled in the middle of 2014 before finally declining.", "cite_spans": [], "ref_spans": []}, {"section": "Influence of Political Stability on Cross-border Banking", "text": "Development of an appropriate strategy for competitiveness requires an assessment of the subsidiary and home country political stability. The bank has to continuously undertake an assessment of the political stability of the home and subsidiary for competitiveness in cross-border banking.", "cite_spans": [], "ref_spans": []}, {"section": "Influence of Judicial System on Cross-Border Banking", "text": "The judicial system is the court system provided in the different jurisdictions for interpretation and application of laws in the different countries. The system provides mechanisms for resolution of disputes in the different jurisdictions. The quantitative study undertaken in the first part of the study argued that the judicial system was not critical in the determination of cross-border strategy, but qualitative study pointed out that judicial system is critical in the determination of the strategy and competitiveness in cross-border banking.", "cite_spans": [], "ref_spans": []}, {"section": "Influence of Judicial System on Cross-Border Banking", "text": "Most of the respondents interviewed during the second part of the study argued that the judicial system in the subsidiary and home country are critical for strategy and competitiveness. The respondents argued that the judicial system is critical in the litigation process in case of breach of contracts. One employee in Rwanda argued that \"the courts are the temples of justice lack of justice will automatically lead to failure in the banks\". The judicial system in the subsidiary and home country provides a backbone for justice to execute. CSU (2010) argues that a good court system sustains firms' expectation that their contractual rights would be honoured in the face of contract breach, allowing them to commit necessary investments and to expand without worrying about contract reneging. Academic literature in law, economics, and finance emphasize the importance of effective contract enforcement to economic performance (Cooter and Ulen, 1988; La Porta et al., 1996) . The concept has become more critical especially with the emergence a notion that judicial systems in the different jurisdictions had different implications on the development of the credit market and economy. The findings are in agreement with Cristini et al., (2001:28) in the study of Argentina established that \"the country's federal structure places responsibility for enforcing these regulations in the hands of independent judiciaries. Local courts took a variety of approaches to enforcement, leading to regional differences in access to credit\". The study further established that the judiciary imputed different costs across different jurisdictions bringing in place difficult mechanisms for resolution of conflicts. It's imperative to note that whereas the judicial system indirectly influences the development of the strategy and competitiveness in cross-border banking. This is as a result of the divers' judicial systems imputing different costs to the penalties and strategy implementation.", "cite_spans": [{"start": 930, "end": 953, "text": "(Cooter and Ulen, 1988;", "ref_id": "BIBREF5"}, {"start": 954, "end": 976, "text": "La Porta et al., 1996)", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "Influence of Judicial System on Cross-Border Banking", "text": "Cross-border banking developing a cross-border strategy has to undertake an assessment of the judicial system of the subsidiary and home country -the dynamics in the different jurisdictions influence strategy especially in the process of litigation. The bank has to continuously undertake an assessment of the judicial systems of the home and subsidiary for competitiveness in cross-border banking.", "cite_spans": [], "ref_spans": []}, {"section": "Influence of Political Ideology on Cross-border Strategy and Competitiveness", "text": "Political ideology is an assortment of principles, ethical ideals, myths, doctrines, symbols of a social movement, class, institution, large group explaining how society should work and offering particular political blueprint for a particular social order (McClellan, 1986) ; rules of the game in the notion of institutional theory used in understanding economic and political systems worldwide that is neither the rules nor the enforcement of those rules is necessarily identical (North, 1991) . The political ideology of the home and subsidiary countries are argued to provide a playing ground for the development of a political system which is critical in the emergence of a strategy. A majority of the respondents interviewed during the qualitative part of the study argued that political ideology influences strategy, subsequently cross-border competitiveness. Academic literature has demonstrates how both formal and informal institutions affect outcomes (Kormendi and Meguire, 1985; Knack and Keefer, 1995; Kaufmann and Kraay, 2002; Zak and Knack, 2001; Beugelsdijk et al., 2004) economic growth, (Anderson and Marcouiller, 2002; de Groot et al., 2004 ) competitiveness.", "cite_spans": [], "ref_spans": []}, {"section": "Influence of Political Ideology on Cross-border Strategy and Competitiveness", "text": "The cross-country variation, therefore, brings into play the diverse institutional set up with different political dynamics as a result of political ideologies across the different jurisdictions. This substantially results in the variation in institutions, governance structures resulting in variation of political and cultural environments in the different jurisdictions (La Porta et al., 1997; Paldam, 2001; Knack and Zak, 2002) . Quantitative finding highlighted that political ideology in the home country didn't influence the cross-border strategy and competitiveness. However, the qualitative findings seemed to argue that political ideology is responsible for the emergence of the cross-border strategy and competitiveness. One of the respondents in his argument said that \"a look at the East African community may look the same, but the countries have different political ideologies that influence the business interactions in the East African countries. Tanzania basically tends to follow the Ujamma political ideology which emphasizes togetherness. Rwanda having emerged from the genocide has taken on strong stance towards respect of authority. The ideologies seem to shape the views of the citizens. The banks have to understand the political ideologies responsible for shaping institutions.\" Political ideology is an underlying variable which shapes the political and socio-cultural environments in the different jurisdictions. This is in agreement with Mullins (1972: 510) defined political ideology as \"a logically coherent system of symbols which, within a more or less sophisticated conception of history, links the cognitive and evaluative perception of one's social conditionespecially its prospects for the future -to a program of collective action for the maintenance, alteration or transformation of society.\"", "cite_spans": [], "ref_spans": []}, {"section": "Influence of Political Ideology on Cross-border Strategy and Competitiveness", "text": "Political ideologies of the subsidiary and home countries are critical in the determination of the political landscape which the cross-border banks. The landscape in the different territories provides for the establishment of appropriate strategies and competitiveness. Managers of cross-border banking have to understand political ideologies governing subsidiaries and headquarters appropriately.", "cite_spans": [], "ref_spans": []}, {"section": "Impact of Political Systems on Cross-border Strategy and Competitiveness", "text": "The political system provides for a coordinated set of laws, principles, ideas, and procedures in relation to a form of government in a given country. The mechanism for coordination of a government in the different jurisdictions provides different political environments for the cross-border bank.", "cite_spans": [], "ref_spans": []}, {"section": "Impact of Political Systems on Cross-border Strategy and Competitiveness", "text": "Most of the respondents at the headquarters and subsidiaries argued that the political systems are critical in the determination of the strategy and competitiveness. One of the headquarters managers in charge strategy argued that; \"systems employed by the government either liberalization or centralization is critical in the decision of the bank to establish and the extent of intervention in a particular economy\". The political system consisting of the principles, laws, ideas, and procedures are critical in determining the decision of investors. The rule of law, for instance, is critical in determining the investors or the bank's decision on how to invest and the form of organisation to invest. The political system provides for institutions formal and informal institutions provide the necessary fabric; the level of trust, social capital, and social network (Knack and Keefer 1997; North 1990; Shirley 2008; Zak and Knack 2001) facilitating transactions relationships. The political system provides a mechanism, such as government policies and behaviours related to the provision of infrastructure, tax burdens, and protection of property rights, labour, and entry regulations (World Bank 2005).", "cite_spans": [], "ref_spans": []}, {"section": "Impact of Political Systems on Cross-border Strategy and Competitiveness", "text": "One of the respondents from Uganda argued that \"the liberalisation of Ugandan economy triggered the emergence of cross-border banks like Kenya Commercial bank and United Bank of Africa, and Stanbic Bank\". Li and Xu (2002) argue that deregulation was critical for the emergence of new players in the telecom industry. African economies in the 1980s in the process of experiencing economic crises as a result of both poor domestic policies and external shocks liberalized their economies (Becks et al., 2014) . Many state-owned banks became insolvent due to political pressure to make unsustainable loans, but also because of the lack of technical expertise and poor management (Brown bridge and Harvey, 1998) .", "cite_spans": [{"start": 486, "end": 506, "text": "(Becks et al., 2014)", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Impact of Political Systems on Cross-border Strategy and Competitiveness", "text": "However, different dynamics in different jurisdictions continued to shape the landscapes in different countries in some African countries especially Nigeria and Kenya the legislation for lower banking requirements enabled the local banks to gain competitiveness by returns in sectors like foreign exchange (Becks et al., 2014) . Specifically in Kenya prudent management and strong market position of Kenya Commercial Bank, control by government, vibrant competition from the private, spurred innovation and, in the 2000s, provided a platform for cross-border expansion in East Africa (Brown Bridge and Harvey (1998) .", "cite_spans": [{"start": 306, "end": 326, "text": "(Becks et al., 2014)", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Impact of Political Systems on Cross-border Strategy and Competitiveness", "text": "The political system, directly and indirectly, influences the strategy in cross-border banking as the players involved in cross-border banking usually play to the rules of the game that have been put by the government of the day. Policies and regulations are a reflection of the political system as the system provides for the actors and the mechanisms that determine the mechanisms of engagement. In order develop an appropriate strategy and gain competitiveness the cross-border bank has to systematically understand the political system in the different jurisdictions and come up with a strategy that effectively exploits the unique attributes of the different political environments.", "cite_spans": [], "ref_spans": []}, {"section": "Influence of Political History on Cross-border Strategy and Competitiveness", "text": "Political history involves an understanding of a history of political events or affairs; an analysis of history in political terms. Analysis of political history in the subsidiary and home country is significant in the contribution towards the political environment of a country. Political history in the current subsidiaries provides insight similarities and differences in the colonial masters, colonisation process, way to independence, post-independence politics, political parties, and post-independence dynamics. An assessment of political parties internal weaknesses, organisational skills, political ideologies, levels of tolerance, structures, membership, the dependence of individuals, cliques, and the process of independence is critical in the development of the prevailing political environment. Quantitative findings highlighted that political history in the subsidiary and home countries doesn't influence strategy and competitiveness.", "cite_spans": [], "ref_spans": []}, {"section": "Influence of Political History on Cross-border Strategy and Competitiveness", "text": "However, the qualitative findings provided a different picture as most of the respondents believed that the current political environments in East African countries are a reflection of the political history of the different countries. One of the political leaders interviewed during the study argued that \"the different East African Countries which Kenya commercial Bank is currently operating is a clear reflection of the political history of the countries. He said Tanzania was historically under communism and the people's political ideology is unison and Kenya which went valued capitalism has a cultural orientation of domineering in business and Uganda was in between. He further argued that countries like Rwanda and Burundi which emerge from French legal system and of recent Rwanda going Anglophone have a mix of two cultural orientation political history end up shaping the political climate of a nation. Political dynamics in the subsidiaries and home countries basically reflect historical phenomenon. The process of understanding current political climates involves unearthing the political history of a country. Beck et al. (2014: 189) argue that \"at the time of independence, most African countries had banking systems dominated by foreign-owned banks from outside African continent and British banks dominated in the British colonies, while French banks did so in the French and Portuguese banks in the Portuguese colonies\". This was partly due to political reasons, and a deliberate outcome negotiated by banks to preserve their market share and avoid competition in order to extract rents (Austin &UgochukwuUche, 2007) . Cross-border banking was shaped by regulatory frameworks favouring former colonial masters to continue doing business in the former colonies.", "cite_spans": [], "ref_spans": []}, {"section": "Influence of Political History on Cross-border Strategy and Competitiveness", "text": "However, in Uganda and Ghana foreign banks maintained their presence unlike Nigeria, Kenya, and Malawi the foreign banks maintained majority shares, but the importance of these banks decreased with the emergence of new state-owned with local private banks (Brownbridge and Harvey (1998) . Political history significantly shaped the concept and dynamics of cross-border banking in Africa.", "cite_spans": [], "ref_spans": []}, {"section": "Influence of Political History on Cross-border Strategy and Competitiveness", "text": "The political history of the subsidiary and home countries shapes the dynamics of the new political environment. The subsidiary and home countries political history is critical in the shaping of the political landscape which the cross-border banks. The landscape in the different territories provides for the establishment of appropriate strategies and competitiveness. Managers of cross-border banking have to understand political ideologies governing subsidiaries and headquarters appropriately.", "cite_spans": [], "ref_spans": []}, {"section": "Influence of Economic Integration on Cross-border Banking", "text": "The revival of the East African Community in accordance with 1999 East African Treaty (EAT) putting in place mechanisms for a cross-border bank have been put in place to stimulate trade within and outside East Africa. The treaty provides mechanisms for cooperation in trade liberalization and development (EAT, 1999) . The various sections of the EAT outline ways for organizations to improve trade across borders; these include: the establishment of customs unions (75) and a common market (76), addressing imbalances arising from customs unions (77), cooperation in investment and industrial development (Chapter 12), promotion of industrial linkages (79), harmonization of macroeconomic policies especially exchange and interest rates and monetary and fiscal policies (82), removal of obstacles to free movement of goods and services and capital (82c), banking and capital market development (85), facilitation of movement of capital (86), joint project financing (87), harmonization of telecommunication services (99), and fostering cooperation in education and training (102).", "cite_spans": [], "ref_spans": []}, {"section": "Influence of Economic Integration on Cross-border Banking", "text": "Different respondents had varying opinions in relation to the influence of the East African community on cross-border banking. Despite the provisions of the treaty, the study established that the framework had not provided adequate mechanisms for the enhancement of cross-border banking. One of the respondents argued that \"the treaty has good provisions that could accelerate the integration process a pre-requisite for integration, but the process has not been adequately undertaken due to limited knowledge among the stakeholders.\"Different actors in East Africa are basically undertaking the initiative on their own as the policies don't give adequate mechanisms for implementation. The respective governments' seem to be having reservations while implementing the treaty. One of the respondents argued that \"the East African Community is taking time due to reservations among member countries. Tanzania has reservations on the integration process because of benefits accruing from SADC region. There seem to be selfish interests among the member countries, and therefore the dream is taking time.\" However, companies that are undertaking cross-border ventures are basically undertaking it in a bid to ensure the dream becomes a reality. East African community policies are not a driving force towards competitiveness as the political leaders are trying to build integration on selfish interests. Collaboration within East African community especially crime prevention and meetings in the region to facilitate discussions on reforms with the region facilitate the integration efforts.", "cite_spans": [], "ref_spans": []}, {"section": "Influence of Economic Integration on Cross-border Banking", "text": "Integration provides mechanisms for the establishment of a common political and socio-cultural environmentestablishment of similar policies, procedures, political systems, economic systems, and social systems in the East African Community aids in effective cross-border banking. However, the study established that limited efforts had been put in place for the integration of the financial systems in the member countries. It's imperative for the member countries to expedite the process for integration of the East African community. The integration of the community would enhance the competitiveness of the regional banks as opposed to other pan African and other foreign banks.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "Pan-Africanism the movement aims at encouraging and strengthening of solidarity by African people is touted to be a driver for development in Africa. Different approaches have been advanced to ensure integration of African society. The emergence and dominance of African banks in Africa have been touted as one of the popular mechanisms leading to a concept termed as Pan-African cross-border banking. African Banks have become dominant in the African market as opposed to European colonial banks substantially increasing their geographic footprints on the continent. African cross-border banks have become economically significant beyond their home countries and of systematic importance in a number of jurisdictions. This study was commissioned to systematically undertake to examine the influence of the political environment on Pan-African cross-border banking. Kenya Commercial bank was used as a case for studying cross-border banking.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "In conclusion, the political environment in the home and subsidiary countries can either be an inhibitor or catalyst in Pan-African cross-border competitiveness. The regional integration and Pan-Africanism has to go beyond just political heretics but should adopt a pragmatic approach in regional and African integration. There has to be a systematic understanding of political elements influencing the political environment and designing of strategic actions to streamline cross-border banking. Regional integration East African Community, South African Community of Economic Community of the West African States and African Union has to streamline the dynamics to capture the critical aspects of the integration. Pan-African banking needs to enhance Pan-Africanism and vice versa. Integration must be systematically undertaken capture political environment that was distorted by history, ideologies, different political systems, different regulatory frameworks between the subsidiaries and home countries. 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{"paper_id": "18980149", "_pdf_hash": "9976a67f189a0cf38ced90c88793db6a4211391b", "abstract": [{"section": "Abstract", "text": "Abstract Cre-responsive dual-fluorescent alleles allow in situ marking of cell lineages or genetically modified cells. Here we report a dual-fluorescent allele, ROSA nT-nG , which directs nuclear accumulation of tdTomato in Crena\u00efve lineages. Cre converts the allele to ROSA nG , which drives nuclear EGFP accumulation. Conditions were established for analyzing marked nuclei by flow cytometry on the basis of red-green fluorescence and ploidy, with a particular focus on liver nuclei. Hydrodynamic delivery of a Cre-expression plasmid was used to time-stamp arbitrary hepatocytes for lineage tracing. The distinct green fluorescence of nuclei from Cre-exposed lineages facilitated analyses of ploidy transitions within clones. To assess developmental transitions in liver nuclei, ROSA nT-nG was combined with the hepatocyte-specific AlbCre transgene, facilitating discrimination between hepatocyte and nonhepatocyte nuclei. Nuclei extracted from postnatal day 2 (P2) livers were 41 % green and 59 % red and reached a stable level of 84 % green by P22. Until P20, green nuclei were [98 % diploid (2N); at P40 they were *56 % 2N, 43 % 4N, and \\1 % 8N; and by P70 they reached a stable distribution of *46 % 2N, 45 % 4N, and 9 % 8N. In conclusion, ROSA nT-nG will facilitate in vivo and ex vivo studies on liver and will likely be valuable for studies on tissues like muscle, kidney, or brain in which cells are refractory to whole-cell flow cytometry, or like trophectoderm derivatives or cancers in which cells undergo ploidy transitions.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Cre-responsive marker alleles in mice have become important tools for cell-lineage or -fate tracing and as surrogate markers to identify cells in which a Cre-responsive conditional allele has undergone conversion (Akagi et al. 1997) . Fluorescent markers have proven advantageous over b-gal-based markers in that they allow live-cell real-time visualization (Kisseberth et al. 1999; Mao et al. 2001; Muzumdar et al. 2007 ). Single-color fluorescent reporters (e.g., ''floxed-stop'' reporters) (Srinivas et al. 2001 ) are useful for visualizing or quantifying minority Cre-exposed populations but are less useful for assessing the purity of majority Cre-exposed populations. For example, it is easy to see a single fluorescent cell (Cre-exposed) in a nonfluorescent (Cre-na\u00efve) background (Srinivas et al. 2001 ), but it can be challenging to see a single nonfluorescent Crena\u00efve cell in an otherwise fluorescent milieu (e.g., Malato et al. 2011) .", "cite_spans": [{"start": 213, "end": 232, "text": "(Akagi et al. 1997)", "ref_id": "BIBREF0"}, {"start": 358, "end": 382, "text": "(Kisseberth et al. 1999;", "ref_id": "BIBREF14"}, {"start": 383, "end": 399, "text": "Mao et al. 2001;", "ref_id": "BIBREF18"}, {"start": 400, "end": 420, "text": "Muzumdar et al. 2007", "ref_id": "BIBREF21"}, {"start": 493, "end": 514, "text": "(Srinivas et al. 2001", "ref_id": "BIBREF35"}, {"start": 788, "end": 809, "text": "(Srinivas et al. 2001", "ref_id": "BIBREF35"}, {"start": 926, "end": 945, "text": "Malato et al. 2011)", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Introduction", "text": "The nonessential ROSA26 gene on chromosome (chr) 6 is weakly ubiquitously expressed (Soriano 1999) , so transgenes knocked into this locus are typically ubiquitously expressed and nondisruptive. The original ROSA26-targeted marker containing a floxed-stop b-gal was useful for analyzing domains of Cre expression (Soriano 1999) . However, early fluorescent protein insertions in this locus were problematic as the weak expression of the locus generally yielded insufficient protein accumulation for direct visualization. Instead, detection often required antibody staining of fixed tissues (Srinivas et al. 2001; Guo et al. 2009; Malato et al. 2011) .", "cite_spans": [{"start": 84, "end": 98, "text": "(Soriano 1999)", "ref_id": "BIBREF34"}, {"start": 313, "end": 327, "text": "(Soriano 1999)", "ref_id": "BIBREF34"}, {"start": 590, "end": 612, "text": "(Srinivas et al. 2001;", "ref_id": "BIBREF35"}, {"start": 613, "end": 629, "text": "Guo et al. 2009;", "ref_id": "BIBREF11"}, {"start": 630, "end": 649, "text": "Malato et al. 2011)", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Introduction", "text": "More recently, a strongly expressed dual-fluorescent reporter allele was developed, here abbreviated ROSA mT-mG (for ROSA26-membrane-tdT-membrane-EGFP) (Muzumdar et al. 2007 ). This allele solves the ''one-color'' problem by having a floxed-tdTomato (tdT, red-fluorescent) cistron upstream of an EGFP (green-fluorescent) cassette. Twocolor-fluorescent reporters allow real-time visualization of both minority and majority cell populations (Muzumdar et al. 2007 ). Thus, it is easy to see either one green (Creexposed) cell in a red (Cre-na\u00efve) milieu (e.g., Suvorova et al. 2009 ), or that an otherwise purely Cre-exposed sample contains a few red cells (e.g., Iverson et al. 2011) . ROSA mT-mG also solved the weak expression problem of ROSA26 by incorporating transcriptional enhancers that make both the red and green fluorescence directly visible in most live or cryosectioned tissues (Muzumdar et al. 2007 ). Finally, ROSA mT-mG incorporated signals that direct the fluorescent proteins to the outer membrane (Muzumdar et al. 2007 ). This last attribute provides outstanding histological recognition on sectioned material and, being at the cell periphery, is favorable for flow cytometry of explanted whole cells (Muzumdar et al. 2007) .", "cite_spans": [{"start": 152, "end": 173, "text": "(Muzumdar et al. 2007", "ref_id": "BIBREF21"}, {"start": 439, "end": 460, "text": "(Muzumdar et al. 2007", "ref_id": "BIBREF21"}, {"start": 558, "end": 578, "text": "Suvorova et al. 2009", "ref_id": "BIBREF37"}, {"start": 661, "end": 681, "text": "Iverson et al. 2011)", "ref_id": "BIBREF12"}, {"start": 889, "end": 910, "text": "(Muzumdar et al. 2007", "ref_id": "BIBREF21"}, {"start": 1014, "end": 1035, "text": "(Muzumdar et al. 2007", "ref_id": "BIBREF21"}, {"start": 1218, "end": 1240, "text": "(Muzumdar et al. 2007)", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Introduction", "text": "In most situations, ROSA mT-mG is an excellent Creresponsive marker allele, and our group has used it for such applications since it became available Weisend et al. 2009; Rollins et al. 2010; Iverson et al. 2011) . However, for some applications, including many concerning liver biology, a version of this allele directing nucleus-targeted fluorescent protein accumulation would also be desirable. Thus, hepatocytes are challenging to explant or analyze by flow cytometry. Also, the hepatocytes exhibit dramatic nuclear transitions, including changes in ploidy or transitions between mono-and binuclear states (e.g., Duncan et al. 2010) , the study of which could be aided by nuclear markers. Therefore, we modified ROSA mT-mG to generate a nucleus-targeted two-color reporter allele entitled ROSA nT-nG (nuclear tdT-nuclear EGFP). From mice bearing this allele, we also generated ROSA nG , which directs ubiquitous accumulation of nuclear EGFP. The description and characterization of these alleles and some analyses using these alleles are presented here.", "cite_spans": [{"start": 150, "end": 170, "text": "Weisend et al. 2009;", "ref_id": "BIBREF41"}, {"start": 171, "end": 191, "text": "Rollins et al. 2010;", "ref_id": "BIBREF27"}, {"start": 192, "end": 212, "text": "Iverson et al. 2011)", "ref_id": "BIBREF12"}, {"start": 617, "end": 636, "text": "Duncan et al. 2010)", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Materials and methods", "text": "Mice, care conditions, and animal procedures C57Bl/6J, B6.Cg-Tg(Alb-cre)21Mgn/J (Postic et al. 1999) (bearing the transgene here abbreviated AlbCre), and STOCK Gt(ROSA)26Sor tm4(ACTB-tdTomato,-EGFP)Luo /J (Muzumdar et al. 2007 ) (abbreviated ROSA mT-mG ) were obtained from the Jackson Laboratory (Bar Harbor, ME, stock Nos. 000664, 003574, and 007576, respectively). The ROSA nTnG allele was targeted into the ROSA26 locus on chr 6 in a C57Bl/6 9 129SvEv hybrid embryonic stem (ES) cell line. Chimeras were produced by blastocyst injection and founders were established by crossing male chimeras to C57Bl/6J. This is the first report of these mice, and with this publication the ROSA nT-nG mice are being made available from the Jackson Laboratory as stock No. 023035.", "cite_spans": [{"start": 80, "end": 100, "text": "(Postic et al. 1999)", "ref_id": "BIBREF26"}, {"start": 205, "end": 226, "text": "(Muzumdar et al. 2007", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Materials and methods", "text": "By convention, defined loci are italicized and allelic quality follows as a superscript with each allele separated by a slash (/). When noted, wild-type alleles are designated by a superscript ?. Unmapped transgenes, when applicable, are italicized and given a superscript designation of 0, 1, or 2 to indicate whether the transgene occurs in 0 (absent), 1 (hemizygous), or 2 (homozygous) copies. Loci are separated by a semicolon. Thus, ROSA nT-nG/? ; AlbCre 1 would have one wild-type and one nT-nG allele at the ROSA26 locus, and would be hemizygous for the AlbCre transgene. Animals received humane care according to the criteria outlined in the Guide for the Care and Use of Laboratory Animals, and all animal procedures were reviewed and approved by the Montana State University Institutional Animal Care and Use Committee. Animals were maintained on a 14:10-h light:dark cycle in HEPA-filtered forced-air conditions (Tecniplast, Buguggiati, Italy) on sterilized bedding with unrestricted access to sterilized water and sterilized feed (PicoLab 5058, LabDiet, St. Louis, MO, USA). Administration of the AdCre vector ) was performed by intravascular inoculation via a retro-orbital route (Rollins et al. 2010) . Hepatocyte-targeted delivery of a Cre-expression plasmid (Mansour et al. 1988 ) was performed by hydrodynamic tail vein (HDTV) delivery, as described previously (Zhu et al. 2006; Keng et al. 2011) , using lactated Ringer's solution of one tenth the body mass and which contained the amounts of plasmid DNA indicated in text or legends. Hepatic oxidative stress was induced by chronic inclusion of 0.07 % (w/v) of phenobarbital (Siegfried Chemical) in the drinking water, as indicated in figure legends and text. Partial (2/3) hepatectomies were performed as described previously (Mitchell and Willenbring 2008; Rollins et al. 2010 ).", "cite_spans": [{"start": 1193, "end": 1214, "text": "(Rollins et al. 2010)", "ref_id": "BIBREF27"}, {"start": 1274, "end": 1294, "text": "(Mansour et al. 1988", "ref_id": "BIBREF17"}, {"start": 1378, "end": 1395, "text": "(Zhu et al. 2006;", "ref_id": "BIBREF42"}, {"start": 1396, "end": 1413, "text": "Keng et al. 2011)", "ref_id": "BIBREF13"}, {"start": 1796, "end": 1827, "text": "(Mitchell and Willenbring 2008;", "ref_id": "BIBREF20"}, {"start": 1828, "end": 1847, "text": "Rollins et al. 2010", "ref_id": "BIBREF27"}], "ref_spans": []}, {"section": "Allelic design, construction, and validation", "text": "The targeting vector for the ROSA mT-mG allele (Muzumdar et al. 2007 ) was kindly made available to us by Dr. L. Luo (Stanford University) through Addgene (Addgene Plasmid No. 17787, Cambridge, MA) . This was modified to remove the membrane-targeting domain from the N-termini of tdT and EGFP, replace these with strong start codons, and append the 50-amino-acid nuclear assembly domain from the human SRm 160 protein to the C-terminus of each protein (Wagner et al. 2003) . Details of allelic design are presented in Supplementary Fig. 1 . The SRm 160 nuclear assembly domain was reported to direct stable integration of proteins, including EGFP, into the nuclear matrix (Wagner et al. 2003 ), which we expected would both prevent loss from isolated nuclei and be unlikely to disrupt nuclear functions. The domain proved effective for nuclear localization; however, we did detect slow diffusion of the proteins from isolated nuclei, which was noticeable in\\1 h at room temperature (data not shown). Cold temperatures, viscous buffers, or mild fixation allowed longer or permanent nuclear retention (see text and legends of specific experiments) and will be important considerations for using this allele on isolated nuclei.", "cite_spans": [{"start": 47, "end": 68, "text": "(Muzumdar et al. 2007", "ref_id": "BIBREF21"}, {"start": 452, "end": 472, "text": "(Wagner et al. 2003)", "ref_id": "BIBREF40"}, {"start": 672, "end": 691, "text": "(Wagner et al. 2003", "ref_id": "BIBREF40"}], "ref_spans": [{"start": 518, "end": 538, "text": "Supplementary Fig. 1", "ref_id": "FIGREF0"}]}, {"section": "Allelic design, construction, and validation", "text": "Liver nuclei preparation and nuclei flow cytometry Nuclei preparation methods were modified from classical protocols for isolation of native rat liver nuclei (Gorski et al. 1986; Tian and Schibler 1991; Schmidt and Schibler 1995) . Briefly, mice were killed and livers were placed in petri dishes on ice. The livers were minced and 1.4 g was transferred to a Teflon-glass homogenizer (loose pestle). To this was added 18 ml of ice-cold 19 nuclei homogenization buffer (2.0 M sucrose, 10 % glycerol, 15 mM KCl, 10 mM HEPES, pH 7.6, 0.5 mM spermidine, 0.15 mM spermine, 0.5 mM EDTA). Homogenization was performed at \\0\u00b0C by having the homogenizer in an ethanol ice bath in a cold room using a motorized pestle drive. If the nuclei were to be used for flow cytometry, 0.6 ml of ice-cold 10 % formalin was added during homogenization (0.3 % final formalin concentration in homogenate); this was replaced with 19 PBS for other applications. The homogenate was layered onto 2.5-ml cushions of 19 nuclei homogenization buffer in SW41Ti tubes and centrifuged for 1 h at 24,000 rpm and 0\u00b0C. Pelleted nuclei were recovered and resuspended in nuclei freezing buffer (50 % glycerol, 10 mM HEPES, pH 7.6, 15 mM KCl, 0.5 mM spermidine, 0.15 mM spermine, 0.5 mM EDTA) and were either snap-frozen in liquid nitrogen and stored at -80\u00b0C or were used fresh.", "cite_spans": [{"start": 158, "end": 178, "text": "(Gorski et al. 1986;", "ref_id": "BIBREF7"}, {"start": 179, "end": 202, "text": "Tian and Schibler 1991;", "ref_id": "BIBREF39"}, {"start": 203, "end": 229, "text": "Schmidt and Schibler 1995)", "ref_id": "BIBREF28"}], "ref_spans": []}, {"section": "Allelic design, construction, and validation", "text": "For flow cytometry, sheath fluid was supplemented with 0.15 mM spermine and 0.5 mM spermidine [polyaminesupplemented sheath (PSS)] to retain chromatin and nuclei integrity. Nuclei were diluted tenfold with PSS and strained through fine mesh. Where indicated, nuclear DNA was quantitatively stained with DRAQ5 following the manufacturer's recommendations (AbCam, Cambridge, MA, USA). Flow cytometry was performed on a FACSAria II (BD Biosciences, Franklin Lakes, NJ, USA) at 70 psi and with a 70-lm nozzle, using excitation lasers of wavelengths 488 nm for EGFP, 561 nm for tdT, and 633 nm for DRAQ5. Emission was measured at 510 nm (EGFP), 582 nm (tdT), or 780 nm (DRAQ5).", "cite_spans": [], "ref_spans": []}, {"section": "Allelic design, construction, and validation", "text": "Histology, fluorescence microscopy, and morphometry Fluorescent dissecting microscope images were taken using a Nikon SMZ-800 binocular dissecting microscope outfitted with an Exfo X-Cite 120Q UV light source, red (Nikon C3394 R/Dil 31002a) and green (Nikon C127265 EN/GFP 83457) filter sets, and a Nikon DS-Fi1 digital camera. For higher-magnification images, cryoblocks of tissue were prepared in Tissue-Tek \u00d2 O.C.T.", "cite_spans": [], "ref_spans": []}, {"section": "TM", "text": "(Sakura Finetek, Torrance, CA) and 5-lm sections were fixed for 7 min in 10 % neutral-buffered formalin, rinsed in PBS, and mounted in Fluoromount-G with DAPI (Electron Microscopy Sciences, Hatfield, PA, USA). Images were taken on a Nikon Eclipse 80i microscope using a Nikon DS Ri1 digital camera, Nikon NIS Elements BR acquisition software, and standard red (TRITC), green (FITC), and DAPI filter sets.", "cite_spans": [], "ref_spans": []}, {"section": "TM", "text": "Morphometric analyses of nuclei size were used as an indication of ploidy. Total nuclei purified as above, or isolated 2N, 4N, or 8N nuclei sorted by flow cytometry, were fixed on slides, stained with DAPI, and photographed with DAPI, tdT, and EGFP filters. The area of the nuclei on images was determined by morphometry using NIH Image J software (http://rsbweb.nih.gov) and was converted to a volumetric function to approximate ploidy. Measurements on flow-sorted hepatocyte nuclei verified that 2N, 4N, and 8N isolates each differed by twofold increments in volume ( Supplementary Fig. 2C ) and were used to calibrate morphometric analyses on slides of total nuclei harvested over a developmental time course. In each case, 150-300 random green nuclei were measured from each animal to establish the ploidy distribution at each stage.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Generation and characterization of ROSA nT-nG mice", "text": "The ROSA mT-mG targeting vector was used as the backbone for producing the ROSA nT-nG targeting vector (Supplementary Fig. 1 ). Conversion from red to green is strictly Cre-dependent. Thus, the allele marks cell lineages and can be used to follow descendants of a single cell (Fig. 1a) . The targeting vector was linearized and electroporated into male C57Bl/6 9 129XI ES cells, and one clone was selected to generate chimeric mice; male chimeras were bred to C57Bl/6 dams. Pups were screened for the allele (founders) and these were bred to C57Bl/6 mice to establish the line.", "cite_spans": [], "ref_spans": [{"start": 118, "end": 124, "text": "Fig. 1", "ref_id": "FIGREF0"}, {"start": 276, "end": 285, "text": "(Fig. 1a)", "ref_id": "FIGREF0"}]}, {"section": "Expression of ROSA", "text": "nT-nG and ROSA nG Postnatal day 10 (P10) tail biopsies from heterozygous founders showed strong red fluorescence (Fig. 1b) . Founders were bred with C57Bl/6 mates and an embryonic day 13.5 (E13.5) litter was harvested. Observation under the epifluorescent dissecting microscope showed that half of the pups were nonfluorescent and half were strongly ubiquitously red fluorescent (Fig. 1c, d ). Other litters were raised to term to establish the line. In subsequent husbandry the allele showed Mendelian distributions; mice heterozygous or homozygous for the allele showed no overt defects (data not shown), consistent with the allele being benign. Tissues showed strong ubiquitous nuclear red fluorescence ( Fig. 1e-j) . ROSA nT-nG mice were bred with a germline-expressing Cre-transgenic mouse (Gu et al. 1993) to generate the subline ROSA nG , which ubiquitously expressed nuclear EGFP. ROSA nG/nG mice are also healthy and they exhibit a pattern of green nuclei that reflects the distribution of red nuclei in ROSA nT-nG/nT-nG . This pattern included more intense nuclear fluorescence in hepatocytes near portal triads (PT) than in hepatocytes near central veins (CV; Fig. 1e , k, n); linear arrangements of fluorescent nuclei along myofibrils in skeletal muscle (Fig. 1i, l, o) ; brighter fluorescence in kidney cortex, in particular in glomeruli (G; Fig. 1m and p) ; and weakly fluorescent nuclei in brain, with the exception of interspersed tracts of small, brightly fluorescent nuclei (Fig. 1h) .", "cite_spans": [{"start": 795, "end": 811, "text": "(Gu et al. 1993)", "ref_id": "BIBREF10"}], "ref_spans": [{"start": 113, "end": 122, "text": "(Fig. 1b)", "ref_id": "FIGREF0"}, {"start": 379, "end": 390, "text": "(Fig. 1c, d", "ref_id": "FIGREF0"}, {"start": 708, "end": 718, "text": "Fig. 1e-j)", "ref_id": "FIGREF0"}, {"start": 1171, "end": 1178, "text": "Fig. 1e", "ref_id": "FIGREF0"}, {"start": 1266, "end": 1281, "text": "(Fig. 1i, l, o)", "ref_id": "FIGREF0"}, {"start": 1355, "end": 1369, "text": "Fig. 1m and p)", "ref_id": "FIGREF0"}, {"start": 1492, "end": 1501, "text": "(Fig. 1h)", "ref_id": "FIGREF0"}]}, {"section": "Expression of ROSA", "text": "Exogenous delivery of Cre activity to ROSA nT-nG hepatocytes Delivery of Cre activity from exogenous sources to hepatocytes having a two-color fluorescent marker can allow one to synchronously convert a few to most hepatocytes in situ (Iverson et al. 2011 ). Here we used delivery of a naked Cre-expressing plasmid (Mansour et al. 1988 ) by HDTV (Sebestyen et al. 2006; Keng et al. 2011) to ROSA nT-nG/nT-nG mice to show the utility of ROSA nT-nG for hepatocyte lineage tracing. HDTV was performed in P21 mice with 5 lg of pMC1-Cre plasmid. 11 days later mice were two-thirds hepatectomized to induce a burst of replication (Mitchell and Willenbring 2008) . 1 week later mice were put under chronic hepatic stress by supplementing their drinking water with phenobarbital. The liver shown in Fig. 2a-c was harvested 110 days after the partial hepatectomy. Imaging the surface of the liver with an epifluorescence dissecting microscope at harvest revealed the lobular structure of the liver (Fig. 2a , representative lobule outlined by black dotted line) and the few timestamped green nuclei in fields of red Cre-na\u00efve nuclei. Clusters of green nuclei were interpreted as clones derived from a single time-stamped hepatocyte ( Fig. 2b, c ; a representative clone is encircled by white dotted line). Use of ROSA nT-nG for this allows one to assess clone sizes and lobular positions. Moreover, based on the relative size and proximities of nuclei, one can roughly discriminate between mononucleate diploid (2N) hepatocytes (Fig. 2c , e.g., orange arrow), mononucleate 4N hepatocytes (pink arrow), binucleate 4N hepatocytes (white arrow), mononucleate 8N hepatocytes (yellow arrow), and binucleate 8N hepatocytes (blue arrow). This will be useful for studying hepatocyte lineages in terms of proliferation, lobular position characteristics, and ploidy transitions over time.", "cite_spans": [{"start": 235, "end": 255, "text": "(Iverson et al. 2011", "ref_id": "BIBREF12"}, {"start": 315, "end": 335, "text": "(Mansour et al. 1988", "ref_id": "BIBREF17"}, {"start": 346, "end": 369, "text": "(Sebestyen et al. 2006;", "ref_id": "BIBREF29"}, {"start": 370, "end": 387, "text": "Keng et al. 2011)", "ref_id": "BIBREF13"}, {"start": 624, "end": 655, "text": "(Mitchell and Willenbring 2008)", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Expression of ROSA", "text": "For other applications, more widespread conversion by exogenous Cre might be useful. Using a single inoculation with 10 8 plaque forming units of AdCre, *95 % of hepatocyte nuclei in ROSA nT-nG/nT-nG mice converted from red to green (Fig. 2d-f) . Flow cytometry of liver nuclei", "cite_spans": [], "ref_spans": []}, {"section": "Expression of ROSA", "text": "One reason for developing ROSA nT-nG was to allow flow analysis of fluorescently marked hepatocyte nuclei. Although fixed nuclei tolerate flow (Tamura et al. 1992) , standard flow conditions disrupt the integrity of native nuclei. By using PSS buffer, we found that we could analyze native nuclei by flow ( Supplementary Fig. 2 ). To calibrate and validate flow parameters for ROSA nT-nG liver nuclei, we used identically prepared liver nuclei from (i) wild-type (nonfluorescent) mice, (ii) ROSA nT-nG/nT-nG mice (red fluorescent), (iii) ROSA nG/nG mice (green fluorescent), (iv) ROSA nG/nT-nG mice (both red-and green-fluorescent alleles), and (v) mixtures of i, ii, and iii nuclei (Fig. 3) . In analyzing the red and green fluorescence of nuclei of type i, ii, iii, or iv, all events were restricted to the lower-left, upper-left, lower-right, or upperright quadrants, respectively (Fig. 3a) . Nuclei type v (a mixture of types i, ii, and iii) segregated to the lower-left, upper-left, and lower-right quadrants, but the upper-right quadrant (''double-positive'' quadrant) remained empty (Fig. 3b, upper panel) . Importantly, there was no fluorescence overlap between genotypes, although increased tdT expression was accompanied by a subtle increased green fluorescence in ROSA nT-nG/nT-nG nuclei, as indicated by the diagonal pattern of nuclei (Fig. 3a, upper-left panel) .", "cite_spans": [{"start": 143, "end": 163, "text": "(Tamura et al. 1992)", "ref_id": "BIBREF38"}], "ref_spans": [{"start": 683, "end": 691, "text": "(Fig. 3)", "ref_id": "FIGREF2"}, {"start": 884, "end": 893, "text": "(Fig. 3a)", "ref_id": "FIGREF2"}, {"start": 1090, "end": 1112, "text": "(Fig. 3b, upper panel)", "ref_id": "FIGREF2"}, {"start": 1347, "end": 1374, "text": "(Fig. 3a, upper-left panel)", "ref_id": "FIGREF2"}]}, {"section": "Expression of ROSA", "text": "By flow cytometry, all types of fluorescent nuclei (types ii, iii, and iv) showed three distinct clusters of fluorescence intensities, labeled in red as ''a,'' ''b,'' and ''c'' in Fig. 3 . These clusters were most pronounced in the ROSA nG/nG nuclei (Fig. 3a , lower-right panel) and were retained in mixed nuclei populations (Fig. 3b, upper panel) . These proved not to be simply differential accumulation of Fig. 2 Exogenous delivery of Cre activity for time-stamping, lineage-tracing, or global conversion of hepatocytes. a-c Clonal analysis of time-stamped hepatocyte nuclei. A mouse was time-stamped with 5 lg of pMC1-Cre plasmid by HDTV at P21 and was two-thirds hepatectomized at P32. Beginning at P39, the drinking water contained 0.07 % phenobarbital. The mouse was harvested at P142 and the liver was photographed with an epifluorescence dissecting stereomicroscope. a is a merge of the red and green channels; black dashed line circumscribes a representative lobule. Because this is an image of the whole organ and nearly all nuclei are red, underlying out-of-focal-plane red nuclei blur visualization of in-focus red nuclei. b is the same frame under green fluorescence only; dashed box indicates the region enlarged in c. White dashed circle denotes a clone of three hepatocytes (one binucleate and two mononucleate) in which all four nuclei are 4N. Orange arrow 2N nucleus in a mononucleate hepatocyte; white arrow 2N nuclei in binucleate hepatocyte; pink arrow 4N nucleus in mononucleate hepatocyte; blue arrow 4N nuclei in binucleate hepatocyte; yellow arrow likely 8N nucleus in mononucleate hepatocyte, although this could be two close vertically juxtaposed 4N nuclei. (Fig. 3b, lower panel) . Interestingly, in livers of genotype ROSA nT-nG/? ; AlbCre 1 mice, in which hepatocyte nuclei will be green and other nuclei in the liver will be red, 2N green nuclei were all of classes ''b'' and ''c,'' and the class ''a'' nuclei were red ( Supplementary Fig. 3 and data not shown), indicating that class ''a'' nuclei were from cells that do not express AlbCre. Our interpretation is that class ''a'' nuclei are from nonhepatocyte cells of the liver, such as endothelial and Kupffer cells, whereas classes ''b'' and ''c'' represent distinct dim-and bright-fluorescent hepatocyte nuclei subpopulations (see Discussion).", "cite_spans": [], "ref_spans": [{"start": 180, "end": 186, "text": "Fig. 3", "ref_id": "FIGREF2"}, {"start": 250, "end": 258, "text": "(Fig. 3a", "ref_id": "FIGREF2"}, {"start": 326, "end": 348, "text": "(Fig. 3b, upper panel)", "ref_id": "FIGREF2"}, {"start": 1687, "end": 1709, "text": "(Fig. 3b, lower panel)", "ref_id": "FIGREF2"}, {"start": 1954, "end": 1974, "text": "Supplementary Fig. 3", "ref_id": "FIGREF2"}]}, {"section": "Postnatal age-dependent transitions in liver nuclei populations", "text": "Nuclei extracted from ROSA nT-nG/nT-nG ; AlbCre 1 mice over a developmental time course from P2 to P180 were evaluated for their proportion of red (Cre-na\u00efve lineages) versus green (Cre-exposed lineages) nuclei (Fig. 4a) . Within the green subpopulation, the proportions of 2N, 4N, and 8N nuclei were assessed by morphometric analyses on micrographs of unsorted nuclei. Fetal livers have a predominant hematopoietic function, which migrates to the bone marrow around birth as the liver takes on its hepatic character ). Consistent with this, nuclei extracted from P2 livers were 41 % green and 59 % red, and the proportion of green nuclei rapidly increase thereafter until about P22, when isolated liver nuclei reach a stable level of *84 % green (Fig. 4a) .", "cite_spans": [], "ref_spans": [{"start": 211, "end": 220, "text": "(Fig. 4a)", "ref_id": "FIGREF3"}, {"start": 747, "end": 756, "text": "(Fig. 4a)", "ref_id": "FIGREF3"}]}, {"section": "Postnatal age-dependent transitions in liver nuclei populations", "text": "As previously established (Shima and Sugahara 1976; Ohtsubo and Nomaguchi 1986) , postnatal increases in hepatocyte nuclei ploidy showed a delay as compared to the increase in liver hepatocyte content and an incremental developmental transition. Thus, whereas by P20 ROSA nT-nG/nT-nG ; AlbCre1 livers were approaching their stable adult ratio of red-to-green nuclei (Fig. 4a , region highlighted in green), their green nuclei remained [97 % 2N (Fig. 4b) . At this time, 4N nuclei began appearing, and these increased until *P40 (Fig. 4b, region highlighted in , ROSA nT-nG/nT-nG , and ROSA nG/nG livers were mixed, stained with DRAQ5, and analyzed by flow for red versus green fluorescence (upper plot) or DRAQ5 versus green fluorescence (lower plot). The ROSA nG/nG nuclei still showed three peaks differing in EGFP intensity in the red versus green plot. When these were analyzed by DRAQ5 versus green, the EGFP fluorescence was found to be independent of ploidy. Thus, 2N nuclei showed all three green peaks, whereas 4N and 8N nuclei were predominantly only in peak ''c.'' Further analysis revealed that peak ''a'' was nonhepatocyte 2N nuclei, and peaks ''b'' and ''c'' were dim or bright hepatocyte nuclei, respectively (see Supplementary Fig. 3) yellow). It was not until *P40 that the first 8N nuclei were counted, and these increased until *P70 (region highlighted in magenta), by which age the hepatocytes had reached a stable distribution of *46 % 2N, 45 % 4N, and 9 % 8N nuclei (region highlighted in peach).", "cite_spans": [{"start": 26, "end": 51, "text": "(Shima and Sugahara 1976;", "ref_id": "BIBREF33"}, {"start": 52, "end": 79, "text": "Ohtsubo and Nomaguchi 1986)", "ref_id": "BIBREF22"}], "ref_spans": [{"start": 366, "end": 374, "text": "(Fig. 4a", "ref_id": "FIGREF3"}, {"start": 444, "end": 453, "text": "(Fig. 4b)", "ref_id": "FIGREF3"}, {"start": 528, "end": 559, "text": "(Fig. 4b, region highlighted in", "ref_id": "FIGREF3"}, {"start": 1229, "end": 1250, "text": "Supplementary Fig. 3)", "ref_id": "FIGREF2"}]}, {"section": "A B", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "The liver undergoes dramatic postnatal transitions, both developmentally and in response to hepatic damage, that can be challenging to quantify (Styles 1993; Celton-Morizur and Desdouets 2010) . Hepatocytes are one of very few differentiated cell types in mammals that can proliferate (Overturf et al. 1997; Grompe et al. 1999; Shafritz and Oertel 2011) . Moreover, hepatocytes undergo atypical replication cycles leading to alterations in nuclei content and in the ploidy of individual nuclei (Duncan et al. 2010 ). Here we report a Cre-responsive dual-fluorescent marker allele that specifically labels nuclei. This allele will facilitate in situ and ex vivo analyses on mouse nuclei.", "cite_spans": [{"start": 144, "end": 157, "text": "(Styles 1993;", "ref_id": "BIBREF36"}, {"start": 158, "end": 192, "text": "Celton-Morizur and Desdouets 2010)", "ref_id": "BIBREF3"}, {"start": 285, "end": 307, "text": "(Overturf et al. 1997;", "ref_id": "BIBREF23"}, {"start": 308, "end": 327, "text": "Grompe et al. 1999;", "ref_id": "BIBREF9"}, {"start": 328, "end": 353, "text": "Shafritz and Oertel 2011)", "ref_id": "BIBREF32"}, {"start": 494, "end": 513, "text": "(Duncan et al. 2010", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Flow analyses on time-stamped nuclei", "text": "We report a system in which Cre-marked fluorescent hepatocyte nuclei could be analyzed by flow cytometry. In preparing liver nuclei, the tissue is chilled on ice immediately at harvest, which will better preserve some in vivo attributes than will the extended 37\u00b0C digestions used for explanting whole hepatocytes (Severin et al. 1984a; Ohtsubo and Nomaguchi 1986; Tamura et al. 1992; Schmidt and Schibler 1995; Lu et al. 2007 ). Also, although whole explanted hepatocytes can be analyzed by flow (Ohtsubo and Nomaguchi 1986; Tamura et al. 1992; Overturf et al. 1999; Duncan et al. 2010) , their large size makes them susceptible to damage by shear forces, and this will be greater for larger hepatocytes (Fung 2000) . By contrast, purified hepatocyte nuclei are rigid, dense, and smaller than whole hepatocytes, approximating the sizes of the immune cells that flow cytometry has been optimized for analyzing. Thus, diploid hepatocyte nuclei are roughly the size of whole resting lymphocytes (7-8 lm) and 8N hepatocyte nuclei are the size of stimulated lymphocytes (12-16 lm) (Ponder and Ponder 1959) .", "cite_spans": [{"start": 314, "end": 336, "text": "(Severin et al. 1984a;", "ref_id": "BIBREF30"}, {"start": 337, "end": 364, "text": "Ohtsubo and Nomaguchi 1986;", "ref_id": "BIBREF22"}, {"start": 365, "end": 384, "text": "Tamura et al. 1992;", "ref_id": "BIBREF38"}, {"start": 385, "end": 411, "text": "Schmidt and Schibler 1995;", "ref_id": "BIBREF28"}, {"start": 412, "end": 426, "text": "Lu et al. 2007", "ref_id": "BIBREF15"}, {"start": 497, "end": 525, "text": "(Ohtsubo and Nomaguchi 1986;", "ref_id": "BIBREF22"}, {"start": 526, "end": 545, "text": "Tamura et al. 1992;", "ref_id": "BIBREF38"}, {"start": 546, "end": 567, "text": "Overturf et al. 1999;", "ref_id": "BIBREF24"}, {"start": 568, "end": 587, "text": "Duncan et al. 2010)", "ref_id": "BIBREF4"}, {"start": 705, "end": 716, "text": "(Fung 2000)", "ref_id": "BIBREF6"}, {"start": 1077, "end": 1101, "text": "(Ponder and Ponder 1959)", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "Flow analyses on time-stamped nuclei", "text": "In the nuclei purification protocols on which we based our approach (Gorski et al. 1986; Tian and Schibler 1991; Schmidt and Schibler 1995) , buffers contain multivalent cations to maintain the integrity of native chromatin and nuclei during purification. Here we supplemented the sheath fluid to these conditions, which sustained nuclear integrity during flow. Our adult ROSA nT-nG/nT-nG ; AlbCre 1 liver nuclei preparations were *84 % green and 16 % red (Fig. 4a) . Since other studies have reported that *30 % of adult mouse hepatocytes are binucleate (Celton-Morizur and Desdouets 2010), our data suggest that adult liver contains *76 % hepatocytes and 24 % nonhepatocytes. This value approximates histology-based estimates (Blouin et al. 1977; Weisend et al. 2009; Celton-Morizur and Desdouets 2010) . The ability to analyze ROSA nT-nG -labeled liver nuclei is expected to provide a useful tool for analyses of liver and hepatocyte biology.", "cite_spans": [{"start": 68, "end": 88, "text": "(Gorski et al. 1986;", "ref_id": "BIBREF7"}, {"start": 89, "end": 112, "text": "Tian and Schibler 1991;", "ref_id": "BIBREF39"}, {"start": 113, "end": 139, "text": "Schmidt and Schibler 1995)", "ref_id": "BIBREF28"}, {"start": 728, "end": 748, "text": "(Blouin et al. 1977;", "ref_id": "BIBREF1"}, {"start": 749, "end": 769, "text": "Weisend et al. 2009;", "ref_id": "BIBREF41"}, {"start": 770, "end": 804, "text": "Celton-Morizur and Desdouets 2010)", "ref_id": "BIBREF3"}], "ref_spans": [{"start": 456, "end": 465, "text": "(Fig. 4a)", "ref_id": "FIGREF3"}]}, {"section": "Flow analyses on time-stamped nuclei", "text": "In addition to 4N and 8N nuclei in hepatocytes, other forms of atypical nuclear ploidy, including uniparental chromosome representation, have been shown (Duncan et al. 2010 ). In the current study, flow analyses of nuclei from young adult ROSA nG/nT-nG livers did not show detectable levels of single-color nuclei, suggesting that all ; AlbCre 1 were killed at the indicated postnatal ages and liver nuclei were purified. Slides of total liver nuclei were analyzed for red versus green fluorescence (a), and green nuclei were morphometrically analyzed for volume as an indication of ploidy (b; see Supplementary Fig. 2C ). The time from P0 to P20 (shaded green) is the period of time when the liver loses its hematopoietic function and becomes specialized for hepatic functions. Only diploid hepatocyte nuclei were detected during this period. From P20 to P40 (yellow), 4N hepatocyte nuclei appeared but no 8N nuclei were detected. From P40 to P70 (magenta), 8N nuclei appeared, and after P70 (peach) the abundance and ploidy of hepatocyte nuclei appeared to be at steady state detected nuclei were from cells that contained both maternal and paternal copies of chr 6 (Fig. 3a) . Further studies will be required to understand whether this resulted from sharing of gene products between nuclei in binucleate cells or from the age or conditions of the mice. Stresses like regeneration impact ploidy (Tamura et al. 1992; Melchiorri et al. 1993; Styles 1993; Celton-Morizur and Desdouets 2010) , and the late onset of the appearance of 8N nuclei (Fig. 4b) suggests that some normal ploidy transitions do not occur until an advanced age (Shima and Sugahara 1976; Severin et al. 1984b) . We anticipate that ROSA nG/nT-nG mice will be useful for future studies of chr 6 misrepresentation.", "cite_spans": [{"start": 153, "end": 172, "text": "(Duncan et al. 2010", "ref_id": "BIBREF4"}, {"start": 1398, "end": 1418, "text": "(Tamura et al. 1992;", "ref_id": "BIBREF38"}, {"start": 1419, "end": 1442, "text": "Melchiorri et al. 1993;", "ref_id": "BIBREF19"}, {"start": 1443, "end": 1455, "text": "Styles 1993;", "ref_id": "BIBREF36"}, {"start": 1456, "end": 1490, "text": "Celton-Morizur and Desdouets 2010)", "ref_id": "BIBREF3"}, {"start": 1633, "end": 1658, "text": "(Shima and Sugahara 1976;", "ref_id": "BIBREF33"}, {"start": 1659, "end": 1680, "text": "Severin et al. 1984b)", "ref_id": "BIBREF31"}], "ref_spans": [{"start": 1168, "end": 1177, "text": "(Fig. 3a)", "ref_id": "FIGREF2"}, {"start": 1543, "end": 1552, "text": "(Fig. 4b)", "ref_id": "FIGREF3"}]}, {"section": "Flow analyses on time-stamped nuclei", "text": "Unanticipated in our development of ROSA nT-nG was that it could segregate hepatocyte nuclei into bright and dim subpopulations (Fig. 3b) . On histological analyses of ROSA mT-mG mice, we previously noted that green fluorescence was stronger in membranes of periportal as compared to centrolobular hepatocytes (Rollins et al. 2010; Iverson et al. 2011 ), like we report for nuclear fluorescence in ROSA nT-nG mice here (Fig. 1e , k, n). Ongoing studies aim to isolate populations of bright and dim hepatocyte nuclei by flow, test whether these indeed reliably reflect identifiable subtypes of hepatocytes, and use these to assess differences between the two populations.", "cite_spans": [{"start": 310, "end": 331, "text": "(Rollins et al. 2010;", "ref_id": "BIBREF27"}, {"start": 332, "end": 351, "text": "Iverson et al. 2011", "ref_id": "BIBREF12"}], "ref_spans": [{"start": 128, "end": 137, "text": "(Fig. 3b)", "ref_id": "FIGREF2"}, {"start": 419, "end": 427, "text": "(Fig. 1e", "ref_id": "FIGREF0"}]}, {"section": "Flow analyses on time-stamped nuclei", "text": "It should be emphasized that the ploidy-based analyses on isolated nuclei shown here do not represent cellular ploidy distributions in liver. Thus, a portion of the isolated 2N nuclei will be from 4N cells having two 2N nuclei. It has been reported that these appear earlier in development than do 4N nuclei (Bohm and Noltemeyer 1981; Styles 1993; Celton-Morizur and Desdouets 2010) . Similarly, whereas 8N nuclei constitute only *9 % of hepatocyte nuclei in mature adults, 8N hepatocytes are likely a substantially higher proportion of the liver, as this will include hepatocytes with two 4N nuclei.", "cite_spans": [{"start": 308, "end": 334, "text": "(Bohm and Noltemeyer 1981;", "ref_id": "BIBREF2"}, {"start": 335, "end": 347, "text": "Styles 1993;", "ref_id": "BIBREF36"}, {"start": 348, "end": 382, "text": "Celton-Morizur and Desdouets 2010)", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Hepatocyte lineage tracing and lineage life histories", "text": "In fetal stages, hepatocyte lineages are born from 2N progenitor cells (Grompe 2005) . Each differentiation event gives rise to a new 2N hepatocyte lineage in which cells can proliferate, accumulate damage, undergo changes in ploidy, and die. Different hepatocytes on a lineage might occupy different sublobular zones, have different metabolic functions, be exposed to different stresses, and have different replicative potentials. Entire lineages might go extinct. We define the hepatocyte lineage life history as the sum of all of these events, starting with birth of a lineage from a progenitor cell to death of the last hepatocyte on that lineage.", "cite_spans": [{"start": 71, "end": 84, "text": "(Grompe 2005)", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Hepatocyte lineage tracing and lineage life histories", "text": "For tissues in which cells are not migratory, synchronous marking of a few cells can allow one to infer clonal relationships between adjacent marked cells at later times (Gehring 1967) . Using HDTV of Cre plasmid to mark small numbers of hepatocytes in ROSA nT-nG livers followed by a period of hepatic stress (Fig. 2a-c) , we identified clones of hepatocytes that had, during the period between time-stamping and harvest, undergone expansion and ploidy diversification. The variance in clonal expansion was remarkable, such that within a liver, some marked hepatocytes had given rise to large clones, whereas other clones were represented by one or few marked cells (Figs. 2 and 5) . Additional information, such as bromodeoxyuridine-and TUNEL-labeling indexes, will be needed to discern the contributions of proliferative rates versus death rates in causing such large differences in clone sizes, and it will be important to investigate whether this difference in clonal size is arbitrary or relates in a predictable way to the life history of that lineage. Interestingly, within clones we frequently found cells having different nuclear or genomic content, consistent with these parameters being rapidly dynamic within hepatocyte lineages (Duncan et al. 2010) .", "cite_spans": [{"start": 1242, "end": 1262, "text": "(Duncan et al. 2010)", "ref_id": "BIBREF4"}], "ref_spans": [{"start": 667, "end": 682, "text": "(Figs. 2 and 5)", "ref_id": "FIGREF4"}]}, {"section": "Hepatocyte lineage tracing and lineage life histories", "text": "Recently, we and others have shown that new hepatocytes can differentiate at low frequencies from progenitor cells in postnatal liver (Iverson et al. 2011; Malato et al. 2011; Espanol-Suner et al. 2012) . It is debated whether this is a physiologically important contribution to the liver. To resolve the debate, it will be useful to trace the fates of individual hepatocytes and map hepatocyte lineage life histories. If, as we have proposed (Iverson et al. 2011) , these ''newborn hepatocytes'' can each give rise to a large lineage, then a low birth rate could feed a substantial turnover in hepatocyte lineages over the course of an animal's lifetime. On the other hand, if newborn hepatocytes do not give rise to expanded lineages, then this contribution might be of little importance (Malato et al. 2011; EspanolSuner et al. 2012 ). 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"suffix": ""}, {"first": "J", "middle": ["L"], "last": "Xue", "suffix": ""}], "year": 2006, "venue": "FEBS Lett", "link": "19210638"}}, "ref_entries": {"FIGREF0": {"text": "Fig. 1 ROSA nT-nG and ROSA nG alleles. a Schematic of the alleles (left) and representative hepatocytes (right) showing nuclear tdT expression in Cre-na\u00efve lineages, allelic conversion by Cre, and nuclear EGFP expression in all members of Cre-exposed lineages. enh enhancer; N, SRm 160 nuclear assembly domain; bent arrow, transcription initiation site; yellow triangles, loxP sites; STOP signs, transcription termination signals. b Tail-snip from a P10 founder under the red channel of an epifluorescence dissecting stereomicroscope. c, d Identical frames of two live littermates from a mating of a ROSA nT-nG/? founder at embryonic day 13.5 (E13.5) photographed under white light (c) or red fluorescence (d) on the dissecting stereomicroscope. e-j Whole organs from a P42 ROSA nT-nG/? mouse photographed under red fluorescence on epifluorescence dissecting stereomicroscope. No fluorescence is visible on the green channel (not shown). The boxed area in e corresponds to the region expanded in f. The tracks of representative central veins (CV) and portal triads (PT) are indicated by yellow and blue dotted lines, respectively. k-p Whole (k, l) or bisected (m) organs, or cryosections of organs (n-p), as indicated, from a P100 ROSA nG/nG mouse. G glomeruli. In k and n, representative lobules are circumscribed; in l and o, arrows denote the orientation of myofibrils; in m, dotted line separates kidney cortex from medulla. Scale bar 5,000 lm (B-D) and 500 lm (E-P) c", "type": "figure"}, "FIGREF1": {"text": "d-f Global marking of hepatocytes using AdCre. A P49 ROSA nT-nG/nT-nG mouse was inoculated IV with 10 8 plaque forming units of AdCre and was sacrificed 1 week later. Whole liver was photographed as above. Although red channel (d) shows many red nuclei, most are deeper in the tissue (in lower focal planes); merged image (f) showed that *95 % of the hepatocytes were green. Scale bar 250 lm (a, b, d-f) and 115 lm (c) fluorescence in 2N, 4N, or 8N nuclei, as type v nuclei (the mixed population) stained with DRAQ5 showed that green 2N nuclei contained classes ''a,'' ''b,'' and ''c,'' green 4N nuclei contained predominantly class ''c'' with a smaller number of class ''b,'' and green 8N nuclei were almost exclusively class ''c''", "type": "figure"}, "FIGREF2": {"text": "Fig. 3 Flow analyses on purified fluorescent liver nuclei. a tdTomatoversus EGFP-fluorescent flow analyses on liver nuclei from mice of genotypes ROSA ?/? (lower-left plot, all nuclei nonfluorescent), ROSA nT-nG/nT-nG (upper-left plot, all nuclei red fluorescent), ROSA nG/nT-nG (upper-right plot, all nuclei both red and green fluorescent), and ROSA nG/nG (lower-right plot, all nuclei green fluorescent), as indicated. The quadrants in each plot are separated by vertical and horizontal lines at intensities that were used uniformly throughout all analyses in this study. For all fluorescent samples, the nuclei segregated into three distinct peaks, labeled in red as ''a,'' ''b,'' and ''c.'' Note that both the red and the green fluorescence was lower in the ROSA nG/nT-nG nuclei than in the ROSA nT-nG/nT-nG or ROSA nG/nG", "type": "figure"}, "FIGREF3": {"text": "Fig. 4 Nuclear transitions during postnatal liver development. Mice of genotype ROSA nT-nG/nT-nG", "type": "figure"}, "FIGREF4": {"text": "Fig. 5 Diversity in clonal expansion of hepatocyte lineages. Three months after time-stamping nuclei in a subset of hepatocytes by HDTV, some clones or clusters of clones have expanded to [30 hepatocytes (blue arrows), some contain only 3-5 hepatocytes (violet arrows), and others are represented by only a single cell (yellow arrows). Individual clones are seen to contain hepatocytes that differ in the number of nuclei they contain, the ploidy of individual nuclei, and the overall ploidy of individual hepatocytes (e.g., small clones denoted by violet arrows)", "type": "figure"}}}
{"paper_id": "18980611", "_pdf_hash": "b4bbcacfa792cea557044a1e1633a43521a9f951", "abstract": [{"section": "Abstract", "text": "In two experiments the potential value of diets based on casein or free amino acids (FAA) for amino acid utilization experiments were examined. In Expt 1 the optimum dietary electrolyte balance (dEB) for a casein-based diet was estimated by supplemention with 10 or 20 g NaHC03/kg, to produce diets containing 64, 183 or 302 mmoykg. In addition, piglet growth performance and efficiency of nutrient deposition of piglets given the casein diets were compared with two multiple protein source diets; Supercreep, a commercial multiple protein source diet or CFS (casein-fishsoyabean-sugar) or a FAA-based diet. Expt 2 was designed to compare piglet response to FAA diet stored at -15\" with twice daily feeding, with FAA diet stored at ambient temperature (13-30') and offered ad libitum. A CFS diet was used as a positive control and the experiment was conducted over the 10-20 kg growth phase. Expt 1 used forty-eight piglets weaned at 20-22 d of age and albcated to one of six treatments formulated to contain at least 0-84 g lysine/MJ digestible energy in a randomized block design. Piglets given the CFS and Supercreep diets produced superior growth rates (518, 491 gld) to those given a FAA diet (353 gld) or casein diet containing 0, 10 or 20 g NaHCO&g respectively (365,417,390 gld) between 5 and 20 kg live weight. Piglets given the casein and FAA diets had higher amino acid digestibilities than those given the Supercreep and CFS diets. The increase in the dEB of the casein diet from 64 to 183 mmoVkg improved piglet growth performance between 5 and 20 kg by 14 %. All piglets given casein diets had similar ileal and faecal digestibilities, empty-body compositions, nutrient deposition rates and retention ratios. The results of Expt 2 showed that there was no beneficial effect on piglet performance of storing the FAA diet at -15\" and feeding twice daily. Based on the results of these two experiments, neither the casein (0, 10, 20 g NaHC03/kg) nor FAA diets were suitable for estimating amino acid utilization by the piglet. There remain unidentified factors which l i t the growth performance of piglets given the casein and FAA diets.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Casein: Amino acids: Pigs A diet formulated on an ideal protein basis, with protein digestibility close to 1, would provide an excellent reference diet for the study of amino acid utilization. This reference diet could be used to identify causes of inefficient utilization of amino acids in diets containing traditional protein sources. The efficiency of utilization of amino acids is typically measured using N balance and/or empty-body retention. Yet there are no empty-body estimates in the literature for the efficiency of utilization of diets (which have been formulated on an ideal protein basis) that contain highly digestible protein sources.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "EXPERIMENTAL", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Expt 1. Comparison of growth performance and nutrient retention of piglets given diets", "text": "with casein, free amino acid and conventional protein sources Diets. The treatments were a commercial Supercreep, Chung & Baker's (1992) IIP diet (FAA), the CFS diet, and three casein diets with 0, 10 and 20 g NaHC03kg (Tables 1 and  2 ). The casein diets (diets 4-6) contained a lactic acid casein with free amino acids added to obtain an ideal amino acid ratio. The ratios of amino acids relative to lysine were taken from published data (Agricultural Research Council, 1981; Zhang et al. 1984; Black et al. 1986; National Research Council, 1988; Wang & Fuller, 1989) and were: lysine 100, methionine 32, methionine + cysteine 63, threonine 65, valine 75, isoleucine 60, leucine 1 10, phenylalanine 61, phenylalanine + tyrosine 120, histidine 42, tryptophan 19 and arginine 43. The essential : non essential amino acid ratio of 46 : 54 was adjusted by the addition of a combination of glutamic acid and glycine. The casein diets were formulated with 97 % of amino acid N assumed to be truly digestible (Kies et al. 1986) . Diets 5 and 6 were the same as diet 4 except that they had 10 and 20 g NaHCOag added.", "cite_spans": [{"start": 114, "end": 136, "text": "Chung & Baker's (1992)", "ref_id": "BIBREF7"}, {"start": 440, "end": 477, "text": "(Agricultural Research Council, 1981;", "ref_id": "BIBREF0"}, {"start": 478, "end": 496, "text": "Zhang et al. 1984;", "ref_id": "BIBREF20"}, {"start": 549, "end": 569, "text": "Wang & Fuller, 1989)", "ref_id": "BIBREF19"}, {"start": 1004, "end": 1022, "text": "(Kies et al. 1986)", "ref_id": "BIBREF12"}], "ref_spans": [{"start": 219, "end": 235, "text": "(Tables 1 and  2", "ref_id": "TABREF0"}]}, {"section": "Expt 1. Comparison of growth performance and nutrient retention of piglets given diets", "text": "The diets were formulated to similar digestible energy (DE) contents which, with the exception of the FAA diet, were all in excess of 15 MJkg to allow unrestricted energy intake (Campbell & Dunkin, 1983) . The carbohydrate sources used were lactose and sucrose (150 g/kg each) plus a variable level of wheat starch (Chung & Baker, 1990) .", "cite_spans": [{"start": 178, "end": 203, "text": "(Campbell & Dunkin, 1983)", "ref_id": "BIBREF3"}, {"start": 315, "end": 336, "text": "(Chung & Baker, 1990)", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Expt 1. Comparison of growth performance and nutrient retention of piglets given diets", "text": "Wheat starch (\"Unigel\", NB Love, Noorooka, Queensland, Australia), rather than maize starch, was used because of its availability. The lactose was white edible grade and the sucrose was unprocessed raw. Soyabean oil was the only source of essential fatty acids in the diet. An antioxidant, ethoxyquin (125 m a g ) , and a dietary fibre source, solka floc (30 g/kg), were included in diets 2, 4, 5 and 6. Both Fuzone 200 (furazolidone 200 mg/g) and neomycin sulfate (neomycycin 700 mg/g) were added to control Cumpylobacter and E. coli. Animals and procedures. Forty-eight male Large White piglets, weaned at 20-22 d of age, were allocated to six dietary treatments. Each treatment comprised eight piglets in a randomized block design. Each piglet was assigned to a block on the basis of its 3 week weight and, where possible, litter of origin. In addition five piglets were killed at 3 weeks of age for measurement of initial body composition.", "cite_spans": [], "ref_spans": []}, {"section": "Expt 1. Comparison of growth performance and nutrient retention of piglets given diets", "text": "Each piglet was individually housed in a raised 0.90 x 0.48m cage with wire mesh floor and fed ad libitum. Feed consumption and weight gain were measured weekly. Feed spillage was collected weekly from plastic trays located below the front of each experimental cage. Water was provided by a single bite nipple at the rear of the pen. House Ileal and faecal nutrient digestibilities was made using the inert marker, Cr203, added to the diet (2 gkg) at least 4 d before digestibility measurements were required. A grab sample of faeces was taken for analysis just before slaughter. Ileal collections were taken immediately post-slaughter from the region 0.15-1.5 m anterior to the ileocaecal junction. Each ileal sample was immediately frozen (-15\") before being freeze-dried, ground and then chemically analysed.", "cite_spans": [], "ref_spans": []}, {"section": "Expt 1. Comparison of growth performance and nutrient retention of piglets given diets", "text": "The piglets were killed by captive bolt pistol, to minimize shedding of the gastrointestinal mucosa into the ileum (Badaway et al. 1957) and then bled. The gastrointestinal contents of all piglets were removed, and the blood, carcass and viscera combined before being frozen. The frozen empty-bodies of piglets were minced, mixed, subsampled, freeze dried and ground before chemical analysis.", "cite_spans": [], "ref_spans": []}, {"section": "Expt 1. Comparison of growth performance and nutrient retention of piglets given diets", "text": "The following factors were used in calculations; 6.38 to convert casein N to protein and 6-25 for all other N sources (Agricultural Research Council, 1981). The energy (MJ) stored in carcass protein was calculated as kg carcass protein x 24.2 (Jordan & Brown, 1970) . Energy stored as fat was calculated as carcass energy minus protein energy, the difference of which was divided by 39.7 (Burlacu et al. 1973 ). Amino acid compositions of the initial slaughter group and those on the experimental treatments were made from a composite sample of mince from the piglets on that treatment.", "cite_spans": [{"start": 243, "end": 265, "text": "(Jordan & Brown, 1970)", "ref_id": "BIBREF11"}, {"start": 388, "end": 408, "text": "(Burlacu et al. 1973", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Expt 1. Comparison of growth performance and nutrient retention of piglets given diets", "text": "All results were analysed using the generalized linear models procedure of the statistical package SAS (Statistical Analysis Systems, Inc., 1989). Least significant differences (5 %) were used to separate treatment means.", "cite_spans": [], "ref_spans": []}, {"section": "Expt 1. Comparison of growth performance and nutrient retention of piglets given diets", "text": "Expt 2. Effect of storage temperature and feeding regimen of a free amino acid diet on piglet growth", "cite_spans": [], "ref_spans": []}, {"section": "Expt 1. Comparison of growth performance and nutrient retention of piglets given diets", "text": "Diets. The two diets were formulated to 0434 g available 1ysineMJ DE. The ingredients and composition of the CFS and FAA diets are detailed in diet 3 of Table 1 and diet 2 of Table 2 . Animals and procedures. This experiment compared ambient storage (22.3 (SD 2.2)\", range 13-30\") and ad libitum feeding with -15\" storage and twice daily feeding of a FAA diet. A diet containing intact proteins (CFS) was offered ad libitum and used as a control. Piglets were grown from 10-20 kg live weight.", "cite_spans": [], "ref_spans": [{"start": 153, "end": 160, "text": "Table 1", "ref_id": "TABREF0"}, {"start": 175, "end": 182, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "Expt 1. Comparison of growth performance and nutrient retention of piglets given diets", "text": "Half the FAA diet was stored at ambient temperature (13-30\") for up to 28 d, the remainder at -15\". The piglets (six per treatment) were allowed to adjust to the experimental treatments from 1 week post weaning (35 d of age) until they reached 10 kg live weight. Piglet performance was then assessed between 10 and 20 kg live weight. The individual cages, allocation, feeding, weighing and reject collection procedures were as described in Expt 1. The results were examined using the generalized linear models procedure of SAS (Statistical Analysis Systems, Inc., 1989) with least significant differences (5 %) being used to separate treatment means.", "cite_spans": [], "ref_spans": []}, {"section": "Chemical analyses", "text": "The methods of the Association of Official Analytical Chemists (1984) were used for proximate analyses. Gross energy was determined by adiabatic bomb calorimetry. Cr in at https:/www.cambridge.org/core/terms. https://doi.org/10.1079/BJN19970071", "cite_spans": [], "ref_spans": []}, {"section": "D. 1. OFFICER ET AL.", "text": "ileal digesta was measured by atomic absorption spectrophotometry (Kimura & Miller, 1957) under nitrous oxide-acetylene, having been digested with nitric and perchloric acids.", "cite_spans": [{"start": 66, "end": 89, "text": "(Kimura & Miller, 1957)", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "D. 1. OFFICER ET AL.", "text": "All amino acid samples were hydrolysed at 110\" for 24 h with constant-boiling-point HCl under N2. The amino acids in the casein, ileal digesta, faeces and empty-body were separated by reverse-phase chromatography and measured after reaction with phenylisothiocyanate, using a-amino butyric acid as the internal standard. Methionine and cystine were not analysed by performic acid oxidation and levels of these two amino acids may be underestimated. Tryptophan was determined by HPLC following LiOH alkaline hydrolysis (Degussa AG, 1986) .", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Expt 1. Comparison of growth peformance and nutrient retention of piglets given diets with casein, free amino acid and conventional protein sources", "text": "There were marked differences in piglet weight gains between treatments after only 7 d (Table 3) . Over the 5-10 kg growth phase the Supercreep and CFS diets produced piglet weight gains and feed conversion efficiencies which were superior (P < 0.001) to all but those on the diet with casein plus 10 g NaHC03kg. The addition of 10 g NaHC03/kg to the casein treatment tended to improve piglet performance compared with the casein (P=O-O65) diet and was superior to the FAA treatment. As the piglets grew, the differences between the casein and FAA treatments diminished. In contrast, the differences between the Supercreep and CFS treatments and all other treatments increased.", "cite_spans": [], "ref_spans": [{"start": 87, "end": 96, "text": "(Table 3)", "ref_id": "TABREF3"}]}, {"section": "Expt 1. Comparison of growth peformance and nutrient retention of piglets given diets with casein, free amino acid and conventional protein sources", "text": "The ileal and faecal digesibilities of N, dry matter and energy were higher (P < 0.001) in the casein and FAA diets than either the Supercreep or CFS diet ( Table 4) . The determined DE contents of the casein diets were 0.2-0-4 MJkg higher than was assumed during formulation. The FAA diet contained 0.9 MJ DEkg more than was formulated. The DE of the CFS and Supercreep diets were similar to their formulated values. The ileal amino acid digestibilities of the casein and FAA diets were generally greater (P < 0.001 for all amino acids except arginine and proline) than the CFS and Supercreep diets ( Table 5 ). The digestibilities of glycine and proline were lower and more variable than the digestibilities of all the other amino acids. The bodies of piglets given the Supercreep and FAA diets contained more energy with a higher proportion of fat (P<O.Ol) than those on either the CFS or casein plus 10 g NaHCO3kg diets (Table 6 ). The amount of empty-body protein was similar across treatments, although those piglets on the FAA diet tended ( P ( 0 . 0 8 ) to contain less protein.", "cite_spans": [], "ref_spans": [{"start": 602, "end": 609, "text": "Table 5", "ref_id": "TABREF6"}, {"start": 924, "end": 932, "text": "(Table 6", "ref_id": "TABREF8"}]}, {"section": "Expt 1. Comparison of growth peformance and nutrient retention of piglets given diets with casein, free amino acid and conventional protein sources", "text": "Both the CFS and Supercreep diets gave 24-41 96 greater (P -c 0401) rates of energy and 21-64 96 faster (P < 0-001) protein deposition rates than the other treatments. Piglets given the CFS treatment deposited more protein (P < 0.001) and less fat (P < 0-05) than those on the Supercreep treatment. Piglets given the FAA diet deposited 20-23% less protein (P < 0.001) than those given the NaHC03-supplemented casein diets. Piglets given the Supercreep and CFS diets retained more energy and protein per unit DE consumed than those given the casein treatments, which in turn had higher energy and protein retention ratios than the FAA-fed animals (P(O.001). The ratio protein retained:protein consumed was highest in piglets given the CFS diet ( P ( O . 0 5 ) . Both the CFS-and Supercreep-fed piglets retained a greater proportion of dietary ileal digestible N (0-82 and 0.78) compared with those given casein or FAA diets (0-61 and 0-59) respectively (P < 0.001).", "cite_spans": [], "ref_spans": []}, {"section": "Expt 1. Comparison of growth peformance and nutrient retention of piglets given diets with casein, free amino acid and conventional protein sources", "text": "at https:/www.cambridge.org/core/terms. https://doi.org/10.1079/BJN19970071 ... ... Mean values within a row not sharing a common superscript letter were significantly different, P Mean values within a row not sharing a common superscript letter were significantly different, P < 0.05.", "cite_spans": [], "ref_spans": []}, {"section": "Expt 1. Comparison of growth peformance and nutrient retention of piglets given diets with casein, free amino acid and conventional protein sources", "text": "* P < 0.05, ** P < 0.01, *** P < 0.001. Expt 2. ESfect of storage temperature and feeding regimen of a free amino acid diet on piglet growth", "cite_spans": [], "ref_spans": []}, {"section": "Expt 1. Comparison of growth peformance and nutrient retention of piglets given diets with casein, free amino acid and conventional protein sources", "text": "Piglets given the FAA diet were slower to reach 10 kg live weight than those given the CFS diet (P < 0.05; Table 7 ). With the exception of the feed conversion ratio (FCR) of piglets receiving the FAA ad libitum, the feed intake, weight gain and FCR for piglets given the FAA diets were inferior to those given the control diet and were unaffected by method of storage or feeding regimen (P < 0.05).", "cite_spans": [], "ref_spans": [{"start": 107, "end": 114, "text": "Table 7", "ref_id": "TABREF9"}]}, {"section": "DISCUSSION", "text": "The growth rates of piglets given the casein and FAA diets were disappointing when compared with the excellent weight gains of those given the CFS and Supercreep diets. The 10-20 kg weight gains of piglets given the CFS and Supercreep diets were similar to those observed by Campbell et al. (1988) . The piglets given the FAA diet (Expt 1) exhibited approximately 10 % lower gains than those reported by Chung & Baker (1992) . The effects of acid-base balance, storage temperature and feeding regimen and other factors on performance of piglets given the casein and FAA diets are discussed.", "cite_spans": [{"start": 404, "end": 424, "text": "Chung & Baker (1992)", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Acid-base balance for casein diets", "text": "Piglets given a casein diet containing 183 mmovkg of dEB grew 14% faster than those given a diet containing 64 mmovkg. The beneficial effect provided by adding 10 g NaHC03/kg diminished as the piglets grew, which may indicate that the piglets adapted over time to the acid-base balance of the diet they were receiving. Alternatively, as the piglets' production of bicarbonate increased with age, their response to bicarbonate supplementation declined. The improvement in the growth rates of piglets given the modified casein diets was insufficient to match the performance of piglets given either the CFS diet or the Supercreep diet. The growth rates of piglets given the Supercreep and CFS diets were between 17 and 24 % greater than those on the best casein-based diet. Both the determined DE content and ileal amino acid digestibilities of the casein diets were close to their formulated values and therefore unlikely to be the cause of reduced growth.", "cite_spans": [], "ref_spans": []}, {"section": "Acid-base balance for casein diets", "text": "Patience et al. (1987) examined a range of acid-base ratios from -85 to 341 mmolkg (dEB) for 8-12-week-old piglets using a diet based on maize and soyabean meal. Piglets showed signs of metabolic acidosis, including reduced blood pH and bicarbonate, when the at https:/www.cambridge.org/core/terms. https://doi.org/10.1079/BJN19970071 dEB was less than 175 mmolkg. Yet, impaired growth and feed intake were not evident until dEB fell below 0 mmolkg. The results of this experiment show that impaired growth may occur at higher dEB (e.g. 64 mmolkg) than was measured by Patience et al. (1987) .", "cite_spans": [{"start": 569, "end": 591, "text": "Patience et al. (1987)", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Acid-base balance for casein diets", "text": "In his review of acid-base balance Patience (1990) states \"changes in acid-base balance influence the metabolic fate of many amino acids\". This means that although the three casein diets had similar DE contents and amino acid digestibilities, the higher dEB of the NaHC03-supplemented treatments probably improved the efficiency with which the absorbed amino acids were metabolized. There was a trend (P > 0.05) for piglets given the NaHC03-supplemented treatments to deposit more protein (g/d) than those given the plain casein diet. This trend may have been clearer if the pigs had been killed at 10 rather than 20 kg.", "cite_spans": [{"start": 35, "end": 50, "text": "Patience (1990)", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "Casein and free amino acid diets: causes of poor nitrogen retention", "text": "The poor retention of N by pigs given the casein and FAA diets compared with the Supercreep and CFS diets can be partly explained by the inefficient use of FAA by the pig when they are consumed in large quantities. Fickler et al. (1994) showed that piglets (10-15 kg) given Chung & Baker's (1991) FAA diet performed poorly compared with those given a grain, soyabean meal, fish meal and skimmed-milk-powder diet. Piglets given the FAA diet had 24% lower growth rates, 14% lower absolute N retention (N balance) despite consuming similar levels of energy (Fickler et al. 1994) . The reduction in N retention measured by FicMer et al. (1994) is confirmed here. The efficiency of protein retention (Table 6 , crude protein : crude-protein intake) for piglets given the FAA diet in Expt 1 was 14 % lower than for those piglets given the CFS diet. It appears that when FAA constitute 35 % or more of N in a diet, as they did in the casein and FAA diets, they are utilized inefficiently.", "cite_spans": [{"start": 274, "end": 296, "text": "Chung & Baker's (1991)", "ref_id": "BIBREF6"}, {"start": 554, "end": 575, "text": "(Fickler et al. 1994)", "ref_id": "BIBREF8"}], "ref_spans": [{"start": 695, "end": 703, "text": "(Table 6", "ref_id": "TABREF8"}]}, {"section": "Casein and free amino acid diets: causes of poor nitrogen retention", "text": "The poor efficiency of N retention of the casein and FAA-fed piglets was not the result of a reduced lysine : DE ratio. The ileal digestible lysine : DE ratios determined for the diets were CFS 0.9 1, casein 0.83, FAA 0.79 and Supercreep 0-73. With the possible exception of the Supercreep diet, these values compare favourably with a requirement of about 0.8 g/MJ DE for piglets of this strain (Officer, 1994) . The piglets given Supercreep consumed less digestible lysine/MJ DE than the casein and FAA piglets but exhibited higher efficiencies of retention. This suggests that the digestible amino acid ratios did not reflect amino acid availability.", "cite_spans": [{"start": 395, "end": 410, "text": "(Officer, 1994)", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Casein and free amino acid diets: causes of poor nitrogen retention", "text": "With the exception of the three casein diets, all diets were formulated to different amino acid ratios. The Supercreep and CFS diets were included in Expt 1 to give the authors reference points against which the casein and FAA diets could be compared. Whilst the casein and FAA diets were formulated to similar lysine : DE ratios they had different amino acid balances. This means that some of the variation in the efficiency of amino acid use may be attributed to these different amino acid ratios.", "cite_spans": [], "ref_spans": []}, {"section": "Casein and free amino acid diets: causes of poor nitrogen retention", "text": "The DE content for the FAA diet was 0.9 MJkg (6%) higher than the formulated value. The estimate for DE content of the FAA diet was made from the lower (14 MJkg) of two metabolizable energy (ME) contents determined by Chung & Baker (1991) . With hindsight the higher ME estimate of 14.4 MJkg would have been more appropriate. As a consequence, the amino acid content per unit DE was lower in the FAA diet than in all but the Supercreep diet. The higher DE of the FAA diet meant that these piglets were receiving between 7 and 9 % less lysine per unit DE than piglets given the casein diets. If the FAA and casein diets had contained similar lysine : DE ratios, the differences in deposition rates and efficiency of protein retention may not have occurred.", "cite_spans": [{"start": 218, "end": 238, "text": "Chung & Baker (1991)", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Casein and free amino acid diets: causes of poor nitrogen retention", "text": "The results of Expt 2 show that the poor growth of piglets given the FAA diets cannot be attributed to the storage temperature and feeding regimen employed. Chemical reactions within the FAA diet stored at ambient temperature do not appear to have caused the lower piglet performance. The results of experiments using liquid amino acid and glucose mixtures heated to 100\" show that there is potential for L-cysteine to be used as an inhibitor of Maillard reactions (Friedman & Molnar-Perl, 1990) . The presence of free L-cysteine in the FAA diet may explain why no difference in piglet performance was measured between the two storage and feeding regimens.", "cite_spans": [{"start": 465, "end": 495, "text": "(Friedman & Molnar-Perl, 1990)", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Casein and free amino acid diets: causes of poor nitrogen retention", "text": "Apart from the differences in protein source the diets also differed in carbohydrate source. For example, the casein diet contained a combination of starch, sucrose and lactose, while the CFS diet contained only sucrose. The importance of the different carbohydrate sources used for feed intake, weight gain and nutrient utilization needs further evaluation.", "cite_spans": [], "ref_spans": []}, {"section": "Effect of methodology on nitrogen retention estimates", "text": "The efficiencies of N retention for the casein and FAA diets were low compared with estimates made by N balance (Moughan et al. 1987; Chung & Baker, 1992) . The difference in methodology is important because Newport & Henschel(l984) showed that N balance overestimates N retention in the carcass by 16-25 %. If the N retention : N intake for Chung & Baker's (1992) FAA diet (called IIP) is a 25 % overestimate, then the efficiency of N retention in the carcass of pigs given IIP should be 0-59. Despite the fact that this 0-59 estimate of the efficiency of N retention is still 9 % higher than what was measured in Expt 1, most of the difference between these results and those found in the literature appears to be methodological.", "cite_spans": [{"start": 112, "end": 133, "text": "(Moughan et al. 1987;", "ref_id": "BIBREF14"}, {"start": 134, "end": 154, "text": "Chung & Baker, 1992)", "ref_id": "BIBREF7"}, {"start": 342, "end": 364, "text": "Chung & Baker's (1992)", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Effect of methodology on nitrogen retention estimates", "text": "Overall, the results indicate that 183 mmovkg dEB in the casein diet is adequate. Even though increasing the casein diet dEB from 63 to 183 mmoukg improved the growth rates of piglets, this formulation did not result in growth rates equivalent to those observed for CFS-and Supercreep-fed piglets. The growth performance of piglets fed on the FAA was also inferior to that of those fed on the control diets. The poor growth of piglets given the FAA diets cannot be attributed to the storage temperature and feeding regimen employed or to reduced amino acid digestibility. This indicates that the casein and FAA diets are not suitable in their current form to be used as a base diet for amino acid utilization studies. 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Experiments by amino acid deletion", "authors": [{"first": "T", "middle": ["C"], "last": "Wang", "suffix": ""}, {"first": "M", "middle": ["F"], "last": "Fuller", "suffix": ""}], "year": 1989, "venue": "British Journal of Nutrition", "link": null}, "BIBREF20": {"title": "Dietary amino acid balance and requirements for pigs weaned at 3 weeks of age", "authors": [{"first": "Y", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "I", "middle": ["G"], "last": "Partridge", "suffix": ""}, {"first": "H", "middle": ["D"], "last": "Keal", "suffix": ""}, {"first": "K", "middle": ["G"], "last": "Mitchell", "suffix": ""}], "year": 1984, "venue": "Animal Production", "link": "87958379"}}, "ref_entries": {"TABREF0": {"text": "Expt 1. Ingredient and nutrient composition of Supercreep and casein-fish meal- soyabean (CFS) diets ( g k g , air-dry)", "type": "table"}, "TABREF1": {"text": "Expt I. Composition of free amino acid (FAA) and casein-based diets (g/kg air dry)DE, digestible energy; dEB, dietary electrolyte balance (Na + K -Cl); EAA : NEAA, essential : non essential amino acid ratio. * Composition of lactic acid casein (gkg air dry): crude protein 822, dry matter 890, gross energy (MJkg) 21.4, lysine", "type": "table"}, "TABREF2": {"text": "at https:/www.cambridge.org/core/terms. https://doi.org/10.1079/BJN19970071 Downloaded from https:/www.cambridge.org/core. IP address: 54.191.40.80, on 02 Apr 2017 at 08:06:57, subject to the Cambridge Core terms of use, available temperature was set at 28\" (air speed 0.3 d s ) and was maintained until the youngest piglet had spent 7 d at that setting. The temperature was then reduced by l\"/week to 25\". There was a 14 d spread in starting date of the experiment. The spread in starting date for piglets within blocks was only 4 d.", "type": "table"}, "TABREF3": {"text": "Expt 1.", "type": "table"}, "TABREF6": {"text": "Expt I . Apparent ileal amino acid digestibility of diets containing casein, free amino acids (FAA) or conventional proteins?", "type": "table"}, "TABREF8": {"text": "Expt 1. Empty-body protein, energy and fat concentrations, deposition rates and eficiencies of retention of", "type": "table"}, "TABREF9": {"text": "Expt 2. Effect of storage temperature and feeding regimen on piglet performance*", "type": "table"}}}
{"paper_id": "18980646", "_pdf_hash": "f43d49fec7f00545d7c35dfa10d6b42147d3de77", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Latest Trends in CDMA Technology", "authors": [{"first": "F", "middle": [], "last": "Adachi", "suffix": ""}, {"first": "M", "middle": [], "last": "Uesugi", "suffix": ""}], "year": 2003, "venue": "IEICE Journal", "link": null}, "BIBREF1": {"title": "Trends in Research and Development of Software Defined Radio", "authors": [{"first": "K", "middle": [], "last": "Uehara", "suffix": ""}, {"first": "K", "middle": [], "last": "Araki", "suffix": ""}, {"first": "M", "middle": [], "last": "Umehira", "suffix": ""}], "year": 2003, "venue": "NTT Technical Review", "link": "67044221"}, "BIBREF2": {"title": "System Capacity Expansion Effect of Multi-hop Access in a Broadband CDMA Cellular System", "authors": [{"first": "A", "middle": [], "last": "Fujiwara", "suffix": ""}, {"first": "S", "middle": [], "last": "Takeda", "suffix": ""}, {"first": "H", "middle": [], "last": "Yoshino", "suffix": ""}, {"first": "T", "middle": [], "last": "Otsu", "suffix": ""}, {"first": "Y", "middle": [], "last": "Yamao", "suffix": ""}], "year": 2002, "venue": "IEICE Trans. B", "link": null}, "BIBREF3": {"title": "The Challenge of Systems beyond IMT-2000-approach from wireless", "authors": [{"first": "T", "middle": [], "last": "Otsu", "suffix": ""}], "year": 2003, "venue": "ITU Journal", "link": null}, "BIBREF4": {"title": "He joined NTT Laboratories in 1987", "authors": [], "year": 1985, "venue": "1992, he transferred to NTT Mobile Communications Network, Inc. (now NTT DoCoMo, Inc.). He has been engaged in research on the radio link control for the personal digital cellular (PDC) system and IMT-2000. His current research interests are in the radio control for 4G mobile communications systems (beyond 3G). He was a co-recipient of the Japan Institute of Invention and Innovation (JIII) Imperial Invention Prize in 1998 and the best paper award of the International Conference on Telecommunications at ICT2002. He is a member of the Institute of Electronics", "link": null}}, "ref_entries": {}}
{"paper_id": "18980725", "_pdf_hash": "c2b719ce8fe8149eeb2d407ff645fe8f1a6ff839", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Incorporating biodiversity into sensitivity maps of the Niger River delta. International Oil Spill Conference", "authors": [{"first": "E", "middle": [], "last": "Gundlach", "suffix": ""}, {"first": "V", "middle": ["O"], "last": "Imevbore", "suffix": ""}, {"first": "B", "middle": [], "last": "Witherspoon", "suffix": ""}, {"first": "J", "middle": [], "last": "Ainodion", "suffix": ""}], "year": 2001, "venue": "", "link": null}, "BIBREF1": {"title": "Oil Spill Sensitivity Atlas for Mauritius' Prepared for IMO, UNDP, Mauritius Ministry of Lands and Environment", "authors": [{"first": "E", "middle": [], "last": "Gundlach", "suffix": ""}, {"first": "M", "middle": [], "last": "Murday", "suffix": ""}], "year": 1987, "venue": "", "link": null}, "BIBREF2": {"title": "Expressing User Profiles for Data Recharging, IEEE Personal Communication", "authors": [{"first": "M", "middle": [], "last": "Cherniack", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Franklin", "suffix": ""}, {"first": "S", "middle": [], "last": "Zdonik", "suffix": ""}], "year": 2001, "venue": "", "link": null}, "BIBREF3": {"title": "Geospatial IT for mobile field data collection", "authors": [{"first": "S", "middle": [], "last": "Nusser", "suffix": ""}, {"first": "L", "middle": [], "last": "Miller", "suffix": ""}, {"first": "K", "middle": [], "last": "Clarke", "suffix": ""}, {"first": "M", "middle": [], "last": "Goodchild", "suffix": ""}], "year": 2003, "venue": "Communication of the ACM", "link": null}, "BIBREF4": {"title": "Adaptive Concepts for Mobile cartography Supplement Journal of Geographical Sciences", "authors": [{"first": "T", "middle": [], "last": "Reichenbacher", "suffix": ""}], "year": 2001, "venue": "", "link": null}, "BIBREF5": {"title": "Design Challenges for an Integrated Disaster Management Communication and Information System", "authors": [{"first": "A", "middle": [], "last": "Meissner", "suffix": ""}, {"first": "T", "middle": [], "last": "Luckenbach", "suffix": ""}, {"first": "T", "middle": [], "last": "Risse", "suffix": ""}, {"first": "T", "middle": [], "last": "Kirste", "suffix": ""}, {"first": "H", "middle": [], "last": "Kirschner", "suffix": ""}], "year": 2002, "venue": "The first IEEE workshop on Disaster Recovery Networks", "link": "590529"}, "BIBREF6": {"title": "Mobile Geographic Services", "authors": [{"first": "D", "middle": [], "last": "Maguire", "suffix": ""}], "year": 2001, "venue": "Map India 2001 Conference", "link": null}, "BIBREF7": {"title": "Mobile Geographic Information Handling Technologies to support Disaster Management", "authors": [{"first": "N", "middle": [], "last": "Erharuyi", "suffix": ""}, {"first": "D", "middle": [], "last": "Fairbairn", "suffix": ""}], "year": "", "venue": "Geography", "link": "126617263"}, "BIBREF8": {"title": "Wireless Internet Applications & Architecture", "authors": [{"first": "M", "middle": [], "last": "Beaulieu", "suffix": ""}, {"first": "M", "middle": [], "last": "Cooper", "suffix": ""}], "year": 2002, "venue": "", "link": null}, "BIBREF9": {"title": "Geographic Information System and Computer Cartography", "authors": [{"first": "C", "middle": [], "last": "Jones", "suffix": ""}], "year": 1997, "venue": "", "link": null}, "BIBREF10": {"title": "A Resource-Adaptive Java Agent Infrastructure, 5 th International Conference on Autonomous Agents Montreal", "authors": [{"first": "Y", "middle": [], "last": "Ding", "suffix": ""}, {"first": "C", "middle": [], "last": "Kray", "suffix": ""}, {"first": "R", "middle": [], "last": "Malaka", "suffix": ""}], "year": 2001, "venue": "", "link": null}, "BIBREF11": {"title": "A framework for adaptive content delivery in heterogeneous network environment", "authors": [{"first": "W", "middle": [], "last": "Ma", "suffix": ""}], "year": 2000, "venue": "SPIE/ACM Conference on Multimedia Computing and Networking", "link": null}}, "ref_entries": {}}
{"paper_id": "18980834", "_pdf_hash": "3c7f3635c052284f1421d040dad205469f1669fc", "abstract": [{"section": "Abstract", "text": "Background: Aspirin and eugenol were esterified to synthesize aspirin eugenol ester (AEE). As a pale yellow and odourless crystal, AEE reduced the gastrointestinal damage of aspirin and vulnerability of eugenol. The study was conducted to evaluate the preventive effects of AEE on blood lipids in rats with high fat diet (HFD). Methods: Suspensions of AEE and simvastatin were prepared in 5% carboxymethyl cellulose sodium (CMC-Na). In order to observe the intervention effects, the drugs and HFD were administrated at the same time. Based on individual weekly body weight (BW), AEE was intragastrically administrated at the dosage of 18, 36 and 54 mg/kg. Simvastatin (10 mg/kg) and CMC-Na (20 mg/kg) were used as control drug. After 6 weeks of administration, the changes of BW and blood lipid indices including triglyceride (TG), low density lipoprotein (LDL), high density lipoprotein (HDL) and total cholesterol (TCH) were determined in the experiment. Results: The rat blood lipids profile in model group was remarkably different after feeding 6-weeks HFD. TG, TCH and LDL indexes in model group were increased significantly compared with those in control group (p < 0.01). AEE at the dosage of 54 mg/kg significantly decreased levels of TG, TCH and LDL (p < 0.01), and slowed the rate of BW gain in comparison with model group (p < 0.05). Moreover, high dose AEE showed better effects than simvastatin on reducing TCH level and similar effects on TG, HDL and LDL. Conclusion: AEE could remarkably reduce levels of TG, TCH and LDL in rats with high fat diet, and slow the rate of body weight gain. It was conducted that AEE was a potential candidate on reducing blood lipids level. The mechanism of action of AEE should be investigated in further studies.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Background", "text": "Hyperlipidemia is a heterogeneous group of disorders characterized by an excess of lipids in blood stream such as the increased serum levels of triglycerides (TG), total cholesterol (TCH), low-density lipoprotein (LDL) as well as decreased levels of high-density lipoprotein (HDL) [1, 2] . Hyperlipidemia, as the major risk factor for the development of cardiovascular diseases, is becoming a major health problem in the world [3] .", "cite_spans": [{"start": 281, "end": 284, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 285, "end": 287, "text": "2]", "ref_id": "BIBREF1"}, {"start": 427, "end": 430, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Background", "text": "Aspirin could ameliorate hyperlipidemia induced by high fat diet and hyperinsulinemia in rats [4] . Moreover, aspirin could diminish hypertriglyceridemia in obese rodents and has potential in hyperlipidemia prevention [5] . Eugenol as volatile oil is extracted from dry alabastrum of Eugenia caryophyllata. Therapeutic effects of eugenol on hyperlipidemia had been proved in previous study [6, 7] . Four-week administration of eugenol could significantly decrease the serum lipid profile in normal albino rabbits [8] .", "cite_spans": [{"start": 94, "end": 97, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 218, "end": 221, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 390, "end": 393, "text": "[6,", "ref_id": "BIBREF5"}, {"start": 394, "end": 396, "text": "7]", "ref_id": "BIBREF6"}, {"start": 513, "end": 516, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Background", "text": "Based on prodrug principle and therapeutic effects of aspirin and eugenol on hyperlipidemia, aspirin eugenol ester (AEE) as a new drug was synthesized [9] . The metabolites of AEE had been confirmed in beagle dog and liver microsomes. AEE could be metabolized into aspirin and eugenol in vitro and in vivo, which could show their original activities and act synergistically [10] . AEE also reduced the side effects of its precursor such as the gastrointestinal damage of aspirin and irritation of eugenol [11] . The acute toxicity of AEE was less than its precursor, which was 0.02 times of aspirin and 0.27 times of eugenol [9, 11] . The teratogenicity and mutagenicity of AEE have been investigated. AEE did not show any mutagenesis in Ames test and the mouse bone marrow micronucleus assay [11, 12] . Moreover, the effects of AEE had been evaluated in animal model. The results showed that AEE had positive effects on antithrombosis, anti-inflammatory, analgesia and antipyretic [9, 11, 13] .", "cite_spans": [{"start": 151, "end": 154, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 374, "end": 378, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 505, "end": 509, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 625, "end": 628, "text": "[9,", "ref_id": "BIBREF8"}, {"start": 629, "end": 632, "text": "11]", "ref_id": "BIBREF10"}, {"start": 793, "end": 797, "text": "[11,", "ref_id": "BIBREF10"}, {"start": 798, "end": 801, "text": "12]", "ref_id": "BIBREF11"}, {"start": 982, "end": 985, "text": "[9,", "ref_id": "BIBREF8"}, {"start": 986, "end": 989, "text": "11,", "ref_id": "BIBREF10"}, {"start": 990, "end": 993, "text": "13]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Background", "text": "Therapeutic strategies for hyperlipidemia treatment depend on reducing blood lipids. There are many chemical drugs that lower cholesterol level in the body such as statins, fibrates, ezetimibe and nicotinic acid. However, most of them are expensive and have undesirable effects [14] . There is an obvious need for more efficacious and alternative treatment options for hyperlipidemia. In our previous study, AEE (50 mg/kg and 160 mg/kg) could reduce TCH and TG in rats with standard diet [11] . Moreover, five-week administration of AEE (54 mg/kg) could normalize blood lipids profile in hyperlipidemic rats [15] . So there are increasing interest to evaluate the intervention effects of AEE on blood lipids in rat with high fat diet. This study will increase the understanding of AEE and provide impetus for further studies.", "cite_spans": [{"start": 278, "end": 282, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 488, "end": 492, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 608, "end": 612, "text": "[15]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Chemicals and reagents", "text": "Aspirin eugenol ester (AEE), transparent crystal with the purity of 99.5% by RE-HPLC, was prepared in Key Lab of New Animal Drug Project of Gansu Province, Key Lab of Veterinary Pharmaceutical Development of Agricultural Ministry, Lanzhou Institute of Husbandry and Pharmaceutical Sciences of CAAS. CMC-Na and simvastatin was supplied by Tianjin Chemical Reagent Company (Tianjin, China). Standard compressed rat feed and high diet food were supplied by Keao Xieli Co., Ltd (Beijing, China). Standard rat diet consisted of 12.3% lipids, 63.3% carbohydrates, and 24.4% proteins (kcal) and high fat diet (standard rat diet 77.8%, yolk power 10%, lard 10%, cholesterol 2%, bile salts 0.2%) consisted of 41.5% lipids, 40.2% carbohydrates, and 18.3% proteins (kcal). The TG, TCH, LDL and HDL kits were provided by Ningbo Medical System Biotechnology Co., Ltd (Ningbo, China). Erba XL-640 analyzer (German) was used to measure the blood lipid indices.", "cite_spans": [], "ref_spans": []}, {"section": "Animals", "text": "Seventy Sprague-Dawley (SD) male rats were purchased from the animal breeding facilities of Gansu University of Chinese Medicine (Lanzhou, China). The rats were housed in plastic cages of appropriate size (50 \u00d7 35 \u00d7 20 cm, ten rats per cage) with stainless steel wire cover and chopped bedding. Rat feed and drinking water were supplied ad libitum. Light/dark regime was 12/12 h and living temperature was 22 \u00b1 2\u00b0C with relative humidity of 55 \u00b1 10%. Animals were acclimatized for 2 weeks before study initiation.", "cite_spans": [], "ref_spans": []}, {"section": "Serum sampling", "text": "At the end of the experiment, rats were fasted for 10-12 h and then anaesthetized with 1% pentobarbital sodium. The blood samples were collected from the heart with vacuum tube. The sera were obtained by centrifuging for 15 mins at the speed of 4000 g at 4\u00b0C. Serum samples were stored at \u221280\u00b0C until the day of analysis.", "cite_spans": [], "ref_spans": []}, {"section": "Drug preparation", "text": "AEE and simvastatin liquid suspensions were prepared in 0.5% of CMC-Na.", "cite_spans": [], "ref_spans": []}, {"section": "Study design", "text": "Rats were randomly divided into seven groups including control, model, CMC-Na, simvastatin and three AEE groups. The detailed design of the experiment is shown in Table 1 . Simvastatin was used as a positive control (10 mg/kg). The administrations of food and drugs were started at the same time. The volumes of CMC-Na and drug suspensions were nearly equal. After 6-weeks administration, the blood lipid levels were analyzed.", "cite_spans": [], "ref_spans": [{"start": 163, "end": 170, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Statistics", "text": "The statistical analyses were carried out using IBM SPSS 19.0 (USA). All data obtained from the experiment are expressed as mean \u00b1 standard deviation (SD). Statistical differences were evaluated by using one-way ANOVA with Tukey's multiple comparison tests. P-values less than 0.05 were considered statistically significant. Rats were divided into seven groups. Control group was received SRD and the rest groups were received HFD, respectively. Based on the individual weekly body weight, rats were given with different drug suspension volume. CMC-Na as a vehicle was used in control group. Simvastatin was designed as positive drug. Different dose of three levels of AEE were administrated in the study. The administration period was 6 weeks and then blood lipids were analyzed AEE aspirin eugenol ester, SRD standard rat diet, HFD high fat diet", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Intervention effects of AEE", "text": "After feeding rats with HFD for 6 weeks, the blood lipid profile was notably different among the groups. There were significant differences between control and model groups ( Table 2) . In model group, TG, TCH and LDL were increased significantly in comparison with the control group (p < 0.01). However, no change was observed in HDL between control and model groups. There was no significant difference between CMC-Na and model groups. In comparing with model group, low and intermediate dose of AEE had no effect on blood lipid indexes except TCH index in AEE low group (p < 0.05). AEE high dose significantly decreased TG, TCH and LDL compared to model group (p < 0.01). AEE in different dosages had no influence on HDL. Simvastatin as a positive drug control could significantly decrease TCH and LDL (p < 0.01). With regard to TG and HDL, no changes were observed between simvastatin and model groups.", "cite_spans": [], "ref_spans": []}, {"section": "Intervention effects of AEE", "text": "The three groups were used to compare with control and statin groups (Fig. 1) . When compared with control group, TG, TCH and LDL in AEE groups were significant increased (p < 0.01 or p < 0.05). Notably, the mean values of TG, TCH and LDL in AEE high group were less than the values in low and intermediate AEE groups. Simvastatin and AEE made similar effects on TG, HDL and LDL indexes. However, simvastatin showed more positive effects on TCH than AEE L and AEE M but not AEE H (p < 0.01 or p < 0.05 Fig. 1d) . In order to find out the relationship between drug effects and the dosage, intermediate and high AEE groups were compared with low dose AEE group. The results showed that there was only significant difference on TCH index in AEE high group (p < 0.01 Fig. 1d) . Interestingly, the mean values of TG and LDL in AEE high group were the smallest in all AEE groups.", "cite_spans": [], "ref_spans": [{"start": 69, "end": 77, "text": "(Fig. 1)", "ref_id": "FIGREF1"}, {"start": 502, "end": 510, "text": "Fig. 1d)", "ref_id": "FIGREF1"}, {"start": 763, "end": 771, "text": "Fig. 1d)", "ref_id": "FIGREF1"}]}, {"section": "Body weight", "text": "The body weights of all groups were recorded at the beginning and ending of the experiment (Table 3) . At the beginning of the experiment, there was no significant difference between all groups. At week 6, the body weights in the group supplemented with AEE high dose were significantly lower than those in model group (p < 0.05). The results showed that high dose of AEE could reduce the rate of body weight gain. The body weights in AEE intermediate and high groups were remarkably lower than control group (p < 0.05 or p < 0.01). No difference was observed among statin and AEE groups. The gains in body weights in AEE high group were significantly lower than those in AEE low group (p < 0.05).", "cite_spans": [], "ref_spans": [{"start": 91, "end": 100, "text": "(Table 3)", "ref_id": "TABREF1"}]}, {"section": "Discussion", "text": "Based on prodrug principle, aspirin and eugenol, as starting precursors, were esterified to synthesize aspirin eugenol ester (AEE). The positive effects of AEE on the symptoms of inflammation, fever, pain and thrombosis had been confirmed in animal disease model [9, 11, 13] . The blood chemistry results in 15-day oral dose toxicity study showed AEE could significantly reduce the values of TG and TCH both in male and female rat, which indicated that this compound was potential for curing hyperlipidemia [11] . In subsequent experiment, the regulation effects of AEE on blood lipid profile in hyperlipidemic rats had been confirmed [15] . Based on this fact, it is essential to evaluate the intervention effects of AEE on blood lipids in rats with high fat diet fed.", "cite_spans": [{"start": 263, "end": 266, "text": "[9,", "ref_id": "BIBREF8"}, {"start": 267, "end": 270, "text": "11,", "ref_id": "BIBREF10"}, {"start": 271, "end": 274, "text": "13]", "ref_id": "BIBREF12"}, {"start": 507, "end": 511, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 635, "end": 639, "text": "[15]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Discussion", "text": "The intervention effect of AEE was evaluated by comparing AEE groups with model group. AEE low and intermediate dose showed no significant effect on blood lipid indices except reducing TCH at AEE low dose. It is noteworthy that high dose of AEE was highly effective in reducing blood lipid indices such as TG and TCH. These meant that the activity of AEE at high dose was better than low and intermediate doses. So there was a positive relationship between drug efficacy and dosage. Under the present experimental conditions, the optimal dose was considered to be 54 mg/kg for normalizing blood lipid profile in high fat diet fed rat.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "HDL is responsible for the transportation of cholesterol to liver, which is essential for cholesterol removal [16] . HDL levels of rat fed with high fat diet for six weeks showed no changes in this study. There are several possible reasons for this result. First of all, HFD compositions such as the lack of saturated fat may be insufficient to make substantial change on HDL. Second, the constant values of HDL may be attributable to the Table 2 The blood lipids levels after drugs administration for six weeks (n = 10) P < 0.01 significant difference compared to model group. TG triglyceride, HDL high density lipoprotein, LDL low density lipoprotein, TCH total cholesterol. Blood lipids indices were increased in model group. The blood lipid levels were reduced in simvastatin and high dose AEE groups in varying degrees short duration of the experiment (only 6 weeks). Finally, animal model used in the experiment may be a potential cause. Literature indicated that most cholesterol in rat blood circulation existed in HDL and this contributed to reducing susceptibility of HDL level to HFD [17, 18] .", "cite_spans": [{"start": 110, "end": 114, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 1095, "end": 1099, "text": "[17,", "ref_id": "BIBREF16"}, {"start": 1100, "end": 1103, "text": "18]", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "Discussion", "text": "HFD is a commonly used material to induce animal disease such as hyperlipidemia, diabetes, obesity and arteriosclerosis [19, 20] . In this experiment, the results of body weight were not consistent with those in our previous study. There was no difference in body weight between control and model group. However, HFD with same components significantly increased body weight at the end of eighth week in Wistar rat [15] . The shortage of HFD consumption time may be the reason for the results of no significant difference in body weight. Metabolism and liver function could be substantially changed with HFD feeding [21] . It was necessary to give the rat time to adjust for HFD gradually, which may slow the rate of the body weight gain in certain period. It was found that AEE dosage had different influence on body weight. AEE high and middle dose made an impact on body weight and there was significant difference between low and high AEE groups. The results of AEE on body weight were also the reason why 54 mg/kg was suggested for optimal dosage.", "cite_spans": [{"start": 120, "end": 124, "text": "[19,", "ref_id": "BIBREF18"}, {"start": 125, "end": 128, "text": "20]", "ref_id": "BIBREF19"}, {"start": 414, "end": 418, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 615, "end": 619, "text": "[21]", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Discussion", "text": "Simvastatin is an inhibiter of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) which plays a crucial role in cholesterol synthesis in liver cells. Simvastatin was used as a positive drug control in this study and it decreased the levels of TCH and LDL. The effects of 10 mg/kg simvastatin on TCH and LDL were similar with 54 mg/kg AEE. However, simvastatin had no influence in TG index and showed significant difference from high dose AEE. From these results, it could be concluded that AEE was more effective than simvastatin on reducing blood lipid level. CMC-Na was widely used as a reliable drug vehicle in pharmaceutical industry [22, 23] . The effect of CMC-Na on blood lipid indexes was eliminated by administrating equal volume CMC-Na to P < 0.01 significant difference compared to control group; b P < 0.05 significant difference compared to AEE low group; Week 1: beginning of the experiment; Week 6: the end of the experiment control group. Therefore, it manifested that the effects of AEE was not related to CMC-Na.", "cite_spans": [{"start": 635, "end": 639, "text": "[22,", "ref_id": "BIBREF21"}, {"start": 640, "end": 643, "text": "23]", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "Discussion", "text": "Therefore, intragastrical administration of AEE had a significant intervention effects in HFD fed rat. AEE was decomposed into salicylic acid and eugenol after absorption. The effects of AEE on reducing blood lipid indexes may be mainly from synergetic action of aspirin and eugenol. More studies are necessary to investigate the action mechanism of AEE such as evaluation of inhibitory effect on digestive enzymes and influence on metabolic targets.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "Under the present study condition, AEE at daily dosage of 54 mg/kg BW for six weeks could remarkably reduce levels of TG, TCH and LDL in rats with high fat diet, and slow the rate of body weight gain. Moreover, AEE at 54 mg/kg showed better effects than simvastatin at 10 mg/kg on reducing TCH level and similar effects on TG, HDL and LDL. 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"", "link": "95432761"}}, "ref_entries": {"FIGREF1": {"text": "Fig. 1 Comparative effects of AEE and simvastatin on blood lipid indexes (n = 10). a P < 0.05, aa P < 0.01 significant difference compared to control group; b P < 0.05, bb P < 0.01 significant difference compared to statin group; c P < 0.05, cc P < 0.01 significant difference compared to AEE L. CMC-Na: carboxymethylcellulose sodium, AEE L: low dose of AEE (18 mg/kg), AEE M: intermediate dose of AEE (36 mg/kg), AEE H: high dose of AEE (54 mg/kg). a, b, c and d were TG, HDL, LDL and TCH, respectively", "type": "figure"}, "FIGREF2": {"text": "Abbreviations AEE: Aspirin eugenol ester; BW: Body weight; CMC-Na: Sodium carboxymethyl cellulose; HDL: High density lipoprotein; HFD: High fat diet; LDL: Low density lipoprotein; SRD: Standard rat diet; TCH: Total cholesterol; TG: Triglycerides", "type": "figure"}, "TABREF0": {"text": "Study design of the experiment", "type": "table"}, "TABREF1": {"text": "Body weights of rats at the beginning and the end of the experiment (n = 10)", "type": "table"}}}
{"paper_id": "18981665", "_pdf_hash": "1ec658efc559125cd7f6e269b8a0376dd29f7e5a", "abstract": [{"section": "Abstract", "text": "Widespread surveillance programs using remote retinal imaging has proven to decrease the risk from diabetic retinopathy, the leading cause of blindness in the US. However, this process still requires manual verification of image quality and grading of images for level of disease by a trained human grader and will continue to be limited by the lack of such scarce resources. Computer-aided diagnosis of retinal images have recently gained increasing attention in the machine learning community. In this paper, we introduce a set of neural networks for diabetic retinopathy classification of fundus retinal images. We evaluate the efficiency of the proposed classifiers in combination with preprocessing and augmentation steps on a sample dataset. Our experimental results show that neural networks in combination with preprocessing on the images can boost the classification accuracy on this dataset. Moreover the proposed models are scalable and can be used in large scale datasets for diabetic retinopathy detection. The models introduced in this paper can be used to facilitate the diagnosis and speed up the detection process.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION", "text": "Diabetic retinopathy (DR) is a severe and common eye disease which is caused by changes in the retinal blood vessels. Diabetic retinopathy is the leading cause of blindness in the working age US population (age 20-74 years). Ninety-five percent of this vision loss is preventable with timely diagnosis. The national eye institute 1 estimates that from 2010 to 2050, the number of Americans with diabetic retinopathy is expected to nearly double, from 7.7 million to 14.6 million. By 2030, a half a billion people worldwide are expected to develop diabetes and a third of these likely will have DR. DR can be detected during a dilated eye exam by an ophthalmologist or optometrist in which the pupils are pharmacologically dilated and the retina is examined with specialized condensing lenses and a light source in real time. Primary barriers for diabetic patients in accessing timely eye care include lack of awareness of needing eye exams, inequitable distribution of eye care providers and the addition costs in terms of travel, time off from work, and additional medical fees of seeing another care provider [1] . Tele-ophthalmology, or using non-mydriatic camera in non-ophthalmic settings, such as primary care offices, to capture digital images of the central region of the retina in diabetic patients has increased the rate of annual diabetic retinopathy detection [2] . This methodology has been validated against dilated retinal examinations by eye specialists and is accepted by the UK National Health Service and US National Center for Quality Assurance. Incorporating an individuals retinal photos for those with diabetic retinopathy has been shown to be associated with better glycemic control for poorly controlled diabetic patients [3] . The procedures for DR detection can often be difficult and dependent on scarce resources such as trained medical professionals. The severity of this wide-spread problem then in combination with the cost and efficiency of the detection procedures motivates computer-aided models that can learn the underlying patterns of this disease and speedup the detection process. In this paper, we introduce a set of neural networks (NNs) that can facilitate diabetic retinopathy detection by training a model on color fundus photography inputs.", "cite_spans": [{"start": 330, "end": 331, "text": "1", "ref_id": "BIBREF0"}, {"start": 1111, "end": 1114, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 1372, "end": 1375, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 1747, "end": 1750, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "Fundus photography or fundography is the process of photographing of the interior surface of the eye, including the retina, optic disc, macula, and posterior pole [4] . Fun- dus photography is used by trained medical professionals for monitoring progression or diagnosis of a disease. Figure 1 illustrates example fundography images from a sample dataset for various stages 2 of diabetic retinopathy disease. The digital fundus images often contain a set of lesions which can indicate the signs of DR. Automated DR detection algorithms are composed of multiple modules: image preprocessing, feature extraction and model fitting (training). Image preprocessing reduces noise and disturbing imaging artifacts, enhances image quality using appropriate filters and defines the region of interest (ROI) within the images [5] . Illumination and quality variations often make preprocessing an important step for DR detection. Several attempts in computer vision literature have been proposed to best represent the ROI [6, 7] in fundus images. Image enhancement, mass screening (including detection of pathologies and retinal features), and monitoring (including feature detection and registration of retinal images) are often cited as three major contributions of preprocessing to DR [7] . Green-plane representation of RGB fundus images to increase the contrast for red lesions [6] and shadow correction to address the background vignetting effect [8] are perhaps among the most popular preprocessing steps for the task in hand [9, 10] . Landmark and feature detection [11] and segmentation [12, 9] on digital fundus images have also been explored as preprocessing steps.", "cite_spans": [{"start": 163, "end": 166, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 816, "end": 819, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 1011, "end": 1014, "text": "[6,", "ref_id": "BIBREF5"}, {"start": 1015, "end": 1017, "text": "7]", "ref_id": "BIBREF6"}, {"start": 1277, "end": 1280, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 1372, "end": 1375, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 1442, "end": 1445, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 1522, "end": 1525, "text": "[9,", "ref_id": "BIBREF8"}, {"start": 1526, "end": 1529, "text": "10]", "ref_id": "BIBREF9"}, {"start": 1563, "end": 1567, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 1585, "end": 1589, "text": "[12,", "ref_id": "BIBREF11"}, {"start": 1590, "end": 1592, "text": "9]", "ref_id": "BIBREF8"}], "ref_spans": [{"start": 285, "end": 293, "text": "Figure 1", "ref_id": "FIGREF0"}]}, {"section": "INTRODUCTION", "text": "The second step in developing an automatic DR detection algorithm is the choice of a learning model or classifier. DR detection has been explored through various classifiers such as fuzzy C-means clustering [13] , neural networks [14] and a set of feature vectors on benchmark datasets [7] . While the detection and preprocessing algorithms appear to be maturing, the automatic detection of DR remains an active area of research. Scalable detection algorithms are often required to validate the results on larger, well-defined, but more diverse datasets. The quality of input fundus photographs, image clarity problem, lack of available benchmark datasets and noisy dataset labels often present challenges in automating the diabetic retinopathy detection of input data or developing a robust set of feature vectors to represent the input data. In this paper, we explore neural networks with domain knowledge preprocessing and introduce manifold learn-ing techniques that can boost the classification accuracy on a sample dataset.", "cite_spans": [{"start": 207, "end": 211, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 230, "end": 234, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 286, "end": 289, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "This paper is organized as follows: In section 2 we present the outline of our proposed model. Preprocessing is presented in Section 2.1. We present the comparative results of DR detection on a sample dataset in Section 3. Finally we conclude this paper in Section 4 and propose future research directions.", "cite_spans": [], "ref_spans": []}, {"section": "METHOD", "text": "The input data to our DR detection model is a set of RGB represented fundus images. The proposed method involves four successive sequences: (i) preprocessing, (ii) data augmentation, (iii) manifold learning and dimensionality reduction techniques, and, (iv) neural network design. In this section we describe each step in details.", "cite_spans": [], "ref_spans": []}, {"section": "Data Preprocessing", "text": "The original digital fundus images in the sample dataset are high resolution RGB images with different sizes. The goal of the preprocessing step is contrast enhancement, smoothing and unifying images (resizing to same pixel resolution across images with minimal ROI loss) and enhancement of the red lesion representation.", "cite_spans": [], "ref_spans": []}, {"section": "Data Preprocessing", "text": "The first step in preprocessing the images is resizing all training and testing images to 256 \u00d7 388 pixel resolution. Once the original images are resized, we then represent the resized images in green channel only. Green channel representation of resized fundus images is considered as the natural basis for vessel segmentation since it normally presents a higher contrast between vessels and retinal background. Using only the green channel also replicates a common image practice in ophthalmology of using a green filter to capture the retinal image. This image, called red-free, is commonly used to increase local contrast to help identify hemorrhage, exudate or other retinal disease signs. Moreover, switching the RGB image to its green channel form also reduces the data dimensionality to one third of the original RGB presentation and reduces the time complexity of the detection algorithm.", "cite_spans": [], "ref_spans": []}, {"section": "Data Preprocessing", "text": "After green channel representation of resized fundus images, we apply a histogram equalization on the green channel to adjust image intensities and enhance the contrast around the red lesion. Figure 3 shows two different images from class 3 (severe) and class 4 (proliferative) stages of DR with green channel representation before and after histogram equalization. In the proposed method we use example duplication and rotation as the augmentation method. The input images have been duplicated within classification folds for under-represented classes 3 . We rotate images with angles of 45\u00b0, 90\u00b0, 135\u00b0, 180\u00b0, 225\u00b0and 270\u00b0degrees. Finally the augmented dataset is randomly sampled among all rotated preprocessed images. Table 1 summarizes the dimensionality of each sample size before and after augmentation for all different classes. We note that the 0-class (normal DR stage label) has been excluded from data augmentation due to large number of examples in the original dataset. 3 The data has been duplicated within folds to avoid classification on samples appearing on both testing and training splits of the classifie.", "cite_spans": [{"start": 553, "end": 554, "text": "3", "ref_id": "BIBREF2"}, {"start": 983, "end": 984, "text": "3", "ref_id": "BIBREF2"}], "ref_spans": [{"start": 192, "end": 200, "text": "Figure 3", "ref_id": "FIGREF2"}, {"start": 721, "end": 728, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Data Augmentation", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Manifold Learning", "text": "Manifold learning is a non-linear dimensionality reduction technique that is often applied in large scale machine learning models to address the curse of dimensionality [15] and reduce the time complexity of the learning models. In this approach, it is often assumed that the original high-dimensional data lies on an embedded non-linear low dimensional manifold within the higher-dimensional space.", "cite_spans": [{"start": 169, "end": 173, "text": "[15]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Manifold Learning", "text": "Let matrix M \u2208 R N \u00d7k represent the input matrix of all preprocessed examples in our dataset, where each row represents an example unrolled preprocessed image vector. N represents the total number of input images and k is the dimensionality of the unrolled image representation in green channel with histogram equalization. If the attribute or representation dimensionality k is large, then the space of unique possible rows is exponentially large and sampling the space becomes difficult and the machine learning models can suffer from very high time complexity. This motivates a set of dimensionality reduction and manifold learning techniques to map the original data points in a lower-dimensional space. In this paper, we use principal component analysis (PCA), supervised locality preserving projections (SLPP) [16] , neighborhood preserving embedding (NPE) [17] and spectral regression (SR) [18] as dimensionality reduction and manifold learning techniques.", "cite_spans": [{"start": 816, "end": 820, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 863, "end": 867, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 897, "end": 901, "text": "[18]", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "Neural Networks Architecture", "text": "The input to our neural network is the preprocessed unrolled image data after dimensionality reduction steps. All networks have been constructed with 2 layers and different number of neurons (160 and 100). The input data matrix M \u2208 R N \u00d7k of unrolled preprocessed fundus images are first normalized by mean subtraction and division by standard deviation. The Rectified Linear Units (ReLUs), \u03c6(x) = max(0, x), has been selected as the activation function to provide the network with invariance to scaling, thresholding above zero, faster learning and non-saturating for large-scale data [19] .", "cite_spans": [{"start": 586, "end": 590, "text": "[19]", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Neural Networks Architecture", "text": "In this paper, we adopt the cross entropy as the similarity measure to penalize wrong guesses for labels and avoiding convergence to local minima in the optimization. The cross entropy is often described as:", "cite_spans": [], "ref_spans": []}, {"section": "Neural Networks Architecture", "text": "Next, we select the regularization of the weights as an integral part of calculating the overall cost function. We adopt an 2 -regularization with penalty \u03bb, where \u03bb is set to 1e \u2212 5 experimentally. Finally, the overall cost function is the sum of cross entropy and weight penalty as: We the back propagate to learn the weights. A variation of the BFGS algorithm, namely the L-BFGS is used in our model to estimate the parameters of the learning model [20] . The L-BFGS does an unconstrained minimization of smooth functions using a linear memory requirement.", "cite_spans": [{"start": 452, "end": 456, "text": "[20]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "EXPERIMENTAL RESULTS", "text": "In this section we explain the details of our experiments on a public sample dataset for a recent Kaggle competition 4 . The dataset is subsampled to include around 1000 fundus photographs of diabetic retinopathy in five different stages: normal, mild, moderate, severe and proliferative labeled by trained medical professionals as illustrated in Figure 2 5 . Table 1 shows the original sample size break-down by class before (second column) and after (third column) data augmentation. All input images have been resized to 256 \u00d7 388 pixels and all experiments are performing a 5-fold cross validation. Gray scale representation of resized fundus images without additional preprocessing and augmentation has been used as the baseline dataset to highlight the contributions of data preprocessing. A baseline classifier, k-nearest neighbors (k-NN) has also been tested against the neural network architectures to emphasize the contributions of the neural networks in DR detection. We report the average classification accuracy rate for the baseline model and neural networks across all experiments. Table 2 summarizes these results.", "cite_spans": [{"start": 117, "end": 118, "text": "4", "ref_id": "BIBREF3"}], "ref_spans": [{"start": 347, "end": 355, "text": "Figure 2", "ref_id": "FIGREF1"}, {"start": 360, "end": 367, "text": "Table 1", "ref_id": "TABREF0"}, {"start": 1097, "end": 1104, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "EXPERIMENTAL RESULTS", "text": "The first round of experiments evaluates the performance of neural network on gray scale fundus photographs. The gray-scale representation of these images have been provided as the input to a 2 layer neural network with 160 neurons.", "cite_spans": [], "ref_spans": []}, {"section": "EXPERIMENTAL RESULTS", "text": "It should be noted that there is no dimensionality reduction technique present in this experiment. As shown in the second row of Table 2 , the average classification accuracy rate for this experiment is 66.43%.", "cite_spans": [], "ref_spans": [{"start": 129, "end": 136, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "EXPERIMENTAL RESULTS", "text": "Next, we experiment with preprocessed fundus images, where images are presented as green channel with histogram equalization (GRH). Rows 3 to 7 shows the classification results on this dataset with preprocessing and augmentation and different dimensionality reduction techniques. The neural networks are all 160 neurons and the baseline k-NN classifier uses k = 5. The NPE reduces the input dimensionality to 154 \u00b1 3 and is achieving the highest classification accuracy on this dataset. PCA with 161, SLPP with 155 \u00b1 2 and SR with 4 as the reduced dimensionality are all outperforming the k-NN with the lowest classification accuracy rate across all experiments.", "cite_spans": [], "ref_spans": []}, {"section": "EXPERIMENTAL RESULTS", "text": "Finally, we repeat the experiments with preprocessed images and no augmentation to highlight the marginal effects of augmentation. Table 2 rows 8 to 11 shows the result of these experiments with different dimensionality reductions for a 2 layer neural networks. The neural networks are all designed with 100 neurons. PCA, SLPP, NPE all reduce the input dimensionality to 256 and SR reduces this to 4. Our experimental results show that, without data augmentation to enhance the robustness to variations in input and imbalanced classes, neural network with NPE is achieving the highest classification accuracy rate in this group (without augmentation).", "cite_spans": [], "ref_spans": [{"start": 131, "end": 138, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "CONCLUSION AND FUTURE WORK", "text": "Diabetic retinopathy detection has been gaining increasing attention in computer vision and machine learning communities. The advanced digital retinal photography known as fundus photographs have often be used as the input for feature extraction, disease classification and detection. In this paper we first introduced a set of preprocessing and data augmentation techniques that can be utilized to enhance the image quality and data presentation in fundus photographs. we explored green channel and histogram equalization to represent the fundus photographs in a more compact manner for a neural network classifier.", "cite_spans": [], "ref_spans": []}, {"section": "CONCLUSION AND FUTURE WORK", "text": "Next, we explored a family of manifold learning techniques in conjunction with neural networks. Our experimental results showed that a neural network classifier with manifold learning and a more revealing preprocessing step can enhance the classification accuracy while providing a scalable model for diabetic retinopathy detection.", "cite_spans": [], "ref_spans": []}, {"section": "CONCLUSION AND FUTURE WORK", "text": "In future, we plan to apply the recently popular convolutional neural networks (CNNs) [21] , which has been shown effective for computer vision tasks, on this dataset. 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Illustration of the stages of DR development: (a) Normal , (b) Mild, (c) Moderate , (d) Severe and (e) Proliferative diabetic retinopathy conditions.", "type": "figure"}, "FIGREF1": {"text": "Fig. 2. Input images from the sample dataset in five labeled classes: (a) Normal , (b) Mild, (c) Moderate , (d) Severe and (e) Proliferative DR are shown.", "type": "figure"}, "FIGREF2": {"text": "Fig. 3. Class 3 and class 4 samples: (a) Original image , (b) Green channel (Red-free) and (c) Green channel histogram equalization for an example of class 3 (severe DR) are illustrated. (d) Original image , (e) Green channel (Red-free) and (f) Green channel histogram equalization for an example of class 4 (proliferative DR) are illustrated.", "type": "figure"}, "TABREF0": {"text": "Sample Dataset Breakdown", "type": "table"}, "TABREF1": {"text": "Classification accuracy (%) on sample dataset:", "type": "table"}}}
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{"paper_id": "18982232", "_pdf_hash": "090a301e6150a949362b0f94708a40e502860245", "abstract": [{"section": "Abstract", "text": "We characterize the pairs of partial homomorphisms of total \u03a3-algebras that have a pushout in the corresponding category, for an arbitrary signature \u03a3. This characterization provides the application condition for the single-pushout approach to the transformation of total algebras.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "The algebraic approach to the transformation of structures is a computation paradigm that was invented 30 years ago. Although it was first applied to graphs, it soon showed its potential to formalize the transformation of more general objects, like hypergraphs, relational systems, unary total and partial algebras etc., yielding relevant applications in practically all computer science areas. As its name hints, in this algebraic approach to transformation the objects to be rewritten are understood as algebraic structures, and its basic rewriting step is the replacement of a subobject of an object by another object, all this being done by means of some categorytheoretical construction.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Several such algebraic approaches have been introduced so far, depending on how the replacement step is formalized. The first one, introduced by H. Ehrig, M. Pfender and H. J. Schneider, 1 is the so-called double-pushout approach (DPO). 2 Its name comes from the fact that the basic rewriting step is modelled by means of a diagram consisting of two pushout squares.", "cite_spans": [{"start": 237, "end": 238, "text": "2", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Introduction", "text": "A decade ago, M. L\u00f6we introduced 3 a new algebraic approach, called singlepushout (SPO) because its basic rewriting step is a pushout in a category of partial morphisms. 4 Formally, in the SPO approach to transformation in a category C (whose morphisms are understood as, in some sense, partial), a production rule is a morphism r : L \u2192 R in this category. Such a rule can be applied to an object G through an occurrence m : L \u2192 G -which is usually taken to be a total morphism in C for practical reasons 3 -when a pushout (H, m : R \u2192 H, r : G \u2192 H) of r and m in C exists. In this case the object H is said to be derived from G by the application of rule r : L \u2192 R through morphism m. Notice that when H exists, it is unique up to isomorphism in C.", "cite_spans": [{"start": 170, "end": 171, "text": "4", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "1", "text": "The SPO approach has been thoroughly developed since its inception, and the objects which it has been applied to have suffered a steady generalization, from graphs and hypergraphs to relational systems and unary partial algebras. During the same period, there has been an increasing interest in the algebraic transformation of total and partial algebras over an arbitrary signature. The motivation for such an interest is twofold.", "cite_spans": [], "ref_spans": []}, {"section": "1", "text": "Firstly, there is the need to model systems with dynamic behavior, which has led to the development of the concept of Dynamic Abstract Data Types (DADT), where notions of algebraic transformation and ADT specification, requiring arbitrary signatures in a natural way, interact. Roughly speaking, a DADT consists of an ADT, corresponding to the instant structures of the DADT, together with a collection of dynamic operations which define transformations between the instances of the ADT. 5 One possible way of specifying these dynamic operations is by using algebra transformation systems: the algebras model the instant structures of the DADT and the transformation of instant structures defined by the dynamic operations is specified by means of rules in an algebra transformation system. 6, 7 . A second motivation is the use of attributes in all graph grammar proposals for Software Engineering, which allow to enrich graph-like structures by means of data type information. Attributed hypergraphs are structures consisting of two components, the graphical part and the data part: the former describes the structural aspects, and the latter is devoted to data type aspects and usually consists of some total algebra of an arbitrary type. Both parts are connected by labeling operators that assign data type attributes to structural items. The SPO transformation of attributed graphs was already introduced ten years ago by M. L\u00f6we, M. Korff and A. Wagner, 8 but they imposed a strict distinction between the structural and the data parts, as the partial homomorphisms used to define the SPO production rules had to be totally defined on the algebras of attributes. This prevents, for instance, the removal of attributes.", "cite_spans": [{"start": 488, "end": 489, "text": "5", "ref_id": "BIBREF5"}, {"start": 791, "end": 793, "text": "6,", "ref_id": "BIBREF6"}, {"start": 794, "end": 795, "text": "7", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "1", "text": "As these authors already pointed out, 8 a possible way to overcome this distinction is by moving to algebras and treating the transformation of attributed hypergraphs as a transformation of algebras of an arbitrary type. After recalling that pushouts in categories of partial and total algebras with partial morphisms do not always exist, their paper finished with a call to the clarification of the theory behind the SPO transformation of partial and total algebras of an arbitrary type.", "cite_spans": [], "ref_spans": []}, {"section": "1", "text": "During the last years, we have laid out the theoretical basis for the DPO approach to the transformation of partial and total algebras of an arbitrary type by solving the corresponding application and uniqueness problems, 9,10 and for the SPO approach to the transformation of partial algebras of an arbitrary type using different types of partial homomorphisms by characterizing which pairs of partial homomorphisms of the same type have a pushout in the corresponding category. 11, 12, 13 In this paper we finally focus our attention on the SPO approach to the transformation of total algebras of an arbitrary type based on the partial homomorphisms introduced by M. L\u00f6we.", "cite_spans": [{"start": 480, "end": 483, "text": "11,", "ref_id": "BIBREF11"}, {"start": 484, "end": 487, "text": "12,", "ref_id": "BIBREF12"}, {"start": 488, "end": 490, "text": "13", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "1", "text": "3 In our main result we give a necessary and sufficient condition for two such partial homomorphisms to have a pushout in the category P-TAlg \u03a3 of total algebras of some type \u03a3 with partial homomorphisms as morphisms, and we translate it into an operational application condition for the SPO approach to the transformation in the category P-TAlg \u03a3 . This application condition turns out to be very involved, and we show that it cannot be simplified. Thus, although it strictly increases the toolkit available in the area of the formal specification of software systems with complex states or dynamic behavior, as for instance it allows the removal of attributes in attributed graphs, we must confess that we do not see any easy way to use it in practice.", "cite_spans": [], "ref_spans": []}, {"section": "1", "text": "Let us finally mention that the characterization of the pairs of partial homomorphisms of total algebras of an arbitrary type that have a pushout is also relevant in the more abstract line of research in universal algebra that aims at an encyclopedic study of category-theoretical notions such as limits, colimits, etc., on different categories of partial and total algebras, initiated by the three-papers-long series 14, 15, 16 by P. Burmeister and B. Wojdy lo. This study has already found applications in, and some times it has been motivated by, the field of the algebraic transformation of (unary) partial algebras. 3, 17, 18 So far, 3, 19, 20, 21, 22 all results obtained in this connection have consisted of characterizations of the signatures for which a certain category-theoretical construction relative to a certain type of morphisms always exists. This paper, together with our previous papers on quomorphisms of partial algebras, 11,12,13 means a step beyond in this study, by addressing a further aspect of this kind of problems: when a construction, say a pushout, is known not to exist for all, say, pairs of morphisms of a given type, for which such pairs does it exist? The answer to questions like this will shed more light on the properties of the different types of partial homomorphisms, and the relationship between them.", "cite_spans": [{"start": 418, "end": 421, "text": "14,", "ref_id": "BIBREF14"}, {"start": 422, "end": 425, "text": "15,", "ref_id": "BIBREF15"}, {"start": 426, "end": 428, "text": "16", "ref_id": "BIBREF16"}, {"start": 621, "end": 623, "text": "3,", "ref_id": "BIBREF3"}, {"start": 624, "end": 627, "text": "17,", "ref_id": "BIBREF17"}, {"start": 628, "end": 630, "text": "18", "ref_id": "BIBREF18"}, {"start": 639, "end": 641, "text": "3,", "ref_id": "BIBREF3"}, {"start": 642, "end": 645, "text": "19,", "ref_id": "BIBREF19"}, {"start": 646, "end": 649, "text": "20,", "ref_id": "BIBREF20"}, {"start": 650, "end": 653, "text": "21,", "ref_id": "BIBREF21"}, {"start": 654, "end": 656, "text": "22", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "Preliminaries", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Partial algebras", "text": "We assume the reader familiar with the basic language and methods of the theory of total and partial algebras, as presented in the first chapters of standard textbooks. 23, 24 However, and to ease his or her task, we recall in this subsection some basic definitions and facts and we take the opportunity to fix some notations and conventions to be used henceforth.", "cite_spans": [{"start": 173, "end": 175, "text": "24", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Partial algebras", "text": "Throughout this paper, \u03a3 = (S, \u2126, \u03b7) denotes a signature (or type of algebras) with set of sorts S, set of operation symbols \u2126 and arity function \u03b7 : \u2126 \u2192 S * \u00d7 S with \u03b7(\u03d5) = (\u03c9(\u03d5), \u03c3(\u03d5)) for every \u03d5 \u2208 \u2126. An operation symbol \u03d5 \u2208 \u2126 is n-ary when the length of \u03c9(\u03d5) is n. We shall denote by \u2126 (n) the set of all n-ary operation symbols in \u03a3 and by \u2126 (+) the set \u2126 \u2212 \u2126 (0) . A partial \u03a3-algebra is a structure A = (A, (\u03d5 A ) \u03d5\u2208\u2126 ), where:", "cite_spans": [], "ref_spans": []}, {"section": "Partial algebras", "text": "\u2022 A = (A s ) s\u2208S is an S-set (i.e., an S-indexed family of sets), called the carrier of the algebra. For every s \u2208 S, the set A s is called the carrier of sort s of A.", "cite_spans": [], "ref_spans": []}, {"section": "Partial algebras", "text": "\u2022 For every \u03d5 \u2208 \u2126, \u03d5 A : An operation \u03d5 A in a partial algebra A is total when it is a total mapping. A partial \u03a3-algebra is total when all operations in it are so. When a nullary operation in an algebra A is total, we say that it is defined in A, and we identify it with its image.", "cite_spans": [], "ref_spans": []}, {"section": "Partial algebras", "text": "Let \u03a3 (+) = (S, \u2126 (+) , \u03b7 \u2126 (+) ) denote the signature obtained from \u03a3 by removing its nullary operation symbols. If A = (A, (\u03d5 A ) \u03d5\u2208\u2126 ) is a partial \u03a3-algebra, then", "cite_spans": [], "ref_spans": []}, {"section": "Partial algebras", "text": ") will always stand for its \u03a3 (+) -reduct: the partial \u03a3 (+) -algebra obtained by simply omitting the nullary operations in A.", "cite_spans": [], "ref_spans": []}, {"section": "Partial algebras", "text": "In the rest of this paper, given a partial algebra denoted by a capital letter in boldface type (A, B, etc.), we shall always denote, usually without any further notice, its carrier by the same capital letter, but in slanted type (A, B, etc.); an operation in it by superscripting the operation symbol with the algebra's name (\u03d5 A , \u03c8 B , . . .); and, if necessary, its carrier of a given sort by the same capital letter in slanted type, but with the sort as a subscript (A s , B t , etc.). However, and in order * The symbol \u03bb stands for the empty word.", "cite_spans": [], "ref_spans": []}, {"section": "Partial algebras", "text": "to lighten the notations, we shall often skip all subscripts corresponding to sorts in the names of the carriers of the algebras, the components of the homomorphisms or the congruences (see below) etc., provided there is no danger of confusion.", "cite_spans": [], "ref_spans": []}, {"section": "Partial algebras", "text": "The relative subalgebra of a partial \u03a3-algebra A = (A, (\u03d5 A ) \u03d5\u2208\u2126 ) supported on a subset B of its carrier is the partial \u03a3-algebra B = (B, (\u03d5 B ) \u03d5\u2208\u2126 ) obtained by restricting the structure of A to B, in the sense that for every \u03d5 \u2208 \u2126,", "cite_spans": [], "ref_spans": []}, {"section": "Partial algebras", "text": ". Such a relative subalgebra B is a closed subalgebra of A when B is a closed subset of A: i.e., when for every", "cite_spans": [], "ref_spans": []}, {"section": "Partial algebras", "text": ". If a relative subalgebra B of partial \u03a3-algebra A is total, then it is a closed subalgebra of it. Conversely, if A is a total algebra, then every closed subalgebra of it is also total. As it is customary in universal algebra, we shall usually refer to closed subalgebras of total algebras as simply subalgebras.", "cite_spans": [], "ref_spans": []}, {"section": "Partial algebras", "text": "There always exists the least closed subset of a partial \u03a3-algebra A containing a given subset X of its carrier; it is denoted by C A (X) and called the closed subset of A generated by X.", "cite_spans": [], "ref_spans": []}, {"section": "Partial algebras", "text": "A homomorphism f :", "cite_spans": [], "ref_spans": []}, {"section": "Partial algebras", "text": "is a mapping of S-sets f : A \u2192 B that preserves the operations defined in A, in the sense that, for every", "cite_spans": [], "ref_spans": []}, {"section": "Partial algebras", "text": ". Such a homomorphism is closed when, moreover, for every \u03d5 \u2208 \u2126, if f (a) \u2208 dom \u03d5 B , then a \u2208 dom \u03d5 A . We shall use often that if A is a total algebra, then any homomorphism f : A \u2192 B is closed, and that if B is a total algebra and f : A \u2192 B is a closed homomorphism, then A is also total.", "cite_spans": [], "ref_spans": []}, {"section": "Partial algebras", "text": "Taking as objects all partial \u03a3-algebras (resp., all total \u03a3-algebras) and their homomorphisms as morphisms, we obtain a category Alg \u03a3 (resp., TAlg \u03a3 ).", "cite_spans": [], "ref_spans": []}, {"section": "Partial algebras", "text": "An equivalence relation \u03b8 = (\u03b8 s ) s\u2208S on the carrier of a partial \u03a3-algebra A = (A, (\u03d5 A ) \u03d5\u2208\u2126 ) is a congruence on A when it is compatible with the operations in A, in the sense that for each \u03d5 \u2208 \u2126 (+) , say with", "cite_spans": [], "ref_spans": []}, {"section": "Partial algebras", "text": "Given a relation X on the carrier of a partial \u03a3-algebra A, there always exists the least congruence on A containing X; we shall call it the congruence on A generated by X.", "cite_spans": [], "ref_spans": []}, {"section": "Partial algebras", "text": "Given a congruence \u03b8 on a partial \u03a3-algebra", "cite_spans": [], "ref_spans": []}, {"section": "Partial algebras", "text": "(where (A/\u03b8) s = A s /\u03b8 s for every s \u2208 S) is defined in the following way: for every \u03d5 \u2208 \u2126,", "cite_spans": [], "ref_spans": []}, {"section": "Partial algebras", "text": "\u2022 if \u03d5 \u2208 \u2126 (0) , then \u03d5 A/\u03b8 is defined if and only if \u03d5 A is defined, and when they are both defined,", "cite_spans": [], "ref_spans": []}, {"section": "Partial algebras", "text": "[a] \u2208 dom \u03d5 A/\u03b8 if and only if there exists a = (a 1 , . . . , a p ) \u2208 dom \u03d5 A such that (a i , a i ) \u2208 \u03b8 si for every i = 1, . . . , p; and if this is the case, then", "cite_spans": [], "ref_spans": []}, {"section": "Partial algebras", "text": "We shall denote then by nat \u03b8 : A \u2192 A/\u03b8 the quotient homomorphism, given by the quotient mapping", "cite_spans": [], "ref_spans": []}, {"section": "Partial algebras", "text": "A free completion of a partial \u03a3-algebra A is a total \u03a3-algebra A together with a homomorphism A : A \u2192 A such that, for every homomorphism f : A \u2192 B with B a total \u03a3-algebra, there exists one, and only one, homomorphismf :", "cite_spans": [], "ref_spans": []}, {"section": "Partial algebras", "text": "Every partial \u03a3-algebra A has a free completion A such that A : A \u2192 A is the embedding of A as a relative subalgebra of A: a construction can be found in 24 \u00a75.3. On the other hand, the free completion of a partial \u03a3-algebra A is unique up to isomorphism, in the sense that if A : A \u2192 A and A : A \u2192 A are two free completions of A, then there exists an isomorphism\u00af : A \u2192 A such that A =\u00af \u2022 A . Therefore, whenever we consider a free completion of a partial \u03a3-algebra A, we shall assume that A is relative subalgebra of it.", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts in Alg \u03a3 and TAlg \u03a3", "text": "It is well known that the categories Alg \u03a3 and TAlg \u03a3 have all pushouts, for every signature \u03a3. In this subsection we recall an explicit construction of them and we take again the opportunity to fix some notations that will be used in the rest of this paper, usually without any further notice.", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts in Alg \u03a3 and TAlg \u03a3", "text": "Let f : K \u2192 A and g : K \u2192 B be two homomorphisms of partial \u03a3-algebras, for some signature \u03a3, and let A (+) and B (+) be the \u03a3 (+) -reducts of A and B, respectively.", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts in Alg \u03a3 and TAlg \u03a3", "text": "The disjoint sum of A (+) and B (+) is the partial \u03a3 (+) -algebra", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts in Alg \u03a3 and TAlg \u03a3", "text": "with carrier the disjoint union \u2020 A B of the carriers of A and B, and operations defined in the following way: for every \u03d5 \u2208 \u2126 (+) , dom \u03d5 Let finallyg : A \u2192 P andf : B \u2192 P be the homomorphisms given by the restrictions to A and B of the quotient mapping A B \u2192 (A B)/\u03b8(f, g).", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts in Alg \u03a3 and TAlg \u03a3", "text": "Theorem 1 With the previous notations, the cocone", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts in Alg \u03a3 and TAlg \u03a3", "text": "is a pushout of f and g in Alg \u03a3 .", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts in Alg \u03a3 and TAlg \u03a3", "text": "If f and g are closed homomorphisms, then", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts in Alg \u03a3 and TAlg \u03a3", "text": "and, say, \u03d5 A 0 is defined, then \u03d5 K 0 is also defined, and then on the one hand \u03d5", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts in Alg \u03a3 and TAlg \u03a3", "text": ") and on the other hand \u03d5 B 0 is also defined and equal to g(\u03d5 K 0 ). As far as pushouts in TAlg \u03a3 goes, we have the following result, which is a simple consequence of the fact that free completions define an epireflection along the inclusion functor TAlg \u03a3 \u2192 Alg \u03a3 ; see Theorem 20 in 10 for an elementary proof of a more general result.", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts in Alg \u03a3 and TAlg \u03a3", "text": "Theorem 2 Let f : K \u2192 A and g : K \u2192 B be two homomorphisms of total \u03a3-algebras, let (P,g : A \u2192 P,f : B \u2192 P) be a pushout of f and g in Alg \u03a3 , and let P : P \u2192 P be a free completion of P. Then, the cocone", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts in Alg \u03a3 and TAlg \u03a3", "text": "is a pushout of f and g in TAlg \u03a3 .", "cite_spans": [], "ref_spans": []}, {"section": "Quomorphisms", "text": "Let A and B be two partial \u03a3-algebras, for some signature \u03a3. Given a partial mapping of S-sets f : A \u2192 B, let Dom f and Dom f denote, respectively, its domain and the relative subalgebra of A supported on it. Then, the partial mapping f : A \u2192 B is:", "cite_spans": [], "ref_spans": []}, {"section": "Quomorphisms", "text": "\u2022 a quomorphism from A to B when it is a homomorphism from Dom f to B;", "cite_spans": [], "ref_spans": []}, {"section": "Quomorphisms", "text": "\u2022 a closed quomorphism from A to B, a c-quomorphism for short, when it is a closed homomorphism from Dom f to B;", "cite_spans": [], "ref_spans": []}, {"section": "Quomorphisms", "text": "\u2022 a closed-domain quomorphism from A to B, a cd-quomorphism for short, when it is a quomorphism and Dom f is a closed subset of A;", "cite_spans": [], "ref_spans": []}, {"section": "Quomorphisms", "text": "\u2022 a closed-domain closed quomorphism from A to B, a cdc-quomorphism for short, when it is simultaneously a c-quomorphism and a cd-quomorphism.", "cite_spans": [], "ref_spans": []}, {"section": "Quomorphisms", "text": "The categories of all partial \u03a3-algebras with quomorphisms, c-quomorphisms, cd-quomorphisms, and cdc-quomorphisms as morphisms will be denoted, respectively, by Q-Alg \u03a3 , CQ-Alg \u03a3 , CDQ-Alg \u03a3 , and CDCQ-Alg \u03a3 . The first two categories have been thoroughly studied by P. Burmeister and B. Wojdy lo 14, 15, 16 and the last two by R. Alberich et al. 19 Furthermore, R. Alberich and F. Rossell\u00f3 11, 12, 13 have characterized the pairs of quomorphisms, c-quomorphisms, cd-quomorphisms and cdc-quomorphisms that have a pushout in Q-Alg \u03a3 , CQ-Alg \u03a3 , CDQ-Alg \u03a3 and CDCQ-Alg \u03a3 , respectively. In this paper we shall use only the characterization for cdc-quomorphisms, which we recall below; for a proof, see Theorem 5 and Corollary 1 in the last aforementioned paper.", "cite_spans": [{"start": 298, "end": 301, "text": "14,", "ref_id": "BIBREF14"}, {"start": 302, "end": 305, "text": "15,", "ref_id": "BIBREF15"}, {"start": 306, "end": 308, "text": "16", "ref_id": "BIBREF16"}, {"start": 348, "end": 350, "text": "19", "ref_id": "BIBREF19"}, {"start": 392, "end": 395, "text": "11,", "ref_id": "BIBREF11"}, {"start": 396, "end": 399, "text": "12,", "ref_id": "BIBREF12"}, {"start": 400, "end": 402, "text": "13", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Quomorphisms", "text": "Theorem 3 Two cdc-quomorphisms of partial \u03a3-algebras f : K \u2192 A and g : K \u2192 B have a pushout in CDCQ-Alg \u03a3 if and only if they satisfy the following three conditions:", "cite_spans": [], "ref_spans": []}, {"section": "Quomorphisms", "text": "CDCPO1) There exist the greatest closed subsets A and B of A and B, respectively, such that:", "cite_spans": [], "ref_spans": []}, {"section": "Quomorphisms", "text": "; let us call K this subset of K; \u2022 if K , A , and B are the closed subalgebras of K, A and B supported on K , A and B , respectively, and if f : K \u2192 A and g : K \u2192 B are the closed homomorphisms between these algebras induced by f and g, then there exist two closed homomorphisms p : A \u2192 C and q :", "cite_spans": [], "ref_spans": []}, {"section": "Quomorphisms", "text": "Let \u03b8(f , g ) be the congruence on A (+) \u2295 B (+) generated by the relation", "cite_spans": [], "ref_spans": []}, {"section": "Quomorphisms", "text": "CDCPO3) For every closed subsets A 0 and B 0 of A and B , respectively, such that f", "cite_spans": [], "ref_spans": []}, {"section": "Quomorphisms", "text": "And if f and g satisfy conditions (CDCPO1) to (CDCPO3) and", "cite_spans": [], "ref_spans": []}, {"section": "Quomorphisms", "text": "is a pushout of f : K \u2192 A and g : K \u2192 B in Alg \u03a3 , then the quomorphisms g : A \u2192 P andf : B \u2192 P defined by the homomorphismsg andf , respectively, are cdc-quomorphisms and", "cite_spans": [], "ref_spans": []}, {"section": "Quomorphisms", "text": "is a pushout of f : K \u2192 A and g : K \u2192 B in CDCQ-Alg \u03a3 .", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": "Let A = (A, (\u03d5 A ) \u03d5\u2208\u2126 ) and B = (B, (\u03d5 B ) \u03d5\u2208\u2126 ) be two total \u03a3-algebras, for some signature \u03a3. A partial mapping f : A \u2192 B is a partial homomorphism (of total \u03a3-algebras) from A to B when it is a cd-quomorphism of partial \u03a3-algebras, i.e., when its domain Dom f is a closed subset of A and f : Dom f \u2192 B is a homomorphism of \u03a3-algebras. We shall denote by P-TAlg \u03a3 the category of total \u03a3-algebras with partial homomorphisms as morphisms.", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": "If f : A \u2192 B is a partial homomorphism, then, since A is total, Dom f is also total and therefore the homomorphism f : Dom f \u2192 B is closed. This shows that every partial homomorphism of total algebras is a cdc-quomorphism and a fortiori a c-quomorphism. On the other hand, if f : A \u2192 B is a c-quomorphism with A and B total \u03a3-algebras, then, since f : Dom f \u2192 B is a closed homomorphism and B is total, Dom f is also total and in particular Dom f is a closed subset of A. This proves the following result.", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": "Proposition 1 P-TAlg \u03a3 is a full subcategory of CQ-Alg \u03a3 , CDQ-Alg \u03a3 , and CDCQ-Alg \u03a3 .", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": "Notice on the other hand that if \u2126 = \u2205, then P-TAlg \u03a3 is not a full subcategory of Q-Alg \u03a3 . Indeed, if \u2126 = \u2205, there always exists a total \u03a3-algebra A with a non-closed subset B, and then the quomorphism A \u2192 A defined by the set-theoretical identity on B is not a partial homomorphism of total algebras. M. L\u00f6we 3 established the following characterization of those signatures \u03a3 such that P-TAlg \u03a3 has all pushouts; for a proof, see Proposition 2.3 and Corollary 2.7 in his cited paper.", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": "Theorem 4 P-TAlg \u03a3 has all pushouts if and only if all operation symbols in \u03a3 are unary.", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": "The main goal of this section is to characterize the pairs of partial homomorphisms of total \u03a3-algebras that have a pushout in P-TAlg \u03a3 , for an arbitrary signature \u03a3. To begin with, we establish a lemma about pushouts of partial homomorphisms of total algebras in CDCQ-Alg \u03a3 . Lemma 1 Let f : K \u2192 A and g : K \u2192 B be two partial homomorphisms of total \u03a3-algebras that have a pushout", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": "Proof. By Theorem 3 and the explicit description of pushouts in Alg \u03a3 given in \u00a72.2, for every \u03d5 \u2208 \u2126 (+)", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": "Since Domg and Domf are total algebras, we have that", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": "and then", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": "which implies that \u03d5 P is total for every \u03d5 \u2208 \u2126 (+) . On the other hand, all nullary operations are defined in Domg and Domf , and then by construction they are also defined in P. This finally implies that P is total.", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": "We can establish now the main result in this paper. Theorem 5 Let f : K \u2192 A and g : K \u2192 B be two partial homomorphisms of total \u03a3-algebras. The following conditions are equivalent: i) f and g have a pushout in CDQ-Alg \u03a3 and it is given by a total \u03a3-algebra.", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": "ii) f and g have a pushout in CDCQ-Alg \u03a3 .", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": "iii) f and g have a pushout in P-TAlg \u03a3 .", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": "And when these equivalent conditions are satisfied, the pushouts of f and g in P-TAlg \u03a3 , in CDQ-Alg \u03a3 and in CDCQ-Alg \u03a3 are equal.", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": "Proof. (i)=\u21d2(ii) Assume that f and g have a pushout", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": "in CDQ-Alg \u03a3 and that Q is a total \u03a3-algebra. Since A and B are total,\u011d andf are cdc-quomorphisms. Let now p : A \u2192 C and q : B \u2192 C be two cdc-quomorphisms of partial \u03a3-algebras such that p \u2022 f = q \u2022 g. Then, by the universal property of pushouts in CDQ-Alg \u03a3 , there exists one, and only one, cd-quomorphism h : Q \u2192 C such that h \u2022\u011d = p and h \u2022f = q. Since Q is total, h is a cdc-quomorphism, and its uniqueness in CDQ-Alg \u03a3 implies its uniqueness in CDCQ-Alg \u03a3 . This shows that (Q,\u011d : A \u2192 P,f : B \u2192 P) is also a pushout of f and g in CDCQ-Alg \u03a3 .", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": "(", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": "be a pushout of f and g in CDCQ-Alg \u03a3 : by Lemma 1, Q is total and hence, by definition,\u011d andf are partial homomorphisms of total algebras. Let now p : A \u2192 C and q : B \u2192 C be two partial homomorphisms of total \u03a3-algebras such that p \u2022 f = q \u2022 g. In particular, they are cdc-quomorphisms and therefore, by the universal property of pushouts in CDCQ-Alg \u03a3 , there exists one, and only one, cdcquomorphism, i.e., one, and only one partial homomorphism of total \u03a3-algebras h : Q \u2192 C such that h \u2022\u011d = p and h \u2022f = q. This shows that the pushout of f and g in CDCQ-Alg \u03a3 is also their pushout in P-TAlg \u03a3 .", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": "be a pushout of f and g in P-TAlg \u03a3 . Set A = Dom\u011d, B = Domf and K = f \u22121 (A ) = g \u22121 (B ), let K , A and B be the subalgebras of K, A and B supported on their closed subsets K , A and B , respectively, let f : K \u2192 A and g : K \u2192 B be the homomorphisms between these total algebras induced by f and g, and let\u011d : A \u2192 Q andf : B \u2192 Q denote the homomorphisms that define the partial homomorphisms\u011d : A \u2192 Q andf : B \u2192 Q.", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": "Let now (P 0 ,g :", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": "be a pushout of f : K \u2192 A and g : K \u2192 B in Alg \u03a3 and let P0 : P 0 \u2192 P 0 be a free completion of P 0 given by an embedding of P 0 into P 0 as a relative subalgebra. By Theorem 2,", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": "is a pushout in TAlg \u03a3 of f and g . The homomorphisms P0 \u2022g : A \u2192 P 0 and P0 \u2022f : B \u2192 P 0 define two partial homomorphisms of total \u03a3-algebras", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": "\u2022 g as partial homomorphisms from K to P 0 . Then, by the universal property of pushouts in P-TAlg \u03a3 , there exists one, and only one, partial homomorphism h : Q \u2192 P 0 such thatg 0 = h \u2022\u011d andf 0 = h \u2022f . If we restrict these equalities to A and B , we obtain the equalities of homomorphisms", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": "On the other hand, since\u011d : A \u2192 Q andf : B \u2192 Q are two homomorphisms of total \u03a3-algebras such that\u011d \u2022 f =f \u2022 g , the universal property of pushouts in TAlg \u03a3 implies the existence of one, and only one, homomorphismh : P 0 \u2192 Q such thath \u2022 ( P0 \u2022g) =\u011d andh \u2022 ( P0 \u2022f ) =f . Since Domg 0 = A = Dom\u011d and Domf 0 = B = Domf , these equalities yield the equalities of partial homomorphisms of total algebrash \u2022g 0 =\u011d andh \u2022f 0 =f in P-TAlg \u03a3 .", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": "Summarizing, we have the following two commutative diagrams:", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": "Working in the left-hand side diagram we obtain the equalities in P-", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": "which imply, by the universal property of pushouts in P-TAlg \u03a3 , thath \u2022 h = Id Q .", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": "In particular, h is a homomorphism. Then, working in the right-hand side diagram given above, we obtain the equalities in TAlg \u03a3", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": "which imply, by the universal property of pushouts in TAlg \u03a3 , that h \u2022h = Id P0 . Therefore,h and h are isomorphisms inverse to each other. This entails that we can take as the pushout of f and g in P-TAlg \u03a3 the cocone (P 0 ,g 0 : A \u2192 P 0 ,f 0 : B \u2192 P 0 ), described above. Let us prove now that the carrier P 0 of the partial \u03a3-algebra P 0 is actually equal to the carrier P 0 of its free completion P 0 . This will imply that P 0 = P 0 , and in particular that P 0 is a total algebra, and that P0 = Id P0 .", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": "Let", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": "and P", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": "0 denote, respectively, the S-sets consisting of (the images of) the nullary operations defined in A, B, P 0 and P 0 . Let H 0 be the closed subset C P0 (P (0) 0 ) of P 0 generated by P (0) 0 . It turns out that H 0 \u2286 P 0 . Indeed, to begin with, notice that since, say, A is a total \u03a3-algebra, all nullary operations are defined in it, which implies by construction that all nullary operations are defined in P 0 and in particular P", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": "). Then we have", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": "where the second inclusion is a consequence of, 24 Proposition 3.6.2.(i). Now, since A is a total algebra, its closed subalgebra supported on C A (A (0) ) is also total, and then the relative subalgebra of P 0 supported ong(C A (A (0) )) is also total and thus closed. This shows thatg(C A (A (0) )) is a closed subset of P 0 lying between P (0) 0 and C P0 (P (0) 0 ), which implies, finally, that", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": "0 \u2208 H 0 . On the other hand, if \u03d5 \u2208 \u2126 (+) and x \u2208 H \u03c9(\u03d5) were such that \u03d5 P0 (x) / \u2208 H, then \u03d5 P0 (x) \u2208 P 0 , and hence, by Definition 5.3.1. (FC1) and Theorem 5.3.4 in, 24 we", "cite_spans": [{"start": 170, "end": 172, "text": "24", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": ". But then, H 0 being closed in P 0 , it would happen that \u03d5 P0 (x) \u2208 H 0 \u2286 H, leading to a contradiction. Therefore, for every \u03d5 \u2208 \u2126 and for every x \u2208 H \u03c9(\u03d5) , \u03d5 P0 (x) \u2208 H and hence H is a closed subset of P 0 .", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": "Let Id H , Id H0 : P 0 \u2192 P 0 be the partial homomorphisms of total \u03a3-algebras defined by the set-theoretical identities on the closed subsets H and H 0 of P 0 , respectively. Since H \u2229 P 0 = H 0 , we have that", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": "By the universal property of pushouts in P-TAlg \u03a3 , this implies that H = H 0 and hence P 0 = P 0 , as we wanted to prove.", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": "Thus, P 0 = P 0 and P0 = Id P0 , and therefore we can take as the pushout in P-TAlg \u03a3 of f and g the cocone", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": "where, now,g 0 : A \u2192 P 0 andf 0 : B \u2192 P 0 are the partial homomorphisms defined by the homomorphismsg : A \u2192 P 0 andf : B \u2192 P 0 in the pushout (P 0 ,g : A \u2192 P 0 ,f : B \u2192 P 0 ) of f : K \u2192 A and g : K \u2192 B in Alg \u03a3 . Since, as we have just proved, P 0 is a total \u03a3-algebra, if we prove that this cocone is also a pushout of f and g in CDQ-Alg \u03a3 , we will be done.", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": "So, let p : A \u2192 C and q : B \u2192 C be two cd-quomorphisms of partial \u03a3-algebras such that p \u2022 g = q \u2022 f , and let C : C \u2192 C be a free completion of C: as always, we assume without any loss of generality that this is an embedding of a relative subalgebra. By the universal property of pushouts in P-TAlg \u03a3 , there exists one, and only one, partial homomorphism h :", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": "C Since, by construction, P 0 =g 0 (A ) \u222af 0 (B ), we have that h(P 0 ) \u2286 C, and since P 0 is total, the relative subalgebra of C supported on h(P 0 ) is also total. This implies that the partial homomorphism h : P 0 \u2192 C is actually a cd-quomorphism h : P 0 \u2192 C. And it is the only cd-quomorphism P 0 \u2192 C such that h \u2022g 0 = p and h\u2022f 0 = q. Indeed, ifh : P 0 \u2192 C is another cd-quomorphism such thath\u2022g 0 = p and h \u2022f 0 = q, then C \u2022h : P 0 \u2192 C is a cd-quomorphism, i.e., a partial homomorphism of total algebras, such that C \u2022h \u2022g 0 = C \u2022 p and C \u2022h \u2022f 0 = C \u2022 q, which implies that C \u2022h = h : P 0 \u2192 C and hence, C being injective, thath = h : P 0 \u2192 C.", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": "This finishes the proof of the fact that the pushout of f and g in P-TAlg \u03a3 given above is also their pushout in CDQ-Alg \u03a3 .", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": "Using Theorems 1 and 3, we can rephrase this result in an operational way. Corollary 1 Two partial homomorphisms of total \u03a3-algebras f : K \u2192 A and g : K \u2192 B have a pushout in P-TAlg \u03a3 if and only if they satisfy the following three conditions:", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": "PHPO1) There exist the greatest closed subsets A and B of A and B, respectively, such that f \u22121 (A ) = g \u22121 (B ).", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": ", let K , A and B be the subalgebras of K, A and B supported on their closed subsets K , A and B , respectively, and let f : K \u2192 A and g : K \u2192 B be the homomorphisms between these algebras induced by the partial homomorphisms f and g. Let finally \u03b8 be the congruence on the disjoint sum A (+) \u2295 B (+) generated by the relation", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": "PHPO3) For every closed subsets A 0 and B 0 of A and B , respectively, such that", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": "And if f and g satisfy these conditions, then a pushout of them in P-TAlg \u03a3 is given by the cocone (P,g : A \u2192 P,f : B \u2192 P)", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": "where:", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": "\u2022 P is the total \u03a3-algebra whose \u03a3 (+) -reduct is (A (+) \u2295 B (+) )/\u03b8 and where", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": "\u2022f : B \u2192 P andg : A \u2192 P are the partial homomorphisms defined by the restrictions to B and A of the quotient mapping nat \u03b8 : A B \u2192 (A B )/\u03b8.", "cite_spans": [], "ref_spans": []}, {"section": "Pushouts of partial homomorphisms of total algebras", "text": "Proof. Notice that, since A and B are total algebras, condition (PHPO1) is equivalent to condition (CDCPO1) in Theorem 3, while conditions (PHPO2) and (PHPO3) are exactly conditions (CDCPO2) and (CDCPO3) therein. Then, the equivalence between (ii) and (iii) in Theorem 5 applies. On the other hand, the description of a pushout in P-TAlg \u03a3 is also a translation of the description of a pushout in CDCQ-Alg \u03a3 given in Theorem 3, using the description of a pushout in Alg \u03a3 given in \u00a72.2 and the fact that, since K , A and B are total algebras, (\u03d5", "cite_spans": [], "ref_spans": []}, {"section": "Remark 1 R. Alberich and F. Rossell\u00f3", "text": "12 proved that, for one-sorted signatures with an operation symbol at least binary, condition (CHPO2) is equivalent to the fact that (A B )/\u03b8 = nat \u03b8 (A ) or (A B )/\u03b8 = nat \u03b8 (B ): see Corollary 4.2 in the cited paper.", "cite_spans": [], "ref_spans": []}, {"section": "Remark 1 R. Alberich and F. Rossell\u00f3", "text": "Remark 2 Although in Theorem 5 and Corollary 1 we only considered pushouts of pairs of partial homomorphisms, these results generalize in a straightforward way to pushouts of arbitrary non-empty families of partial homomorphisms of total algebras with the same source algebra.", "cite_spans": [], "ref_spans": []}, {"section": "Remark 1 R. Alberich and F. Rossell\u00f3", "text": "Conditions (PHPO1), (PHPO2) and (PHPO3) in Corollary 1 are independent of each other, as the following examples show.", "cite_spans": [], "ref_spans": []}, {"section": "Remark 1 R. Alberich and F. Rossell\u00f3", "text": "Example 1 Let \u03a3 be a one-sorted signature with only one operation symbol \u03d5, which is binary. Let K, A and B be the total \u03a3-algebras with carriers K = {k 1 , k 2 }, A = {a 1 , a 2 , a 3 } and B = {b}, respectively, and their operations defined as follows:", "cite_spans": [], "ref_spans": []}, {"section": "Remark 1 R. Alberich and F. Rossell\u00f3", "text": "Let f : K \u2192 A and g : K \u2192 B be the partial homomorphisms defined by f (k 1 ) = a 1 and f (k 2 ) = a 2 , and g(k 1 ) = b, respectively. These partial homomorphisms do not satisfy condition (PHPO1), because A 1 = {a 1 } and B 1 = B are two closed subsets of A and B with the same preimage in K, as well as A 2 = {a 3 } and B 2 = \u2205, and the only closed subset of A containing A 1 and A 2 is its carrier A, but there does not exist any closed subset B of B such that f \u22121 (A) = g \u22121 (B ). Example 2 Let \u03a3 be the same signature as in the last example, and let now K, A and B be the total \u03a3-algebras with carriers K = {k}, A = {a 1 , a 2 } and B = {b 1 , b 2 }, respectively, and their operations defined as follows:", "cite_spans": [], "ref_spans": []}, {"section": "Remark 1 R. Alberich and F. Rossell\u00f3", "text": "Let f : K \u2192 A and g : K \u2192 B be the homomorphisms defined by f (k) = a 1 and g(k) = b 1 . If we consider them as partial homomorphisms, it is clear that they satisfy condition (PHPO1), with A = A and B = B. Now, the congruence \u03b8 on A \u2295 B generated by E(f, g) only identifies a 1 with b 1 , and it is straightforward to prove that f and g satisfy condition (PHPO3). But they do not satisfy condition (PHPO2):", "cite_spans": [], "ref_spans": []}, {"section": "Remark 1 R. Alberich and F. Rossell\u00f3", "text": "Example 3 Let be again \u03a3 the same signature as in the last two examples, and let now K, A and B be the total \u03a3-algebras with carriers K = {k 1 , k 2 }, A = {a} and B = {b 1 , b 2 , c, d 1 , d 2 }, respectively, and their operations defined as follows:", "cite_spans": [], "ref_spans": []}, {"section": "Remark 1 R. Alberich and F. Rossell\u00f3", "text": "Let f : K \u2192 A and g : K \u2192 B be the homomorphisms defined by f (k 1 ) = f (k 2 ) = a and g(k 1 ) = b 1 , g(k 2 ) = b 2 , respectively. As before, these homomorphisms satisfy condition (PHPO1) with A = A and B = B, and in this case the congruence \u03b8 on A \u2295 B generated by E(f, g) identifies on the one hand a, b 1 and b 2 , and on the other hand d 1 and d 2 . It is clear then that f and g satisfy condition (PHPO2): actually, the restriction of nat \u03b8 : A B \u2192 (A B)/\u03b8 to B is surjective. But they do not satisfy condition (PHPO3): A 0 = \u2205 and B 0 = {d 1 , d 2 } are closed subsets of A and B such that f \u22121 (A 0 ) = g \u22121 (B 0 ) and the congruence on their disjoint sum generated by the restriction of E(f, g) is clearly the identity relation, while", "cite_spans": [], "ref_spans": []}, {"section": "Remark 1 R. Alberich and F. Rossell\u00f3", "text": "Condition (PHPO3) is quite involved. It was shown in Theorem 6 and Proposition 7 of 11 that, for quomorphisms, a similar condition could be replaced by a simpler one, and one could wonder whether it would also happen in the partial homomorphisms setting. So, let us introduce the condition for partial homomorphisms that would correspond to that simpler condition for quomorphisms and check whether it can replace (PHPO3).", "cite_spans": [], "ref_spans": []}, {"section": "Remark 1 R. Alberich and F. Rossell\u00f3", "text": "Let f : K \u2192 A and g : K \u2192 B be two partial homomorphisms of total \u03a3-algebras satisfying condition (PHPO1). As in Corollary 1, let A and B be the greatest closed subsets of A and B, respectively, such that f \u22121 (A ) = g \u22121 (B ), let K denote this subset of K, let K , A and B be the subalgebras of K, A and B supported on their closed subsets K , A and B , respectively, let f : K \u2192 A and g : K \u2192 B be the homomorphisms between these algebras induced by the partial homomorphisms f and g, and let", "cite_spans": [], "ref_spans": []}, {"section": "Remark 1 R. Alberich and F. Rossell\u00f3", "text": "Consider the following condition on f and g.", "cite_spans": [], "ref_spans": []}, {"section": "PHPO4)", "text": "The equivalence relation \u03b8 e on A B generated by E(f , g ) is a congruence on A (+) \u2295B (+) (and therefore it is equal to the congruence \u03b8 introduced in Corollary 1).", "cite_spans": [], "ref_spans": []}, {"section": "PHPO4)", "text": "Proposition 2 Let f : K \u2192 A and g : K \u2192 B be two partial homomorphisms of total \u03a3-algebras satisfying condition (PHPO1). If they satisfy condition (PHPO4), then they satisfy condition (PHPO3).", "cite_spans": [], "ref_spans": []}, {"section": "PHPO4)", "text": "Proof. Assume that f and g satisfy conditions (PHPO1) and (PHPO4). Let A and B be the closed subsets of A and B given by condition (PHPO1), let A 0 and B 0 be closed subalgebras of A and B , supported respectively on A 0 and B 0 , such that f \u22121 (A 0 ) = g \u22121 (B 0 ), and let \u03b8 0 be the congruence on A", "cite_spans": [], "ref_spans": []}, {"section": "PHPO4)", "text": "and thus d \u2208 A 0 B 0 and there exist some", "cite_spans": [], "ref_spans": []}, {"section": "PHPO4)", "text": "and then, since d \u2208 D 0 , we have that", "cite_spans": [], "ref_spans": []}, {"section": "PHPO4)", "text": "Unfortunately, the converse implication is false, even for partial homomorphisms satisfying also condition (PHPO2), as the following example shows. Therefore, although (PHPO4), together with (PHPO1) and (PHPO2), provides a sufficient condition for the existence of a pushout in P-TAlg \u03a3 of two partial homomorphisms of total algebras, it is not necessary, and therefore it cannot replace (PHPO3).", "cite_spans": [], "ref_spans": []}, {"section": "PHPO4)", "text": "Example 4 Let \u03a3 be a one-sorted signature with only a binary operation symbol \u03d5 and two unary operation symbols \u03c8 and \u03c8 1 . Let K, A and B be the total \u03a3-algebras with carriers K = {k 1 , k 2 }, A = {a} and B = {b 1 , b 2 , c, d 1 , d 2 }, respectively, and their operations defined by:", "cite_spans": [], "ref_spans": []}, {"section": "PHPO4)", "text": "Let f : K \u2192 A and g : K \u2192 B be the homomorphisms defined by f (", "cite_spans": [], "ref_spans": []}, {"section": "PHPO4)", "text": "Since f and g are total, they satisfy condition (PHPO1) with A = A and B = B. The equivalence \u03b8 e on A B generated by E(f, g) identifies b 1 , b 2 and a, while the congruence \u03b8 on A \u2295 B generated by E(f, g) identifies moreover d 1 and d 2 . Therefore, \u03b8 e = \u03b8 and hence f and g do not satisfy condition (PHPO4). In particular, by Corollary 5.2 in, 12 they do not have a pushout in CQ-Alg \u03a3 . Now, it is clear that f and g satisfy condition (PHPO2): the restriction of nat \u03b8 : A B \u2192 (A B)/\u03b8 to B is surjective. And they turn out to satisfy also condition (PHPO3). Indeed, it is easy to check that the only pairs of closed subsets of A and B with the same preimage in K are f (K), g(K) and A, B, and that on these pairs of sets the inclusion of relations required by condition (PHPO3) is satisfied. Therefore, f and g have a pushout in P-TAlg \u03a3 , and it is given by their pushout in Alg \u03a3 .", "cite_spans": [], "ref_spans": []}, {"section": "PHPO4)", "text": "Let us point out that an argument similar to the one used in the proof of the implications (i)=\u21d2(ii) and (ii)=\u21d2(iii) in Theorem 5 proves also the following result. We leave the details to the reader. Corollary 2 Let f : K \u2192 A and g : K \u2192 B be two partial homomorphisms of total \u03a3-algebras. If f and g have a pushout in CQ-Alg \u03a3 and it is given by a total \u03a3-algebra, then they have a pushout in P-TAlg \u03a3 and it equal to their pushout in CQ-Alg \u03a3 .", "cite_spans": [], "ref_spans": []}, {"section": "PHPO4)", "text": "Example 4 shows that the converse implication in this proposition is false: two partial homomorphisms of total \u03a3-algebras having a pushout in P-TAlg \u03a3 need not have a pushout in CQ-Alg \u03a3 . On the other hand, it is not difficult to produce (similar) examples showing that:", "cite_spans": [], "ref_spans": []}, {"section": "PHPO4)", "text": "\u2022 two partial homomorphisms of total \u03a3-algebras having a pushout in Q-Alg \u03a3 given by a total \u03a3-algebra need not have a pushout in P-TAlg \u03a3 ;", "cite_spans": [], "ref_spans": []}, {"section": "PHPO4)", "text": "\u2022 two partial homomorphisms of total \u03a3-algebras having a pushout in P-TAlg \u03a3 can have a pushout in CQ-Alg \u03a3 given by a non-total \u03a3-algebra.", "cite_spans": [], "ref_spans": []}, {"section": "PHPO4)", "text": "The interested reader can find such examples in, 25 Chapter 8. Furthermore, and against what happens in the unary case, 3 the SPO transformation in the category P-TAlg \u03a3 for an arbitrary signature \u03a3 is independent of the double-pushout transformation of total \u03a3-algebras in TAlg \u03a3 as introduced by P. Burmeister, M. Llabr\u00e9s and F. Rossell\u00f3, 10 in the sense that, if we translate a partial homomorphism of total \u03a3-algebras r : L \u2192 R into the DPO production rule P r = (L\u2190 Dom r r \u2192 R), then there exist homomorphisms f : L \u2192 G of total \u03a3-algebras such that:", "cite_spans": [{"start": 49, "end": 51, "text": "25", "ref_id": "BIBREF25"}, {"start": 120, "end": 121, "text": "3", "ref_id": "BIBREF3"}, {"start": 341, "end": 343, "text": "10", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "PHPO4)", "text": "\u2022 r and f have a pushout in P-TAlg \u03a3 but P r cannot be applied to G through f in TAlg \u03a3 ;", "cite_spans": [], "ref_spans": []}, {"section": "PHPO4)", "text": "\u2022 P r can be applied to G through f in TAlg \u03a3 but r and f do not have a pushout in P-TAlg \u03a3 ;", "cite_spans": [], "ref_spans": []}, {"section": "PHPO4)", "text": "\u2022 P r can be applied to G through f in TAlg \u03a3 and r and f have a pushout in P-TAlg \u03a3 , but the corresponding derived algebras are different.", "cite_spans": [], "ref_spans": []}, {"section": "PHPO4)", "text": "The interested reader can find the corresponding examples in, 26 Chapter 5. To finish this paper, let us give an easy example of SPO transformation of total algebras.", "cite_spans": [{"start": 62, "end": 64, "text": "26", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "PHPO4)", "text": "Example 5 Let \u03a3 G be the one-sorted signature of groups, with a nullary operation e (corresponding to the neutral element), a unary operation \u22121 (corresponding to the inversion), and a binary operation * . Let F(x) be the free group generated by one element x, let E be a trivial group, with only one element, and let r : F(x) \u2192 E be the partial homomorphism defined simply by r(e F(x) ) = e E . Let now G be any group and f : F(x) \u2192 G any homomorphism of groups, which is uniquely determined by the image f (x). Then, we can understand r as an SPO transformation rule that can be applied to G through the occurrence f when they have a pushout in P-TAlg \u03a3G . Corollary 1 allows us to decide when such an application is possible and what is its result.", "cite_spans": [], "ref_spans": []}, {"section": "PHPO4)", "text": "It turns out that f and r satisfy condition (PHPO1) if and only if there exists the greatest subgroup H of G whose intersection with the subgroup f (x) generated by f (x) is the neutral element of G, in which case the closed subsets of E and G asked by this condition are (the carriers of ) E itself and H. Now, the congruence \u03b8 on E (+) \u2295 H (+) defined in Corollary 1 simply identifies the neutral elements of E and H and (E (+) \u2295 H (+) )/\u03b8 \u223c = H (+) . It is straightforward to check then that f and r satisfy conditions (PHPO2) and (PHPO3).", "cite_spans": [], "ref_spans": []}, {"section": "PHPO4)", "text": "Summarizing, r can be applied to G through f if and only if there exists the greatest subgroup H of G such that H \u2229 f (x) = {e G }, and when it can be applied, the derived \u03a3 G -algebra is, up to isomorphism, this subgroup H.", "cite_spans": [], "ref_spans": []}, {"section": "PHPO4)", "text": "For instance, if G is a permutation group generated by several pairwise disjoint transpositions \u03c3 1 , . . . , \u03c3 k , and if the homomorphism f : F(x) \u2192 G is defined by f (x) = \u03c3 1 , then r can be applied to G through it and the result of this application is the subgroup \u03c3 2 , . . . , \u03c3 k of G generated by the other transpositions. This kind of permutation groups are used by C. Reidys and P. 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{"paper_id": "18982535", "_pdf_hash": "ab506500981d1f2b6f6f0bf94ba0403da8748387", "abstract": [{"section": "Abstract", "text": "A possible building block for a scalable quantum computer has recently been demonstrated [M. Mariantoni et al., Science 334, 61 (2011)]. This architecture consists of superconducting qubits capacitively coupled both to individual memory resonators as well as a common bus. In this work we study a natural primitive entangling gate for this and related resonator-based architectures, which consists of a controlled-\u03c3 z (CZ) operation between a qubit and the bus. The CZ gate is implemented with the aid of the non-computational qubit |2 state [F. W. Strauch, et al., Phys. Rev. Lett. 91, 167005 (2003)]. Assuming phase or transmon qubits with 300 MHz anharmonicity, we show that by using only low frequency qubit-bias control it is possible to implement the qubit-bus CZ gate with 99.9% (99.99%) fidelity in about 17 ns (23 ns) with a realistic two-parameter pulse profile, plus two auxiliary z rotations. The fidelity measure we refer to here is a state-averaged intrinsic process fidelity, which does not include any effects of noise or decoherence. These results apply to a multiqubit device that includes strongly coupled memory resonators. We investigate the performance of the qubit-bus CZ gate as a function of qubit anharmonicity, indentify the dominant intrinsic error mechanism and derive an associated fidelity estimator, quantify the pulse shape sensitivity and precision requirements, simulate qubit-qubit CZ gates that are mediated by the bus resonator, and also attempt a global optimization of system parameters including resonator frequencies and couplings. Our results are relevant for a wide range of superconducting hardware designs that incorporate resonators and suggest that it should be possible to demonstrate a 99.9% CZ gate with existing transmon qubits, which would constitute an important step towards the development of an error-corrected superconducting quantum computer. ", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Reaching the fidelity threshold for fault-tolerant quantum computation with superconducting electrical circuits [1-3] will probably require improvement in three areas: qubit coherence, readout, and qubit-qubit coupling tunability. Fortunately, the coherence times of superconducting transmon qubits [4, 5] have increased dramatically, exceeding 10\u00b5s in the three-dimensional version [6, 7] . Fast, threshold-fidelity nondestructive measurement has not yet been demonstrated, but is being actively pursued [8] [9] [10] [11] [12] . Some method for turning off the interaction between device elements-beyond simple frequency detuning-is also desirable for high-fidelity operations.", "cite_spans": [{"start": 303, "end": 305, "text": "5]", "ref_id": "BIBREF4"}], "ref_spans": []}], "body_text": [{"section": "", "text": "Reaching the fidelity threshold for fault-tolerant quantum computation with superconducting electrical circuits [1] [2] [3] will probably require improvement in three areas: qubit coherence, readout, and qubit-qubit coupling tunability. Fortunately, the coherence times of superconducting transmon qubits [4, 5] have increased dramatically, exceeding 10\u00b5s in the three-dimensional version [6, 7] . Fast, threshold-fidelity nondestructive measurement has not yet been demonstrated, but is being actively pursued [8] [9] [10] [11] [12] . Some method for turning off the interaction between device elements-beyond simple frequency detuning-is also desirable for high-fidelity operations. A variety of tunable coupling circuits have been demonstrated [13] [14] [15] [16] [17] [18] [19] , but these considerably increase the complexity of the hardware and it is not clear whether they will be practical for large scale implementation. The coupling can also be controlled by the application of microwave pulses [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] .", "cite_spans": [{"start": 112, "end": 115, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 309, "end": 311, "text": "5]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "", "text": "An alternative approach has been introduced by Mariantoni et al. [33] and theoretically analyzed in Ref. [34] . In this quantum von Neumann (QVN) architecture, superconducting qubits are capacitively coupled both to individual memory resonators as well as a common bus, as illustrated in Fig. 1 . The crossed boxes in Fig. 1 represent the phase qubits [35] employed by Mariantoni et al. [33] , however other qubit designs such as the transmon may be used here as well. The key feature of this architecture is that information (data) is stored in memory resonators that are isolated by two detuned coupling steps from the bus. Qubits are used to transfer information to and from the bus or entangle with it, and to implement single-qubit operations, but are otherwise kept in their ground states. No more than one qubit (attached to the same bus) is to be occupied at any time. Such an approach significantly improves the effective on/off ratio without introducing the added complexity of nonlinear tunable coupling circuitry. The spectral crowding problem of the usual qubit-bus architecture is greatly reduced because the four-step coupling between memory resonators is negligible. And an added benefit of the QVN approach is that the longer coherence times of the memory elements reduce the overall decoherence rate of the device. (In Ref. [34] , the architecture we consider is referred to as the resonator-zero-qubit architecture, but here we will follow the QVN terminology of [33] .)", "cite_spans": [], "ref_spans": [{"start": 288, "end": 294, "text": "Fig. 1", "ref_id": "FIGREF0"}, {"start": 318, "end": 324, "text": "Fig. 1", "ref_id": "FIGREF0"}]}, {"section": "", "text": "The QVN architecture of Mariantoni et al. [33] is not, by itself, capable of large-scale, fault-tolerant quantum computation, nor is it known how multiple QVN devices might be integrated into a scalable design. The problem of designing scalable, fault-tolerant architectures for superconducting qubits is of great interest and importance [36, 37] , but is still in its infancy. We expect the gate design approach discussed here to be applicable to future architecture designs incorporating qubits coupled to resonators, and perhaps beyond.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Along with high-fidelity single-qubit rotations [38, 39] , quantum computing with the QVN processor requires two additional types of operations. The first is state transfer between the different physical components, which has to be performed frequently during a computation. The simplest case of state transfer is between a qubit and its associated memory (or the reverse). This case is investigated in Ref. [34] , where two important observations are made: First, in contrast with the usual SWAP or iSWAP operation, which must be able to simultaneously transfer quantum information in two directions, only unidirectional state transfers are required in the QVN system. This is because adjacent qubits and resonators are-by agreement-never simultaneously populated. Second, the phase of a transferred |1 state is immaterial, as it can always be adjusted by future qubit z rotations [40, 41] . These two simplifications allow the resulting state transfer operation, called a MOVE gate, to be carried out with extremely high intrinsic fidelity-perfectly for a truncated model-with a simple four-parameter pulse profile. By intrinsic fidelity we mean the process fidelity (defined below) in the absence of noise or decoherence. The need for four control parameters immediately follows from the requirement that after a MOVE gate, the probability amplitudes must vanish on two device components, the component (q or m) the state is leaving, and the bus b. Each zero imposes two real parameters, and no other probability amplitudes acquire weight (in the truncated model). Fixing the phase of the MOVE gate, if desired, requires one additional control parameter in the form of a local z rotational angle.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "State transfer between a qubit and the bus (or the reverse) can be analyzed in the same way, although in this case more pulse-shape parameters are required. In an n-qubit QVN processor (consisting of n qubits, n mem- (1) for the case of \u03c9on/2\u03c0 = 6.8 GHz, \u03c9 off /2\u03c0 = 7.5 GHz, tramp = 7 ns, \u03c3 = 1.24 ns, and ton = 10 ns. The total gate time excluding auxiliary z rotations is tgate = 17 ns. The example shown is representative of a 99.9% fidelity gate for a qubit with 300 MHz anharmonicity.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "ory resonators, and the bus), zero-amplitude conditions must be enforced on the additional n \u2212 1 qubits, leading to a total of 2(n + 1) pulse parameters, plus one z rotation angle. This makes quasi-exact state transfer to and from the bus a considerably more challenging operation. Simpler three-parameter approximate transfers, however, can still be implemented with very high fidelity, even when the coupling is strong (see below).", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Quantum computing with the QVN system also requires a universal SU(4) entangling gate, the most natural being a controlled-\u03c3 z (CZ) operation between a qubit and the bus. The CZ gate investigated here makes essential use of the non-computational qubit |2 state and was first proposed by Strauch and coworkers [42] . The Strauch gate has been investigated by many authors and has been demonstrated in several systems [43] [44] [45] [46] [47] [48] .", "cite_spans": [{"start": 436, "end": 440, "text": "[47]", "ref_id": "BIBREF47"}, {"start": 441, "end": 445, "text": "[48]", "ref_id": "BIBREF48"}], "ref_spans": []}, {"section": "", "text": "The present paper extends previous work by considering device parameters and pulse shapes appropriate for the QVN system, and by optimizing the CZ fidelity in a multi-qubit device. We are especially interested in whether the absence of an active tunable coupler results in any significant limitation on the obtainable fidelity, given a reasonable amount of qubit coherence, and whether very high intrinsic fidelities can be reached with a simple and experimentally realistic (filtered rectangular) pulse shape. We also study how the gate performance rapidly improves with increasing qubit anharmonicity, show that the dominant intrinsic error is caused by a nonadiabatic excitation of the bus |2 state that occurs during the switching the qubit frequency, derive a fidelity estimator based on that mechanism, analyze pulse shape errors, and simulate qubit-qubit CZ gates mediated by the bus. Finally, we address the interesting problem of system optimization, by using gate and idling error estimates to deduce optimal values of resonator frequencies and couplings.", "cite_spans": [], "ref_spans": []}, {"section": "II. SUMMARY OF RESULTS", "text": "We find that very high intrinsic fidelites-in the range of 99.9% to 99.99% and with corresponding total gate times in the range of 17 to 23 ns-can indeed be obtained with a four-parameter gate. Two control parameters are pulse-shape parameters and two are auxiliary local z rotation angles. We emphasize that only low-frequency pulses are required, and that the number of control parameters does not depend on the number of qubits in the QVN device. The results quoted above assume four phase or transmon qubits with 300 MHz anharmonicity; other values of anharmonicity are considered below. The CZ gate referred to here is between qubit q 1 and the bus (see Fig. 1 ), not between a pair of qubits as is usually considered.", "cite_spans": [], "ref_spans": [{"start": 659, "end": 665, "text": "Fig. 1", "ref_id": "FIGREF0"}]}, {"section": "II. SUMMARY OF RESULTS", "text": "The two-parameter low frequency pulse profile we use throughout this work is", "cite_spans": [], "ref_spans": []}, {"section": "II. SUMMARY OF RESULTS", "text": "an example of which is shown in Fig. 2 . Here \u01eb is the qubit frequency, \u03c9 off and \u03c9 on are the frequencies off and near resonance (with the bus), and the pulse switching time is determined by \u03c3, the standard deviation of the Gaussians inside (1) . The value of t ramp determines how the pulse is truncated at t = 0 and t gate as explained in Sec. III F; throughout this work we assume that", "cite_spans": [], "ref_spans": []}, {"section": "II. SUMMARY OF RESULTS", "text": "The relation (2) allows the switching time to be alternatively characterized by t ramp , which, as Fig. 2 illustrates, is a measure of the width of the ramps. The variable t gate is the total execution time of the gate excluding z rotations. The two control parameters \u03c9 on and", "cite_spans": [], "ref_spans": []}, {"section": "II. SUMMARY OF RESULTS", "text": "are determined by the numerical optimization procedure described in Sec. III G. From (3) we infer that t on is the time interval between the midpoints of the ramps, or the full-width at half-maximum (FWHM) of the pulse. We note that the optimal values of t on are somewhat longer than the value", "cite_spans": [], "ref_spans": []}, {"section": "II. SUMMARY OF RESULTS", "text": "that applies in the sudden, \u03c3 \u2192 0 limit. In addition to \u03c9 on and t on , two auxiliary local z rotations-on the qubit and resonator-are used to implement the CZ gate. As we explain below, adjusting the two control parameters \u03c9 on and t on zeros the population left in the non-computational qubit |2 state after the gate and (along with the auxiliary z rotations) sets the controlled phase equal to \u22121. The pulse shape (1) describes a rectangular current or voltage pulse sent to the qubit frequency bias through a Gaussian filter of width \u03c3, and is believed to be an accurate (although not exact) representation of the actual profile seen by the qubits in Ref. [33] . Our main results are given in Table I . Here \u03b7 is the qubit anharmonicity. The 200 MHz results apply to the phase qubits of Ref. [33] , while the larger anharmonicities might be relevant for future implementations with transmons. The bus couplings g b are determined by the \"g optimization\" procedure described in Sec. V, which leads to the simple formula", "cite_spans": [], "ref_spans": [{"start": 697, "end": 704, "text": "Table I", "ref_id": "TABREF1"}]}, {"section": "II. SUMMARY OF RESULTS", "text": "for the (approximately) optimal bus coupling. Let \"QVN n \" refer to a quantum von Neumann processor with n qubits coupled to n memory resonators and a bus; the Hamiltonian for such a device is discussed in Sec. III A.", "cite_spans": [], "ref_spans": []}, {"section": "II. SUMMARY OF RESULTS", "text": "As indicated in Table I , the memory resonators are always strongly coupled to allow for fast (less than 5 ns) MOVE operations in and out of memory. CZ fidelities well above 99.99% are also obtainable (see Sec. III J). ", "cite_spans": [], "ref_spans": [{"start": 16, "end": 23, "text": "Table I", "ref_id": "TABREF1"}]}, {"section": "II. SUMMARY OF RESULTS", "text": "These expressions indicate that CZ gates with very high intrinsic fidelity can be implemented in about 20 ns with existing superconducting qubits, a conclusion which applies not only to QVN n but also to a wide range of similar resonator-based architectures. The intrinsic gate (or process) fidelity F ave is the squared overlap of ideal and realized final states, averaged over initial states (see Sec. III E). By intrinsic we mean that noise and decoherence are not included in the gate simulation. The fidelity estimate is developed in Sec. III H. The results given in Table I apply specifically to the n = 4 processor, but similar results are expected for other (not too large) values of n. Two strategies are critical for obtaining this high performance: Separating two control parameters in the form of auxiliary local z rotations, and defining the computational states in terms of interacting system eigenfunctions. These strategies were used in Ref. [34] and are discussed in more detail below. The gate fidelities achievable with a transmon-based QVN device are in line with that required for fault-tolerant quantum computation with topological stabilizer codes [49] [50] [51] . Qubit anharmonicity is an important resource that will help us achieve that goal. The CZ gate of Table I is between qubit q 1 and the bus in the QVN 4 device, and begins (typically) with a superposition of qubit-bus eigenstates, with the other qubits and all memory resonators in their ground states. In Sec. IV we also comment on several extensions and variations of this basic qubit-bus CZ gate: To begin with, the same gate but with qubit q 4 (which has a different memory frequency) is considered in Sec. IV A. In Sec. IV B we simulate a CZ gate between two qubits in QVN 4 , starting in the idling configuration where the qubits are empty and all data is stored in memory. In this case the qubitbus CZ gate of Table I is supplemented with MOVE gates to effect a CZ between qubits. And in Sec. IV C we discuss the CZ implemented between a pair of directly coupled anharmonic qubits, instead of a qubit and resonator. This is the system originally considered by Strauch et al. [42] .", "cite_spans": [{"start": 1171, "end": 1175, "text": "[49]", "ref_id": "BIBREF49"}], "ref_spans": [{"start": 572, "end": 579, "text": "Table I", "ref_id": "TABREF1"}, {"start": 1285, "end": 1292, "text": "Table I", "ref_id": "TABREF1"}, {"start": 1903, "end": 1910, "text": "Table I", "ref_id": "TABREF1"}]}, {"section": "III. CZ GATE DESIGN", "text": "In this section we discuss the qubit-bus CZ gate design problem.", "cite_spans": [], "ref_spans": []}, {"section": "A. QVN model", "text": "The QVN n processor consists of n superconducting qubits [1] [2] [3] capacitively coupled [42, 52, 53] to n memory resonators and to a common bus resonator. Here we assume parameters appropriate either for phase qubits [35] or transmon qubits [4, 5] with tunable transition frequencies. We write the qubit angular frequencies as \u01eb i , with i = 1, \u00b7 \u00b7 \u00b7 , n. These are the only controllable parameters in the QVN Hamiltonian (in contrast with Refs. [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] we do not make use of microwave pulses). The memory frequencies are written as \u03c9 mi , and the bus frequency is \u03c9 b . The (bare) frequencies of all resonators are assumed here to be fixed.", "cite_spans": [{"start": 57, "end": 60, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 247, "end": 249, "text": "5]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "A. QVN model", "text": "Because we are interested in very high fidelities, a realistic model is required. However, we have shown (in unpublished work) that the CZ performance is extremely robust with respect to the model details, so we only report results for a simplified Hamiltonian; the approximations used are discussed below. For the qubit-bus CZ simulations, the Hilbert space is truncated to allow for up to three excitations. The CZ gate naively involves no more than two excitations, so to properly account for leakage we include up to three. Therefore, four-level qubits and resonators (which include the |3 states) are required in the model. The QVN Hamiltonian we use is", "cite_spans": [], "ref_spans": []}, {"section": "A. QVN model", "text": "excluding single-qubit terms for microwave pulses that are not used in this work. Here \u03b7 and \u03b7 \u2032 are qubit anharmonic detuning frequencies, g m and g b are the qubitmemory and qubit-bus interation strengths, and", "cite_spans": [], "ref_spans": []}, {"section": "A. QVN model", "text": "The matrices in (7) act nontrivially in the spaces indicated by their subscripts, and as the identity otherwise. The matrix Y results from a harmonic oscillator approximation for the qubit eigenfunctions. Factors of are suppressed throughout this paper.", "cite_spans": [], "ref_spans": []}, {"section": "A. QVN model", "text": "The main approximations leading to (7) are the neglect of the \u01eb-dependence of the interaction strengths g m and g b , and the neglect of a small direct coupling between the memories and bus [54] . We have verified that including these does not change the main conclusions of this work. The \u01eb-dependence of the anharmonicities \u03b7 and \u03b7 \u2032 , and small anharmonic corrections to the interaction terms in (7) , are also neglected.", "cite_spans": [], "ref_spans": []}, {"section": "A. QVN model", "text": "The parameter values we use in our simulations are provided in Table II . We assume \u03b7 \u2032 = 3\u03b7, which is appropriate for qubic anharmonicity. As discussed in Sec. V, the value of the bus coupling g b is chosen to give the shortest CZ gate time (for a range of fidelities). The choice of resonator frequencies is also discussed in Sec. V. We simulate n = 4 qubits. The fidelities quoted in this paper are numerically exact for the model (7); the rotating-wave approximation is not used. Although the CZ and MOVE gates considered here do not involve microwave pulses, the single-qubit gates are assumed to be implemented with microwaves in the usual manner at the qubit frequency \u03c9 off . This frequency is also used to define an experimental \"rotating\" reference frame or local clock for each qubit: All qubit frequencies are defined relative to \u03c9 off [33] . This is discussed below in Sec. III C.", "cite_spans": [], "ref_spans": [{"start": 63, "end": 71, "text": "Table II", "ref_id": "TABREF1"}]}, {"section": "B. Strauch CZ gate", "text": "In this section we give a detailed description of the CZ gate introduced by Strauch et al. [42] . In particular, we explain the specific roles played by the two pulse-shape parameters t on and \u03c9 on , and by the two auxiliary z rotation angles \u03b3 1 and \u03b3 2 . To accomplish this we introduce several approximations that allow for an analytic treatment of the CZ gate dynamics.", "cite_spans": [], "ref_spans": []}, {"section": "B. Strauch CZ gate", "text": "First, we consider a truncated model consisting of a single superconducting qubit with frequency \u01eb and anharmonic detuning \u03b7, capacitively coupled to a bus resonator with frequency \u03c9 b ,", "cite_spans": [], "ref_spans": []}, {"section": "B. Strauch CZ gate", "text": "In this case Y reduces to", "cite_spans": [], "ref_spans": []}, {"section": "B. Strauch CZ gate", "text": "This Hamiltonian is written in the basis of bare eigenstates, which are the system eigenfunctions when the qubit and resonator are uncoupled. We write these bare states as |qb , with q, b \u2208 {0, 1, 2}. The energies of the interacting eigenstates, which we write with an overline as |qb , are plotted in Fig. 3 as a function of \u01eb/2\u03c0 for the case of \u03c9 b /2\u03c0 = 6.5 GHz, \u03b7/2\u03c0 = 300 MHz, and g b /2\u03c0 = 45 MHz. The interacting eigenstates are labeled such that |qb is perturbatively connected to |qb when \u01eb \u226b \u03c9 b . Second, we assume a short switching time and ignore the dynamical phases acquired during the ramps. As we will see below, this approximation is valid when g b \u226a \u03b7, so that the switching can be made sudden with respect to the coupling g b , but still adiabatic with respect to the anharmonicity \u03b7.", "cite_spans": [], "ref_spans": [{"start": 302, "end": 308, "text": "Fig. 3", "ref_id": "FIGREF1"}]}, {"section": "B. Strauch CZ gate", "text": "The CZ gate of Strauch et al. [42] , adapted to the qubitresonator system, works by using the anticrossing of the |11 channel with the auxiliary state |20 . In terms of the pulse parameters defined in (1), the qubit-resonator state is prepared at a qubit frequency \u01eb = \u03c9 off , and the frequency is then switched to \u01eb = \u03c9 on for a FWHM time duration t on . In the simplified model considered in this section,", "cite_spans": [], "ref_spans": []}, {"section": "B. Strauch CZ gate", "text": "and", "cite_spans": [], "ref_spans": []}, {"section": "B. Strauch CZ gate", "text": "Equation (11) gives the qubit frequency for which the bare state |11 is degenerate with |20 , and is at a frequency \u03b7 above the usual resonance condition. Equation (12) is the sudden-limit value defined in (4) and derived below. The qubit frequency is then returned to the detuned value \u03c9 off . The complete pulse profile is also shown in Fig. 3 (solid black curve) for the case of \u03c9 on /2\u03c0 = 6.8 GHz and \u03c9 off /2\u03c0 = 7.5 GHz. Let's follow the evolution resulting from an initial (normalized) qubit-resonator state a 00 00 + a 01 01 + a 10 10 + a 11 11 .", "cite_spans": [], "ref_spans": [{"start": 339, "end": 345, "text": "Fig. 3", "ref_id": "FIGREF1"}]}, {"section": "B. Strauch CZ gate", "text": "Because the |00 channel is very well separated from the others, the |00 component will only acquire a dynamical phase factor", "cite_spans": [], "ref_spans": []}, {"section": "B. Strauch CZ gate", "text": "where E 00 is the energy of the 00 eigenstate. Without loss of generality we can shift the entire spectrum so that E 00 = 0 [as in (9) ] and the phase factor (14) becomes unity. This freedom results from the fact that any unitary gate operation only needs to be defined up to an overall multiplicative phase factor. With this phase convention the CZ gate acts as the identity on this component, so we have the map 00 \u2192 00 .", "cite_spans": [], "ref_spans": []}, {"section": "B. Strauch CZ gate", "text": "The |01 component will mostly return to |01 , also with an acquired phase, but a small component will be left in |10 due to the nonadiabatic excitation of that channel, which is only separated in energy from |01 by about \u03b7 when \u01eb = \u03c9 b + \u03b7. The |10 component similarly suffers from a small noniadabatic coupling to |01 . As we will explain below, these nonadiabatic errors are exponentially suppressed when the functional form of \u01eb(t) is properly designed. Then we have", "cite_spans": [], "ref_spans": []}, {"section": "B. Strauch CZ gate", "text": "and", "cite_spans": [], "ref_spans": []}, {"section": "B. Strauch CZ gate", "text": "where E 1 is a small nonadiabatic population error (below we refer to E 1 as a switching error). In the E 1 \u2192 0 limit, \u03b1 and \u03b2 are dynamical phases given by", "cite_spans": [], "ref_spans": []}, {"section": "B. Strauch CZ gate", "text": "where the second approximate quantities neglect phase accumulation during the ramps and use perturbative expressions for the energies E 01 and E 10 when \u01eb = \u03c9 b + \u03b7. The expressions (16) and (17) neglect an extremely small leakage out of the {|01 , |10 } subspace. Neglecting this leakage, the evolution in the {|01 , |10 } subspace is unitary, leading to the phase condition", "cite_spans": [], "ref_spans": []}, {"section": "B. Strauch CZ gate", "text": "Using (20) to eliminate \u03b2 \u2032 leads to", "cite_spans": [], "ref_spans": []}, {"section": "B. Strauch CZ gate", "text": "10 \u2192 e", "cite_spans": [], "ref_spans": []}, {"section": "B. Strauch CZ gate", "text": "where \u03c6 \u2261 \u03b1 \u2032 \u2212 \u03b2. The evolution of the eigentates |01 and |10 is therefore characterized by the cross-excitation probability E 1 and three phase angles \u03b1, \u03b2, and \u03c6. Now we consider the |11 component. The |11 channel couples strongly with the |20 channel, as well as weakly with |02 . The simplest way to understand the dynamics of the |11 component is to use two different representations to describe these two effects. We will describe strong interaction with |20 in the bare basis and the weak, nonadiabatic coupling with |02 in the eigenstate basis. Suppose we begin with the qubit strongly detuned from the bus, so that |11 \u2248 |11 (the detuned interacting eigenstate is well approximated by the bare |11 state). Then we quickly switch \u01eb from \u03c9 off to \u03c9 b +\u03b7. By \"quickly\" we mean that we strongly mix with the |20 channel. The interaction with |02 is always weak, even in the sudden limit. This asymmetric excitation is possible because |20 is protected (separated in energy from |11 ) by an energy gap 2 \u221a 2g b , whereas |02 is protected by a much larger gap of \u03b7 \u2212 \u221a 2g b (this expression accounts for level repulsion from |20 , and we have assumed that g b \u226a \u03b7). We can informally say that the desired switching is nonadiabatic with respect to the energy scale g b , but is adiabatic with respect to \u03b7 [42] .", "cite_spans": [], "ref_spans": []}, {"section": "B. Strauch CZ gate", "text": "Focusing first on the strong coupling to |20 , the suddenly switched |11 state is no longer an eigenstate when \u01eb = \u03c9 on , as the relevant eigenfunctions at this setting are", "cite_spans": [], "ref_spans": []}, {"section": "B. Strauch CZ gate", "text": "The nonstationary state", "cite_spans": [], "ref_spans": []}, {"section": "B. Strauch CZ gate", "text": "therefore rotates in the {|11 , |20 } subspace, and after a time duration t becomes", "cite_spans": [], "ref_spans": []}, {"section": "B. Strauch CZ gate", "text": "1 + e \u2212i\u2206Et 2 11", "cite_spans": [], "ref_spans": []}, {"section": "B. Strauch CZ gate", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "B. Strauch CZ gate", "text": "Holding \u01eb fixed at \u03c9 b + \u03b7 for a FWHM time (12) , corresponding to a 2\u03c0 rotation, (26) becomes", "cite_spans": [], "ref_spans": []}, {"section": "B. Strauch CZ gate", "text": "When \u01eb = \u03c9 b + \u03b7, the energy of eigenstate |11 is", "cite_spans": [], "ref_spans": []}, {"section": "B. Strauch CZ gate", "text": "After detuning quickly we therefore obtain", "cite_spans": [], "ref_spans": []}, {"section": "B. Strauch CZ gate", "text": "or, using expressions (18) and (19),", "cite_spans": [], "ref_spans": []}, {"section": "B. Strauch CZ gate", "text": "The two phase angles \u03b1 and \u03b2 can be cancelled by the application of independent auxiliary single-qubit z rotations", "cite_spans": [], "ref_spans": []}, {"section": "B. Strauch CZ gate", "text": "to the qubit and bus. Qubit z rotations are implemented by frequency excursions, whereras resonator z rotations are implemented in software (they are compiled into future qubit rotations). Following the pulse sequence that leads to (15) , (21), (22), and (31), with the operation", "cite_spans": [], "ref_spans": []}, {"section": "B. Strauch CZ gate", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "B. Strauch CZ gate", "text": "leads to the map 00 \u2192 00 ,", "cite_spans": [], "ref_spans": []}, {"section": "B. Strauch CZ gate", "text": "apart from a global phase factor. The use of auxiliary z rotations is discussed further Sec. III D.", "cite_spans": [], "ref_spans": []}, {"section": "B. Strauch CZ gate", "text": "The minus sign in (38) is the key to the Strauch CZ gate. However, as mentioned above, the analysis leading to (38) neglected a weak nonadiabatic excitation of the |02 channel caused by the switching of \u01eb. Including this effect in (38) leads to the modification", "cite_spans": [], "ref_spans": []}, {"section": "B. Strauch CZ gate", "text": "where E 2 is another switching error. Both E 1 and E 2 vanish exponentially with \u03c3 (or t ramp ), and for the regimes studied in this work E 2 is the dominant source of intrinsic gate fidelity loss. We note that the analysis leading to (39) assumed implementation of the ideal values [ (11) and (12)] of \u03c9 on and t on . Errors in these two control parameters, which we refer to as pulse shape errors and study in Sec. III I, lead instead to", "cite_spans": [], "ref_spans": []}, {"section": "B. Strauch CZ gate", "text": "where the controlled-phase error angle \u03b4 and rotation error E \u03b8 depend on the errors in \u03c9 on and t on , respectively. Finally, it is also interesting to consider the fully adiabatic limit of the Strauch CZ gate. By this we mean that the switching is adiabatic with respect to both g b and \u03b7. For the gate time to be competitive with the nonadiabatic gate of Table I , a larger coupling g b is required, which might lead to significant higher-order and cross-coupling errors in a multi-qubit device, but in the fully adiabatic limit only one pulse control parametereither \u03c9 on or t on -needs to be optimized (two z rotations are still required). This is because adiabaticity now assures that the |11 population is preserved (apart from exponentially small switching errors), taking over the role previously played by t on , and a single pulse shape parameter is sufficient to specify the controlled phase. A highly adiabatic CZ gate was demonstrated in Ref. [43] .", "cite_spans": [], "ref_spans": [{"start": 358, "end": 365, "text": "Table I", "ref_id": "TABREF1"}]}, {"section": "B. Strauch CZ gate", "text": "There are a few important differences between the Strauch CZ gate applied to a pair of directly coupled qubits (as in Ref. [42] ) and to the qubit-bus system considered here. These differences result from the harmonic spectrum of the resonator in the latter case and are discussed below in Sec. IV C.", "cite_spans": [], "ref_spans": []}, {"section": "C. Eigenstate basis", "text": "The Hamiltonian (7) is written in the usual bare basis of uncoupled system eigenstates, but information processing itself is best performed in the basis of interacting eigenfunctions of H idle , where H idle is given by (7) with the qubits in a dispersive idling configuration [34] . This choice of computational basis assures that idling qubits suffer no population change in the decoherence-free limit, and evolve in phase in a way that can be almost exactly compensated for by an appropriate choice of only n rotating frames or local clocks, one for each qubit [34] . Here we briefly review this important concept.", "cite_spans": [], "ref_spans": []}, {"section": "C. Eigenstate basis", "text": "In principal, any complete orthonormal basis of the physical Hilbert space that can be appropriately prepared, unitarily transformed, and measured-essentially, any basis where one can implement the DiVincenzo criteria [55] -is a valid basis on which to run a quantum computation. Defining the computational states to be interacting system eigenfunctions gives them the simplifying property that the time evolution can be decomposed into a sequence of gates, between which (almost) no evolution occurs. In other words, idling between gates generates the identity operation. This property, which is implicitly assumed in the standard circuit model of quantum computation, could be realized in an architecture where the Hamiltonian H can be completely switched off between gates. However, it is not possible to set H = 0 in the QVN architecture; nor can H itself be made negligibly small between gates. Therefore, nonstationary states such as uncoupled-qubit eigenstates accumulate errors (including population oscillations) between gates unless a correction protocol such as dynamical decoupling [56] is used. By defining computational states in terms of interacting system eigenfunctions {|\u03c8 } at some predefined dispersive idling configuration (qubit frequencies), the only evolution occuring during an idle from time t 1 to t 2 is a pure phase evolution,", "cite_spans": [{"start": 218, "end": 222, "text": "[55]", "ref_id": "BIBREF55"}], "ref_spans": []}, {"section": "C. Eigenstate basis", "text": "where E is the exact energy eigenvalue (and we neglect decoherence). Furthermore, it is possible to compensate for-or effectively remove-the pure phase evolution in (41) by applying phase shifts (after the idle period) to each eigenfunction to cancel the e \u2212iE(t2\u2212t1) phase factors; doing so would result in the ideal between-gate evolution", "cite_spans": [], "ref_spans": []}, {"section": "C. Eigenstate basis", "text": "The idling dynamics (42) is evidently equivalent to setting H = 0 between gates. We will discuss below how the compensating phase shifts are actually implemented in practice. This use of interacting system eigenfunctions and compensating phase shifts as described above provides a computational basis that evolves ideally between gates, but such an approach is not scalable; for example, there are 2 2n+1 such computational states in QVN n . In Ref. [34] an approximate but scalable implementation of this approach was introduced. The idea is that the exact energy E of a computational state in QVN n is, to an extremely good approximation, the sum of uncoupled qubit and resonator frequencies, i.e., essentially noninteracting. This is not simply a consequence of the dispersive regime energies (eigenvalues of H idle ), which have non-negligible interaction corrections, but because only a special subset of the eigenfunctions are used for information processing:", "cite_spans": [], "ref_spans": []}, {"section": "C. Eigenstate basis", "text": "In the QVN n system we only make use of H idle eigenfunctions in which there are no more than n excitations present, and such that two directly coupled elementsqubits or resonators-are not simultaneously occupied (except during the CZ gate). For example, when the data is stored in memory, the residual memory-memory coupling is fourth order in the qubit-resonator coupling g (for simplicity we assume here that g b = g m ). This leads to an eighth-order conditional frequency shift (order g 16 idling error) [34] . Next, suppose an excitation is transferred from memory to a qubit via a MOVE gate. Now the dominant frequency shift is sixth order. And when an excitation is in the bus the largest shift is fourth order [34] . The largest idling error (associated with the phase compensation) is therefore eighth order in g and can be made negligible with proper system design. The compensating phase shifts could be implemented through additional local z rotations, one for each qubit and resonator. However, these phase shifts evolve in time with very high (> 1 GHz) frequency, and it is therefore experimentally more practical to introduce a local clock/rotating frame for each qubit and resonator. This is achieved by introducing a fixed-frequency microwave line for each qubit and resonator, and measuring each qubit and resonator phase relative to the phase of its reference. By choosing the frequency of the qubit (resonator) reference microwave equal to the idle frequency (resonator frequency), the component frequencies [and therefore the quantity E in (41)] are effectively zeroed, and no more than 2n + 1 different reference frequencies or local clocks are required. This procedure corresponds to implementing the experiment in a multi-qubit rotating frame. And, in a further simplification, the local clocks/rotating frames for the resonators are replaced by additional qubit z rotations that are handled in software (i.e., combined with future rotations). Therefore, in practice only n local clocks/rotating frames are needed, one for each qubit.", "cite_spans": [], "ref_spans": []}, {"section": "C. Eigenstate basis", "text": "Because the CZ gate simulations reported in Table I are already supplemented with local z rotations, these local clocks/rotating frames do not need to be included in those simulations; we simulate the lab frame. How-ever, they are included in the pulse-shape error simulations reported after (94) and in the CZ 23 qubit-qubit gate simulation reported in Sec. IV B.", "cite_spans": [], "ref_spans": [{"start": 44, "end": 51, "text": "Table I", "ref_id": "TABREF1"}]}, {"section": "C. Eigenstate basis", "text": "Having motivated the use of interacting system eigenfunctions for computational basis states, it is still necessary to establish that such states can actually be prepared and measured. Because we can assume the processor to initially start in its interacting ground state-a computational basis state-preparation of the other computational states can be viewed as a series of \u03c0 pulses and MOVE gates. We expect that such operations on the interacting eigenfunctions can be performed at least as accurately as when applied to bare states. Eigenfunction readout is a more subtle (and model-dependent) question, but the analysis of Ref. [34] suggests that interacting-eigenfunction readout is actually better than bare-state readout (in the model considered there).", "cite_spans": [], "ref_spans": []}, {"section": "C. Eigenstate basis", "text": "We also note that the idling configuration and associated eigenstate basis generally changes between consecutive gates (an example is given below in Sec. IV B). In Table I , the idling configuration has qubit q 1 at \u03c9 off and the others at \u03c9 park . Therefore, our entangling gate design is constrained by the requirement that we start and end in eigenstates of this particular H idle .", "cite_spans": [], "ref_spans": [{"start": 164, "end": 171, "text": "Table I", "ref_id": "TABREF1"}]}, {"section": "C. Eigenstate basis", "text": "The discussion above motivating the use of interacting eigenstates is based on their nearly ideal idling dynamics. It is still interesting, then, to consider whether the CZ gate can be generated equally well in either (bare or interacting eigenfunction) basis. We find that for the parameter regimes considered here, it is not possble to achieve better than about 99% fidelity in the bare basis with the same two-parameter pulse profile (it should be possible using more complex pulse shapes). The remaining error is consistent with the size of the perturbative corrections to the bare states in the idling configuration. This exercise emphasizes the importance of performing quantum logic with the system eigenfunctions, which have the built-in protection of adiabiticity against unwanted transitions.", "cite_spans": [], "ref_spans": []}, {"section": "C. Eigenstate basis", "text": "One might object to the use of interacting eigenfunctions as a design tool, the exact calculation of which is not scalable. However, approximate dispersive-regime eigenfunctions are efficiently computable. A particularly simple way to do this is to calculate the generator S of the diagonalizing transformation V = e \u2212iS by a power series In this work we denote the exact or approximate H idle eigenfunction perturbatively connected to the bare state", "cite_spans": [], "ref_spans": []}, {"section": "C. Eigenstate basis", "text": "following the overline notation introduced above. Note that (43) is not a tensor product of single-qubit/resonator eigenstates as is usually the case.", "cite_spans": [], "ref_spans": []}, {"section": "D. Auxiliary z rotations and CZ equivalence class", "text": "The standard CZ gate in the bare two-qubit basis", "cite_spans": [], "ref_spans": []}, {"section": "D. Auxiliary z rotations and CZ equivalence class", "text": "However in the QVN processor, local z rotations can be performed quickly and accurately, typically by brief qubit frequency excursions. Thus, we will consider the limit where SU(2) operations of the form exp[\u2212i(\u03b8/2)\u03c3 z ] can be done on the qubits and bus with negligible error and in a negligible amount of time (fidelity loss resulting from errors in these rotations are discussed in Sec. III I). We therefore want to define our entangling gate modulo these z rotations. We will do this by constructing a local-z equivalence class for an arbitrary element (gate) in SU(4), and then specialize to the CZ gate.", "cite_spans": [], "ref_spans": []}, {"section": "D. Auxiliary z rotations and CZ equivalence class", "text": "We define two elements U and U \u2032 of SU(4) to be equivalent, and write U \u2032 \u229c U , if", "cite_spans": [], "ref_spans": []}, {"section": "D. Auxiliary z rotations and CZ equivalence class", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "D. Auxiliary z rotations and CZ equivalence class", "text": "for some rotation angles \u03b3 k . The local-z equivalence class {U } corresponding to U is the set of elements u post U u pre for all u pre , u post . For a given gate U , {U } typically occupies a four-dimensional manifold, depending on four rotation angles. But because (44) is diagonal, {CZ} instead forms a two-dimensional sheet,", "cite_spans": [], "ref_spans": []}, {"section": "D. Auxiliary z rotations and CZ equivalence class", "text": "The CZ gate (44) ", "cite_spans": [], "ref_spans": []}, {"section": "D. Auxiliary z rotations and CZ equivalence class", "text": "We note that bus rotations, which cannot be directly implemented with microwave pulses or frequency excursions, are compiled into future qubit rotations.", "cite_spans": [], "ref_spans": []}, {"section": "D. Auxiliary z rotations and CZ equivalence class", "text": "The discussion above assumed a pair of qubits or a qubit and resonator, but it applies to a QVN processor in the interacting eigenfunction basis (43) after a minor modification. In the bare basis, the CZ gate is typically defined through its action (44) on a pair of qubits (or a qubit and resonator). Then, action on a bare computational basis state such as |q 1 q 2 \u00b7 \u00b7 \u00b7 q n m 1 m 2 \u00b7 \u00b7 \u00b7 m n b follows from the tensor-product form of that bare state. In the eigenstate basis the CZ gate must be defined through its action on", "cite_spans": [], "ref_spans": []}, {"section": "D. Auxiliary z rotations and CZ equivalence class", "text": "such as to reproduce the ideal action on the bare states to which they are perturbativey connected. For example, the CZ gate on qubit q 1 and the bus acts ideally as ", "cite_spans": [], "ref_spans": []}, {"section": "E. Fidelity definitions", "text": "The gate or process fidelity measure we use in this work is based on a state fidelity defined by the inner product of the ideal and realized final (pure) states, squared. This leads to a state-averaged fidelity given by [57, 58] ", "cite_spans": [], "ref_spans": []}, {"section": "E. Fidelity definitions", "text": "where U is the realized time-evolution operator in the interacting eigenfunction basis after auxiliary z rotations, projected into the relevant computational subspace, and (44)]. Note that the projected U is not necessarily unitary here, and that the first term in (50) characterizes the possible leakage from the computational basis (non-unitarity) whereas the second term is proportional to the square of the Hilbert-Schmidt inner product of U with U target . Although U is not assumed to be unitary, the expression (50) assumes a pure state and is (obviously) not valid in the presence of decoherence.", "cite_spans": [], "ref_spans": []}, {"section": "E. Fidelity definitions", "text": "[The formula (50) assumes that the Kraus representation for the completely positive process is not necessarily trace preserving, but it has only one term.] The form (50) also assumes an average over a 4-dimensional Hilbert space; in the N -dimensional generalization the denominator is N + N 2 , which is necessary (note numerator) to assure that F ave (U target , U target ) is unity.", "cite_spans": [], "ref_spans": []}, {"section": "E. Fidelity definitions", "text": "It is also useful to calculate the minimum or worst-case fidelity. The minimum fidelity of interest here is the state fidelity minimized over initial computational states, for a gate that has already been optimized (by maximizing F ave ). In Sec. III B we argued that the dominant intrinsic error mechanism (for an optimal pulse) in the truncated qubit-resonator model (9) is the nonadiabatic excitation of the |02 channel, in which there are two photons left in the bus resonator. Therefore, in the model (9), the minimum state fidelity occurs for the initial eigenstate |11 . In the QVN 4 processor, this worst-case state is written [in the notation of (43)] as", "cite_spans": [], "ref_spans": []}, {"section": "E. Fidelity definitions", "text": "where we have assumed a CZ gate between qubit q 1 and the bus. Numerical simulation of this gate in the QVN 4 processor confirms that the minimum CZ fidelity indeed occurs for the initial state (51), and is due to leakage from the computational subspace. We therefore define the minimum fidelity to be the state fidelity for initial condition (51),", "cite_spans": [], "ref_spans": []}, {"section": "E. Fidelity definitions", "text": "Note that this expression is not sensitive to the value of the controlled phase, and only accounts for leakage from the computational subspace. Simulated values of F |11 for the qubit-bus CZ gate are given in Table I , along with estimates of this same quantity that are discussed below in Sec. III H.", "cite_spans": [], "ref_spans": [{"start": 209, "end": 216, "text": "Table I", "ref_id": "TABREF1"}]}, {"section": "F. Pulse shape", "text": "In the QVN Hamiltonian (7), the qubit frequencies \u01eb i are the only available experimental controls. [There are also single-qubit terms for microwave pulses that are not shown in (7) and not used in this work.] During a CZ gate between a given qubit and the resonator bus, the frequency of that qubit is varied according to (1) , where", "cite_spans": [], "ref_spans": []}, {"section": "F. Pulse shape", "text": "with the other qubits remaining at the parking frequency \u03c9 park (given in Table II) . Two quantities related to the pulse switching-\u03c3 and t ramp -appear in the pulse profile function (1). We do this to emphasize that, in principal, two independent quantities could be used to quantify the shape of the switching profile. The first is the time duration (or width) of the switching, characterized by the standard deviation \u03c3. The second is the trunction time of the pulse, measured from the center (half maximum) of the frequency switch, which is equal to t ramp /2. However in this work we always use the (somewhat arbitrary) relation (2), which amounts to cutting off the pulse at 2 \u221a 2 standard deviations from the switching midpoints.", "cite_spans": [], "ref_spans": [{"start": 74, "end": 83, "text": "Table II)", "ref_id": "TABREF1"}]}, {"section": "F. Pulse shape", "text": "If the pulse shape function (1) is used only when 0 \u2264 t \u2264 t gate , and \u01eb is set to \u03c9 off otherwise, there will be small pulse discontinuities at t = 0 and t gate , the size of which is determined by the condition (2). Assuming t ramp \u226a t gate , we have", "cite_spans": [], "ref_spans": []}, {"section": "F. Pulse shape", "text": "which differs from the asymptotic value \u03c9 off by an amount", "cite_spans": [], "ref_spans": []}, {"section": "F. Pulse shape", "text": "where 1 \u2212 Erf(2) \u2248 0.5%. However, in an experiment these discontinuities are usually smoothed over by additional pulse shaping. Moreover, our simulations begin t = 0 and end at t = t gate , so the truncation only slightly affects the pulse shape: The initial and final detuned qubit frequency is actually a few MHz smaller than \u03c9 off . Having fixed the relation (2), there are then two measures of the pulse switching time, \u03c3 and t ramp , with t ramp providing a convenient measure of the time duration of the ramps. This property can be seen in the pulse shape example of Fig. 2 .", "cite_spans": [], "ref_spans": []}, {"section": "G. Gate optimization", "text": "We numerically optimize the two pulse-shape control parameters \u03c9 on and t on , as well as the two auxiliary z rotation angles, \u03b3 1 and \u03b3 2 , to maximize the average gate fidelity (50) . All other pulse parameters (\u03c9 off , \u03c3, t ramp ) are fixed. The values of \u03c9 off and t ramp are determined by the system optimization analysis of Sec. V, and then \u03c3 is obtained through relation (2) . The roles played by the control parameters \u03c9 on and t on are discussed above in Sec. III B.", "cite_spans": [], "ref_spans": []}, {"section": "G. Gate optimization", "text": "The fidelity optimization procedure is carried out in two stages: In the first stage we take \u03c9 on to be equal to its approximate value [see (11) ]", "cite_spans": [], "ref_spans": []}, {"section": "G. Gate optimization", "text": "and optimize t on to get close to the two-dimensional equivalence class {CZ} defined in (47) . We do this by minimizing a sum of two positive errors, one measuring the deviation of the absolute values of the matrix elements of the evolution operator U (projected into the q 1 -b subspace) from that of the four-dimensional identity matrix, the other measuring the deviation from the ideal relationship between the phases of the diagonal elements indicated in (47) . This first stage yields an approximate value of t on , as well as approximate rotation angles", "cite_spans": [], "ref_spans": []}, {"section": "G. Gate optimization", "text": "In the second stage of optimization, we use the approximate values of \u03c9 on , t on , \u03b3 1 , and \u03b3 2 , obtained from the first stage, as seeds for a full four-dimensional (\u03c9 on , t on , \u03b3 1 , \u03b3 2 ) nonlinear maximization of the average fidelity (50) between", "cite_spans": [], "ref_spans": []}, {"section": "G. Gate optimization", "text": "and the standard CZ gate (44) . Here U is the projected evolution operator and u \u2208 SU(2) \u2297 SU(2) is defined in (46) . There are two obvious approaches to simulating the gate evolution in the interacting eigenfunction basis (43) . The first is to use the appropriate H idle eigenstates to transform the target gate (44) to the bare basis, and perform the actual simulation in the bare basis. However this approach requires that the subspace projection operators-which are naturally defined in the eigenstate basis-also be transformed. The second approach, which we follow here, is to transform the QVN Hamiltonian (7) to the eigenstate basis and perform the simulation in that basis.", "cite_spans": [], "ref_spans": []}, {"section": "H. Switching error and fidelity estimate", "text": "In this section we calculate the transition probability caused by a change of the qubit frequency during a CZ pulse, MOVE gate, or any other operation in the QVN system or related superconducting architectures. The problem will be treated quite generally and then applied to the Strauch CZ gate of Table I , resulting in a simple fidelity estimator for that gate. The quantities A, p sw , and F (est) |11 appearing in Table I are discussed in this section. Imagine that we have prepared an initial interacting system eigenfunction |a prior to performing a CZ operation or other gate that involves changing the frequency of one or more qubits. We assume that the ideal (target) behavior during the frequency switch or ramp itself is the identity map (times a phase factor), and that the |a channel does not cross any others in the system. The population loss during the ramp will therefore be exponentially suppressed if the switching time is long enough.", "cite_spans": [], "ref_spans": [{"start": 298, "end": 305, "text": "Table I", "ref_id": "TABREF1"}, {"start": 418, "end": 425, "text": "Table I", "ref_id": "TABREF1"}]}, {"section": "H. Switching error and fidelity estimate", "text": "In a multi-qubit system there is typically a large number of nonresonant channels coupled to |a that can be excited by the frequency switch. However, when the ramp fidelity is high and the probabilities of the undesired transitions", "cite_spans": [], "ref_spans": []}, {"section": "H. Switching error and fidelity estimate", "text": "are small, they can be individually estimated perturbatively (neglecting interference), thereby reducing the problem to a sum of independent two-channel problems", "cite_spans": [], "ref_spans": []}, {"section": "H. Switching error and fidelity estimate", "text": "each characterized by a time-dependent detuning \u2206 and a coupling G. Without loss of generality we can shift the energy of a given two-channel problem so that the bare final state has zero energy. Each nonadiabatic transition can therefore be described by a general two-channel model of the form", "cite_spans": [], "ref_spans": []}, {"section": "H. Switching error and fidelity estimate", "text": "in the bare basis spanned by {|a , |b }. The undesired final state |b has a fixed energy 0 and the energy of |a varies in time with detuning \u2206. The coupling G is assumed to be a real, positive constant. The instantaneous eigenstates of (62) are", "cite_spans": [], "ref_spans": []}, {"section": "H. Switching error and fidelity estimate", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "H. Switching error and fidelity estimate", "text": "The instantaneous energies are", "cite_spans": [], "ref_spans": []}, {"section": "H. Switching error and fidelity estimate", "text": "and", "cite_spans": [], "ref_spans": []}, {"section": "H. Switching error and fidelity estimate", "text": "The |b channel is initially unoccupied at time t = 0, and we are interested in the probability p sw that the system, prepared in |a , is found in |b after changing the detuning \u2206 from one value to another. We refer to this probability as the nonadiabatic switching error, which we calculate by expanding the wave function in the basis of instantaneous eigenstates (63) and (64), as", "cite_spans": [], "ref_spans": []}, {"section": "H. Switching error and fidelity estimate", "text": "This leads to", "cite_spans": [], "ref_spans": []}, {"section": "H. Switching error and fidelity estimate", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "H. Switching error and fidelity estimate", "text": "The nonadiabatic matrix element (70) has been written so that the second term approaches unity in the G \u226a \u2206 perturbative limit. At time t = 0, \u03c8 a = 1. An approximate expression for", "cite_spans": [], "ref_spans": []}, {"section": "H. Switching error and fidelity estimate", "text": "can be obtained from (69) by assuming that |\u03c8 b | \u226a 1 throughout the evolution, so that \u03c8 a \u2248 1 for all t. Then", "cite_spans": [], "ref_spans": []}, {"section": "H. Switching error and fidelity estimate", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "H. Switching error and fidelity estimate", "text": "is the instantaneous splitting. We can simplify (72) further by assuming G \u226a \u2206, which will be the case for the applications considered below. In this perturbative limit we therefore obtain", "cite_spans": [], "ref_spans": []}, {"section": "H. Switching error and fidelity estimate", "text": "We emphasize that the form (74) assumes that \u2206 does not pass through zero, which would cause Landau-Zener tunneling and invalidate the perturbative analysis. In this work we are specifically interested in p sw for a single switch of the detuning from \u2206 on to \u2206 off (or the reverse) according to the smooth, error-function based profile shown in Fig. 4 . The standard deviation \u03c3 characterizes the switching time of the pulse and t ramp [related to \u03c3 through (2)] specifies its truncation, as discussed in Sec. III F. We use this switching profile for both CZ and MOVE gates. The switching error for the single switch profile defined in (75) and shown in Fig. 4 can be expressed as", "cite_spans": [], "ref_spans": [{"start": 345, "end": 351, "text": "Fig. 4", "ref_id": "FIGREF5"}, {"start": 654, "end": 660, "text": "Fig. 4", "ref_id": "FIGREF5"}]}, {"section": "H. Switching error and fidelity estimate", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "H. Switching error and fidelity estimate", "text": "The dimensionless quantity |A| 2 is plotted in Fig. 5 for five instances of \u2206 on and \u2206 off relevant to this work. We note that p sw evidently decreases as an exponential function of \u03c3, as expected for a nonadiabatic process. However, the dependence of |A| 2 on \u03c3 for large \u03c3 is somewhat intricate, a consequence of the error-function ramp shape. For very large values of \u03c3-not shown in Fig. 5 -the decay of |A| 2 becomes slower (the location of the crossover depends on the details of the pulse truncation). Although an approximate analytic expression for |A| 2 can be derived for this large-\u03c3 limit, the formula is not useful for the regimes of interest here. We now turn to the application of the switching error formula (76) to the CZ gate of Table I . As we have explained above in Sec. III E, the initial condition in the QVN 4 processor with the minimum fidelity after a CZ gate (between qubit q 1 and the bus) is the eigenstate (51) . For a perfect CZ gate this state would map to", "cite_spans": [], "ref_spans": [{"start": 746, "end": 753, "text": "Table I", "ref_id": "TABREF1"}]}, {"section": "H. Switching error and fidelity estimate", "text": "but in practice we will find population in other channels as well, the dominant error (for an optimal pulse) occuring in |000000002 , which has two excitations in the bus. This dominant error mechanism involves only a single qubit and resonator, and can be understood entirely within the truncated model (9) . In the language of that model, where the bare states (interacting eigenstates) are written as |qb (|qb ), the dominant fidelity loss of the |11 eigenstate is caused by nonadiabatic leakage to |02 . We call this leakage error E 2 .", "cite_spans": [], "ref_spans": []}, {"section": "H. Switching error and fidelity estimate", "text": "It is possible to understand this dominant |11 \u2192 |02 leakage error in a further simplified two-channel model that only includes the channels |11 and |02 . Given the strong interaction of the bare |11 state with |20 , it is not at all obvious that such a simplification is possible. However, during most of the switching, the detuning between |11 and |20 is much larger than their interaction strength \u221a 2g b , so they are effectively decoupled. (And while the qubit sits at the \u03c9 on frequency, the Hamiltonian is time-independent.) Therefore a two-channel description should be possible, although it will slightly overestimate the excitation of |02 . Numerical investigation confirms that the |20 channel can indeed be disregarded except for the level repulsion it produces on the |11 state (see below), which is crucial for obtaining an accurate fidelity estimate.", "cite_spans": [], "ref_spans": []}, {"section": "H. Switching error and fidelity estimate", "text": "In the bare {|11 , |02 } basis, (9) reduces to", "cite_spans": [], "ref_spans": []}, {"section": "H. Switching error and fidelity estimate", "text": "At the beginning of the CZ pulse of Table I , the qubit frequency is 1.0 GHz above the bus. \u01eb then decreases to \u03c9 on \u2248 \u03c9 b + \u03b7 and returns to the detuned configuration in the manner of Fig. 2 . The total leakage to |02 can be estimated as twice-because there are two switching events, which we assume to contribute incoherently-the value of p sw . Therefore the error E 2 introduced in (39) is given by", "cite_spans": [], "ref_spans": [{"start": 36, "end": 43, "text": "Table I", "ref_id": "TABREF1"}]}, {"section": "H. Switching error and fidelity estimate", "text": "To evaluate the switching error in this case, we use (76) with the parameter values", "cite_spans": [], "ref_spans": []}, {"section": "H. Switching error and fidelity estimate", "text": "The value of \u2206 on accounts for the level repulsion caused by the neglected |20 state, which causes the |11 channel to shift downwards towards |02 ; this large effect is evident in Fig. 3. [We ignore here a smaller repulsion by |02 , which would lead to the addition of a small positive correction to (82).] \u2206 off /2\u03c0 is always 1.0 GHz for the gates listed in Table I . The required |A| 2 values are obtained from Fig. 5 and are provided in Table I along with p sw .", "cite_spans": [], "ref_spans": [{"start": 180, "end": 187, "text": "Fig. 3.", "ref_id": "FIGREF1"}, {"start": 359, "end": 366, "text": "Table I", "ref_id": "TABREF1"}, {"start": 440, "end": 447, "text": "Table I", "ref_id": "TABREF1"}]}, {"section": "H. Switching error and fidelity estimate", "text": "The minimum fidelity estimate", "cite_spans": [], "ref_spans": []}, {"section": "H. Switching error and fidelity estimate", "text": "is also given in Table I and compared to simulated QVN 4 values of F ave and F |11 . We find that (84) is a reliable predictor of the worst-case fidelity F |11 in QVN 4 , confirming that the nonadiabatic switching error is the dominant fldelity loss mechanism here. Although this error will always be present, it can be exponentially suppressed by increasing the switching time.", "cite_spans": [], "ref_spans": [{"start": 17, "end": 24, "text": "Table I", "ref_id": "TABREF1"}]}, {"section": "H. Switching error and fidelity estimate", "text": "Finally, we briefly comment on the nonadiabatic switching errors between the |01 and |10 eigenstates, which we have argued to be subdominant to the excitation of |02 , but which naively are of the same order. There are two reasons why the |01 and |10 switching errors are considerably smaller: First, the matrix element coupling |01 and |10 is a factor of \u221a 2 smaller than that between |11 and |02 , and this factor gets squared in (76). And the second-but quantativitely more important-reason is that while level repulsion considerably enhances the |02 excitation [recall (82)], it (slightly) suppresses transitions between |01 and |10 .", "cite_spans": [], "ref_spans": []}, {"section": "H. Switching error and fidelity estimate", "text": "We can estimate the switching errors between the |01 and |10 channels during a CZ gate by using (76) with parameters", "cite_spans": [], "ref_spans": []}, {"section": "H. Switching error and fidelity estimate", "text": "and with \u2206 off /2\u03c0 = 1 GHz as before. The expression (86) for \u2206 on accounts for the level repulsion between |01 and |10 , which suppresses the switching error, in contrast with the strong enhancement indicated in (82). Considering, for example, the 99.9% CZ gate of Table  I designed for the \u03b7/2\u03c0 = 300 MHz qubit, we find that |A| 2 = 2.2\u00d710 \u22123 and", "cite_spans": [], "ref_spans": [{"start": 266, "end": 274, "text": "Table  I", "ref_id": "TABREF1"}]}, {"section": "H. Switching error and fidelity estimate", "text": "The total error in this case is E 1 = 2p sw . The estimate (87) for the switching error between |01 and |10 is more than an order-of-magnitude smaller than that between |11 and |02 , which is p sw = 1.2\u00d710 \u22123 (see Table I ).", "cite_spans": [], "ref_spans": [{"start": 214, "end": 221, "text": "Table I", "ref_id": "TABREF1"}]}, {"section": "I. Pulse shape errors", "text": "In Sec. III H we discussed the intrinsic error of the qubit-bus CZ gate-assuming an optimal pulse shape-and identified its dominant source as a nonadiabatic switching error E 2 . In this section we discuss and quantify the fidelity loss caused by pulse shape and auxiliary z rotation errors. By a pulse shape error we mean that the correct functional form (1) is seen by the qubit, but with values of the parameters t on and \u03c9 on that deviate from the optimal values. It is possible to develop simple analytic models for these error mechanisms (supported by numerical simulation) by noting that when the fidelity is very close to unity, the different error mechanisms present contribute independently and can be calculated separately. We then use these results to estimate the experimental pulse-control precision required during the implementation of a given 99.9% or 99.99% CZ gate to keep any accompanying pulse shape error less than the base 10 \u22123 or 10 \u22124 gate error. The simplest situation to consider is that where the correct values of t on and \u03c9 on are used, but where the local z rotation angles \u03b3 k (k = 1, 2) applied experimentally deviate from their optimal values by amounts \u03d5 k \u226a 1. We estimate the resulting fidelity loss by imagining that we have achieved a perfect CZ-class gate", "cite_spans": [], "ref_spans": []}, {"section": "I. Pulse shape errors", "text": "for some phase angles \u0398 k , but then apply z rotation angles", "cite_spans": [], "ref_spans": []}, {"section": "I. Pulse shape errors", "text": "that have errors \u03d5 k . From (50) we find that this leads to a leading order error E \u2261 1 \u2212 F ave given by", "cite_spans": [], "ref_spans": []}, {"section": "I. Pulse shape errors", "text": "Next we consider t on and \u03c9 on errors. An error in either t on or \u03c9 on has two consequences, the first is to modify the accumulated phases \u0398 k in (88), and the second is to cause population and phase errors on the |11 channel. Therefore we consider two types of pulse shape errors, the first where t on or \u03c9 on is changed with no compensating changes in the auxiliary z rotation angles, and the second where the \u03b3 k are reoptimized.", "cite_spans": [], "ref_spans": []}, {"section": "I. Pulse shape errors", "text": "In the first case, in which the error is clearly the largest, the resulting error is dominated by the z rotation angle error itself, which can be estimated from (90). Changing t on by an amount \u03b4t on , or \u03c9 on by an amount \u03b4\u03c9 on , changes the accumulated phase of the qubit (recall discussion of the qubit reference frame in Secs. III A and III C) by", "cite_spans": [], "ref_spans": []}, {"section": "I. Pulse shape errors", "text": "and that of the bus by", "cite_spans": [], "ref_spans": []}, {"section": "I. Pulse shape errors", "text": "We note that \u03b4t on and \u03b4\u03c9 on can be positive or negative here, and that the total gate time t gate is also (slightly) changed by \u03b4t on . The additional accumulated phase (91) can be regarded as a rotation angle error because, by assumption, it is not compensated by the applied z rotations (hence the notation). The error angle \u03d5 2 is zero because of our choice of the local clock/reference frame for a resonator. Therefore, an error in either t on or \u03c9 on with no compensating adjustment of the auxiliary z rotation angles leads to a leading-order fidelity loss of", "cite_spans": [], "ref_spans": []}, {"section": "I. Pulse shape errors", "text": "For an order-of-magnitude estimate it is sufficient to approximate \u03c9 on here by \u03c9 b and t on by t sudden on [see (4)], leading to the simpler estimate", "cite_spans": [], "ref_spans": []}, {"section": "I. Pulse shape errors", "text": "Considering the 99.9% CZ gate of Table I designed for the \u03b7/2\u03c0 = 300 MHz transmon, we estimate from (94) that a 10 ps error in t on (or a 1 MHz error in \u03c9 on /2\u03c0) would lead to a fidelity loss of 7.9\u00d710 \u22124 (or 4.9\u00d710 \u22124 ), whereas numerical simulation of the same error in QVN 4 , which includes all subdominant processes, yields 4.5\u00d7 10 \u22124 (or 1.2\u00d710 \u22123 ). Next we consider the case where there is an error in t on or \u03c9 on , but the auxiliary z rotation angles are optimal. Here the analysis closely follows that of Sec. III B, which is based on the truncated qubit-resonator model (9) . In this situation the fidelity loss is dominated by deviations from the ideal evolution", "cite_spans": [], "ref_spans": [{"start": 33, "end": 40, "text": "Table I", "ref_id": "TABREF1"}]}, {"section": "I. Pulse shape errors", "text": "of the |11 channel. Pulse shape errors will lead to both population and phase errors on the right-hand-side of (95). We therefore parameterize the nonideal CZ gate by", "cite_spans": [], "ref_spans": []}, {"section": "I. Pulse shape errors", "text": "In (96) we have assumed perfect auxiliary z rotations and have neglected the subdominant errors in the |00 , |01 , and |10 channels. The population error has been written in terms of a rotation angle error \u03b8, which will be interpreted (see below) as the deviation from 2\u03c0 of the rotation angle in the two-dimensional subspace spanned by |11 and |20 . The expression (96) does not include switching errors because we are evaluating the effect of pulse-shape errors on an otherwise perfect, large-\u03c3 CZ gate. The average fidelity loss E \u2261 1 \u2212 F ave associated with (96) is, to leading order,", "cite_spans": [], "ref_spans": []}, {"section": "I. Pulse shape errors", "text": "What remains is to express the controlled phase error \u03b4 and rotation error angle \u03b8 in terms of \u03b4t on and \u03b4\u03c9 on . This involves only the two channels |11 and |20 of the qubitresonator model (9) , and we will use the same small-\u03c3 approximation used in Sec. III B for our analysis of the |11 channel dynamics. In the {|11 , |20 } basis, (9) can be written as", "cite_spans": [], "ref_spans": []}, {"section": "I. Pulse shape errors", "text": "The eigenstates of (98) are", "cite_spans": [], "ref_spans": []}, {"section": "I. Pulse shape errors", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "I. Pulse shape errors", "text": "and the energies are", "cite_spans": [], "ref_spans": []}, {"section": "I. Pulse shape errors", "text": "Here we have used the expression (11) for \u03c9 on , which is appropriate for the model (98). The analysis below follows that of the |11 channel evolution given Sec. III B, except here we introduce a timing error \u03b4t on and a tuning error \u03b4\u03c9 on . Starting in the strongly detuned configuration with \u01eb \u2212 \u03c9 on \u226b g b in the eigenstate |11 \u2248 |11 , and quickly switching to \u01eb = \u03c9 on + \u03b4\u03c9 on , leaves the system in the state", "cite_spans": [], "ref_spans": []}, {"section": "I. Pulse shape errors", "text": "Here \u03b6 on \u2261 arctan(2 \u221a 2g b /\u03b4\u03c9 on ), and the eigenstates in (104) are for \u01eb = \u03c9 on + \u03b4\u03c9 on . Note that (104) reduces to (24) in the \u03b4\u03c9 on \u2192 0 limit. Evolution with \u01eb fixed at \u03c9 on + \u03b4\u03c9 on for a time", "cite_spans": [], "ref_spans": []}, {"section": "I. Pulse shape errors", "text": "would implement a 2\u03c0 rotation in the {|11 , |20 } subspace, returning to |11 with a phase shift that depends on \u03b4\u03c9 on . We intentionally introduce a t on pulse shape error and instead evolve for a time", "cite_spans": [], "ref_spans": []}, {"section": "I. Pulse shape errors", "text": "after which we detune and find the final state \u2212 e i\u03b4 cos \u03b8 2 11 + phase factor \u00d7 E \u03b8 20", "cite_spans": [], "ref_spans": []}, {"section": "I. Pulse shape errors", "text": "\u2248 \u2212 e i\u03b4 cos \u03b8 2 11 + phase factor \u00d7 E \u03b8 20 , (107)", "cite_spans": [], "ref_spans": []}, {"section": "I. Pulse shape errors", "text": "and", "cite_spans": [], "ref_spans": []}, {"section": "I. Pulse shape errors", "text": "These expressions are valid to leading order in \u03b4\u03c9 on or \u03b4t on , neglecting cross terms. Here E \u03b8 is the probability of leakage to |20 resulting from a t on error, which, as discussed above, causes a rotation error of angle \u03b8. An alternative estimate for \u03b8 (and hence E \u03b8 ) is", "cite_spans": [], "ref_spans": []}, {"section": "I. Pulse shape errors", "text": "which also gives (109) [after using the sudden limit result (4) for t on ]. Note that the leakage error E \u03b8 is independent of \u03b4\u03c9 on (to this order), enabling the phase \u03b4 to be intentionally adjusted by varying \u03c9 on only. ", "cite_spans": [], "ref_spans": []}, {"section": "I. Pulse shape errors", "text": "for small \u03b4, with alternative controlled phases [46] . Gates (approximately) of the form (111) with arbitrary-not necessarily small-values of \u03b4 can be implemented by varying both \u03c9 on and t on away from their optimal values.", "cite_spans": [], "ref_spans": []}, {"section": "I. Pulse shape errors", "text": "Referring again to the 99.9% CZ gate of Table I designed for the \u03b7/2\u03c0 = 300 MHz transmon, we estimate from (97), (108), and (109) that a 10 ps error in t on (or a 1 MHz error in \u03c9 on /2\u03c0) with optimal z rotations would lead to a fidelity loss of about 4.0 \u00d7 10 \u22126 (or 9.1\u00d7 10 \u22125 ), whereas numerical simulation of the same error in QVN 4 , which includes all subdominant processes, yields 3.0\u00d7 10 \u22126 (or 1.1\u00d710 \u22124 ). Finally, it is interesting to use the above estimates to bound the magnitude of the allowable t on and \u03c9 on errors, such that the resulting pulse shape errors (97) are subdominant to the 10 \u22123 or 10 \u22124 base gate error. This is done in Table III . For example, a 99.9% CZ gate from Table I with a t on error of 160 ps will have an additional intrinsic error of 10 \u22123 (and a total error of about 2\u00d710 \u22123 ). Current experimental limitations on the control of t on and \u03c9 on are considerably better than that required to suppress pulse shape errors below the 10 \u22124 level. Higher fidelities are also possible with the pulse shape (1). An example is provided in Table IV for the 300 MHz qubit. For this design we did not perform a separate g b optimization for this higher fidelity, but instead used the value from Table I optimized for the lower fidelities. The main focus of this paper is the CZ gate between qubit q 1 and the bus in the QVN 4 processor. Results for the other qubits are very similar, with the worst case being q 4 , because the detuning to memory during the gate is slightly smaller. We find that the intrinsic fidelity of the 99.9% CZ gate for the 300 MHz qubit given in Table I changes from 99.928% to 99.925% if qubit q 4 is used instead of q 1 .", "cite_spans": [], "ref_spans": [{"start": 40, "end": 47, "text": "Table I", "ref_id": "TABREF1"}, {"start": 652, "end": 661, "text": "Table III", "ref_id": "TABREF1"}, {"start": 1072, "end": 1080, "text": "Table IV", "ref_id": "TABREF1"}, {"start": 1225, "end": 1232, "text": "Table I", "ref_id": "TABREF1"}, {"start": 1602, "end": 1609, "text": "Table I", "ref_id": "TABREF1"}]}, {"section": "B. CZ between two qubits in QVN 4", "text": "In this section we explain how to perform a CZ gate between two qubits-or more precisely, between two memories-in the QVN architecture. Such an operation is not elementary, as it can be composed of the qubit-bus CZ combined with MOVE gates. (There are also proposals for the direct implementation of a qubit-qubit CZ gate in a QVN device [47, 59 ].) Figure 6 shows the experimental protocol for implementing the gate CZ 23 between qubits q 2 and q 3 , suppressing auxiliary z rotations, and with all data starting and ending in memory. This mode diagram shows the time-dependence of all 9 device frequencies. The color indicates whether the qubit or resonator would be in the ground state (blue) or possibly excited state (red) in the weakly coupled limit. Modes are colored red if there is a finite occupation of the |1 state (in the weakly coupled limit), for some choice of initial conditions. All qubits are initially parked at the strongly detuned frequency of 10 GHz. Horizontal lines 1-4 represent memories, and b is the bus. No red or red and blue lines with first-order or second-order couplings cross (to avoid Landau-Zener transitions), and no more than one qubit is occupied at any time (to avoid secondorder qubit-qubit interactions mediated by the bus).", "cite_spans": [{"start": 338, "end": 342, "text": "[47,", "ref_id": "BIBREF47"}], "ref_spans": []}, {"section": "B. CZ between two qubits in QVN 4", "text": "Beginning with the four memory registers in an arbitrary (possibly entangled) state, the bus is loaded by a 5 ns MOVE gate from m 3 \u2192 q 3 followed by a 10 ns MOVE to the bus. These are approximate gate times (time estimates for these gates are given in Sec. V and a concrete example is provided below). Qubit q 2 is then loaded and tuned to the frequency \u03c9 on determined by optimization. This central portion of the gate is close (but not exactly the same as) the qubit-bus CZ gate of Table I , which, for the purposes of comparison, is shown in Fig. 7 .", "cite_spans": [], "ref_spans": [{"start": 485, "end": 492, "text": "Table I", "ref_id": "TABREF1"}]}, {"section": "B. CZ between two qubits in QVN 4", "text": "We simulated the gate CZ 23 shown in Fig. 6 , using the 99.99% CZ of Table I for a 300 MHz qubit, and starting with the memory register in the GHZ state", "cite_spans": [], "ref_spans": [{"start": 69, "end": 76, "text": "Table I", "ref_id": "TABREF1"}]}, {"section": "B. CZ between two qubits in QVN 4", "text": "The ", "cite_spans": [], "ref_spans": []}, {"section": "B. CZ between two qubits in QVN 4", "text": "and the final state fidelity (overlap squared) is", "cite_spans": [], "ref_spans": []}, {"section": "B. CZ between two qubits in QVN 4", "text": "In addition to the 23 ns qubit-bus CZ gate, there are four MOVE to/from memory operations, each taking about 3.5 ns, and two MOVE to/from bus gates, each taking about 9 ns. There are also local z rotations (not shown) between each gate. A few remarks about the encouraging result (114) are in order: The seven elementary gates making up the CZ 23 operation are optimized individually to an error of about 10 \u22124 , and then combined without any additional optimization of the composite pulse sequence or control parameters, respecting the modularity required by scalable, gate-based quantum computation. And the total intrinsic error E \u2261 1 \u2212 F = 6\u00d710 \u22124 implied by (114) is consistent with a linear (incoherent) accumulation of errors with number of elementary steps E inc \u223c = 7\u00d710 \u22124 , but is not consistent with a quadratic (coherent) accumulation", "cite_spans": [], "ref_spans": []}, {"section": "B. CZ between two qubits in QVN 4", "text": "C. Beyond QVN: CZ gate between directly coupled superconducting qubits", "cite_spans": [], "ref_spans": []}, {"section": "B. CZ between two qubits in QVN 4", "text": "The main focus of this work is the CZ gate between a directly coupled qubit and resonator in a multi-qubit QVN device. However many of our results-especially the error analysis-will also be relevant for hardware designs incorporating pairs of directly coupled superconducting qubits, the system originally considered by Strauch et al. [42] . Here we summarize the principal differences between the qubit-bus CZ gate of Sec. III and the directly coupled qubit-qubit gate. For the latter case we assume qubits with anharmonic detunings \u03b7 1 and \u03b7 2 [defined as in (7)] and a purely transverse (off-diagonal) capacitive coupling with interaction strength g.", "cite_spans": [], "ref_spans": []}, {"section": "B. CZ between two qubits in QVN 4", "text": "The first difference concerns a frequency asymmetry of the qubit-bus gate. Recall from Sec. III B that the CZ gate is implemented by decreasing the qubit frequency \u01eb from a value far above \u03c9 b to (approximately)", "cite_spans": [], "ref_spans": []}, {"section": "B. CZ between two qubits in QVN 4", "text": "where \u03b7 > 0 is the qubit anharmonicity. By contrast, the qubit-qubit CZ gate can be implemented either by decreasing the frequency \u01eb 1 of qubit 1 from a value far above that of a second qubit with a (fixed) frequency \u01eb 2 , until", "cite_spans": [], "ref_spans": []}, {"section": "B. CZ between two qubits in QVN 4", "text": "which is directly analogous to (115), or from below by increasing to", "cite_spans": [], "ref_spans": []}, {"section": "B. CZ between two qubits in QVN 4", "text": "The conditions (116) and (117) specify the crossings of the bare |11 state with |20 and |02 , respectively (in the basis |q 1 q 2 ). The frequency asymmetry of the qubitbus gate is a consequence of the harmonic spectrum of the bus and can be understood from Fig. 3 , which shows that when |11 reaches the |02 crossing from below, |01 and |10 also become degenerate [as expected from (117) when \u03b7 2 \u2192 0]. This would result in unwanted phase shifts of the |01 and |10 channels, as well as large switching errors between them. The second major difference between the qubit-bus and qubit-qubit gates is that the additional anharmonicity in the latter case further suppresses the nonadiabatic switching errors and leads to better gate performance. This can be understood from the analysis of Sec. III H, noting that in the qubit-qubit case, adiabaticity of the |11 channel is protected by an energy gap of size \u03b7 1 + \u03b7 2 \u2212 \u221a 2g, where g is the qubit-qubit interaction strength. Let's estimate the |11 \u2192 |02 switching error E 2 for a qubit-qubit CZ gate at the upper frequency (116), with \u03b7 1 = \u03b7 2 = 2\u03c0 \u00d7 300 MHz, g = 45 MHz, and t ramp = 7 ns. In this application we use formula (76) with parameter values", "cite_spans": [], "ref_spans": [{"start": 258, "end": 264, "text": "Fig. 3", "ref_id": "FIGREF1"}]}, {"section": "B. CZ between two qubits in QVN 4", "text": "We note from (119) that the anharmonicity suppressing the |11 \u2192 |02 switching error is effectively doubled in the qubit-qubit system. With these parameters we obtain |A| 2 = 5.8\u00d710 \u22126 and p sw = 8.2\u00d710 \u22128 . Although the |11 \u2192 |02 switching error is greatly reduced in the qubit-qubit CZ gate, the actual gate fidelity does not fully benefit from this reduction. This is because the dominant intrinsic error in the qubit-qubit gate is the switching error E 1 between |01 and |10 , or the reverse, which is subdominant in the qubit-bus case (see Sec. III H). In fact, the |01 \u2194 |10 switching error estimate (87) also applies to the qubit-qubit system (with \u03b7 1 = \u03b7 2 = 2\u03c0\u00d7300 MHz, g = 45 MHz, and t ramp = 7 ns), resulting in an estimated minumim fidelity of", "cite_spans": [], "ref_spans": []}, {"section": "B. CZ between two qubits in QVN 4", "text": "V. SYSTEM OPTIMIZATION In this section we discuss an approach for choosing optimal QVN n device parameters. This is a complex global optimization problem that we will solve in a simple but approximate way, emphasizing the main ideas of the procedure instead of its most precise implementation.", "cite_spans": [], "ref_spans": []}, {"section": "B. CZ between two qubits in QVN 4", "text": "First we consider resonator frequencies. The QVN n processor includes n memory resonators, with frequencies \u03c9 m1 , \u03c9 m2 , \u00b7 \u00b7 \u00b7 . These need to be mutually detuned (to lift degeneracies), and for simplicity we space them by 100 MHz (a smaller value could be used). The band of memory frequencies itself needs to be well detuned from the bus to keep the idle error (to be discussed below) in check.", "cite_spans": [], "ref_spans": []}, {"section": "B. CZ between two qubits in QVN 4", "text": "Because the qubit frequency during a qubit-bus CZ gate must approach the bus frequency from above (Sec. IV C), the bus frequency must be below the memory band. The choice of bus frequency therefore determines the lowest transition frequency that needs to be accessible by a qubit. Specifically, the qubits will need to tune 500 MHz or so below the bus (see Fig. 6 ). However, the minimum transition frequency may be constrained by qubit design (in addition to other considerations). In the tunable-E J transmon, for example, this minimum frequency depends on the qubit anharmonicity \u03b7. Here we will choose a minimum qubit frequency and corresponding bus frequency appropriate for a 300 MHz transmon. This leads to our choice of 6.5 GHz for the bus frequency. Optimal resonator frequencies for smaller \u03b7 are unchanged, whereas for larger \u03b7 they need to be rigidly shifted upward in frequency. In particular, system frequencies for a 400 MHz transmon will be shifted upward in frequency by about 2 GHz. Apart from this large but simple change, we expect the system optimization results, such as g b values, to be valid for the 400 MHz case as well.", "cite_spans": [], "ref_spans": []}, {"section": "B. CZ between two qubits in QVN 4", "text": "The frequency \u03c9 off can be viewed as defining a boundary between MOVE and CZ gates, or between consecutive MOVE gates (see Fig. 6 , for example). It is also natural to perform single-qubit operations with microwave pulses at the qubit frequency \u03c9 off . If \u03c9 off is too low, the error of the (approximate two-parameter) MOVE to/from memory gate becomes significant (this is determined by the qubit-bus detuning because the dominant error is nonadiabatic leakage to the bus), whereas if \u03c9 off is too high the fidelity of the qubit-bus CZ degrades (because d\u01eb/dt increases). We find that 7.5 GHz works well. At least 500 MHz is required between \u03c9 off /2\u03c0 and the memory band to keep the MOVE errors (to/from the bus) under control. Thus we arrive at the memory frequencies given in Table II. Having obtained prospective resonator frequencies, we turn to couplings. The most frequently used gate is expected to be the MOVE to/from memory, which must be as fast as possible. Figure 6 includes four examples. The gate time for this operation is approximately", "cite_spans": [], "ref_spans": [{"start": 779, "end": 788, "text": "Table II.", "ref_id": "TABREF1"}]}, {"section": "B. CZ between two qubits in QVN 4", "text": "The first term is the \u03c0 rotation time, and the second and third are switching times (the detuning ramp can be fast because the qubit is unoccupied). Choosing g m /2\u03c0 = 100 MHz makes the first term 2.5 ns. It might be possible to increase g m further, but suppresssing the resulting idling error (see below) would require an even higher empty-qubit parking frequency. The value of t ramp is determined by the desired MOVE gate fidelity. Because the dominant error is nonadiabatic excitation of the bus, we can estimate it using our expression (76) for the switching error p sw , with G = g b , \u2206 on /2\u03c0 = 1.0 GHz, and \u2206 off /2\u03c0 = 1.8 GHz (corresponding to m 4 , the worst case). These values depend on our initial resonator frequency assignments. From Fig. 5 we obtain |A| 2 = 0.03 (9.8 \u00d7 10 \u22124 ) for a 1 ns (2 ns) ramp. Considering the largest (worst case) value for g b /2\u03c0 of 60 MHz gives p sw = 1.1\u00d710 \u22124 (3.5\u00d710 \u22126 ) for a 1 ns (2 ns) ramp. Thus we conclude that the MOVE to/from memory can be done in about 5 ns if g m /2\u03c0 = 100 MHz. (Here we assumed the simplest 2+1-parameter MOVE to/from memory gate, having two pulse-shape parameters and one auxiliary z rotation angle. It is also possible to implement this gate with even higher fidelity with 4+1 parameters [34] .)", "cite_spans": [], "ref_spans": []}, {"section": "B. CZ between two qubits in QVN 4", "text": "The bus coupling is found by the following \"goptimization\" procedure: Consider the set of discretized g b /2\u03c0 values, varying from 10 to 100 MHz in steps of 1 MHz. For each value of g b , calculate the minimum value of t ramp and the associated t gate required to achieve a target fidelity, say 99.9%. We do this by stepping through t ramp values, estimating the fidelity using (76) and (84) from Sec. III H, which is very efficient, then confirming through a full optimization on QVN 1 . We then obtain, for each g b , the gate time of a 99.9% CZ gate, or equivalently, the function t (99.9%) gate", "cite_spans": [], "ref_spans": []}, {"section": "B. CZ between two qubits in QVN 4", "text": "The function (123) gives the time required for a CZ gate with a given target fidelity as a function of g b . Strict goptimization requires choosing g b to minimize t gate , and this procedure leads to the best performance in any given situation. However, carrying this out leads to a different g b for each target fidelity. Fortunately, the curvature at the minimum in (123) is small and the simpler g b values reported in Table I , which are independent of the target fidelity and are also constrained to be multiples of 5 MHz, lead to very little performance loss, typically 1-2 ns in gate time.", "cite_spans": [], "ref_spans": [{"start": 423, "end": 430, "text": "Table I", "ref_id": "TABREF1"}]}, {"section": "B. CZ between two qubits in QVN 4", "text": "Having obtained prospective resonator frequencies and couplings, we choose the empty qubit parking frequency \u03c9 park to control the idle error", "cite_spans": [], "ref_spans": []}, {"section": "B. CZ between two qubits in QVN 4", "text": "where \u2126 ZZ is the effective \u03c3 z \u2297 \u03c3 z coupling frequency between a memory resonator and the bus, induced by their shared qubit [34] . The n-dependence in (124) assumes the worst case. Assuming \u03c9 park /2\u03c0 = 10 GHz, g b /2\u03c0 = 60 MHz (the worst case), and \u03b7/2\u03c0 = 400 MHz (also the worst case) leads to", "cite_spans": [], "ref_spans": []}, {"section": "B. CZ between two qubits in QVN 4", "text": "It will be necessary to keep (124) less than the faulttolerant threshold during a (potentially) long error correction cycle. If we assume t = 1 \u00b5s, the idle error in QVN 4 is 4.9 \u00d7 10 \u22124 , which is acceptable. Reducing the parked qubit frequency to 9.5 GHz (9.0 GHz) increases the idle error to 3.8\u00d710 \u22123 (7.3\u00d710 \u22122 ). We are now able to calculate the gate time of the MOVE to/from bus operation. The gate time is approximately \u03c0 2g b + t ramp + 1 ns,", "cite_spans": [], "ref_spans": []}, {"section": "B. CZ between two qubits in QVN 4", "text": "where the first term is between 4 and 8 ns for the bus couplings in Table I . As before, t ramp is determined by the desired gate fidelity. The dominant error is nonadiabatic transition to memory, which we estimate using (76) with G = g m , \u2206 on /2\u03c0 = 0.5 GHz (the worst case), and \u2206 off /2\u03c0 = 1.5 GHz. Note that this error is enhanced by the large value of g m . From Fig. 5 we obtain |A| 2 = 5.9\u00d710 \u22122 (1.6\u00d710 \u22122 ) for a 2 ns (3 ns) ramp. Then p sw = 2.4\u00d710 \u22124 (6.4\u00d710 \u22124 ) for a 2 ns (3 ns) ramp. Thus we conclude that the MOVE to/from bus takes between 7 and 12 ns, depending on the actual value of g b and on the desired fidelity.", "cite_spans": [], "ref_spans": [{"start": 68, "end": 75, "text": "Table I", "ref_id": "TABREF1"}]}, {"section": "B. CZ between two qubits in QVN 4", "text": "Finally, we confirm that the assumed qubit parameters are compatible with transmons. In the large E J /E C transmon regime, the qubit frequency \u01eb and anharmonicity \u03b7 are given by [4] ", "cite_spans": [], "ref_spans": []}, {"section": "B. CZ between two qubits in QVN 4", "text": "and \u03b7 = E C .", "cite_spans": [], "ref_spans": []}, {"section": "B. CZ between two qubits in QVN 4", "text": "We assume a split-junction flux-biased Cooper-pair box so that E J is tunable [43] . (Note that the tunable-E J transmon is sensitive to flux noise, which will degrade T 2 .) Combining (127) and (128) leads to the relation \u01eb = \u03b7( 8E J /E C \u2212 1) plotted in Fig. 8 for 300 and 400 MHz anharmonicity. Because E J /E C needs to be above about 50 to effectively suppress charge noise, we see that the 300 MHz transmon can have a transition frequency as small as 5.5 GHz, whereas the 400 MHz transmon has a minimum frequency of about 7.5 GHz. Our choice of bus frequency is indeed consistent with the 300 MHz transmon, whereas \u03c9 b /2\u03c0 and the entire spectrum of device frequencies would have to be increased by about 2 GHz for the 400 MHz transmon. ", "cite_spans": [], "ref_spans": []}, {"section": "VI. CONCLUSIONS", "text": "We have investigated the problem of CZ gate design for the superconducting QVN architecture based on a realistic, two-parameter filtered rectangular pulse (1). The gate operates by using the non-computational qubit |2 state as first proposed by Strauch et al. [42] . The main results are summarized in Table I . The use of interacting eigenfunctions as computational basis states, and the use of auxiliary z rotations on the qubits and bus are critical to obtaining this high performance. The ability to perform SU(2) operations on the bus resonator is nontrivial because they cannot be implemented directly with microwave pulses or frequency excursions; instead, they must be compiled into future qubit rotations.", "cite_spans": [], "ref_spans": [{"start": 302, "end": 309, "text": "Table I", "ref_id": "TABREF1"}]}, {"section": "VI. CONCLUSIONS", "text": "Our investigation is limited to and constrained by the pulse profile (1) . Fidelity optimization determines the amount of time to spend switching the qubit and how long to stay at the \"on\" frequency. We find that this pulse shape correctly captures the relevant pulse degreesof-freedom for fidelities up to about 99.99%. For higher fidelity gates, which are slower and which would require larger coupling, alternative few-parameter pulse shapes where most of the time is spent switching, could become competitive with (1). Although we are able to obtain fidelities well above 99.99% with profile (1), it is possible that alternative few-parameter pulse shapes would be able to achieve the same intrinsic fidelity in less gate time.", "cite_spans": [], "ref_spans": []}, {"section": "VI. CONCLUSIONS", "text": "One can also consider more complex pulse shapes with many control parameters, which can achieve nearly perfect intrinsic fidelity in a time t gate (depending on g b ) significantly shorter than obtained with pulse shape (1). Egger et al. [59] have recently investigated this optimal control approach (using the gradient pulse shape engineering method of Khaneja et al. [60] ), and have obtained about a factor of two speedup for a qubit-qubit CZ gate similar to that of Sec. IV B. This approach clearly warrants further investigation and experimental implementation.", "cite_spans": [{"start": 238, "end": 242, "text": "[59]", "ref_id": "BIBREF59"}], "ref_spans": []}, {"section": "VI. CONCLUSIONS", "text": "We did not include the effects of decoherence (or flux noise) in this work. However, an order-of-magnitude estimate of the T 1 decay error E \u2248 t gate /T 1 suggests that it should be possible to demonstrate a 99.9% CZ gate with existing transmon qubits, which would be an important step towards the development of fault-tolerant quantum computation.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Superconducting circuits and quantum information", "authors": [{"first": "J", "middle": ["Q"], "last": "You", "suffix": ""}, {"first": "F", "middle": [], "last": "Nori", "suffix": ""}], "year": 2005, "venue": "Physics Today", "link": "10969948"}, "BIBREF4": {"title": "Quantum Inf. Process", "authors": [{"first": "A", "middle": ["A"], "last": "Houck", "suffix": ""}, {"first": "J", "middle": [], "last": "Koch", "suffix": ""}, {"first": "M", "middle": ["H"], "last": "Devoret", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Girvin", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Schoelkopf", "suffix": ""}], "year": 2009, "venue": "", "link": null}, "BIBREF47": {"title": "Single-step implementation of the controlled-Z gate in a qubit/bus/qubit device", "authors": [{"first": "A", "middle": [], "last": "Galiautdinov", "suffix": ""}], "year": "", "venue": "", "link": "118346224"}, "BIBREF48": {"title": "Two-qubit gate operations in superconducting circuits with strong coupling and weak anharmonicity", "authors": [{"first": "X.-Y", "middle": [], "last": "Lu", "suffix": ""}, {"first": "S", "middle": [], "last": "Ashhab", "suffix": ""}, {"first": "W", "middle": [], "last": "Cui", "suffix": ""}, {"first": "R", "middle": [], "last": "Wu", "suffix": ""}, {"first": "F", "middle": [], "last": "Nori", "suffix": ""}], "year": "", "venue": "", "link": "9233270"}, "BIBREF49": {"title": "Quantum codes on a lattice with boundary", "authors": [{"first": "S", "middle": ["B"], "last": "Bravyi", "suffix": ""}, {"first": "A", "middle": ["Y"], "last": "Kitaev", "suffix": ""}], "year": "", "venue": "", "link": "10722101"}, "BIBREF55": {"title": "The physical implementation of quantum computation", "authors": [{"first": "D", "middle": ["P"], "last": "Divincenzo", "suffix": ""}], "year": "", "venue": "", "link": "15439711"}, "BIBREF59": {"title": "Notes on creating a controlled-Z gate with GRAPE", "authors": [{"first": "D", "middle": [], "last": "Egger", "suffix": ""}, {"first": "S", "middle": ["T"], "last": "Merkel", "suffix": ""}, {"first": "F", "middle": ["K"], "last": "Wilhelm", "suffix": ""}], "year": "", "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "FIG. 1. Layout of the four-qubit QVN processor. The qi represent superconducting qubits capacitively coupled to memory resonators mi as well as a resonator bus b.", "type": "figure"}, "FIGREF1": {"text": "FIG. 3. (Color online) Energies of eigenstates |qb of a single qubit q coupled to a resonator bus b. Here \u03c9 b /2\u03c0 = 6.5 GHz, \u03b7/2\u03c0 = 300 MHz, and g b /2\u03c0 = 45 MHz. The time dependence of the qubit frequency during a CZ gate (solid black curve) is indicated at the top of the figure.", "type": "figure"}, "FIGREF2": {"text": "the condition i[S, H 0 ] + \u03b4H = 0, which is im- mediately solvable in the bare basis |q 1 q 2 \u00b7 \u00b7 \u00b7 m 1 m 2 \u00b7 \u00b7 \u00b7 b . Here q i , m i , b \u2208 {0, 1, 2, . . . }. Other efficient eigenfunc- tion approximation schemes are also possible.", "type": "figure"}, "FIGREF3": {"text": "can be obtained by reaching any point in the {CZ} plane and then performing auxiliary z rotations. And it is straightforward to confirm that [43]", "type": "figure"}, "FIGREF4": {"text": "0q 2 q 3 q 4 m 1 m 2 m 3 m 4 1 = 0q 2 q 3 q 4 m 1 m 2 m 3 m 4 1 CZ 1q 2 q 3 q 4 m 1 m 2 m 3 m 4 0 = 1q 2 q 3 q 4 m 1 m 2 m 3 m 4 0 CZ 1q 2 q 3 q 4 m 1 m 2 m 3 m 4 1 = \u2212 1q 2 q 3 q 4 m 1 m 2 m 3 m 4 1 , where q i , m i \u2208 {0, 1, 2, . . . }.", "type": "figure"}, "FIGREF5": {"text": "FIG. 4. Detuning pulse profile (75) for a single frequency switch.", "type": "figure"}, "FIGREF6": {"text": "FIG. 5. (Color online) |A| 2 versus switching time \u03c3 for indicated values of \u2206on and \u2206 off .", "type": "figure"}, "FIGREF8": {"text": "FIG. 6. (Color online) QVN 4 mode diagram for the CZ23 gate. Gaussian filtering of the pulse is not shown.", "type": "figure"}, "FIGREF9": {"text": "FIG. 8. (Color online) Transition frequency for transmon with 300 and 400 MHz anharmonicity.", "type": "figure"}, "TABREF0": {"text": "FIG. 2. Two-parameter CZ pulse profile", "type": "table"}, "TABREF1": {"text": "Optimal state-averaged process fidelity Fave for the Strauch CZ gate between qubit q1 and the bus, in the QVN 4 processor of Fig. 1. No decoherence or noise is included here. Specifications for 99.9% and 99.99% gates are provided for three values of qubit anharmonicity \u03b7. The parameters tramp and \u03c3 characterize the pulse switching time, and tgate is the total gate time excluding auxiliary z rotations. F |11 is the minimum fidelity. Data after double vertical lines give the nonadiabatic switching error and minimum fidelity estimates; these quantities are defined and discussed in Sec. III H.", "type": "table"}, "TABREF2": {"text": "", "type": "table"}, "TABREF3": {"text": "Device parameters used in this work.", "type": "table"}, "TABREF4": {"text": "", "type": "table"}, "TABREF5": {"text": "Optimal QVN 4 gate fidelity for a Strauch CZ gate between qubit q1 and the bus.IV. ADDITIONAL CZ GATES A. CZ between bus and qubit q4", "type": "table"}}}
{"paper_id": "18982789", "_pdf_hash": "426fea77b5562bc825d1471a53c4256f4edd5207", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Lipid peroxidation triggers neurodegeneration: a redox proteomics view into the Alzheimer disease brain", "authors": [{"first": "R", "middle": [], "last": "Sultana", "suffix": ""}, {"first": "M", "middle": [], "last": "Perluigi", "suffix": ""}, {"first": "Allan", "middle": [], "last": "Butterfield", "suffix": ""}, {"first": "D", "middle": [], "last": "", "suffix": ""}], "year": 2013, "venue": "Free Radic Biol Med", "link": "3982742"}, "BIBREF1": {"title": "Lipid oxidation and peroxidation in CNS health and disease: from molecular mechanisms to therapeutic opportunities", "authors": [{"first": "R", "middle": ["M"], "last": "Adibhatla", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "Hatcher", "suffix": ""}], "year": 2010, "venue": "Antioxid Redox Signal", "link": "16283910"}, "BIBREF2": {"title": "Chemistry and biochemistry of 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{"paper_id": "18983681", "_pdf_hash": "8fda77620cbfbf6f2fcdcde94fe0a8381d0f8485", "abstract": [{"section": "Abstract", "text": "We investigate the properties of astrophysical electromagnetic cascades in matter, photon gas and magnetic fields, and discuss similarities and differences between characteristics of electron-photon showers developed in these 3 substances. We apply the same computational technique based on solution of the adjoint cascade equations to all 3 types of cascades, and present precise numerical calculations of cascade curves and broad-band energy spectra of secondary electrons and photons at different penetration lengths.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Relativistic electrons -directly accelerated, or being secondary products of various hadronic processes -may result in copious \u03b3-ray production caused by interactions with ambient targets in forms of gas (plasma), radiation and magnetic fields. In different astrophysical environments \u03b3-ray production may proceed with high efficiency through bremsstrahlung, inverse Compton scattering and synchrotron (and/or curvature) radiation, respectively. Generally, \u03b3-ray production is effective when the cooling time that characterizes the rate of the process does not significantly exceed (i) the source (accelerator) age (ii) the characteristic time of non-radiative losses caused by adiabatic expansion of the source or particle escape and (iii) the cooling time of competing radiation mechanisms that result in low-energy photons outside the \u03b3-ray domain. As long as the charged particles are effectively confined in the \u03b3-ray production region, at some circumstances these condition could be fulfilled even in environments with a relatively low gas and photon densities or weak magnetic field. More specifically, the \u03b3-ray production efficiency could be close to 1 even when t rad \u226b R/c (R is the characteristic linear size of the production region, c is the speed of light). In such cases the secondary \u03b3-rays escape the source without significant internal absorption. Each of the above mentioned \u03b3-ray production mechanisms has its major \"counterpart\" -\u03b3-ray absorption mechanism of same electromagnetic origin resulting in electronpositron pair production in matter (the counterpart of bremsstrahlung), in photon gas (the counterpart of inverse Compton scattering), and in magnetic field (the counterpart of synchrotron radiation). The \u03b3-ray production mechanisms and their absorption counterparts have similar cross-sections, therefore the condition for radiation t rad \u2265 R/c generally implies small optical depth for the corresponding \u03b3-ray absorption mechanism, \u03c4 abs \u2264 1. But in many astrophysical scenarios, in particular in compact galactic and extragalactic objects with favorable conditions for particle acceleration, the radiation processes proceed so fast that t rad \u2265 R/c. At these conditions the internal \u03b3-ray absorption becomes unavoidable. If the \u03b3-ray production and absorption processes occur in relativistic regime, namely when (i) E \u03b3,e \u2265 10 3 m e c 2 in the hydrogen gas, (ii) E \u03b3,e \u01eb \u226b m 2 e c 4 in photon gas (often called Klein-Nishina regime; \u01eb is the average energy of the target photons), or (iii) (E \u03b3,e /m e c 2 )(H/H cr ) \u226b 1 in the magnetic field (often called quantum regime; H cr \u2243 4.4 \u00d7 10 13 G is the so-called critical strength of the magnetic field), the problem cannot be reduced to a simple absorption effect. In this regime, the secondary electrons produce new generation of high energy \u03b3-rays, these photons again produce electron-positron pairs, so the electromagnetic cascade develops.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The characteristics of electromagnetic cascades in matter have been comprehensively studied, basically in the context of interactions of cosmic rays with the Earth's atmosphere (see e.g. [1] ) as well as for calculations of performance of detectors of high energy particles (e.g. [2] ). The theory of electromagnetic cascades in matter can be applied to some sources of high energy cosmic radiation, in particular to the \"hidden source\" scenarios like massive black holes in centers of AGN or young pulsars inside the dense shells of recent supernovae explosions (see e.g. [3] ). Within another, so-called \"beam dump\" models (see e.g. Ref. [3, 5] ) applied to X-ray binaries, protons accelerated by the compact object (a neutron star or black hole), hit the atmosphere of the normal companion star, and thus result in production of high energy neutrinos and \u03b3-rays [4] . In such objects, the thickness of the surrounding gas can significantly exceed 100 g/cm 2 , thus the protons produced in the central source would initiate (through production of high energy \u03b3-rays and electrons) electromagnetic showers. These sources perhaps represent the \"best hope\" of neutrino astronomy, but they are generally considered as less attractive targets for gamma-ray astronomy. However, the \u03b3-ray emission in these objects is not fully suppressed. The recycled radiation with spectral features determined by the thickness (\"grammage\") of the gas shell, should be seen in \u03b3-rays in any case, unless the synchrotron radiation of secondary electrons dominates over the bremsstrahlung losses and channels the main fraction of the nonthermal energy into the sub gamma-ray domains.", "cite_spans": [{"start": 865, "end": 868, "text": "[4]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Introduction", "text": "The development of electromagnetic cascades in photon gas and magnetic fields is a more common phenomenon in astrophysics. In photon fields such cascades can be created on almost all astronomical scales, from compact objects like accreting black holes [6] [7] [8] [9] [10] , fireballs in gamma-ray bursts [11] and sub-pc jets of blazars [12] to large-scale (up to \u2265 100 kpc) AGN jets [13, 14] and \u2265 1 Mpc size clusters of galaxies [15] . Electromagnetic cascades in the intergalactic medium lead to formation of huge (\u2265 10 Mpc) nonthermal structures like hypothetical electron-positron pair halos [16] . Finally, there is little doubt that the entire Universe is a scene of continuous creation and development of electromagnetic cascades. All \u03b3-rays of energy \u2265 a few GeV emitted by astrophysical objects have a similar fate. Sooner or later they terminate on Hubble scales due to interactions with the diffuse extragalactic background. Since the energy density of 2.7 K CMBR significantly exceeds the energy density of intergalactic magnetic fields, these interactions initiate electron-photon cascades [17] . The superposition of contributions of \u03b3-rays from these cascades should constitute a significant fraction of the observed diffuse extragalactic background.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Bonometto and Rees [18] perhaps where the first who realized the astrophysical importance of development of electron-photon cascades supported by \u03b3-\u03b3 pair-production and inverse Compton scattering in dense photon fields. When the so called compactness parameter [19] ", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "3 ) (L is the luminosity and R is the radius of the source) is less than 10, then the cascade is developed in the linear regime, i.e. when the soft radiation produced by cascade electrons do not have a significant feedback effect on the cascade development. In many cases, including the cascade development in compact objects, this approximation works quite well.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The first quantitative study of characteristic of linear cascades in photon fields has been performed using the method of Monte Carlo simulations [20] . Generally, the kinetic equations for the cascade particles can be solved only numerically. However, with some simplifications it is possible to derive useful analytical approximations [7, 8] which help to understand the features of the steady-state solutions for cascades in photon fields.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The cascade development in the magnetic field is a key element to understand the physics of pulsar magnetospheres [21, 22] , therefore it is generally treated as a process associated with very strong magnetic fields. However, such cascades could be triggered in many other (at first glance unusual) sites like the Earth's geomagnetic field [23] [24] [25] , accretion disks of massive black holes [26] , etc. In general, the pair cascades in magnetic fields are effective when the product of the particle (photon or electron) energy and the strength of the field becomes close to the \"quantum threshold\" of about H crit m e c 2 \u2243 2 \u00d7 10 7 TeV \u00b7 G, unless we assume a specific, regular field configuration. An approximate approach, similar to the so-called approximation A of cascade development in matter [1] , has been recently applied by Akhiezer et al. [27] . Although this theory quite satisfactorily describes the basic features of photon-electron showers, it does not provide an adequate accuracy for quantitative description of the cascade characteristics [24] . Note that in both studies approximate cross-sections for magnetic bremsstrahlung and magnetic pair-production have been used, thus reducing the validity of the results to the limit EH \u226b 10 7 TeV \u00b7 G (E is the minimum energy of secondary particles being under consideration).", "cite_spans": [{"start": 340, "end": 344, "text": "[23]", "ref_id": "BIBREF40"}], "ref_spans": []}, {"section": "Introduction", "text": "As long as we are interested in the one-dimensional cascade development (which seems to be quite sufficient for many astrophysical purposes), all 3 types of cascades can be described by the same integro-differential equations like the ones derived by Landau and Rumer [28] , but in each case specifying the cross-sections of relevant interaction processes. The solution of these equations in a broad range of energies is however not a trivial task. In this paper we present the results of our recent study of cascade characteristics in 3 substances -matter, photon gas and magnetic field -with emphasis on the analysis of similarities and differences between these 3 types of cascades. For quantitative studies of these characteristics we have chosen the so-called technique of adjoint cascade equations. Although this work has been initially motivated by methodological and pedagogical objectives, some results are rather original and may present practical interest in certain areas of high energy astrophysics.", "cite_spans": [], "ref_spans": []}, {"section": "Technique of adjoint cascade equations", "text": "The results of this study are based on numerical solutions of the so-called adjoint cascade equations. The potential of this computational technique, in particular its possible applications to different problems of cosmic ray physics has been comprehensively described in Ref. [29] . Below we briefly discuss the main features of solution of the adjoint cascade equations. For our purposes it is quite sufficient to consider only the longitudinal development of electromagnetic cascades neglecting the emission angles of secondary particles and, thus, assuming that all cascade particles are moved along the shower axis. Besides, we neglect the differences in interactions of electrons and positrons, i.e. do not consider positron annihilation, both in flight and after thermalization in the ambient plasma. This is a quite good approximation as long as we are interested in \u03b3-ray energies exceeding \u03b1 \u22121 f m e c 2 \u2243 70 MeV (\u03b1 f = 1/137 is the fine structure constant). Under these assumptions, the system of adjoint cascade equations reads", "cite_spans": [{"start": 277, "end": 281, "text": "[29]", "ref_id": "BIBREF46"}], "ref_spans": []}, {"section": "Technique of adjoint cascade equations", "text": "The adjoint functions f (t, \u03b5) and g(t, \u03b5) in Eqs. (1) and (2) describe the contributions (averaged over random realizations of the cascade development) from cascade initiated by a primary electron (f ) or a photon (g) of energy \u03b5 (all energies are expressed in units m e c 2 ); t is the cascade penetration depth; \u03b5 th is the minimum energy of cascade particles being under consideration.", "cite_spans": [], "ref_spans": []}, {"section": "Technique of adjoint cascade equations", "text": "The parameter \u03bb \u03b1 in Eqs. (1) and (2) defines the mean free path length of cascade particles of type \u03b1 (\u03b1 = e or \u03b3). It can be expressed through the total cross-sections (\u03c3 \u03b1 ) of interaction with the ambient medium. In the most general case, when the medium consists of matter (M), magnetic field (F ) and photon gas (G),", "cite_spans": [], "ref_spans": []}, {"section": "Technique of adjoint cascade equations", "text": "where n are the number density of the matter atoms and the ambient photons, respectively. The parameters", "cite_spans": [], "ref_spans": []}, {"section": "Technique of adjoint cascade equations", "text": "are differential cross-sections over the energy \u03b5 \u2032 of the secondary particle of type \u03b2 (\u03b2 = e or \u03b3). They are normalized as", "cite_spans": [], "ref_spans": []}, {"section": "Technique of adjoint cascade equations", "text": "\u03b1\u03b2 are the mean multiplicities of secondary particles of type \u03b2 produced by a particle of type \u03b1.", "cite_spans": [], "ref_spans": []}, {"section": "Technique of adjoint cascade equations", "text": "Properties of the particle \"detector\" located at the depth t are defined by the right hand side functions F and G in Eqs. (1) and (2) and by the boundary conditions f (t = 0, \u03b5) and g(t = 0, \u03b5). For example, if the \"detector\" measures the number of cascade electrons above some threshold energy, \u03b5 \u2265 \u03b5 th , then", "cite_spans": [], "ref_spans": []}, {"section": "Technique of adjoint cascade equations", "text": "where H(x) = 1 for x \u2265 0 and H(x) = 0 for x < 0. Analogously, if the \"detector\" measures the number of cascade photons with energy \u03b5 \u2265 \u03b5 th , then", "cite_spans": [], "ref_spans": []}, {"section": "Technique of adjoint cascade equations", "text": "For solution of the adjoint cascade equations we use the numerical method proposed in Ref. [30] . To apply this approach to Eqs. (1) and (2) we introduce an increasing subsequence {\u03b5 k } = \u03b5 0 = \u03b5 th , \u03b5 1 , . . . , \u03b5 k , . . . of energy points, and corresponding values of adjoint functions {f k (t), g k (t)}. Let's write now the Lagrange polynomial interpolation formulae for an approximate presentation of functions f and g inside the energy intervals \u2206\u03b5 k = (\u03b5 k\u22121 , \u03b5 k ) for k = 1, 2, . . . through their values at the support points {\u03b5 k },", "cite_spans": [{"start": 91, "end": 95, "text": "[30]", "ref_id": "BIBREF47"}], "ref_spans": []}, {"section": "Technique of adjoint cascade equations", "text": "where n \u2261 n(k) = min(N, k) and N is the maximum available power of the Lagrange polynomial.", "cite_spans": [], "ref_spans": []}, {"section": "Technique of adjoint cascade equations", "text": "For the first k energy intervals \u2206\u03b5 k the support values from f 0 , g 0 to f k , g k are used; in this case the polynomial power n is equal to k. For intervals with", "cite_spans": [], "ref_spans": []}, {"section": "Technique of adjoint cascade equations", "text": "in the interpolation with use of the power n = N.", "cite_spans": [], "ref_spans": []}, {"section": "Technique of adjoint cascade equations", "text": "Let's adopt now \u03b5 = \u03b5 k in Eqs. (1) and (2), and present the integral members of these equations in the form of the sum over the energy intervals \u2206\u03b5 i (i = 1, 2, . . . , k):", "cite_spans": [], "ref_spans": []}, {"section": "Technique of adjoint cascade equations", "text": "Then, after some simple calculations, we find the following equations", "cite_spans": [], "ref_spans": []}, {"section": "Technique of adjoint cascade equations", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "Technique of adjoint cascade equations", "text": "The coefficients a jk , b jk , c ik and d jk can be expressed through cross-sections of relevant processes:", "cite_spans": [], "ref_spans": []}, {"section": "Technique of adjoint cascade equations", "text": "with \u03b4 js = 1 if j = s, and \u03b4 js = 0 if j = s.", "cite_spans": [], "ref_spans": []}, {"section": "Technique of adjoint cascade equations", "text": "Thus, this method allows us to reduce the integro-differential Eqs. (1) and (2) to the system of ordinary differential equations (10) . The solution of Eq. (10) can be obtained in two steps:", "cite_spans": [], "ref_spans": []}, {"section": "Technique of adjoint cascade equations", "text": "(1) for \u03b5 = \u03b5 0 = \u03b5 th in formulae (1) and (2), we find the following equations for functions f 0 (t) and g 0 (t)", "cite_spans": [], "ref_spans": []}, {"section": "Technique of adjoint cascade equations", "text": "(2) after solving Eqs. (14) we can calculate the functions f 1 (t), g 1 (t), because for k = 1 Eq. (10) contains only f 0 (t), g 0 (t), f 1 (t) and g 1 (t); after that one can find by the same way the functions", "cite_spans": [], "ref_spans": []}, {"section": "Technique of adjoint cascade equations", "text": "For a fixed value of k, we introduce an increasing subsequence of the depth", "cite_spans": [], "ref_spans": []}, {"section": "Technique of adjoint cascade equations", "text": "For each interval (t l\u22121 , t l ) one can evaluate f k,l , g k,l by solving Eq. (10) for which the values f k,l\u22121 , g k,l\u22121 serve as boundary conditions. This leads to", "cite_spans": [], "ref_spans": []}, {"section": "Technique of adjoint cascade equations", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "Technique of adjoint cascade equations", "text": "Note that for the homogeneous environment these relations are valid for an arbitrary value of \u03c4 l , otherwise they can be applied only for \u03c4 l \u226a t l .", "cite_spans": [], "ref_spans": []}, {"section": "Technique of adjoint cascade equations", "text": "The knowledge of f k,0 and g k,0 (these quantities can be calculated on the basis of boundary conditions like Eq. (6) or Eq. (7) ) and the multiple application of Eqs (15) - (17) allow to calculate quantities f k,l , g k,l for l = 1, 2, etc.", "cite_spans": [], "ref_spans": []}, {"section": "Technique of adjoint cascade equations", "text": "The approach of solution of adjoint cascade equations described above provides an accuracy better than a few per cent and gives results for an arbitrary region (\u03b5 th , \u03b5 max ) of the primary energy in just one run of calculations. Also we notice that the computational time consumed by this method does not exceed on average a few minutes for a 1 GHz PC type computer and increases only weakly (logarithmically) with the primary energy. In summary, the important feature of this technique is its flexibility to describe the cascade processes in 3 different substances. It allows large number of calculations with a good accuracy throughout very large energy intervals of both primary and secondary energies. This is an important condition for the quantitative analysis and for clear understanding of similarities and differences in cascade development in environments dominated by matter, photon gas or magnetic field.", "cite_spans": [], "ref_spans": []}, {"section": "Elementary processes", "text": "The above described technique requires specification of elementary processes that initiate and support the cascade development. If we are interested in the longitudinal development of cascades, the input should consist of total cross-sections of interactions and the differential cross-sections as functions of energy but integrated over the emission angles of secondary particles. In many astrophysical situations, especially at very high energies, this is a fair approximation, given the very small (of order \u223c m e c 2 /E \u226a 1) emission angles of secondary products. The one-dimensional treatment of the cascade development perfectly works, if electrons move along the lines of the regular magnetic field. Otherwise, the deviation of particles from the cascade core is determined by reflection of secondary electrons by magnetic inhomogeneities rather than the emission angles. In these cases the diffusion effects must be appropriately incorporated into the cascade equations. This question is beyond the present paper.", "cite_spans": [], "ref_spans": []}, {"section": "Elementary processes", "text": "All processes involved in the electromagnetic cascades are well known. The cross-sections of these processes have been calculated and comprehensively studied with very high precision within the quantum electrodynamics.", "cite_spans": [], "ref_spans": []}, {"section": "Elementary processes", "text": "In the case of cascades in matter we take into account the ionization losses and bremsstrahlung for electrons (positrons), and the pair production, Compton scattering and photoelectric absorption for photons. At extremely high energies the so-called Landau-Pomeranchuk-Migdal (LPM) effect that results in suppression of the bremsstrahlung and pair-production cross-sections, may have significant impact on the cascade development. The energy region where the LPM effect becomes noticeable, depends on the atomic number of the ambient matter. In the hydrogen dominated medium this energy region appears well beyond E \u2265 10 20 eV, therefore in many astrophysical scenarios the LPM effect can be safely ignored.", "cite_spans": [], "ref_spans": []}, {"section": "Elementary processes", "text": "Two pairs of coupled processes -the inverse Compton scattering and \u03b3-\u03b3 pair production in the photon gas and the magnetic bremsstrahlung (synchrotron radiation) and magnetic pair production in the magnetic field -determine the basic features of cascade produced in radiation and magnetic fields. At extremely high energies the higher order QED processes may compete with these basic channels. Namely, when the product of energies of colliding cascade particles (electrons or photons) E and the background photons \u01eb significantly exceed 10 5 \u2212 10 6 m 2 e c 4 , the processes \u03b3\u03b3 \u2192 e + e \u2212 e + e \u2212 [31] and e\u03b3 \u2192 e\u03b3e + e \u2212 [32] dominate over the single (e + , e \u2212 ) pair production and the Compton scattering, respectively. For example, in the 2.7 K CMBR the first process stops the linear increase of the mean free path of highest energy \u03b3-rays around 10 21 eV, and puts a robust limit on the mean free path of \u03b3-rays of about 100 Mpc. Analogously, above 10 20 eV the second process becomes more important than the conventional inverse Compton scattering. Because \u03b3\u03b3 \u2192 2e + 2e \u2212 and e\u03b3 \u2192 e\u03b3e + e \u2212 channels result in production of 2 additional electrons, they significantly change the character of the pure Klein-Nishina pair cascades. However, an effective realization of these processes is possible only at very specific conditions with an extremely low magnetic field and narrow energy distribution of the background photons.", "cite_spans": [], "ref_spans": []}, {"section": "Elementary processes", "text": "Because this study has methodological objectives, below we do not include these processes in calculations of cascade characteristics. This allows us to avoid unnecessary complications and make the analysis more transparent. For the same reason we do not include in this study the effect of the photon splitting [33] which becomes quite important in pulsars with magnetic field close to H crit = 4.4 \u00d7 10 13 G (see e.g. Ref. [22] ).", "cite_spans": [], "ref_spans": []}, {"section": "Total cross-sections", "text": "In Figs. 1,2 and 3 we show the photon-and pair-production cross-sections in hydrogen gas and in radiation and magnetic fields, respectively. The energies of electrons and \u03b3-rays are expressed in units of m e c 2 . Total cross-sections of the bremsstrahlung (\u03c3 br ) and pair production (\u03c3 p ) processes in hydrogen gas normalized to the asymptotic value (\u03c3 0 ) of the pair production cross-section at \u03b5 0 \u2192 \u221e. The bremsstrahlung cross-sections are calculated for secondary \u03b3-rays produced with energies exceeding (1) the pair-production threshold, \u03b5 th = 2; (2) the critical energy, \u03b5 th \u2243 700; (3) half of the energy of the primary electron, \u03b5 th = \u03b5 0 /2.", "cite_spans": [], "ref_spans": []}, {"section": "10", "text": "In Fig. 1 the total cross-sections for matter are presented. They are normalized to the asymptotic value of the pair production cross-section at \u03b5 0 \u2192 \u221e:", "cite_spans": [], "ref_spans": []}, {"section": "10", "text": "where Z is the charge of the target nucleus, r e is the classical electron radius. This actually implies introduction of the so-called radiation length Table 1 The asymptotic behaviour of the total cross-sections of electron and photon interactions at high energies.", "cite_spans": [], "ref_spans": []}, {"section": "10", "text": "Environment Matter Photon gas Magnetic field", "cite_spans": [], "ref_spans": []}, {"section": "10", "text": "has a meaning of the average distance over which the ultrarelativistic electron loses all but 1/e of its energy due to bremsstrahlung. The same parameter approximately corresponds to the mean free path of \u03b3-rays. Therefore, the cascade effectively develops at depths exceeding the radiation length. Usually the radiation length is expressed in units g/cm 2 . For the hydrogen gas X (M ) 0 = 63 g/cm 2 . The second important parameter that characterizes the cascade development is the so-called critical energy below which the ionization energy losses dominate over bremsstrahlung losses. In the hydrogen gas \u03b5 cr \u2243 700. Effective multiplication of particles due to the cascade processes is possible only at energies \u03b5 \u2265 \u03b5 cr . At lower energies electrons dissipate their energy by ionization rather than producing more high energy \u03b3-rays which would support further development of the electron-photon shower.", "cite_spans": [], "ref_spans": []}, {"section": "10", "text": "The bremsstrahlung differential cross-section has a 1/\u03b5 \u03b3 type singularity at \u03b5 \u03b3 \u2192 0 (\u03b5 \u03b3 is the energy of the emitted photon), but because of the hard spectrum of bremsstrahlung photons the energy losses of electrons are contributed mainly by emission of high energy \u03b3-rays. In Fig. 1 we show the bremsstrahlung total cross-sections calculated for 3 different values of minimum energy of emitted photons: \u03b5 th = 2, \u03b5 cr and \u03b5 e /2. The first value corresponds to the cross-section of production of all \u03b3-rays capable to produce electron-positron pairs. The second value corresponds to the cross-section of production of \u03b3-rays produced above the critical energy, and thus capable to support the cascade. And finally, the third value corresponds to the crosssection of production of the \"most important\" \u03b3-rays which play the major role in the cascade development. It is seen from Fig. 1 that while for \u03b5 th = 2 the total cross-section of pair-production is an order of magnitude lower compared to the bremsstrahlung cross-section, for \u03b5 th = \u03b5 e /2 the cross-sections of two processes become almost identical at energies \u03b5 \u2265 100.", "cite_spans": [], "ref_spans": []}, {"section": "10", "text": "Both cross-sections grow significantly with energy until \u03b5 0 \u223c 10 3 . At higher energies the pair-production cross-section becomes energy-independent, but for \u03b5 th = 2 the bremsstrahlung cross-section continues to grow, although very slowly (logarithmically).", "cite_spans": [], "ref_spans": []}, {"section": "10", "text": "In Fig. 2 we show the total cross-sections of the inverse Compton scattering and pair-production for the mono-energetic and Planckian isotropic pho- In the mono-energetic radiation field the pair production has a strict kinematic threshold at \u03ba 0 = 1. At small values of \u03ba 0 \u2264 2 the cross-section rapidly increases with \u03ba 0 achieving its maximum of about \u2243 0.2\u03c3 T at \u03ba 0 \u2243 3.5\u22124, and decreases with further increase of \u03ba 0 as \u221d (\u03ba 0 \u00b7 ln\u03ba 0 ) \u22121 . Thus in this regime the pair-production cross-section behaves quite similar to the Compton scattering in the Klein-Nishina regime, but its absolute value is higher by a factor of 1.5.", "cite_spans": [], "ref_spans": []}, {"section": "10", "text": "In the case of interactions of electrons and photons with the magnetic field it is more convenient to introduce, instead of standard total cross-sections, the interaction probabilities [24] . But in the literature this parameter is still formally called as cross-section. These probabilities normalized to the strength of the magnetic field are shown in Fig. 3 . The probabilities of both processes -photon production by electrons (synchrotron radiation) and pair production by photons -depend only on the parameter \u03c7 0 = \u03b5 0 H/H cr , where H is the component of magnetic field intensity perpendicular to the velocity of the particle. The parameter \u03c7 0 = H/H cr \u03b5 0 is an apparent analog of the parameter . Table 2 The singularities in the differential cross-sections of cascade processes.", "cite_spans": [], "ref_spans": [{"start": 354, "end": 360, "text": "Fig. 3", "ref_id": "FIGREF3"}]}, {"section": "Elementary process Singularity point Behaviour", "text": "Bremsstrahlung", "cite_spans": [], "ref_spans": []}, {"section": "Elementary process Singularity point Behaviour", "text": "Pair production in photon gas", "cite_spans": [], "ref_spans": []}, {"section": "Elementary process Singularity point Behaviour", "text": "Pair production in photon gas", "cite_spans": [], "ref_spans": []}, {"section": "Elementary process Singularity point Behaviour", "text": "Synchrotron radiation", "cite_spans": [], "ref_spans": []}, {"section": "Elementary process Singularity point Behaviour", "text": "While the probability of the synchrotron radiation at \u03c7 0 \u226a 1 is constant, the probability of the pair production drops dramatically below \u03c7 0 = 1. After achieving its maximum at \u03c7 0 \u2243 10, the probability of the pair production decreases with \u03c7 as \u221d \u03c7", "cite_spans": [], "ref_spans": []}, {"section": "Elementary process Singularity point Behaviour", "text": ". The same behaviour at large \u03c7 has also the probability of synchrotron radiation, but the absolute value of the latter always exceeds by a factor of 3 the probability of the pair production. Table 3 The mean portion of primary energy (\u03b5 \u03b3 /\u03b5 0 ) transferred to the secondary photon in the inverse Compton scattering (ics) and the synchrotron radiation (syn) processes via the values of parameters \u03ba 0 = \u03b5 0 \u03c9 0 and \u03c7 0 = \u03b5 0 H/H cr , respectively. Table 4 The mean portion of primary energy (\u03b5 e /\u03b5 0 ) transferred to the leading secondary particle for the processes of pair production in a mono-energetic photon gas (G) and in the magnetic field (F ) via the values of parameters \u03ba 0 = \u03b5 0 \u03c9 0 and \u03c7 0 = \u03b5 0 H/H cr , respectively. ", "cite_spans": [], "ref_spans": []}, {"section": "Differential cross-sections of cascade processes", "text": "The differential cross-sections of cascade processes are presented in Figs. 4,5 and 6. The bremsstrahlung and pair-production cross-sections are from Ref. [34, 35] . The cross-sections for the inverse Compton scattering and pair production in the mono-energetic isotropic photon field are from Ref. [35] and Ref. [36] , respectively. The cross-sections of processes in the magnetic field are from Ref. [27] .", "cite_spans": [{"start": 155, "end": 159, "text": "[34,", "ref_id": "BIBREF52"}], "ref_spans": []}, {"section": "Differential cross-sections of cascade processes", "text": "All three cross-sections of pair-production are symmetric functions in respect to the point x = \u03b5 e /\u03b5 0 = 0.5. The photon production processes are asymmetric functions. The bremsstrahlung, synchrotron radiation, the inverse Compton scattering and the pair production in the photon gas have singularities. The location of singularities and the cross-section behaviour near the singularity points are summarized in Table 2 .", "cite_spans": [], "ref_spans": []}, {"section": "Differential cross-sections of cascade processes", "text": "The character of cascade development is largely determined by the fraction of energy of electrons and photons lost per interaction. In Table 3 we present mean fractions of the electron energy transferred to the secondary photons in the inverse Compton and synchrotron radiation processes at different values of \u03ba 0 and \u03c7 0 . In the classical regime (\u03ba 0 \u226a 1 and \u03c7 0 \u226a 1) the mean energy lost by the electron per interaction is very small, \u2206\u03b5/\u03b5 \u226a 1. In the \"quantum\" regime (\u03ba 0 \u226b 1 and \u03c7 0 \u226b 1) the interactions have a catastrophic character; the secondary photons get a significant fraction of the energy of parent electrons. In the photon gas at \u03ba 0 \u226b 1 this fraction exceed 0.5, approaching asymptotically to 1. In the magnetic field the energy transfer is smaller; at \u03c7 0 \u223c 1 it is approximately 0.1, and asymptotically approaches to 1/4 at extremely large \u03c7 0 .", "cite_spans": [], "ref_spans": []}, {"section": "Differential cross-sections of cascade processes", "text": "The pair production processes in all 3 substances have (by definition) catastrophic character (the photon always disappears). Since the differential spectra of secondary electrons are quite flat with increase towards the maximum energy \u03b5 e \u2192 \u03b5 \u03b3 (in the ultrarelativistic regime), these processes proceed with formation of leading electron with energy x = \u03b5 e /\u03b5 \u03b3 \u2192 1 in the photon gas and somewhat smaller (\u2243 0.8) in the magnetic field (see Table 4 ). ", "cite_spans": [], "ref_spans": []}, {"section": "Cascades", "text": "In this section we discuss and compare the so-called cascade curves and the energy spectra of electrons and photons for showers produced in matter, photon gas and magnetic field. ", "cite_spans": [], "ref_spans": []}, {"section": "Cascade curves", "text": "The cascade curve N \u03b2 (t, \u03b5 0 , \u03b5 th ) describes the average number of cascade electrons (\u03b2 = e) or photons (\u03b2 = \u03b3) above \u03b5 th , as a function of the penetration depth t.", "cite_spans": [], "ref_spans": []}, {"section": "Matter", "text": "In Fig. 7 we show the cascade curves for electrons calculated for different values of the primary (\u03b5 0 ) and threshold (\u03b5 th ) energies using the adjoint equation technique. For comparison we also show the cascade curves calculated within the approximation A of the analytical theory of electromagnetic cascades [1] (valid for \u03b5 th \u226b \u03b5 cr ), as well as the cascade curves obtained by Monte Carlo simulations using the ALTAI code [37] . The results obtained by 3 different methods are in a good agreement with each other.", "cite_spans": [], "ref_spans": [{"start": 3, "end": 9, "text": "Fig. 7", "ref_id": "FIGREF11"}]}, {"section": "Matter", "text": "One of the basic parameters characterizing the cascade development is the depth t m (expressed in units of radiation length X (M ) 0", "cite_spans": [], "ref_spans": []}, {"section": "Matter", "text": ") at which the cascade curve achieves its maximum. Generally t m grows logarithmically with the primary energy. In particular, for light materials (with the nucleus charge number Z \u2264 10) and for \u03b5 0 \u226b \u03b5 cr , the parameter t m for electrons of a cascade initiated by a primary photon can be approximated as [1] : t e m \u2243 ln(\u03b5 0 /\u03b5 th ) for \u03b5 th \u226b \u03b5 cr ; t m \u2243 ln(\u03b5 0 /\u03b5 cr ) for \u03b5 th \u2192 0.", "cite_spans": [], "ref_spans": []}, {"section": "Matter", "text": "The primary electron interacts with matter somewhat earlier than the primary \u03b3-ray (see Fig. 1 ), therefore t Another important parameter is the total number of electrons at the shower maximum: N max = N e (t m , \u03b5 0 , \u03b5 th ). This number is approximately proportional to the primary energy. In the energy region \u03b5 th \u226b \u03b5 cr the electron number", "cite_spans": [], "ref_spans": []}, {"section": "Matter", "text": "th ; however it does not depend on \u03b5 th , if \u03b5 th \u2192 0.", "cite_spans": [], "ref_spans": []}, {"section": "Matter", "text": "In Fig. 8 we present the ratio of the number of the cascade photons to electrons as a function of the penetration depth. For \u03b5 th \u226b \u03b5 cr , the number of cascade photons N \u03b3 is comparable to the electron number N e . At small threshold energies, (\u03b5 th \u226a \u03b5 cr ) the number of \u03b3-rays considerably exceeds the number of electrons. This is explained by the break of symmetry between the electrons and \u03b3-rays caused by ionization losses of electrons.", "cite_spans": [], "ref_spans": [{"start": 3, "end": 9, "text": "Fig. 8", "ref_id": "FIGREF12"}]}, {"section": "Photon gas", "text": "For description of the cascade development in the mono-energetic photon gas it is convenient to introduce, analogously to the cascade in matter, the radiation length X (G) 0 in the following form", "cite_spans": [], "ref_spans": []}, {"section": "Photon gas", "text": "where n", "cite_spans": [], "ref_spans": []}, {"section": "Photon gas", "text": "is the number density of photons. Apparently, X (G) 0 corresponds, with accuracy up to logarithmic terms, to the mean free path of \u03b3-rays in the photon field at \u03ba 0 \u226b 1.", "cite_spans": [], "ref_spans": []}, {"section": "Photon gas", "text": "Note that unlike to the radiation length in matter, the primary energy enters, through the parameter \u03ba 0 = \u03b5 0 \u03c9 0 , in X (G) 0 . Obviously, for the ambient photon gas with a broad band energy distribution this parameter becomes meaningless. At the same time in a narrow band radiation fields, e.g. with Planckian distribution, this parameter can work effectively by substitutin\u1e21 \u03c9 0 \u2248 3kT /m e c 2 . Note that for the black-body radiation the density of photons is determined by temperature, therefore (22) In particular, in the 2.7 K CMBR X (BB) 0", "cite_spans": [], "ref_spans": []}, {"section": "Photon gas", "text": "The results shown in Fig. 9 are cascade curves of electrons and photons in the blackbody photon gas calculated for the fixed value of \u03ba th = \u03b5 th\u03c90 = 1 corresponding to the threshold energy of cascade particles, \u03b5 th = m e c 2 /3kT , but for different values of the parameter \u03ba 0 , i.e. for different primary photons energies \u03b5 0 = \u03ba 0 \u00b7 m e c 2 /3kT .", "cite_spans": [], "ref_spans": [{"start": 21, "end": 27, "text": "Fig. 9", "ref_id": "FIGREF13"}]}, {"section": "Photon gas", "text": "We can see that the depth t m of the shower maximum measured in units of radiation length X linear decrease of the cross-sections and correspondingly by the increase of mean free path of electrons and \u03b3-rays interacting with the ambient photons in the Klein-Nishina (quantum) regime (see Fig. 2 ).", "cite_spans": [], "ref_spans": []}, {"section": "Photon gas", "text": "The number of cascade particles in the Klein-Nishina regime increases with \u03b5 0 slowly. Even near the shower maximum this number does not exceed a few particles. This is explained by an extremely high efficiency of conversion of energy of the photon to the leading electron at \u03b3-\u03b3 interactions, and vice versathe electron energy to the upscattered photon at the Compton scattering (see Figure 5 and Tables 3,4) . As a result, the energy of the second (secondary) particle appears too small for noticeable contribution to the cascade development. Since in this regime the cross-sections of the Compton scattering and photon-photon pair production are quite similar, the cascade process in the zeroth approximation can be considered as propagation of a single composite \u03b3/e \u2032\u2032 particle which spends 2/5 of its time in the \"\u03b3 state\" and 3/5 in the \"electron state\" (these times are determined by the ratio 1.5 of the corresponding cross-sections in the Klein-Nishina limit). Fig. 10 illustrates dependence of the cascade curve on the threshold energy \u03b5 th with the corresponding parameter \u03ba th below and above 1. With reduction of \u03ba th , the cascade curves of both \u03b3-rays and electrons increase, especially in the regime of \u03ba th \u2264 1. This has a simple explanation. Although in this (Thompson) regime of scattering the cross-section is large, the energy transferred to the secondary photon is quite small (see Table 3 ). Consequently, the mean free path of these electrons increases with reduction of their energy as 1/\u03b5. These electrons produce large number of \u03b3-rays with energy below the effective pairproduction threshold 3 , which therefore penetrate very large distances without interacting with the ambient background radiation. Consequently, the number of these photons remains almost constant. Following to Ref. [24] we express the depth of penetration of cascade particles in units of the radiation length in the magnetic field", "cite_spans": [], "ref_spans": [{"start": 385, "end": 393, "text": "Figure 5", "ref_id": "FIGREF8"}, {"start": 971, "end": 978, "text": "Fig. 10", "ref_id": "FIGREF4"}]}, {"section": "Magnetic field", "text": "where \u03c7 0 = \u03b5 0 H/H cr . Similar to the cascade in the photon gas, the radiation length in the magnetic field depends on the primary energy, but in this case the dependence is slower, X [24] are also shown (dashed curves). Fig. 11 illustrates dependence of cascade curves on the primary energy in a deep quantum regime with the threshold value of the parameter \u03c7 th = 10 3 . It is seen that the location of the cascade curve maximum t m ranges within 2 \u00f7 3 radiation lengths. In geometrical units this implies that the position of the cascade curve maximum increases with energy proportional to \u03b5 1/3 0 . The maximum electron number, N m , grows with \u03b5 0 as \u223c \u03b5 0.7 0 . Thus, the cascade development in the magnetic field in the quantum regime is somewhat intermediate between the cascades in matter and the photon gas.", "cite_spans": [], "ref_spans": [{"start": 223, "end": 230, "text": "Fig. 11", "ref_id": "FIGREF15"}]}, {"section": "Magnetic field", "text": "In Fig. 12 we present the cascade curves of electrons and photons for different values of the threshold energy \u03b5 th . It is seen that in the regime \u03c7 th \u226a 1 the cascade curves have a behaviour quite similar to that for the cascade curves in the photon gas shown in Figure 10 . This can be explained by similarities of the synchrotron radiation and the Compton scattering in the non-quantum regime. In both cases the electrons suffer a large number of collisions but with small energy transfer to secondary photons. In addition, in both cases \u03b3-rays stop to interact effectively with the ambient medium. Table 5 demonstrates the dependence of the N \u03b3 /N e ratio on \u03c7 th and t. It The corresponding values for \u03c7 th are presented in Table 5 . Table 5 The ratio N \u03b3 /N e for cascade curves presented in Figure 12 . behaves quite similar to cascades in matter. Particularly, for large threshold energies \u03b5 th the electron and photon numbers are comparable; for small \u03b5 th the photon number is considerably larger, and the ratio N \u03b3 /N e increases with the depth.", "cite_spans": [], "ref_spans": [{"start": 3, "end": 10, "text": "Fig. 12", "ref_id": "FIGREF17"}, {"start": 265, "end": 274, "text": "Figure 10", "ref_id": "FIGREF4"}, {"start": 799, "end": 808, "text": "Figure 12", "ref_id": "FIGREF17"}]}, {"section": "Energy spectra of cascade particles", "text": "Compared to the cascade curves, the energy spectra of electrons and photons at different stages of the cascade propagation contain more circumstantial information about the shower characteristics. In Fig. 13 we show the energy spectra of cascade electrons and photons at different penetration depths in the hydrogen gas. At energies exceeding the critical energy, \u03b5 \u226b \u03b5 cr , the spectra of both electrons and photons are described by power-law dN/d\u03b5 \u223c \u03b5 \u2212\u03b1 , where the spectral index is function of the penetration depth. Near the shower maximum, \u03b1 \u22432 for both electron and photon spectra. With depth the spectra become steeper.", "cite_spans": [], "ref_spans": [{"start": 200, "end": 207, "text": "Fig. 13", "ref_id": "FIGREF3"}]}, {"section": "Energy spectra of cascade particles", "text": "Below the critical energy, the cross-sections of the bremsstrahlung and pairproduction processes are not sufficiently large to support the cascade development against the dissipative processes like ionization and Compton scattering. Thus the multiplication of cascade particles is dramatically reduced. The cooling time of electrons due to ionization losses is proportional to energy, therefore below the critical energy this process leads to significant hardening of the electron, and correspondingly also the photon spectrum that behaves as dN/d\u03b5 \u221d \u03b5 \u22121 .", "cite_spans": [], "ref_spans": []}, {"section": "Energy spectra of cascade particles", "text": "In Fig. 14 we show the differential energy spectra of cascade particles in the radiation field with Planckian type spectral distribution. These spectra are quite different from the ones that appear in the cascades developed in matter.", "cite_spans": [], "ref_spans": [{"start": 3, "end": 10, "text": "Fig. 14", "ref_id": "FIGREF7"}]}, {"section": "Energy spectra of cascade particles", "text": "In the high energy (Klein-Nishina) region, \u03ba = \u03b5\u03c9 0 \u226b 1, and for not very large depths (t \u2264 10 r.l.) the shape of the differential spectra of electrons and photons is quite insensitive to the depth (contrary to the cascade in matter). At these energies the differential spectra are characterized by slopes with indices between 1 and 1.5.", "cite_spans": [], "ref_spans": []}, {"section": "Energy spectra of cascade particles", "text": "At \u03ba \u223c 1 there exists a pronounced transition region where the energy spectra undergo dramatic changes. The reason for the appearance of the transition region is the change of the character of Compton scattering (from the Thompson to the Klein-Nishina regime) and the sharp reduction of the pair production cross-section. Obviously, a broader energy distribution of background photons would make this transition smoother and less pronounced. At low energies (\u03ba \u223c 1) the cascade development is not supported by pairproduction. Here we deal with an ensemble of photons not interacting with the environment and an ensemble of electrons continuously cooling down with the characteristic (Thompson) time t T \u223c 1/\u03b5. This results in standard electron spectra with spectral index \u03b1 = 2. During propagating into deeper layers of the photon gas, these electrons produce large number of low energy photons with energy spectrum dN \u03b3 /d\u03b5 \u221d \u03b5 \u22121.5 .", "cite_spans": [], "ref_spans": []}, {"section": "Energy spectra of cascade particles", "text": "For any finite depth t, electrons do not have enough time to be cooled down to energies \u03b5 \u2192 0. Therefore the electron spectrum drops dramatically below some energy\u03b5 e which decreases with depth as \u223c 1/t. This effect is clearly seen Fig. 14 . The corresponding response in the photon spectrum is also quite distinct. Below the break energy around \u223c \u03c9 0\u03b5 2 e , the photon spectrum becomes extremely hard, dN \u03b3 /d\u03b5 \u2248 const.", "cite_spans": [], "ref_spans": [{"start": 232, "end": 239, "text": "Fig. 14", "ref_id": "FIGREF7"}]}, {"section": "Energy spectra of cascade particles", "text": "The energy spectra of electrons and photons produced during the cascade development in the magnetic field are quite similar to the spectra of electromagnetic cascades in the radiation field with Planckian distribution of target photons. These spectra are shown in Fig. 15 . All features discussed above in the context of cascading in the photon gas, are clearly seen also in cascades developed in the magnetic field, if we express the penetration depths in units of radiation lengths, and the energies of electrons and photons in the form of products \u03b5\u03c9 0 and \u03b5(H/H cr ). The cascade spectra in radiation and magnetic fields are not, however, identical. For example, because of significant differences in the asymptotics of relevant cross-sections, \u03b3-ray spectra in the magnetic field in the quantum regime are flatter than the corresponding \u03b3-ray spectra in the photon gas in the Klein-Nishina regime (compare Figs. 14 and 15).", "cite_spans": [], "ref_spans": [{"start": 264, "end": 271, "text": "Fig. 15", "ref_id": "FIGREF8"}]}, {"section": "Mixed environment", "text": "In order to reveal peculiarities of the cascade development in different substances, in previous sections we limited our discussion to the \"clean\" environments dominated by matter, radiation or magnetic fields. The \"pure cascade\" concept is not only a convenient theoretical approximation. In fact, under certain realistic conditions and within limited energy regions, this could be the most likely realization of particle interactions with then ambient medium. The relativistic electron-photon cascades in the Earth's atmosphere, in the intergalactic medium and in pulsar magnetospheres are 3 characteristic examples of \"pure\" cascade developments in matter, photon gas and magnetic field, respectively.", "cite_spans": [], "ref_spans": []}, {"section": "Mixed environment", "text": "In some cases, however, \"parallel\" interactions of electrons and photons with 2 or 3 substances can proceed simultaneously and with comparable efficiencies. The outcome of the interference of several competing processes could be quite different and complex depending on relative densities of the ambient plasma, radiation and magnetic fields, as well as on the energy of primary particles. For example, interactions of \u2265 10 20 eV protons with 2.7 K CMBR leads to production of secondary electrons, positrons and \u03b3-rays of Table 6 Parameters of the mixed environment used for calculations of the cascade curves shown in Fig. 16 . H is the strength of the magnetic field, T is the temperature of the black-body radiation, w F and w G are energy densities of the magnetic field and black-body radiation, respectively. 21 eV (this could be the case, for example, of secondary products from decays of the socalled topological defects), then the synchrotron photons appear in the TeV energy range. The TeV \u03b3-rays effectively interact with the diffuse extragalactic infrared radiation, and trigger new, low energy electron-photon cascades. In both cases the synchrotron radiation changes the character of the cascade development in the radiation field, but cannot support its \"own\" cascade in the magnetic field.", "cite_spans": [], "ref_spans": [{"start": 619, "end": 626, "text": "Fig. 16", "ref_id": "FIGREF9"}]}, {"section": "Mixed environment", "text": "Below we briefly discuss a more interesting scenario, when the cascade develops both in the radiation and magnetic fields. Let's assume that a \u03b3-ray photon of energy E \u03b3 = 10 20 eV is injected into a highly magnetized low-density plasma with thermal radiation density comparable to the energy density of the magnetic field H 2 /8\u03c0. In principle such a situation can occur in the vicinity of central engines of AGN. Fig. 16 illustrates the impact of the magnetic field and the temperature of blackbody radiation on cascade curves. Five different combinations of these parameters presented in Table 6 have been analyzed. The minimum particle energy for the cascade curves was taken 5\u00d710", "cite_spans": [], "ref_spans": [{"start": 415, "end": 422, "text": "Fig. 16", "ref_id": "FIGREF9"}]}, {"section": "Mixed environment", "text": "11 eV, i.e. comparable or larger (for the assumed radiation temperatures) to the effective pair production threshold in the black-body radiation , E For the chosen parameters, the radiation length in the magnetic field is much smaller than the mean free path of primary \u03b3-rays in the photon field. At absence of magnetic field (parameter combination 2) primary \u03b3-rays penetrates with energy E \u2265 E th = 5 \u00b7 10 11 eV for showers initiated by a primary photon of energy E 0 = 10 20 eV in a mixed environment consisting of the magnetic field and the blackbody radiation. The calculations are performed for 5 combinations of parameters characterizing the target radiation and magnetic fields. These parameters are listed in Table 6 .", "cite_spans": [], "ref_spans": []}, {"section": "Mixed environment", "text": "very deep into the source without interacting with the ambient photon gas. Consequently, the cascade starts very late and remains as underdeveloped.", "cite_spans": [], "ref_spans": []}, {"section": "Mixed environment", "text": "The presence of a strong magnetic field makes the cascade development much more effective, which now is supported by magnetic pair production and synchrotron radiation. The cascade develops in this regime until the energy of \u03b3-rays is reduced down to the effective threshold of the magnetic pair production, E", "cite_spans": [], "ref_spans": []}, {"section": "Mixed environment", "text": "th \u2243 10 17 (H/100 G) \u22121 eV. Therefore, in the case of pure magnetic field we have quite simple and predictable cascade curves (parameter combination 1).", "cite_spans": [], "ref_spans": []}, {"section": "Mixed environment", "text": "The presence of photon gas changes significantly the character of cascade development. At energies above E (F ) th both electrons and \u03b3-rays interact mainly with magnetic field. When the cascade particles enter the energy interval determined by the pair-production thresholds in the radiation and magnetic fields, [E (G) th , E (F ) th ], the \u03b3-rays interact effectively with the photon gas, while the electrons continue to interact mainly with the magnetic field. Although for kT = 3 eV, the blackbody radiation density considerably exceeds the energy density of 100 G magnetic field (see Table 6 ), because of the Klein-Nishina effect the interactions of electrons with photon gas become significant only when the electrons are cooled down to energies \u2264 100 GeV. The mean free path of \u03b3-rays in the black-body radiation field has minimum around E (G) th . Therefore, \u03b3-rays start to interact intensively with the ambient photons at depths comparable with the mean free path \u039b min \u223c \u039b \u03b3 (E (G) th ). This results in a rapid growth of the electron cascade curve and reduction of the high energy photon cascade curve (parameter combinations 3-5). Due to the rapid synchrotron cooling, the mean free paths of very energetic electrons in the magnetic field are very short, therefore for each given depth the main source of these electrons are \u03b3-rays which can penetrate much deeper. On the other hand, due to the same synchrotron losses, the electrons cannot support reproduction of very high energy \u03b3-rays. Therefore, the at depths \u226b \u039b min both the electron and photon curves are suppressed.", "cite_spans": [], "ref_spans": []}, {"section": "Mixed environment", "text": "The increase of the temperature increases the energy density of the photon gas (\u221d T 4 ) and makes interactions of cascade particles with radiation more intensive. This results in faster absorption of cascade particles (parameter combination 4). The reduction of the magnetic field (parameter combination 5) leads to the increase of the magnetic radiation length, as well as to the increase of the magnetic pair production threshold. As a result, the cascade develops slower. Figure 17 illustrates the spectral evolution of cascade \u03b3-rays calculated for H = 100 G and two different temperatures of the black-body radiation, kT = 0.3 and 3 eV (parameter combinations 3 and 4). It is seen that at small depths (t \u2264 10 10 cm for the upper panel and t \u2264 10 8 cm for the bottom panel) the spectra are fully determined by interactions with the magnetic field. At these depths a \"standard\" power-law spectrum with \u03b1 = 1.5 is formed in a broad energy region below E (F ) th . At larger depths the interactions with the photon gas start to deform the shape of the spectrum. These interactions lead to absorption of photons above E (G) th . At the same time, synchrotron radiation of the photo-produced pairs appears in the energy region E \u2264 E (G) th . Thus, only the photons with energy below E (G) th can survive at large depths. The spectrum of these photons is close to power-law with photon index 1.8-1.9, i.e. steeper than the the canonical \u03b5 \u22121.5 cascade photon spectrum formed in the pure photon gas or pure magnetic field. This is explained by the break of symmetry between electrons and \u03b3-rays. While at late stages of the cas-cade development \u03b3-rays continue to produce high energy electron-positron pairs, the synchrotron cooling of these electrons does not anymore support the cascade, but rather destroys it.", "cite_spans": [], "ref_spans": [{"start": 475, "end": 484, "text": "Figure 17", "ref_id": "FIGREF11"}]}, {"section": "Mixed environment", "text": "Finally, in Fig. 18 we show the spectral evolution of cascade \u03b3-rays calculated for a less extreme combination of model parameters. Namely, compared to Fig. 17 , we assume a smaller energy for primary \u03b3-rays (E = 10 17 eV) and weaker magnetic field (H = 1 G). At these conditions the primary photons do not interact with the magnetic field. Instead, the cascade development starts with pair production in the radiation field. Nevertheless, we can see that many basic features, in particular the \u03b5 \u22122 type spectrum at low energies, are quite similar to the spectra shown in Fig. 17 ", "cite_spans": [], "ref_spans": [{"start": 12, "end": 19, "text": "Fig. 18", "ref_id": "FIGREF12"}, {"start": 152, "end": 159, "text": "Fig. 17", "ref_id": "FIGREF11"}, {"start": 573, "end": 580, "text": "Fig. 17", "ref_id": "FIGREF11"}]}, {"section": "Summary", "text": "In this study, the technique of adjoint cascade equations has been applied to investigate properties of electron-photon cascades in hydrogen gas and in ambient radiation and magnetic fields. We also have inspected the main features of cross-sections of relevant processes that initiate and support cascade developments in these substances.", "cite_spans": [], "ref_spans": []}, {"section": "Summary", "text": "The cascade curves of electrons and photons in the photon gas and magnetic field have features quite different from the cascade curves in matter. The energy spectra of cascade particles are also considerably different from the conventional cascade spectra in matter. The spectra for the magnetic field have properties intermediate between those for cascade spectra in matter and in the photon field. Although for certain astrophysical scenarios the development of cascades in \"pure\" environments can be considered as an appropriate and fair approximation, at some conditions the interference of processes associated with interactions of cascade electrons and \u03b3-rays with the ambient photon gas and magnetic field (or matter) can significantly change the character of cascade development, and consequently the spectra of observed \u03b3-rays. The impact is very complex and quite sensitive to the choice of specific parameters. Therefore each practical case should be subject to independent studies.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF1": {"title": "Handbuch der Physik Bd", "authors": [{"first": "J", "middle": [], "last": "Nishimura", "suffix": ""}], "year": 1967, "venue": "", "link": null}, "BIBREF2": {"title": "Electromagnetic Cascade Processes", "authors": [{"first": "I", "middle": [], "last": "Ivavenko", "suffix": ""}], "year": 1968, "venue": "", "link": null}, "BIBREF3": {"title": "Cosmic Rays and Particle Physics", "authors": [{"first": "T", "middle": ["K"], "last": "Gaisser", "suffix": ""}], "year": 1990, "venue": "", "link": "118086087"}, "BIBREF6": {"title": "Proc. 1976 DUMAND Summer Workshop", "authors": [{"first": "V", "middle": ["S"], "last": "Berezinsky", "suffix": ""}, {"first": "; D", "middle": [], "last": "Eichler", "suffix": ""}, {"first": "W", "middle": ["T"], "last": "Westrand", "suffix": ""}], "year": 1976, "venue": "", "link": null}, "BIBREF27": {"title": "Proc 22nd ICRC (Dublin)", "authors": [{"first": "I", "middle": ["P"], "last": "Ivanenko", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "Lagutin", "suffix": ""}], "year": 1991, "venue": "", "link": null}, "BIBREF40": {"title": "Voprosy atomnoy nauki i techniki", "authors": [{"first": "B", "middle": ["L"], "last": "Kanevsky", "suffix": ""}, {"first": "A", "middle": ["I"], "last": "Goncharov", "suffix": ""}], "year": 1999, "venue": "", "link": null}, "BIBREF46": {"title": "The Stochastic Theory of Transport of High Energy Particles", "authors": [{"first": "V", "middle": ["V"], "last": "Uchaikin", "suffix": ""}, {"first": "V", "middle": ["V"], "last": "Ryzhov", "suffix": ""}], "year": 1998, "venue": "", "link": null}, "BIBREF47": {"title": "Proc. of 16th ICRC", "authors": [{"first": "A", "middle": ["V"], "last": "Plyasheshnikov", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "Lagutin", "suffix": ""}, {"first": "V", "middle": ["V"], "last": "Uchaikin", "suffix": ""}], "year": 1979, "venue": "", "link": null}, "BIBREF52": {"title": "Quantum Electrodynamics", "authors": [{"first": "A", "middle": ["I"], "last": "Akhiezer", "suffix": ""}, {"first": "V", "middle": ["B"], "last": "Berestetskii", "suffix": ""}], "year": 1965, "venue": "", "link": null}}, "ref_entries": {"FIGREF1": {"text": "Fig. 1. Total cross-sections of the bremsstrahlung (\u03c3 br ) and pair production (\u03c3 p ) processes in hydrogen gas normalized to the asymptotic value (\u03c3 0 ) of the pair production cross-section at \u03b5 0 \u2192 \u221e. The bremsstrahlung cross-sections are calculated for secondary \u03b3-rays produced with energies exceeding (1) the pair-production threshold, \u03b5 th = 2; (2) the critical energy, \u03b5 th \u2243 700; (3) half of the energy of the primary electron, \u03b5 th = \u03b5 0 /2.", "type": "figure"}, "FIGREF2": {"text": "Fig. 2. Total cross-sections of the inverse Compton scattering and pair production. Two spectral distributions for the ambient photon gas are assumed -mono-energetic with energy \u03c9 0 (curves 1 and 3) and Planckian with the same mean photon energy \u03c9 0 \u2243 3kT /m e c 2 . ton fields, normalized to the Thompson cross section \u03c3 T = 8/3\u03c0r 2 e = 6.65 \u00d7 10 \u221225 cm 2 . Both cross sections depend on the product \u03ba 0 = \u03b5 0 \u03c9 0 of the primary (\u03b5 0 ) and ambient (\u03c9 0 = \u01eb/m e c 2 ) photon energies. At \u03ba 0 \u2192 0 the inverse Compton cross-section \u03c3 IC \u2192 \u03c3 T . At high energies it decreases with \u03ba 0 , as \u221d (\u03ba 0 \u00b7 ln\u03ba 0 ) \u22121 .", "type": "figure"}, "FIGREF3": {"text": "Fig. 3. Total cross-sections of the synchrotron radiation and magnetic pair production. Solid curves -our calculations; points -calculations of Anguelov et.al. [24].", "type": "figure"}, "FIGREF4": {"text": "syn 0.44 \u00b7 10 \u22122 0.033 0.118 0.241 0.250 0.250", "type": "figure"}, "FIGREF7": {"text": "Fig. 4. Differential cross-sections of the bremsstrahlung (upper panel) and pair production (bottom panel) processes in hydrogen. The cross-sections are normalized to one radiation length. The energies of primary electrons and \u03b3-rays \u03b5 0 are indicated at the curves.", "type": "figure"}, "FIGREF8": {"text": "Fig. 5. Differential cross-sections of the inverse Compton (upper panel) and pair production (bottom panel) processes for the case of a mono-energetic gas of ambient photons. The parameters \u03b5 \u03b3max , \u03b5 emin and \u03b5 emax are defined as \u03b5 \u03b3max = 4\u03b5 0 (\u03ba 0 /1 + 4\u03ba 0 ) and \u03b5 emin, emax = 0.5\u03b5 0 (1 \u2213 1 \u2212 1/\u03ba 0 ). Different values of the parameter \u03ba 0 = \u03b5 0 \u03c9 0 are indicated at the curves.", "type": "figure"}, "FIGREF9": {"text": "Fig. 6. Differential cross-sections of synchrotron radiation (upper panel) and the magnetic pair production (bottom panel) normalized to the total cross-sections of these processes. Different values of parameter \u03c7 0 = H/H cr \u03b5 0 are indicated at the curves.", "type": "figure"}, "FIGREF11": {"text": "Fig. 7. Cascade curves of electrons for showers initiated by primary electrons (solid curves) and photons (dashed curves). The calculations are performed for the following primary energies \u03b5 0 = 2 \u00b7 10 8 (curve 1), 2 \u00b7 10 7 (curve 2), 2 \u00b7 10 4 (curve 3) and the ratio \u03b5 th /\u03b5 cr = 125 (curves 1 and 2), 0.05 (curve 3). For comparison, the results derived from the analytical cascade theory [1] (boxes) and by simulations with the ALTAI code [37] (triangles) are also shown", "type": "figure"}, "FIGREF12": {"text": "Fig. 8. The depth dependence of the N \u03b3 /N e ratio for cascades initiated by primary electrons (solid curves) and photons (dashed curves). Primary energy \u03b5 0 = 2 \u00b7 10 8 ; \u03b5 th /\u03b5 cr = 0 (curves 1), 125 (curves 2).", "type": "figure"}, "FIGREF13": {"text": "Fig. 9. Cascade curves of electrons (upper panel) and photons (bottom panel) for showers produced in the Planckian gas of ambient photons by high energy photons. The results are obtained for \u03ba th = \u03b5 th\u03c90 = 1, and several values of \u03ba 0 = \u03b5 0\u03c90 indicated at the curves.", "type": "figure"}, "FIGREF14": {"text": "Fig. 10. Cascade curves of electrons (upper panel) and photons (bottom panel) for showers produced in the Planckian gas of ambient photons by high energy photons. The results are obtained for \u03ba 0 = \u03b5 0\u03c90 = 10 3 and for values of \u03ba th = \u03b5 th\u03c90 indicated at the curves.", "type": "figure"}, "FIGREF15": {"text": "Fig. 11 shows the cascade curves of electrons in the magnetic field obtained with the adjoint equation technique. The comparison with the Monte Carlo simulations [24] shows nice agreement between results obtained by two different methods.", "type": "figure"}, "FIGREF16": {"text": "Fig. 11. Cascade curves of electrons for showers initiated by primary electrons in the magnetic field. Different values (indicated at the curves) of the ratio of primary and threshold energies are assumed for the fixed \u03c7 th = \u03b5 th H/H cr = 10 3 . For comparison, the results obtained in Ref. [24] are also shown (dashed curves).", "type": "figure"}, "FIGREF17": {"text": "Fig. 12. Cascade curves of electrons (upper panel) and photons (bottom panel) for showers initiated by primary electrons (solid curves) and photons (dashed curves) in the magnetic field. Different values of the threshold energy (\u03b5 th ) are assumed for the fixed \u03b5 0 = 2 \u00b7 10 7 and H = 10 11 G. The \u03b5 0 /\u03b5 th ratios are indicated at the curves. The corresponding values for \u03c7 th are presented in Table 5.", "type": "figure"}, "FIGREF18": {"text": "Fig. 13. Differential energy spectra of electrons (solid curves) and photons (dashed curve) for cascades initiated in the hydrogen gas by a primary photon with energy \u03b5 0 = 2 \u00b7 10 8 . Different values of depths in units of the cascade maximum t m are shown at the curves.", "type": "figure"}, "FIGREF19": {"text": "Fig. 14. Differential energy spectra of cascade electrons (upper panel) and photons (bottom panel) in the cascade initiated by a primary photon (\u03ba 0 = 10 3 ) in the radiation field with Planckian spectral distribution. The spectra are calculated for different penetration depths indicated (in units of radiation lengths) at the curves.", "type": "figure"}, "FIGREF20": {"text": "Fig. 15. Differential energy spectra of cascade electrons (upper panel) and photons (bottom panel) in showers initiated in the magnetic field of intensity H = 10 11 G by a primary photon of energy \u03b5 0 = 2 \u00b7 10 7 . The spectra are calculated at different depths indicated (in units of radiation lengths) at the curves.", "type": "figure"}, "FIGREF21": {"text": "kT \u2243 10 11 (kT /1 eV) \u22121 eV.", "type": "figure"}, "FIGREF22": {"text": "Fig. 16. The cascade curves of electrons (upper panel) and photons (bottom panel) with energy E \u2265 E th = 5 \u00b7 10 11 eV for showers initiated by a primary photon of energy E 0 = 10 20 eV in a mixed environment consisting of the magnetic field and the blackbody radiation. The calculations are performed for 5 combinations of parameters characterizing the target radiation and magnetic fields. These parameters are listed in Table 6.", "type": "figure"}, "FIGREF23": {"text": "Fig. 17. Differential energy spectra of \u03b3-rays of the cascade initiated by a primary photon of energy E 0 = 10 20 eV in the compound environment consisting of a blackbody radiation of temperature T and a homogeneous magnetic field H=100 G. Upper panel -kT = 0.3 eV ; bottom panel -kT = 3 eV. The spectra are calculated at different depths (in cm) indicated at the curves.", "type": "figure"}, "FIGREF24": {"text": "Fig. 18. The same as in Fig. 17, but for the energy of primary photons E 0 = 10 17 eV and the magnetic field H = 1 G. The temperature of the black-body radiation is assumed 0.3 eV.", "type": "figure"}, "TABREF1": {"text": "energy \u2265 10 19 eV, which in their turn trigger electromagnetic cascades in the same radiation field. However, due to the synchrotron cooling of elec- trons this process would be significantly suppressed if the intergalactic mag- netic field exceeds 10 \u221210 G. The characteristic energy of synchrotron photons \u223c 5 \u00d7 10eV is too small for interactions with the diffuse photon fields on the Hubble scales. However, if the energy of electrons and/or photons injected into the intergalactic medium exceeds \u2265 10", "type": "table"}, "TABREF2": {"text": ".", "type": "table"}}}
{"paper_id": "18983926", "_pdf_hash": "d7856ed0d35a2f213a5958c4776fd62b787df6af", "abstract": [{"section": "Abstract", "text": "Summary A series of hydroxamates, which are not metalloprotease inhibitors, have been found to be selectively toxic to a range of transformed and human tumour cells without killing normal cells (fibroblasts, melanocytes) at the same concentrations. Within 24 h of treatment, drug action is characterized by morphological reversion of tumour cells to a more normal phenotype (dendritic morphology), and rapid and reversible acetylation of histone H4 in both tumour and normal cells. Two hydroxamates inhibited growth of xenografts of human melanoma cells in nude mice; resistance did not develop in vivo or in vitro. A third hydroxamate, trichostatin A, was active in vitro but became inactivated and had no anti-tumour activity in vivo. Development of dendritic morphology was found to be dependent upon phosphatase activity, RNA and protein synthesis. Proliferating hybrid clones of sensitive and resistant cells remained sensitive to ABHA, indicating a dominant-negative mechanism of sensitivity. Histone H4 hyperacetylation suggests that these agents act at the chromatin level. This work may lead to new drugs that are potent, and selective anti-tumour agents with low toxicity to normal cells.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "An alternative and perhaps more desirable approach is to selectively convert cancer cells to a differentiated, non-proliferating phenotype. This strategy has the potential to be tissue-specific and to avoid the genotoxic side-effects of current anticancer drugs Rifkind et al, 1996) . A few differentiating agents of relatively low potency have reached clinical trial (Beere and Hickman, 1993) , with retinoic acid showing promise for some lymphoid neoplasms. However, the success of this approach has not been fully explored due to the low potency and lack of selectivity for tumour cells of drugs in this class. Expression of many genes in a particular cell type are also affected by these non-selective agents, confounding mechanistic studies of cell arrest.", "cite_spans": [{"start": 262, "end": 282, "text": "Rifkind et al, 1996)", "ref_id": "BIBREF22"}, {"start": 368, "end": 393, "text": "(Beere and Hickman, 1993)", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "", "text": "Hexamethylene bisacetamide (HMBA) is one such differentiating agent that has low potency in various murine and human leukaemic and solid tumour cell lines . Nevertheless, it has produced remissions in patients with myelodysplastic syndrome and acute myoblastic leukaemia (Andreef et al, 1992) , although it suffers from rapid degradation (deacylation) in vivo and side-effects such as acidosis and neurotoxicity . The lack of tumour selectivity has been noted (Rowinsky et al, 1992) and combination with other agents has been suggested as a way of enhancing its activity. In murine erythroleukaemic cells, HMBA induces arrest in G1, translocation of protein kinase C (PKC) from the cytosol to the membrane, decrease in c-myb, c-myc and p53 proteins and increase in c-fos mRNA Rifkind et al, 1996) . A transient increase in hypophosphorylated retinoblastoma protein pRB was found 12 h after treatment, followed by enhanced production of the hyperphosphorylated form ppRB, p107 mRNA, and protein during the next 2-3 days Marks et al, 1994) . Binding of the key cell cycle-regulating transcription factor E2F to its DNA motif was inhibited by HMBA within 8 h (Richon and Ventaperez, 1996) . HMBA also inhibits poly(ADP)ribosylation (Thyberg et al, 1995) and expression of cyclin A (Nakamura et al, 1995) , and causes hypomethylation of DNA (Palliti et al, 1993) .", "cite_spans": [{"start": 460, "end": 482, "text": "(Rowinsky et al, 1992)", "ref_id": "BIBREF23"}, {"start": 776, "end": 796, "text": "Rifkind et al, 1996)", "ref_id": "BIBREF22"}, {"start": 1019, "end": 1037, "text": "Marks et al, 1994)", "ref_id": "BIBREF8"}, {"start": 1156, "end": 1185, "text": "(Richon and Ventaperez, 1996)", "ref_id": "BIBREF19"}, {"start": 1229, "end": 1250, "text": "(Thyberg et al, 1995)", "ref_id": "BIBREF27"}, {"start": 1278, "end": 1300, "text": "(Nakamura et al, 1995)", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "", "text": "Recently, a number of HMBA-related agents that contain one or more hydroxamate groups have been examined as differentiating agents (Breslow et al, 1991; Schroy et al, 1994; Parsons et al, 1997) . This behaviour is different from that known for other hydroxamates that inhibit matrix metalloproteases and also show promise as anti-tumour agents (Rasmussen and McCann, 1997) . Azelaic bishydroxamate (ABHA) is not a metalloprotease inhibitor but induces differentiation in murine erythroleukaemic cell lines, human promyelocytic cells (HL-60), and human colon carcinoma cells (Breslow et al, 1991; Schroy et al, 1994) . This compound and certain analogues are up to 100-fold more active than HMBA in vitro and several have been found to inhibit histone deacetylase (Richon et al, 1998) and induce apoptosis (McBain et al, 1997) .", "cite_spans": [{"start": 131, "end": 152, "text": "(Breslow et al, 1991;", "ref_id": "BIBREF3"}, {"start": 153, "end": 172, "text": "Schroy et al, 1994;", "ref_id": "BIBREF25"}, {"start": 173, "end": 193, "text": "Parsons et al, 1997)", "ref_id": "BIBREF16"}, {"start": 344, "end": 372, "text": "(Rasmussen and McCann, 1997)", "ref_id": "BIBREF18"}, {"start": 574, "end": 595, "text": "(Breslow et al, 1991;", "ref_id": "BIBREF3"}, {"start": 596, "end": 615, "text": "Schroy et al, 1994)", "ref_id": "BIBREF25"}, {"start": 763, "end": 783, "text": "(Richon et al, 1998)", "ref_id": "BIBREF21"}, {"start": 805, "end": 825, "text": "(McBain et al, 1997)", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "", "text": "Upon comparing the in vitro effects of azelaic acid, HMBA and ABHA, we found that ABHA was selectively toxic for some human tumour cell lines and SV40-transformed melanocytes compared with normal cells (Parsons et al, 1997) . After treatment with ABHA, dendritic morphology was the only detected indicator of increased differentiation, markers for the pigmentation pathway being unchanged or down-regulated. ABHA resembled a more potent form of butyrate in some transcriptional activities, raising the possibility that it regulates gene expression via hyperacetylation of histones. Acetylation of the N-terminal lysine side-chains (Wolffe and Pruss, 1996) . Butyrate and the potent differentiating agents trichostatin A (TSA) and trapoxin cause hyperacetylation by inhibiting histone deacetylase (Kijima et al, 1993; Yoshida et al, 1995) . We now show that ABHA and a related hydroxamate are active in vivo against xenografts of a drug-resistant human melanoma cell line as well as being active in vitro against most of the human tumour cell lines tested. We also demonstrate that the action of ABHA requires macromolecular synthesis and phosphatase activity, and causes hyperacetylation of histone H4, in sensitive and resistant cells.", "cite_spans": [{"start": 202, "end": 223, "text": "(Parsons et al, 1997)", "ref_id": "BIBREF16"}, {"start": 631, "end": 655, "text": "(Wolffe and Pruss, 1996)", "ref_id": "BIBREF29"}, {"start": 796, "end": 816, "text": "(Kijima et al, 1993;", "ref_id": "BIBREF6"}, {"start": 817, "end": 837, "text": "Yoshida et al, 1995)", "ref_id": "BIBREF30"}], "ref_spans": []}, {"section": "MATERIALS AND METHODS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Chemistry", "text": "Azelaic-1-hydroxamate-9-anilide (AAHA) Azelaic acid (20 g, 106 mmol) was treated with thionyl chloride (25 ml) and the mixture refluxed for 30 min. Solvent was removed in-vacuo and to the residue was added drop-wise a solution containing aniline (10.65 mL, 117 mmol), N-methylmorpholine (12.85 ml, 117 mmol) and dichloromethane (100 ml). After addition was complete, the mixture was allowed to stir at room temperature for 20 min before evaporating the dichloromethane in vacuo. The residue was taken up into 200 ml of 5% sodium hydroxide and extracted with 3 \u00d7 100 ml aliquots of ethyl acetate. The basic layer was separated, acidified with 6 M hydrochloric acid (HCl) and extracted with 3 \u00d7 100 ml aliquots of ethyl acetate. The organic extracts were combined, dried (magnesium sulphate (MgSO 4 )) and concentrated to yield the anilide (15.6 g, 56%). To a sample of the crude anilide (200 mg, 0.76 mmol) in dry tetrahydrofuran (20 mL) was added N-methylmorpholine (0.092 ml, 0.85 mmol) and isobutylchloroformate (0.110 mL, 0.85 mmol). The mixture was stirred for 10 min before a solution containing hydroxylamine hydrochloride (58.2 mg, 0.85 mmol), ethanol (10 ml) and 5% sodium hydroxide (0.94 ml) was added. After a further 10 min, the solvent was removed in-vacuo and the residue taken up into 100 ml of 1 M HCI and extracted with 3 \u00d7 30 ml aliquots of dichloromethane. The organic extracts were combined, dried (MgSO 4 ) and concentrated to yield 130 mg of crude material which was purified by reverse phase high performance liquid chromatography (HPLC) to give 15 mg (7.1%) of the desired bis-hydroxamic acid: 1H NMR (300 MHz, DMSO-d 6); d 1.29 (6H, m), 1.48 (2H, m), 1.58 (2H, m), 1.94 (2H, t), 2.28 (2H, t), 7.00 (1H, t), 7.26 (2H, t), 7.58 (2H, d), 8.65 (1H, br.s), 9.85 (1H, s), 10.3 (1H, br.s); 13C NMR (75.6 MHz, DMSO-d 6); d 25.27,28.65, 28.70, 28.75, 32.43, 36.58, 119.19, 123.08, 128.04, 139.51, 169.27, 171.41 .", "cite_spans": [], "ref_spans": []}, {"section": "Cell culture", "text": "Cell lines (Maynard and Parsons, 1986) were grown in RPMI-1640 culture medium supplemented with 5% heat inactivated fetal calf serum (FCS), at 37\u00b0C in a humidified atmosphere containing 5% carbon dioxide air. Human melanocytes were maintained in culture media supplemented with 10% FCS, 10 ng ml -1 TPA (12-Otetradecanoylphorbol-13-acetate) and 6 ng ml cholera toxin. All cell lines were tested monthly for Mycoplasma using a Hoescht staining technique (Chen, 1977) . Cell survival was determined on cells treated in microtitre plates for 24 h and allowed to recover for 5 days before determination of incorporation of 3 H-thymidine (Maynard and Parsons, 1986) , or reduction of MTT (3-(4,5-dimethylthiazal-2-yl)-2,5-diphenyltetrazolium bromide (Mossman, 1983) . These methods give similar results to clonal-type assays or counting cell number (Parsons et al, 1991 (Parsons et al, , 1997 .", "cite_spans": [{"start": 11, "end": 38, "text": "(Maynard and Parsons, 1986)", "ref_id": "BIBREF9"}, {"start": 453, "end": 465, "text": "(Chen, 1977)", "ref_id": "BIBREF4"}, {"start": 633, "end": 660, "text": "(Maynard and Parsons, 1986)", "ref_id": "BIBREF9"}, {"start": 844, "end": 864, "text": "(Parsons et al, 1991", "ref_id": "BIBREF15"}, {"start": 865, "end": 887, "text": "(Parsons et al, , 1997", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Cell fusion", "text": "The double marker HeLa cell line, HHM, was obtained by selection with 100 \u00b5M 2-amino-6-mercaptopurine to generate HPRT-clones, followed by transfection with the plasmid p294MetM3 (Parsons et al, 1997 ) that expresses hygromycin resistance. HHM cells were resistant to 100 \u00b5g ml -1 hygromycin B and sensitive to HAT (5 mM hypoxanthine, 20 \u00b5M aminopterin, 0.8 mM thymidine).", "cite_spans": [{"start": 179, "end": 199, "text": "(Parsons et al, 1997", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Cell fusion", "text": "A2058 or NFF cells were co-cultivated with HHM at a ratio of 10:1 respectively until confluent, in RPMI-1640-10% FCS. The cell monolayer was washed twice with RPMI-1640 serum-free medium and exposed to 500 \u00b5l of RPMI-1640 serum-free medium per 50% v/v PEG 1500 for 30 s. Medium was aspirated and cells maintained for a further 60 s. The monolayer was washed stringently (5 \u00d7) with RPMI-1640 serum-free medium and incubated for a further 2 h in 2 ml RPMI-1640 serum-free medium. This was replaced with RPMI-1640 medium supplemented with 10% FCS. Double selection with HAT and 100 \u00b5g ml -1 hygromycin B was commenced 24 h postfusion. Colonies were picked and propagated. ", "cite_spans": [], "ref_spans": []}, {"section": "Mouse experiments", "text": "Xenografts of melanoma MM96L were produced by subcutaneous (s.c.) injection of 2 \u00d7 10 6 cells per site on the flanks of nude (nu/nu) mice as previously described (Parsons et al, 1991) . After 1 week to allow the cells to become established as tumours, the mice were treated once daily (5 days per week) intraperitoneally (i.p.) with 4 mg ABHA in 0.5 ml phosphate-buffered saline (PBS), 5 mg AAHA in 50 \u00b5l 80% dimethyl sulphoxide (DMSO) or 25 \u00b5g TSA in 0.2 ml PBS. The animals were euthanized when a tumour reached 1 cm diameter.", "cite_spans": [{"start": 162, "end": 183, "text": "(Parsons et al, 1991)", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "Histone acetylation", "text": "Histones were extracted in HCl and analysed directly on Triton-urea 15% polyacrylamide gels with Coomassie blue (Saito et al, 1991) . Gels were scanned with a laser densitometer (Molecular Dynamics, Sunnyvale, CA, USA) and quantitated with ImageQuant software.", "cite_spans": [{"start": 112, "end": 131, "text": "(Saito et al, 1991)", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "RESULTS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Cell morphology and survival", "text": "Treatment of normal cells (melanocytes, fibroblasts) with ABHA for 24 h led to some enlargement of the cytoplasm but no major morphological changes (Figure 1 ). Tumour cells (MM96L, HeLa), became highly dendritic following similar treatment, with the MM96L melanoma cells resembling the morphology of normal melanocytes ( Figure 1C, D) . Some membrane damage was evident with vesicles forming from the plasma membrane in some cells, as well as cells undergoing apoptosis.", "cite_spans": [], "ref_spans": [{"start": 148, "end": 157, "text": "(Figure 1", "ref_id": "FIGREF0"}, {"start": 322, "end": 335, "text": "Figure 1C, D)", "ref_id": "FIGREF0"}]}, {"section": "Cell morphology and survival", "text": "Simultaneous treatment of cells with ABHA and a range of inhibitors demonstrated that formation of dendritic morphology was dependent on protein and RNA synthesis, and to a lesser extent, phosphatase activity ( Figure 2) .", "cite_spans": [], "ref_spans": []}, {"section": "Cell morphology and survival", "text": "As found previously in cell growth assays (Parsons et al, 1997 ), incorporation of 3 -H-thymidine 5 days after a 24-h treatment confirmed that the human melanoma cell line MM96L and the cervical carcinoma cell line HeLa were sensitive to killing by ABHA compared with fibroblasts (NFF) ( Figure 3A ). The melanoma cell line MM229 had intermediate sensitivity. AAHA, the anilide derivative of ABHA, showed similar discrimination and was more potent ( Figure 3B ). TSA ( Figure 3C ) was approximately 100-fold more potent than the two previous drugs, but was somewhat less selective for killing fibroblasts. A survey of other human cell types (Table 1 and Figure 8A ) showed that only two tumour cell lines (MM229 and A2058) of 11 human tumour and transformed cell lines were as resistant to ABHA and AAHA as proliferating normal cells (NFF and NM). ", "cite_spans": [{"start": 42, "end": 62, "text": "(Parsons et al, 1997", "ref_id": "BIBREF16"}], "ref_spans": [{"start": 641, "end": 649, "text": "(Table 1", "ref_id": "TABREF1"}, {"start": 654, "end": 663, "text": "Figure 8A", "ref_id": "FIGREF5"}]}, {"section": "Inhibition of the growth of human melanoma xenografts in nude mice", "text": "Preliminary experiments showed that daily i.p. doses of ABHA up to 8 mg had no discernible toxicity to BALB/c mice. ABHA administered at 4 mg per day, commencing 7 days after implantation of tumour cells, led to significant inhibition of tumour growth ( Figure 4A ). AAHA was also effective, whereas TSA, applied daily at a dose calculated from cell survival curves to be approximately fivefold the in vitro toxicity of ABHA, was inactive ( Figure 4B ). Incubation of the drugs with near-confluent cultures of NFF or MM96L cells for up to 3 days, followed by bioassay of the remaining toxicity by transfer of the medium to fresh cultures of MM96L cells, revealed that TSA was slowly inactivated ( Figure 5 ). No weight loss or other evidence of toxicity was observed in the treated mice. The small tumours remaining on the treated mice were re-cultured and found to retain the same in vitro sensitivity to ABHA as MM96L cells from the untreated tumours.", "cite_spans": [], "ref_spans": [{"start": 254, "end": 263, "text": "Figure 4A", "ref_id": "FIGREF2"}, {"start": 441, "end": 450, "text": "Figure 4B", "ref_id": "FIGREF2"}, {"start": 697, "end": 705, "text": "Figure 5", "ref_id": "FIGREF3"}]}, {"section": "Hyperacetylation of histones", "text": "Analysis of histones extracted from MM96L or NFF cells after 24 h treatment with ABHA showed a distinct laddering of the H4 region (Figure 6 ), indicative of increasing levels of acetylation of this histone. Similar results were obtained using 10 \u00b5g ml -1 AAHA, 100 nM TSA or 5 mM butyrate (not shown). The temporal response, measured from laser densitometer traces ( Figure 7A ), showed that acetylation commenced within 2 h of treatment, the tetra-acetylated form becoming prominent by 24 h. In repeated experiments, however, no significant difference could be found between MM96L and NFF in the amount of tetra-acetylated form induced by ABHA (Table 2) .", "cite_spans": [], "ref_spans": [{"start": 646, "end": 655, "text": "(Table 2)", "ref_id": "TABREF2"}]}, {"section": "Hyperacetylation of histones", "text": "Since it was possible that ABHA selectivity for cell killing may have arisen from decreased rate of removal of acetyl groups from H4 histone after removal of drug, cells were analysed at different times during recovery from a 2-h treatment with ABHA. The results, however, revealed that H4 acetylation in the drug-resistant NFF cells decayed more slowly than in the sensitive MM96L cells ( Figure 7B ), thus ruling out delayed recovery from acetylation as the cause of sensitivity. ", "cite_spans": [], "ref_spans": []}, {"section": "Sensitivity of cell hybrids to ABHA", "text": "Fusion of ABHA-sensitive (HHM) with resistant cells (NFF, A2058) followed by double selection with HAT and hygromycin to remove homokaryons produced stable, proliferating clones. These were identified as hybrids by DNA flow cytometry, which revealed the G1 DNA content to be the sum of the G1 DNA of the fusion partners. The presence of the NFF or A2058 genomes was confirmed independently by increased resistance of the hybrids to the methylating agent N-methyl-N\u00b4-nitro-N-nitrosoguanidine compared with HeLa, which is sensitive to DNA methylating agents (Maynard and Parsons, 1986) . No clones were obtained from fusions carried out with HeLa cells that lacked either of the selection markers. Clones of both NFF/HHM and A2058/HHM cell hybrids displayed distinct sensitivity to ABHA and AAHA, compared with the resistant partner cell line (Figure 8 ).", "cite_spans": [{"start": 556, "end": 583, "text": "(Maynard and Parsons, 1986)", "ref_id": "BIBREF9"}], "ref_spans": [{"start": 841, "end": 850, "text": "(Figure 8", "ref_id": "FIGREF5"}]}, {"section": "DISCUSSION", "text": "A large number of hydroxamate-containing compounds are now known to possess anti-tumour properties. Most such compounds non-selectively inhibit matrix metalloproteases, which are associated with growth and spread of malignant tumours in models of metastasis, angiogenesis and tumour progression. In contrast, ABHA does not inhibit metalloproteases even at mM concentrations (unpublished), yet has anti-tumour activity. A wide variety of tumour cell types and SV40-transformed melanocytes (Parsons et al, 1997) are sensitive to ABHA and derivatives (Table 1 ). Selectivity appears to be a novel property of this drug class, since normal cells and only two melanoma cell lines (MM229, A2058) were resistant to the agents.", "cite_spans": [{"start": 488, "end": 509, "text": "(Parsons et al, 1997)", "ref_id": "BIBREF16"}], "ref_spans": [{"start": 548, "end": 556, "text": "(Table 1", "ref_id": "TABREF1"}]}, {"section": "DISCUSSION", "text": "The morphological changes illustrated in Figure 1 occur within 24 h of treatment with ABHA and are attributed to some form of differentiation or 'redifferentiation' and partial reversion to a normal phenotype. While some of the melanoma cells have enhanced dendritic, melanocytic morphology after treatment, there is also some accompanying apoptosis, and the tumour cells ultimately die. Protein and RNA synthesis de novo was required for this phenotype reversion, as found previously for TSA-induced differentiation of HeLa cells (Hoshikawa et al, 1994) , suggesting that ABHA is not acting solely as an inhibitor of cellular functions but also induces the transcription of genes necessary for differentiation and possibly cell death.", "cite_spans": [{"start": 531, "end": 554, "text": "(Hoshikawa et al, 1994)", "ref_id": "BIBREF5"}], "ref_spans": [{"start": 41, "end": 49, "text": "Figure 1", "ref_id": "FIGREF0"}]}, {"section": "DISCUSSION", "text": "Xenografts of the melanoma MM96L cells were significantly inhibited by daily treatments with ABHA, the first drug of any kind to show significant activity against this cell line. Although this is a relatively high dose (200 mg kg -1 ), other differentiating agents such as butyrate have been used safely at similar levels to treat children with sickle cell anaemia (Perrine et al, 1994) . Established from a metastasis, having a mutator phenotype (Must et al, 1996) and resistant to current anticancer agents in vitro and in vivo (Maynard and Parsons, 1986) , MM96L cells represent a rigorous, but probably realistic, human model for testing new agents. MM96L cells cultured from the small tumours that survived treatment of the mice by ABHA were still sensitive to ABHA. The inability of such a tumour cell line to develop resistance to ABHA is notable, and suggests that even higher doses of ABHA could be given, since there were no overt signs of toxicity or side-effects in the mice. AAHA, administered in DMSO because of poor solubility in aqueous PBS, had even better activity. Metabolic inactivation of TSA, detected here for the first time, is expected to be more marked in vivo due to exposure to the liver and kidney, and is a possible explanation for its complete lack of activity against human melanoma xenografts. Resistance of cultured fibroblasts to TSA is unlikely to be due to metabolism of TSA because the exposure was limited to 24 h. Thus, although TSA is now widely established as a potent inhibitor of histone deacetylases in vitro, metabolically stable inhibitors may be required to obtain useful activities in vivo.", "cite_spans": [{"start": 365, "end": 386, "text": "(Perrine et al, 1994)", "ref_id": "BIBREF17"}, {"start": 530, "end": 557, "text": "(Maynard and Parsons, 1986)", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "Acetylation of histone H4 was found to be induced by ABHA and AAHA, presumably by inhibition of histone deacetylase activity as shown previously for this class (Richon et al, 1998) and for TSA (Wolffe and Pruss, 1996) . This could be expected to profoundly alter gene expression and may be a necessary condition for cell toxicity to occur. However, the present comparison of acetylation and deacetylation rates in intact sensitive and resistant cells failed to find any evidence that differences in H4 acetylation could be responsible for differential toxicity. It is possible that other histone modifications may be involved in selectivity, or that other drug targets are important. It should also be noted that some of the changes in gene expression induced by this type of agent, presumably by histone hyperacetylation, may be remote from the origin of toxicity and selectivity. Protein tyrosine phosphatase activity is involved in regulating cell survival and differentiation (Stoker and Dutta, 1998) and was required for ABHA to differentiate HeLa cells. This may provide a focus for identifying signalling pathways relevant to the selective action of ABHA.", "cite_spans": [{"start": 160, "end": 180, "text": "(Richon et al, 1998)", "ref_id": "BIBREF21"}, {"start": 193, "end": 217, "text": "(Wolffe and Pruss, 1996)", "ref_id": "BIBREF29"}, {"start": 980, "end": 1004, "text": "(Stoker and Dutta, 1998)", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "The dominant-negative sensitivity to ABHA of somatic cell hybrids contrasts with the more usual complementation towards resistance found with other agents such as cisplatin (Wang et al, 1996) , and in this study with a DNA methylating agent. It could be speculated that ABHA sensitivity involves a dominant, mutated sequence vital to the growth of the transformed phenotype. Loss of this gene or further mutation under ABHA selection pressure would lead to non-viable clones. The similar, dominant-negative phenotype of hybrids from the ABHA-resistant A2058 cells suggests that malignant transformation may not always be accompanied by such changes. The results also show that functional complementation would not be an appropriate method for cloning the gene(s) involved in ABHA sensitivity.", "cite_spans": [{"start": 173, "end": 191, "text": "(Wang et al, 1996)", "ref_id": "BIBREF28"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "Overall, ABHA and AAHA represent a unique class of histone deacetylase inhibitors that is selectively toxic to transformed cells, stable in culture, and unlike the more potent inhibitor TSA, active against human melanoma cells in vivo with no evidence of adverse effects on the animal or development of drug resistance. Further refinement in structure may be needed to increase potency and hence efficacy in vivo.", "cite_spans": [], "ref_spans": []}, {"section": "ACKNOWLEDGEMENT", "text": "This work was supported by the Queensland Cancer Fund. 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Left panels, untreated. Right panels, treated. (A,B) MM96L melanoma; (C, D) melanocytes; (E, F) HeLa; (G, H) NFF fibroblasts", "type": "figure"}, "FIGREF1": {"text": "Figure 2 Formation of dendritic HeLa cells during a 24-h treatment with 100 \u00b5g ml -1 ABHA was inhibited by co-treatment with 10 \u00b5g ml -1 cycloheximide (s s), 2 \u00b5g ml -1 actinomycin D (s) or 1 mM sodium vanadate (q q). Addition at 0 h represents 24-h treatment with inhibitors, giving maximum inhibition of dendrite formation. Points are means of triplicates", "type": "figure"}, "FIGREF2": {"text": "Figure 4 Inhibition of the growth of the human melanoma cell line MM96L as xenografts in nude mice. (A) ABHA (4 mg per day). (B) AAHA (5 mg per day) and TSA (25 \u00b5g per day). Points are mean and s.d. (n = 7-11 per group)", "type": "figure"}, "FIGREF3": {"text": "Figure 5 Loss of potency of TSA during incubation with confluent MM96L cells. At each time, aliquots of culture medium were bioassayed for toxicity by 24-h treatment of separate cultures of MM96L cells. v, TSA (100 ng ml -1 ); s, ABHA (100 \u00b5g ml -1 ). Points are mean and s.d. (n = 4)", "type": "figure"}, "FIGREF4": {"text": "Figure 6 Separation of histones on a Triton-urea polyacrylamide gel showing induction of histone H4 acetylation in cells treated for 24 h with 100 \u00b5g ml -1 of ABHA (+)", "type": "figure"}, "FIGREF5": {"text": "Figure 8 Dose-response for survival of hybrids between the HeLa fusion partner HHM and A2058 (A) or NFF (B). x, HHM; s, A2058 (A) or NFF (B); \u2022 and v, hybrid clones. Points are mean and s.d. (n = 4)", "type": "figure"}, "TABREF0": {"text": "Anti-tumour activity in vitro and in vivo of selective differentiating agents containing hydroxamate", "type": "table"}, "TABREF1": {"text": "Toxicity of histone deacetylase inhibitors in human cells", "type": "table"}, "TABREF2": {"text": "", "type": "table"}}}
{"paper_id": "18983998", "_pdf_hash": "e290366f3c143d6fec40f37d55f2951eda6eb071", "abstract": [{"section": "Abstract", "text": "Background: Brain-water content (BWC) decreases with maturation of the brain and potentially affects parameters of cerebral oxygenation determined by near-infrared spectroscopy (NIRS). Most commercially available devices do not take these maturational changes into account. The aim of this study was to determine the effect of different assumptions for BWC on parameters of cerebral oxygenation in preterm infants. Methods: Concentrations of oxy-, deoxy-and total hemoglobin and regional cerebral oxygen saturation (rcStO 2 ) were calculated based on absolute coefficients of absorption and scattering determined by multi-distance Frequency-Domain-NIRS assuming BWCs of 75-95%, which may be encountered in newborn infants depending on gestational and postnatal age. Results: This range of BWC gave rise to a linear modification of the assessed NIRS parameters with a maximum change of 10%. This may result in an absolute overestimation of rcStO 2 by (median (range)) 4 (1-8)%, if the calculation is based on the lowest BWC (75%) in an extremely preterm infant with an anticipated BWC of 95%. Conclusion: Clinicians wishing to rely on parameters of cerebral oxygenation determined by NIRS should consider that maturational changes in BWC not taken into account by most devices may result in a deviation of cerebral oxygenation readings by up to 8% from the correct value.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Background", "text": "Near-infrared spectroscopy (NIRS) is a tool to noninvasively evaluate tissue oxygenation in term and preterm infants. As reported previously [1] [2] [3] , there are several instruments commercially available which use different techniques to measure tissue oxygenation, e.g. in the brain.", "cite_spans": [{"start": 141, "end": 144, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 145, "end": 148, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 149, "end": 152, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Background", "text": "NIRS quantifies the interaction of near-infrared photons with biological tissue, which can be described by two different properties: the light absorption and the reduced scattering coefficient (\u03bc a and \u03bc s '). Since deoxyand oxyhemoglobin (HHb, O 2 Hb) are the most relevant chromophores absorbing light of the near-infrared spectrum their concentrations can be calculated from \u03bc a . NIRS is able to determine \u03bc a by the diffusion approximation or changes in \u03bc a by the modified law of Lambert and Beer if the optical path length and geometrical properties are known. An important factor in these calculations is the brain water content (BWC) because water also absorbs near-infrared light, although to a lesser extent than O 2 Hb and HHb.", "cite_spans": [], "ref_spans": []}, {"section": "Background", "text": "As far as the underlying algorithms for the determination of measures of tissue oxygenation are revealed at all, most NIRS devices do not allow adjustment for maturational changes in BWC and their underlying algorithms may assume BWCs as low as 75%.", "cite_spans": [], "ref_spans": []}, {"section": "Background", "text": "Considering that due to physiological maturation BWC varies from 75% to 95% [4] [5] [6] , one has to expect that this maturational change in BWC will have an effect on readings of cerebral oxygenation determined by NIRS, which might be therapeutically relevant in the clinical setting.", "cite_spans": [{"start": 76, "end": 79, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 80, "end": 83, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 84, "end": 87, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Background", "text": "We aimed to quantify the impact of different assumptions for brain water content (75% for adults, 85% for term infants and 95% for very preterm infants [6] ) in a series of measurements of cerebral oxygenation in preterm infants.", "cite_spans": [{"start": 152, "end": 155, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Methods", "text": "This prospective observational study was approved by the ethics committee of Tuebingen University Hospital and written informed parental consent was obtained in all infants.", "cite_spans": [], "ref_spans": []}, {"section": "Study population", "text": "A convenience sample of 17 preterm infants was studied in the neonatal intensive and high dependency care units of Tuebingen University Children's Hospital. Patient characteristics are shown in Table 1 . Only infants who were hemodynamically stable, i.e. who had normal blood pressure and normal skin colour and capillary refill time without cardiocirculatory support were included. Those with chromosomal or syndromal abnormalities were excluded.", "cite_spans": [], "ref_spans": [{"start": 194, "end": 201, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "NIRS-Measurements", "text": "All measurements were performed with the infant sleeping in a supine position with the head slightly elevated and turned to the contralateral side by less than 30\u00b0. The probe was positioned at the right temporo-parietal-region accurately in the middle between the tragus and the sagittal suture to avoid the sagittal sinus and the Sylvian fissure. Care was taken to comb any existing newborn hair apart before placing the optode. The optode was applied to the infants skull held by the hand of the examiner with gentle pressure.", "cite_spans": [], "ref_spans": []}, {"section": "NIRS-Measurements", "text": "For each measurement, a recording lasting at least 2 minutes was performed at a sampling rate of 1Hz.", "cite_spans": [], "ref_spans": []}, {"section": "NIRS-Device", "text": "We employed the ISS Oxiplex TS (ISS Inc., Champaign, IL, USA), a frequency-domain near infrared spectroscope. Each channel is equipped with 8 near-infrared light sources at two different wavelengths (four emitting at 692 nm and four at 834 nm) with emitter-detector distances of 1.5, 2, 2.5 and 3 cm, enabling a tissue penetration of 2-3 cm in depth according to the manufacturer's specifications. To enable assessment of the path length as measured by a phase-shift, the light intensity is modulated with a frequency of 110 MHz.", "cite_spans": [], "ref_spans": []}, {"section": "NIRS-Device", "text": "Light intensity and phase shift are recorded for each emitter-optode distance using the proprietary software package OxiTS, and the absolute \u03bc a and \u03bc s ' are calculated based on the slope of the respective regression lines at each wavelength using the diffusion equation for homogeneous, semi-infinite media [1, 2] . Based on \u03bc a at two wavelengths, absolute concentrations of HHb and O 2 Hb and consequently also absolute values for total hemoglobin (tHb) and rcStO 2 are calculated.", "cite_spans": [{"start": 309, "end": 312, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 313, "end": 315, "text": "2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Calculation of hemoglobin concentrations and hemoglobin oxygen saturation for different water contents", "text": "Calculations of O 2 Hb, HHb, tHb and rcStO 2 were performed using the equations given below and assuming BWCs of 95%, 85% and 75% [6] . HHb \u00bc deoxygenated hemoglobin \u00f0\u03bcM\u00de;", "cite_spans": [{"start": 130, "end": 133, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Calculation of hemoglobin concentrations and hemoglobin oxygen saturation for different water contents", "text": "tHb \u00bc total hemoglobin \u00f0\u03bcM\u00de: ", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "Different assumptions for BWC resulted in relevant changes in calculated concentrations of O 2 Hb and to a lesser extent of HHb. With the assumption of a higher BWC the computed concentration of O 2 Hb decreased and the computed concentration of HHb increased. Consequently, the tHb concentration and the rcStO 2 decreased as shown in Figure 1 . All comparisons between different assumptions for BWC yielded p-values < 0.0001 for all parameters evaluated. The computed values for O 2 Hb, HHb, tHb and rcStO 2 at different BWC are shown in Table 2 . Assuming BWC = 75% instead of BWC = 95% resulted in an overestimation of rcStO 2 of 4 (1-8)%.", "cite_spans": [], "ref_spans": [{"start": 539, "end": 546, "text": "Table 2", "ref_id": "TABREF2"}]}, {"section": "Results", "text": "In Figure 1 (A-D), oxygenated hemoglobin, deoxygenated hemoglobin, total hemoglobin and regional cerebral oxygen saturation are plotted against assumed BWCs.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "NIRS is increasingly used in neonatal intensive care. Instruments suitable and approved for continuous monitoring in this age group give readings on a measure of cerebral oxygenation based on several assumptions that may not hold true in a given infantand hence displayed values of cerebral oxygenation may not be appropriate in certain individuals.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Our study addressed the question whether the assumption of different BWCs consistently influences O 2 Hb, HHb, tHb and rcStO 2 readings in a realistic sample of clinically stable preterm infants using computations based on absolute coefficients \u03bc a and \u03bc s ' determined by multi-distance FD-NIRS and the diffusion equation for homogeneous, semi-infinite media.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "A clinically relevant overestimation of \"true\" rcStO 2 by up to 8% may result if BWC is incorrectly assumed to be only 75% in an extremely immature infant with a true BWC of 90-95%. This influence of different BWCs within the physiological range encountered in the neonatal intensive care unit on parameters of cerebral oxygenation is disregarded by most manufacturers of NIRS devices and also neglected by many clinicians who rely on readings of parameters of cerebral oxygenation for guiding cardiovascular therapy.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "This systematic overestimation of rcStO 2 by 4% (1%-8%), is probably not important in settings where rcStO 2 trend monitoring is used e.g., during surgical interventions, and whenever relative changes of cerebral oxygenation in relation to a 'normal' baseline are observed to indicate cardiovascular interventions. Neonatal applications of cerebral oxygenation monitoring frequently lack a 'normal baseline' as rcStO 2 monitoring is used in extremely preterm [7] [8] [9] and asphyxiated infants after resuscitation [10] . Furthermore, neonatal cerebral oxygenation monitoring is intended for days rather than just a few hours (e.g., [9] ). As indicated in an European collaborative phase 2 trial of rcStO 2 -monitoring in extremely preterm infants, neonatologists are indeed interested in long-term continuous rcStO 2 monitoring and, in the absence of a 'normal baseline' , do rely on absolute rcStO 2 readings [7] . Furthermore, suggested treatment algorithms indicate cardiovascular interventions if absolute cut-off values of rcStO 2 are exceeded [8] . Whenever absolute readings of rcStO 2 are relied upon for clinical decision making, a systematic over-/underestimation of rcStO 2 may be of clinical importance.", "cite_spans": [{"start": 459, "end": 462, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 463, "end": 466, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 467, "end": 470, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 515, "end": 519, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 633, "end": 636, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 911, "end": 914, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 1050, "end": 1053, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Discussion", "text": "For various reasons, including inhomogeneity of the tissue and issues of probe placement (underlying blood vessels, skin, background absorbers, different scattering properties, hair and texture, etc.), the signal-to-noise ratio is poorer and the limits of agreement after repeated repositioning of the NIRS-probe are greater in rcStO 2monitoring than in SaO 2 -monitoring using pulse oximetry (reviewed in [11] ). Bland-Altman bias analyses revealing poor agreement with 95% limits of agreement of up to \u221217% to +17% have been reported previously [12] . More recently, using the ISS Oxiplex TS which was also used in this study, Arri et al. demonstrated that the test retest variability of rcStO 2 measurements was approximately 5% for preterm infants [13] , similar to test retest variability of 5% reported by Sorensen using the NIRO 300 [14] . Based on this more recent data, a systematic overestimation of rcStO 2 by 4% (1%-8%) due to incorrect assumptions of BWC is considerable. Moreover, this systematic bias will add to the imprecision of the method and, in contrast to random factors, it is a systematic error that will not be overcome by averaging. Figure 1 (A-D): Calculated changes assuming different brain water contents. O2Hb (A), HHb (B), tHb (C) and rcStO2 (D) calculated assuming different brain water contents of 75, 85 and 95%, respectively.", "cite_spans": [{"start": 406, "end": 410, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 547, "end": 551, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 752, "end": 756, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 840, "end": 844, "text": "[14]", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Discussion", "text": "Our findings may also be of importance in the interpretation of longitudinal studies: Previously reported longitudinal data suggested that rcStO 2 values decrease in preterm infants during the first 6 weeks of life despite stable cerebral blood flow index, which was interpreted as an increase in metabolic rate of oxygen [15] . In this study, rcStO 2 was calculated based on the probably incorrect assumption of a constant BWC of 75% throughout the study period. The results of our simulation suggest that incorrect underestimation of BWC early on, may have contributed to the findings and that the postnatal decrease in rcStO2 and the increase in the metabolic rate of oxygen may have been overestimated.", "cite_spans": [{"start": 322, "end": 326, "text": "[15]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Discussion", "text": "It is obvious that smaller differences between assumed and actual BWC will result in smaller deviations of O 2 Hb, HHb, tHb, and rcStO 2 from reality. In fact, depending on postmenstrual and postnatal age most BWC-values will range between 80% and 90% [6] . Furthermore, our data are only applicable to the wavelengths used herein. Different wavelengths with different ratios between the extinction coefficients for O 2 Hb, HHb and water will result in different degrees of deviation from reality if BWC is not taken into account. In general, the higher the extinction coefficient of water in relation to that of O 2 Hb or HHb at a given wavelength, the more relevant will be the impact of the difference between assumed and actual BWC.", "cite_spans": [{"start": 252, "end": 255, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Discussion", "text": "Effects of different assumptions of BWC on rcStO 2 readings of different devices will depend on the wave lengths used (as outlined above) and on the underlying algorithms for determination of rcStO 2 . In contrast to the instrument used for our study, unfortunately, many manufacturers of NIRS oximeters did not publish their algorithms and it is unknown how they deal with the water assumption.", "cite_spans": [{"start": 198, "end": 199, "text": "2", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Discussion", "text": "We have previously described [16] that introducing a water term into equations describing the relation between the absorption coefficient, \u03bca, and the slope of the decrease in light intensity using multi-distance FD-NIRS resulted in minor changes in StO 2 -measurements of the neonatal head if a constant BWC of 90% was assumed. However, this introduction of a water term resulted in large changes (absolute change in StO 2 of up to 18% or relative change up to 30%) if the water content was assumed to be 70% in StO 2 -measurements on the adult arm. The present data complement our previous results, accounting for different assumptions for BWC in the range encountered between extremely preterm infants and early childhood. Those different assumptions for BWC will systematically bias results of HHb, O 2 Hb, tHb and StO 2 measurements, overestimating StO 2 if too low BWC is assumed. Although the median bias introduced by incorrect assumptions of BWC may be small (Table 2 ), in the occasional infant overestimation of StO 2 may be clinically relevant.", "cite_spans": [{"start": 29, "end": 33, "text": "[16]", "ref_id": "BIBREF15"}], "ref_spans": [{"start": 968, "end": 976, "text": "(Table 2", "ref_id": "TABREF2"}]}, {"section": "Discussion", "text": "Developmental changes in BWC should be considered in the clinical setting, especially in preterm infants, because a median difference in rcStO 2 of 4% and a difference in rcStO 2 of up to 8% in individual patients could change therapeutic decisions with potential long-term consequences.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "Changing assumptions of BWC resulted in systematic modifications of computed O 2 Hb and HHb and in consecutive clinically relevant changes in rcStO 2 of up to 8%. Disregarding maturational changes in BWC is another factor contributing to inadequate accuracy of absolute measures of cerebral oxygenation by standard NIRS devices. 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WC\u00de \u00c2 \u00feaO 2 Hb 692 \u00c3 \u00f0\u03bca 834 \u2212E H2O 834 \u00f0 \u00de \u00c3 WC\u00de HHb \u00bc 1000 \u00c3 \u00bdaHHb 834 \u00c3 \u00f0\u03bca 692 \u2212E H2O 692 \u00f0 \u00de \u00c3 WC\u00de \u00feaHHb 692 \u00c3 \u00f0\u03bca 834 \u2212E H2O 834", "type": "table"}, "TABREF1": {"text": "Hb, tHb and rcStO 2 was calculated three times, assuming BWCs of 75, 85 and 95%, respectively. Data are depicted as median (minimummaximum) of the 17 individual medians for each parameter and each assumption for BWC.Differences in NIRS-parameters brought about by the different assumptions for BWC were evaluated for normal distribution using a Shapiro-Wilk-test, showing non-normal distribution. Hence data were evaluated for statistical significance using the non-parametric sign-test. Analyses were performed using SPSS for Windows, Version 15.0 (SPSS Inc., Chicago, IL, USA).", "type": "table"}, "TABREF2": {"text": "Hemoglobin concentrations and hemoglobin oxygen saturation for different assumptions of brain water content", "type": "table"}}}
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{"paper_id": "18984915", "_pdf_hash": "0f4f1b10de1b51706079af2c847fafd591c0eda5", "abstract": [{"section": "Abstract", "text": "Abstract. Some of the rapidly oscillating (CP2) stars, have frequencies which are larger than the theoretical acoustic cut-off frequency. As the cut-off frequency depends on the T (\u03c4 ) relation in the atmosphere, we have computed models and adiabatic frequencies for pulsating Ap stars with T (\u03c4 ) laws based on Kurucz model atmospheres and on Hopf's purely radiative relation.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "The frequency-dependent treatment of radiative transfer as well as an improved calculation of the radiative pressure in Kurucz model atmospheres increase the theoretical acoustic cut-off frequency by about 200 \u00b5Hz, which is closer to the observations. For \u03b1 Cir we find models with Kurucz atmospheres which have indeed a cut-off frequency beyond the largest observed frequency and which are well within the T eff -L error box. For HD 24712 only models which are hotter by about 100 K and less luminous by nearly 10% than what is actually the most probable value would have an acoustic cut-off frequency large enough.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "One may thus speculate that the old controversy about a mismatch between observed largest frequencies and theoretical cut-off frequencies of roAp star models is resolved. However, the observational errors for the astrophysical fundamental parameters have to be reduced further and the model atmospheres refined.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Further details can be found in Audard et al. (1997) ", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "It has been argued by Shibahashi and Saio (1985) that the cut-off frequency is largely influenced by the T (\u03c4 ) relation which requires a careful modelling of these layers. Frequently, atmospheres in stellar models are based on an Eddington or Hopf law (e.g. Mihalas 1978) , where the radiative transfer is considered to be frequency independent (grey case), and convection is not included.", "cite_spans": [{"start": 259, "end": 272, "text": "Mihalas 1978)", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Introduction", "text": "Contrib. Astron. Obs. Skalnat\u00e9 Pleso 27, (1998), 304-308. We used the LTE Kurucz atlas9 code (Kurucz, 1993) without the \"overshooting option\" (Castelli 1996) to calculate an interpolation table for T (\u03c4, T eff ). Model atmospheres with solar composition were computed for log g = 4.2 and for T eff ranging from 7400 to 10000 K, and no additional contribution to line opacity by microturbulence has been assumed.", "cite_spans": [{"start": 93, "end": 107, "text": "(Kurucz, 1993)", "ref_id": "BIBREF6"}, {"start": 142, "end": 157, "text": "(Castelli 1996)", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Introduction", "text": "The internal structure models of 1.8 M \u2299 representative for CP2 stars were computed with the CESAM code (Morel 1993 and 1997) . We do not include effects from a magnetic field.", "cite_spans": [{"start": 104, "end": 119, "text": "(Morel 1993 and", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Introduction", "text": "We shall call \"Hopf\" and \"Kurucz\" models full stellar models whose atmospheres are derived from Hopf's law and Kurucz model atmospheres respectively.", "cite_spans": [], "ref_spans": []}, {"section": "Cut-off frequencies", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Theoretical background", "text": "To calculate the cut-off frequencies we make the assumptions that for low-degree modes the displacement is essentially vertical, so that the horizontal component can be neglected. Consequently, we consider only radial modes and, because we investigate modes of high radial orders, we adopt the Cowling approximation. We do not include the effects of a magnetic field.", "cite_spans": [], "ref_spans": []}, {"section": "Theoretical background", "text": "The cut-off frequency, \u03bd M , is the maximum value of the frequency above which modes are not at all reflected towards the stellar interior but propagate outwards in the atmosphere. We have calculated the cut-off frequency according to three expressions for the acoustic potential: the formulation by Vorontsov & Zarkhov (1989) ", "cite_spans": [], "ref_spans": []}, {"section": "Theoretical background", "text": "M ), and the approximation of an isothermal atmosphere (\u03bd Gough, 1986) . Table 1 gives the values of these cut-off frequencies for the Hopf and Kurucz models of 1.8 M \u2299 and age 500 Myr. Along the main sequence, the relative difference between the cut-off frequencies from Kurucz and Hopf models of 1.8 M \u2299 models remains almost unchanged and is about 8.5% (see Tab. 1) (see also Shibahashi, 1991) .", "cite_spans": [{"start": 58, "end": 70, "text": "Gough, 1986)", "ref_id": "BIBREF4"}, {"start": 379, "end": 396, "text": "Shibahashi, 1991)", "ref_id": "BIBREF15"}], "ref_spans": [{"start": 73, "end": 80, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Theoretical background", "text": "This result is in agreement with results of Shibahashi & Saio (1985) and of Matthews et al. (1990 Matthews et al. ( , 1996 .", "cite_spans": [], "ref_spans": []}, {"section": "Comparison with observations", "text": "For about 5 out of 28 known roAp stars, the largest published frequency exceeds the expected theoretical acoustic cut-off frequency determined from stellar models whose atmospheres are derived from an Eddington or Hopf law. We do not consider here roAp stars for which the highest observed frequency probably is a harmonic of their nonlinear oscillation.", "cite_spans": [], "ref_spans": []}, {"section": "Comparison with observations", "text": "Since the uncertainty in the age determination can introduce a significant error in the computed acoustic cut-off frequency , we will focus our discussion on those two roAp stars, HD 24712 and HD 128898, for which we have more reliable mass estimates due to the availability of hipparcos parallaxes. The photometric and spectroscopic properties of the roAp star HD 24712 can be reproduced with a model of 1.63 M \u2299 , Z = 0.02 and an age of about 900 Myr. The cut-off frequency \u03bd", "cite_spans": [], "ref_spans": []}, {"section": "Comparison with observations", "text": "(1) M is 2280 \u00b5Hz and 2480 \u00b5Hz for the Hopf and Kurucz models respectively.", "cite_spans": [], "ref_spans": []}, {"section": "Comparison with observations", "text": "We have also computed Hopf and Kurucz models with appropriate age for HD 128898 (\u03b1 Cir). A Kurucz model atmosphere was calculated with an opacity distribution function specific to the composition of \u03b1 Cir (Piskunov & Kupka 1997 ). Stellar models with 1.93 M \u2299 , Z = 0.03 and an age of 400 Myr, fit the observed values (Kupka et al. 1996) . The cut-off frequencies \u03bd", "cite_spans": [{"start": 205, "end": 227, "text": "(Piskunov & Kupka 1997", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "Comparison with observations", "text": "(1) M for the Hopf and Kurucz models are 2346 and 2600 \u00b5Hz, respectively. The acoustic cut-off frequency computed for the Kurucz model is compatible with the largest observed frequency. However, the cut-off frequency depends on the model input parameters and one must therefore account for uncertainties inherent to observations and modelling. Evolutionary tracks and lines of constant cut-off frequency for Kurucz models are plotted in Fig. 1a together with the observational error boxes.", "cite_spans": [], "ref_spans": [{"start": 437, "end": 444, "text": "Fig. 1a", "ref_id": "FIGREF0"}]}, {"section": "Comparison with observations", "text": "Asteroseismology is a powerful tool for determining the evolutionary status of stars via the frequency separation \u03bd 0 = (2 R 0 (dr/c)) \u22121 \u223c \u03bd n,\u2113 \u2212 \u03bd n\u22121,\u2113 (see e.g. Shibahashi 1991, and Martinez 1993) . If \u03bd 0 can be measured, a more reliable estimate of the evolutionary status can be derived than with our classical approach. Fig. 1b shows lines of constant frequency spacing \u03bd 0 for the same models as for Fig. 1a . The observed value \u03bd 0 = 68 \u00b5Hz for HD 24712 (Kurtz et al. 1989 ) is consistent with our classically determined error box, while there is a serious problem for \u03b1 Cir, because the observed value of \u03bd 0 is 50 \u00b5Hz (Kurtz et al. 1994) which cannot be reconciled with the spectroscopically determined effective temperature and/or the luminosity.", "cite_spans": [{"start": 166, "end": 186, "text": "Shibahashi 1991, and", "ref_id": "BIBREF15"}, {"start": 187, "end": 201, "text": "Martinez 1993)", "ref_id": "BIBREF8"}], "ref_spans": [{"start": 329, "end": 336, "text": "Fig. 1b", "ref_id": "FIGREF0"}, {"start": 410, "end": 417, "text": "Fig. 1a", "ref_id": "FIGREF0"}]}, {"section": "Conclusion", "text": "We have shown that along the main sequence, Kurucz model atmospheres increase the cut-off frequency by about 8.5 % relative to the value derived from the Hopf T (\u03c4 ) relation. \u22121 for the same models, from 80 to 65 \u00b5Hz for Z = 0.02, and from 70 to 60 \u00b5Hz for Z = 0.03. For HD 24712 the frequency splitting \u03bd0 = 68 \u00b5Hz (Kurtz et al. 1989) , and 50 \u00b5Hz (Kurtz et al. 1994) for HD 128898 (b).", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "For HD 24712 and \u03b1 Cir, we find models with Kurucz atmospheres and with parameters in agreement with the observational error box which have a theoretical cut-off frequency larger than the largest observed frequency and hence are in agreement with observations. One may thus speculate that the old controversy about a mismatch between observed largest frequencies and theoretical cut-off frequencies of roAp star models is resolved.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "However, effects from e.g. an abundance different from solar might affect the cut-off frequency. Abundant rare-earth elements, through blanketing effects, could decrease the surface temperature and thus increase the cut-off frequency. This frequency might also be affected by a chemical composition gradient (Vauclair & Dolez 1990) . Magnetic field (Dziembowski & Goode 1996) and NLTE effects should also be taken into account.", "cite_spans": [{"start": 308, "end": 331, "text": "(Vauclair & Dolez 1990)", "ref_id": "BIBREF17"}], "ref_spans": []}], "bib_entries": {"BIBREF2": {"title": "Model Atmospheres and Spectrum Synthesis, 5 th vienna Workshop", "authors": [{"first": "F", "middle": [], "last": "Castelli", "suffix": ""}], "year": 1996, "venue": "", "link": null}, "BIBREF4": {"title": "Hydrodynamic and magnetohydrodynamic problems in the Sun and stars", "authors": [{"first": "D", "middle": ["O"], "last": "Gough", "suffix": ""}], "year": 1986, "venue": "", "link": "117903551"}, "BIBREF6": {"title": "CDROM13: atlas9. 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Baglin", "authors": [{"first": "D", "middle": ["; W H"], "last": "Mihalas", "suffix": ""}, {"first": "", "middle": [], "last": "Freeman", "suffix": ""}, {"first": "", "middle": [], "last": "Company", "suffix": ""}, {"first": "P", "middle": [], "last": "San Fransisco Morel", "suffix": ""}], "year": 1978, "venue": "", "link": null}, "BIBREF15": {"title": "Challenges to theories of the structure of moderate-mass stars", "authors": [{"first": "N", "middle": ["E"], "last": "Piskunov", "suffix": ""}, {"first": "F", "middle": [], "last": "Kupka", "suffix": ""}, {"first": "H", "middle": [], "last": "Shibahashi", "suffix": ""}], "year": 1991, "venue": "", "link": null}, "BIBREF17": {"title": "Progress of Seismology of the Sun and stars", "authors": [{"first": "S", "middle": [], "last": "Vauclair", "suffix": ""}, {"first": "N", "middle": [], "last": "Dolez", "suffix": ""}], "year": 1990, "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Figure 1. HR diagram for stars with 1.58 M\u2299 to 1.69 M\u2299 for Z = 0.02 (age up to 1000 Myr), and with 1.90 and 1.93 M\u2299 for Z = 0.03 (age up to 700 Myr) (dashed lines). The roAp stars HD 24712, HD 134214 and HD 128898 are indicated by circles and error boxes. Full lines are lines of constant cut-off frequency \u03bd (1) M for the Kurucz models, for 2300, 2500, 2800 and 3000 \u00b5Hz for Z = 0.02, and for 2300 and 2600 \u00b5Hz for Z = 0.03 (a), and lines of constant frequency spacing \u03bd0 = (2 R 0 (dr/c)) \u22121 for the same models, from 80 to 65 \u00b5Hz for Z = 0.02, and from 70 to 60 \u00b5Hz for Z = 0.03. For HD 24712 the frequency splitting \u03bd0 = 68 \u00b5Hz (Kurtz et al. 1989), and 50 \u00b5Hz (Kurtz et al. 1994) for HD 128898 (b).", "type": "figure"}, "TABREF0": {"text": "Acoustic cut-off frequencies \u03bdM in \u00b5Hz, for the Hopf and Kurucz models. \u2206\u03bd is the difference between the respective Kurucz and Hopf models.", "type": "table"}}}
{"paper_id": "18984973", "_pdf_hash": "932945de6877f5c346cbff3d20bcf7648f7e525d", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Culture, categorization, and inductive reasoning", "authors": [{"first": "I", "middle": [], "last": "Choi", "suffix": ""}, {"first": "R", "middle": ["E"], "last": "Nisbett", "suffix": ""}, {"first": "E", "middle": ["E"], "last": "Smith", "suffix": ""}], "year": 1997, "venue": "Cognition", "link": null}, "BIBREF1": {"title": "Similarity and property effects in inductive reasoning", "authors": [{"first": "E", "middle": [], "last": "Heit", "suffix": ""}, {"first": "J", "middle": [], "last": "Rubinstein", "suffix": ""}], "year": 1994, "venue": "Journal of Experimental Psychology: Learning, Memory, and Cognition", "link": "9806284"}, "BIBREF3": {"title": "The role of theories in conceptual coherence", "authors": [{"first": "L", "middle": [], "last": "Murphy", "suffix": ""}, {"first": "M", "middle": [], "last": "Medin", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "", "suffix": ""}], "year": 1985, "venue": "Psychological Review", "link": "14525617"}, "BIBREF4": {"title": "Human inference: strategies and shortcomings of social judgments", "authors": [{"first": "R", "middle": ["E"], "last": "Nisbett", "suffix": ""}, {"first": "L", "middle": [], "last": "Ross", "suffix": ""}], "year": 1980, "venue": "", "link": "124895197"}, "BIBREF5": {"title": "Category based induction", "authors": [{"first": "D", "middle": ["N"], "last": "Osherson", "suffix": ""}, {"first": "E", "middle": ["E"], "last": "Smith", "suffix": ""}, {"first": "O", "middle": [], "last": "Wilkie", "suffix": ""}, {"first": "A", "middle": [], "last": "Lopez", "suffix": ""}, {"first": "E", "middle": [], "last": "Shafir", "suffix": ""}], "year": 1990, "venue": "Psychological Review", "link": "5607160"}, "BIBREF6": {"title": "Expertise and category-based induction", "authors": [{"first": "J", "middle": ["B"], "last": "Proffitt", "suffix": ""}, {"first": "D", "middle": [], "last": "Coley", "suffix": ""}, {"first": "D", "middle": ["L"], "last": "Medin", "suffix": ""}], "year": 2000, "venue": "Journal of Experimental Psychology: Learning, Memory, and Cognition", "link": "10935972"}, "BIBREF7": {"title": "Inductive judgments about natural categories Journal of Verbal Learning and Verbal Behavior", "authors": [{"first": "L", "middle": ["J"], "last": "Rips", "suffix": ""}], "year": 1975, "venue": "", "link": null}, "BIBREF8": {"title": "Strategies of information search in causal analysis", "authors": [{"first": "H", "middle": [], "last": "Shaklee", "suffix": ""}, {"first": "B", "middle": [], "last": "Fischhoff", "suffix": ""}], "year": 1982, "venue": "Memory & Cognition", "link": "143469202"}, "BIBREF9": {"title": "Feature-based induction", "authors": [{"first": "S", "middle": ["A"], "last": "Sloman", "suffix": ""}], "year": 1993, "venue": "Cognitive Psychology", "link": "54325335"}, "BIBREF10": {"title": "When explanations compete: The role of explanatory coherence on judgements of likelihood", "authors": [{"first": "S", "middle": ["A"], "last": "Sloman", "suffix": ""}], "year": 1994, "venue": "Cognition", "link": "13522349"}, "BIBREF11": {"title": "Explanatory coherence and the induction of property", "authors": [{"first": "S", "middle": ["A"], "last": "Sloman", "suffix": ""}], "year": 1997, "venue": "Thinking and Reasoning", "link": "145520839"}, "BIBREF12": {"title": "Similarity, plausibility, and judgments of probability", "authors": [{"first": "E", "middle": ["E"], "last": "Smith", "suffix": ""}, {"first": "E", "middle": [], "last": "Shafir", "suffix": ""}, {"first": "D", "middle": ["N"], "last": "Osherson", "suffix": ""}], "year": 1993, "venue": "Cognition", "link": "28995407"}, "BIBREF13": {"title": "Conceptual revolution", "authors": [{"first": "P", "middle": [], "last": "Thagard", "suffix": ""}], "year": 1992, "venue": "", "link": null}, "BIBREF14": {"title": "On the failure to eliminate hypotheses in a conceptual task", "authors": [{"first": "P", "middle": ["C"], "last": "Wason", "suffix": ""}], "year": 1960, "venue": "Quarterly Journal of Experimental Psychology", "link": "19237642"}}, "ref_entries": {}}
{"paper_id": "18985112", "_pdf_hash": "da061fca36d60faadce44a6f0a5e17a65f1a153b", "abstract": [{"section": "Abstract", "text": "1. Time with Julie in his laboratory at the NIH in the early 1970s is remembered. The experience led to a life-long interest in the regulation of catecholamine secretion. Here are summarized aspects of this work.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "2. The relationship between ATP-dependent priming of exocytosis and the polyphosphoinositides is reviewed. In addition, studies are summarized in which total internal reflection fluorescent microscopy (TIRFM) was used to visualize secretory granule behavior before exocytosis and individual exocytotic events.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "3. Quantitative optical analysis indicates that chromaffin granule motion is highly restricted but regulated. Granules can undergo significant motion in the 100 ms prior to fusion and interactions with the plasma membrane leading to fusion can occur within this time. The small motions may permit granules adjacent to the plasma membrane to repetitively sample microdomains of the plasma membrane, thereby increasing the probability of fruitful interactions that lead to fusion.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "lunch, he would tell me that he had read an interesting paper about a topic similar to what I was working on. Oh, he forgot the author, but by the way, he would ask, when are you going to write it up?", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "I was helped in my endeavors in the laboratory by incredible colleagues. They graciously introduced me to the world of biochemistry and pharmacology.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "The thrust of my research continues to concern catecholamines, especially catecholamine secretion from adrenal medullary cells. With the development of techniques to maintain these primary, non-dividing cells in culture, chromaffin cells have become one of the most studied model systems for regulated exocytosis. Because large numbers of cells can be obtained from bovine adrenal medulla, the cultures are suitable for biochemical as well as physiological studies. We and others discovered that secretion was maintained in cells when the plasma membrane was permeabilized by electroporation (Baker and Knight, 1978) or low concentrations of digitonin (Dunn and Holz, 1983; Wilson and Kirshner, 1983; Brooks and Treml, 1983) or streptolysin O (Ahnert-Hilger et al., 1989) . This opened the way for a large number of studies in which the cell interior could be manipulated and secretion stimulated directly by micromolar Ca 2+ .", "cite_spans": [{"start": 592, "end": 616, "text": "(Baker and Knight, 1978)", "ref_id": "BIBREF6"}, {"start": 652, "end": 673, "text": "(Dunn and Holz, 1983;", "ref_id": "BIBREF15"}, {"start": 674, "end": 700, "text": "Wilson and Kirshner, 1983;", "ref_id": "BIBREF48"}, {"start": 701, "end": 724, "text": "Brooks and Treml, 1983)", "ref_id": "BIBREF10"}, {"start": 743, "end": 771, "text": "(Ahnert-Hilger et al., 1989)", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "THE ATP-DEPENDENCY OF SECRETION AND THE MAINTENANCE OF PTDINS(4,5)P 2", "text": "Studies in permeabilized chromaffin cells first demonstrated that the secretory pathway could be separated into distinct kinetic steps with different biochemical characteristics (Holz et al., 1989; Bittner and Holz, 1992a,b) . A slow ATP-dependent priming step precedes a rapid Ca 2+ -dependent triggering step.", "cite_spans": [{"start": 178, "end": 197, "text": "(Holz et al., 1989;", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "THE ATP-DEPENDENCY OF SECRETION AND THE MAINTENANCE OF PTDINS(4,5)P 2", "text": "Ca 2+ , in addition to triggering exocytosis, also enhances ATP-dependent priming. Similar pathways exist in PC12 cells (Hay and Martin, 1992) , melanotrophs (Parsons et al., 1995) and bipolar neurons (Heidelberger, 1998) and are likely to operate in most if not all differentiated secretory cells. It was subsequently discovered that a major component (as much as 70%) of the ATP-dependency of secretion in permeabilized chromaffin cells reflects the maintenance of the polyphosphoinositides (Eberhard et al., 1990) . The enzymatic removal of PtdIns in permeabilized cells results in the subsequent decline in PtdIns(4,5)P 2 and PtdIns(5)P and the specific inhibition of ATP-dependent secretion (Eberhard et al., 1990) . The study demonstrated that the removal of either substrate of PtdIns-4 kinase, PtdIns or ATP, inhibited exocytosis. Studies in PC12 cells strongly advanced the concept of the role of the polyphosphoinositides in secretion. Two cytosolic factors that are necessary for ATP dependent priming of exocytosis were identified as a phosphatidylinositol transfer protein (Hay and Martin, 1993) and PtdIns(4)P-5 kinase (Hay et al., 1995) . These studies implicated the following reactions in ATP-dependent priming of The experiments in chromaffin (Eberhard et al., 1990 ) and PC12 cells (Hay and Martin, 1993; Hay et al., 1995) were the first evidence that the polyphosphoinositides play important roles in vesicular trafficking reactions. Subsequently, polyphosphoinositides were implicated in numerous vesicular trafficking pathways (reviewed in (De Camilli et al., 1996) including synaptic vesicle exocytosis (Wiedemann et al., 1998; Khvotchev and Sudhof, 1998) , ARF1-dependent trafficking, endocytic recycling of synaptic vesicle membrane, and endocytosis of G-protein coupled receptors (Sorensen et al., 1999) . Polyphosphoinositides labeled in the three position of the inositol ring are necessary for vesicular trafficking between the Golgi and vacuole/lysosome in yeast and mammalian cells (Schu et al., 1993; Wurmser et al., 1999) .", "cite_spans": [{"start": 120, "end": 142, "text": "(Hay and Martin, 1992)", "ref_id": "BIBREF21"}, {"start": 158, "end": 180, "text": "(Parsons et al., 1995)", "ref_id": "BIBREF39"}, {"start": 201, "end": 221, "text": "(Heidelberger, 1998)", "ref_id": "BIBREF23"}, {"start": 493, "end": 516, "text": "(Eberhard et al., 1990)", "ref_id": "BIBREF16"}, {"start": 696, "end": 719, "text": "(Eberhard et al., 1990)", "ref_id": "BIBREF16"}, {"start": 1086, "end": 1108, "text": "(Hay and Martin, 1993)", "ref_id": "BIBREF22"}, {"start": 1133, "end": 1151, "text": "(Hay et al., 1995)", "ref_id": "BIBREF20"}, {"start": 1261, "end": 1285, "text": "(Eberhard et al., 1990 )", "ref_id": "BIBREF16"}, {"start": 1301, "end": 1323, "text": "(Hay and Martin, 1993;", "ref_id": "BIBREF22"}, {"start": 1324, "end": 1341, "text": "Hay et al., 1995)", "ref_id": "BIBREF20"}, {"start": 1562, "end": 1587, "text": "(De Camilli et al., 1996)", "ref_id": "BIBREF14"}, {"start": 1626, "end": 1650, "text": "(Wiedemann et al., 1998;", "ref_id": "BIBREF47"}, {"start": 1651, "end": 1678, "text": "Khvotchev and Sudhof, 1998)", "ref_id": "BIBREF29"}, {"start": 1806, "end": 1829, "text": "(Sorensen et al., 1999)", "ref_id": "BIBREF43"}, {"start": 2013, "end": 2032, "text": "(Schu et al., 1993;", "ref_id": "BIBREF42"}, {"start": 2033, "end": 2054, "text": "Wurmser et al., 1999)", "ref_id": "BIBREF49"}], "ref_spans": []}, {"section": "THE ATP-DEPENDENCY OF SECRETION AND THE MAINTENANCE OF PTDINS(4,5)P 2", "text": "PtdIns-4,5-P 2 is generally thought to be located on the plasma membrane (Whipps et al., 1987; Hokin and Hokin, 1964; Eichberg and Dawson, 1965) . However, it has also long been known that PtdIns-4 kinase is an integral membrane protein of the chromaffin granule membrane (Buckley et al., 1971; Phillips, 1973; Muller and Kirshner, 1975; Husebye and Flatmark, 1988) . PtdIns-4 kinase is also associated with synaptic vesicles (Wiedemann et al., 1998) and mast cell granules (Kurosawa and Parker, 1986) . It is, therefore, possible that PtdIns-4,5-P 2 could be synthesized on the secretory granule membrane through the sequential action of granule PtdIns-4 kinase and PtdIns-4-P-5 kinase. We investigated the localization of PtdIns-4,5-P 2 that is involved in exocytosis by transiently expressing in chromaffin cells a pleckstrin homology (PH) domain that specifically binds PtdIns-4,5-P 2 and is fused to green fluorescent protein (GFP). Transiently expressed PH-GFP almost exclusively labeled the plasma membrane of chromaffin cells, with no detectable labeling of chromaffin granules (Holz et al., 2000) .", "cite_spans": [{"start": 73, "end": 94, "text": "(Whipps et al., 1987;", "ref_id": "BIBREF46"}, {"start": 95, "end": 117, "text": "Hokin and Hokin, 1964;", "ref_id": "BIBREF24"}, {"start": 118, "end": 144, "text": "Eichberg and Dawson, 1965)", "ref_id": "BIBREF17"}, {"start": 272, "end": 294, "text": "(Buckley et al., 1971;", "ref_id": "BIBREF11"}, {"start": 295, "end": 310, "text": "Phillips, 1973;", "ref_id": "BIBREF40"}, {"start": 311, "end": 337, "text": "Muller and Kirshner, 1975;", "ref_id": "BIBREF35"}, {"start": 338, "end": 365, "text": "Husebye and Flatmark, 1988)", "ref_id": "BIBREF27"}, {"start": 426, "end": 450, "text": "(Wiedemann et al., 1998)", "ref_id": "BIBREF47"}, {"start": 474, "end": 501, "text": "(Kurosawa and Parker, 1986)", "ref_id": "BIBREF30"}, {"start": 1086, "end": 1105, "text": "(Holz et al., 2000)", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "THE ATP-DEPENDENCY OF SECRETION AND THE MAINTENANCE OF PTDINS(4,5)P 2", "text": "Expression of PH-GFP on the plasma membrane inhibited secretion measured biochemically in intact and permeabilized cells, and electrophysiologically by capacitance changes (Holz et al., 2000) . Thus, it is the plasma membrane pool of PtdIns-4,5-P 2 that is required for exocytosis.", "cite_spans": [{"start": 172, "end": 191, "text": "(Holz et al., 2000)", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "THE ATP-DEPENDENCY OF SECRETION AND THE MAINTENANCE OF PTDINS(4,5)P 2", "text": "This work has been expanded to neurons. The regulation by neuronal activity of presynaptic PtdIns-4,5-P 2 was investigated in cultured hippocampal neurons transiently expressing PH-GFP (Micheva et al., 2001) . As in chromaffin cells, PH-GFP selectively labeled the plasma membrane. Synaptic vesicles were not labeled. Upon electrical stimulation PH-GFP accumulated in the center of boutons where endocytic, clathrin-coated vesicles accumulate. Because PtdIns-4,5-P 2 is metabolized by the lipid phosphatase synaptojanin to permit uncoating of clathrin from endocytic vesicles (Cremona et al., 1999) , the dynamics of PH-GFP labeling may reflect a PtdIns-4,5-P 2 cycle important in exocytosis and endocytosis. Newly formed endocytic vesicles contain PtdIns-4,5-P 2 from the plasma membrane but must lose the lipid in order to mature into synaptic vesicles. The lack of PtdIns-4,5-P 2 in the membranes of both synaptic vesicles and secretory granules from the protein biosynthetic pathway (e.g., chromaffin granules) may have important implications for the process of exocytosis itself. Surprising, PtdIns-4,5-P 2 in the bouton is regulated by a retrograde signaling pathway involving post-synaptic, NMDA receptors and the formation of NO with effects on endocytosis and exocytosis (Micheva et al., 2001; Micheva et al., 2003) .", "cite_spans": [{"start": 185, "end": 207, "text": "(Micheva et al., 2001)", "ref_id": "BIBREF34"}, {"start": 576, "end": 598, "text": "(Cremona et al., 1999)", "ref_id": "BIBREF13"}, {"start": 1280, "end": 1302, "text": "(Micheva et al., 2001;", "ref_id": "BIBREF34"}, {"start": 1303, "end": 1324, "text": "Micheva et al., 2003)", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "THE ATP-DEPENDENCY OF SECRETION AND THE MAINTENANCE OF PTDINS(4,5)P 2", "text": "How might plasma membrane PtdIns(4,5)P 2 be involved in exocytosis? The initial experiments ruled out the involvement of PtdIns(4,5)P 2 in secretion as a substrate for phospholipase C (Eberhard et al., 1990) . Instead, the lipid is likely to act in the secretory pathway as an allosteric regulator of specific protein function. Three proteins associated with the chromaffin granule membrane bind in a specific manner PtdIns-4,5-P 2 -synaptotagmin (Schiavo et al., 1996; Bai et al., 2004) , Rabphilin3 (Chung et al., 1998) and calcium-dependent activator protein for secretion (CAPS) (Loyet et al., 1998) . The Ca 2+ -regulated interaction of one or more of the proteins with PtdIns-4,5-P 2 in the plasma membrane may modulate protein function and could possibly be directly involved in the fusion reaction.", "cite_spans": [{"start": 184, "end": 207, "text": "(Eberhard et al., 1990)", "ref_id": "BIBREF16"}, {"start": 447, "end": 469, "text": "(Schiavo et al., 1996;", "ref_id": "BIBREF41"}, {"start": 470, "end": 487, "text": "Bai et al., 2004)", "ref_id": "BIBREF5"}, {"start": 501, "end": 521, "text": "(Chung et al., 1998)", "ref_id": "BIBREF12"}, {"start": 583, "end": 603, "text": "(Loyet et al., 1998)", "ref_id": "BIBREF31"}], "ref_spans": []}, {"section": "THE ATP-DEPENDENCY OF SECRETION AND THE MAINTENANCE OF PTDINS(4,5)P 2", "text": "Additionally, the requirement of plasma membrane PtdIns-4,5-P 2 in secretion may reflect a role for the lipid in regulating cytoskeletal dynamics immediately adjacent to the plasma membrane during exocytosis. Chromaffin cells have a 200 nm thick actin layer immediately adjacent to the plasma membrane (Nakata and Hirokawa, 1992) . The polyphosphoinositides including PtdIns-4,5-P 2 and 3-phosphorylated forms interact with and regulate numerous cytoskeletal proteins and proteins involved in vesicular trafficking (reviewed in (Martin, 1997; Wurmser et al., 1999) ). The actin cytoskeleton in chromaffin cells is especially sensitive to reductions in PtdIns-4,5-P 2 (Bittner and Holz, 2005) . Cortical actin is decreased by transient expression of PH-GFP in intact cells and by removal of ATP in permeabilized cells. Surprisingly, the cortical actin network in chromaffin cells is resistant to latrunculin B, mycalide and cytochalasin D, drugs which by binding actin disrupt lamellapodia and stress fibers. These results suggest differences in the manner in which f-actin is controlled in different cellular locations.", "cite_spans": [{"start": 302, "end": 329, "text": "(Nakata and Hirokawa, 1992)", "ref_id": "BIBREF36"}, {"start": 528, "end": 542, "text": "(Martin, 1997;", "ref_id": "BIBREF32"}, {"start": 543, "end": 564, "text": "Wurmser et al., 1999)", "ref_id": "BIBREF49"}, {"start": 667, "end": 691, "text": "(Bittner and Holz, 2005)", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "SECRETORY GRANULE BEHAVIOR ADJACENT TO THE PLASMA MEMBRANE BEFORE AND DURING EXOCYTOSIS", "text": "Virtually all models of exocytosis invoke granule movement to the plasma membrane and a plasma membrane docking step. The precise nature of these events has been surmised but not directly investigated. \"Morphological\" docking has been defined by static electron microscopic images (Steyer et al., 1997) . Inferences concerning the dynamics of events immediately before fusion are based upon the kinetics of secretion. In these experiments granule pools are defined by the rates at which granules fuse with the plasma membrane after a Ca 2+ stimulus and the manner in which the kinetics are altered by biochemical manipulations. Another view of granule behavior comes from quantitative studies of granule motion using wide field, confocal and especially total internal reflection fluorescence microscopy (TIRFM) of fluorescent-tagged secretory granules. The latter technique selectively illuminates the aqueous phase immediately adjacent to a glass interface with an exponentially decaying excitation (the evanescent field, decay constant 50-100 nm) (Axelrod, 1981 (Axelrod, , 2003 . A distance into the cell extending less than a granule diameter is selectively visualized. Motions of granules labeled with GFP-tagged lumenal cargo or granule membrane protein can be determined with resolution of \u223c10 nm. Motions perpendicular to the glass interface (z-motions) are calculated from changes in fluorescence intensity, whereas granule motions parallel to the glass interface (Rmotions) are determined by extrapolated center of intensity measurements (Johns et al., 2001; Allersma et al., 2004) . A common finding in TIRFM studies in chromaffin cells is that most (>98%) of the granules adjacent to the plasma membrane are highly restricted in their motion (Steyer et al., 1997; Oheim et al., 1998; Han et al., 1999; Johns et al., 2001; Ohara-Imaizumi et al., 2002) , as if tethered or caged.", "cite_spans": [{"start": 281, "end": 302, "text": "(Steyer et al., 1997)", "ref_id": "BIBREF44"}, {"start": 1049, "end": 1063, "text": "(Axelrod, 1981", "ref_id": "BIBREF3"}, {"start": 1064, "end": 1080, "text": "(Axelrod, , 2003", "ref_id": "BIBREF4"}, {"start": 1548, "end": 1568, "text": "(Johns et al., 2001;", "ref_id": "BIBREF28"}, {"start": 1569, "end": 1591, "text": "Allersma et al., 2004)", "ref_id": "BIBREF2"}, {"start": 1754, "end": 1775, "text": "(Steyer et al., 1997;", "ref_id": "BIBREF44"}, {"start": 1776, "end": 1795, "text": "Oheim et al., 1998;", "ref_id": "BIBREF38"}, {"start": 1796, "end": 1813, "text": "Han et al., 1999;", "ref_id": "BIBREF19"}, {"start": 1814, "end": 1833, "text": "Johns et al., 2001;", "ref_id": "BIBREF28"}, {"start": 1834, "end": 1862, "text": "Ohara-Imaizumi et al., 2002)", "ref_id": "BIBREF37"}], "ref_spans": []}, {"section": "SECRETORY GRANULE BEHAVIOR ADJACENT TO THE PLASMA MEMBRANE BEFORE AND DURING EXOCYTOSIS", "text": "Granules undergo priming steps before secretion that are regulated by ATP and calcium (see above). Recent studies indicate that these co-factors also affect granule motion (Allersma et al., 2006) . Removal of ATP in permeabilized cells caused granule motion to decrease. Nicotinic stimulation caused a calciumdependent increase in average granule motion. This effect was more pronounced for granules that undergo exocytosis than for those that do not. Thus, there is a regulated component to these small motions that may be important in exocytosis.", "cite_spans": [{"start": 172, "end": 195, "text": "(Allersma et al., 2006)", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "SECRETORY GRANULE BEHAVIOR ADJACENT TO THE PLASMA MEMBRANE BEFORE AND DURING EXOCYTOSIS", "text": "TIRFM was used to investigate fusion events from the point of view of a membrane protein that diffuses from the granule to the plasma membrane upon fusion (Allersma et al., 2004) . Secretory granules labeled with the v-SNARE, VAMP-GFP, showed distinct signatures upon exocytosis when viewed by TIRFM. In approximately 90% of fusion events, we observed a large increase in fluorescence intensity coupled with a transition from a small punctate appearance to a larger, spreading cloud with free diffusion of the VAMP-GFP into the plasma membrane (Fig. 1) . Quantitation indicates that these events reflect an initially fused and spherical granule, with subsequent free diffusion of VAMP-GFP through the fusion junction Fig. 1 . An intensity burst characterizes the fusion of an individual VAMP-GFP-labeled granule with the plasma membrane. Successive frames show the fusion of a VAMP-GFPcontaining granule and the subsequent spread of the VAMP-GFP in the plasma membrane in TIRFM. The frame just prior to fusion is t = 0.0 s. Below each image is the VAMP-GFP intensity (with background subtracted) averaged as a function of radial distance r away from the granule center. Peak intensity is in the center of the intensity profile. The fluorescence almost completely disappeared after one second. [from (Allersma et al., 2004) ].", "cite_spans": [{"start": 155, "end": 178, "text": "(Allersma et al., 2004)", "ref_id": "BIBREF2"}, {"start": 1299, "end": 1322, "text": "(Allersma et al., 2004)", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "SECRETORY GRANULE BEHAVIOR ADJACENT TO THE PLASMA MEMBRANE BEFORE AND DURING EXOCYTOSIS", "text": "with possible flattening of the granule membrane into the plane of the plasma membrane (Allersma et al., 2004) .", "cite_spans": [{"start": 87, "end": 110, "text": "(Allersma et al., 2004)", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "SECRETORY GRANULE BEHAVIOR ADJACENT TO THE PLASMA MEMBRANE BEFORE AND DURING EXOCYTOSIS", "text": "Most of the granules that undergo exocytosis are observed jittering in place adjacent to the plasma membrane, undergoing motions of 10-200 nm within 100-200 ms of fusion. Absence of correlation of motions of even immediately adjacent granules suggests that the motions of these granules are not directly coupled to hypothetical motions of extended areas of the plasma membrane. However, granules may by attached directly or indirectly by flexible tethers to the plasma membrane.", "cite_spans": [], "ref_spans": []}, {"section": "SECRETORY GRANULE BEHAVIOR ADJACENT TO THE PLASMA MEMBRANE BEFORE AND DURING EXOCYTOSIS", "text": "These observations of granule motion before exocytosis contrast with the common assumption that granules that are morphologically close to the plasma membrane (within a granule diameter) are stably interacting with the membrane and that this bound state is required for priming and subsequent exocytosis. Instead, they suggest that granule can undergo significant motion within 100 ms of fusion and that interactions with the plasma membrane leading to fusion can occur within this time (Fig. 2) . These considerations may also apply to fast synaptic transmission. Indeed, rapid interactions between synaptic vesicles and the plasma membrane occur in the very fast events associated with synaptic transmission in inner hair cells (Griesinger et al., 2005) . Fig. 2 . Behavior of granules before exocytosis. A standard model for exocytosis is that granules translocate from the cell interior to the plasma membrane and stably bind or dock to the plasma membrane. After subsequent priming steps, the granule is able to fuse with the plasma membrane in respond to elevated Ca 2+ . A recent study indicates that granules that undergo exocytosis can have numerous behaviors immediately preceding fusion. (Allersma et al., 2006) . Some granules do not undergo detectable motion and may be bound to the plasma membrane. Others are jittering in place within 100 ms of fusion, as if on flexible tethers. A few granules are not present in the evanescent field before fusion and may move through it within 100 ms of fusion. Granule and plasma membrane priming events can occur before the final docking step leading to fusion.", "cite_spans": [{"start": 730, "end": 755, "text": "(Griesinger et al., 2005)", "ref_id": "BIBREF18"}, {"start": 1199, "end": 1222, "text": "(Allersma et al., 2006)", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "SECRETORY GRANULE BEHAVIOR ADJACENT TO THE PLASMA MEMBRANE BEFORE AND DURING EXOCYTOSIS", "text": "What is the significance to exocytosis of the small, regulated motions of secretory granules? They may permit granules adjacent to the plasma membrane to repetitively sample microdomains of the plasma membrane, thereby increasing the probability of fruitful interactions that lead to fusion. 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{"paper_id": "18985214", "_pdf_hash": "56a46f0b8fa4d2001202a202dd8969f550ccec80", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Alternative Numerical Solutions of Stationary Queueing-Time Distributions in Discrete-Time Queues: GI/G/1", "authors": [{"first": "M", "middle": ["L"], "last": "Chaudry", "suffix": ""}], "year": "", "venue": "Journal of the Operation Research Society", "link": "120269285"}, "BIBREF1": {"title": "Some Tactical Problems in Digital Simulation", "authors": [{"first": "R", "middle": ["W"], "last": "Conway", "suffix": ""}], "year": "", "venue": "Management Science", "link": "62680612"}, "BIBREF2": {"title": "Queueing for Telecommunications", "authors": [{"first": "J", "middle": [], "last": "Daigle", "suffix": ""}], "year": 1992, "venue": "", "link": null}, "BIBREF3": {"title": "Statistical Analysis for Queueing Simulations", "authors": [{"first": "G", "middle": ["S"], "last": "Fishman", "suffix": ""}], "year": "", "venue": "Management 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{"paper_id": "18986160", "_pdf_hash": "258daa6ec6f1ec051c63e83f4c5b6e2a547ca3be", "abstract": [{"section": "Abstract", "text": "To determine effects of curcumin on N-methyl-N-nitrosourea (MNU) and saturated sodium chloride (s-NaCl)-induced gastric cancer in rats. Male Wistar rats were divided into 5 groups: control (CO), control supplemented with 200 mg/kg curcumin (CC), MNU + s-NaCl, MNU + s-NaCl supplemented with 200 mg/kg curcumin daily for the first 3 weeks (MNU + s-NaCl + C3W), and MNU + s-NaCl supplemented with curcumin for 20 weeks (MNU + s-NaCl + C20W). To induce stomach cancer, rats except for CO and CC were orally treated with 100 mg/kg MNU on day 0 and 14, and s-NaCl twice-a-week for the first 3 weeks. The experiment was finished and rats were sacrificed at the end of 20 weeks. Cancers were found in forestomachs of all rats in MNU + sNaCl. The expressions of phosphorylated inhibitor kappaB alpha (phospho-I\u03baB\u03b1), 8-hydroxy-2 -deoxyguanosine (8-OHdG), and cyclin D1 significantly increased in MNU + s-NaCl compared with CO. Curcumin treatments for 3 and 20 weeks reduced the cancer incidence resulting in a decrease of phospho-I\u03baB\u03b1 expression in benign tumor-bearing rats compared with MNU + s-NaCl. Curcumin treatment for 20 weeks also decreased 8-OHdG expression in benign tumor-bearing rats compared with MNU + sNaCl. Curcumin can attenuate cancer via a reduction of phospho-I\u03baB\u03b1 and 8-OHdG expressions, which may play a promising role in gastric carcinogenesis.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Gastric cancer can generate in any part of the stomach. Poorly detected, gastric cancer causes nearly one million annual deaths worldwide [1, 2] . Gastric cancer is closely associated with dietary factors and Helicobacter pylori infection. Previous studies have reported that consumption of salty foods and N-nitroso compounds and a low intake of fresh fruits and vegetables increases the risk of gastric cancer [3, 4] . Hypertonic NaCl solutions induce gastric cancer in animal models through the enhancement of tissue damage resulting in cell proliferation [5] . Experimental animal models have also provided support for the hypothesis that salt promotes gastric carcinogenesis induced by N-nitroso carcinogen, such as N-methyl-N-nitro-N-nitrosoguanidine (MNNG) or Nmethyl-N-nitrosourea (MNU) [6] [7] [8] [9] . MNU, a mutagen and genotoxic substance, is a potent inducer of cellular stress leading to chromosomal aberrations, point mutations, cell death, and DNA damage [10] . Other studies reported that administration of MNU by oral gavage induced gastric cancer in rats and mice [11, 12] . Thus, the association between saturated NaCl and N-nitroso carcinogen could promote gastric carcinogenesis in rats by inflammation, mutation, and compensatory cell proliferation.", "cite_spans": [{"start": 138, "end": 141, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 142, "end": 144, "text": "2]", "ref_id": "BIBREF1"}, {"start": 412, "end": 415, "text": "[3,", "ref_id": "BIBREF2"}, {"start": 416, "end": 418, "text": "4]", "ref_id": "BIBREF3"}, {"start": 559, "end": 562, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 795, "end": 798, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 799, "end": 802, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 803, "end": 806, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 807, "end": 810, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 972, "end": 976, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 1084, "end": 1088, "text": "[11,", "ref_id": "BIBREF10"}, {"start": 1089, "end": 1092, "text": "12]", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "Introduction", "text": "A range of stimuli such as reactive oxygen species (ROS) and cytokines from inflammatory response can activate inhibitor kappaB kinase (IKK) complex resulting in inhibitor kappaB (I\u03baB) phosphorylation and proteolysis. Phosphorylation of I\u03baB\u03b1 elicits I\u03baB\u03b1 degradation, allowing the nuclear translocation of nuclear factor kappaB (NF-\u03baB) complex and activation of target genes that are involved in the control of cellular proliferation and carcinogenesis such as cyclin D1 [13, 14] . The interaction of ROS with the nucleobases of the DNA strand, such as guanine, leads to the formation of 8-hydroxy-2 -deoxyguanosine (8-OHdG) and structural alteration in DNA. The 8-OHdG is a potential biomarker of oxidative damage of DNA and a factor of initiation and promotion of carcinogenesis [15] . These molecules play a pivotal role in carcinogenesis and may be targets for therapeutic approaches.", "cite_spans": [{"start": 471, "end": 475, "text": "[13,", "ref_id": "BIBREF12"}, {"start": 476, "end": 479, "text": "14]", "ref_id": "BIBREF13"}, {"start": 781, "end": 785, "text": "[15]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Introduction", "text": "Chemoprevention is promising as a preventive approach for cancers. Curcumin (diferuloylmethane), a polyphenol compound, is an active ingredient of tumeric (Curcuma longa). Curcumin has chemopreventive properties. Importantly, curcumin is safe for humans and animals [16] . Curcumin shows beneficial effects in many cancers including colorectal cancer, breast cancer, skin cancer, and oral cancer [17] . Several signalling pathways implicated in carcinogenesis including NF-\u03baB signalling have been modulated by curcumin treatment [18] . However, data concerning the effect of curcumin on in vivo study of gastric cancer and key proteins involved in carcinogenesis induced by MNU and saturated NaCl (s-NaCl) have not been confirmed.", "cite_spans": [{"start": 266, "end": 270, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 396, "end": 400, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 529, "end": 533, "text": "[18]", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "Introduction", "text": "Therefore, the present study aims to examine the protective effect of curcumin on gastric cancer in rats induced by MNU and s-NaCl administration. In addition, activation of NF-\u03baB, expressions of oxidative damage of DNA and cell cycle regulator cyclin D1 will be investigated.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Experimental", "text": "Design. 6-week-old male Wistar rats (National Laboratory Animal Centre, Mahidol University, Bangkok, Thailand) were used. All experiments and procedures carried out on the animals were approved by the Ethics Committee of the Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand. Rats were housed in a controlled temperature room at 25 \u00b1 1", "cite_spans": [], "ref_spans": []}, {"section": "Experimental", "text": "\u2022 C under standard conditions (12-h dark-light cycle). Thirty rats were randomized into five groups (six rats each) as follows.", "cite_spans": [], "ref_spans": []}, {"section": "Experimental", "text": "Control rats (CO) were fed citrate buffer, pH 4.5 (1 mL/rat) orally via intragastric tube on days 0 and 14 of the experiment. In addition, rats were fed normal saline (1 mL/rat) orally twice a week for the first 3 weeks of the experiment. Corn oil (2.5 mL/kg) was administrated daily by intragastric tube for 20 weeks.", "cite_spans": [], "ref_spans": []}, {"section": "Experimental", "text": "Control rats supplemented with curcumin (CC) were fed citrate buffer, pH 4.5 and normal saline as previously described. 200 mg/kg curcumin (95% purified curcumin, Cayman Chemical, MI, USA) was dissolved in corn oil and given daily to rats by intragastric tube for 20 weeks.", "cite_spans": [], "ref_spans": []}, {"section": "Experimental", "text": "MNU-and saturated NaCl-induced rats (MNU + sNaCl) were treated for gastric carcinogenesis by MNU (Sigma-Aldrich, MO, USA) and s-NaCl (Merck, Germany) according to Thong-Ngam et al. [19] . Briefly, rats were fed 100 mg/kg MNU (dissolved in citrate buffer, pH 4.5) via intragastric tube on days 0 and 14 of the experiment. In addition, rats were fed s-NaCl (30% NaCl solution, 1 mL/rat) orally twice weekly for the first 3 weeks of the experiment. Corn oil was administrated daily by intragastric tube for 20 weeks.", "cite_spans": [{"start": 181, "end": 185, "text": "[19]", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Experimental", "text": "MNU-and s-NaCl-induced rats, supplemented with curcumin for 3 weeks (MNU + s-NaCl + C3W), were given with MNU and s-NaCl as previously describe. The 200 mg/kg curcumin was fed daily to rats by intragastric tube during administration of MNU and s-NaCl for the first 3 weeks. MNU-and s-NaCl-induced rats, supplemented with curcumin for 20 weeks (MNU + s-NaCl+C20W), were induced with MNU and s-NaCl. The 200 mg/kg curcumin was fed daily to rats by intragastric tube for 20 weeks.", "cite_spans": [], "ref_spans": []}, {"section": "Stomach Tissues Preparation.", "text": "After 20 weeks, all animals were sacrificed by intraperitoneal injection of Thiopental (Abbott, Italy, 120 mg/kg) after overnight fasting. Then, the stomach was excised and divided into 2 parts symmetrically along the greater and lesser curves. One part was fixed in liquid nitrogen and kept at \u221280", "cite_spans": [], "ref_spans": []}, {"section": "Stomach Tissues Preparation.", "text": "\u2022 C for western blot analysis. Another part was fixed in 4% paraformaldehyde in phosphate-buffered saline (PBS) for histological study.", "cite_spans": [], "ref_spans": []}, {"section": "Histopathological Study.", "text": "The tissue was fixed with 4% paraformaldehyde fixed and paraffin embedded. Multiple 2 \u03bcm-thick histological sections were stained with hemotoxylin and eosin (H&E). The alterations of gastric epithelial cells and the incidence of gastric carcinogenesis were determined by a pathologist. In addition, the cancer incidence was calculated as percentage using the following formula:", "cite_spans": [], "ref_spans": []}, {"section": "Histopathological Study.", "text": "Cancer incidence = 100 \u00d7 numbers of cancer-bearing rats numbers of induced rats .", "cite_spans": [], "ref_spans": []}, {"section": "Western Blot Analysis.", "text": "The tissue sample (0.05 g) was homogenized in 0.5 mL of ice-cold lysis RIPA buffer (Cell Signalling Technology Inc., MA, USA) with protease inhibitor (Sigma-Aldrich) and phosphatase inhibitor (SigmaAldrich). The homogenate was sonicated for 15 seconds and centrifuged at 11,000 g for 10 minutes at 4", "cite_spans": [], "ref_spans": []}, {"section": "Western Blot Analysis.", "text": "\u2022 C. The supernatant was retained. Protein concentration was measured with the BCA Protein Assay Kit (Thermo Scientific). The extracted proteins were mixed with loading buffer and boiled for 5 min. Then, the extracted proteins (35 \u03bcg/lane) were applied to 10% sodium dodecyl sulfate polyacrylamide gel electrophoresis. The separated proteins were transferred to polyvinylidene fluoride membrane (Pall Corporation, FL, USA). The blotted membrane was incubated with 5% nonfat dried milk in TBS (0.02 M Tris, pH 7.6, and 0.15 M NaCl) for 1 hour at room temperature. Then, the membrane was probed with mouse monoclonal anti-phosphorylation of inhibitor kappaB alpha (Phospho-I\u03baB\u03b1, Ser32/36) antibody (1 : 1000; Cell Signalling Technology Inc.) overnight at 4", "cite_spans": [], "ref_spans": []}, {"section": "Western Blot Analysis.", "text": "\u2022 C. Moreover, the membrane was also probed with anti-\u03b2-actin antibody (sc-47778, 1 : 5,000; Santa Cruz Biotechnology Inc., CA, USA) for 1 hour at room temperature. After three-time washing in TBS/0.01% Tween-20), the membrane was incubated with goat anti-mouse IgG HRP secondary antibody (1 : 4,000; Cayman Chemical) for 1 hour at room temperature. The bands of protein expression were developed with a commercial chemiluminescence detection kit (Amersham ECL plus western blotting system, GE Healthcare, UK). The luminescence was exposed to film (Fujiflim, Japan). Expression levels of proteins were quantified by ImageJ program (US National Institutes of Health, Bethesda, MA, USA). ", "cite_spans": [], "ref_spans": []}, {"section": "Western Blot Analysis.", "text": "The level of phospho-I\u03baB\u03b1 (Ser32/36) expression was normalized by \u03b2-actin density.", "cite_spans": [], "ref_spans": []}, {"section": "Immunohistochemistry.", "text": "In this study, we used BenchMark XT Instrument (Ventana, Medical System Inc., AZ, USA). Immunostaining for 8-OHdG or cyclin D1 was performed in paraffin embedded sections by the following processes. Briefly, the tissue sections were deparaffinized with EZ prepTM. After that, the sections were retrieved the antigen (8-OHdG or cyclin D1) with Sodium Chloride Sodium Citrate pH 6.5-7.5 (SSCTM). Next, 1% Hydrogen peroxide (H 2 O 2 , UltraViewTM Inhibitor) was used to block endogenous peroxidase activity. Then, the primary antibody used for 8-OHdG (1 : 400; Japan Institute for the Control of Aging, Japan) or cyclin D1 (1 : 200; Thermo Scientific, MI, USA) was applied and incubated at 37", "cite_spans": [], "ref_spans": []}, {"section": "Immunohistochemistry.", "text": "\u2022 C for 60 minutes or 32 minutes, respectively. After that, the goat anti-Mouse IgG (UltraViewTM HRP Multimer) was used as secondary antibody. Color was developed by UltraViewTM DAB chromogen, UltraViewTM H 2 O 2 , and UltraViewTM copper. Then, the slides were counterstained with Hematoxylin II and Lithium Carbonate. Under light microscope (Nikon E50i, Nikon Corporation, Japan), immunoreactive cells of 8-OHdG and cyclin D1 were defined as those with dark-brown-stained nuclei of gastric epithelial cells. To verify the expressions of 8-OHdG and cyclin D1 in all animals, digital images were taken in high magnification field (400x) from each sample using a microscope equipped with digital camera (Nikon Digital Sight DS-Fi1, Nikon Corporation, Japan). Ten images from two sections per animals were analyzed. The numbers of dark brown stained in nuclei of epithelial cells were counted manually using Point tool in the IMAGE-PRO PLUS software program (version 6.1). A thousand gastric epithelial cells were counted for each rat. The data were shown as the percentage (%) of immunoreactive cells calculating from following equation: ", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Gastric Cancer Incidence and Histopathological Studies of MNU and s-NaCl-Associated Gastric Carcinogenesis and", "text": "Effects of Curcumin. During the whole-study period, there was only one rat death. At 3 weeks, the rat in MNU + sNaCl + C3W died from aspiration after feeding. The results of autopsy showed congestion and bleeding spots in both lungs. There was hyperkeratosis in forestomach mucosa, but no precancerous lesions or tumor was detected by histological examination. 29 rats survived the 20 weeks of the study. Gastric cancer incidence was shown in Table 1 . There was no squamous cell carcinoma (SCC) in CO and CC groups. In MNU + s-NaCl group, SCC was found in forestomach of all rats (100%). SCC showed tumors scattered in the forestomach. In gross view, the tumor masses were coliform-like (Figure 1(a) ). Histopathology of SCC showed dyskeratosis and invasion of cancerous tissue through all layers of stomach wall. The cancerous tissue invaded the submucosal layer (Figure 1(b) ), the muscle layer (Figure 1(c) ), or the serosa (Figure 1(d) ). 3/5 (60%) rats in MNU + s-NaCl + C3W developed SCC. 2 rats in this group showed tumor-like lesions. Papillary growth or tumor-like lesion displayed hyperproliferation of epithelial cells, hyperkeratosis, but no invasion. These lesions were not diagnosed as cancers. In MNU + s-NaCl + C20W group, three rats developed SCC with submucosal invasion. The cancer incidence was 50%. One rat did not exhibit a cancerous lesion. Another 2 rats developed papillary growths.", "cite_spans": [], "ref_spans": [{"start": 443, "end": 450, "text": "Table 1", "ref_id": "TABREF0"}, {"start": 688, "end": 700, "text": "(Figure 1(a)", "ref_id": "FIGREF1"}, {"start": 865, "end": 877, "text": "(Figure 1(b)", "ref_id": "FIGREF1"}, {"start": 898, "end": 910, "text": "(Figure 1(c)", "ref_id": "FIGREF1"}, {"start": 928, "end": 940, "text": "(Figure 1(d)", "ref_id": "FIGREF1"}]}, {"section": "Curcumin Supplementation for 3 and 20 Weeks Attenuated Development of Carcinogenesis Associated with Phospho-I\u03baB\u03b1", "text": "Expression. From histopathological results (Table 1) , rats in MNU + s-NaCl + C3W and MNU + s-NaCl + C20W groups were divided into subgroup C3W benign group (N = 2), C3W cancer group (N = 3), C20W benign group (N = 3), and C20W cancer group (N = 3). Results showed that the expression of phosphorylated I\u03baB\u03b1 was not significantly different between CO and CC. Compared with CO, phosphorylated I\u03baB\u03b1 expression in MNU + s-NaCl increased These data were presented as the mean \u00b1 SD. * Represented significant difference compared with CO group (P < 0.05). * * Represented significant difference compared with CO group (P < 0.01). \u2020 Represented significant difference compared with MNU + s-NaCl group (P < 0.05). \u2020 \u2020 Represented significant difference compared with MNU + s-NaCl group (P < 0.01).", "cite_spans": [], "ref_spans": [{"start": 43, "end": 52, "text": "(Table 1)", "ref_id": "TABREF0"}]}, {"section": "Curcumin Supplementation for 3 and 20 Weeks Attenuated Development of Carcinogenesis Associated with Phospho-I\u03baB\u03b1", "text": "significantly (P = 0.010). Curcumin supplementations for 3 and 20 weeks in C3W benign and C20W benign groups significantly declined the expression of phosphorylated I\u03baB\u03b1 compared with MNU + s-NaCl (P = 0.028 and P = 0.031, resp.) ( Table 2 ). The represented bands of phospho-I\u03baB\u03b1 and \u03b2-actin were shown in Figure 2 .", "cite_spans": [], "ref_spans": [{"start": 307, "end": 315, "text": "Figure 2", "ref_id": "FIGREF2"}]}, {"section": "Curcumin Supplementation for 20 Weeks Attenuated Development of Carcinogenesis Associated with 8-OHdG and", "text": "Cyclin D1 Expressions. 8-OHdG and cyclin D1 expressions were studied by immunohistochemistry and shown as nuclei-stained cells. The average percentages of immunoreactive cells of all groups were shown in Table 2 . From the results, the mean percentages of 8-OHdG and cyclin D1-immunoreactive cells were not significantly different between CO and CC. They were significantly increased in MNU + s-NaCl compared with CO (P = 0.002 and P = 0.000, resp.). Curcumin supplementation for 20 weeks reduced gastric cancer incidence and significantly decreased 8-OHdG expression in C20W benign group compared with", "cite_spans": [], "ref_spans": []}, {"section": "Curcumin Supplementation for 20 Weeks Attenuated Development of Carcinogenesis Associated with 8-OHdG and", "text": "Journal of Biomedicine and Biotechnology MNU + s-NaCl (P = 0.015) ( Table 2 ). The average percentage of cyclin D1 stained cells in the C20W benign group tended to reduce, but not reach a statistically significant level when compared with MNU + s-NaCl (P = 0.062; Table 2 ). 8-OHdG was expressed primarily in gastric epithelial cells (Figure 2(a) ). This expression was increased in the mucosa of SCC in both MNU + s-NaCl and C20W cancer groups (Figures 3(b) and 3(c) ). This enhanced expression was limited to a small number of epithelial cells in C20W benign group (Figure 3(d) ).", "cite_spans": [], "ref_spans": [{"start": 334, "end": 346, "text": "(Figure 2(a)", "ref_id": "FIGREF2"}, {"start": 445, "end": 467, "text": "(Figures 3(b) and 3(c)", "ref_id": "FIGREF4"}, {"start": 567, "end": 579, "text": "(Figure 3(d)", "ref_id": "FIGREF4"}]}, {"section": "Discussion", "text": "This study demonstrated that oral gavage of MNU-and sNaCl-induced a 100% cancer incidence in rats. The histological results showed that curcumin could attenuate the gastric carcinogenesis induced by MNU and s-NaCl in rats. Administration of curcumin in both MNU + s-NaCl + C3W and MNU + s-NaCl + C20W groups showed 40% and 50% reduction of cancer incidence, respectively. These observations indicated that early administration of curcumin (during the first 3 weeks of cancer induction) might prevent the initiation of carcinogenesis. This is in agreement with previous studies. Feeding 0.5 and 2.0% of commercial grade curcumin in the diet during the initiation period (2 weeks before, during, and 1 week after benzo(a)pyrene administration) reduced the number of mice with forestomach tumors [20] . Daily feeding of 1 and 2 g/mL radix curcumae extract solution during MNNG administration for 40 weeks also showed the reduction of tumor incidences in 10% NaCl and MNNG-induced gastric cancer in rats [21] . Phosphorylation of I\u03baB\u03b1 could imply the activation of NF-\u03baB, which plays a major role in carcinogenesis [13, 14] . In gastric carcinoma patients, NF-\u03baB activation correlated with I\u03baB\u03b1 phosphorylation and degradation [22, 23] . Our study showed that overexpression of phosphorylated I\u03baB\u03b1 was associated with cancer. This finding coincided with other reports [24, 25] . Activation of NF-\u03baB appeared to be a key step of keratinocyte transformation into SCC in mice [24] . 49% of prostate adenocarcinoma patients showed NF-\u03baB overexpression that correlated with advanced tumor stage [25] . Curcumin has a chemopreventive property resulting in suppressing NF-\u03baB activation. Many studies confirmed that a pivotal role of curcumin is inhibiting IKK activity with declining I\u03baB\u03b1 phosphorylation [26, 27] . Our results showed that curcumin supplementations for 3 and 20 weeks significantly decreased phosphorylated I\u03baB\u03b1 in benign tumorbearing rats. Curcumin supplementation in this study prevented carcinogenesis by declining I\u03baB\u03b1 phosphorylation.", "cite_spans": [{"start": 793, "end": 797, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 1000, "end": 1004, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 1111, "end": 1115, "text": "[13,", "ref_id": "BIBREF12"}, {"start": 1116, "end": 1119, "text": "14]", "ref_id": "BIBREF13"}, {"start": 1223, "end": 1227, "text": "[22,", "ref_id": "BIBREF21"}, {"start": 1228, "end": 1231, "text": "23]", "ref_id": "BIBREF22"}, {"start": 1364, "end": 1368, "text": "[24,", "ref_id": "BIBREF23"}, {"start": 1369, "end": 1372, "text": "25]", "ref_id": "BIBREF24"}, {"start": 1469, "end": 1473, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 1586, "end": 1590, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 1794, "end": 1798, "text": "[26,", "ref_id": "BIBREF25"}, {"start": 1799, "end": 1802, "text": "27]", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "Discussion", "text": "8-OHdG is a potential biomarker of oxidative DNA damage and a factor of initiation and promotion of carcinogenesis [15] . In this study, we also showed that 8-OHdG expression significantly increased in the MNU + s-NaCl group compared with CO group. This observation confirmed many previous results obtained from various types of cancers in patients. The level of 8-OHdG expression is elevated in colorectal cancer [28] , hepatocellular carcinoma [29] , oral SCC [30] , and gastric cancer patients [31] . Considering the number of reports demonstrating a close relation between 8-OHdG formation and carcinogenicity, including this study, it is likely that 8-OHdG formations might participate in carcinogen-induced forestomach SCC. Curcumin showed a potent scavenger of reactive species (RS), such as superoxide anion, hydroxyl radical, singlet oxygen, nitric oxide, and peroxynitrite [32] . The reduction of RS could prevent the formation of 8-OHdG. This study demonstrated that 200 mg/kg curcumin supplementations for 3 and 20 weeks in MNU + s-NaCl-induced SCCs diminished 8-OHdG expression. In addition, 8-OHdG expression in C20W benign group was significantly reduced compared to MNU + s-NaCl. These results suggested that curcumin administration could protect carcinogenesis against formation of 8-OHdG.", "cite_spans": [{"start": 115, "end": 119, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 414, "end": 418, "text": "[28]", "ref_id": "BIBREF27"}, {"start": 446, "end": 450, "text": "[29]", "ref_id": "BIBREF28"}, {"start": 462, "end": 466, "text": "[30]", "ref_id": "BIBREF29"}, {"start": 497, "end": 501, "text": "[31]", "ref_id": "BIBREF30"}, {"start": 883, "end": 887, "text": "[32]", "ref_id": "BIBREF31"}], "ref_spans": []}, {"section": "Discussion", "text": "Oxidative damage of DNA as well as deregulation of cell cycle control causes cancer. This study demonstrated that the immunoreactive cells of cyclin D1, the positive cell cycle regulator, significantly increased in MNU + s-NaCl compared with CO. The nuclear accumulation of cyclin D1 is an essential indicator of oncogenicity. Previous studies showed that nuclear immunoreactivity for cyclin D1 positively correlated with tumor cell proliferation of gastric cancer patients [33] . Moreover, cyclin D1 overexpression occurred in patients with oral SCC [34] . Cyclin D1 expression in the C20W benign subgroup tended to decrease, but not reach a statistically significant level when compared with MNU + sNaCl. This study suggested that curcumin could not prevent carcinogenesis through improvement of dysregulation of cell cycle as shown by cyclin D1 accumulation.", "cite_spans": [{"start": 474, "end": 478, "text": "[33]", "ref_id": "BIBREF32"}, {"start": 551, "end": 555, "text": "[34]", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "Conclusion", "text": "MNU and s-NaCl led to increase of phosphorylated I\u03baB\u03b1, 8-OHdG, and cyclin D1 that are associated with forestomach carcinogenesis. 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significance, correlation with clinicopathological parameters, proliferation and apoptosis", "authors": [{"first": "K", "middle": ["H"], "last": "Lee", "suffix": ""}, {"first": "H", "middle": ["E"], "last": "Lee", "suffix": ""}, {"first": "S", "middle": ["J"], "last": "Cho", "suffix": ""}], "year": 2008, "venue": "Pathobiology", "link": "207692875"}, "BIBREF33": {"title": "Cyclin D1 expression in oral squamous cell carcinoma and verrucous carcinoma: correlation with histological differentiation", "authors": [{"first": "P", "middle": ["V"], "last": "Angadi", "suffix": ""}, {"first": "R", "middle": [], "last": "Krishnapillai", "suffix": ""}], "year": 2007, "venue": "Oral Radiology and Endodontology", "link": "22710885"}}, "ref_entries": {"FIGREF1": {"text": "Figure 1: Macroscopic (a) and microscopic (b-d, H&E staining, 40x) appearance of squamous cell carcinoma (SCC) in the forestomachs. The multiple polypoid tumors developed in the stomach after MNU and saturated NaCl administration (a). SCCs in the gastric epithelium show the invasion of cancerous tissue with dyskeratosis through submucosal layer (b), muscle layer (c), or serosa (d). Note: the arrows indicate SCC with submucosal invasion (b), muscle-layer invasion (c), and stomach perforation (d). MM: muscularis mucosae, SM: submucosa, and M: muscle layer.", "type": "figure"}, "FIGREF2": {"text": "The results of phospho-I\u03baB\u03b1-relative expression, 8-OHdG-immunoreactive cells (%), and cyclin D1-immunoreactive cells (%). Parameters/Group CO (N = 6) CC (N = 6) MNU + s-NaCl (N = 6) MNU + s-NaCl + C3W (N = 5) MNU + s-NaCl + C20W (N =51 \u00b1 0.11 \u2020 0.54 \u00b1 0.18 \u2020 0.82 \u00b1 0.18 * 0.46 \u00b1 0.04 \u2020 0.60 \u00b1 0.29 0.51 \u00b1 0.08 \u2020 1.16 \u00b1 0.34 * * , \u2020", "type": "figure"}, "FIGREF3": {"text": "Figure 2: Western blot analysis of phospho-I\u03baB\u03b1 expression. Curcumin supplementation in C3W benign group declined the expression of phosphorylated I\u03baB\u03b1 compared with MNU + s-NaCl (a), whereas the expression of phosphorylated I\u03baB\u03b1 in C3W cancer group did not decrease (b). Curcumin supplementation for 20 weeks in C20W benign decreased the expression of phosphorylated I\u03baB\u03b1 compared with MNU + s-NaCl (c), whereas the expression of phosphorylated I\u03baB\u03b1 in C20W cancer group did not decline (d). An antibody for \u03b2-actin was used as an internal control.", "type": "figure"}, "FIGREF4": {"text": "Figure 3: Immunohistochemical staining of 8-OHdG antibodies in the representative tissue specimens (400x): CO group (a), MNU + s-NaCl group (b), C20W cancer group (c), and C20W benign group (d). DAB stained immunoreactive cells (dark brown, arrows); nuclear counterstaining was performed with Hematoxylin II and Bluing reagent. LP: laminar propria and MM: muscularis mucosae.", "type": "figure"}, "TABREF0": {"text": "Histopathological changes of gastric mucosa in the experimental groups.", "type": "table"}, "TABREF1": {"text": "The percentage of immunoreactive cells (%)", "type": "table"}, "TABREF2": {"text": "", "type": "table"}}}
{"paper_id": "18986576", "_pdf_hash": "0a5f97cfb07d507d2b05e812fec8a700294be2a5", "abstract": [{"section": "Abstract", "text": "Mechanisms of Development is an international journal whose purpose is to communicate contemporary studies in developmental biology with special emphasis on the characterization of molecular mechanisms underlying developmental processes in either vertebrates, invertebrates or plants. Areas of particular interest include embryogenesis, pattern formation, cell movement and morphogenesis, cell determination and differentiation, specification of tissue type, targeted disruption of developmental control genes, the roles of transcription factors in development, regulatory hierarchies of gene expression, cell-cell communication and signal transduction in development, as well as post-transcriptional controls of developmental processes such as regulated splicing and protein modification. Such a focus should provide a unique forum for comparing and contrasting strategies of development among a wide spectrum of organisms. The Editors are strongly committed to establishing the highest standards of quality and scientific merit.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "The journal will publish full-length articles describing original, high quality research and some invited Minireviews.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Gene Expression Patterns will be published in a separate section.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Submission of papers", "text": "Submission of papers to Mechanisms of Development is understood to imply that the data contained therein have not previously been published (except in abstract form) nor are being considered for publication elsewhere, and that they have been tacitly or explicitly approved by all authors and by the responsible authorities in the laboratories where the work was carried out. If accepted, the paper shall not be published either in whole or in part elsewhere in the same or any other language without the consent of the Publisher. Submission also implies the transfer of the copyright from the author to the Publisher. Only submissions in English will be considered. One original plus two copies should be submitted to any one of the Managing Editors. Copies of submitted manuscripts will not be returned except in the case of rejected articles, where only the figures are returned to the author. Papers that do not conform to the general criteria for publication in Mechanisms of Development will be returned immediately to authors. The decision of the Editors is final; the Editors cannot enter into correspondence about a paper that is considered unsuitable for publication. For complete information on final submission of papers, please see the MOD checklist at the end of this guide. Please read this checklist carefully and cross-check items before final submission. ", "cite_spans": [], "ref_spans": []}, {"section": "Organisation of the manuscript", "text": "The general organisation of the sections, nomenclature, reference system, etc., are the same as those adopted by the major cell/developmental biology journals (e.g., Cell, Developmental Cell, The EMBO Journal). Manuscripts should be typewritten/printed double-spaced with wide margins throughout. Title page, abstract, tables, legends to figures and reference list should each be provided on separate sheets of paper. The title page should include: title of paper, name(s) and affiliation(s) of all author(s), a name and address for correspondence, and telephone/fax numbers and e-mail address for editorial queries. An abstract of up to 250 words and a list of up to 10 keywords should be provided. The main text should be ordered under the following headings: Introduction, Results, Discussion (which may be combined with Results), Experimental Procedures, Acknowledgements (when appropriate), References.", "cite_spans": [], "ref_spans": []}, {"section": "Illustrations", "text": "Photographs should be presented on semi-matt or matt paper (please do not use high gloss paper on lower end printers). Magnification should be indicated by a line representing the actual scale of reproduction; the use of magnification factors is to be avoided where possible. Illustrations will not be redrawn by the Publisher: line figures should be suitable for direct reproduction. They should be prepared with black ink on white paper, or be high-quality prints: they should be completely and consistently lettered, the size of the lettering being appropriate to that of the illustration, taking into account the necessary reduction in size. Nucleic acid sequences should be submitted as sharp, clear prints already reduced close to the required width while retaining perfect legibility (e.g. the letters C and G must be perfectly distinguishable).", "cite_spans": [], "ref_spans": []}, {"section": "Illustrations", "text": "Illustrations should be designed to fit either a single column (84 mm wide) or the full text width (175 mm). However, if specifically requested by the author(s) and approved by the receiving editor, plates may be reproduced larger than the typeset area; all originals for these should have the same proportions to achieve uniformity in their presentation. N.B. When plates are required to fill the entire page, the originals should have the dimensions 215 \u00a3 285 mm and contain no essential information or labelling near the edges. Each illustration should be clearly marked on the reverse side with the name of the author(s), the number of the illustration and its orientation (top); use a soft pencil or preferably a felt-tipped pen for marking photographs.", "cite_spans": [], "ref_spans": []}, {"section": "Colour figures", "text": "The cost of colour reproduction will not be charged to the author. However, the decision to publish figures in colour will be left to the Editors' discretion.", "cite_spans": [], "ref_spans": []}, {"section": "Tables", "text": "All tables must be cited in the text and have titles. Number them consecutively with Arabic numerals. ", "cite_spans": [], "ref_spans": []}, {"section": "Electronic media and format", "text": "Authors are encouraged to submit electronically through the website: http://www.elsevier.com/locate/modo (click on 'Author gateway'). However, if submitting a new manuscript by post, please do not send disks. For the processing of accepted papers, electronic versions are obligatory. After final acceptance your diskette plus two, final and exactly matching printed versions should be submitted together. The preferred medium is a 3.5 inch disk in MS-DOS format, although other systems are also supported, e.g. NEC and Macintosh (in the latter case, save your file in the usual manner, do not use the option 'save in MS-DOS format'). Double density (DD) or high density (HD) diskettes are acceptable. Large figures can be submitted on a SyQUEST 270 Mbyte. CD disk or an IOmega Zipdisk 100 Mbyte. All major word processing and graphics programs such as WordPerfect, Word for Windows, Word, Adobe Photoshop, etc. are acceptable. Graphic files should preferably be submitted in TIFF or JPEG format. It is important, both for text and figures/pictures, that the file is saved in the native format on the packages used. Label the disks with the name of the computer and clearly indicate which word processing package for the text, or graphics package to create the figures, has been used.", "cite_spans": [], "ref_spans": []}, {"section": "Ethics of experimentation", "text": "Authors describing investigations in animals or on human tissue must specify that the research conformed to the stipulations of the appropriate institutional review body and ethics committee.", "cite_spans": [], "ref_spans": []}, {"section": "Materials", "text": "Publication of a research article in Mechanisms of Development is taken to imply that the authors are prepared to distribute materials, used in the published experiments (e.g. cells, DNA, antibodies), to academic researchers for their own use. All nucleic acid and protein sequences must have been deposited in the appropriate databases and the Accession Numbers cited in the paper.", "cite_spans": [], "ref_spans": []}, {"section": "Proofs", "text": "One set of proofs will be supplied to the author to check for typesetting accuracy: no changes to the original manuscript will be allowed at this stage. In the interests of publication time, authors should respond as quickly as possible, preferably by e-mail.", "cite_spans": [], "ref_spans": []}, {"section": "Page charges", "text": "Mechanisms of Development has NO page charges. 25 free reprints are supplied per contribution: an additional number may be ordered at the prices quoted on the order form sent to the corresponding author.", "cite_spans": [], "ref_spans": []}, {"section": "Page charges", "text": "Elsevier will do everything possible to get your article corrected and published as quickly and accurately as possible. Therefore, it is important to ensure that all of your corrections are sent back to us in one communication. Subsequent corrections will not be possible, so please ensure your first sending is complete.", "cite_spans": [], "ref_spans": []}, {"section": "Check list", "text": "For papers submitted as hard copy: -A front page containing:", "cite_spans": [], "ref_spans": []}, {"section": "Check list", "text": "Manuscript title Authors' names and affiliations Full contact details (address, telephone number, fax number, e-mail address) of corresponding author Up to 10 keywords -Abstract up to 250 words -3 copies of the manuscript -3 sets of publication quality figures -Please do not send electronic versions on first submission For papers submitted electronically:", "cite_spans": [], "ref_spans": []}, {"section": "Check list", "text": "-Log on to http://www.elsevier.com/locate/modo -Go to Author Gateway -Follow instructions on the screen Flow charts to help authors decide whether papers are suitable for Mechanisms of Development or Gene Expression Patterns are printed on pp. 641-642.", "cite_spans": [], "ref_spans": []}], "bib_entries": {}, "ref_entries": {"TABREF0": {"text": "Managing Editors: S. Aizawa, Center for Developmental Biology, Group Dir. Lab. for", "type": "table"}, "TABREF1": {"text": "authors of the unpublished information have given their permission for it to be cited. In the text a reference should be cited by author and date; where there are more than two authors, state first author's name followed by 'et al.' References should be listed alpha- betically at the end of the paper and include, in the following order: all authors (surnames followed by initials), year, the full title of the article, journal title (abbreviated according to the International List of Period-Tijssen, P., 1993. Hybridization with Nucleic Acid Probes, Elsevier, Amsterdam, Laboratory Techniques in Biochemistry and Molecular Biology, Vol. 24, 554 pp. McConnell, S.K., 1995. Plasticity and commitment in the developing cerebral cortex. In: Yu, A.C.H. (Ed.), Gene Expression in the", "type": "table"}}}
{"paper_id": "18986655", "_pdf_hash": "8b2c4d73e9d0f270c20465ec513f48723b914037", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Robust Monte Carlo Localization for Mobile Robots", "authors": [{"first": "Sebastian", "middle": [], "last": "Thrun", "suffix": ""}, {"first": "Dieter", "middle": [], "last": "Fox", "suffix": ""}, {"first": "Wolfram", "middle": [], "last": "Burgard", "suffix": ""}, {"first": "Frank", "middle": [], "last": "Dellaert", "suffix": ""}], "year": 2001, "venue": "", "link": "128871"}, "BIBREF1": {"title": "Robust Mapping and Localization in Indoor Environments Using Sonar Data", "authors": [{"first": "Paul", "middle": ["M"], "last": "Newman", "suffix": ""}, {"first": "John", "middle": ["J"], "last": "Leonard", "suffix": ""}, {"first": "Juan", "middle": ["D"], "last": "Tardos", "suffix": ""}, {"first": "Jose", "middle": [], "last": "Neira", "suffix": ""}], "year": 2001, "venue": "", "link": "9191786"}, "BIBREF2": {"title": "Intel Image Processing Library Reference Manual, Intel Corporation. Document Number 663791\u2212005", "authors": [], "year": 1997, "venue": "", "link": null}, "BIBREF3": {"title": "Progressive Probabalistic Hough Transform", "authors": [{"first": "", "middle": [], "last": "Matas", "suffix": ""}], "year": 1998, "venue": "", "link": null}, "BIBREF4": {"title": "Investigation of Image Feature Extraction by a Genetic Algorithm", "authors": [{"first": "", "middle": [], "last": "Brumby", "suffix": ""}], "year": 1998, "venue": "", "link": "15224598"}}, "ref_entries": {}}
{"paper_id": "18986914", "_pdf_hash": "a46e1c668813cb7c0266dd2eafc0b3c158bb8566", "abstract": [{"section": "Abstract", "text": "Data mining is the process of extracting patterns from data. Basically Data mining is the analysis of observational data sets to find unsuspected associations and to sum up the data in new ways that are both clear and useful to the data owner .It is seen as an increasingly important tool by modern business to transform data into business intelligence giving an informational advantage. The automated, prospective analyses offered by data mining move beyond the analyses of past events provided by retrospective tools typical of decision support systems. Data mining tools can answer business questions that traditionally were too time consuming to resolve..Data mining is becoming increasingly common in both the private and public sectors. Industries such as banking, insurance, medicine, and retailing commonly use data mining to reduce costs, enhance research, and increase sales. While data mining represents a significant advance in the type of analytical tools currently available, there are limitations to its capability. One limitation is that although data mining can help reveal patterns and relationships, it does not tell the user the value or significance of these patterns. These types of determinations must be made by the user. A second limitation is that while data mining can identify connections between behaviors and/or variables, it does not necessarily identify a causal relationship. To be successful, data mining still requires skilled technical and analytical specialists who can structure the analysis and interpret the output that is created.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "I. Introduction", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Fig. 1 : Data Mining", "text": "Data mining is the withdrawal of hidden predictive information from large databases. It allows us to find the needles hidden in our haystacks of data. It is a prevailing new technology which has great potential to help companies that focus on the most important information in their data warehouses. Tools of data mining predict future trends and behaviours, allowing businesses to make proactive and the knowledge-driven decisions. Data mining offers the automated, prospective analyses beyond the analyses of past events provided by retrospective tools typical of decision support systems. Data mining tools can answer business questions that traditionally were too time consuming to resolve. They search databases for hidden patterns, finding analytical information that experts may miss because it lies outside their expectations. It is playing increasingly important role in both private and public sectors. E.g the insurance and banking industries use data mining applications to detect fraud and assist in risk assessment. Data mining can be used in a predictive manner for a variety of applications. Data Mining is also popularly known as Knowledge Discovery in Databases (KDD). Usually data mining and knowledge discovery in databases are taken as synonyms, but in actual data mining is part of the knowledge discovery process.", "cite_spans": [], "ref_spans": []}, {"section": "Fig. 1 : Data Mining", "text": "The Knowledge Discovery in Databases process comprises of following steps leading from unprocessed data collections to some form of useful knowledge: 1. Data cleansing or data cleaning: In this phase noise data and irrelevant data are removed from the whole collection. 2. Data assimilation: In this phase, multiple data sources, often mixed, may be combined in a common source. 3. Data assortment: In this phase the data relevant to the analysis is decided on and retrieved from the data collection. 4. Data transformation: In this phase in the selected data is transformed into forms appropriate for the mining procedure. 5. Data mining: It is the vital step in which knowledgeable techniques are applied to extract patterns potentially useful. 6. Pattern evaluation: In this step, firmly interesting patterns representing knowledge are identified based on given measures. 7. Knowledge representation: is the last phase in which the discovered knowledge is visually represented to the user. This essential step uses visualization techniques to help users understand the data mining results.", "cite_spans": [], "ref_spans": []}, {"section": "Fig. 1 : Data Mining", "text": "Normally some of the above steps are being combines. For example, data cleaning and data assimilation can be performed together as a pre-processing phase to generate a data warehouse. Data assortment and data transformation can also be combined where the consolidation of the data is the result of the selection, or, as for the case of data warehouses, the selection is done on transformed data. This is an iterative process. Once the discovered knowledge is presented to the user, the evaluation measures can be enhanced, the mining can be further refined, new data can be selected or further transformed, or new data sources can be integrated, in order to get different, more appropriate results.", "cite_spans": [], "ref_spans": []}, {"section": "II. Need for Data Mining", "text": "Nowadays, large quantities of data are being accumulated. The amount of data collected is said to be almost doubled every 12 months. Seeking knowledge from massive data is one of the most desired attributes of Data Mining. Data could be large in two senses. In terms of size, e.g. for Image Data or in terms of dimensionality, e.g. for Gene expression data. Usually there is a huge gap from the stored data to the knowledge that could be construed from the data. This transition won't occur automatically, IV. Architecture for data mining To best apply these advanced techniques, they must be fully integrated with a data warehouse as well as flexible interactive business analysis tools. Many data mining tools currently operate outside of the warehouse, requiring extra steps for extracting, importing, and analyzing the data. Furthermore, when new insights require operational implementation, integration with the warehouse simplifies the application of results from data mining. The resulting analytic data warehouse can be applied to improve business processes throughout the organization, in areas such as promotional campaign management, fraud detection, new product rollout, and so on. Fig. 1 illustrates architecture for advanced analysis in a large data warehouse.", "cite_spans": [], "ref_spans": []}, {"section": "Fig. 2:", "text": "The ideal starting point is a data warehouse containing a combination of internal data tracking all customer contact coupled with external market data about competitor activity. Background information on potential customers also provides an excellent basis for prospecting. This warehouse can be implemented in a variety of relational database systems: Sybase, Oracle, Redbrick, and so on, and should be optimized for flexible and fast data access. An OLAP (On-Line Analytical Processing) server enables a more sophisticated end-user business model to be applied when navigating the data warehouse. The multidimensional structures allow the user to analyze the data as they want to view their business -summarizing by product line, region, and other key perspectives of their business. The Data Mining Server must be integrated with the data warehouse and the OLAP server to embed ROI-focused business analysis directly into this infrastructure. An advanced, process-centric metadata template defines the data mining objectives for specific business issues like campaign management, prospecting, and promotion optimization. Integration with the data warehouse enables operational decisions to be directly implemented and tracked. As the warehouse grows with new decisions and results, the organization can continually mine the best practices and apply them to future decisions. This design represents a fundamental shift from conventional decision support systems. Rather than simply delivering data to the end user through query and reporting software, the Advanced Analysis Server applies users' business models directly to the warehouse and returns a proactive analysis of the most relevant information. These results enhance the metadata in the OLAP Server by providing a dynamic metadata layer that represents a distilled view of the data. Reporting, visualization, and other analysis tools can then be applied to plan future actions and confirm the impact of those plans.", "cite_spans": [], "ref_spans": []}, {"section": "V. Data Mining Techniques", "text": "Neural Networks/Pattern Recognition -Neural Networks are used in a black box fashion. One creates a test data set, lets the neural network learn patterns based on known outcomes, then sets the neural network loose on huge amounts of data. For example, a credit card company has 3,000 records, 100 of which are known fraud records. The data set updates the neural network to make sure it knows the difference between the fraud records and the lawful ones. The network learns the patterns of the fraud records. Then the network is run against company's million record data set and the network spits out the records with patterns the same or similar to the fraud records. Neural networks are known for not being very helpful in teaching analysts about the data, just finding patterns that match. Neural networks have been used for optical character recognition to help the Post Office automate the delivery process without having to use humans to read addresses. Memory Based Reasoning -MBR looks for \"neighbor\" kind of data, rather than patterns. If we look at insurance claims and want to know which the adjudicators should look at and which they can just let go through the system, we would set up a set of claims we want adjudicated and let the technique find similar claims. Cluster Detection/Market Basket Analysis -This is where the classic beer/diapers bought together analysis came from. It finds groupings. Basically, this technique finds relationships in product or customer or wherever we want to find associations in data. Link Analysis -This is another technique for associating like records. Not used too much, but there are some tools created just for this. As the name suggests, the technique tries to find links, either in customers, transactions, etc. and demonstrate those links. Visualization -This technique helps users understand their data. Visualization makes the bridge from text based to graphical presentation. Such things as decision tree, rule, cluster and pattern visualization help users see data relationships rather than read about them. Many of the stronger data mining programs have made strides in improving their visual content over the past few years. This is really the vision of the future of data mining and analysis. Data volumes have grown to such huge levels, it is going to be impossible for humans to process it by any text-based method effectively, soon. We will probably see an approach to data mining using visualization appear that will be something like Microsoft's Photosynth. The technology is there, it will just take an analyst with some vision to sit down and put it together. Decision Tree/Rule Induction -Decision trees use real data mining algorithms. Decision trees help with classification and spit out information that is very descriptive, helping users to understand their data. A decision tree process will generate the rules followed in a process. For example, a lender at a bank goes through a set of rules when approving a loan. Based on the loan data a bank has, the outcomes of the loans (default or paid), and limits of acceptable levels of default, the decision tree can set up the guidelines for the lending institution. These decision trees are very similar to the first decision support (or expert) systems.", "cite_spans": [], "ref_spans": []}, {"section": "V. Data Mining Techniques", "text": "Genetic Algorithms -. We can set up a data set then give the GA ability to do different things for whether a direction or outcome is favorable. The GA will move in a direction that will hopefully optimize the final result. Gas are used mostly for process optimization, such as scheduling, workflow, batching, and process re-engineering. OLAP -Online Analytical Processing is an approach to swiftly answer multi-dimensional analytical queries. OLAP allows users to browse data following logical questions about the data. OLAP generally includes the ability to drill down into data, moving from highly summarized views of data into more detailed views. This is generally achieved by moving along hierarchies of data. For example, if one were analyzing populations, one could start with the most populous continent, then drill down to the most populous country, then to the state level, then to the city level, then to the neighborhood level. OLAP also includes browsing up hierarchies (drill up), across different dimensions of data (drill across), and many other advanced techniques for browsing data, such as automatic time variation when drilling up or down time hierarchies. OLAP is by far the most implemented and used technique. It is also generally the most intuitive and easy to use", "cite_spans": [], "ref_spans": []}, {"section": "VI. Advantages", "text": "Marking/Retailing:-Data mining can aid direct marketers by \u2022 providing them with useful and accurate trends about their customers' purchasing behavior. Based on these trends, marketers can direct their marketing attentions to their customers with more precision. For example, marketers of a software company may advertise about their new software to consumers who have a lot of software purchasing history.", "cite_spans": [], "ref_spans": []}, {"section": "VI. Advantages", "text": "In addition, data mining may also help marketers in predicting which products their customers may be interested in buying. Through this prediction, marketers can surprise their customers and make the customer's shopping experience becomes a pleasant one. Retail stores can also benefit from data mining in similar ways. For example, through the trends provide by data mining, the store managers can arrange shelves, stock certain items, or provide a certain discount that will attract their customers. Banking/Crediting:-Data mining can assist financial institutions \u2022 in areas such as credit reporting and loan information. For example, by examining previous customers with similar attributes, a bank can estimated the level of risk associated with each given loan. In addition, data mining can also assist credit card issuers in detecting potentially fraudulent credit card transaction. Although the data mining technique is not a 100% accurate in its prediction about fraudulent charges, it does help the credit card issuers reduce their losses. Law enforcement:-Data mining can aid law enforcers in \u2022 identifying criminal suspects as well as apprehending these criminals by examining trends in location, crime type, habit, and other patterns of behaviors.", "cite_spans": [], "ref_spans": []}, {"section": "VI. Advantages", "text": "Researchers:-Data mining can assist researchers by speeding \u2022 up their data analyzing process; thus, allowing them more time to work on other projects.", "cite_spans": [], "ref_spans": []}, {"section": "VII. Limitations of data mining", "text": "While data mining products can be very powerful tools, they are not self sufficient applications. To be successful, data mining requires skilled technical and analytical specialists who can structure the analysis and interpret the output that is created. Consequently, the limitations of data mining are primarily data or personnel related, rather than technology-related. Although data mining can help reveal patterns and relationships, it does not tell the user the value or significance of these patterns. These types of determinations must be made by the user. Similarly, the validity of the patterns discovered is dependent on how they compare to \"real world\" circumstances. For example, to assess the validity of a data mining application designed to identify potential terrorist suspects in a large pool of individuals, the user may test the model using data that includes information about known terrorists. However, while possibly re-affirming a particular profile, it does not necessarily mean that the application will identify a suspect whose behavior significantly deviates from the original model. Another limitation of data mining is that while it can identify connections between behaviors and/or variables, it does not necessarily identify a causal relationship. For example, an application may identify that a pattern of behavior, such as the propensity to purchase airline tickets just shortly before the flight is scheduled to depart, is related to characteristics such as income, level of education, and Internet use. However, that does not necessarily indicate that the ticket purchasing behavior is caused by one or more of these variables. In fact, the individual's behavior could be affected by some additional variable(s) such as occupation (the need to make trips on short notice), family status (a sick relative needing care), or a hobby .", "cite_spans": [], "ref_spans": []}, {"section": "VIII. Issues", "text": "One of the key issues raised by this technology is social one. It is the issue of human being's privacy. Data mining makes it possible to analyze routine business transactions and collect a significant amount of information about individuals buying behavior and preferences.", "cite_spans": [], "ref_spans": []}, {"section": "VIII. Issues", "text": "Second issue is that of data reliability. Clearly, data analysis can only be as good as the data that is being analyzed. A key implementation challenge is integrating contradictory or redundant data from different sources. For example, a bank may maintain credit cards accounts on several different databases. The addresses (or even the names) of a single cardholder may be different in each. Software must translate data from one system to another and select the address most recently entered. Third issue is whether it is better to set up a relational database structure or a multidimensional one. In a relational structure, data is stored in tables, permitting ad hoc queries. In a multidimensional structure, on the other hand, sets of cubes are arranged in arrays, with subsets created according to category. While multidimensional structures facilitate multidimensional data mining, relational structures thus far have performed better in client/server environments. And, with the explosion of the Internet, the world is becoming one big client/server environment. Last issue is of cost. Data mining and data warehousing tend to be self-reinforcing. The more powerful the data mining queries, the greater the utility of the information being gleaned from the data, and the greater the pressure to increase the amount of data being collected and maintained, which increases the pressure for faster, more powerful data mining queries. This increases pressure for larger, more rapid systems, which are more costly.", "cite_spans": [], "ref_spans": []}, {"section": "IX. Future of data mining", "text": "In the short-term, the results of data mining will be in profitable, if ordinary, business related areas. Micro-marketing campaigns will explore new heights. Advertising will target potential customers with new accuracy.", "cite_spans": [], "ref_spans": []}, {"section": "IX. Future of data mining", "text": "In the medium term, data mining may be as common and easy to use as e-mail. We may use these tools to find the best airfare to Australia, root out a phone number of a long-lost classmate, or find the best prices on lawn mowers. The long-term prospects are truly exciting. Imagine intelligent agents turned loose on medical research data or on sub-atomic particle data. 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{"paper_id": "18987047", "_pdf_hash": "2d39d799e397f544700e59b23347fd73b833db96", "abstract": [{"section": "Abstract", "text": "ABSTRACT Macromolecules gain access to the cytoplasm of eukaryotic cells using one of several ways of which clathrin-dependent endocytosis is the most researched. Although the mechanism of clathrin-mediated endocytosis is well understood in general, novel adaptor proteins that play various roles in ensuring specific regulation of the mentioned process are being discovered all the time. This review provides a detailed account of the mechanism of clathrin-mediated internalization of activated G protein-coupled receptors, as well as a description of the major proteins involved in this process.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION", "text": "endocytosis is a fundamental process that ensures delivery of extracellular or membrane-localized macromolecules to the cytoplasm. endocytosis is necessary for nutrients to reach the cell, the regulation of the activity of transmembrane receptors, and synaptic vesicle recycling. clathrin-mediated endocytosis represents the entry of fragments of the cytoplasmic membrane, along with all of their contents, into the cell in the form of vesicles coated on the outside with a lattice consisting of polymerized clathrin. In particular, the clathrin-mediated mechanism is utilized to carry out the endocytosis of activated cell surface receptors. Binding of the receptor molecule to the ligand and activation of the former render possible the subsequent binding of the intracellular part of the receptor to the adaptor proteins. these proteins mediate the interaction between receptors and clathrin molecules, resulting in the formation of the clathrin coat. Several classes of adaptor proteins have been identified.", "cite_spans": [], "ref_spans": []}, {"section": "ENDOCYTOSIS OF G-PROTEIN-COUPLED RECEPTORS AS AN ExAMPLE OF CLATHRIN-MEDIATED ENDOCYTOSIS", "text": "the superfamily of G-protein-coupled receptors (GPcr) is considered to be the largest family of membrane proteins involved in intracellular signal transduction [1] . the general structural feature of GPcr is the presence of seven \u03b1-helical transmembrane hydrophobic segments each consisting of 25-35 amino acid residues [2] . the n-terminal portion of GPcr and three loops between the transmembrane segments are found outside the cell, and the c-terminal part and the other three loops are found on the cytoplasmic side of the plasma membrane.", "cite_spans": [{"start": 160, "end": 163, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "ENDOCYTOSIS OF G-PROTEIN-COUPLED RECEPTORS AS AN ExAMPLE OF CLATHRIN-MEDIATED ENDOCYTOSIS", "text": "the ligands of various GPcr include ions, organic odorants, amines, peptides, proteins, lipids, nucleotides, and photons. Activation of the receptors by their corresponding ligands leads to the formation of complexes consisting of receptors and heterotrimeric G-proteins (consisting of 3 subunits) and the associated exchange of GDP for GtP. this exchange causes the dissociation of a G-protein into a GtP-bound \u03b1-subunit and a complex consisting of \u03b2-and \u03b3-subunits, as well as the dissociation of all three subunits of the G-protein from the receptor. It is now proven that both the \u03b1-subunit and the \u03b2\u03b3 complex serve as signal transducers by activating or inhibiting enzymes and ion channels [3] . Bound GtP is hydrolyzed following interaction with the effector and re-association of the \u03b1-subunit and \u03b2\u03b3 to form a complex consisting of three subunits with a bound GDP. this complex is again able to interact with the activated receptor [4] .", "cite_spans": [], "ref_spans": []}, {"section": "ENDOCYTOSIS OF G-PROTEIN-COUPLED RECEPTORS AS AN ExAMPLE OF CLATHRIN-MEDIATED ENDOCYTOSIS", "text": "Binding of the ligand to the receptor leads to conformational changes that give rise to the G-protein-mediated signal transduction and conversion of the receptor into the protein kinase GrK substrate (G-protein-coupled receptor Kinases). the serine or threonine residues of the ligand-activated receptor located in the cytoplasmic domain and/or in the third cytoplasmic loop are phosphorylated. then, \u03b2-arrestins bind to the activated and phosphorylated receptor [5] . \u03b2-Arrestins play a significant role in the process of internalization of GPcr as their binding leads to clathrin-mediated endocytosis of the receptor attributed to interaction with the components of the endocytotic mechanism -clathrin and the AP-2 adaptor protein complex [6, 7] .", "cite_spans": [{"start": 745, "end": 747, "text": "7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "ENDOCYTOSIS OF G-PROTEIN-COUPLED RECEPTORS AS AN ExAMPLE OF CLATHRIN-MEDIATED ENDOCYTOSIS", "text": "newly formed clathrin-coated vesicles containing the receptor detach from the cytoplasmic membrane by means of the protein called dynamin tightening the neck of the forming vesicles [8] . the internalized receptor-ligand complex detached as part of the vesicles further undergoes intracellular transport. the first stage of this pathway is the formation of early endosomes. It is believed that canonical early endosomes contain a small GtPase rab5 and the early endosome antigen 1 (eeA1). In the majority of cases, the internalized receptor remains accessible to the molecules of the intracellular signaling cascade and, therefore, can continue to participate in the signal transduction as if it was localized on the surface of the membrane [9] . then, depending on the type of the receptor, one of two scenarios is possible. the receptor either dissociates from the bound ligand and is recycled back to the cell surface (re-sensitization) or is transferred to late endosomes and is subjected to degradation within lysosomes (Fig. 1) . the fate of specific receptors depends on whether the activation was of a short-term nature or was a prolonged type of activation/reactivation [10] . thus, for instance, the \u03b22-adrenergic receptor following short-term activation by an agonist recycles back primarily to the cytoplasmic membrane; however, upon prolonged activation it can be transferred to the lysosome for degradation, thereby [10] .", "cite_spans": [], "ref_spans": [{"start": 1025, "end": 1033, "text": "(Fig. 1)", "ref_id": "FIGREF1"}]}, {"section": "ENDOCYTOSIS OF G-PROTEIN-COUPLED RECEPTORS AS AN ExAMPLE OF CLATHRIN-MEDIATED ENDOCYTOSIS", "text": "recycling to the cytoplasmic membrane can occur via a rapid pathway through rab4-containing endosomes, and via a slow pathway through rab11-containing recycling endosomes [11] . It is believed that late endosomes contain receptors intended for degradation. transition from early to late endosomes is accompanied by the replacement of protein rab5 with protein rab7 -the so-called \"rab conversion\" [12] .", "cite_spans": [], "ref_spans": []}, {"section": "MECHANISM OF CLATHRIN-MEDIATED INTERNALIZATION", "text": "clathrin-coated vesicles have a three-layered structure: the outer layer is formed by clathrin (clathrin lattice), the internal layer is a lipid membrane with protein inclusions, while adaptor proteins are found in between. the adaptor protein complexes interact directly with the lipid bilayer, and clathrin in turn binds to the adaptors [13] .", "cite_spans": [], "ref_spans": []}, {"section": "MECHANISM OF CLATHRIN-MEDIATED INTERNALIZATION", "text": "It is presumed that endocytosis begins with the formation of pits on the inner surface of the cytoplasmic membrane containing clathrin, the AP-2 adaptor protein complex, and accessory proteins [14] . the subunits of the adaptor complex trigger the formation of the clathrin lattice at specific sites of the cytoplasmic membrane and mediate the interaction between clathrin and the cargo protein [15] . AP-2 plays an important role in selecting the target for endocytosis by binding either directly to a transmembrane cargo protein containing the necessary sequences or via helper proteins, such as \u03b2-arrestins [16] . Binding of AP-2 to the membrane is a two-stage process. First the \u03b1-subunit of AP-2 binds weakly to phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2). AP-2 affinity for the corresponding endocytic motifs increases upon phosphorylation of a threonine residue in the \u00b52-subunit of AP-2 [17] by adaptor-associated kinase, AAK1 [18, 19] . this phosphorylation enables the \u00b52-subunit to bind to motifs of the cargo protein undergoing endocytosis and to PtdIns(4,5)P2 in the membrane creating the foundation for the formation of a clathrin-coated vesicle. then, the adaptor complex can bind to the other accessory proteins, such as cALM, required for the formation of a clathrin lattice. removal of this protein from the cell leads to the formation of large asymmetric clathrincoated pits [20] . Simultaneously with the polymerization of clathrin, the process involves a variety of other proteins required for the control of the invagination of the cytoplasmic membrane and the formation of the pit on it. It is believed that the bending of the membrane is attributed to the action of several proteins containing BAr-domains (Bin/amphiphysin/rvs) [21] , such as amphiphysin [22] and endophilin [23] . the protein epsin is also able to stimulate the bending of the membrane [24] . Polymerizing clathrin forms the lattice (consisting of hexagons and pentagons) surrounding the emerging pits and, thus, stabilizes the membrane curvature [25] .", "cite_spans": [{"start": 1762, "end": 1766, "text": "[21]", "ref_id": "BIBREF19"}, {"start": 2049, "end": 2053, "text": "[25]", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "MECHANISM OF CLATHRIN-MEDIATED INTERNALIZATION", "text": "Subsequent deformation of the membrane and polymerization of clathrin lead to the clathrin-coated vesicle remaining attached to the main part of the membrane via a narrow neck requiring GtPase dynamin for the completion of the detachment of the vesicle. Amphiphysin already being a part of the vesicle contains binding sites for both clathrin and dynamin. It is presumed that it \"attracts\" dynamin to the forming vesicle and facilitates its oligomerization [26] . According to the two proposed models, after polymerization of dynamin around the neck of the vesicle, a GtP hydrolysis-dependent change in its structure results in the constriction (first model) or stretching (second model) of the neck and detachment of the vesicle from the remainder of the membrane [27] .", "cite_spans": [{"start": 765, "end": 769, "text": "[27]", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "MECHANISM OF CLATHRIN-MEDIATED INTERNALIZATION", "text": "removal of the clathrin coat from the surface of the vesicle is necessary for further fusion of the vesicle with the target membrane and delivery of endocytosed \"cargo\" to the target destination. the primary participants in the process of depolymerization of the clathrin coat include the proteins Hsc70 and auxilin. Auxilin, an homologue of Hsp40, binds to clathrin and attracts Hsc70, which interacts with its J-domain. As a result of interaction with auxilin, the AtPase activity of Hsc70 increases and it binds to clathrin with increased affinity, thus distorting the conformation and contributing to the dismantling of the clathrin lattice into individual molecules [28, 29] . the layer formed by the adaptor complex is removed as a result of dephosphorylation of the AP-proteins by phosphatases, as it was shown for the \u00b51-subunit of the AP-1 [30] . the proteins synaptojanin and endophilin dephosphorylate membrane phospholipids, thereby reducing the affinity of the adaptors for vesicles [31] .", "cite_spans": [], "ref_spans": []}, {"section": "KEY PROTEINS INVOLVED IN CLATHRIN-MEDIATED ENDOCYTOSIS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "G-protein-coupled receptor kinases and \u03b2-arrestins", "text": "A large number of proteins that are capable of direct interactions with the GPcr have been described [32] . However, only two classes of proteins, other than G-proteins, that specifically interact with ligand-activated receptors are known: GPcr kinases (GrK) and \u03b2-arrestins [33] .", "cite_spans": [], "ref_spans": []}, {"section": "G-protein-coupled receptor kinases and \u03b2-arrestins", "text": "the GrK family comprises products of seven different genes. the expression of GrK1 and -7 is limited to retinal rods and cones, respectively. GrK4 is exclusively expressed in the cerebellum, testis and kidneys. GrK2, -3, -5 and -6, in contrast, are expressed in vari-ous mammalian tissues. Seven kinases are divided into three subfamilies with respect to amino acid sequence homology. GrK1 and -7; GrK2 and -3 contain pleckstrin homology (PH) domain, and association of these kinases with plasma membranes is dependent on the interaction with the G \u03b2\u03b3 -subunit of the G-proteins and PtdIns(4,5)P2; GrK4-6 proteins are continuously associated with the membrane [34] .", "cite_spans": [], "ref_spans": []}, {"section": "G-protein-coupled receptor kinases and \u03b2-arrestins", "text": "Arrestins comprise 4 proteins. Arrestins 1 and 4 (x-arrestin) are expressed in retinal rods and cones, respectively. Arrestins 2 and 3 (also known as \u03b2-arrestins 1 and 2) are present in all tissues [5] . GrK and arrestins control GPcr activity at three levels: (1) silencingfunctional detachment of the receptor from its G-protein; (2) regulation of transport -removal of the receptor from the cytoplasmic membrane (internalization), recycling back to the membrane and/or degradation; and (3) signal transduction -activation or inhibition of the intracellular signaling pathways independent of G-proteins. the n-terminal portion of arrestin 1 [35] and arrestins 2 and 3 [36, 37] contains the regions responsible for the recognition of agonist-activated phosphorylated GPcr. According to the proposed model, the charged phosphate groups of the receptor destroy the polar core of the arrestin resulting in the release of its c-terminal part, which is responsible for binding to the proteins involved in endocytosis -clathrin and AP-2 [38] .", "cite_spans": [], "ref_spans": []}, {"section": "G-protein-coupled receptor kinases and \u03b2-arrestins", "text": "Clathrin the major protein of clathrin-coated vesicles isolated by Pierce [39] was named clathrin as it was characterized by an ability to form structures with an ordered lattice, or \"clathrates.\" the clathrin molecule resembles a triskelion (derived from Greek. \u03c4\u03c1\u03b9\u03c3\u03ba\u03b5\u03bb\u03b7\u03c2 -three-legged -a symbolic mark resembling three running legs that extend from one point) and consists of three heavy and three light chains [40] (Fig. 2) .", "cite_spans": [], "ref_spans": []}, {"section": "G-protein-coupled receptor kinases and \u03b2-arrestins", "text": "A clathrin heavy chain (Hc) isolated from a rat's brain is composed of 1,675 amino acid residues and has a molecular weight slightly exceeding 191 kDa (approximately 180 kDa as determined by denaturing polyacrylamide gel electrophoresis (SDS-PAGe)). the amino acid sequences of the clathrin heavy chain isolated from the brain of a human, rat or bovine are highly conserved (~ 99%) [41] . clathrin heavy chains have also been isolated from the clathrin-coated vesicles of yeast [42] and plants [43] .", "cite_spans": [], "ref_spans": []}, {"section": "G-protein-coupled receptor kinases and \u03b2-arrestins", "text": "each clathrin heavy chain is in a complex with one of the light chains, Lc a or Lc b , encoded by different genes. the amino acid sequences of the light chains are highly conserved across different species (95-98%) . [40] reVIeWS and the acidic n-terminal. the homology of both chains at the amino acid sequence level reaches 60% [41] . the region consisting of 22 amino acid residues located at the n-terminus, the clathrin heavy chain binding site, the cysteine residues near the c-terminal portion, and the serine residues enriched casein kinase II phosphorylation site of the light chain Lc b are highly conserved [44] . Light chains bind the proximal domains of the clathrin heavy chains [45] ; primary binding is provided by the amino acid residues 1267-1522 of the heavy chain, the residues 93-160 of the light chain Lc a, and the residues 90-157 of the Lc b [46] . the regions that are necessary for the trimerization of heavy chains, binding of light chains, and formation of the clathrin lattice are located at the intersection of clathrin heavy chains [47, 48] . the domain that ensures the trimerization of heavy chains is localized between the amino acid residues 1488 and 1587.", "cite_spans": [], "ref_spans": []}, {"section": "G-protein-coupled receptor kinases and \u03b2-arrestins", "text": "two sites for the binding of clathrin to adaptor proteins are located in the n-terminal domain. the first site interacts with peptides containing the \"clathrin box\" (L\u00d8X\u00d8[D/e], where \u00d8 is a large hydrophobic amino acid). examples of proteins containing such a motif include \u03b2-adaptins (the LLnLD sequence is found in \u03b2-adaptins 1 and 2, the LLDLD sequence is found in \u03b2-adaptin 3), \u03b2-arrestins 1 (LIeLD) and 2 (LIeFe) and amphiphysins 1 and 2 (LLDLD) [49] . the second site binds proteins containing the W-box motif (PWXXW, where X is any amino acid); e.g., the molecules of the aforementioned amphiphysins 1 and 2 [50] .", "cite_spans": [{"start": 451, "end": 455, "text": "[49]", "ref_id": "BIBREF46"}], "ref_spans": []}, {"section": "G-protein-coupled receptor kinases and \u03b2-arrestins", "text": "clathrin molecules spontaneously self-assemble in weakly acidic ca 2+ -containing buffers with a low ionic strength to form a heterogeneous population of closed polyhedral structures resembling a lattice [51, 52] . the vertex of each triskelion is located at the vertex of the lattice. the heavy chain legs and associated light chains extend outwardly from the vertices forming the edges of the lattice (Fig. 3) .", "cite_spans": [], "ref_spans": [{"start": 403, "end": 411, "text": "(Fig. 3)", "ref_id": "FIGREF3"}]}, {"section": "G-protein-coupled receptor kinases and \u03b2-arrestins", "text": "All heavy chains form the two adjacent edges of a polyhedral lattice. the legs appear to interact via their proximal and distal domains. each edge consists of two antiparallel proximal domains located above two antiparallel distal domains [53] . the fragments of clathrin obtained by expression in a heterologous system and consisting of a proximal domain and a region necessary for trimerization are able to self-assemble into trimers but cannot form lattices. Formation of the clathrin lattice requires distal domains that are correctly oriented by binding of the terminal domains to adaptor proteins [54] . terminal domains in the lattice are directed inwardly towards the center and are located under the vertex, which is positioned at a distance of two vertices from the center of the triskelion. Here, the terminal domains assume the shape of hooks-projections providing a points of contact with the inner layer formed by adaptor proteins [55] .", "cite_spans": [], "ref_spans": []}, {"section": "G-protein-coupled receptor kinases and \u03b2-arrestins", "text": "It is worth mentioning that clathrin is also involved in mitosis. It is presumed that it is necessary for the stabilization of the microtubules that attach to kinetochores (called K-fibers) [56] .", "cite_spans": [], "ref_spans": []}, {"section": "G-protein-coupled receptor kinases and \u03b2-arrestins", "text": "AP adaptor protein complexes the second major protein of clathrin-coated vesicles is the adaptor protein complex. Its discovery was made possible by its ability to stimulate the assembly of the clathrin lattice under physiological conditions [57] . At least two adaptor complexes -AP-1 and AP-2 -have been extensively researched. these complexes have structural similarities and are composed of two different subunits of high molecular weight ~ 100 kDa (typically called adaptins), two subunits of medium size (47-50 kDa), and two low-molecular-weight subunits (17-19 kDa). the AP-2 complex comprises the following subunits: \u03b1 and \u03b22 (or \u03b2) adaptins, the \u00b52 subunit (50 kDa) or AP50 and the \u03c32 subunit (17 kDa) or AP17. the AP-1 complex comprises \u03b3 and \u03b21 (or \u03b2') adaptins, AP47 (or \u00b51) and AP19 (or \u03c31) [58] .", "cite_spans": [], "ref_spans": []}, {"section": "G-protein-coupled receptor kinases and \u03b2-arrestins", "text": "the designation that uses the same letters of the Greek alphabet reflects the structural and presumably [40] functional similarity of the subunits of the AP-1 and AP-2 complexes [59, 60] . \u03b1-and \u03b3-adaptins differ most significantly (~ 30% amino acid sequence homology), while the \u00b5-and \u03c3-subunits of the AP-1 complex exhibit high levels (~ 50%) of homology to the corresponding \u00b5-and \u03c3-subunits of the AP-2 complex, and \u03b21-and \u03b22-adaptins are highly homologous (> 90%). AP-3 and AP-4 complexes that are similar in subunit composition have also been identified: \u03b4 and \u03b23, \u00b53, \u03c33 -in the AP-3 complex; \u03b5 and \u03b24, \u00b54, \u03c34 -in the AP-4 complex [61, 62] .", "cite_spans": [], "ref_spans": []}, {"section": "G-protein-coupled receptor kinases and \u03b2-arrestins", "text": "the complex of subunits forms a structure resembling Mickey Mouse's head (Fig. 4) , where the center is formed by the \u00b5 and \u03b4 subunits, and the two \"ears\" are composed of the c-terminal domains of the two large subunits, \u03b1 and \u03b2, connected to the \"head\" via a flexible neck [63] .", "cite_spans": [], "ref_spans": [{"start": 73, "end": 81, "text": "(Fig. 4)", "ref_id": "FIGREF4"}]}, {"section": "G-protein-coupled receptor kinases and \u03b2-arrestins", "text": "While the assembly of the clathrin lattice occurs on the membrane, it has been established that clathrin itself has no affinity with lipids. It is therefore considered that clathrin is attracted to the membrane by adaptor proteins [64, 65] .", "cite_spans": [], "ref_spans": []}, {"section": "G-protein-coupled receptor kinases and \u03b2-arrestins", "text": "AP-2 is the main protein adaptor found on the plasma membrane and is involved in the formation of clathrin-coated vesicles during endocytosis. Immunofluorescence and immunoelectron microscopy demonstrated that AP-1, -3 and -4 are localized in endosomes and the Golgi complex [66] . AP-1 mediates the transport of proteins from the Golgi complex to early or late endosomes.", "cite_spans": [], "ref_spans": []}, {"section": "G-protein-coupled receptor kinases and \u03b2-arrestins", "text": "AP-1 and AP-2 directly interact with the n-terminal domain of the clathrin heavy chain via the clathrinbinding site in the \u03b2-chain. In 1998, cryoelectron microscopy was utilized to elucidate the structure of the AP-2 complex with clathrin [55] . It was established that AP-2 forms a shell of continuous density in the center of the lattice. Based on the images obtained, it was also concluded that AP-2 forms contacts with the terminal domains of the clathrin lattice. Subsequently, an X-ray diffraction analysis confirmed that the \u03b2-subunits of the AP-1, -2, and -3 containing the clathrin-binding motif interact with the terminal domain of the clathrin heavy chain [49] .", "cite_spans": [{"start": 667, "end": 671, "text": "[49]", "ref_id": "BIBREF46"}], "ref_spans": []}, {"section": "G-protein-coupled receptor kinases and \u03b2-arrestins", "text": "In addition to clathrin, AP complexes interact with integral membrane proteins. the YXX\u00d8 sequence, located in the intracellular domains of many receptors, is recognized by the \u00b5-subunit of all AP-complexes [67] .", "cite_spans": [], "ref_spans": []}, {"section": "G-protein-coupled receptor kinases and \u03b2-arrestins", "text": "[De]XXXL[LI] motifs, which are also found in the cytoplasmic domain of the receptors, bind to the \u03b2-subunits of the AP-complexes, and these subunits exhibit different affinities to different [De]XXXL[LI] motifs. For instance, AP-1 and AP-2, but not AP-3, interact with the DDQrDLI and neQLPML sites [68] . the DerA-PLI and eeKQPLL signals interact with AP-3, but not AP-1 or AP-2 [69] .", "cite_spans": [], "ref_spans": []}, {"section": "G-protein-coupled receptor kinases and \u03b2-arrestins", "text": "Adaptor protein complexes are capable of binding to cell membrane lipids. two lipid binding sites have been described [70] . the first site is located in the n-terminal part of the \u03b1-subunit of AP-2, and the second site is localized on the surface of the \u00b52 subunit [71] . Binding to the membrane is determined by the interaction of the phosphates PtdIns(4,5)P2 and side chains of the basic amino acid residues of the adaptor protein.", "cite_spans": [], "ref_spans": []}, {"section": "Auxilin", "text": "Auxilin is a multi-domain protein with a molecular weight of 100 kDa containing a clathrin-binding domain, a J-domain, and a region homologous to phosphoinositide phosphatase Pten (Fig. 5A) [72, 73] . the n-terminal domain binds to phosphoinositol derivatives and PtdIns(4,5)P2 [74, 75] . the auxilin central domain interacts with clathrin, the AP-2 complex [76] , and dynamin [77] .", "cite_spans": [{"start": 283, "end": 286, "text": "75]", "ref_id": "BIBREF72"}], "ref_spans": []}, {"section": "Auxilin", "text": "cryoelectron microscopy at a 20\u00c5 resolution was utilized to obtain images of full-sized auxilin [78] and its fragment (549-910) [79] with a clathrin lattice. Auxilin forms a shell of density within the lattice with points of contact with the clathrin terminal domains. Auxilin is capable of interaction with the terminal domain of the clathrin heavy chain via the LLGLe motif comprising the amino acid residues 496-500. It was established that reVIeWS the fragment containing the J-and clathrin-binding domains of auxilin interacts with the two \"ankles\" of the clathrin heavy chain at their point of intersection and with the subsequent terminal domain. Binding of auxilin to the clathrin lattice causes the terminal domains to twist outwards, which is attributed to a change in the position of the \"ankle.\" this change in the position of terminal domains causes global changes throughout the entire lattice, increasing its diameter. It is believed that auxilin attracts Hsc70 to these areas, which are important for interaction within the lattice [55, 79] .", "cite_spans": [], "ref_spans": []}, {"section": "Hsc70", "text": "Hsc70 is a constitutively expressed chaperone involved in many cellular processes, including protein folding, degradation, and translocation. Another interesting function of Hsc70 is its ability to \"dismount\" the clathrin lattice. thus, addition of AtP and Hsc70 to clathrincoated vesicles in vitro causes disassembly of the clathrin lattice [80] . this is a stoichiometric reaction that requires 3 mol of Hsc70 and AtP for the dissociation of 1 mol of clathrin triskelions [80] [81] [82] . Similary to all Hsp70 family members, Hsc70 requires a protein containing a J-domain to \"work\" with a particular substrate [83] . Auxilin, which binds to clathrin and contains a J-domain, plays that function. the J-domain in the auxilin molecule is positioned in a way that the motif required for the interaction with the Hsc70 protein is exposed on the outside of the lattice. the QLMLt sequence (1638-1642) located in the c-terminal portion of the clathrin heavy chain is also required [84] (Fig. 5B) . the following model of lattice disassembly is proposed: bending at the location of intersection of \"ankles\" caused by the interaction with auxilin enables Hsc70 to bind to its site near the c-terminus of the clathrin molecule. It is assumed that one vertex of the triskelion binds one molecule of Hsc70 and for the strong interaction to be achieved hydrolysis of AtP is required. therefore, deformation of the clathrin lattice which had begun after binding to auxilin is enhanced [85] .", "cite_spans": [], "ref_spans": []}, {"section": "Other clathrin-interacting proteins", "text": "Apart from the AP-2 adaptor complex, clathrin-coated vesicles also contain other proteins. A vast array of monomeric adaptors that bind to clathrin and are able to interact with integral membrane proteins, PtdIns(4,5)P2 and AP-2, in order to ensure the occurrence of clathrin-mediated endocytosis of transmembrane proteins have been identified (Fig. 6) . examples of such adaptors include epsins, the cALM/AP180 protein, HIP1, and HIP1r. the n-terminal domain of these proteins that binds to PtdIns(4,5)P2 is called entH (epsin n-terminal homology) or AntH (AP180 n-terminal homology domain). Another group of monomeric proteins includes Dab2, ArH, and numb. these proteins bind to AP-2, and some of them interact with clathrin. they all contain a phosphotyrosine-binding domain (PtB) responsible for interaction with membrane lipids and for recognition of the FXnPXY motif localized in the cytoplasmic portions of LDLrs. It was demonstrated that phosphorylation of tyrosine at this motif is not a prerequisite for the binding of monomeric adaptors [71] .", "cite_spans": [], "ref_spans": [{"start": 344, "end": 352, "text": "(Fig. 6)", "ref_id": "FIGREF6"}]}, {"section": "Other clathrin-interacting proteins", "text": "In addition to binding to cell membrane lipids, the adaptors recognize the signals localized in the cytoplasmic portion of the receptors. these may include posttranslational modifications (phosphorylation, ubiquitination), short peptide motifs, or both [86] . It is presumed that binding of the adaptor to the cytoplasmic membrane is stabilized upon simultaneous interac- tion of the adaptor with PtdIns(4,5)P2 and the receptor [70, 87] . the role of all these adaptor proteins is poorly understood. Perhaps, the use of various proteins enables to avoid simultaneous accumulation of various GPcr in the same clathrin-coated vesicle [88] .", "cite_spans": [], "ref_spans": []}, {"section": "Other clathrin-interacting proteins", "text": "Specific recognition of the receptor for its subsequent removal from the membrane is the role of adaptors that has been most researched. this recognition leads to disruption of the delivery of the receptor to the ligand responsible for its activation and often to the transfer of the receptor to lysosomes for degradation.", "cite_spans": [], "ref_spans": []}, {"section": "Other clathrin-interacting proteins", "text": "Internalization of the receptor mediated by a specific adaptor may also result in the receptor being directed to another cellular compartment with its own set of signaling molecules [89] . Another consequence of the selective removal of the receptor from the cell surface may be such a cellular development, which is associated with one of the daughter cells receiving a different set of adaptors responsible for the endocytosis of certain receptors. For instance, during the development of Drosophila sense organs, the adaptor numb is transferred to only one of the two daughter cells. numb is responsible for the adjustment of the development of HIP 1 reVIeWS the cell it is located in by inhibiting transduction of signals along the notch-pathway. Inhibition is attributed to receptor endocytosis; however, it is unclear whether the protein numb controls the endocytosis of notch directly or via the transmembrane regulator of notchSandopo [90, 91] .", "cite_spans": [], "ref_spans": []}, {"section": "Other clathrin-interacting proteins", "text": "As mentioned above, the proteins numb, Dab2, and ArH contain a domain that specifically recognizes the FXnPXY sequence in the cytoplasmic portion of the receptors. It was demonstrated that the proteins ArH and Dab2 are involved in the endocytosis of the LDL receptor, and the numb protein regulates the endocytosis of the integral membrane proteins, including the eGF and notch receptors [88] .", "cite_spans": [], "ref_spans": []}, {"section": "Other clathrin-interacting proteins", "text": "the epsin protein is involved in clathrin-mediated endocytosis in mammalian cells, where it plays an important role in the cytoplasmic membrane bending attributed to the action of the entH domain. the occurrence of this process is associated with the c-terminal portion of the protein binding to clathrin coat components (clathrin and AP-2 n-terminal domains, and eHdomain of the protein eps15), which leads to the assembly of the clathrin lattice. the uIM-repeats of the epsin protein that acts as an adaptor protein facilitate recognition of the ubiquitinated \"cargo\": in particular transmembrane proteins [88, 92] .", "cite_spans": [], "ref_spans": []}, {"section": "Other clathrin-interacting proteins", "text": "the proteins AP180 and cALM ease the assembly of the clathrin-coated vesicles and regulate their size [20, 93, 94] . It is assumed that AP180 and cALM play an important role in ensuring the polarity and control of the growth of the axons and dendrites of the hippocampal neurons [95] .", "cite_spans": [], "ref_spans": []}, {"section": "Other clathrin-interacting proteins", "text": "TRIP8b -novel clathrin-binding protein and a potential endocytosis adaptor trIP8b (tPr-containing rab8b interacting protein) is one of the recently discovered potential adaptors involved in the regulation of endocytosis. Being expressed predominantly in brain tissue, trIP8b was initially identified as a protein that interacts with the small GtP-ase rab8b [96] . Six tPr-motifs are located in the c-terminal part of trIP8b, forming the tPr-domain (Fig. 7) . tPr-motifs represent repeats consisting of 34 amino acids. these motifs are found in many proteins and are involved in protein-protein interactions [97] . these repeats are often arranged consecutively, resulting in a spatial structure consisting of two antiparallel \u03b1-helices connected by a short loop [98] . the n-terminal portion of trIP8b does not contain sequences homologous to other known proteins and undergoes alternative splicing [99] .", "cite_spans": [], "ref_spans": [{"start": 448, "end": 456, "text": "(Fig. 7)", "ref_id": "FIGREF7"}]}, {"section": "Other clathrin-interacting proteins", "text": "It is known that trIP8b is 40% identical to the Pex5 protein (peroxin protein) and their c-terminal portion containing tPr-domains are 57% identical (other names for the trIP8b include Pex5rp, Pex5p related protein) [100] . the Pex5 protein is found in many organisms ranging from yeast to mammals; it is responsible for the recognition and import of peroxisomal proteins containing the c-terminal SKL motif (peroxisometargeting signal type 1, PtS1) from the cytosol into peroxisomes. Despite the fact that trIP8b recognizes the PtS1 sequence it has been established that it is not involved in peroxisomal protein import [100] .", "cite_spans": [], "ref_spans": []}, {"section": "Other clathrin-interacting proteins", "text": "trIP8b interacts with the rab8b protein and also directly with a protein that forms the Hcn-channel (Hyperpolarization-activated, cyclic nucleotide-regulated channel) [99, 101] . It was found that trIP8b binds to the cIrL1 receptor [102] , which belongs to the GPcr class, and to the transmembrane protein called caspr [103] .", "cite_spans": [], "ref_spans": []}, {"section": "Other clathrin-interacting proteins", "text": "Hcn channels belong to the family of voltage-dependent channels [104] [105] [106] . these channels are involved in the control of the heart and brain pacemakers' activity, ensuring resting membrane potential and synaptic transmission (see reviews [107] and [108] ). Investigations into the interactions between trIP8b and the Hcn channel demonstrated that trIP8b regulates the functions and surface expression of the channel [99, 101, 109, 110] . It is assumed that trIP8b acts as an auxiliary adaptor for Hcn and that the interaction is mediated by at least two different regions in the trIP8b and Hcn molecules [111, 112] .", "cite_spans": [{"start": 64, "end": 69, "text": "[104]", "ref_id": "BIBREF100"}], "ref_spans": []}, {"section": "Other clathrin-interacting proteins", "text": "All of the previously identified interactions of trIP8b with other proteins were mediated by the tPr-domains localized in the c-terminal part of trIP8b [96, 99, 100] or a segment located in the conserved central region of the protein [109, 111, 112] .", "cite_spans": [], "ref_spans": []}, {"section": "Other clathrin-interacting proteins", "text": "As mentioned above, the n-terminal portion of trIP8b undergoes alternative splicing. Isoforms of the protein generated as a result of splicing affect the Hcn transport and its localization on the cytoplasmic membrane differently: some isoforms increase the surface expression of Hcn1 and others decrease it [109, 110] . It was found that trIP8b interacts with clathrin and this interaction involves the n-terminal portion of the protein trIP8b [103, 113] . the clathrin-binding site in the trIP8b molecule consists of two short motifs reminiscent of the \"clathrin box\" motif.", "cite_spans": [], "ref_spans": []}, {"section": "Other clathrin-interacting proteins", "text": "In order to investigate the trIP8b functions two types of knockout mice were obtained. the phenotype of mice lacking certain trIP8b isoforms was identical to that of wild-type mice [114] . Abnormalities in the motor learning and increased resistance during the behavioral despair test were observed in mice with a complete absence of the protein (trIP8b -/-) [115] . the need to conduct further investigations into clathrin-mediated endocytosis is unquestionable. Internalization of ligand-activated receptors and the functions of various accessory proteins are of significant interest. Interactions between clathrin and numerous adaptor proteins are currently being actively investigated. clathrin is involved in various processes: endocytosis, intracellular traffic, and segregation of chromosomes. It is assumed that abnormalities in the functioning of clathrin can lead to the development of certain diseases. In this regard, investigations into the structure and functions of clathrin-coated vesicles, as well as the proteins involved in the formation of the latter, is of interest from the point of view of molecular biology and biomedicine. ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Premont r.t., Lefkowitz r.J. // nat. rev", "authors": [{"first": "K", "middle": ["L"], "last": "Pierce", "suffix": ""}], "year": 2002, "venue": "Mol. cell. Biol", "link": null}, "BIBREF6": {"title": "Proc. natl. Acad. Sci. uSA", "authors": [{"first": "S", "middle": ["A"], "last": "Laporte", "suffix": ""}, {"first": "", "middle": ["H"], "last": "Oakley R", "suffix": ""}, {"first": "J", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Holt", "suffix": ""}, {"first": "S", "middle": ["S"], "last": "Ferguson", "suffix": ""}, {"first": "M", "middle": ["G"], "last": "Caron", "suffix": ""}, {"first": "L", "middle": [], "last": "Barak", "suffix": ""}], "year": 1999, "venue": "", "link": null}, "BIBREF19": {"title": "Proc. natl. Acad. Sci. uSA. 2006. V. 103. P", "authors": [{"first": "P", "middle": ["D"], "last": "Blood", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF23": {"title": "Boucrot e. // nat. rev", "authors": [{"first": "H", "middle": ["T"], "last": "Mcmahon", "suffix": ""}], "year": 2011, "venue": "Mol. cell. Biol", "link": null}, "BIBREF25": {"title": "De camilli P. // nat. rev", "authors": [{"first": "S", "middle": ["M"], "last": "Ferguson", "suffix": ""}], "year": 2012, "venue": "Mol. cell. Biol", "link": null}, "BIBREF46": {"title": "Proc. natl. Acad. Sci. uSA", "authors": [{"first": "", "middle": [], "last": "Ter Haar E", "suffix": ""}, {"first": "S", "middle": [], "last": "Harrison", "suffix": ""}], "year": 2000, "venue": "", "link": null}, "BIBREF72": {"title": "Proc. natl. Acad. Sci. uSA. 2006. V. 103. P", "authors": [{"first": ".", "middle": ["H"], "last": "Massol R", "suffix": ""}, {"first": "W", "middle": [], "last": "Boll", "suffix": ""}, {"first": "A", "middle": [], "last": "Griffin", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF100": {"title": "Proc. natl. Acad. Sci. uSA", "authors": [{"first": "B", "middle": [], "last": "Santoro", "suffix": ""}, {"first": "S", "middle": ["G"], "last": "Grant", "suffix": ""}, {"first": "D", "middle": [], "last": "Bartsch", "suffix": ""}], "year": 1997, "venue": "", "link": null}}, "ref_entries": {"FIGREF1": {"text": "Fig 1. Schematic diagram of clathrin-mediated internalization of a receptor following its activation", "type": "figure"}, "FIGREF2": {"text": "Fig 2. Clathrin molecule (triskelion). Segments of the clathrin heavy chain are indicated. The terminal domain is the N-terminal domain and the C-terminal domains are localized in the center of the molecule. The position of the light chains is shown schematically. Figure adapted from [40]", "type": "figure"}, "FIGREF3": {"text": "Fig 3. Hexagonal clathrin barrel model (7.9\u00c5 resolution). Only the heavy chains of clathrin are indicated. Figure adapted from [40]", "type": "figure"}, "FIGREF4": {"text": "Fig 4. Schematic diagram of the AP complexes. All complexes consist of two large subunits, one medium subunit, and a small subunit. Figure adapted from [63]", "type": "figure"}, "FIGREF5": {"text": "Fig 5. Domain organization of auxilin and Hsc70. Numbers indicate the boundaries of various domains. Figure adapted from [85]", "type": "figure"}, "FIGREF6": {"text": "Fig. 6. Monomeric clathrin-binding adaptors. Schematic representation of the overall domain structure. Figure adapted from [70]", "type": "figure"}, "FIGREF7": {"text": "Fig 7. Schematic representation of the protein TRIP8b domain organization", "type": "figure"}, "FIGREF9": {"text": "This work was supported by the Russian Foundation for Basic Research (Grant \u2116 11-04-12151-ofi-m-2011, 12-04-01817-a, 12-04-32099 mol_a).", "type": "figure"}}}
{"paper_id": "18987071", "_pdf_hash": "b6772a3adc040d417dd9c756a7d175011df16cc9", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Underwater acoustic sensor networks: research challenges", "authors": [{"first": "I", "middle": ["F"], "last": "Akyildiz", "suffix": ""}, {"first": "D", "middle": [], "last": "Pompili", "suffix": ""}, {"first": "T", "middle": [], "last": "Melodia", "suffix": ""}], "year": 2005, "venue": "", "link": "17313334"}, "BIBREF1": {"title": "Rdf vocabulary description language 1.0: Rdf schema w3c recommendation", "authors": [{"first": "D", "middle": [], "last": "Brickley", "suffix": ""}, {"first": "R", "middle": [], "last": "Guha", "suffix": ""}, {"first": "B", "middle": [], "last": "Mcbride", "suffix": ""}], "year": 2004, "venue": "", "link": null}, "BIBREF2": {"title": "A framework for modeling sensor networks", "authors": [{"first": "R", "middle": [], "last": "Jurdak", "suffix": ""}, {"first": "C", "middle": ["V"], "last": "Lopes", "suffix": ""}, {"first": "P", "middle": [], "last": "Baldi", "suffix": ""}], "year": 2004, "venue": "roceedings of the Building Software for Pervasive Computing Workshop at OOPSLA'04", "link": "16945630"}, "BIBREF3": {"title": "Tmotesky ultra low power ieee 802.15.4 compliant wireless sensor module", "authors": [{"first": "", "middle": [], "last": "Moteiv", "suffix": ""}], "year": 2007, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "18987075", "_pdf_hash": "2b958bd3ca5c6560349c4f06f4053a382b5f289f", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "18987559", "_pdf_hash": "fe622eed7ae52adbbbc4f70f6016c1d4a7c5b8cc", "abstract": [{"section": "Abstract", "text": "It is shown that the Lie algebra of the automorphic, meromorphic sl(2, C)-valued functions on a torus is a geometric realization of a certain infinite-dimensional finitely generated Lie algebra. In the trigonometric limit, when the modular parameter of the torus goes to zero, the former Lie algebra goes over into the sl(2, C)-valued loop algebra, while the latter one -into the Lie algebra (A (1) 1 ) \u2032 /(centre).", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "The Inverse Scattering Transform Method has been a source of many important algebraic constructions. The most spectacular of them are quantum groups associated with the quantum R-matrices, and their classical limits -the Lie bialgebras associated with the classical r-matrices. It is well-known, that the classical r-matrices can be classified into three categories: rational, trigonometric and elliptic r-matrices [2] . While the Lie bialgebras, as well as the quantum groups, associated with the rational ( Yangians ) and the trigonometric ( quantized Kac-Moody affine Lie algebras ) solutions of the Yang-Baxter equation are well understood by now [4, 5] , not so much is known about those associated with the elliptic R-matrices. Important exceptions are the Lie algebras of the automorphic, meromorphic sl(n, C)-valued functions on a torus introduced by Reyman and Semenov-Tyan-Shanskii [1] .", "cite_spans": [{"start": 651, "end": 654, "text": "[4,", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Introduction", "text": "These algebras are related to the elliptic solutions of the classical Yang-Baxter equation , the simplest of whic h ( sl(2, C)-case ) is being the r-matrix of the classical Landau-Lifshitz model [8] .", "cite_spans": [{"start": 195, "end": 198, "text": "[8]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Introduction", "text": "The construction of Reyman and Semenov-Tyan-Shanskii is semi-geometric. Having in view the problem of quantization it is important to give a purely algebraic definition of their algebras in terms of finite number of generators and defining relations. The example of what we are looking for is provided by the trigonometric case, where the loop algebras can be considered as the geometric realizations of the appropriate affine Kac-Moody Lie algebras [7] .", "cite_spans": [{"start": 450, "end": 453, "text": "[7]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Introduction", "text": "As it is shown is this letter, it indeed can be done, at least in the sl(2, C) case. We define an infinite-dimensional, finitely generated Lie algebra E k,\u03bd \u00b1 , and show that the Lie algebra of automorphic, meromorphic sl(2, C)-valued functons on a torus provides a geometric realization of E k,\u03bd \u00b1 . It will be also shown that in the trigonometric limit, when the modular parameter of the torus goes to zero, the Lie algebra E k,\u03bd \u00b1 goes over into the Lie algebra", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "It turns out that the Lie (bi)algebra E k,\u03bd \u00b1 can be quantized, the corresponding quantum group being related to the eight-vertex R-matrix.This will be the subject of the subsequent paper [9] .", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "2 Definition of the Lie algebra E k,\u03bd \u00b1 and the main Theorem.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Let k, k \u2032 \u2208 C\\{0, 1} , and k 2 + k \u2032 2 = 1 . Let T = C/(Z4K + Z4iK \u2032 ) be a torus with the periods defined by the complete elliptic integrals K and K \u2032 of the 1-st kind of the moduli k and k \u2032 correspondingly.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Introduce three meromorphic functions {w i } i=1,2,3 on T defined in the following way [6] :", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "where the Jacobi elliptic functions are of the modulus k . These functions obey the following quadratic equations [6] :", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Definition E k,\u03bd \u00b1 is a complex Lie algebra generated by six generators {x", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "which obey the following defining relations:", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "[", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "[", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "c).", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "[g", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "m, n \u2208 Z \u22650 , and the coefficients w ", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Proof of the theorem is given in the Appendix.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Remark : Commutation relations in E k,\u03bd \u00b1 can be compactly written down using the generating functions and the r-matrix representation. Let us define:", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "then the commutation relations in the basis {g", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "} can be recovered from the following commutation relations for the generating functions:", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "[", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "3 Geometric realization of E k,\u03bd \u00b1", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "In this section we describe a geometric realization of the Lie algebra E k,\u03bd \u00b1 -an \"elliptic analog\" of the loop Lie algebras. This turns out to be the Lie algebra of the sl(2, C)-valued automorphic meromorphic functions on T [1] .", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Consider a setF = {\u03d5", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": ", n \u2208 Z \u22650 of meromorphic functions on T defined as follows: ", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "where, in the 2\u00d72 matrix realization of G , one has T (n 1 ,n 2 ) = \u03c3", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "\u2297 s i is an isomorphism, as can be readily checked using the relations :", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "being given by the following formulae :", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "or, in terms of the generating functions:", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "and I is an identity in UG-the universal enveloping algebra of G.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "4 Trigonometric limit of E k,\u03bd \u00b1 In this section it is shown that the trigonometric limit:", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "1 .", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Let us fix \u03bd", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "K \u2032 , let us also make a change of the generators of E k,\u03bd \u00b1 :", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": ". Then the defining relations of E k,\u03bd \u00b1 acquire a form (from now on we drop the prime):", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "If k = 0 , it follows from the above relations that", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Let us add these new ( non-independent only if k = 0) relations to the relations (25-28) and then take a limit k \u2192 0. As a result E k,\u03bd \u00b1 goes over into the Lie algebraL generated by the elements {y", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": ". In the geometric realization this limit has the following explicit form:", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "{y \u00b1 i } obey the following defining relations:", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "[y", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "[y", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "[y", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Proposition 2L contains an ideal \u0131 generated by the elements:", "cite_spans": [], "ref_spans": []}, {"section": "Proposition 3 Lie algebra L =L/\u0131 is isomorphic to the sl(2, C)-loop Lie algebra (\u011c) \u2032 /(centre)", "text": ",\u011c = A", "cite_spans": [], "ref_spans": []}, {"section": "Proposition 3 Lie algebra L =L/\u0131 is isomorphic to the sl(2, C)-loop Lie algebra (\u011c) \u2032 /(centre)", "text": "1 .", "cite_spans": [], "ref_spans": []}, {"section": "Proposition 3 Lie algebra L =L/\u0131 is isomorphic to the sl(2, C)-loop Lie algebra (\u011c) \u2032 /(centre)", "text": "Remark: Non-independent relations (29) in E k,\u03bd \u00b1 go over , as k \u2192 0 into the Serre relations in L.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "The fact, that the Lie algebra of the automorphic, meromorphic sl(2, C)-valued functions on a torus admits a purely algebraic description as the finitely generated infinite dimensional Lie algebra, suggests that it is possible to develop a theory of the algebras of such a type which would be parallel to the theory of the Kac-Moody affine Lie algebras [7] . Such a developement would be clearly important taking into account an abundance of physical and mathematical constructions related to the latter. Among the more immediate ramifications of the result given in this letter, one can point out the problem of finding the quantum groups related to the elliptic quantum R-matrices [9] .", "cite_spans": [{"start": 353, "end": 356, "text": "[7]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Acknowlegement", "text": "The author is grateful to I.T.Ivanov and L.A.Takhtadjan for many helpful discussions.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix", "text": "Proof of the theorem . From the defining relations (3-6) and the Jacobi identity it follows that E k,\u03bd \u00b1 = E + \u222a E \u2212 , where E + and E \u2212 are Lie subalgebras generated by {x", "cite_spans": [], "ref_spans": []}, {"section": "Appendix", "text": "n is a linear subspace of E + spanned by all the elements of the form [x", "cite_spans": [], "ref_spans": []}, {"section": "Appendix", "text": "In what follows g", "cite_spans": [], "ref_spans": []}, {"section": "Appendix", "text": ", i \u2208 {1, 2, 3}, n \u2265 0. We remind, that the indices {i, j, k} denote any cyclic permutation of {1, 2, 3}. We will prove the statements 2 and 3 a).,b). of the theorem using induction.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix", "text": "Fix n \u2208 Z, n \u2265 2 and assume, that:", "cite_spans": [], "ref_spans": []}, {"section": "Appendix", "text": "A n . The elements {g", "cite_spans": [], "ref_spans": []}, {"section": "Appendix", "text": "The fact that these assumptions are true for n = 2 , and that", "cite_spans": [], "ref_spans": []}, {"section": "Appendix", "text": "J ij , follows immediately from the defining relations (3, 4) . We will show that under the above assumptions the statements A n+1 , B n+1 , C n+1 hold true . Under the assumptions A n , B n , C n :", "cite_spans": [{"start": 59, "end": 61, "text": "4)", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Appendix", "text": "2. The coefficients B ", "cite_spans": [], "ref_spans": []}, {"section": "Appendix", "text": ", where \u03b8(x \u2265 (<)0) = 1(0). (39) Proof. Let n = 2p or n = 2p + 1.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix", "text": "Let 0 \u2264 m \u2264 p \u2212 1 . According to the assumption C n : Thus it is shown, that the statements A n+1 , B n+1 , C n+1 are true if the A n , B n , C n are true. From this the statements 2. and 3. a). of the theorem follow for the subalgebra E + .", "cite_spans": [], "ref_spans": []}, {"section": "Appendix", "text": "For the subalgebra E \u2212 which is isomorphic to E + a proof is identical.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix", "text": "By a direct calculation using the relations (22) To finish the proof of the theorem we need to check that the Lie bracket in E k,\u03bd \u00b1 as given by the formulas (11-14) satisfies the Jacobi identity. This follows from the r-matrix representation (18,19) of the commutation relations (11-14), and the well-known fact that r(u) (see (7)) satisfies the Classical Yang-Baxter equation 2.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF3": {"title": "Proceedings of the ICM", "authors": [{"first": "&apos;", "middle": [], "last": "Drinfel", "suffix": ""}, {"first": "V", "middle": ["G"], "last": "", "suffix": ""}], "year": 1986, "venue": "", "link": null}, "BIBREF7": {"title": "Infinite dimensional Lie Algebras", "authors": [{"first": "V", "middle": ["G"], "last": "Kac", "suffix": ""}], "year": 1990, "venue": "", "link": "122481190"}, "BIBREF8": {"title": "Hamiltonian Methods in the theory of solitons", "authors": [{"first": "L", "middle": ["D"], "last": "Faddeev", "suffix": ""}, {"first": "L", "middle": ["A"], "last": "Takhtadjan", "suffix": ""}], "year": 1987, "venue": "", "link": "118056309"}}, "ref_entries": {"FIGREF0": {"text": "\u03bd) are defined by the formulae:", "type": "figure"}, "FIGREF1": {"text": "be a linear span ofF over C . Consider a tensor product A = F \u2297 C G. Single out a linear subspace of A spanned by the elements of the form \u03d5 (n),\u00b1 i \u2297 s i . Denote this subspace by\u1ebc k,\u03bd \u00b1 . The elements of this subspace satisfy the following automorphicity condition with respect to the action of the group Z 2 2 = Z/2Z \u00d7 Z/2Z:", "type": "figure"}, "FIGREF2": {"text": "A n it follows that E + n+1 is a linear span of {[g} i,i \u2032 \u2208{1,2,3};0\u2264m\u2264n . Let us show that among the elements {", "type": "figure"}, "FIGREF4": {"text": "one can verify that the structure constants appearing in the RHS of the statement 3. b). satisfy the recurrent relations (47),1. follows from the explicit form of the bases in E + and E \u2212 . The proof of the statements 3 c).,d). is very similar to that one of the statements 3 a)., b)., for this reason we describe it only schematically. Using induction one can derive recurrent relations for the structure constants appearing in the decompositions of the. Then, we uniquely resolve these -the initial conditions being provided by the defining relations (3-6). The relation (22) again plays the crucial role in this solution.", "type": "figure"}, "TABREF0": {"text": "recurrent relations for A (l,m) k,s .From these relations it is evident, that all the coefficients A", "type": "table"}}}
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{"paper_id": "18988149", "_pdf_hash": "6f0e0570a71ce2feb85ae6f1e9a49e560289896f", "abstract": [{"section": "Abstract", "text": "Skeletal muscle protein turnover is modulated by intracellular signaling pathways involved in protein synthesis, degradation, and inflammation. The proinflammatory status of muscle cells, observed in pathological conditions such as cancer, aging, and sepsis, can directly modulate protein translation initiation and muscle proteolysis, contributing to negative protein turnover. In this context, branched-chain amino acids (BCAAs), especially leucine, have been described as a strong nutritional stimulus able to enhance protein translation initiation and attenuate proteolysis. Furthermore, under inflammatory conditions, BCAA can be transaminated to glutamate in order to increase glutamine synthesis, which is a substrate highly consumed by inflammatory cells such as macrophages. The present paper describes the role of inflammation on muscle remodeling and the possible metabolic and cellular effects of BCAA supplementation in the modulation of inflammatory status of skeletal muscle and the consequences on protein synthesis and degradation.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Skeletal muscle presents unique features that allow it to respond to several exogenous stimuli. This characteristic is named \"plasticity\" [1] . Exercise and nutrition are examples of such stimuli that may promote adaptive responses in skeletal muscle in terms of structure and function [2] [3] [4] . For example, there are some reports describing that mechanical stimuli, particularly resistance exercise, may induce histological changes such as fiber type transition and profile and increase in cross-sectional area [5] , and alterations in muscle function [6, 7] . Branched-chain amino acids (BCAA), especially leucine, are also well-known nutrients that may influence the adaptive response of skeletal muscle. Leucine supplementation has been described as a potential nonpharmacological tool able to stimulate both muscle anabolism and decrease catabolism [8, 9] and to modulate glucose homeostasis [10] . Furthermore, leucine can act synergistically with exercise to improve the efficiency and effectiveness of these adaptive responses [11] .", "cite_spans": [{"start": 138, "end": 141, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 286, "end": 289, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 290, "end": 293, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 294, "end": 297, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 517, "end": 520, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 558, "end": 561, "text": "[6,", "ref_id": "BIBREF5"}, {"start": 562, "end": 564, "text": "7]", "ref_id": "BIBREF6"}, {"start": 859, "end": 862, "text": "[8,", "ref_id": "BIBREF7"}, {"start": 863, "end": 865, "text": "9]", "ref_id": "BIBREF8"}, {"start": 902, "end": 906, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 1040, "end": 1044, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Introduction", "text": "Currently, there are some cellular pathways that partially explain why BCAA supplementation may promote such responses in skeletal muscle. Most of these consistent evidences were observed on incubated cells, which have contributed to elucidate important mechanisms regarding amino acids modulation of skeletal muscle protein turnover. However, we have to consider that such conditions are considerably different from the human body. Although experimental animals (rodents) represent an in vivo model, it may also present distinct results when compared to humans. Recently, our group observed that due to differences in muscle metabolism, rodents may respond differently from humans to amino acids supplementation [12] . Although the same signaling pathways are found in rodent and human cells the response of these models to amino acids supplementation present individualities that may compromise the extrapolation of results.", "cite_spans": [{"start": 713, "end": 717, "text": "[12]", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "Introduction", "text": "The mammalian target of rapamycin (mTOR) pathway is a signal-dependent cascade that responds to a variety of stimuli ranging from growth factors and mitogens to amino acid deprivation and hypoxic stress. It has been well characterized that mTOR pathway has a pivotal role in modulating protein translation initiation through eukaryotic initiation factors (eIFs) and kinases, which in turn alter the phosphorylation status and activity of several proteins in this cellular pathway [13] . Amino acids supplementation is involved in signaling to upstream proteins, responsible for sensing and triggering (mTOR, human vacuolar protein sorting 34 (hVps4), calcium-related proteins) [14] , as well as downstream proteins, responsible for ribosome initiation complex formation (eIF4E, eIF4E-binding protein 1 (4E-BP1), eIF4F complex) [15, 16] . Additionally, it has been shown that BCAA can also interact with the proteolytic machinery (ubiquitin proteasome system-UPS) in order to attenuate muscle wasting [17] . This response may partially involve the protein kinase Akt/PKB, which also participates in glucose homeostasis and muscle hypertrophy. Regarding the proteolytic machinery, Akt/PKB is known to phosphorylate the transcription factor forkhead box class-O (FoxO), which translates the two majority genes (or E3 ligases) of muscle atrophy: atrogin-1 and muscle RING-finger protein-1 (MuRF-1) [12, 18, 19] , to phosphorylate mTOR and stimulate protein synthesis, and to modulate glucose transporter 4 (GLUT4) to the sarcolemma [20] . In view of this, these cellular pathways (synthesis and degradation) are not distinct and may be controlled by amino acids through indirect genomic and nongenomic actions.", "cite_spans": [{"start": 480, "end": 484, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 677, "end": 681, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 827, "end": 831, "text": "[15,", "ref_id": "BIBREF14"}, {"start": 832, "end": 835, "text": "16]", "ref_id": "BIBREF15"}, {"start": 1000, "end": 1004, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 1394, "end": 1398, "text": "[12,", "ref_id": "BIBREF11"}, {"start": 1399, "end": 1402, "text": "18,", "ref_id": "BIBREF17"}, {"start": 1403, "end": 1406, "text": "19]", "ref_id": "BIBREF18"}, {"start": 1528, "end": 1532, "text": "[20]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "Introduction", "text": "Although much attention has been given to the role of amino acids in these pathways, the responsiveness of skeletal muscle to these nutrients may be limited. For instance, amino acids infusion stimulate muscle protein accretion until it reaches a plateau [21] . This condition, known as \"anabolic resistance to amino acids\"-the inability of skeletal muscle to maintain or increase its protein mass by appropriate nutritional stimulation [22] occurs because skeletal muscle protein synthesis is refractory to hyperaminoacidemia. Thus, it appears that the optimal action of amino acids on skeletal muscle growth occur in combination with other exogenous stimuli (e.g., exercise) or in situations characterized by disruption of organic homeostasis (e.g., cancer, diabetes, muscle disuse, sepsis, chronic heart failure). In this context, the inflammatory status has a considerable role and the innate immune system (responsible for cytokines and chemokines production) should be carefully considered.", "cite_spans": [{"start": 255, "end": 259, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 437, "end": 441, "text": "[22]", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Introduction", "text": "The focus of this paper is to discuss the possible metabolic and cellular roles of BCAA supplementation on the inflammatory status of skeletal muscle and the effects on protein synthesis and degradation. It is possible that, in some conditions, the administration of these amino acids could exert an anti-inflammatory role or indirectly modulate the inflammatory status and balance of the system and/or the muscle cell in order to favor the biological response and tissue adaptation.", "cite_spans": [], "ref_spans": []}, {"section": "The Role of Inflammation in Skeletal Muscle", "text": "The healing of injured muscle is composed of sequential but overlapped phases of injury, inflammation, regeneration, and fibrosis. Injury and inflammation predominate the first few days after injury, followed by regeneration. When there is a severe injury the muscle does not recover completely and forms fibrotic tissue approximately two weeks after injury [23] (Figure 1 ).", "cite_spans": [{"start": 358, "end": 362, "text": "[23]", "ref_id": "BIBREF22"}], "ref_spans": [{"start": 363, "end": 372, "text": "(Figure 1", "ref_id": "FIGREF0"}]}, {"section": "The Role of Inflammation in Skeletal Muscle", "text": "The inflammatory response is an important phase of the natural healing process. During this phase there is a release of several types of cytokines and growth factors to increase the permeability of blood vessels and chemotaxis of inflammatory cells, such as neutrophils and macrophages. These cells contribute to the degradation of damaged muscle tissue by releasing reactive oxygen species (ROS) and producing proinflammatory cytokines [24] [25] [26] [27] such as tumor necrosis factor alpha (TNF-\u03b1), interleukin-1 (IL-1), and IL-6 that regulate the inflammatory process [28, 29] . The role of these cells is quite complex and they can promote both injury and repair. A detailed discussion of their action is beyond the scope of this paper and has been reviewed elsewhere [30] .", "cite_spans": [{"start": 437, "end": 441, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 442, "end": 446, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 447, "end": 451, "text": "[26]", "ref_id": "BIBREF25"}, {"start": 452, "end": 456, "text": "[27]", "ref_id": "BIBREF26"}, {"start": 572, "end": 576, "text": "[28,", "ref_id": "BIBREF27"}, {"start": 577, "end": 580, "text": "29]", "ref_id": "BIBREF28"}, {"start": 773, "end": 777, "text": "[30]", "ref_id": "BIBREF29"}], "ref_spans": []}, {"section": "Tumor Necrosis Factor Alpha (TNF-\u03b1).", "text": "Some systemic inflammatory cytokines such as TNF-\u03b1 and IL-1\u03b2 have direct catabolic effects on skeletal muscle. The cytokine TNF-\u03b1 plays a key role in the skeletal muscle wasting present in chronic diseases, such as cancer, sepsis, and rheumatoid arthritis, conditions in which a raise in the plasma TNF-\u03b1 concentration have been described [27, 31] . TNF-\u03b1 impairs muscle protein synthesis [32, 33] by destabilizing myogenic differentiation and altering transcriptional activity [34] and increases muscle loss [35, 36] by targeting proteins to the ubiquitin-proteasome-mediated degradation pathway [37] [38] [39] . TNF-\u03b1 has also an effect on satellite cells and muscle regeneration. In vitro studies have shown that exposure of myoblasts to TNF-\u03b1 inhibits their differentiation [40, 41] . The release of ROS induced by TNF-\u03b1 induces degradation of the inhibitor-\u03baB (I\u03baB), which allows the nuclear factorkappaB (NF-\u03baB) to translocate to the nucleus and to activate the transcription of several \u03baB-dependent genes such as those encoding proinflammatory cytokines, and breakdown of MyoD and myogenin (regulators of the transition from proliferation to differentiation) in the proteasome [34] .", "cite_spans": [{"start": 339, "end": 343, "text": "[27,", "ref_id": "BIBREF26"}, {"start": 344, "end": 347, "text": "31]", "ref_id": "BIBREF30"}, {"start": 389, "end": 393, "text": "[32,", "ref_id": "BIBREF31"}, {"start": 394, "end": 397, "text": "33]", "ref_id": "BIBREF32"}, {"start": 478, "end": 482, "text": "[34]", "ref_id": "BIBREF33"}, {"start": 509, "end": 513, "text": "[35,", "ref_id": "BIBREF34"}, {"start": 514, "end": 517, "text": "36]", "ref_id": "BIBREF35"}, {"start": 597, "end": 601, "text": "[37]", "ref_id": "BIBREF36"}, {"start": 602, "end": 606, "text": "[38]", "ref_id": "BIBREF37"}, {"start": 607, "end": 611, "text": "[39]", "ref_id": "BIBREF38"}, {"start": 778, "end": 782, "text": "[40,", "ref_id": "BIBREF39"}, {"start": 783, "end": 786, "text": "41]", "ref_id": "BIBREF40"}, {"start": 1184, "end": 1188, "text": "[34]", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "Tumor Necrosis Factor Alpha (TNF-\u03b1).", "text": "Although most research has focused on the muscle wasting effects of TNF-\u03b1, under specific conditions this cytokine can also promote muscle protein synthesis and stimulate satellite cell proliferation and differentiation [38, 42] . Among the factors that mediate the different effects of TNF-\u03b1 on protein synthesis or degradation are the state of cell differentiation and the concentration of TNF-\u03b1. Chen et al. [42] have shown that the effects of TNF-\u03b1 on myogenesis and muscle regeneration are concentration dependent: a low concentration of TNF-\u03b1 (0.05 ng/mL) promoted the differentiation of cultured myoblasts while higher concentrations (0.5 and 5 ng/mL) inhibited it. Furthermore, differences in the expression of the TNF-\u03b1 receptor on the surface of different cell types may explain the variable effects of this cytokine. In primary myotubes, low doses of TNF-\u03b1 (1 ng/mL) stimulated maximal protein synthesis, while a much higher dose (50 ng/mL) was required to stimulate maximal protein synthesis in C2C12 myotubes [43] . Therefore, the effects of TNF-\u03b1 depend on the concentration and exposure duration: low concentrations help the repair process, while high and prolonged exposure impairs the regeneration process. It is possible that other factors, such as insulin growth factor 1 (IGF-1) and inflammatory cytokines mediate the effects of TNF-\u03b1 on protein synthesis/degradation, but their roles are still unclear [43, 44] .", "cite_spans": [{"start": 220, "end": 224, "text": "[38,", "ref_id": "BIBREF37"}, {"start": 225, "end": 228, "text": "42]", "ref_id": "BIBREF41"}, {"start": 411, "end": 415, "text": "[42]", "ref_id": "BIBREF41"}, {"start": 1022, "end": 1026, "text": "[43]", "ref_id": "BIBREF42"}, {"start": 1423, "end": 1427, "text": "[43,", "ref_id": "BIBREF42"}, {"start": 1428, "end": 1431, "text": "44]", "ref_id": "BIBREF43"}], "ref_spans": []}, {"section": "Tumor Necrosis Factor Alpha (TNF-\u03b1).", "text": "Elevated levels of TNF-\u03b1 have also been implicated in sarcopenia, the age-related loss of muscle mass, strength, and function [45] . It is a key factor contributing to loss of functional mobility, frailty, and mortality in the elderly [46, 47] . Inflammation, which generally increases with age, is a key factor contributing to sarcopenia, and high level of TNF-\u03b1 is partly responsible for the decrease in muscle protein synthesis that occurs in the elderly [48] [49] [50] [51] . Greiwe et al. [52] have found elevated levels of TNF-\u03b1 mRNA and protein in the skeletal muscle of elderly (81 \u00b1 1 years) when compared to young (23 \u00b1 1 years) men and women. The same authors also showed that resistance exercise decreased TNF-\u03b1 expression in the elderly group, suggesting that TNF-\u03b1 contributes to the age-related muscle wasting, and that resistance exercise may attenuate this process by suppressing TNF-\u03b1 expression.", "cite_spans": [{"start": 126, "end": 130, "text": "[45]", "ref_id": "BIBREF44"}, {"start": 235, "end": 239, "text": "[46,", "ref_id": "BIBREF45"}, {"start": 240, "end": 243, "text": "47]", "ref_id": "BIBREF46"}, {"start": 458, "end": 462, "text": "[48]", "ref_id": "BIBREF47"}, {"start": 463, "end": 467, "text": "[49]", "ref_id": "BIBREF48"}, {"start": 468, "end": 472, "text": "[50]", "ref_id": "BIBREF49"}, {"start": 473, "end": 477, "text": "[51]", "ref_id": "BIBREF50"}, {"start": 494, "end": 498, "text": "[52]", "ref_id": "BIBREF51"}], "ref_spans": []}, {"section": "Lipopolysaccharides (LPS)", "text": ". LPS are components of the outer wall of Gram-negative bacteria. It is well known that Gram-negative infection (or the administration of lipopolysaccharides) causes loss of skeletal muscle protein. The decrease in muscle mass results from increases in the rate of proteolysis and decreased rates of protein synthesis [53, 54] . A decrease in mTOR activity may explain, at least in part, the impaired muscle protein synthesis. Frost et al. [55] have shown that a combination of LPS and IFN-gamma dramatically downregulated the autophosphorylation of mTOR and its substrates S6K1 and 4E-BP1 via an increased expression of iNOS (NOS2) and excessive production of nitric oxide (NO).", "cite_spans": [{"start": 318, "end": 322, "text": "[53,", "ref_id": "BIBREF52"}, {"start": 323, "end": 326, "text": "54]", "ref_id": "BIBREF53"}, {"start": 440, "end": 444, "text": "[55]", "ref_id": "BIBREF54"}], "ref_spans": []}, {"section": "Interleukin-6 (IL-6).", "text": "Studies in mice have shown that overexpression of IL-6 may increase muscle atrophy [56] . However, under certain conditions IL-6 can also promote muscle growth. In vitro data has shown that recombinant IL-6 stimulates myoblasts differentiation [57] . Furthermore, AlShanti et al. [58] demonstrated that IL-6 in combination with TNF-\u03b1 stimulate growth of myoblasts. Therefore, the role of IL-6 in regulating muscle mass appears to be concentration dependent: when overexpressed it may stimulate muscle atrophy, whereas its insufficiency inhibits muscle growth.", "cite_spans": [{"start": 83, "end": 87, "text": "[56]", "ref_id": "BIBREF55"}, {"start": 244, "end": 248, "text": "[57]", "ref_id": "BIBREF56"}, {"start": 280, "end": 284, "text": "[58]", "ref_id": "BIBREF57"}], "ref_spans": []}, {"section": "Nuclear Factor Kappa B (NF-\u03baB).", "text": "The NF-\u03baB serves as a key responder to changes in the environment. It mainly controls the expression of genes involved in the immune response, but it also regulates the expression of genes outside the immune system and is therefore able to influence several aspects of normal and disease physiology [59, 60] . The classic form of NF-\u03baB, a heterodimer of the p50 and p65 subunits, is retained in the cytoplasm through interactions with I\u03baB inhibitory proteins. Inducing stimuli lead to the phosphorylation and degradation of I\u03baB by I\u03baB kinases (IKK), allowing NF-\u03baB to enter the nucleus and regulate gene expression [61] . Chronic activation of NF-\u03baB is related to skeletal muscle pathology. In mice, NF-\u03baB activation causes severe muscle wasting [62] and NF-\u03baB is a key factor in cytokine induced loss of skeletal muscle [63] .", "cite_spans": [{"start": 299, "end": 303, "text": "[59,", "ref_id": "BIBREF58"}, {"start": 304, "end": 307, "text": "60]", "ref_id": "BIBREF59"}, {"start": 615, "end": 619, "text": "[61]", "ref_id": "BIBREF60"}, {"start": 746, "end": 750, "text": "[62]", "ref_id": "BIBREF61"}, {"start": 821, "end": 825, "text": "[63]", "ref_id": "BIBREF62"}], "ref_spans": []}, {"section": "Nuclear Factor Kappa B (NF-\u03baB).", "text": "Exercise may activate several signaling cascades and increase the production of ROS, which activate NF-\u03baB [42, 64] in muscle [65, 66] . The exercise induced increase in NF-\u03baB induces acute-phase proteins and also proinflammatory genes that facilitate the regenerative response in damaged tissues. The involvement of NF-\u03baB in muscle damage has been shown in several reports where exhaustive exercise has caused increases in NF-\u03baB binding activity [67] . Roberts et al. [68] have also shown that the inflammatory response to exercise is attenuated by chronic training, demonstrating that the activity of NF-\u03baB can be seen as a beneficial mediator of exercise-induced adaptations to cellular stress. Furthermore, exercise training may induce local anti-inflammatory effects in skeletal muscle [69] .", "cite_spans": [{"start": 106, "end": 110, "text": "[42,", "ref_id": "BIBREF41"}, {"start": 111, "end": 114, "text": "64]", "ref_id": "BIBREF63"}, {"start": 125, "end": 129, "text": "[65,", "ref_id": "BIBREF64"}, {"start": 130, "end": 133, "text": "66]", "ref_id": "BIBREF65"}, {"start": 446, "end": 450, "text": "[67]", "ref_id": "BIBREF66"}, {"start": 468, "end": 472, "text": "[68]", "ref_id": "BIBREF67"}, {"start": 790, "end": 794, "text": "[69]", "ref_id": "BIBREF69"}], "ref_spans": []}, {"section": "Nuclear Factor Kappa B (NF-\u03baB).", "text": "A training program can also exert an inhibitory effect on NF-\u03baB DNA binding [70, 71] . Regular physical training leads to several adaptations in the vascular, oxidative, and inflammatory systems, suggesting that transcriptional regulators of the various nitric oxide synthase (NOS) isoforms by NF-\u03baB play a key role in training-induced adaptations [72, 73] . Lima-Cabello et al. [74] have demonstrated that the effects observed after a bout of acute exercise on the NF-\u03baB signaling were attenuated by submaximal eccentric exercise training for 8 weeks. Also, the levels of nNOS, iNOS and eNOS expression and nitrotyrosine formation decreased when compared to the acute group.", "cite_spans": [{"start": 76, "end": 80, "text": "[70,", "ref_id": "BIBREF70"}, {"start": 81, "end": 84, "text": "71]", "ref_id": "BIBREF71"}, {"start": 348, "end": 352, "text": "[72,", "ref_id": "BIBREF72"}, {"start": 353, "end": 356, "text": "73]", "ref_id": "BIBREF73"}, {"start": 379, "end": 383, "text": "[74]", "ref_id": "BIBREF74"}], "ref_spans": []}, {"section": "The Possible Role of BCAA Supplementation on Muscle Inflammation", "text": "Unlike other amino acids, the most active enzyme system for BCAA transamination is found in the skeletal muscle rather than the liver [75] . The first reaction involved in the catabolism of BCAA is the reversible reaction of transamination by isoenzymes BCAT (branched-chain aminotransferase) found in both cytosol and mitochondria, which convert amino acids into their respective keto acids (branchedchain keto acids-BCKA), being the \u03b1-ketoisocaproic acid (KIC) for leucine, \u03b1-keto-\u03b2-methylvaleric acid (KMV) for isoleucine, and \u03b1-ketoisovaleric acid (KIV) for valine. The BCKAs formed may undergo oxidative decarboxylation reactions and/or be released in the blood stream and taken up by different tissues, where they are resynthesized to BCAA or oxidized [75] . It is well known that the amino group from BCAA can be incorporated into the \u03b1-keto-glutarate (\u03b1-KG) producing glutamate through glutamate dehydrogenase (GDH). The glutamate can lose the amino group for oxalacetate (OAA) through glutamate-oxalacetate aminotransferase (GOT) producing aspartate to be used in the purine cycle for regeneration of adenosine monophosphate (AMP) from inosinic acid. Glutamate can also be metabolized by glutamine synthetase producing glutamine through ATP-dependent incorporation of NH + 3 [76] (Figure 2 ). Muscle cells present very high concentrations of glutamate and a low activity of GDH [77] . Therefore, the amino group released from BCAA could be easily reincorporated by BCKA (reamination) to produce BCAA or directed to the liver to be oxidized. Alanine can also be synthetized from BCAA since the glutamate-pyruvate aminotransferase can produce pyruvate which can be transaminated to alanine through pyruvate aminotransferase [78, 79] . However, this reaction appears to occur only in situations characterized by absence of energy (i.e., fasting) since skeletal muscle also presents high concentrations of alanine [75] .", "cite_spans": [{"start": 134, "end": 138, "text": "[75]", "ref_id": "BIBREF75"}, {"start": 758, "end": 762, "text": "[75]", "ref_id": "BIBREF75"}, {"start": 1284, "end": 1288, "text": "[76]", "ref_id": "BIBREF76"}, {"start": 1387, "end": 1391, "text": "[77]", "ref_id": "BIBREF77"}, {"start": 1731, "end": 1735, "text": "[78,", "ref_id": "BIBREF78"}, {"start": 1736, "end": 1739, "text": "79]", "ref_id": "BIBREF79"}, {"start": 1919, "end": 1923, "text": "[75]", "ref_id": "BIBREF75"}], "ref_spans": [{"start": 1289, "end": 1298, "text": "(Figure 2", "ref_id": "FIGREF1"}]}, {"section": "The Possible Role of BCAA Supplementation on Muscle Inflammation", "text": "The intracellular pool of amino acids can be derived from biosynthesis (i.e., nonessential amino acids) or from transfer across the plasma membrane (i.e., essential amino acids). Transfer across biological membranes can occur through active (Na 2+ -dependent) or passive transport (Na 2+ -independent) due to their ionic nature [80] . In some instances the process of transfer involves not only the entry but exit of amino acids (exchange). The transport system of glutamine is called System A (Na 2+ -dependent) and the one of leucine is called System l (L; Na 2+ -independent), which are integrated. The glutamine entry in the cell requires Na 2+ , while leucine entry requires exit of glutamine. In conditions where the requirement of glutamine is increased (i.e., catabolic illness), theoretically the intracellular content of glutamine is decreased [81] . The decrement in intracellular pool of glutamine may impair leucine transport to inside the cell. On the other hand, the increase of glutamine transport outside the cell may favor the entry of leucine into the cell. If leucine transport is stimulated, the final result of catabolism could increase the availability of glutamine to the cell through glutamate. However, there are no studies evaluating the effects of leucine and glutamine supplementation under inflammatory conditions. BCAA can indirectly modulate the inflammatory status of muscle cells through glutamine production but this reaction appears to occur only in situations characterized by high glutamine consumption and/or decreased glutamate concentrations (i.e., catabolic illnesses, cancer, burning, and sepsis).", "cite_spans": [{"start": 328, "end": 332, "text": "[80]", "ref_id": "BIBREF80"}, {"start": 854, "end": 858, "text": "[81]", "ref_id": "BIBREF81"}], "ref_spans": []}, {"section": "The Possible Role of BCAA Supplementation on Muscle Inflammation", "text": "Glutamine is an amino acid that plays an important role in maintaining cell function. Ehrensvard et al. [82] first described the importance of glutamine to survival and proliferation of cells such as kidney, intestine, liver, specific neurons in the central nervous system (CNS), pancreatic \u03b2 cells, and cells of the immune system. It is widely known that cells of the immune system such as lymphocytes, macrophages, and neutrophils use high rates of glutamine and many functional parameters of immune cells such as Tcell proliferation, B-lymphocyte differentiation, macrophage phagocytosis, antigen presentation, and cytokine production, plus neutrophil superoxide production and apoptosis are enhanced by glutamine. Under pathological conditions, which increase the activity of these cells glutamine is extremely used as substrate [83] [84] [85] .", "cite_spans": [{"start": 104, "end": 108, "text": "[82]", "ref_id": "BIBREF82"}, {"start": 833, "end": 837, "text": "[83]", "ref_id": "BIBREF83"}, {"start": 838, "end": 842, "text": "[84]", "ref_id": "BIBREF84"}, {"start": 843, "end": 847, "text": "[85]", "ref_id": "BIBREF85"}], "ref_spans": []}, {"section": "The Possible Role of BCAA Supplementation on Muscle Inflammation", "text": "It has already been demonstrated that the availability of glutamine influences the production of cytokines such as interleukin-(IL-) 2 in cultured rodent lymphocytes [86] and, IL-2, IL-10, and interferon-\u03b3 (IFN-\u03b3) in cultured human lymphocytes [87, 88] . Studies have also demonstrated that glutamine may play an important role on NF-\u03baB signal transduction pathways, contributing to the attenuation of local inflammation [89] [90] [91] [92] . When inhibited in the cytoplasm NF-\u03baB is bound to an inhibitory protein: I\u03baB. In inflammatory conditions, the I\u03baBs are phosphorylated by the action of specific protein kinases, such as the IKB kinase complex (IKK) at two serine residues with addition of ubiquitin by ubiquitin ligase and degraded by 26S proteasome complex resulting in liberation of NF-\u03baB. Activated NF-\u03baB then binds to the cognate DNA-binding sites inducing gene transcription that regulates the innate and adaptive immune response (i.e., T-cell development, maturation, and proliferation) [93] [94] [95] .", "cite_spans": [{"start": 166, "end": 170, "text": "[86]", "ref_id": "BIBREF86"}, {"start": 244, "end": 248, "text": "[87,", "ref_id": "BIBREF87"}, {"start": 249, "end": 252, "text": "88]", "ref_id": "BIBREF88"}, {"start": 421, "end": 425, "text": "[89]", "ref_id": "BIBREF89"}, {"start": 426, "end": 430, "text": "[90]", "ref_id": "BIBREF90"}, {"start": 431, "end": 435, "text": "[91]", "ref_id": "BIBREF91"}, {"start": 436, "end": 440, "text": "[92]", "ref_id": "BIBREF92"}, {"start": 1001, "end": 1005, "text": "[93]", "ref_id": "BIBREF93"}, {"start": 1006, "end": 1010, "text": "[94]", "ref_id": "BIBREF94"}, {"start": 1011, "end": 1015, "text": "[95]", "ref_id": "BIBREF95"}], "ref_spans": []}, {"section": "The Possible Role of BCAA Supplementation on Muscle Inflammation", "text": "Regarding skeletal muscle remodeling, NF-\u03baB acts as FoXO, a transcription factor of MuRF-1 gene which promotes sarcomeric degradation by UPS [62] . Several cytokines also have their gene expression modulated by NF-\u03baB (i.e., TNF-\u03b1 and IL-1\u03b2). It was demonstrated that IL-1\u03b2 presents significant correlation with skeletal muscle cross-sectional area and, therefore, can be considered as an atrophic modulator [96] . NF-\u03baB also promotes the transcription of the inducible isoform of nitric oxide synthase (iNOS) [97] which leads to insulin resistance through nitrosylation of the insulin receptor (IR) [98] . Under such conditions, the mTOR translation pathway has impaired signal transduction through proteins involved in translation initiation such as insulin receptor substrates (IRS), Akt, and 4E-BP1 [18] . Therefore, inflammation may modulate muscle remodeling through both synthetic and catabolic pathways.", "cite_spans": [{"start": 141, "end": 145, "text": "[62]", "ref_id": "BIBREF61"}, {"start": 407, "end": 411, "text": "[96]", "ref_id": "BIBREF96"}, {"start": 509, "end": 513, "text": "[97]", "ref_id": "BIBREF97"}, {"start": 599, "end": 603, "text": "[98]", "ref_id": "BIBREF98"}, {"start": 802, "end": 806, "text": "[18]", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "The Possible Role of BCAA Supplementation on Muscle Inflammation", "text": "Counteracting such effects, BCAA (especially leucine) has demonstrated to be a strong nutritional stimulus able to increase skeletal muscle protein synthesis and attenuate protein degradation. For example, Hamel et al. [99] demonstrated that leucine presents one of the strongest inhibitory effects upon UPS in muscle cells when compared to the other essential amino acids (for details about the antiproteolytic effects of leucine, please see Zanchi et al. [8] and Nicastro et al. [9] . Furthermore, it has already been demonstrated that BCAA can stimulate the phosphorylation of proteins involved in the mTOR pathway such as Akt, mTOR, 4E-BP1, eIFs, p70S6k in order to improve the protein turnover of the cell [100, 101] . Since BCAA do not present kinase nor phosphatase activity, their effects appear to be mediated by hVpS34 and calcium-related proteins [102] .", "cite_spans": [{"start": 219, "end": 223, "text": "[99]", "ref_id": "BIBREF99"}, {"start": 457, "end": 460, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 481, "end": 484, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 711, "end": 716, "text": "[100,", "ref_id": "BIBREF100"}, {"start": 717, "end": 721, "text": "101]", "ref_id": "BIBREF101"}, {"start": 858, "end": 863, "text": "[102]", "ref_id": "BIBREF102"}], "ref_spans": []}, {"section": "The Possible Role of BCAA Supplementation on Muscle Inflammation", "text": "Thus, BCAA can directly modulate the protein turnover of the muscle cell in order to counteract the catabolic and anti-anabolic effects of the inflammatory stimulus. Additionally, under pathological conditions, BCAA may influence the inflammatory status of the cell through glutamine production. However, this reaction appears to occur only in situations characterized by a high need of glutamine synthesis.", "cite_spans": [], "ref_spans": []}, {"section": "A Possible Link between Oxidative Stress and BCAA-Mediated Inflammatory Effects", "text": "Skeletal muscle cells continuously produce reactive oxygen species (ROS), which can be generated by various cell organelles and enzymes, such as mitochondria, NAD(P)H oxidases, xanthine oxidoreductases, and nitric oxide synthases, whereas their biological activity is opposed by an array of endogenous enzymatic and nonenzymatic antioxidants [103] . Normally ROS play important physiological roles in skeletal muscle homeostasis and function [104, 105] . However, a disturbance in the state of the well-balanced control of oxidant production and antioxidant activity, known as oxidative stress, in turn, is commonly observed during aging and is characteristic of several pathological conditions Journal of Nutrition and Metabolism such as cancer, diabetes, muscle disuse, sepsis, and chronic heart failure [106] . It has been reported that this oxidative stress directs muscle cells into a catabolic state and that chronic exposure leads to wasting [107] . Oxidative damage may contribute to skeletal muscle dysfunction [108] and oxidants may stimulate expression and activity of skeletal muscle protein degradation pathways [38, 109] . There are several evidences showing that the generation of ROS is one mechanistic link between inflammation and skeletal muscle dysfunction and degradation. ROS produced by infiltrating immune cells may cause direct injury to muscle tissue or activate catabolic signaling. Alternatively, inflammatory cytokines can interact with muscle receptors to initiate catabolic signaling wherein ROS are key mediators of this response, acting as second messengers [107, 110, 111] . Accordingly, overexpression of TNF-\u03b1 in transgenic mice [112] and single intraperitoneal doses of this cytokine [103] promotes muscle wasting that can be attenuated by antioxidants [103, 108] . On the other hand, ROS activate transcription factors (e.g., NF-\u03baB and AP-1) and upregulate expression of proinflammatory genes such as TNF-\u03b1, IL-6 and C-reactive protein, which are involved in the pathogenesis of inflammation [113, 114] .", "cite_spans": [{"start": 342, "end": 347, "text": "[103]", "ref_id": "BIBREF103"}, {"start": 442, "end": 447, "text": "[104,", "ref_id": "BIBREF104"}, {"start": 448, "end": 452, "text": "105]", "ref_id": "BIBREF105"}, {"start": 806, "end": 811, "text": "[106]", "ref_id": "BIBREF106"}, {"start": 949, "end": 954, "text": "[107]", "ref_id": "BIBREF107"}, {"start": 1020, "end": 1025, "text": "[108]", "ref_id": "BIBREF108"}, {"start": 1125, "end": 1129, "text": "[38,", "ref_id": "BIBREF37"}, {"start": 1130, "end": 1134, "text": "109]", "ref_id": "BIBREF109"}, {"start": 1591, "end": 1596, "text": "[107,", "ref_id": "BIBREF107"}, {"start": 1597, "end": 1601, "text": "110,", "ref_id": "BIBREF110"}, {"start": 1602, "end": 1606, "text": "111]", "ref_id": "BIBREF111"}, {"start": 1665, "end": 1670, "text": "[112]", "ref_id": "BIBREF112"}, {"start": 1721, "end": 1726, "text": "[103]", "ref_id": "BIBREF103"}, {"start": 1790, "end": 1795, "text": "[103,", "ref_id": "BIBREF103"}, {"start": 1796, "end": 1800, "text": "108]", "ref_id": "BIBREF108"}, {"start": 2030, "end": 2035, "text": "[113,", "ref_id": "BIBREF113"}, {"start": 2036, "end": 2040, "text": "114]", "ref_id": "BIBREF114"}], "ref_spans": []}, {"section": "A Possible Link between Oxidative Stress and BCAA-Mediated Inflammatory Effects", "text": "Although administration of BCAA has been investigated as a tool that could exert an anti-inflammatory role or indirectly modulate the inflammatory status in order to favor the biological response and tissue adaptation, less is known about the relationship between this strategy and oxidative stress modulating skeletal muscle structure and function. There are some emerging reports describing that ROS modulate the efficiency and effectiveness of the adaptive responses of skeletal muscle induced by some BCAA, especially leucine [115, 116] . Regarding BCAA supplementation and oxidative stress, an interesting study [117] has shown that this nonpharmacological strategy increases expression of genes involved in antioxidant defense and reduces ROS production in cardiac and skeletal muscles in middle-aged mice, which was accompanied by preserved skeletal muscle fiber size, enhanced physical endurance and increased average life span. Of interest, BCAA-mediated effects were even more remarkable in middle-aged mice submitted to longterm exercise training (running 30 to 60 min 5 days/week for 4 weeks). In young animals (4-6 months old), BCAA supplementation was ineffective.", "cite_spans": [{"start": 530, "end": 535, "text": "[115,", "ref_id": "BIBREF115"}, {"start": 536, "end": 540, "text": "116]", "ref_id": "BIBREF116"}, {"start": 617, "end": 622, "text": "[117]", "ref_id": "BIBREF117"}], "ref_spans": []}, {"section": "A Possible Link between Oxidative Stress and BCAA-Mediated Inflammatory Effects", "text": "Aging has been described as a condition characterized by anabolic resistance to nutrients, especially amino acids, which impairs muscle protein synthesis and contributes to muscle wasting. Such resistance is partially associated to oxidative stress and low-grade inflammation and may be attenuated by chronic anti-inflammatory treatment. Recently, Smith et al. [118] demonstrated that older adults who received omega-3 fatty acids for 8 weeks increased the hyperaminoacidemia-hyperinsulinemia-induced muscle protein synthesis when compared to the control group (corn oil), which was accompanied by greater phosphorylation of mTOR Ser2448 and p70S6k Thr389 . Furthermore, the authors observed decreased serum levels of TNF-\u03b1 in the omega-3-supplemented group. Therefore, the anti-inflammatory action of nutrients such as omega-3 may attenuate anabolic resistance in order to favor amino acid-induced muscle protein synthesis.", "cite_spans": [{"start": 361, "end": 366, "text": "[118]", "ref_id": "BIBREF118"}], "ref_spans": []}, {"section": "A Possible Link between Oxidative Stress and BCAA-Mediated Inflammatory Effects", "text": "Concerning BCAA supplementation, Marzani et al. [115] demonstrated that old rats supplemented with leucine and with an antioxidant mixture (rutin, vitamin E, vitamin A, zinc, and selenium) showed higher protein synthesis when compared to old-control animals and that these effects could be mediated through a reduction in the inflammatory state, which decreased with antioxidant supplementation. Under inflammatory conditions, such as aging, anabolic resistance occurs mainly because of elevated proinflammatory cytokines. Thus, antioxidant supplementation may attenuate anabolic resistance and therefore favor leucine action on skeletal muscle protein turnover.", "cite_spans": [{"start": 48, "end": 53, "text": "[115]", "ref_id": "BIBREF115"}], "ref_spans": []}, {"section": "Conclusion and Perspectives", "text": "BCAAs present unique features in skeletal muscle protein metabolism. It is well accepted that their catabolic reactions can be easily modulated through alterations in metabolic demands, such as in inflammatory status. However, it is unknown if BCAA can directly modulate the status of proteins involved in inflammatory pathways and if this effect could reflect on protein turnover. Since glutamine is highly consumed by inflammatory cells, it appears to be a mediator of BCAA and inflammation but this reaction is dependent of glutamate content and GDH activity in skeletal muscle. Future studies should address the effects of BCAA, glutamine and the amino acids transporter activity under proinflammatory conditions.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Resistance exercise biology: manipulation of resistance exercise programme variables determines the responses of cellular and molecular signalling pathways", "authors": [{"first": "B", "middle": ["A"], "last": "Spiering", "suffix": ""}, {"first": "W", "middle": ["J"], "last": "Kraemer", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Anderson", "suffix": ""}], "year": 2008, "venue": "Sports Medicine", "link": "41217740"}, "BIBREF1": {"title": "Resistance exercise and appropriate nutrition to counteract muscle wasting and promote muscle hypertrophy", "authors": [{"first": "E", "middle": ["I"], "last": "Glover", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Phillips", "suffix": ""}], "year": 2010, "venue": "Current Opinion in Clinical Nutrition and Metabolic 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middle-aged mice", "authors": [{"first": "G", "middle": [], "last": "D&apos;antona", "suffix": ""}, {"first": "M", "middle": [], "last": "Ragni", "suffix": ""}, {"first": "A", "middle": [], "last": "Cardile", "suffix": ""}], "year": 2010, "venue": "Cell Metabolism", "link": "9790472"}, "BIBREF118": {"title": "Dietary omega-3 fatty acid supplementation increases the rate of muscle protein synthesis in older adults: a randomized controlled trial", "authors": [{"first": "G", "middle": ["I"], "last": "Smith", "suffix": ""}, {"first": "P", "middle": [], "last": "Atherton", "suffix": ""}, {"first": "D", "middle": ["N"], "last": "Reeds", "suffix": ""}], "year": 2011, "venue": "American Journal of Clinical Nutrition", "link": "5028093"}}, "ref_entries": {"FIGREF0": {"text": "Figure 1: Signaling pathways linking skeletal muscle inflammation and remodeling Possible role of BCAA action. Skeletal muscle inflammation can increase the expression and activity of factors such as TNF-\u03b1B, ROS, IL-6, and NF-\u03baB which in turn could contribute to protein degradation and attenuate protein synthesis. On the other hand, BCAA supplementation could counteract such effects by suppressing skeletal muscle proteolysis and stimulation protein synthesis. BCAA: branched-chain amino acids; IL-6: interleukin 6: NF-\u03baB, nuclear factor kappa B: ROS: reactive oxygen species; TNF-\u03b1: tumor necrosis alpha.", "type": "figure"}, "FIGREF1": {"text": "Figure 2: Possible role of glutamine as an intermediary of BCAA action on skeletal muscle inflammation. BCAA could modulate inflammatory response through glutamine synthesis. Such reaction occurs through BCAA transamination and generation of glutamate from \u03b1-KG. Glutamate is then converted to glutamine by glutamine synthetase. \u03b1-KG: alpha-ketoglutarate; \u03b1-KIC, \u03b1-ketoisocaproate; BCAA: branched-chain amino acids; GDH: glutamate dehydrogenase.", "type": "figure"}}}
{"paper_id": "18988371", "_pdf_hash": "5d43bc2a6bcaa9ced173ffed94c2359e87d9f0a4", "abstract": [{"section": "Abstract", "text": "Strongly self-dual Yang-Mills fields in even dimensional spaces are characterised by a set of constraints on the eigenvalues of the YangMills fields F \u00b5\u03bd . We derive a topological bound on", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "1 where p 1 is the first Pontrjagin class of the SO(n) Yang-Mills bundle and k is a constant. Strongly self-dual Yang-Mills fields realise the lower bound. 0 1. Introduction.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction.", "text": "Self-dual Yang-Mills fields in four dimensions have many remarkable properties. But the notion of self-duality cannot be easily generalised to higher dimensions. Let us first highlight the main points concerning the self dual Yang-Mills theory in four dimensions before we discuss a generalisation to higher dimensions. Our notation and conventions are given in the Appendix.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction.", "text": "1. In four dimensions the Yang-Mills functional is the L 2 norm of the curvature 2-form F", "cite_spans": [], "ref_spans": []}, {"section": "Introduction.", "text": "where * denotes the Hodge dual of F . The Yang-Mills equations are the critical points of the Yang-Mills functional. They are of the form", "cite_spans": [], "ref_spans": []}, {"section": "Introduction.", "text": "where d E is the bundle covariant derivative and \u2212 * d E * is its formal adjoint. 2. F is self-dual or anti-self-dual provided * F = \u00b1F.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction.", "text": "Self-dual or anti-self-dual solutions of (2) are the global extrema of the YangMills functional (1) . This can be seen as follows: The Yang-Mills functional has a topological bound", "cite_spans": [{"start": 41, "end": 44, "text": "(2)", "ref_id": "BIBREF1"}, {"start": 96, "end": 99, "text": "(1)", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Introduction.", "text": "The term tr(F \u2227 F ) is related to the Chern classes of the bundle [1] . Actually if E is a complex 2-plane bundle with c 1 (E) = 0,then the topological bound is proportional to c 2 (E) and this lower bound is realised by a (anti)self-dual connection. Furthermore, SU(2) bundles over a four manifold are classified by c 2 (E), hence self-dual connections are minimal representatives of the connections in each equivalence class of SU(2) bundles [2] . This is a generalisation of the fact that an SU(2) bundle admits a flat connection if and only if it is trivial.", "cite_spans": [{"start": 66, "end": 69, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 444, "end": 447, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Introduction.", "text": "3. Self-dual Yang-Mills equations form an elliptic system in the Coulomb gauge divA = 0. The importance of this property is that, in gauge theory, elliptic equations lead to finite dimensional moduli spaces [3] .", "cite_spans": [{"start": 207, "end": 210, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Introduction.", "text": "4. Hodge duality can equivalently be defined by requiring that F is an eigen bi-vector of the completely antisymmetric \u01eb ijkl tensor. In four dimensions such a tensor is unique and have the same constant coefficients in all coordinate systems. Thus self-dual Yang-Mills equations are linear equations that have the same constant coefficients in all coordinate systems that leave the Euclidean metric invariant .", "cite_spans": [], "ref_spans": []}, {"section": "Introduction.", "text": "5. Self-dual Yang-Mills equations can be written in terms of the commutator of two linear operators depending on a complex parameter. Then their solution can be reduced to the solution of a Riemann problem and this case is considered as completely solvable in integrable system theory .", "cite_spans": [], "ref_spans": []}, {"section": "Introduction.", "text": "The earliest attempt at a generalisation of self-duality to higher dimensions is due to Tchrakian [4] . His approach is pursued further for physical applications [5] . In a similar vein, Corrigan,Devchand,Fairlie and Nuyts [6] studied the first-order equations satisfied by Yang-Mills fields in spaces of dimension greater than four (property 4 above) and derived SO (7) self-duality equations in R 8 . This construction was followed by an investigation of completely solvable Yang-Mills equations (property 5 above) in higher dimensions by Ward [7] . A different approach is taken by Feza G\u00fcrsey and his coworkers [8] who showed that the notion of self-duality can be carried over to eight dimensions by making use of octonions. This observation proved fruitful as SO(7) self-duality equations in R 8 can be solved in terms of octonions [9] . The existence of the so called octonionic instantons is closely tied to the properties of the Cayley algebra. These turned out to be relevant to superstring models. In fact soliton solutions of the string equations of motion to the lowest order in the string tension parameter, that preserve at least one supersymmetry, are given by octonionic instantons [10, 11] . A further connection between strings and octonions is provided by the existence of supersymmetric Yang-Mills theories and superstring actions only in dimensions 3,4,6,10. The number of transverse dimensions 1,2,4,8 coincide with the dimensions of the division algebras R,C, H and O [12] . These are related with the four Hopf fibrations, the last of which S 15 \u2192 S 8 is realised by the octonionic instantons [13] .", "cite_spans": [], "ref_spans": []}, {"section": "Introduction.", "text": "Here we present a characterisation of strongly self-dual Yang-Mills fields by an eigenvalue criterion in even dimensional spaces. In particular, the selfdual Yang-Mills equations in four dimensions and the self-duality equations of Corrigan et al in eight dimensions are consistent with our strong self-duality criteria.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction.", "text": "2. Self-duality of a 2-form as an eigenvalue criterion.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction.", "text": "Any 2-form in 2m dimensions can be represented by a 2m \u00d7 2m skew symmetric real matrix. Such a matrix \u2126 has pure imaginary eigenvalues that are pairwise conjugate. Let \u03bb k , k = 1, . . . m be these eigenvalues. This is equivalent to the existence of a basis {X k , Y k } such that", "cite_spans": [], "ref_spans": []}, {"section": "Introduction.", "text": "for each k. In this basis the matrix \u2126 takes the block diagonal form:", "cite_spans": [], "ref_spans": []}, {"section": "Introduction.", "text": "We first consider the case m = 2. In four dimensions self-duality can be described by the following eigenvalue criterion which allows an immediate generalisation to higher dimensions. Let \u2126 be the skew symmetric matrix representing a 2-form F in four dimensions. Then it can be seen that the eigenvalues of the matrix \u2126 satisfy", "cite_spans": [], "ref_spans": []}, {"section": "Introduction.", "text": "Thus for self-duality", "cite_spans": [], "ref_spans": []}, {"section": "Introduction.", "text": "while for anti-self-duality", "cite_spans": [], "ref_spans": []}, {"section": "Introduction.", "text": "In both cases the absolute values of the eigenvalues are equal. Two cases are distinguished by the sign of", "cite_spans": [], "ref_spans": []}, {"section": "Introduction.", "text": "In higher dimensions we propose the following Definition Let F be a 2-form in 2m dimensional space and \u00b1i\u03bb k , k = 1, . . . , m be its eigenvalues. Then F is strongly self-dual if it can be brought to block diagonal form (6) with respect to an oriented basis such that", "cite_spans": [], "ref_spans": []}, {"section": "Introduction.", "text": "The strong self-duality or strong anti-self-duality can be characterised by requiring the equality of the absolute values of the eigenvalues:", "cite_spans": [], "ref_spans": []}, {"section": "Introduction.", "text": "There are 2 m possible ways to satisfy the above set of equalities. The half of these correspond to strongly self-dual 2-forms, while the remaining half correspond to strongly anti-self-dual 2-forms. Now consider a 2-form F in eight dimensions and let the corresponding matrix be \u2126. Then", "cite_spans": [], "ref_spans": []}, {"section": "Introduction.", "text": "where, provided the eigenvalues of \u2126 are \u03bb 1 , \u03bb 2 , \u03bb 3 , \u03bb 4 , we have ", "cite_spans": [], "ref_spans": []}, {"section": "Introduction.", "text": "The sign of square root of the determinant", "cite_spans": [], "ref_spans": []}, {"section": "Introduction.", "text": "distinguishes between the self-dual and anti-self-dual cases.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction.", "text": "In the next section we will need various estimates involving the norm of F . To this end we prove the following", "cite_spans": [], "ref_spans": []}, {"section": "Introduction.", "text": "Proof. From above it can be seen that 2 + (\u03bb", "cite_spans": [], "ref_spans": []}, {"section": "Introduction.", "text": "Proof. From above we have", "cite_spans": [], "ref_spans": []}, {"section": "Introduction.", "text": "Equality holds in both the above lemmas if and only if the absolute values of all eigenvalues are equal.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction.", "text": "The computation above allows us also to prove the following", "cite_spans": [], "ref_spans": []}, {"section": "Introduction.", "text": "and F \u00b5\u03bd be its coordinate components. If \u00b1\u03bb k , k = 1, . . . , 4 are the corresponding eigenvalues, then \u03bb 1 = \u03bb 2 = \u03bb 3 = \u03bb 4 if the following equations are satisfied:", "cite_spans": [], "ref_spans": []}, {"section": "Introduction.", "text": "Proof. From the proof of Lemma 1, 3\u03c3 2 2 \u2212 8\u03c3 4 = 0 if and only if \u03bb 1 = \u03bb 2 = \u03bb 3 = \u03bb 4 . On the other hand, by direct computation with the EXCALC package in REDUCE it is shown that this condition holds when the above equations are satisfied. 2", "cite_spans": [], "ref_spans": []}, {"section": "Introduction.", "text": "These are precisely the self-duality equations of Corrigan,Devchand, Fairlie and Nuyts [6] .", "cite_spans": [], "ref_spans": []}, {"section": "A topological lower bound", "text": "How to choose the action density and its topological lower bound? The idea underlying the self-dual Yang-Mills theory is that the Yang-Mills action F 2 (that is a second order curvature invariant) is bounded below by a topological invariant of the bundle. In the case of an SU(2) bundle over a four manifold, the bundle is classified by the second Chern number c 2 (E). This lower bound is achieved for self-dual fields, hence a self-dual connection on an SU(2) bundle is the connection whose norm is minimal among all connections on that bundle.", "cite_spans": [], "ref_spans": []}, {"section": "A topological lower bound", "text": "In higher dimensions, we want similarly to find a lower bound for the norm of a curvature invariant in terms of topological invariants of the bundle. If the base manifold is eight dimensional, we will need to integrate an 8-form, hence assuming that the first Chern class of the bundle vanishes c 1 (E) = 0 , an appropriate lower bound can be given by a linear combination of the only available Pontryagin classes :", "cite_spans": [], "ref_spans": []}, {"section": "A topological lower bound", "text": "But then the topological lower bound would be a fourth order expression in F , so that it is natural to seek a lower bound to some fourth order curvature invariant. The action density should be written in terms of the local curvature 2-form matrix in a way independent of the local trivilization of the bundle. Hence it should involve invariant polynomials of the local curvature matrix. We want to express the action as an inner product in the space of k-forms, which gives a quantity independent of the local coordinates. This leads to the following generic action density", "cite_spans": [], "ref_spans": []}, {"section": "A topological lower bound", "text": "The action density proposed by Grossman,Kephardt and Stasheff [13] corresponds to the choice a = c = 0. Then the self-duality (in the Hodge sense) of F 2 gives global minima of this action involving the characteristic number p 2 (E).", "cite_spans": [], "ref_spans": []}, {"section": "A topological lower bound", "text": "We derive an alternative lower bound involving the other characteristic number p 1 (E)", "cite_spans": [], "ref_spans": []}, {"section": "A topological lower bound", "text": "2 . In analogy with the fact that in four dimensions the L 2 norm of the curvature is bounded below by a topological number, we give a lower bound for the expression (F, F ) 2 for an SO(n) bundle. However, from the Schwarz inequality, it can be seen that for a compact manifold M,", "cite_spans": [], "ref_spans": []}, {"section": "A topological lower bound", "text": "hence lower bounds on the (F, F ) 2 cannot be related to the L 2 norm of F .", "cite_spans": [], "ref_spans": []}, {"section": "A topological lower bound", "text": "Consider an SO(n) valued curvature 2-form matrix F = (F ab ). Then", "cite_spans": [], "ref_spans": []}, {"section": "A topological lower bound", "text": "and", "cite_spans": [], "ref_spans": []}, {"section": "A topological lower bound", "text": "On the other hand", "cite_spans": [], "ref_spans": []}, {"section": "A topological lower bound", "text": "From the Schwarz inequality we have", "cite_spans": [], "ref_spans": []}, {"section": "A topological lower bound", "text": "Then from Lemma 1 we obtain", "cite_spans": [], "ref_spans": []}, {"section": "A topological lower bound", "text": "while from Lemma 2 (trF 2 , trF 2 ) \u2265 * trF 4 .", "cite_spans": [], "ref_spans": []}, {"section": "A topological lower bound", "text": "In both (24) and (25) the lower bound is realised by strongly (anti)self-dual fields.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "In this paper we have characterised strongly (anti)self-dual Yang-Mills fields in even dimensional spaces by putting constraints on the eigenvalues of F . The previously known cases of self-dual Yang-Mills fields in four and eight dimensions are consistent with our characterisation. We believe this new approach to self-duality in higher dimensions deserves further study.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "We have also derived a topological bound", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "that is achieved by strongly (anti)self-dual Yang-Mills fields. This is to be compared with a topological bound obtained earlier", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "As already noted, the self-duality of F 2 in the Hodge sense attains the lower bound in (27). But as opposed to the self duality of F in four dimensions, this condition is too restrictive since it yields an overdetermined system for the connection , namely 21 nonlinear equations for 8 variables.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "The new topological bound we found here will also be important for applications because, for instance, there are bundles such that p 2 (E) = 0 while p 1 (E) 2 = 0. [14] Given any sequence of numbers p 1 , p 2 , ..., p n , they possibly cannot be realised as Pontryagin numbers of a 4n-manifold. But it can be shown that for an appropriate k, the multiples kp 1 , kp 2 , ..., kp n can be realised. As a corollary, there are infinitely many distinct 8=manifolds with p 2 = 0 but p 1 = 0.", "cite_spans": [{"start": 164, "end": 168, "text": "[14]", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "Appendix: Notation and Conventions", "text": "Let M be an m dimensional differentiable manifold, and E be a vector bundle over M with standard fiber R n and structure group G. A connection on E can be represented by G valued connection 1-form A, where G is a linear representation of the Lie algebra of the structure group G. Then the curvature F of the connection A can be represented locally by a G valued 2-form given by", "cite_spans": [], "ref_spans": []}, {"section": "Appendix: Notation and Conventions", "text": "We omit the wedge symbols in what follows. The local curvature 2-form depends on a trivilization of the bundle, but its invariant polynomials \u03c3 k defined by", "cite_spans": [], "ref_spans": []}, {"section": "Appendix: Notation and Conventions", "text": "are invariants of the local trivialization. We recall that \u03c3 k 's are closed 2k-forms, hence they define the deRham cohomology classes in H 2k . Furthermore these cohomology classes depend only on the bundle. They are the Chern classes of the bundle E up to some multiplicative constants [10] . It is also known that the 2k-form \u03c3 k can be obtained as linear combinations of trF k where F k means the product of the matrix F with itself k times, with the wedge multiplication of the entries.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix: Notation and Conventions", "text": "(A, B) denotes the inner product in the fibre where A, B are Lie algebra valued forms. In particular if \u03b1, \u03b2 are scalar valued p-forms on M then (\u03b1, \u03b2) = \u03b1 \u2227 * \u03b2. The L 2 norm squared of A on the manifold ||A|| 2 = M (A, A)dvol. The indices (\u00b5, \u03bd . . .) will be used as space-time indices while the indices (a, b, . . .) for Lie algebra basis. Let e \u00b5 , \u00b5 = 1, . . . , 8 be any orthonormal basis of 1-forms \u039b 1 (R 8 ). Then e \u00b5\u03bd = e \u00b5 e \u03bd , \u00b5 < \u03bd will denote the basis of 2-forms. Similarly, e \u00b5\u03bd\u03b1\u03b2 , \u00b5 > \u03bd > \u03b1 > \u03b2 will be a basis of 4-forms. Let E a be a basis for the Lie algebra of the structure group. 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{"paper_id": "18988391", "_pdf_hash": "771beda98bae40745eeb5ced77262b91e3c6da95", "abstract": [], "body_text": [], "bib_entries": {"BIBREF1": {"title": "A TransitionBased Fault-Tolerant Routing Methodology For InfiniBand Networks", "authors": [{"first": "J", "middle": ["M"], "last": "Monta\u00f1ana", "suffix": ""}, {"first": "J", "middle": [], "last": "Flich", "suffix": ""}, {"first": "A", "middle": [], "last": "Robles", "suffix": ""}, {"first": "J", "middle": [], "last": "Duato", "suffix": ""}], "year": 2004, "venue": "Workshop on Communication Architecture for Clusters on Int'l Parallel and Distributed Processing Symposium", "link": "8044027"}, "BIBREF2": {"title": "A Scalable Methodology for Computing Fault-Free Paths in InfiniBand Torus Networks", "authors": [{"first": "J", "middle": ["M"], "last": "Monta\u00f1ana", "suffix": ""}, {"first": "J", "middle": [], "last": "Flich", "suffix": ""}, {"first": "A", "middle": [], "last": "Robles", "suffix": ""}, {"first": "J", "middle": [], "last": "Duato", "suffix": ""}], "year": 2005, "venue": "The sixth International Symposium on High Performance Computing (ISHPC-VI)", "link": "27595752"}, "BIBREF3": {"title": "Simple Deadlock-Free Dynamic Reconfiguration\" in Int'l Conference on High Performance Computing", "authors": [{"first": "O", "middle": [], "last": "Lysne", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Monta\u00f1ana", "suffix": ""}, {"first": "T", "middle": ["Mark"], "last": "Pinkston", "suffix": ""}, {"first": "J", "middle": [], "last": "Duato", "suffix": ""}, {"first": "T", "middle": [], "last": "Skeie", "suffix": ""}, {"first": "J", "middle": [], "last": "Flich", "suffix": ""}], "year": 2004, "venue": "", "link": null}, "BIBREF4": {"title": "Immunet: A Cheap and Robust Fault-Tolerant Packet Routing Mechanism", "authors": [{"first": "V", "middle": [], "last": "Puente", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Gregorio", "suffix": ""}, {"first": "F", "middle": [], "last": "Vallejo", "suffix": ""}, {"first": "R", "middle": [], "last": "Beivide", "suffix": ""}], "year": 2004, "venue": "31th Annual International Symposium on Computer Architecture", "link": "2684507"}, "BIBREF5": {"title": "An effective methodology to improve the performance of the up*/down* routing algorithm\". 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{"paper_id": "18988851", "_pdf_hash": "71581305b4b5a008e70941ef7da2deee77aa7802", "abstract": [{"section": "Abstract", "text": "For stochastic programs with recourse and with (several joint) probabilistic constraints, respectively, we derive quantitative continuity properties of the relevant expectation functionals and constraint set mappings. This leads to qualitative and quantitative stability results for optimal values and optimal solutions with respect to perturbations of the underlying 9 probability distributions. Earlier stability results for stochastic programs with recourse and for those with probabilistic constraints are refined and extended, respectively. Emphasis is placed on equipping sets of probability measures with metrics that one can handle in specific situations. To illustrate the general stability results we present possible consequences when estimating the original probability measure via empirical ones.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "When formulating a stochastic programming model, one tacitly assumes the underlying probability distribution to be given. In practical situations, however, this is rarely the case; moreover, one often has to live with incomplete information and approximations. Furthermore, also under full information about the underlying distributions one is led to approximations, since exact computation of expectations and probabilities typically arising in stochastic programming is beyond the present numerical capabilities for a large class of distributions (e.g. multivariate continuous ones). These circumstances motivate a stability analysis for optimal values and optimal solutions to stochastic programs with respect to perturbations of the underlying probability distributions (cf. [10, 17, 31, 33, 43] ). In the present paper, we pursue this for two basic problem classes in stochastic programming -for stochastic programs with recourse and for stochastic programs with probabilistic (or chance) constraints. We lay stress on structural properties of expectation functionals and of certain multifunctions defined by probabilities, on implications of these properties with respect to stability, on a proper selection of metrics in spaces of probability measures to guarantee the structural properties, on the one hand, and to be able to compute (or to estimate) distances of probability measures in specific situations, on the other hand.", "cite_spans": [{"start": 779, "end": 783, "text": "[10,", "ref_id": "BIBREF9"}, {"start": 784, "end": 787, "text": "17,", "ref_id": "BIBREF16"}, {"start": 788, "end": 791, "text": "31,", "ref_id": "BIBREF30"}, {"start": 792, "end": 795, "text": "33,", "ref_id": "BIBREF32"}, {"start": 796, "end": 799, "text": "43]", "ref_id": "BIBREF42"}], "ref_spans": []}, {"section": "Introduction", "text": "In section 2, we analyze stochastic programs with linear and quadratic recourse, respectively. We prove a general Lipschitz continuity result for a mapping which assigns to a probability measure a certain integral expression, where the metric on the space of probability measures is an Lp-Wasserstein metric [9, 15, 26] . This leads to (local) upper semicontinuity of optimal solutions and to (local) Lipschitz continuity of optimal values for the mentioned recourse problems. For stochastic programs with linear recourse and random right-hand sides we establish (local) H61der continuity of the Hausdorff distance of optimal solutions. Compared to [33, 36] where a similar analysis was carried out with respect to the bounded Lipschitz metric (cf. [9, 15] for details about the metric) the progress consists of less restrictive integrability conditions for the involved measures and of better possibilities to estimate distances between probability measures. The above mentioned H/51der continuity result for solution sets extends a result in [35] (theorem 4.4) to recourse problems with a convex quadratic portion in the objective. Among the consequences of our general stability results for specific situations we present an asymptotic convergence result for optimal solution sets when the true distribution is estimated by empirical ones.", "cite_spans": [{"start": 308, "end": 311, "text": "[9,", "ref_id": "BIBREF8"}, {"start": 312, "end": 315, "text": "15,", "ref_id": "BIBREF14"}, {"start": 316, "end": 319, "text": "26]", "ref_id": "BIBREF25"}, {"start": 649, "end": 653, "text": "[33,", "ref_id": "BIBREF32"}, {"start": 654, "end": 657, "text": "36]", "ref_id": "BIBREF35"}, {"start": 749, "end": 752, "text": "[9,", "ref_id": "BIBREF8"}, {"start": 753, "end": 756, "text": "15]", "ref_id": "BIBREF14"}, {"start": 1044, "end": 1048, "text": "[35]", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "Introduction", "text": "Section 3 is devoted to stochastic programs with several joint probabilistic constraints. Using discrepancies (cf. [12] ), we identify a suitable metric to ensure a certain Lipschitz property for the mapping which assigns the probabilistic constraint set to a probability measure. As implications for stability we again obtain (local) upper semicontinuity of optimal solutions and (local) Lipschitz continuity of optimal values, thus extending results in [33, 34, 36] to problems with several probabilistic constraints. We apply the general result to a model where the measure has a certain convexity property and to a specific chance constrained program with random technology matrix.", "cite_spans": [{"start": 115, "end": 119, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 455, "end": 459, "text": "[33,", "ref_id": "BIBREF32"}, {"start": 460, "end": 463, "text": "34,", "ref_id": "BIBREF33"}, {"start": 464, "end": 467, "text": "36]", "ref_id": "BIBREF35"}], "ref_spans": []}, {"section": "Introduction", "text": "Let us add some further bibliographical comments: Approximation techniques for solving stochastic programs with complete information on the underlying measures are presented in [4, 12, 37, 42] . When having only incomplete information about the measures it is possible to use parametric as well as non-parametric statistical estimators instead of the true distributions. For parametric estimators, the stability of the stochastic program with respect to changes of finite dimensional parameters is essential (cf. e.g. [10] ). In connection with non-parametric statistical estimators there exist a number of contributions to stochastic programming [11, 18, 19, 38, 40] . The conclusions in the present paper with respect to asymptotic properties of statistical estimators fit into this line of research.", "cite_spans": [{"start": 177, "end": 180, "text": "[4,", "ref_id": "BIBREF3"}, {"start": 181, "end": 184, "text": "12,", "ref_id": "BIBREF11"}, {"start": 185, "end": 188, "text": "37,", "ref_id": "BIBREF36"}, {"start": 189, "end": 192, "text": "42]", "ref_id": "BIBREF41"}, {"start": 518, "end": 522, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 647, "end": 651, "text": "[11,", "ref_id": "BIBREF10"}, {"start": 652, "end": 655, "text": "18,", "ref_id": "BIBREF17"}, {"start": 656, "end": 659, "text": "19,", "ref_id": "BIBREF18"}, {"start": 660, "end": 663, "text": "38,", "ref_id": "BIBREF37"}, {"start": 664, "end": 667, "text": "40]", "ref_id": "BIBREF39"}], "ref_spans": []}, {"section": "Wasserstein metrics and stability of recourse problems", "text": "Let (Z, p) be a separable metric space, denote by ~(Z) the set of all Borel probability measures on Z and consider a mapping h: Z~ R which is ~oTh-l=/a,-qo~rf'=v} and %, % are the first and second projections, respectively.", "cite_spans": [], "ref_spans": []}, {"section": "Wasserstein metrics and stability of recourse problems", "text": "In [15] it is shown that (Mgp(Z), Wp) is a metric space. In [26] , the following equivalence is established:", "cite_spans": [{"start": 3, "end": 7, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 60, "end": 64, "text": "[26]", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "Wasserstein metrics and stability of recourse problems", "text": "Let /~ ~p(Z) and t~ ~ :~(Z) (n = 1, 2 .... ); then Wp(t,,,, t*)~ 0 as n ~ oo iff the sequence {/~,, } converges weakly to/~ and", "cite_spans": [], "ref_spans": []}, {"section": "fzp(Z, O)Pl.t,,(dz) = fzO(Z, O)P#(dz).", "text": "A sequence {/,,,} is said to converge weakly to /~, if for any bounded continuous function g : Z ~ N we have", "cite_spans": [], "ref_spans": []}, {"section": "fzg(z)tL,(dz ) + s", "text": "as n-+ oo (cf. [31) .", "cite_spans": [{"start": 15, "end": 19, "text": "[31)", "ref_id": "BIBREF30"}], "ref_spans": []}, {"section": "fzg(z)tL,(dz ) + s", "text": "Concerning the announced continuity we state ", "cite_spans": [], "ref_spans": []}, {"section": "fzg(z)tL,(dz ) + s", "text": "we can continue", "cite_spans": [], "ref_spans": []}, {"section": "<~, [L,,(p(z,O))]t~(dz)) +(fz[L,,(o(e,O))].(de)) ]", "text": "Passing to the infimum with respect to ~ ~ D(~, .) yields the assertion and this remains valid even for p = 1. Note that, in this situation, the result may also be gained as a consequence of the Kantorovich-Rubinstein theorem (e.g. [15] , p. 233). For the moment, let us assume all ingredients to be taken in such a way that the above integral exists. Precise assumptions will be given when considering the specified problems. The (global) optimal value of P(g) and the set of (global) minimizers are denoted O(~t) and q,(g), respectively. ", "cite_spans": [{"start": 232, "end": 236, "text": "[15]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "<~", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Proof", "text": "We show that the assertion follows from lemma A.2 in the appendix. Assumption (a) in lemma A.2 is a consequence of (1) ", "cite_spans": [], "ref_spans": []}, {"section": "Remark 2.6", "text": "Using the same approach, it is possible to cover more general situations where the Lipschitz modulus of f(x, 9 ) grows faster than linearly. The crucial point is to \"compensate\" the growth of the Lipschitz modulus by more restrictive moment conditions on /~ and u. Of course, the stability results one then obtains are with respect to less convenient metrics (l, Vp with p > 2). Now, let us discuss instances of f(x, z) which lead to recourse models in stochastic programming. As a basic structure we always assume", "cite_spans": [], "ref_spans": []}, {"section": "Remark 2.6", "text": "with some convex function g: R \" ---, R.", "cite_spans": [], "ref_spans": []}, {"section": "Remark 2.6", "text": "In models with linear recourse we have Q_(x, z)=min{qVy: Wy=b-Ax, y>~O}, Then we have Q(x, z)~ R whenever x ~ ~m, 2 ~,.~. Now, the only further assumptions one must impose to achieve the stability asserted in theorem 2.4 are that /* ~..r ~) and that q'(t*) is nonempty and bounded. Indeed, assumptions (2) and (3) in theorem 2.4 are both consequences of well-known facts in linear parametric programming (consult [16] for (2) and lemma 3.2 in [36] for (3)).", "cite_spans": [{"start": 413, "end": 417, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 443, "end": 447, "text": "[36]", "ref_id": "BIBREF35"}], "ref_spans": []}, {"section": "Remark 2.6", "text": "Moreover, if q in (2.1) is non-random and {u~R'2: WTu~q):~ ~, then, with z formed by the components of b and A, the function Q(x, 9 ) is globally Lipschitzian uniformly with respect to x varying in a compact set. Thus, remarks 2.2 and 2.5 apply, and we can relax the assumption /* e..l/2(R s) to/, e..l/l(R') (s := (m + 1)sz) which leads to stability for perturbations v ~111(N *) with respect to the metric I,V~.", "cite_spans": [], "ref_spans": []}, {"section": "Remark 2.6", "text": "A specific instance of (2.1) to be dealt with subsequently in this paper is the linear recourse model with random right-hand side, which is given by", "cite_spans": [], "ref_spans": []}, {"section": "Remark 2.6", "text": "where A is non-random and ~ coincides with R * (s = Sz). Of course, also for this model the statements made in theorem 2.4 remain valid when considering (Jt'l(N'), W1) as parameter space.", "cite_spans": [], "ref_spans": []}, {"section": "Remark 2.6", "text": "Models with quadratic recourse are given by Again, assumptions (2) and (3) are implications of known convexity results and of representations for infima of (now) quadratic programs which depend on parameters (consult [33] , proof of proposition 3.2). To have the stability asserted in theorem 2.4 it suffices hence to claim /,~.//t'2(N s) and ~p(/,) nonempty and bounded.", "cite_spans": [{"start": 217, "end": 221, "text": "[33]", "ref_id": "BIBREF32"}], "ref_spans": []}, {"section": "Remark 2.6", "text": "For stochastic programs with linear recourse and random fight-hand side we can quantify the upper semicontinuity of ~p(.) asserted in theorem 2.4. In its setting, the following theorem differs from theorem 4.4 in [35] merely by allowing g to be convex quadratic instead of linear. However, since the refinement of the corresponding proof needs some effort, and to make the argument more transparent to the reader we will present the complete proof, although it sometimes parallels that in [35] . Since there is no hope of obtaining the following result for general convex g and C (cf. remark 2.9 below), subclasses of convex problems where the result still holds are interesting. Our motivation to consider the extension to convex quadratic g stems from a recourse model in optimal power dispatch about which we will report in a subsequent paper. Then, for arbitrary x, .~ ~ R\", ~ ~ R, 0 ~< X ~< 1, we have the identity", "cite_spans": [{"start": 213, "end": 217, "text": "[35]", "ref_id": "BIBREF34"}, {"start": 489, "end": 493, "text": "[35]", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "Remark 2.6", "text": "where [l\" II, as in the remainder of the proof, denotes the Euclidean norm. Strong convexity of Q,(-) together with the above identity yields To establish hypothesis (c) recall that, due to the general setting, F(-, u) is a convex function for all u e../{l(R\"). Furthermore, for each x r R\" and each v e.//gl(R s)", "cite_spans": [], "ref_spans": []}, {"section": "a(z-Ax).(dz)-fn,a(z-Ax)~(dz).", "text": "From linear parametric programming it is known that h is a piecewise linear convex real-valued function on Rs; hence, /~ is globally Lipschitzian with some constant La > 0. By the Kantorovich-Rubinstein theorem (e.g. [15] , p. 233) we obtain for all x ~ [t~ m and all v ~t'~(Rs):", "cite_spans": [{"start": 217, "end": 221, "text": "[15]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "a(z-Ax).(dz)-fn,a(z-Ax)~(dz).", "text": "f-is Lipschitzian with modulus less than or equal to 1}", "cite_spans": [], "ref_spans": []}, {"section": "<. Lr, W~(~, ~).", "text": "This verifies hypothesis (c) in lemma A.3.", "cite_spans": [], "ref_spans": []}, {"section": "<. Lr, W~(~, ~).", "text": "Since hypothesis (a) in lemma A.3 is also fulfilled, we obtain that there exist L > 0 and 8 > 0 such that 4,(v) 4= O and ", "cite_spans": [], "ref_spans": []}, {"section": "~e(+(,,)~{y+~,~'\u2022", "text": "Conversely, let x~CnU,,~p(+(,~)(y+~~177 Then x E C, and there exists y ~ P(+(v)) such that x -y ~s \u2022 Therefore,", "cite_spans": [], "ref_spans": []}, {"section": "Ax=A-),, which yields F(x, v)= F(y, v). By y ~P(+(v)) there exists p ~.qo\u2022 such that y +.i3 ~ g,(v). This implies q~(v) = F(y +~, v) = F(y, v).", "text": "Thus, x ~ C and F(x, v)= ~(v), which yields x c 4'(~') and verifies the asserted representation of q~(v).", "cite_spans": [], "ref_spans": []}, {"section": "Ax=A-),, which yields F(x, v)= F(y, v). By y ~P(+(v)) there exists p ~.qo\u2022 such that y +.i3 ~ g,(v). This implies q~(v) = F(y +~, v) = F(y, v).", "text": "Denoting C(y)-'= (x E C: Ax = Ay} we obtain U U C(y). (2.5)", "cite_spans": [], "ref_spans": []}, {"section": "Ax=A-),, which yields F(x, v)= F(y, v). By y ~P(+(v)) there exists p ~.qo\u2022 such that y +.i3 ~ g,(v). This implies q~(v) = F(y +~, v) = F(y, v).", "text": "In a third step, select 8\"> 0 with 6\"< 8 (cf. (2.6) with suitable constants L 1 > 0, L 2 > 0.", "cite_spans": [], "ref_spans": []}, {"section": "Icrx-cW2l ~ LIWI(tx, v)+ L2(I[H1/2x-HI/297[I+IIAx-A9711 ),", "text": "For the last estimates we used that both x and 97 are contained in the compact set q,(/~)+ Bm and that Q,(.), as a convex function, is Lipschitzian on the compact set A(q,(/x)+ Bin). Now weare able to perform the final step of the proof.", "cite_spans": [], "ref_spans": []}, {"section": "Icrx-cW2l ~ LIWI(tx, v)+ L2(I[H1/2x-HI/297[I+IIAx-A9711 ),", "text": "Let v ~/gl(Rs), W~(bt, v) < 8*. By (2.5) we have", "cite_spans": [], "ref_spans": []}, {"section": "Icrx-cW2l ~ LIWI(tx, v)+ L2(I[H1/2x-HI/297[I+IIAx-A9711 ),", "text": "By Hoffman's theorem (cf. [28] , p. 760) there exists L > 0 such that we can continue the estimate as follows", "cite_spans": [{"start": 26, "end": 30, "text": "[28]", "ref_id": "BIBREF27"}], "ref_spans": []}, {"section": "Icrx-cW2l ~ LIWI(tx, v)+ L2(I[H1/2x-HI/297[I+IIAx-A9711 ),", "text": "Using (2.6) and (2.4) we continue this estimate", "cite_spans": [], "ref_spans": []}, {"section": "Remark 2.8", "text": "When relating theorem 2.7 to specific instances of (2.2) it is crucial to verify the strong convexity of the functional Q~,. For the case that Q,, is differentiable with locally Lipschitzian gradient, general sufficient conditions for strong convexity of Q, were derived in [35] (proposition 3.1, lemma 3.2). A sufficient condition for O~, to have locally Lipschitzian gradient is that for each non-singular transformation B ~ L(R', R ~) the distribution function of # o B is locally Lipschitzian (cf. the analysis in [35] ). In theorem 3.5 in [35] it is shown that Q~ is strongly convex on a convex compact set Vc IR\", if, in addition,/* ~,/g~(R\") has a density such that there exists ", "cite_spans": [{"start": 274, "end": 278, "text": "[35]", "ref_id": "BIBREF34"}, {"start": 518, "end": 522, "text": "[35]", "ref_id": "BIBREF34"}, {"start": 544, "end": 548, "text": "[35]", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "Remark 2.10", "text": "In [33] , the stability of recourse models was investigated with respect to the bounded Lipschitz metric/9 (cf. [9] for its definition). For instance, theorem 3.3 in [33] is a quantitative continuity result for optimal values of stochastic programs with linear and quadratic recourse, respectively, stating that I,/,(tt)-,/,(p) I ~< L./3(~, ,)'-'/P for some constant L > 0 and for all v close to/~. The main assumption in that result, however, is that the moments M2p(~' ) := frllzll2pu(dz) (p> 1) are uniformly bounded. Hence, the moment conditions in the present section are weaker and more natural, because they correspond to the assumptions on the existence of finite second moments in the underlying basic theory for recourse models (cf. e.g. [16] ). We also refer to the relation between W 1 and /3 mentioned in remark 4.8 in [35] .", "cite_spans": [{"start": 3, "end": 7, "text": "[33]", "ref_id": "BIBREF32"}, {"start": 112, "end": 115, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 166, "end": 170, "text": "[33]", "ref_id": "BIBREF32"}, {"start": 748, "end": 752, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 832, "end": 836, "text": "[35]", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "Remark 2.11", "text": "Explicit formulae for Lp-Wasserstein metrics are known for probability measures on R (i.e. for s = 1) and for multivariate probability distributions (s > 1) belonging to special classes (cf. [14, 15] ) in the case p = 2. It is known (e.g. [26] ) that, for/~, v ~t'l(N ) (where R is equipped with the natural distance 1. -. I),", "cite_spans": [{"start": 191, "end": 195, "text": "[14,", "ref_id": "BIBREF13"}, {"start": 196, "end": 199, "text": "15]", "ref_id": "BIBREF14"}, {"start": 239, "end": 243, "text": "[26]", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "WI(tz, ~) = f_ L F~( t)-F.(t)ldt , OG", "text": "where F~ and F, are the distribution functions of/~ and u, respectively. This has an important consequence for recourse models having a separability structure (e.g. the above mentioned linear simple recourse case and the box-diagonal case for quadratic recourse, cf. e.g. proposition 4.7 in [33] ). Since these models only depend on the one-dimensional marginal distributions of the involved measures, we may assume that /z and v are measures with independent one-dimensional marginal distributions. If we consider the norm ", "cite_spans": [{"start": 291, "end": 295, "text": "[33]", "ref_id": "BIBREF32"}], "ref_spans": []}, {"section": "i)) .", "text": "This is possible according to proposition 1 in [15] . Hence, ( ( ,J0 , rt", "cite_spans": [{"start": 47, "end": 51, "text": "[15]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "i)) .", "text": "Hence, for recourse models with separability structure we arrive at stability results with respect to distances which are computable in practical situations.", "cite_spans": [], "ref_spans": []}, {"section": "i)) .", "text": "We end this section with an application to asymptotic properties of statistical estimators in stochastic programs. Let z 1, z z .... be independent random varia-bles (with values in R s) on some probability space (f2, .~r P) with identical distribution /, ~ 9~(Rs). We consider the empirical measures . Convergence rates for the mean of Wp(~, ~,,(.)) (n ~ I%1) can be derived from [8, 26] . We show how to combine our stability results with speed-of-convergence properties for empirical measures to obtain asymptotic properties of statistical estimators in stochastic programs. ", "cite_spans": [{"start": 381, "end": 384, "text": "[8,", "ref_id": "BIBREF7"}, {"start": 385, "end": 388, "text": "26]", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": ". d} for each v~N d and u~(R').", "text": "Hence problem P(/~) becomes min( f(x): x ~ Cp(/z)}. Our approach to study stability of P(~) is to identify a suitable topology (metric) on ~(Ns) such that the mapping which assigns to each I, ~ ~(R') the set Cp(r) enjoys certain continuity properties at the unperturbed measure /~. It is known (cf. the discussion in [17, 33, 34] ) that continuity properties of that mapping (especially lower semicontinuity) with respect to the topology of weak convergence on ~(R s) can be achieved only at measures /~ with certain smoothness properties.", "cite_spans": [{"start": 317, "end": 321, "text": "[17,", "ref_id": "BIBREF16"}, {"start": 322, "end": 325, "text": "33,", "ref_id": "BIBREF32"}, {"start": 326, "end": 329, "text": "34]", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": ". d} for each v~N d and u~(R').", "text": "Extending the ideas of our earlier work (cf. [36, 33, 34] ) we consider the following distance on ~(R'):", "cite_spans": [{"start": 45, "end": 49, "text": "[36,", "ref_id": "BIBREF35"}, {"start": 50, "end": 53, "text": "33,", "ref_id": "BIBREF32"}, {"start": 54, "end": 57, "text": "34]", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": ". d} for each v~N d and u~(R').", "text": "where each ~j is a class of Borel subsets of R s such that ( Hj(x): x ~ R\" } c ~j (j= 1 ..... d) and that a forms a metric. The latter holds if, for some j (1 ..... d}, ~j is a determining class, i.e. it has the property that if any two measures agree on ~j then they must agree on the whole of ~(Rs). Following e.g. [13] we call this distance \"discrepancy\". A first step in our stability analysis of P(/~) now is . Necessary and sufficient conditions for ~ to be a /*-uniformity class may be found in [2] and in the recent paper [211. Especially, we mention Range Rao's result (theorem 2.11 in [2] ) that the class Nc := { B c R': B convex and Borel} is a if-uniformity class iff /~(0B)= 0, 0B denoting the topological boundary of B, for all B ~ ~c. If each class .~j (j = 1 ..... d) is a /*-uniformity class, weak convergence of {/%, } to/~ implies a(/L,, ~) ---' 0. In this case, theorem 3.2 represents a stability result for P(t~) with respect to the topology of weak convergence.", "cite_spans": [{"start": 317, "end": 321, "text": "[13]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Remark 3.4", "text": "The last (and most essential) assumption in theorem 3.2 reads in the terminology of [32] : Assume that the nmltifunction v ~ C,(/z) is pseudo-Lipschitzian at each (x0, p) ~ ~pO(/Z) \u2022 { p} (see theorem 2.3 in [32] ). Rockafellar's paper contains a detailed study of pseudo-Lipschitzian multifunctions including a variety of sufficient conditions for a multifunction to have this property. It is well-known that constraint qualifications of mathematical programming play an important role in this context.", "cite_spans": [{"start": 84, "end": 88, "text": "[32]", "ref_id": "BIBREF31"}, {"start": 208, "end": 212, "text": "[32]", "ref_id": "BIBREF31"}], "ref_spans": []}, {"section": "Remark 3.4", "text": "We shall make use of the following two results which give sufficient conditions for a multifunction to be pseudo-Lipschitzian. In the literature, this result is known as the Robinson-Ursescu theorem (cf. e.g. [29] ).", "cite_spans": [{"start": 209, "end": 213, "text": "[29]", "ref_id": "BIBREF28"}], "ref_spans": []}, {"section": "Remark 3.4", "text": "The next result is a particular case of theorem 3.2 in [32] . [5, 24] ). ", "cite_spans": [{"start": 55, "end": 59, "text": "[32]", "ref_id": "BIBREF31"}, {"start": 62, "end": 65, "text": "[5,", "ref_id": "BIBREF4"}, {"start": 66, "end": 69, "text": "24]", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Proof", "text": "We apply theorem 3.2 noting that q'(I*)= q~Q(/*). It remains to show that the mapping v ~ C,(~) is pseudo-Lipschitzian at each pair (x0, p)~ +(t*)x (p). We even show that this is true for each (x0, p) with x 0 ~ Cp(/*).", "cite_spans": [], "ref_spans": []}, {"section": "Proof", "text": "To this end, we consider the multifunction where we assume without loss of generality that r < O. We consider the extended-real-valued function gj defined on R\" such that ", "cite_spans": [], "ref_spans": []}, {"section": "Remark 3.8", "text": "If the set C describing the deterministic constraints of P(p.) is even compact, Q may be chosen such that C c Q and corollary 3.7 then yields upper semicontinuity of ~ and (local) Lipschitz continuity of q5 at ~. Corollary 3.7 extends corollary 2.1 of [34] and theorem 6 of [41] . It applies to a number of practical models which are known from the literature (see chapter 3 of [34] ).", "cite_spans": [{"start": 252, "end": 256, "text": "[34]", "ref_id": "BIBREF33"}, {"start": 274, "end": 278, "text": "[41]", "ref_id": "BIBREF40"}, {"start": 378, "end": 382, "text": "[34]", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "Remark 3.8", "text": "Secondly, we consider a particular stochastic program given by ", "cite_spans": [], "ref_spans": []}, {"section": "Remark 3.11", "text": "In corollaries 3.7 and 3.10 we obtain stability with respect to a discrepancy a(/*, v; .~):= sup{ I/*(B)-u(B) I: B ~ ~'} where 5~ is a subset of \u2022c-Hence, remark 3.3 applies and both results assert stability with respect to the topology of weak convergence if ~'c is a/*-uniformity class. The latter property is fulfilled in case of corollary 3.7, since a measure/, which is r-convex for some r ~ (-~, 0] also has a density. The same is true in case of corollary 3.10 if the covariance matrix S in P(/*) is non-singular.", "cite_spans": [], "ref_spans": []}, {"section": "Remark 3.11", "text": "We also note that under certain assumptions on/* there exist estimates for the discrepancy a(/*, u; ~c) (cf. [22] ).", "cite_spans": [], "ref_spans": []}, {"section": "Remark 3.12", "text": "Let/* ~ ~a(Rs) and/*,,(w) be the empirical measure based upon n independent RS-valued random variables (on some probability space (/2, sg, P)) with common distribution /*. From corollaries 3.7 and 3.10 we then obtain for each e > 0", "cite_spans": [], "ref_spans": []}, {"section": "Remark 3.12", "text": ".< e((to: e((to: e.< 2V({to: a(/*, /*,(to); ~) >--min( 3, e/L } } ). where the function p grows at most polynomially in n. For this inequality, further details on VC classes and about empirical measures on general sample spaces we refer to chapter 26 in [39] , where it is also stated that the set of all half-spaces of a Euclidean space is a VC class. Hence, the above remarks apply to the situation in corollary 3.10 and lead to convergence rates for optimal values when the original measure/* is estimated by empirical ones.", "cite_spans": [{"start": 254, "end": 258, "text": "[39]", "ref_id": "BIBREF38"}], "ref_spans": []}, {"section": "Remark 3.13", "text": "In [34] , the counterpart of theorem 3,2 for the case d= 1 was applied to nonconvex problems where", "cite_spans": [{"start": 3, "end": 7, "text": "[34]", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "H(x):=(z~a~: Ax>_-z}, A~L(R\",Rs).", "text": "We mention that using the methodology of the present section it is possible to extend these results to the case of several probabilistic constraints.", "cite_spans": [], "ref_spans": []}, {"section": "H(x):=(z~a~: Ax>_-z}, A~L(R\",Rs).", "text": "Here, (T, d) is a metric space, G a real-valued function on ~mx T and C a multifunction from T into R\". Given Q c R \" we set for t e T", "cite_spans": [], "ref_spans": []}, {"section": "CQ(t) = C(t) A cl Q,", "text": "q,Q(t)=inf{G(x, /): xe CQ(t)}, qvQ(t) = {x~ CQ(t): G(x, t) = qsQ(t)}. DEFINITION A.1 [30, 20] Given P(t o) for fixed t = t o we call a nonempty subset M of R\" a complete local minimizing set (CLM set) for P(t o) with respect to Q, if Q is an open subset of R '~ such that M c Q and M = q,e(to).", "cite_spans": [{"start": 85, "end": 89, "text": "[30,", "ref_id": "BIBREF29"}, {"start": 90, "end": 93, "text": "20]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "CQ(t) = C(t) A cl Q,", "text": "Examples of CLM sets are the set of global minimizers and strict local minimizers.", "cite_spans": [], "ref_spans": []}, {"section": "CQ(t) = C(t) A cl Q,", "text": "The following quantitative stability results for the abstract problem P(t) go back to results for the standard non-linear programming problem with differentiable data and (in-)equality constraints obtained by Alt [1] . In the above setting, the stability analysis is presented in Klatte [20] . A proof of lemma A.3 can also be found in [35] . (ii) There exist constants L > 0 and 8 > 0 such that O 4= q,Q(t) c Q and I q)e(t) -", "cite_spans": [{"start": 213, "end": 216, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 287, "end": 291, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 336, "end": 340, "text": "[35]", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "ePQ(to) I <~ L. d(t, to) whenever t ~ T, d(t, to) < 8.", "text": "If we specify P(t) to the situation where C(t) = C for all t ~ T, with some nonempty, closed, convex set C c R'\"; and if we denote by ,# and 4' the global optimal value and the set of global minimizers, respectively, then the following holds. 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Optim. Theory Appl", "link": null}, "BIBREF41": {"title": "Stochastic programming: solution techniques and approximation schemes, in: Mathematical Programming -The State of the Art", "authors": [{"first": "R", "middle": ["J"], "last": "", "suffix": ""}, {"first": "-B", "middle": [], "last": "Wets", "suffix": ""}], "year": 1982, "venue": "", "link": null}, "BIBREF42": {"title": "Stochastic programming", "authors": [{"first": "R", "middle": ["J"], "last": "", "suffix": ""}, {"first": "-B", "middle": [], "last": "Wets", "suffix": ""}], "year": 1989, "venue": "Handbooks in Operations Research and Management Science", "link": "18025293"}}, "ref_entries": {"FIGREF1": {"text": "h:Z--, IR be Lipschitzian on bounded subsets of Z. Then, for all /*, v ~J4p(Z) I fzh(z)t.(dz)-s < (M~(~,)+ M,(,)) 9 W.(#, ,), IV. Rgmisch, R. Schultz / Stabifty analysish( z I.(dz I -f h(el~(de) l", "type": "figure"}, "FIGREF2": {"text": "~ h(z)l~(dz)-fwh(z)v(dz) l ~ LW2(lx, v), whenever v ~J/~2(Ns), W2(I~, v) < & Proof Specifying proposition 2.1 (p = 2 and Z = N\" with norm II\" II), we obtain", "type": "figure"}, "FIGREF3": {"text": "Lo Hzll2bt(dz)) + s IIz, whenever/~, v e~'2(R~). The characterization of convergence with respect to W 2 now yields that there exist 3 > 0 and M > 0 such that fRI Izll2v( dz)~M whenever W2(~, v)<3. This completes the proof. [] The recourse problems, whose stability we are going to analyze, all fit into the following class of parametric programs: P(/z) min{F(x, /~): x~C}, where C _ R'\" is nonempty, closed, convex and F: R\" \u2022 ~(R s) ~ R is given by F(x, ix):= fo/(x, z)g(dz), with some function f: R\" \u2022 R s ~ R and some/z ~ ~(R').", "type": "figure"}, "FIGREF4": {"text": "the function f(., z) be convex for each z ~ Rs; (3) there exists Vc N', open and bounded, and L 0 > 0 such that q,(/~) c [f(x, z)-f(x, ~)] <~L o max(llzll, II~l[).[Iz-ff[], whenever x ~ cl V and z, ~ e R", "type": "figure"}, "FIGREF5": {"text": ", and (b), (c) hold since the constraint set C is closed and does not depend on the parameter. Hence it remains to verify (d). Indeed, for arbitrary x, Y ~ cl V and p ~..r ~) we have IF( x, It) -F(Y~, u) I <~ IF( x,/~) -F(:~, /z) I + IF( y, /~) -F(2, u) 1. In view of (2), the function F is convex in x and thus Lipschitzian on bounded sets. Hence, the first term on the right is bounded above by/~, [I x-~ I1 with a suitable constant /~ > 0. To see that there exist constants L > 0, 6 > 0 such that the second term on the right is bounded above by L. W2(/~ , u) whenever I, V2( #, u) < 6, we apply corollary 2.3 (for h(z) .'= f(Y, z)), whose assumptions are fulfilled in view of (3). [] Remark 2.5 If f(x, 9 ) is globally Lipschitzian (uniformly with respect to x ~ cl V), then, by remark 2.2, the above remains valid for/~, ~ ~Jgl(R ~) with respect to W v", "type": "figure"}, "FIGREF6": {"text": "s', W~L(R ~', gU 2) such that W(R~)=R s~ (complete recourse), A ~ L(R m, R~2), b ~ R ~2. (Throughout, superscript T denotes transposition.) The vector z is formed by the components of q, A and b. We suppose the supports of the measure/z and all its perturbations ,, to be contained in the set ~={z~R~:3u~gC~2, WVu<~q} (s=sa+(m+l)sz).", "type": "figure"}, "FIGREF7": {"text": ", b ~ g~s,, A ~ L(R m, R\"), D z is formed by the components of b, A and d; of the measures /* and v is d, y>~0} (s=(m+l)s,+s2).", "type": "figure"}, "FIGREF8": {"text": ", ff ~ V. Furthermore, let us introduce the notation h( v) = rrfin{ qS,: Wy= v,general setting given above together with the specification (2.2). Let g be convex quadratic and C polyhedral. Fix/, ~.///l(Rs), let q,(>) be nonempty, bounded and let the function Q/R\" ~ JR, given by Q~,(~') = f.,;, (z-~')p.(dz), be strongly convex on a convex open set I \"7 containing A(q,(/,)). Then there exist constants L* > 0 and 8\" > 0 such that dH (1# (/.L), ~(V)) ~. g*\" WI(~L, l') 1/2, whenever v ~d/e'l(N~), Wl(l~, v) < 8\". (d H denotes the Hausdorff distance.) Proof In a first step we are going to apply lemma A.3 in the appendix to the parametric program P(v) min{F(x, v): x~C), with parameter space (T, d) = (./#'l([Rs), W1), t o =/, and objective function F(x, u) =g(x) + Q,,(Ax). By assumption, the function g admits a representation g(x)=xVHx +cTx, with H~L(R m, \u2022\") symmetric and positive semidefinite, and c~R'\". The assumptions on H imply that there exists H1/2~ L(N'\", N'\") symmetric and positive semidefinite, such that H ~/2 9 H a/2 = H.", "type": "figure"}, "FIGREF9": {"text": "for all x, Y ~ R\"' such that Ax, A,~ ~ I7\" and all X ~ [~, 0 ~< ~. ~< 1. Now, consider a bounded open set V containing 4,(t~) with the property that Ax ~ I7\" for all x ~ V. With )t = 1/2 we obtain for arbitrary x ~ C r3 cl V and arbitrary x. ~ q'(t~) X(x., ,) <~ F( 89 + x.),H~:x.ll = -88 II Ax -dx. II 2, whence F(x, It) >I F(x., ~) + 311H'/2x -H1/2x*ll 2 + 89 l[ Ax -Ax. H z Thus, hypothesis (b) in lemma A.3 is fulfilled when setting x o := x. for some x, e 4'(>) and a(~) := 89 I[ Hl/2~ I1 2 + 89 II A~ 112, ~ e R\"", "type": "figure"}, "FIGREF10": {"text": "second step let us consider the matrix ,~ L(N\", N \"'+~+~) given by ~r= (AT, H1/2, c). Denote P the orthogonal projection from gR\" onto ,s im X r, the image of A~r. Due to the choice of A we then obtain after some calculation that F(x, v)= F(Px, v) whenever x ~ N\", v ~.A'I(N'). Furthermore, for each v ~,/gl(orthogonal complement of ~,o. To see this, let x ~ g,(v). Then there exists ~ ~&~ \u2022 such that x = Px + ~. Furthermore, x ~ C, implying x~CnU.,.", "type": "figure"}, "FIGREF11": {"text": "(/~) [ ~< L, Wl(tz, v) and ~b(v) c ~b(F ) + B,,, whenever v ..~/'~(~'), W~(t x, v)< 8\" (cf. theorem 2.4 for the specification (2.2)). Let v~ ..g~(N') such that W~( F, v) <6\" and x ~ ~b(~a), 2~b(v). Then we have [cTx --C~\" I = [qS(F ) --xTHx --Qv( Ax ) -CO(v) + .eTn2 + Q,,( A.~) I ~< I q~(F) -eO(v)l+lxTgx--2TH2I+IQ,,(AY) -Qu(AY) + [Qu(AY) -Q,(Ax)[ + I Q~,(A2) -Q~(Ax)[ (the second term in the above estimate is a consequence of the Kantorovich- Rubinstein theorem) = + + I(l-Ia/ x + - I + [Qv(AX) -Qu(Ax)1, and hence", "type": "figure"}, "FIGREF12": {"text": "r> 0 with O(t) > r for all t from an open set Up V and either W~L(R s+l,R'), q~im W \"r or W~L(R 2\",R'), W=(I, -I), q++q- > 0 (componentwise). The case W= (I, -I) is referred to as simple recourse; here, I E L(IR *, R *) denotes the identity and q+, q ~ R\" are the subvectors of q which correspond to the splitting of W into I and -I.", "type": "figure"}, "FIGREF13": {"text": "Several examples show that the above result is the best possible in various respects. All the examples are based on the specification Q(x, z)=min{y++y-: y+-y-=z-Ax, y+>_.O, y->~0} and on the sequence /~,, E~(R) which converges in W 1 to /~0 ~(R) -the uniform distribution on [-1/2, 1/2] -and which is given by t~,=c,,l~o,+e,3(_~.,)+e,,3~,+c,,fio,, (n > 4), where e,=n -1/2, c,= 89 ~o,, and rio,, are the uniform distributions on [-1/2, -e,,] and [e,,, 1/2], respectively, 3(_,,,) and 3~., the measures with unit mass at -e,, and e,,, respectively. Using the formula for W~ in remark 2.11 below we obtain Wl(~.~0) = n -1 Example 4.5 in [35] (where g -= 0, C = \u2022, A = 1) shows that the exponent 1/2 on the right-hand side of the estimate is optimal, namely we have in that case q~(~,,) = [ -n-1/2, n-1/2], +(~0) = {0}. Thus dH(q~(/~,), +(/~o)) = n-1/2 Example 4.6 in [35] (where g-O,C={x~R2:-xl+(xz)2<~O},A~ L(R 2, R~), A = (1, 0) shows that the result does not hold for a general convex set C. Here, we have +(~0) = (0}, and the points (n -1/2, n -1/4) belong to q~(/z,,). Thus dH(4,(/~,), 4'(/%)) >/n -1/4 To see that the result is lost for a general convex function g, let g be a convex function which is zero on {x ~ R2: -x~ + (x2) 2 ~< 0} and greater than zero outside this set and put C= R2, A E L(R 2, R1), A = (1, 0). Again +(/~o) = {0} and (n -1/2, n -1/4) ~ +(/%), yielding dH(+(/z,,), +(/z0)) >~ n -1/4.", "type": "figure"}, "FIGREF14": {"text": "let /x i, ~,i (i = 1 ..... s) denote the marginal distributions of ~, ~, and let ~ ~ D(/~, v~) be chosen such that Wp(l~i,\",)= \u2022 Iz,-Zil r/,(dz,,d~.", "type": "figure"}, "FIGREF15": {"text": ". denotes the measure with unit mass at z ~ R~.) Then it is known that, if ~dgp(R ~)", "type": "figure"}, "FIGREF16": {"text": "assumptions of theorem 2.7 be fulfilled and let /~ ~'~(R s) for each p >/1. Let C be bounded. Then E[dH(+(/*), ~b(/,,,(~)))] = O(n -1/2K) for each K> max{2, s}. Proof Let a,,(w):= dH(+(/*), +(/*,,(~))) and put e,,:=(~: w1(~,~.(~))<8\"} (.~), where 8\" and (later on) L* are chosen as in theorem 2.7. Then E[a.(~l] = f a~ f~ a,,(~Ie(d~) ~n n ~ c*. s[w,(...,,(~)) '~ ] + diam C.P({r W, (/,, /,,,(o~)) >~ 8\" }) L*( E[WI(t~, ~t,,(~o))])l/2 + diam C. ~-~ E[WI(~t, /,,(~o))], where we used HSlder's and Chebyshev's inequalities, and diam C denotes the diameter of C. Hence we obtain E[a,,(~)] = O(( e[w,(., .,,(~))l) 'j2) and it remains to study the convergence rate of E[WI(I*, /*,(~))]. Theorem 6 in [26] reads in our specific situation (by putting there h-1, a .'= 1, a .'= 0): If /, ~r(R s) for some r > 1 and if there exist numbers k > 2 and Ka > 0 such that N(t*, e, gk/(k-2}) ~ K18-k for each e ~ (0, 1], then s[w,(~, ~~ = o(.-('-'/r~/k). (Here N(/~, e, 8) is the minimal number of sets of diameter at most 2e which cover R s except for a set A with/~(A) . %< 8.) Since ~t ~..r ~) for each r > 1, the above hypothesis holds if k > max(2, s } (proposition 3.4 in [8]). Hence, we have E[W~(I.t, /~,(~0))] = O(n -~/K) if K> max(2, s} and the proof is complete, n 3. Stability of stochastic programs with probabilistic constraints The problem we shall consider in this section is P(tL) min{f(x):x~C,l~(Hi(x))>~pj, j=l,...,d}, where f is a mapping from R \" into R, C is a nonempty closed subset of R\", Hj is a set-valued mapping from R \" into R s having closed graph (j = 1 ..... d), pj ~(0, 1) (j=l .... ,d) and /~ ~(Rs). In the following, we make use of the notations p := (Pl ..... pd)T~ R d and Cv(u):='(x~C: p(Hj(x))>~oj, j=l ....", "type": "figure"}, "FIGREF17": {"text": "z, ~ Cp(~,) from (9~(R'), a) into N\" has a closed graph. Proof Let G-'--((1,, x): ~,~(R'), x~Cp(u)} and fix (u,.x) with 1,~9~(R'), x~ N\"', (u,, x,) ~ G (n ~ N) such that a(~,,, p) ~ 0 and x, --* x. We have to show that this implies x ~ Cp(u). Since C is closed, we have x E C, and it remains to prove that v(Hj(x)) >_,&. Since the multifunctions //i (J= 1 ..... d) have closed graphs, there holds for each j = 1 ....H,(x)) = infv(cl{z\" z~H,(y), ][x-Y[I ~<6}). \" 8>0 Let e > 0 be chosen arbitrarily. Then there exists 6 o > 0 such that for each j = 1 ..... d we have v(/-/j (x)) >/ v(cl{ z: z~/-/j (),), [[x-yll ~ 6o })-e/2. Furthermore, there exists n 0 ~ ~ such that a(v, I,,,) ~ e/2 and ]1 x -x,, [I ~ 8o for all n >/no. Then we obtain for each j = 1 ..... d and n >_-no >/v(H/(x))-v( Hj (x.))-Iv(//,. (x,,))-v,,(H,(x,,)) I + u,,(Hi(x.) ) >/ -e/2 -a(v, '5,)+pj>~pj-e. Since e > 0 was arbitrary, this yields the assertion. [] Now we state the central stability result of this section.", "type": "figure"}, "FIGREF18": {"text": "be Lipschitz continuous on bounded subsets of R'\" and assume that M is a CLM set for P(B) with respect to Q, where Q c R\" is bounded (i.e. M = +Q(tt)). Assume that, for each x0 ~ ~o(~), the function (x, v)~inf( I[x-Yl]: y~ C,,(/~)} is Lipschitz continuous on some neighbourhood of (Xo, p). Then the multifunc- tion +Q (from (~(Rs), a) into R'\") is upper semicontinuous at ~,Again we show that the assertion follows from lemma A.2 in the appendix. In view of the assumptions and of proposition 3.1 it remains to verify condition (c) of lemma A.2. In our terminology condition (c) reads as follows: For each xo ~ q'o(ff) there exist a neighbourhood U = U(xo), positive reals 80 and X such that the following holds for all v ~(R ~) with a(ff, v) < 8o; x ~ Cp(~) C3 U implies d(x, Cp(v)) ~ X. a(Ix, v) and x ~ Cp(v) n U implies d(x, Cp(~)) <~ X. a(p,, v). (Here d(x, A):=inf{[Ix-y][: y~A} for each subset A of R\".) So let x0~ +Q(iZ) be fixed. Our last assumption (in theorem 3.2) is equivalent to the existence of neighbourhoods U of x o, V of p and of a constant )t > 0 such that d(x, Co(tz)) is finite and d(:,. <.,(~,))~d(x, co:(~))+ xHo,-o~11oo. for all x e U and all v, v 1, v 2 ~ V. Here, II\" II ~ denotes the max-norm on R d. This holds, since d(-, C,,(~)) is Lipschitzian with modulus 1 for each v ~ If. Let 8o>0 such that {v: ]] v -p }l --< 80} c V, and let v~(R \"~) such that a(ff, v)~< 80. Now, observe that by definition of the distance a the following inclusions hold c~+o,,.~,(,,) c c,,(,,) c c,,_,,,,.~,(~). Let x~ U, set v l:=p+ tively. Then we obtain d(x, Cp(p))~d(x, and d(:,-, c,,(~)) .< d(x, For x ~ Cp(ff) A U and the desired implications. a(~t, v), v2:= p and vl :=p, v2:=p-a(ff, v), respec- c,+o,,,.,,,(~)) ~d(x. c~(~))+ x-,~(~. ,,1 %~ + x. ~(~. ,,). x ~ Cp(v) r3 U, respectively, these estimates now yield [] Remark 3.3 Recall that a class N' of Borel subsets of R\" is a /z-uniformity class if sup{ [ if(B) -/~,(B) ]: B ~ ~ } ~ 0 holds for every sequence {/1, } converging weakly to/~ [2]", "type": "figure"}, "FIGREF19": {"text": "be a multifunction from R a into II~\" having closed convex graph. Then F is pseudo-Lipschitzian at each pair (x 0, v0) ~ F(vo) \u2022 Nd with v0 ~ int(dom F) where dom P := { v ~ I~d: F( v) 4~ ~ }.", "type": "figure"}, "FIGREF20": {"text": "F(v):=Ix~C:G(v,x)~O ) (v~Ra), where CcR\"' is closed and G: \u2022a\u2022 R\" -+ R/ is locally Lipschitzian. Let Vo ~ R a, x0 ~ F(v0) and assume that the only y~R / such that y>lO, y~Gi(v o, Xo)=O, i=l ..... l, and {--ATy: A ~r 2 3G(v o, x0) ) ~Nc(xo) 4: ~, is y=0. Then F is pseudo- Lipschitzian at (x 0, v0). (Here, aG(vo, Xo) denotes the Clarke generalized Jacobian, cf. [6], containing l \u2022 (d+ m) matrices, and ~r 2 OG(v 0, Xo) denotes the set of all l \u2022 m matrices A such that there exists an l\u2022 matrix A-with (A', A)~3G(v o, Xo). Nc(xo) denotes the Clarke normal cone to C at x0.) Next, we study stability of specific probabilistic constrained programs by revealing conditions on the measure/z and on the multifunctions Hj (j = 1 ..... d) to have the mapping v ~ Cv(/z) pseudo-Lipschitzian at some pair (x 0, p). First, we consider a situation where f, C, Hj (j = 1 ..... d) and ~ have certain convexity properties. Following [7] we introduce the notation MrX(a, b), for all r~R\\{0}, ?~ ~[0, 1], a, b>~0, defined by MrX( a' b ) := { ( ~ar + (1-x ifab>0,ifab=0. This definition can be extended for r = 0, r = -oo in the following natural way MoX(a, b):= limM)(a, b)=aXb a-x ifab>0, r~0 MX__~(a, b)'.= lim M)(a, b)=min(a, b}. A Borel probability measure ~t on R s is called r-convex, r ~ [-oo, + oo) (cf. [5,7,25]), if for each ~ ~ [0, 1] tL(XB, + (1 -X)B2) >/M?(tL(B1) , ~(B2) ) holds for all Borel subsets B a, B z of R ~ such that ;kB 1 + (1 -h)B 2 is Borel. For r= 0 and r =-oo, tL is also called logarithmic concave and quasi-concave, respectively [24]. Since M~(a, b) is increasing in r, when all other variables are fixed, the sets of all r-convex measures are decreasing if r is increasing. It is known (cf. [5,7,27]) that /~e~(R ~) is r-convex (re[-cc, l/s]) iff tL has a density O, such that ~9,(Xx + (1 -X))7) >/MS, x_,~)(lg~(x), (9,(~7)) for all X ~ [0, 1], x, 2 ~ ~. We note that a number of multivariate distributions are r-convex for some r ~ -c~, 0], e.g. the (non-degenerate) multivariate normal distribution (cf.", "type": "figure"}, "FIGREF21": {"text": "in P(/,) f xs convex, C is convex, Hi (j = 1,..., d) have convex graphs and that /, is r-convex with r ~ (-oo, 0]. Suppose there exists .~ ~ C such that It(Hi(Y))>pj, j= 1 ..... d (Slater condition). Let +(~) be nonempty and Q c R\" be open, bounded such that ~p(/l) c Q. Then q)Q is upper semicontinuous at ~t. Furthermore, there exist constants L > 0, 8 > 0 such that +o(V) is a nonempty set of local minimizers of P(u) and L qS(~t) -qSQ(V) [ ~< La(~, v) whenever a(/z, u) < ~. (Here, the classes ~j (j= 1 ..... d) in the definition of a may be chosen such that ~j c_ ~c.)", "type": "figure"}, "FIGREF22": {"text": "gj(x) := [,(-jex))] r Applying the fact that Hj has convex graph and p. is r-convex, we obtain for all xl, x2 ~ R m and XE[O, 1] gj(Xx, + (1-?t)x2)~< [l~(~tHj(x1) + (1-X)Hj(x2))] r < xgj(x,) + (1 -x)gj(x2). Hence, each gj (j = 1,..., d) is convex, and the multifunction F from Rd into R '~ has closed convex graph. We note that Co(/~) = F(vr), where v r := (v~ ..... v~) T, vj~(0, 1), j= 1 ..... d. Moreover, since gj(Y) <pf for each j= 1 ..... d, the point (p~ ..... p,~)r belongs to the interior of dom F. Now, lemma 3.5 applies, and we conclude that F is pseudo-Lipschitzian at (x 0, pr) where x 0 ~ F(p~)= Cp(~). This means that, for each x o ~ Cp(~), the mapping (x, v) ~ d(x, F(v)) is Lipschitz continuous on some neigJabourhood of (x 0, v0) where v o := pL Since the mapping (x, v)~ (x, v ~) is Lipschitz continuous on some neighbourhood of (xo,p), the same holds true for the composition of both mappings. Hence, (X, V)~ d(x, I~( vr))= d(x, Cv(l~)) is Lipschitz continuous on some neighbour- hood of (x 0, p). The assertion now follows from theorem 3.2. []", "type": "figure"}, "FIGREF23": {"text": "(x):= z~l~ re+l\" ~ zix i>~z.,+l , i=1 and /.t ~(R ''+1) is the multivariate normal distribution with mean a ~ R r~+l and covariance matrix S ~ L(R \"+1, Rm+l). The following result is welt-known [23] (see also [42])., the constraint set Cp(/Z) = {x ~ C: ~(H(x)) >lp} is convex and can be expressed as Cp(~) = {x ~-C: ~2)-l(p)o(x) -l(x) ~ 0}, where 9 is the standard normal distribution function, o2(x) is a positive semidefinite quadratic form and l(x) is affine linear in x.", "type": "figure"}, "FIGREF24": {"text": "Estimates for P((to: a(/*, /,,(to): ~) >/X}) (h > 0) are known if ~' is a so-called Vapnik-Chervonenkis (VC) class of subsets of R s. If ~ is a VC class, then for all 2, > 0 and n >/2 there exists K(>,) > 0 such that P({to: a(/*, /*,(to); .@)>~h})<~K(h)p(n) exp(-2X2n),", "type": "figure"}, "FIGREF25": {"text": "the parametric program P(t), fix some t o ~ T. (a) Assume that M is a CLM set for P(t o) with respect to Q, where Q c R\" is bounded (i.e. M = q~Q(t0) ). (b) Let the multifunction C be closed-valued and closed at t 0. (c) Suppose that for each pair (x0, to)~ q~o(to)\u2022 { to} there exist a neighbour- hood U= U(x0), positive reals 80 and X such that C(t) n Uc C(to) + X. d(t, to)\" B,, and C(to)N Uc C(t) + A.d(t, t0)'Bm, for all t ~ T such that d(t, to) < 8 o. (Bm denotes the closed unit ball in R\".) (d) Suppose there are real numbers L c > 0, 8 c > 0 such that G(., t) is continu- ous at clQ and lG(x, to)-a(Yc, t)l~<tG(llx-~ll+d(t, to)), for all x, Y ~ cl Q and each t ~ T with d(t, to) < 86 . Then we have (i) The multifunction ~kQ is upper semicontinuous at t 0, i.e. for each e > 0 there exists 8' > 0 such that qJ(t) c ~b(to) + e. B,, whenever t ~ T, d(t, to) < 8'.", "type": "figure"}, "FIGREF26": {"text": "exists a bounded open set Q c R\" such that +(t0) c Q. (b) There exist x 0 ~P(t0) and a: I~'\" ~ R+ such that c~(0)= 0 and G(x, to)>1 G(x o, to) + a(x-Xo) for all x ~ Cr cl Q. (c) There exist a neighbourhood U= U(to) and a constant L> 0 such that G(., t) isaconvex function for each t~Uand I G(x, t)-G(x, t0)] ~<L. d(t, to) for all x ~ cl V and all t ~ U. Then there exists a constant 8 > 0 such that for all t ~ T with d(t, to) < 6 we have and", "type": "figure"}, "TABREF0": {"text": "Lipschitzian on bounded sets, i.e.the integral fzh(z)~t(dz). Subsequently, these results will serve to establish stability of stochastic programs with recourse. Studying quantitative continuity in the above setting requires a suitable metric on ~(Z). In this respect we address Wasserstein metrics.", "type": "table"}, "TABREF1": {"text": "I fzh(z~,(dzl-fzh(zl.(dzll <.Lh. W~(., .) (~, ~.(Z)),", "type": "table"}}}
{"paper_id": "18988855", "_pdf_hash": "68b1b4763535599b92ac1c989d641ccd9ee05466", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Hermes: A Scalable Sensor Network Architecture for Robustness & Time-Energy Awareness, A Dissertation Proposal", "authors": [{"first": "Tian", "middle": [], "last": "He", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF1": {"title": "The distinctive design characteristic of a wireless sensor network: the energy map", "authors": [{"first": "A", "middle": ["F"], "last": "Raquel", "suffix": ""}, {"first": "Antonio", "middle": ["A F"], "last": "Mini", "suffix": ""}, {"first": "Badri", "middle": [], "last": "Loureiro", "suffix": ""}, {"first": "", "middle": [], "last": "Nath", "suffix": ""}], "year": 2004, "venue": "", "link": "14524352"}, "BIBREF2": {"title": "Wireless Sensor Networks: An Information Processing Approach", "authors": [{"first": "Feng", "middle": [], "last": "Zhao", "suffix": ""}, {"first": "Leonidas", "middle": [], "last": "Guibas", "suffix": ""}], "year": 2004, "venue": "", "link": "62625977"}, "BIBREF3": {"title": "MANNA: A Management Architecture for Wireless Sensor Networks", "authors": [{"first": "B", "middle": [], "last": "Linnyer", "suffix": ""}, {"first": "Jos\u00e9", "middle": ["M"], "last": "Ruiz", "suffix": ""}, {"first": "Antonio", "middle": ["A F"], "last": "Nogueira", "suffix": ""}, {"first": "", "middle": [], "last": "Loureiro", "suffix": ""}], "year": 2003, "venue": "IEEE Communications Magazine", "link": null}, "BIBREF4": {"title": "JooSeok Song, A SelfManagement Framework for Wireless Sensor Networks", "authors": [{"first": "Si-Ho", "middle": [], "last": "Cha", "suffix": ""}, {"first": "Jongoh", "middle": [], "last": "Choi", "suffix": ""}], "year": 2006, "venue": "APWEB 2006", "link": null}, "BIBREF5": {"title": "Intelligent SelfOrganization Management Mechanism for Wireless Sensor Networks", "authors": [{"first": "Chien-An", "middle": [], "last": "Lee", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF6": {"title": "Protocols and Architectures for Wireless Sensor Networks", "authors": [{"first": "Holger", "middle": [], "last": "Karl", "suffix": ""}, {"first": "Andreas", "middle": [], "last": "Willing", "suffix": ""}], "year": 2005, "venue": "", "link": null}, "BIBREF7": {"title": "Low Energy Adaptive Clustering Hierarchy with Deterministic Cluster-Head Selection", "authors": [{"first": "M", "middle": ["J"], "last": "Handy", "suffix": ""}, {"first": "M", "middle": [], "last": "Haase", "suffix": ""}, {"first": "D", "middle": [], "last": "Timmermann", "suffix": ""}], "year": 2002, "venue": "", "link": "14259581"}, "BIBREF8": {"title": "An Application-Specific Protocol Architecture for Wireless Microsensor Networks", "authors": [{"first": "Wendi", "middle": ["B"], "last": "Heinzelman", "suffix": ""}, {"first": "Anantha", "middle": ["P"], "last": "Chandrakasan", "suffix": ""}, {"first": "Hari", "middle": [], "last": "Balakrishnan", "suffix": ""}], "year": 2002, "venue": "", "link": "206821011"}, "BIBREF9": {"title": "The network simulator -ns-2", "authors": [{"first": "Vint", "middle": [], "last": "The", "suffix": ""}, {"first": "", "middle": [], "last": "Project", "suffix": ""}], "year": "", "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "18988998", "_pdf_hash": "98c2ee799701f6b7f9b2cf017cb51784959b3835", "abstract": [{"section": "Abstract", "text": "This paper reviews the linearized path integral approach for computing time dependent properties of systems that can be approximated using a mixed quantum-classical description. This approach is applied to studying vibrational pure dephasing of ground state molecular iodine in a rare gas matrix. The Feynman-Kleinert optimized harmonic approximation for the full system density operator is used to sample initial conditions for the bath degrees of freedom. This extremely efficient approach is compared with alternative initial condition sampling techniques at low temperatures where classical initial condition sampling yields dephasing rates that are nearly an order of magnitude too slow compared with quantum initial condition sampling and experimental results.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "I. INTRODUCTION", "text": "Detailed analysis of the vibrational spectroscopy of chromophores in solution can be used to investigate intermolecular interactions in condensed phases. The theory of vibrational pure dephasing and its contribution to spectral line shapes and shifts has been worked out in detail in various limits. Perturbation theory (see references 1, 2, 3, 4 and the and the literature cited therein), which assumes that the interaction between vibrational degrees of freedom and the environment is weak, gives an expression that enables the pure dephasing time to be computed from the zero frequency component of the time correlation function of the fluctuations in the energy gap between the vibrational levels. In many experiments, however, there may be strong initial environmental interactions associated with how the system is initially excited so techniques to study dephasing and dissipation beyond the limits of perturbation theory are important, and several non-perturbative ways to study vibrational dynamics have appeared in the literature 4, 5, 6, 7, 8 . One very fruitful way to go beyond perturbation theory, for example, is to employ an idealized model which can be worked out analytically such as a two level system appropriately coupled to a harmonic bath for which the effects of environmental dephasing on lineshape and spectral shifts have been worked out in detail 4, 5, 6 . Several general predictions emerge from this analysis concerning, for example, how lineshapes are affected by characteristics of bath spectral density, and temperature, etc. Experimentalists can use the predictions of this theory to interpret their findings in terms of the nature of the underlying interactions in condensed phase systems. The interactions between the vibrational coordinate and the environment can depend on vibrational excitation in a complex way and this can complicate use of the two level system theory described above. Also employing a harmonic bath when anharmonicity may be significant could make the use of such a theory questionable.", "cite_spans": [{"start": 1049, "end": 1051, "text": "7,", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "An alternative non-perturbative method that has received considerable attention in the quantum optics literature 9, 10 and recently has become a focus in molecular science applications 8 is the so-called stochastic wave function approach 7 . With this method the evolution of the density matrix is assumed to take a simplified Bloch form parameterized by phenomenological coefficients governing the decay of coherence and the transfer of population. Rather than propagating the n \u00d7 n density matrix elements, a stochastic wave function represented in terms of n relevant basis functions is evolved using statistical rules designed in such a way so that the reduced density constructed from an ensemble of evolved stochastic wave functions reproduces the evolution of the Bloch equations. Since this approach relies on a Bloch model form containing phenomenological parameters it thus provides an efficient, linear scaling approach for fitting experimental data to such models. As these models are often discussed in terms of gas phase collision processes, interpreting such fits in a meaningful way and extracting information about a microscopic mechanism of the relevant decoherence processes operating in condensed phase systems is not straightforward.", "cite_spans": [{"start": 238, "end": 239, "text": "7", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "A further possible alternative approach is the use of a realistic microscopic model with vibrational state dependent interactions as has been developed in various contexts over the last few years 11, 12, 13 . Such an approach requires a quantum dynamical treatment of dephasing and microscopic simulation methods to address this problem have recently been developed 14, 15, 16, 17, 18, 19, 20, 21 . In this paper we extend these methods to include quantum initial condition sampling that should accurately capture the relevant underlying spectral density of the realistic model system. Thus unlike the theories discussed above which are built on use of different models (e.g. Debye or pseudolocal mode spectral densities), with the approach employed here we do not need to assume anything about the spectral density arising from the interactions. As such direct, model free, interpretation of the experimental results is possible.", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "The specific set of experiments which we will study with this alternative approach come from recent work from Apkarian and coworkers 22, 23, 24, 25, 26, 27, 28, 29, 30 in which they use Time Resolved Coherent Anti-Stokes Raman Scattering (TR-CARS) to directly probe the de-phasing of vibrationally excited I 2 wave-packet components due to interactions of this chromophore with a rare gas matrix. This well studied system is chosen as a benchmark on which to evaluate the approach due to the availability of accurate interaction potential data. Also, as distinct from traditional frequency domain experiments in which lineshapes and frequency shifts are indirectly interpreted in terms of the evolution of the density matrix, these time domain experiments can be directly connected to the theory of decoherence which we outline below.", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "The phenomenon of vibrational dephasing can be probed when a vibrational subsystem, described by Hamiltonian\u0124 s , with eigenstates given by\u0124 s |v 0 = \u01eb v0 |v 0 , is prepared in some coherent superposition state, |\u03c8(0) = v0 c v0 |v 0 , for example, in the presence of an environmental subsystem in state |\u03c7(0) which is unaffected by this preparation. Thus the composite system initial state can be described by a separable product state |\u03a8(0) = |\u03c8(0) |\u03c7(0) . Important deviations from this separable product initial condition in the limit of strong system -environment coupling have been discussed 31, 32, 33 . If the quantum subsystem and the environment are uncoupled, the initial coherent superposition of vibrational states will be maintained as the whole system evolves, i.e. the amplitudes and relative phases of the component state contributions will be constant, and the composite system wave function will remain separable. In the more general situation, however, the dynamics of the full system is governed by the coupled system-bath Hamiltonian,\u0124 =\u0124 s +\u0124 b +\u0124 s\u2212b and the above initially separable wave function will evolve into an entangled state |\u03a8(t) = v0 c v0 exp[\u2212 i \u0124 t]|\u03c7(0)v 0 = vN |\u03c7 vN (t) |v N in which the amplitudes and relative phases of the different vibrational state contributions will change with time. In the last equality in the previous result we have projected the composite state onto the diabatic vibrational basis states |v N , and the bath states that appear in this entanglement, labelled according to this basis, are obtained as |\u03c7 vN ", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "The timescale for the variation in the phase of the different vibrational state components is known synonymously as the vibrational dephasing or decoherence time. The variation in the amplitude, on the other hand, reflects the vibrational state population relaxation time. With this description, the bath states |\u03c7 vN (t) contain all the relative phase and amplitude information of the contributions from the different vibrational basis states. With the view outlined here we are assuming that the details of the shapes of the exciting radiation field pulses can be neglected and that we can focus our attention on the evolution of the reduced density matrix. A complete description of the experiments would require considering details of the time dependent interactions of the full system with the radiation field and is beyond the scope of the current investigation of vibrational pure dephasing times.", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "In the vibrational pure dephasing limit it is assumed that the composite system dynamics results in slow ", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "This is equivalent to the vibrationally adiabatic approximation. The timescale for the vibrational pure dephasing process is governed by the distribution of fluctuations in the phase of the state |\u03c7 vN (t) which is determined by two factors: (1) the strength of the interactions between the vibrational subsystem and its environment which will in general depend on the particular vibrational state |v N , and (2) the distribution of initial states of the environment |\u03c7(0) . This paper develops a general approach for computing vibrational pure dephasing rates in condensed phase systems which incorporates both the varying strength of environmental interactions with quantum subsystem state, and the effect of quantum dispersion on the nature of the distribution of the initial environmental states.", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "The quantum vibrational state dependent intermolecular potential idea developed in the late 1990's 11,12,13 provides a framework for the representation that we employ here to account for the the variation of environmental interaction strength with vibrational state. Specifically the model of Martens and co-workers 34, 35, 36, 37 is adopted for this purpose. The main goal of the work here is to explore how thermal and quantum fluctuations of the initial environment influence vibrational pure dephasing in a model system with realistic interactions. Thus we will compare classical and approximate quantum descriptions of the thermal environmental initial distribution and explore their effects on dephasing dynamics. In addition a complete and general derivation of the Feynman-KleinertWigner (FK-Wigner) approach for sampling quantum initial conditions is presented.", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "The paper is organized as follows: First we outline a general approximate approach for treating the evolution of the vibrational reduced density matrix. With this linearized approximation, quasi-classical trajectories are evolved from quantum initial conditions sampled from the Wigner transform of the initial density. The main methods section of the paper summarizes the FK-Wigner approach used for this sampling. Details of the complete derivation of this approach are given in the appendices. The final methods subsection makes comparisons of this approach with other published techniques. Finally in section III we outline the implementation of these methods for application to computing vibrational pure dephasing rates and compare these data computed using different approximations with available experimental results. Concluding remarks are given in section IV.", "cite_spans": [], "ref_spans": []}, {"section": "II. METHODS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "A. Vibrational Pure dephasing", "text": "The density matrix formulation offers a convenient way to rewrite the wave function description outlined above in a useful form for making further approximations and interpretations. As noted earlier, the experiments of interest involve exciting the vibrational subsystem independently of the environment. The bath degrees of freedom are thus assumed to be initially prepared in thermal equilibrium with the quantum subsystem. The quantum vibrational subsystem is then prepared by rapid pulsed laser excitation, for example, in a non-equilibrium coherent superposition of excited vibrational states |\u03c8(0) as described in the Introduction. We assume that the non-equilibrium composite system is thus initially described by a density operator which is a product form \u03c1(0) =\u03c1 s (0)\u03c1 e b (0), where\u03c1 e b is the bath part of the equilibrium density operator for which we will develop approximations, and the non-equilibrium quantum subsystem density for the initially excited coherent superposition state is\u03c1 s (0) = |\u03c8(0) \u03c8(0)|, which has various component operators, for example, c v0 c", "cite_spans": [], "ref_spans": []}, {"section": "A. Vibrational Pure dephasing", "text": "that depend on what states of the quantum subsystem are coherently excited by the laser pulses.", "cite_spans": [], "ref_spans": []}, {"section": "A. Vibrational Pure dephasing", "text": "The coherently excited composite system will evolve from this factored initial state to an entangled state as a result of the coupled full system evolution as discussed above. This entanglement will thus be described by the full system time dependent density matrix with elements in the environmental coordinate and vibrational subsystem state representation given as", "cite_spans": [], "ref_spans": []}, {"section": "A. Vibrational Pure dephasing", "text": "The experiments of interest probe only the quantum subsystem states so we will study the reduced density matrix elements obtained by tracing over all the bath degrees of freedom i.e. \u03c1", "cite_spans": [], "ref_spans": []}, {"section": "A. Vibrational Pure dephasing", "text": "Suppose the preparation selects out the\u03c1 s (0) = |v 0 v \u2032 0 | component sub-system density operator initially, then the reduced density operator matrix elements at time t will have the form", "cite_spans": [], "ref_spans": []}, {"section": "A. Vibrational Pure dephasing", "text": "and involve forward and backward propagator matrix elements as well as initial bath density operator matrix elements. Suppose the full Hamiltonian i\u015d", "cite_spans": [], "ref_spans": []}, {"section": "A. Vibrational Pure dephasing", "text": "which can be expressed in our quantum subsystem diabatic vibrational basis as\u0124 =P", "cite_spans": [], "ref_spans": []}, {"section": "A. Vibrational Pure dephasing", "text": "Here \u03a6 s\u2212b is the system-bath interaction potential. In the case of vibrational pure dephasing we suppose that h \u03b1\u03b2 (R) \u223c 0 for \u03b1 = \u03b2, i.e. the off-diagonal elements are small compared to the diagonal elements, so we can approximate the full system Hamiltonian by the diagonal form\u0124 d =P 2 /2M b + \u03b1 |\u03b1 h \u03b1\u03b1 (R) \u03b1| for all important R. In this case there is no population relaxation between our vibrational basis states so the propagator matrix elements appearing in Eq.(1) can be written in the composite bath subsystem path integral forms as follows:", "cite_spans": [], "ref_spans": []}, {"section": "A. Vibrational Pure dephasing", "text": "and", "cite_spans": [], "ref_spans": []}, {"section": "A. Vibrational Pure dephasing", "text": "where the forward path action, for example, is", "cite_spans": [], "ref_spans": []}, {"section": "A. Vibrational Pure dephasing", "text": "and a similar expression for the action along the backward path is obtained by modifying the vibrational state accordingly to v \u2032 0 . Combining these expressions, the reduced density matrix in the pure dephasing limit can be written as", "cite_spans": [], "ref_spans": []}, {"section": "A. Vibrational Pure dephasing", "text": "In the above expression the bath evolution is still described at the full quantum level.", "cite_spans": [], "ref_spans": []}, {"section": "A. Vibrational Pure dephasing", "text": "To proceed to a computable expression for the time dependence of the reduced density matrix elements we follow various authors 14, 15, 16, 17, 18, 19 and combine the forward and backward propagators in Eq. (6) and write the product in terms of mean,R(t) = [R(t) + R \u2032 (t)]/2, and difference, Z(t) = R(t) \u2212 R \u2032 (t), bath subsystem path coordinates (with a similar transformation for the bath momenta, P (t) = [P (t) + P \u2032 (t)]/2 and Y (t) = P (t) \u2212 P \u2032 (t)). Next, the phase of the integrand in Eq. (6) is expanded in the path difference variables. In condense phase systems various arguments can be given to justify keeping only low order terms in the path difference 14, 20, 38, 39, 40 . Thus we proceed by truncating the expansion of the phase to linear order in the path difference variables. With this approximation the integrals over the initial difference coordinate Z 0 can be performed defining the Wigner transform of the initial density operator", "cite_spans": [], "ref_spans": []}, {"section": "A. Vibrational Pure dephasing", "text": "If we discretize the paths appearing in Eq. (6) by inserting N resolutions of the identity in the bath subsystem phase space and take small time steps \u03b4t = t/N , thus writing the discrete path variables as R k = R(k\u03b4t), for example, we find that all integrals over the difference coordinates, Z k , and difference momenta, Y k for 0 < k < N that appear in the discretized result can also be performed in the linearized approximation since they are integral representations of \u03b4-functions 20, 41 . Thus, the linearized approximation for the evolution of the reduced density operator becomes", "cite_spans": [], "ref_spans": []}, {"section": "A. Vibrational Pure dephasing", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "A. Vibrational Pure dephasing", "text": "and", "cite_spans": [], "ref_spans": []}, {"section": "A. Vibrational Pure dephasing", "text": "This result indicates that the time evolution of the density operator matrix elements can be approximated by first sampling the initial environment phase space from the Wigner transform of the bath part of the thermal equilibrium density of the full system. In our low temperature calculations we approximate this equilibrium density by assuming that the environment experiences interactions with only the ground state of the vibrational subsystem. At higher temperatures excited vibrational states should be included in this initial sampling. Next, the product of \u03b4-functions in Eq. (8) indicates that with in the linearized approximation the time dependence of the density matrix elements can be obtained by evolving classical trajectories with the sampled initial conditions and subject to the mean of the forces arising from the quantum states involved in the prepared superposition state. Finally Eq. (8) gives that the contributions from each sampled trajectory to the density are obtained by adding coherently phase factors computed along these trajectories. An approach based on the same approximations outlined above has been used in other work 20, 41 to compute various quantum time correlation functions exploring electron transport, and vibrational energy relaxation, for example. In fact, approaches like this which employ the Wigner transform 42 of the equilibrium density as the distribution of initial conditions and evolve the classical dynamics with a mean Hamiltonian have a long history in computing spectroscopic correlation functions, for example, 43, 44 . The work of Egorov et al. 45 provides an important comparison of this type of approach with alternative classical and mixed quantum-classical methods in the context of computing model condensed phase vibronic spectra.", "cite_spans": [], "ref_spans": []}, {"section": "A. Vibrational Pure dephasing", "text": "The rest of the paper describes the computational approach we adopt for sampling the Wigner density and the mean Hamiltionian dynamics calculations that we have conducted to explore the characteristics of the vibrational pure dephasing process in low temperatures crystals. In Fig. 1 were obtained using different ways of propagating the classical trajectories. The solid curve presents results obtained using the average state force (ASF) to drive the environmental dynamics as suggested by Eq.(8) and discussed above. An alternative approach is to evolve the environmental dynamics using forces arising from the ground vibrational state potential only 43, 45 . The curve labeled GSF (Ground vibrational State Force) in Fig. 1 is obtained in this way. We see that both sets of calculated dephasing rates are generally faster than the experimentally observed results. These discrepancies with experiment probably reflect inaccuracy in the model interactions employed in these calculations which we outline later. However, we generally find that the dephasing rates computed using the average surface force are in better agreement with experiment than results computed using the ground vibrational state force. The two calculated dephasing rate curves should coalesce at low vibrational state number where the average potential from states 0 and \u03bd is essentially that of the ground state. As we increase \u03bd the average force experienced by the environment F 0,\u03bd = [\u2207Rh 0,0 (R) + \u2207Rh \u03bd,\u03bd (R)]/2 in our ASF calculations becomes more and more different from the ground state force F 0,0 = \u2207Rh 0,0 (R) employed in the GSF calculations and the deviation between the two curves is apparent. As discussed above, according to Eq. (8), the dephasing rates are obtained by averaging the phase factor in the energy gap between the two relevant vibrational states. If the forces governing the fluctuations in the energy gap arise from both of the states we expect that each state energy will fluctuate in a similar way leading to slower dephasing. If, on the other hand, the solvent responds to only the ground state force, as in the GSF calculations, the excited state energy may fluctuated more strongly as it does not play a role in influencing the environmental dynamics. This explains why the dephasing rates computed with the average force dynamics are slower than those obtained with the ground state force.", "cite_spans": [], "ref_spans": []}, {"section": "A. Vibrational Pure dephasing", "text": "The main goal of our work is to study the effect of the distribution of environmental states on vibrational pure dephasing, making particular contact with low temperature experiments. Under these conditions quantum dispersion and tunneling of the environmental degrees of freedom may play a significant role. Thus we will employ various approximations to the Wigner transform of the initial density and compute their effect of the linearized approximation to the dephasing dynamics given in Eq. (8) . General methods for computing the Wigner transform of the Boltzmann operator are as yet unavailable. In our work we thus employ an approximation to this operator. First we assume that the temperature is sufficiently high, and that particle masses are large, so that identical particle statistics complications can be ignored. Next, as detailed below, we employ an approach pioneered by Feynman and Kleinert that approximates the many body Boltzmann operator assuming a locally quadratic form for the interactions. This approximate approach has recently been implemented in various condensed phase applications studying quantum effects on transport and spectroscopy by Poulsen and co-workers 14, 46, 47 . Our study will compare vibrational dephasing results obtained using this approximate Boltzmann operator which can incorporate some quantum initial distribution effects, with classical initial condition sampling techniques which ignore quantum dispersion and tunneling. Our results from all these various calculations will be compared with available experimental results enabling a detailed understanding of the reliability of the different approximations underlying these calculations.", "cite_spans": [], "ref_spans": []}, {"section": "B. Sampling the quantum initial density for the environment", "text": "In this section we review the method developed by Poulsen and co-workers 14, 46, 47, 48, 49, 50, 51, 52, 53, 54 that adapts the Feynman-Kleinert variational approach for obtaining an optimal local harmonic approximation to the Boltzmann operator which can be easily Wigner transformed. In our application to vibrational dephasing we suppose that the quantum vibration is prepared initially in some superposition state while the environmental degrees of freedom are unaffected by the vibrational excitation and are initially in thermal equilibrium with the vibrational degrees of freedom. As outlined in the previous section this quantity plays a central role as the phase space distribution function that must sampled to provide trajectory initial conditions in linearized approximations for the density matrix dynamics. We will explore the effects of the quantum nature of this initial equilibrium distribution on vibrational pure dephasing of the excited coherence. The development below in terms of the general Boltzmann operator is easily adapted to the case of the environmental degrees of freedom being in equilibrium with the quantum subsystem by supposing that the vibrational degree of freedom acts to provide an external force on the environment. As mentioned above we suppose that the experiments of interest can be interpreted as though the environment was initially in equilibrium with the ground state of the quantum subsystem so the Hamiltonian in the Boltzmann operator below describes interactions of the environment with the external field due to the ground state quantum subsystem.", "cite_spans": [], "ref_spans": []}, {"section": "B. Sampling the quantum initial density for the environment", "text": "The principle assumption underlying the Poulsen et al.", "cite_spans": [], "ref_spans": []}, {"section": "B. Sampling the quantum initial density for the environment", "text": "14,46,47 approach to generating an approximate Wigner transform of the Boltzmann operator,\u03c1 = exp[\u2212\u03b2\u0124], is that the off-diagonal elements of the thermal density matrix \u03c1 \u03b2 (R, R \u2032 ) that enter the Wigner transform expression", "cite_spans": [], "ref_spans": []}, {"section": "B. Sampling the quantum initial density for the environment", "text": "(11) can be just as well represented as the diagonal elements that appear in the trace expression for the partition function. Accepting this proposal the approach proceeds as follows: First the Feynman-Kleinert method for computing the partition function is employed to obtain a local harmonic approximation to the Euclidian action that is variationally optimized for computing the trace of the density matrix. Next we assume that the off-diagonal elements can be approximated using the optimized local harmonic approximation and this form is employed to compute the Wigner transformation. With this approach a local harmonic approximation is never directly made to the potential, rather an optimal local harmonic approximation to the Euclidean time action is found variationally using the partition function which involves integration over all space and thus contains global information. This local harmonic fitting procedure, however, is not influenced by any off-diagonal information. So it is unclear why it should provide a reliable approximation for generating the Wigner phase space density. One of our goals is to explore this question. In section II C we will directly compare density matrix elements for a simple model computed with in this approximation with exact results to explore the reliability of the off-diagonal density obtained with this and other approximate methods.", "cite_spans": [], "ref_spans": []}, {"section": "B. Sampling the quantum initial density for the environment", "text": "As outlined above the derivation of the approach starts by following Feynman and Kleinert and considering the partition function, Z, at inverse temperature, \u03b2 = 1/k B T , for the environmental variables, R, written as a path integral over cyclic paths (R(\u03c4 ) :", "cite_spans": [], "ref_spans": []}, {"section": "B. Sampling the quantum initial density for the environment", "text": "Where, D[R(\u03c4 )], means integrate over all points in the path, R(\u03c4 ), including the common starting and finishing points, and the Euclidian action is", "cite_spans": [], "ref_spans": []}, {"section": "B. Sampling the quantum initial density for the environment", "text": "T (\u03c4 )M\u1e58(\u03c4 )+V (R(\u03c4 ))}. Here, M, is the mass tensor, and V (R), is the inter-particle interaction potential including the effects of external fields (such as, for example, coming from interactions with the vibrator in its ground state). In mass weighted cartesian coordinates, q(\u03c4 ) = M 1/2 R(t), we can write", "cite_spans": [], "ref_spans": []}, {"section": "B. Sampling the quantum initial density for the environment", "text": "Since the paths of interest for Z are real and periodic on 0 \u2264 \u03c4 \u2264 \u03b2 their Euclidean time dependence can be written in terms of a Fourier series i.e.", "cite_spans": [], "ref_spans": []}, {"section": "B. Sampling the quantum initial density for the environment", "text": "where \u2126 n = 2\u03c0n/\u03b2 are the Matsubara frequencies, the real zero frequency Fourier coefficient,", "cite_spans": [], "ref_spans": []}, {"section": "B. Sampling the quantum initial density for the environment", "text": ", is the path centroid, and all other Fourier coefficients, q n , are in general complex.", "cite_spans": [], "ref_spans": []}, {"section": "B. Sampling the quantum initial density for the environment", "text": "If the configuration of the system is of dimension d then the cyclic path space integration can be mapped onto an integration over Fourier coefficient vectors of length d according to 55, 56, 57, 58 ", "cite_spans": [{"start": 192, "end": 195, "text": "57,", "ref_id": "BIBREF56"}, {"start": 196, "end": 198, "text": "58", "ref_id": "BIBREF57"}], "ref_spans": []}, {"section": "B. Sampling the quantum initial density for the environment", "text": "and the partition function can be shown to be", "cite_spans": [], "ref_spans": []}, {"section": "B. Sampling the quantum initial density for the environment", "text": "Following Feynman and Kleinert 55,56 the effective classical potential, W (q c ), is defined as (17) and the quantum partition function is cast in the suggestive classical form (18) identifying motion of the path centroid over the effective potential as a classical-like way to compute quantum properties using classical statistical mechanics ideas 55, 56, 59 . Since \u03b2\u2126 2 n = 4\u03c0 2 n 2 / 2 \u03b2, at high temperature (lim \u03b2 \u2192 0), the Gaussian factors in the integrand of Eq.(17), for example, will be dominated by small values of |q n |, so under these conditions q(\u03c4 ) will fluctuate only slightly from q c and, as Feynman and Kleinert suggested 55 , the effective potential might be computed using a local harmonic approximation to the full potential in the region around each path centroid location. They used the Gibbs-Bogoliobov-Feynman variational principle to determine the optimal local harmonic approximation at each centroid position.", "cite_spans": [{"start": 357, "end": 359, "text": "59", "ref_id": "BIBREF58"}], "ref_spans": []}, {"section": "B. Sampling the quantum initial density for the environment", "text": "This approach starts from the exact expression for the partition function obtained by multiplying and dividing by some trial partition function", "cite_spans": [], "ref_spans": []}, {"section": "B. Sampling the quantum initial density for the environment", "text": "] associated with some, yet to be specified, locally harmonic trial action, S trial , thus", "cite_spans": [], "ref_spans": []}, {"section": "B. Sampling the quantum initial density for the environment", "text": "Due to the concavity of the exponential function, e \u2212f \u2265 e \u2212 f , so we replace the average of the exponential by the exponential of a more simply computed average and obtain the following variational result", "cite_spans": [], "ref_spans": []}, {"section": "B. Sampling the quantum initial density for the environment", "text": "2 (\u03c4 ) + V trial (q(\u03c4 ))} to be the Euclidian time action associated with motion in some trial potential V trial , then", "cite_spans": [], "ref_spans": []}, {"section": "B. Sampling the quantum initial density for the environment", "text": "and the value of the cyclic path integral should be independent of the value of the time at which the function f is evaluated since all \u03c4 \u2032 should be equivalent under the trace we can write 60 , for example,", "cite_spans": [{"start": 190, "end": 192, "text": "60", "ref_id": "BIBREF59"}], "ref_spans": []}, {"section": "B. Sampling the quantum initial density for the environment", "text": "To proceed we follow Feynman and Kleinert and suppose that the trial action is quadratic in displacements about the path centroid location thus", "cite_spans": [], "ref_spans": []}, {"section": "B. Sampling the quantum initial density for the environment", "text": "The term linear in displacement, (q(\u03c4 ) \u2212 q c ), multiplying a derivative vector evaluated at q c vanishes identically when integrated over \u03c4 due to the cyclic nature of the paths on the interval 0 \u2264 \u03c4 \u2264 \u03b2 (Eq. (14)), so with this quadratic form only the offset term, L(q c ), and the local curvature matrix, K(q c ), need to be determined variationally. Suppose the matrix, U(q c ), diagonalizes the curvature matrix giving a diagonal matrix of frequencies, \u03c9(q c ),", "cite_spans": [], "ref_spans": []}, {"section": "B. Sampling the quantum initial density for the environment", "text": "\u2212i\u2126n\u03c4 ], we find that the trial partition function is obtained as", "cite_spans": [], "ref_spans": []}, {"section": "B. Sampling the quantum initial density for the environment", "text": "The Gaussian integrals over the components of the \u03b7 n can be performed analytically provided the frequencies \u03c9 j have appropriate values (see detailed discussion below on the restrictions that this places on the matrix K) and, using the fact that", "cite_spans": [], "ref_spans": []}, {"section": "B. Sampling the quantum initial density for the environment", "text": "the trial partition function becomes (27) so in analogy to Eq.(17) we can write", "cite_spans": [], "ref_spans": []}, {"section": "B. Sampling the quantum initial density for the environment", "text": "The other quantities that need to be computed to apply the variational result in Eq. (20) according to Eqs. (21) - (23), are averages of the potentials over the trial density. In Appendix A we outline the computation of these quantities obtaining the following general result written in terms of different Gaussian smeared potential forms: (29) where V A (R c ) is the Gaussian smeared full potential", "cite_spans": [], "ref_spans": []}, {"section": "B. Sampling the quantum initial density for the environment", "text": "(30) which can also be computed in Fourier space according to Eq.(A7). The Gaussian smeared local harmonic approximate trial potential is", "cite_spans": [], "ref_spans": []}, {"section": "B. Sampling the quantum initial density for the environment", "text": "which can be used in Eq. (29) to compute V trial (R(0)) trial .", "cite_spans": [], "ref_spans": []}, {"section": "B. Sampling the quantum initial density for the environment", "text": "In these results the smearing width matrix A is", "cite_spans": [], "ref_spans": []}, {"section": "B. Sampling the quantum initial density for the environment", "text": "as obtained in Appendix A (See Eq.(A5) and Eq.(A6)). Thus we find the trial averaged action difference appearing in the variational expression, Eq.(20), can be written as", "cite_spans": [], "ref_spans": []}, {"section": "B. Sampling the quantum initial density for the environment", "text": "Using the above result we follow Feynman and ", "cite_spans": [], "ref_spans": []}, {"section": "B. Sampling the quantum initial density for the environment", "text": "Here the optimal curvature matrix is found from the gaussian smeared result", "cite_spans": [], "ref_spans": []}, {"section": "B. Sampling the quantum initial density for the environment", "text": "(36) Where D(R) is the mass weighted Hessian", "cite_spans": [], "ref_spans": []}, {"section": "B. Sampling the quantum initial density for the environment", "text": "As outlined above the approach requires the computation of Gaussian smeared averages of various functions. The evaluation of such multidimensional integrals is in general complicated and could be performed with a MC procedure. In the application described here, however, the interaction potential functions being smeared are pair decomposable and, as outlined in Appendix C, can be fit to Gaussian forms and the smearing integrals performed analytically.", "cite_spans": [], "ref_spans": []}, {"section": "B. Sampling the quantum initial density for the environment", "text": "The structure of the above equations suggests the following iterative procedure for computing the smearing matrix A: (1) Choose an initial guess for the A (0) matrix. We use the previously converged smearing matrix for the last accepted centroid configuration. (2) Compute the full K (0) matrix at the new centroid configuration using Eq.(36) (or Eq.(C4)). This can be done efficiently employing the symmetry of the local curvature matrix. (3) Diagonalize K (0) to obtain the local harmonic frequencies \u03c9 (0) (R c ) and the eigenvector matrix U (0) as defined above Eq. (25) . Finally, (4), use these in Eqs.(33) (or (B16)) and (32) to obtain a new estimate of the smearing matrix, A (1) , then return to step (2) and iterate this process till convergence.", "cite_spans": [], "ref_spans": []}, {"section": "B. Sampling the quantum initial density for the environment", "text": "Using the converged set of parameters, we compute the various Gaussian smeared quantities (using Eq. (30) for example) and obtain the variationally optimized value for the energy offset parameter L(R c ) as in Eq.(35) at the new centroid configuration.", "cite_spans": [], "ref_spans": []}, {"section": "B. Sampling the quantum initial density for the environment", "text": "The final steps in the approach involve writing the density operator approximately as the integral over centroid locations of the variationally optimized local harmonic form around each centroid position and then analytically Wigner transforming this locally harmonic result. Detail of these calculations are given in Appendix D. The approximate density has the form", "cite_spans": [], "ref_spans": []}, {"section": "B. Sampling the quantum initial density for the environment", "text": "Here we define the quantity \u03b1 i = coth \u03b2 \u03c9 i /2 \u2212 2/\u03b2 \u03c9 i and Wigner transformation yields", "cite_spans": [], "ref_spans": []}, {"section": "B. Sampling the quantum initial density for the environment", "text": "The integral in Eq. (39) is easily computed by importance sampled Monte Carlo. Thus a Cartesian centroid configuration, R c , is sampled. The procedure outlined above Eq. (38) is employed to iterate the width, A (n) , and curvature, K (n) , matrices to convergence. As indicated, this involves diagonalizing K (n) at each iteration to obtain the local harmonic frequencies and normal modes. The converged value of W trial computed from Eq.(28) is used to accept or reject the sampled centroid configuration. Next, to sample the (Q, P Q ) phase space distribution associated with the approximate Wigner transformed Boltzmann operator, a set of k = 1, M normal mode displacements with components \u03be Qi which are transformed to cartesian initial momenta according to", "cite_spans": [], "ref_spans": []}, {"section": "B. Sampling the quantum initial density for the environment", "text": "The numerical factor (. . . ) 1/2 in Eq.(39) provides an automatic centroid configuration dependent normalization for the sampling of these Gaussian distributions, and so each sample phase space configuration generated in this way carries unit weight.", "cite_spans": [], "ref_spans": []}, {"section": "C. Comparison of Initial Condition Sampling Methods for Model System", "text": "To test the reliability of our implementation of the Feynman-Kleinert approach for sampling the Wigner distribution outlined in the previous subsection we have applied it to several simple exactly solvable one dimensional model systems. In this section we present these results and compare with exact calculations and with another approximate approach due to Shi and Geva (SG) 15, 16, 61 . These authors proceed by multiplying and dividing the Wigner transform expression of the Boltzmann operator by the diagonal elements of the thermal density operator, thus", "cite_spans": [], "ref_spans": []}, {"section": "C. Comparison of Initial Condition Sampling Methods for Model System", "text": "They make the Local Harmonic Approximation (LHA) to the potential, expanding to quadratic order about the position Q. Note this approximation is made only in the ratio of off-diagonal to diagonal density matrix elements in the integrand, however, the full anharmonic dependence of prefactor diagonal element is included through path integral calculations. With this local harmonic form, the Gaussian integrals can be performed analytically yielding the following result for the case of one dimension:", "cite_spans": [], "ref_spans": []}, {"section": "C. Comparison of Initial Condition Sampling Methods for Model System", "text": "Where \u03c7(Q) depends on the local curvature of the potential about the point Q and has the form \u03c7(Q) = coth", "cite_spans": [], "ref_spans": []}, {"section": "C. Comparison of Initial Condition Sampling Methods for Model System", "text": ". For the purpose of comparison with exact results we computed the density matrix for our 1D model using the numerical matrix multiplication (NMM) approach 62, 63 . It is most convenient to make direct comparison with the full density matrix. The approximate Wigner densities can be inverse Wigner transformed to give approximate coordinate space density matrices using to the following result:", "cite_spans": [], "ref_spans": []}, {"section": "C. Comparison of Initial Condition Sampling Methods for Model System", "text": "Thus the SG approximation to the density matrix becomes", "cite_spans": [], "ref_spans": []}, {"section": "C. Comparison of Initial Condition Sampling Methods for Model System", "text": "(43) withQ = (Q + Q \u2032 )/2. The corresponding FK approximation to the density matrix takes the form:", "cite_spans": [], "ref_spans": []}, {"section": "C. Comparison of Initial Condition Sampling Methods for Model System", "text": "The FK form in Eq. (44) and the SG approximate density matrix of Eq. (43) share some similar features. Setting Q = Q \u2032 in Eq. (44) gives an expression for the diagonal elements Q |e \u2212\u03b2\u0124 |Q F K . If we evaluate the gaussian in (Q \u2212 Q \u2032 ) of Eq. (44) at the maximum of the first gaussian in this equation i.e. Q c =Q in an effort to approximate the Q c integration, we recover a form similar to the SG approximation of Eq. (43) . In general however the full integral over the centroid position must be performed so we expect differences between these results. The most significant differences must be due to the fact that the SG form employs a single local harmonic frequency \u03c9(Q) to compute the off-diagonal elements. The FK expression, on the other hand, combines results from a range of smeared frequencies that are not obtained by local harmonic approximation to the bare potential.", "cite_spans": [], "ref_spans": []}, {"section": "C. Comparison of Initial Condition Sampling Methods for Model System", "text": "These differences are apparent in the results presented in Figures. 2, and 3 . In these calculations we explored the approximate density matrixes for an asymmetric double well potential (the Veneziano potential 64 ) of the form", "cite_spans": [], "ref_spans": []}, {"section": "C. Comparison of Initial Condition Sampling Methods for Model System", "text": "2 with the following parameter values in atomic units: E c = 1 \u00d7 10 \u22124 , m = 0.2 and M = 1600. Results are presented with a temperature corresponding T=50K.", "cite_spans": [], "ref_spans": []}, {"section": "C. Comparison of Initial Condition Sampling Methods for Model System", "text": "From Fig. 2 it is clear that under these conditions the FK approximation reproduces the density matrix very accurately across the entire region, even when barrier tunneling is important. In Fig. 3 , on the other hand, we see that the SG approach gives undefined results for the density matrix in the tunneling region. Moreover, the density matrix difference results presented in the right hand panel show that even though the SG density matrix is exact along the diagonal (when it can be defined) the off diagonal elements differ considerably from the exact results compared to the significantly smaller differences observed with the FK approximation.", "cite_spans": [], "ref_spans": []}, {"section": "C. Comparison of Initial Condition Sampling Methods for Model System", "text": "The general condition for convergence of the various multidimensional Gaussian integrals like Eq.(A7) in kspace, or analogously Eq. (30) in R-space is that the gaussian width matrix, A, appearing in these expressions should be positive definite, i.e., all its eigenvalues should be positive. From the definition of A in Eq.(32) the eigenvalues are proportional to \u039b ll as given in Eq.(33) (or Eq.(B16)). The right hand side of this expression is positive provided all the eigenvalues of K satisfy \u03c9", "cite_spans": [], "ref_spans": []}, {"section": "C. Comparison of Initial Condition Sampling Methods for Model System", "text": "i.e. some negative frequencies can be tolerated with in the FK approach and this is an important factor in reproducing the density matrix in the tunneling region. Analysis of the SG density matrix expression in Eq.(43) reveals that it too can tolerate negative curvature regions. It is found that", "cite_spans": [], "ref_spans": []}, {"section": "C. Comparison of Initial Condition Sampling Methods for Model System", "text": "15 . Thus the maximum negative curvatures K F K m that the FK approach can tolerate are 4 times those of the SG approach. Moreover, due to the use of the smeared potential in the FK approach as distinct from the bare potential in the SG formulation, curvatures with the FK approach are generally significantly smaller in absolute value than those of the SG approach. Thus the FK approach is expected to have a considerably wider range of applicability.", "cite_spans": [], "ref_spans": []}, {"section": "III. RESULTS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "A. Outline of Experiments", "text": "The TR-CARS experiments of Apkarian and coworkers 22, 23, 24, 25, 26, 27, 28, 29, 30 involve exciting controllable coherent superpositions of I 2 vibrational states in rare gas matrices. After the excitation pulses that prepare the initial vibrational superposition on a chosen electronic state, probing pulses project the evolving packet onto other electronic states and the time dependence of the emission from these states gives a signal that can be related to the evolution of the initial coherence. Apkarian and co-workers use a model of these experiments to extract dephasing rates of the different vibrational superposition states they prepare. Their work exploring these dephasing rates for vibrational superpositions prepared in the ground X electronic state is the focus of our studies here. In our work we assume that the pure dephasing rate can be obtained from the long time exponential decay rate of the off-diagonal elements of the density matrix in an appropriately chosen vibrational representation. Martens and co-workers 34, 35, 36, 37 have used their semi-classical Liouville dynamics approach (which is formally equivalent to the linearized dynamics employed here) to study this problem and have presented a useful model of the relevant vibrational state dependent interactions. We follow these workers and assume that the eigenstates of a Morse oscillator whose parameters are fit to give solution phase experimental vibrational data for the ground X electronic state provides such an appropriate vibrational representation. Using this model of the interactions we explore the linearized approach for computing the dynamics of the vibrational density matrix with different distributions of initial conditions. The main difference between our calculations and this previous work is the use of the FK-Wigner quantum initial condition sampling approach developed in the previous section. Green surface presents differences between exact density matrix and SG approximation.", "cite_spans": [], "ref_spans": []}, {"section": "B. Computational Model", "text": "The computational model employed in our studies of vibrational dephasing is closely related to that of Martens and co-workers 34, 35, 36, 37 ", "cite_spans": [], "ref_spans": []}, {"section": "B. Computational Model", "text": "Here \u00b5 is the reduced mass of the diatomic whose position is specified byr,\u03b8,\u03c6,r com andQ describes the configuration of the bath. In our calculations we represent the quantum vibration in terms of a basis set of eigen states of system Hamiltonian, i.e.\u0124 s |v = \u01eb v |v . We employ the approach of Martens and co-workers 35, 36, 37 and approximate the density associated with these vibrational basis states using two weighted \u03b4-functions. Thus we write the vibrational wave functions density as , which are state dependent, are fit to gas phase vibrational bond length moments 67 . Here we explore vibrational pure dephasing so h \u03b1\u03b2 for \u03b1 = \u03b2 are assumed to be small and the full Hamiltonian become\u015d", "cite_spans": [{"start": 576, "end": 578, "text": "67", "ref_id": "BIBREF66"}], "ref_spans": []}, {"section": "B. Computational Model", "text": "where the diagonal Hamiltonian matrix elements are obtained by summing interactions of the different bond length molecular representations with the environment", "cite_spans": [], "ref_spans": []}, {"section": "B. Computational Model", "text": "In our calculations we employed the Morse potential model of Martens and coworkers 35, 36, 37 to describe the I 2 vibrator and the interactions between the iodine atoms and the krypton particles as well as the solvent-solvent interactions are modeled using the Lennard-Jones potentials of these workers.", "cite_spans": [], "ref_spans": []}, {"section": "B. Computational Model", "text": "This Hamiltonian model is incorporated in Eq.(8) which gives that the reduced vibrational density matrix elements can be computed by averaging the basis state energy gap phase factor along a classical trajectory in which the environment moves on the mean potential surface produced by the two states involved in the coherence. In our studies the initial conditions for the environmental variables are sampled from either the classical distribution (as used in Marten's earlier work) or the FK approximation to the Wigner transform of the bath density matrix. In our implementation of this quantum initial condition sampling the rotor is fixed at the minimum energy orientation and center of mass position for the ground vibrational state and optimized solvent geometry. The solvent particle positions and momenta are then sampled from the approximate Wigner transform in the presence of the fixed rotor. This approach thus neglects the quantum rotational dispersion. The rotational dynamics, however is incorporated, as the system evolves on the mean potential surface using rigid rotor MD 68 with the weighted moment of inertia appearing in the second last term in Eq. (49) .", "cite_spans": [{"start": 1090, "end": 1092, "text": "68", "ref_id": "BIBREF67"}], "ref_spans": []}, {"section": "B. Computational Model", "text": "In our studies the iodine molecule replaces two krypton atoms in a double substitutional site in a 108 particle FCC lattice.", "cite_spans": [], "ref_spans": []}, {"section": "B. Computational Model", "text": "In implementing the FK sampling approach of Eq.(39) we perform regular Metropolis MC sampling of the centroid position and accept configurations based on the change in W trial . The solution of the variational equations was generally found to converge in a very small number of iterations, typically two or three. For each sampled centroid position we use gaussian sampling to generate 5 phase space points according to the FK approximate Wigner distribution which serve as trajectory initial conditions. All the results presented below have been averaged over 5000 independent trajectories.", "cite_spans": [], "ref_spans": []}, {"section": "C. Dephasing Time Results", "text": "In Fig. 4 we present results showing the time dependence of the off-diagonal elements (ground and excited state) of the reduced vibrational density matrix. As ex- pected the coherence decays extremely slowly for excitation of low energy superposition states. However, due to the disparate nature of the interactions between the ground state molecule with its environment and a highly excited molecule and its environment, the large fluctuations in energy gap between these states, in this situation, cause rapid decay of these off-diagonal density matrix elements.", "cite_spans": [], "ref_spans": [{"start": 3, "end": 9, "text": "Fig. 4", "ref_id": "FIGREF4"}]}, {"section": "C. Dephasing Time Results", "text": "We have extracted the dephasing rates from our linearized dynamics calculations of the reduced density matrix by fitting the long time behavior of the data in Fig. 4 to an exponential decay form. The computed dephasing rates, for classical and FK-Wigner initial condition sampling calculations are compared with the experimental results of Apkarian and co-workers 28, 29 in Fig. 5 . Here it is clear that at the higher temperatures, T=20K and 32K, (center and right hand panels) the nature of the initial condition sampling has little effect on the calculated dephasing rate and that these calculation results agree well with the experimental results. The fact that the results from FK-Wigner and classical initial condition sampling agree reasonably well at high temperatures suggests that our implementation of the FK-Wigner sampling approach is reliable.", "cite_spans": [], "ref_spans": [{"start": 159, "end": 165, "text": "Fig. 4", "ref_id": "FIGREF4"}]}, {"section": "C. Dephasing Time Results", "text": "At low temperatures, for example T=2.6K, however, (see left panel in Fig. 5 ) the approach used to sample initial conditions has a significant influence on the computed dephasing rates. The rates obtained with classical initial conditions are almost and order of magnitude smaller than the experimental dephasing rates observed at this low temperature. Dephasing rates obtained with the FK-Wigner sampling approach, however, are on the same order as experimental results and show a very similar increase in dephasing rate with vibrational state. As discussed in detail by Apkarian and co-workers 28, 29 , these low temperature experimental results presented in Fig.  5 are influenced by strain induced inhomogeneity of the trapping sites. They suggest that their results at the low quantum numbers are thus sensitive to sample preparation at these low temperatures. The fact that the slope of the experimental curve agrees well with our computed dephasing rates when FK-Wigner initial condition sampling is employed suggests that this approach is a reasonably accurate way of incorporating quantum dispersion effects in linearized path integral dynamics calculations.", "cite_spans": [], "ref_spans": []}, {"section": "C. Dephasing Time Results", "text": "While showing good qualitative behavior, generally the dephasing rates obtained with FK-Wigner sampling are about a factor of 2 too fast. This discrepancy could arise from two possible sources: First the use of the FK variational approach for approximating the Wigner transform means that the trial harmonic free energy is always larger than the true free energy. Thus the approach overestimates the effects of quantum fluctuations and dispersion which is essentially equivalent to a higher effective temperature and could result in too rapid dephasing. The second source of deviation is the semiclassical nature of the linearized dynamics in which classical trajectories are evolved over the mean surface from the approximate initial condition distribution.", "cite_spans": [], "ref_spans": []}, {"section": "C. Dephasing Time Results", "text": "In the next section we explore the reasons behind the difference between classical and FK-Wigner dephasing rates by comparing structural differences in the simulated environments.", "cite_spans": [], "ref_spans": []}, {"section": "D. Equilibrium Structure", "text": "In Fig. 6 we compare pair distributions computed with FK-Wigner equilibrium distribution sampling using Eq.(39) and results from classical Boltzmann distribution sampling in a pure Krypton crystal. At T=32K the classical and quantum pair distributions agree very closely, suggesting that the temperature is sufficiently high under these conditions that quantum effects are unimportant. These distributions provide initial conditions for the dynamics underlying the dephasing rate calculations. Thus the similarities in structure manifest themselves in similar dephasing rates as presented in the right panel of Fig.  5 . At T=2.6K, however, the classical pair distribution function is strongly peaked compared to the FK-Wigner result (see right panel in Fig. 6 ) so the distribution of trajectory energy gap fluctuations resulting from classical sampling will be narrow, leading to slow dephasing compared to the FK-Wigner result as discussed in connection with Fig. 5 .", "cite_spans": [], "ref_spans": []}, {"section": "D. Equilibrium Structure", "text": "In Fig. 7 we see that the quantum structure is fairly insensitive to a more than ten fold increase in temperature (T=2.6K to T=32K). The width of the pair distribution function peaks in this figure increase monotonically by about 20% over this temperature range. Figure 8 compares experimental and calculated dephasing rates which show comparable monotonic increases with increasing temperature over this range.", "cite_spans": [], "ref_spans": [{"start": 263, "end": 271, "text": "Figure 8", "ref_id": "FIGREF6"}]}, {"section": "IV. CONCLUSION", "text": "Approximate quantum dynamics methods which are based on combining path integral expressions for forward and backward propagators and linearizing in the difference between these paths provide a popular approach for incorporating some quantum effects with in a trajectory based framework. In this paper this type of approach has been implemented to study evolution of the off-diagonal elements of the vibrational density matrix which describe vibrational pure dephasing. In this approach trajectories of \"bath\" variables that influence the quantum subsystem evolve on the \"mean potential\" associated with the relevant states. This quasi-classical mean potential dynamics emerges naturally from the linearization theory which also gives a unique prescription for the initial conditions of these trajectories. With this approach the Wigner transform of the full quantum equilibrium density operator is found to provide the initial phase space distribution for the quasi-classical trajectories. In this paper we have explored the accuracy of various methods for obtaining approximations to this quantum initial density. Our measure of quality here is the reliability with which these different methods can reproduce vibrational pure dephasing dynamics over a range of temperatures. Thus, for example, we found that the classical initial phase space distribution gives pure dephasing rates that agree with experiments in higher temperature crystals. As a consistency check the FK-Wigner approach for approximately sampling the full quantum phase space distribution which is developed in detail in this paper gives results that also reproduce the experimental findings in these higher temperature solids. However, in low temperature solids we find that the classical initial phase space distribution combined with the quasi-classical dynamics can not reproduce the experimental dephasing dynamics. When the quasi-classical trajectory initial conditions, however, are sampled from the FK-Wigner approximate quantum equilibrium density excellent agreement between experimental and calculated dephasing rates is found.", "cite_spans": [], "ref_spans": []}, {"section": "IV. CONCLUSION", "text": "There has been considerable theoretical work exploring vibrational dephasing in condensed phases. For example, Zewail and co-workers give a detailed exposition of the perturbation theory results applied to the anharmonic oscillator in a harmonic bath model 1,2,3 . Skinner and coworkers explored dephasing for a model two level system coupled to a harmonic bath where they obtained nonperturbative results 4, 5, 6 . Generally when the Debye-like spectral density is employed in these different theoretical results the dephasing rates they predict have a very strong temperature dependence with \u03b3 \u223c T 7 . Similar sensitivity of dephasing rates to spectral density has been found in numerical simulations employing the stochastic classical trajectory approach 69,70 which ignores quantum effects. As discussed in section III our realistic microscopic model calculations, which make no assumptions about interaction strength, anharmonicity, or assump- tions about the nature of the underlying spectral density, and include quantum nuclear initial conditions effects, reproduce the very weak temperature dependence observed in the experiments. Increasing the temperature by about a factor of 10 (2.6K to 32K) results in a modest increase in dephasing by about a factor of two for most vibrational levels. Using their non-perturbative theory and a pseudo-local mode spectral density model which assumes that the vibrational dephasing occurs by coupling to low frequency modes that arise from, for example, hindered rotation and translation of the vibrating impurity in the crystal, Skinner and co-workers (and others 71, 72, 73, 74 ) obtained various Arrhenius like forms for the temperature dependence of the dephasing rate. Such forms are consistent with the much weaker temperature dependence that we find in our calculations and in the experiments. A \"back of the envelope\" estimate using a single Arrhenius form, and assuming a temperature independent preexponential factor gives an activation energy or pseudolocal mode frequency of about 20 cm \u22121 . In future work we will explore the nature of these pseudo-local modes responsible for this dephasing dynamics by examining the microscopic motions responsible for dephasing in our re- alistic simulation model 75 . The study of dephasing dynamics in condensed phase systems is just one example that highlights the importance of reliable methods for including quantum effects in condensed phase calculations. With in the framework of linearization these quantum effects are incorporated principally in the initial distribution sampling. At present there are no direct ways to generate the Wigner transform of the thermal density operator and sample the exact full quantum distribution. Thus all current methods for implementing linearized dynamics for general applications use local Harmonic approximations. As shown in section II B the FK-Wigner approach employs a thermodynamic variational calculation to parameterize a locally quadratic approximate form for the Euclidean action appearing in the partition function. This form is then employed to approximate the Wigner transform of the density operator. With such an approach no local harmonic approximation is made to the potential. Thus the method incorporates global information from the partition function integral in order to fit the gaussian approximate form for the density. This leads to a form for the density operator that contains frequencies computed from a gaussian smearing of the interactions which can be implemented in a very computationally efficient means.", "cite_spans": [], "ref_spans": []}, {"section": "IV. CONCLUSION", "text": "This situation is contrasted with that of alternative methods such as that of Shi and Geva 61 , in which a local Harmonic approximation to the bare potential is made. While these methods can use full PIMC calculations to accurately represent diagonal elements of the density matrix, using a local harmonic approximation for the off-diagonal elements can degrade the results. Thus the studies outlined in this paper suggest that the FKWigner approach is the method of choice for a balance of computational efficiency and accuracy.", "cite_spans": [], "ref_spans": []}, {"section": "Acknowledgments", "text": "This work was partially supported by a grant from the National Science Foundation (CHE-0616952). DFC acknowledges a travel grant from HPC-Europa and the hospitality of Prof. Ciccotti during his collaborative visit to the University of Rome, \"La Sapienza\". We also acknowledge a grant of supercomputer time from Boston University's office of information technology and scientific computing and visualization.", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX A: COMPUTATION OF POTENTIAL AVERAGES OVER TRIAL VARIATIONAL DISTRIBUTION", "text": "In order to apply the variational result in Eq.(20) the various potentials averaged over the trial density defined in Eqs. (21) - (23) must be computed. These calculations are most conveniently performed in Fourier space, thus we write", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX A: COMPUTATION OF POTENTIAL AVERAGES OVER TRIAL VARIATIONAL DISTRIBUTION", "text": "Further since R(\u03c4 ) = M \u22121/2 U\u03b7(\u03c4 ) we find that", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX A: COMPUTATION OF POTENTIAL AVERAGES OVER TRIAL VARIATIONAL DISTRIBUTION", "text": "The integrals over the real and imaginary parts of the \u03b7 nj can be performed analytically using the same result that lead to the expression in Eq. (27) , and the final result has the form", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX A: COMPUTATION OF POTENTIAL AVERAGES OVER TRIAL VARIATIONAL DISTRIBUTION", "text": "where we have used the following", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX A: COMPUTATION OF POTENTIAL AVERAGES OVER TRIAL VARIATIONAL DISTRIBUTION", "text": "defining the smearing width matrix A as", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX A: COMPUTATION OF POTENTIAL AVERAGES OVER TRIAL VARIATIONAL DISTRIBUTION", "text": "and defining V A (R c ) as follows, we see that", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX A: COMPUTATION OF POTENTIAL AVERAGES OVER TRIAL VARIATIONAL DISTRIBUTION", "text": "Using the Fourier convolution theorem (", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX A: COMPUTATION OF POTENTIAL AVERAGES OVER TRIAL VARIATIONAL DISTRIBUTION", "text": "we can write", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX A: COMPUTATION OF POTENTIAL AVERAGES OVER TRIAL VARIATIONAL DISTRIBUTION", "text": "so V A (R c ), defined above, can be interpreted as the Gaussian smeared potential since", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX A: COMPUTATION OF POTENTIAL AVERAGES OVER TRIAL VARIATIONAL DISTRIBUTION", "text": "We can compute the Gaussian smeared local harmonic approximate trial potential in a similar fashion obtaining", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX B: VARIATIONAL CALCULATION DETAILS", "text": "To simplify notation we define", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX B: VARIATIONAL CALCULATION DETAILS", "text": "and", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX B: VARIATIONAL CALCULATION DETAILS", "text": "so we can write", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX B: VARIATIONAL CALCULATION DETAILS", "text": "Following Feynman and Kleinert 55 we proceed to optimize the right hand side of Eq. (20) , f = exp[\u2212 1 S \u2212 S trial trial ]Z trial = e \u2212I/Z trial Z trial , with respect to the variational parameter functions K(R c ) and L(R c ). Here we have defined", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX B: VARIATIONAL CALCULATION DETAILS", "text": "and since, for example,", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX B: VARIATIONAL CALCULATION DETAILS", "text": "Where the partial derivative notation means regard the functional ", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX B: VARIATIONAL CALCULATION DETAILS", "text": "The only way to get both terms in the curly brackets in this expression for \u03b4 L f to vanish for arbitrary", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX B: VARIATIONAL CALCULATION DETAILS", "text": "is zero for each R c , giving the following local relationship between the parameter functions characterizing the extrema with respect to L", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX B: VARIATIONAL CALCULATION DETAILS", "text": "(B8) With this result I = 0, and we now must optimize", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX B: VARIATIONAL CALCULATION DETAILS", "text": "with respect to variations in the functions K with L fixed at L e . Now", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX B: VARIATIONAL CALCULATION DETAILS", "text": "and W trial for L = L e is obtained by substituting Eq.(B8) into Eq.(28) to give the following expression for the trial effective potential that depends only on the local curvature parameter matrix K", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX B: VARIATIONAL CALCULATION DETAILS", "text": "Functional optimization with respect to each of the functions K ij requires", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX B: VARIATIONAL CALCULATION DETAILS", "text": "For this to be true for arbitrary variation functions \u03b4K ij (R c ), (\u2202W trial /\u2202K ij )(R c ) must vanish locally for each function K ij . Since A is a complicated function of K given by Eq.(A5) we write W trial = W trial (K, A(K)) and apply the chain rule to obtain", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX B: VARIATIONAL CALCULATION DETAILS", "text": "After some straightforward manipulations we find that", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX B: VARIATIONAL CALCULATION DETAILS", "text": "1/2 and thus", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX B: VARIATIONAL CALCULATION DETAILS", "text": "Moreover, since", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX B: VARIATIONAL CALCULATION DETAILS", "text": "it is easily shown that", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX B: VARIATIONAL CALCULATION DETAILS", "text": "(B16) and thus the first term on the right hand side of Eq.(B12) vanishes identically using the results around Eq.(A5). Thus Eq.(B12) gives the optimization condition as (\u2202W trial /\u2202A ij ) K = 0, since in general \u2202A ij /\u2202K ij is nonzero.", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX B: VARIATIONAL CALCULATION DETAILS", "text": "Differentiating W trial with respect to a particular element of A keeping all others fixed (and pretending that K can be held fixed during this process consistent with the application of the chain rule) we find, using the Fourier space form of V A in Eq.(A7), that", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX B: VARIATIONAL CALCULATION DETAILS", "text": "Packing all these terms into a d\u00d7d matrix, the extremum condition requires that all elements are zero and the result can be written in matrix form as follows ", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX B: VARIATIONAL CALCULATION DETAILS", "text": "the remaining k m integral can be readily performed yielding the following expression for the 3\u00d73 K mn sub-matrix", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX B: VARIATIONAL CALCULATION DETAILS", "text": "Where u mn = (\u03b3 mn ) \u22121 (R cm \u2212 R cn ). This approach is readily simplified to compute V A (R c ). Proceeding in a similar fashion to that outlined above employing the kspace expression of Eq.(A7) we obtain With a = 2i\u03ba n /\u03b2 as in Eq.(D3), I has a Gaussian form in \u03ba n and the Gaussian integrals over these components in Eq.(D3) can be performed analytically. The final result of these manipulations is", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX B: VARIATIONAL CALCULATION DETAILS", "text": "Here we define the quantity \u03b1 i = coth \u03b2 \u03c9 i /2 \u2212 2/\u03b2 \u03c9 i (D6)", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX B: VARIATIONAL CALCULATION DETAILS", "text": "The above locally Gaussian form in the normal mode variables \u03b7 \u2032 , and \u03b7 \u2032\u2032 for the Boltzmann operator is particularly convenient for approximately evaluating thermally averaged time correlation functions in the linearized approximation 14, 20, 41 where quantities like Wigner transforms of products of operators of interest with the Boltzmann operator i.e.", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX B: VARIATIONAL CALCULATION DETAILS", "text": "(\u03c1 \u03b2\u00d4 ) W (Q, P ) = dz Q + z/2|\u03c1 \u03b2\u00d4 |Q \u2212 z/2 e \u2212 i P z (D7) are required. For simplicity we will focus on the Wigner transform of the Boltzmann operator itself. In the applications to computing linearized approximations to time correlation functions mentioned above the quantity (\u03c1 \u03b2\u00d4 ) W (Q, P ) serves both to provide a distribution for initial conditions for classical-like trajectories and includes the measurement of the initial operator. Depending on the nature of the initial operator\u00d4, the product Wigner transform may be dominated by the Wigner transform of the Boltzmann operator. This is the case in the applications to vibrational dephasing that we will report in a subsequent publication 76 as the operator in question just involves the vibrational states of the solute chromophore. The solvent initial degrees of freedom must thus be sampled from the Wigner transform of the solvent Boltzmann operator. Here we thus explore the accuracy of the Feynman-Kleinert approximation for the initial Wigner phase space distribution and the underlying approximation to the thermal density matrix. The Wigner transform of the trial Boltzmann operator written in the local normal mode phase space representation thus has the form (e ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF6": {"title": "Quantum Dissipative Systems", "authors": [{"first": "U", "middle": [], "last": "Weiss", "suffix": ""}], "year": 1999, "venue": "", "link": "118204109"}, "BIBREF56": {"title": "Path Integral Approach to Quantum Physics An Introduction", "authors": [{"first": "G", "middle": [], "last": "Roepstorff", "suffix": ""}], "year": 1994, "venue": "", "link": "118072389"}, "BIBREF57": {"title": "Path Integrals in Quantum Mechanics,Statistics, Polymer Physics, and Financial Markets", "authors": [{"first": "H", "middle": [], "last": "Kleinert", "suffix": ""}], "year": 2004, "venue": "", "link": "118272312"}, "BIBREF58": {"title": "Statistical Mechanics,a set of lectures", "authors": [{"first": "R", "middle": ["P"], "last": "Feynman", "suffix": ""}], "year": 1998, "venue": "", "link": "119359543"}, "BIBREF59": {"title": "Quantum mechanics and path integrals", "authors": [{"first": "R", "middle": ["P"], "last": "Feynman", "suffix": ""}, {"first": "A", "middle": ["R"], "last": "Hibbs", "suffix": ""}], "year": 1965, "venue": "", "link": "117361245"}, "BIBREF66": {"title": "Molecular Spectra and Molecular Structure I. Spectra of Diatomic Molecules (D. Van Noshtrand Company", "authors": [{"first": "G", "middle": [], "last": "Herzberg", "suffix": ""}], "year": 1950, "venue": "", "link": null}, "BIBREF67": {"title": "Computer Simulation of Liquids", "authors": [{"first": "M", "middle": ["P"], "last": "Allen", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Tildesley", "suffix": ""}], "year": 1987, "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Kleinert 55 and optimize the right hand side of Eq.(20), f = exp[\u2212 1 S \u2212 S trial trial ]Z trial ,with respect to the variational parameter functions K(R c ) and L(R c ). The details of this variational calculation are given in Ap- pendix B and it gives the following relationships between the different optimized parameters:", "type": "figure"}, "FIGREF1": {"text": "\u2212 \u03b7 ci are sampled from the component Gaus- sian distributions with variances \u03c3 Qi = (\u03b1 i /2\u03c9 i ) 1/2 and the set of M points in Cartesian space R (k) = R c + M \u22121/2 U(R c )\u03be (k) is generated to provide a sam- pling of initial configurations around the point R c . Simi- larly, Gaussian random numbers \u03b6 (k) i are sampled with variance \u03c3 P i = ( \u03c9 i /2 tanh(\u03b2 \u03c9 i /2)) 1/2 to provide a set of normal mode momentum vectors P (k)", "type": "figure"}, "FIGREF2": {"text": "FIG. 2: Left panel: Veneziano asymmetric double well potential. Right panel: Asymmetric double well density matrix, green surface is exact numerical calculation and red surface are results from FK approximation.", "type": "figure"}, "FIGREF4": {"text": "FIG. 4: Decay of various ground -excited state elements of the reduced vibrational density matrix of I2 in for solid krypton at T=2.6K obtained with FK Wigner initial condition sampling.", "type": "figure"}, "FIGREF5": {"text": "FIG. 5: Comparison of experimental and calculated vibrational pure dephasing rates as functions of vibrational quantum state. Each panel compares FK-Wigner and Classical initial condition sampling calculations with experimental results. The different panels report results for various temperatures: left panel, T=2.6K; center panel, T=20K; right panel, T=32K", "type": "figure"}, "FIGREF6": {"text": "FIG. 8: Comparison of experimental (left panel) and calculated (right panel) vibrational dephasing rates as functions of initial vibrational state superposition (0, \u03bd) for iodine in solid krypton.", "type": "figure"}, "FIGREF7": {"text": "limit n \u2192 \u221e as a multidimensional function of L evalu- ated at various points R i c , and differentiate with respect to L(R c ) at the point R c while keeping all other values of L(R \u2032 c = R c ), and the values of the functions K at all points fixed. Thus we find", "type": "figure"}, "FIGREF8": {"text": "the same manipulations based on the convolu- tion theorem that lead to the result in Eq.(A9) we obtainleft hand side of Eq.(B18) is conveniently evalu- ated in Fourier space if the interaction potential is pair- wise additive V (R) = i<j v ij (r ij ), and each pair func- tion of the inter-particle distance r ij = |R i \u2212 R j | is fit to a sum of Gaussians v ij (r ij ) = k ami ([A mimj + A ninj ] \u2212 [A minj + A nimj ])k mj ] Constructing the symmetric 3\u00d73 matrix \u03b3 nm for particles n and m with elements of the form \u03b3 nm xx = [A mxmx + A nxnx ] \u2212 [A mxnx + A nxmx ]= [A mxmy + A nxny ] \u2212 [A mxny + A nxmy ]", "type": "figure"}, "FIGREF9": {"text": "Tq (\u03c4 ) + L(q c ) + 1 2 (q(\u03c4 ) \u2212 q c ) T K(q c )(q(\u03c4 ) \u2212 q c )}] (D1) or writing the \u03b4-function in integral representation we havenormal mode vectors \u03b7 = U T q where U diagonalizes the variationally optimized local curvature matrix so that K(q c ) = U\u03c9 2 (q c )U T as in Eq.(25), and defining y(\u03c4 ) = (\u03b7(\u03c4 ) \u2212 \u03b7 c )", "type": "figure"}, "TABREF0": {"text": "am- plitude relaxation of the chosen vibrational basis states on the fast timescale of the fluctuations in the phases of the different component basis states. Thus we sup- pose that contributions to final state v N amplitude that originate from initial states v 0 , different from v N , are negligible and we approximate the above expression as |\u03c7 vN", "type": "table"}, "TABREF1": {"text": "we present our dephasing results for I 2 in solid krypton and compare with experiments in order to demonstrate the sensitivity of these type of calculations to the potential field used in the underlying dynamics. The calculation results presented in this fig- ure both use the FK-Wigner initial condition sampling approach detailed in the next section. The different sets of calculated dephasing rates presented here, however,", "type": "table"}, "TABREF2": {"text": "and Meier and Beswick 65,66 . Thus we write the Hamiltonian as\u0124 =\u0124 s +\u0124 b +\u0124 s\u2212b where\u0124", "type": "table"}}}
{"paper_id": "18989117", "_pdf_hash": "524fa93606fe6100f48a3e254d9051b518fa6df3", "abstract": [{"section": "Abstract", "text": "Background: Curcuma purpurascens BI. is a medicinal plant from the Zingiberaceae family, which is widely used as a spice and as folk medicine. The aim of the present study is to investigate the gastroprotective activity of C. purpurascens rhizome hexane extract (CPRHE) against ethanol-induced gastric ulcers in rats.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Methods: Acute toxicity test was carried out on 36 rats (18 males and 18 females) with low dose of CPRHE (1 g/kg), high dose of CPRHE (2 g/kg) and vehicle (5% Tween 20). To determine the gastroprotective effect of CPRHE, gastric juice acidity, gross and histological gastric lesions, mucus content and ulcer index were evaluated in ethanol-induced ulcer in rats. In addition, superoxide dismutase activity, nitric oxide level and immunohistochemical evaluation of Bax and HSP70 proteins were examined.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "The CPRHE acute toxicity test on rats did not reveal any signs of mortality and toxicity up to 2 g/kg. The oral administration of CPRHE at doses of 200 mg/kg and 400 mg/kg and omeprazole (positive control) at a dose of 20 mg/kg to rats remarkably attenuated gastric lesions induced by ethanol. Pre-treatment of rats with CPRHE significantly replenished the depletion of mucus content caused by ethanol administration and decreased the acidity of gastric walls. Further examination of gastric mucosal homogenate revealed significant elevation of superoxide dismutase and nitric oxide activities and reduction in malondialdehyde level in CPRHE-treated group, compared to the lesion control group. Histological assessment of gastric walls obtained from rats pre-treated with CPRHE demonstrated a noteworthy decrease in hemorrhagic mucosal lesions. Immunohistochemical staining showed down-regulation of Bax protein and up-regulation of Hsp70 protein.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Conclusion: Taken together, these findings confirmed the gastroprotective effect of Curcuma purpurascens rhizome against gastric damage.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Background", "text": "Ulcer is a lesion or open sore which generally pertains to the mucous membrane or skin of the body. In the digestive system, peptic ulcer in the lining of the duodenum or stomach is an irritating disease which has afflicted a noticeable proportion of the world population [1] . The disruption in the protective effect of the stomach mucosa against gastric acid is a common cause of peptic ulcer [2] . Studies have shown that the etiology of this disorder is related to cigarette smoking, stress, infections, nutritional deficiencies and alcohol consumption [3] . Helicobacter pylori infection in particular, contributes to the occurrence of 90% of duodenal ulcers and 80% of gastric ulcers [4] . In addition, the administration of non-steroidal anti-inflammatory drugs remains as one of the drug-related causes of peptic ulcer disease [5] . In recent years, exposure of human to a variety of noxious chemicals and agents has significantly elevated the risk of gastric attacks [6] . Numerous anti-ulcer agents, which are presently being used in the market, exhibit limited efficacy and considerable severe side effects on the human body [7] . Therefore, screening for new agents capable of treating peptic ulcers needs to continue in order to find compounds with reduced side effects while maintaining high-therapeutic efficacy.", "cite_spans": [{"start": 272, "end": 275, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 395, "end": 398, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 557, "end": 560, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 690, "end": 693, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 835, "end": 838, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 976, "end": 979, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 1136, "end": 1139, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Background", "text": "Development of pharmaceutical products relies substantially on nutraceuticals, including an extensive range of categories such as spices, herbal products, dietary supplements and functional foods [8] . Numerous plants from a variety of taxonomic families have been studied for their anti-ulcer activities [5, [9] [10] [11] . One such taxonomic family with extensive medicinal uses against gastric mucosal lesions is Zingiberaceae. Numerous plant species in this family, such as Boesenbergia rotunda [9] , Curcuma longa [12] , Zingiber officinale [7] , Alpinia galanga [13] and Elettaria cardamomum [14] have been elucidated for their gastroprotective properties.", "cite_spans": [{"start": 196, "end": 199, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 305, "end": 308, "text": "[5,", "ref_id": "BIBREF4"}, {"start": 309, "end": 312, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 313, "end": 317, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 318, "end": 322, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 499, "end": 502, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 519, "end": 523, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 546, "end": 549, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 568, "end": 572, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 598, "end": 602, "text": "[14]", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Background", "text": "Curcuma purpurascens BI. is a member of the Zingiberaceae family. This plant originally grew in Indonesia and its rhizome is used as a spice [15] . The C. purpurascens plant commonly known also as \"Temu tis\" and \"Koneng tinggang\" has been reported to have extensive traditional uses in rural communities, similar to other curcuma species [15, 16] . Rhizome of this plant has been used in folk medicine for the treatment of wounds, scabies, itch, fever, cough and boils. The mixture of the rhizomes with Alyxia stellata is used as a poultice after childbirth [15] . Despite these traditional applications, there is no scientific investigation for the potential bioactivities of this plant. Since natural products with a long history of folk application can provide new therapeutic approaches for the treatment of various diseases and ailments [17] , the current study is conducted to evaluate the acute toxicity and gastroprotective activity of the C. purpurascens rhizome against ethanol-induced ulceration in rats.", "cite_spans": [{"start": 141, "end": 145, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 338, "end": 342, "text": "[15,", "ref_id": "BIBREF14"}, {"start": 343, "end": 346, "text": "16]", "ref_id": "BIBREF15"}, {"start": 558, "end": 562, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 842, "end": 846, "text": "[17]", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Chemical and drugs", "text": "In this study, omeprazole as the reference anti-ulcer medicine was obtained from the University of Malaya Medical Center and dissolved in 10% Tween 20 (Merck, Germany). A dilution of Tween 20 (5% v/v) was used as the vehicle.", "cite_spans": [], "ref_spans": []}, {"section": "Sample collection", "text": "The C. purpurascens rhizome was collected from Yogyakarta, Indonesia. The botanical identification was made by Mr. Teo Leong Eng., Faculty of Science, University of Malaya. A voucher specimen KL 5793 was deposited in the herbarium of the Department of Chemistry, Faculty of Science, University of Malaya, Kuala Lumpur, Malaysia.", "cite_spans": [], "ref_spans": []}, {"section": "Preparation of the extract", "text": "The air-dried and powdered rhizomes (1.0 kg) were macerated with n-hexane at room temperature for three days. The resulting filtrate of the rhizome was concentrated by a rotary evaporator at 40\u00b0C and stored at \u221220\u00b0C until use. The C. purpurascens rhizome hexane extract (CPRHE) was dissolved in carboxymethylcellulose for in vivo animal study.", "cite_spans": [], "ref_spans": []}, {"section": "Gas chromatography of CPRHE", "text": "The analysis of the hexane extract was performed using an Agilent and LECO RESTEK, Rxi-5MS capillary column (30 m, 0.25 mm i.d., 0.25 \u03bcm film thickness) and a mass spectrometer Pengasus HT High Throughput TOFMS, as previously described [18] . Compounds were identified from their mass spectra, by comparison of the retention times of peaks with interpretation of MS fragmentation patterns from data library.", "cite_spans": [], "ref_spans": []}, {"section": "Animals and ethical issues", "text": "Healthy female and male Sprague Dawley rats (150-180 g, 6-8 weeks old) were obtained from the Animal Experimental Unit, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia. The animals were housed in an isolated cabin under controlled conditions of temperature (~24\u00b0C), humidity (~50%) and light (a daily ratio of 1:1). The animals were allowed access to standard rat pellets and RO water. All the animal experiments were carried out in compliance with the National Institutes of Health Guide for the care and use of Laboratory Animals and with the prior approval from the committee of Animal House, Faculty of Medicine, University of Malaya (Ethics No. 2014-03-05/ PHAR/R/ER).", "cite_spans": [], "ref_spans": []}, {"section": "Acute toxicity study", "text": "To determine a safe range of doses for CPRHE, toxicity evaluation of CPRHE was carried out as previously described [19] . In brief, 36 rats, including 18 males and 18 females were divided into three groups labeled as the vehicle (5% Tween 20), low dose of CPRHE (1 g/kg) and high dose of CPRHE (2 g/kg). The rats were fasted for 16 h prior to the dosing (water was accessible except for the last 2 h). Following the dosing, food was withheld for another 1 to 3 h. Any other signs of toxicities and mortality were further recorded during the period of two weeks. On day 15, the animals were sacrificed for hematological and histological analysis.", "cite_spans": [{"start": 115, "end": 119, "text": "[19]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "Ethanol-induced gastric ulceration", "text": "The preventive potential of CPRHE against superficial hemorrhagic mucosal lesions were investigated in the normal rats. Prior to the experiment, Sprague Dawley male rats were fasted for 24 h (water was accessible except for the last 2 h). Thirty rats were divided randomly into 5 groups of 6 rats each and pre-treated accordingly ( Table 1 ). After 1 h of pre-treatment, all the rats were gavaged with 5% Tween 20 (5 ml/kg) or absolute ethanol (5 ml/kg) based on the animal experimental design. The rats were sacrificed 1 h later with an over-dose of xylazine and ketamine and their stomachs were immediately excised.", "cite_spans": [], "ref_spans": [{"start": 332, "end": 339, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Determination of the loss in mucosal content and gastric juice acidity", "text": "The stomach of each rat was dissected along the greater curvature, and pH-meter titration with 0.1 N NaOH was used to analyze the hydrogen ion concentration in the gastric contents expressed in mEq/I value. Then, a glass slide was applied to gently scrape the gastric mucosa of the rats followed by the weighing of the obtained mucus with a precision electronic balance.", "cite_spans": [], "ref_spans": []}, {"section": "Macroscopic analysis of lesions", "text": "In accordance with several studies, ethanol-induced ulcers on the gastric mucosa were characterized as elongated bands of hemorrhagic lesions parallel to the long axis of the stomach [11, 20] . The hemorrhagic damage of the stomach was determined by assessment of luminal surface. The protective potential (P%) of each pre-treatment was calculated using a planimeter (10 \u00d7 10 mm 2 ) and dissecting microscope (1.8\u00d7) where UC and UT were the ulcer area of the control and treated group, respectively. The measurement of ulcer area was performed as previously described in detail by Abdelwahab et al. [9] .", "cite_spans": [{"start": 183, "end": 187, "text": "[11,", "ref_id": "BIBREF10"}, {"start": 188, "end": 191, "text": "20]", "ref_id": "BIBREF20"}, {"start": 599, "end": 602, "text": "[9]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Histological evaluation of gastric lesions", "text": "Histological analysis of the specimens of the gastric walls was carried out using 10% buffered formalin for the fixation. The samples were embedded in paraffin followed by the 5 \u03bcm sectioning and staining with hematoxylin and eosin.", "cite_spans": [], "ref_spans": []}, {"section": "Determination of lipid peroxidation activity using the thiobarbituric acid reactive substance assay", "text": "To measure malondialdehyde (MDA) concentration, we carried out thiobarbituric acid reactive substance (TBARS) assay as described previously [21] . In brief, the homogenated stomach (10% w/v) in 0.1 mol/l PBS was centrifuged at 4\u00b0C for 10 min. Then, the supernatant (3 ml) was mixed with 20% trichloroacetic acid solution and 0.67% 2-thiobarbituric acid followed by heating in a water-bath (95\u00b0C) for 30 min. Next, the MDA concentration of the obtained supernatant was determined spectrophotometrically at 532 nm. The protein concentrations were expressed as MDA \u03bcmol/g protein using the Lowry method [22] .", "cite_spans": [{"start": 140, "end": 144, "text": "[21]", "ref_id": "BIBREF21"}, {"start": 600, "end": 604, "text": "[22]", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "Determination of superoxide dismutase (SOD) activity", "text": "The activity of SOD enzyme was estimated by determining its potential to suppress the photochemical reaction of NBT (nitroblue tetrazolium), as previously described by Sun and colleagues [23] . In this assay, the homogenated tissues were centrifuged twice at 4\u00b0C for 10 and 20 min. In a dark chamber, the reactant (1 ml, 50 mM phosphate buffer, 100 nM EDTA and 13 mM l-methionine, pH 7.8) was mixed with the resulting supernatant (30 \u03bcl), NBT (150 \u03bcl, 75 \u03bcM) and riboflavin (300 \u03bcl, 2 \u03bcM). The resulting solution was exposed to fluorescent light bulbs (15 W) for 15 min and the absorbance was determined at 560 nm wavelength using a spectrophotometer. ", "cite_spans": [{"start": 187, "end": 191, "text": "[23]", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Nitric oxide level", "text": "To evaluate the effect of CPRHE on nitric oxide (NO) generation in the gastrointestinal tract, Griess reaction was used to determine total nitrite/nitrate levels, as previously described by Tsikas and colleagues [24] . In brief, the supernatant (50 \u03bcl) of the homogenated stomach was mixed with the Griess reagent. After 10 min, the subsequent colorimetric analysis was carried out at 540 nm using a Tecan Infinite 200 Pro microplate reader (Tecan, M\u00e4nnedorf, Switzerland). The generated NO in the culture supernatant was determined using a standard curve of sodium nitrite and results were expressed as \u03bcmoles nitrite/nitrate per gram of protein.", "cite_spans": [{"start": 212, "end": 216, "text": "[24]", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Immunohistochemical evaluation", "text": "Immunohistochemical analysis of Bax and HSP70 proteins was carried out as previously described with some modifications [25] . In brief, tissues were paraffinized in xylene and rehydrated using graded alcohol. The boiling sodium citrate buffer (10 mM) was used for antigen retrieval process followed by immunohistochemical staining according to the manufacture's instruction (Dakocytomation, USA). After blocking the endogenous peroxidase with peroxidase block, Bax (1:200) or Hsp70 (1:500) biotinylated primary antibodies were applied and the sections were incubated for 15 min. Next, sections were incubated with the appropriate amount of streptavidin-HRP for 15 min. Next, the sections were exposed to diaminobenzidine substratechromagen for 5 s, then dipped in weak ammonia (0.037 mol/L) for ten times. Brown stains on the slides indicated positive findings of the immunohistochemical staining as observed under a light microscope.", "cite_spans": [{"start": 119, "end": 123, "text": "[25]", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "Statistical analysis", "text": "All values were reported as mean \u00b1 SD. The statistical significant differences between groups were determined using one-way ANOVA followed by post hoc Tukey's multiple comparison test. A value of p <0.05 was considered significant.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Gas chromatography profile of CPRHE", "text": "As shown in Figure 1 , the hexane extract was characterized by use of GC-MS-TOF. The chromatogram showed that the major compounds in CPRHE are c-elemene (1), benzofuran, 6-ethenyl-4,5,6,7-tetrahydro-3,6-dimethyl-5isopropenyl (2), 3,7-cyclodecadien-1-one,3,7-dimethyl-10-(1-methylethylidene) (3), turmerone (4) and curlone (5) ( Table 2) .", "cite_spans": [], "ref_spans": [{"start": 12, "end": 20, "text": "Figure 1", "ref_id": "FIGREF0"}, {"start": 328, "end": 336, "text": "Table 2)", "ref_id": "TABREF1"}]}, {"section": "Acute toxicity study", "text": "In the acute toxicity study, all rats survived and did not manifest any sign of toxicity and abnormality at 1 and 2 g/kg dosage. For a duration of 14 days, there was no behavioral or body weight changes and no abnormal signs were observed. As shown in Table 3 , the serum biochemical parameters were reported to be normal. Hematological analysis of kidney and liver did not elicit any noteworthy changes in the treated group compared to the control group (Figure 2) . The 50% oral lethal dose (LD 50 ) for the male and female rats was greater than 2 g/kg body weight.", "cite_spans": [], "ref_spans": [{"start": 252, "end": 259, "text": "Table 3", "ref_id": "TABREF2"}]}, {"section": "pH of gastric content and determination of mucus production", "text": "The acidity of gastric content in rodents administered orally with ethanol was significantly increased compared to the normal control group, as shown in Table. 4. After treatment with omeprazole (positive control), the acidity was significantly attenuated (P <0.05) and animals pretreated with CPRHE at high dose and low dose elicited significant (P <0.05) elevation of pH. The gastric mucus content was significantly depleted in animals pre-treated with ethanol. Meanwhile, omeprazole and CPRHE treatment significantly replenished the loss in mucosal content P <0.05, Table 4 ). The findings of both parameters suggested the anti-ulcer effect of CPRHE.", "cite_spans": [], "ref_spans": [{"start": 569, "end": 576, "text": "Table 4", "ref_id": "TABREF3"}]}, {"section": "Macroscopic evaluation of gastric lesions", "text": "The administration of ethanol to the rats induced noticeable black hemorrhagic lesions in the gastric walls ( Figure 3B ) with ulcer area of 880 \u00b1 16.23 (mm) 2 ( Table 4 ). As shown in Figure 3 , rodents pre-treated with CPRHE ( Figure 3D and E) and omeprazole ( Figure 3C ) had markedly reduced areas of gastric ulcer formation in comparison with lesion control group ( Figure 3B ). Pretreatment of rats with CPRHE at doses of 200 mg/kg and 400 mg/kg suppressed the ulcer area formation to 455 \u00b1 12.24 (mm) 2 and 325 \u00b1 10.67 (mm) 2 , which was comparable to the suppressive effect of omeprazole 195 \u00b1 8.97 (mm) 2 . The incidence of ulcer was decreased by 48% and 63% after treatment with CPRHE at doses of 200 mg/kg and 400 mg/kg, respectively (Table 4 ). It is worthy to note that CPRHE treatment helped to flatten the gastric mucosal folds in rodents ( Figure 3D and E).", "cite_spans": [], "ref_spans": [{"start": 110, "end": 119, "text": "Figure 3B", "ref_id": "FIGREF1"}, {"start": 162, "end": 169, "text": "Table 4", "ref_id": "TABREF3"}, {"start": 185, "end": 193, "text": "Figure 3", "ref_id": "FIGREF1"}, {"start": 229, "end": 238, "text": "Figure 3D", "ref_id": "FIGREF1"}, {"start": 263, "end": 272, "text": "Figure 3C", "ref_id": "FIGREF1"}, {"start": 371, "end": 380, "text": "Figure 3B", "ref_id": "FIGREF1"}, {"start": 745, "end": 753, "text": "(Table 4", "ref_id": "TABREF3"}, {"start": 856, "end": 865, "text": "Figure 3D", "ref_id": "FIGREF1"}]}, {"section": "Histological assessment of gastric lesions", "text": "Microscopic analysis of the gastric lesions in the ulcer control group elicited extensive damage to the gastric mucosa of the rodents characterized by disrupted surface epithelium and deeply penetrated necrotic lesions into mucosa associated with conspicuous leucocytes infiltration and severe edema of submucosal layer ( Figure 4B ). Pretreatment with CPRHE ( Figure 4D and E) and omeprazole ( Figure 4C ) revealed a protective effect by reduction in leucocytes infiltration and submucosal edema. The replenishment of the loss in mucus content by CPRHE was evidenced by the stumpy amount of magenta color in the histological analysis as compared to the control group ( Figure 4D and E) . The results showed that CPRHE pre-treatment at high dose and low dose markedly disrupted ethanol-induced destruction of gastric mucosa.", "cite_spans": [], "ref_spans": [{"start": 322, "end": 331, "text": "Figure 4B", "ref_id": "FIGREF3"}, {"start": 361, "end": 370, "text": "Figure 4D", "ref_id": "FIGREF3"}, {"start": 395, "end": 404, "text": "Figure 4C", "ref_id": "FIGREF3"}, {"start": 670, "end": 686, "text": "Figure 4D and E)", "ref_id": "FIGREF3"}]}, {"section": "Assessment of stomach malondialdehyde and superoxide dismutase", "text": "To determine the effects on lipid peroxidation and oxidative stress, we determined the level of MDA in gastric tissue homogenate. After treatment with ethanol, the MDA level (28 \u00b1 2.98 \u03bcmol/g) was significantly (P <0.05) elevated compared to the normal control group (10 \u00b1 1.1 \u03bcmol/g).", "cite_spans": [], "ref_spans": []}, {"section": "Assessment of stomach malondialdehyde and superoxide dismutase", "text": "The results showed that administration of CPRHE and omeprazole before ethanol significantly (P <0.05) decreased the MDA level compared to the lesion control group (Table 4 ). Ethanol treated rodents elicited a significantly lower SOD activity compared to the normal control group (P <0.05), which was elevated upon treatment with CPRHE ( Table 4 ).", "cite_spans": [], "ref_spans": [{"start": 163, "end": 171, "text": "(Table 4", "ref_id": "TABREF3"}, {"start": 338, "end": 345, "text": "Table 4", "ref_id": "TABREF3"}]}, {"section": "Assessment of nitric oxide level", "text": "The perturbation in nitric oxide levels of the stomach was investigated using Griess reagent, as shown in Table 4 .", "cite_spans": [], "ref_spans": [{"start": 106, "end": 113, "text": "Table 4", "ref_id": "TABREF3"}]}, {"section": "Assessment of nitric oxide level", "text": "In gastric tissue homogenate, the nitric oxide level in lesion control group was markedly (P <0.05) lower (5.9 \u00b1 0.47 \u03bcmol/g protein) compared to the normal control group (10 \u00b1 1.3 \u03bcmol/g protein). Administration of CPRHE significantly (P <0.05) elevated nitric oxide level, which was comparable to the nitric oxidegeneration effect of omeprazole.", "cite_spans": [], "ref_spans": []}, {"section": "Immunohistochemistry", "text": "Immunohistochemical analysis of the gastric injuries revealed that pre-treatment with CPRHE at the doses of 200 mg/kg and 400 mg/kg caused conspicuous upregulation of Hsp70 protein when compared with the ulcer control group ( Figure 5 ). In addition, the expression of Hsp70 in normal control group was relatively higher than the expression in ulcer control group. Immunohistochemical examination of Bax protein indicated a downregulation of this protein after administration of CPRHE and omeprazole. Meanwhile, the expression of Bax was up-regulated in ulcer control group in comparison with normal control group.", "cite_spans": [], "ref_spans": [{"start": 226, "end": 234, "text": "Figure 5", "ref_id": "FIGREF2"}]}, {"section": "Discussion", "text": "Numerous species of Zingiberaceae family, such as Curcuma phaeocaulis, Curcuma longa, Amomum villosum, Zingiber officinale, Alpinia oxyphylla and Alpinia officinarum are used as folk medicine by the natives from various countries. Traditional uses and scientific inspections of these plants have confirmed the safety of these plants as complementary medicine [26] [27] [28] [29] . In the present study, the acute toxicity of C. purpurascens was evaluated in rats. Our findings showed no sign of renal or hepatic toxicity as investigated by biochemical and histological analysis.", "cite_spans": [{"start": 359, "end": 363, "text": "[26]", "ref_id": "BIBREF26"}, {"start": 364, "end": 368, "text": "[27]", "ref_id": "BIBREF27"}, {"start": 369, "end": 373, "text": "[28]", "ref_id": "BIBREF28"}, {"start": 374, "end": 378, "text": "[29]", "ref_id": "BIBREF29"}], "ref_spans": []}, {"section": "Discussion", "text": "One of the contributing factors in gastric ulcer formation is ethanol. Due to the rapid penetration of ethanol into the gastric mucosa, it is widely utilized to induce experimental gastric ulcer in numerous in vivo studies [29] [30] [31] . The elevation in mucosal permeability and release of vasoactive products by ethanol result in vascular damage and gastric cell necrosis prior to the ulcer formation. Furthermore, it is believed that the generation Figure 2 Histological sections. Histopathology of kidney (first row) and liver (second row) in acute toxicity study representing the rats treated with vehicle (5% Tween 20), CPRHE (1 g/kg) and CPRHE (2 g/kg). The result did not show significant differences in the structures of kidney and liver between treated and control groups (20\u00d7 magnifications). Values expressed as mean \u00b1 SEM. ALT, alanine aminotransferase; AST, aspartate aminotransferase; AP, alkaline phosphatase; CB, conjugated bilirubin; GGT: G-glutamyl transferase; HCT, hematocrit; HGB, hemoglobin; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; MCV, mean corpuscular volume; RBC, red cell count; RDW, red cell distribution width; TB: total bilirubin; WBC, white cell. The results did not show any significant difference between groups.", "cite_spans": [{"start": 223, "end": 227, "text": "[29]", "ref_id": "BIBREF29"}, {"start": 228, "end": 232, "text": "[30]", "ref_id": "BIBREF30"}, {"start": 233, "end": 237, "text": "[31]", "ref_id": "BIBREF31"}], "ref_spans": []}, {"section": "Discussion", "text": "of reactive oxygen species (ROS) by ethanol has a significant role in ulcer formation [32] . Therefore, in our study, the administration of ethanol to rats was used to induce gastric lesions. Our findings in this study showed that CPRHE can effectively suppress gastric acidity and also suppress the destruction of gastric wall mucus. It was reported earlier that herbal products could elevate the gastro-defensive system, especially gastric wall mucus secretion in patients with gastric ulcer [33] . The depletion of mucus secretion is one of the pathogenic mechanisms accountable for gastric mucosal erosions [34] . Previous studies have explained the close correlation between suppression of gastric acidity and effectiveness of treatment. The ability to attenuate the gastric acid secretion is considered to be the mainstay of treatment for gastric ulceration [35, 36] . One of the standard drug, omeprazole, has shown remarkable healing rates among patients with peptic ulcer because of its ability to minimize the degree of gastric acidity through inhibition of the proton pump [37] .", "cite_spans": [{"start": 86, "end": 90, "text": "[32]", "ref_id": "BIBREF32"}, {"start": 494, "end": 498, "text": "[33]", "ref_id": "BIBREF33"}, {"start": 611, "end": 615, "text": "[34]", "ref_id": "BIBREF34"}, {"start": 864, "end": 868, "text": "[35,", "ref_id": "BIBREF35"}, {"start": 869, "end": 872, "text": "36]", "ref_id": "BIBREF36"}, {"start": 1084, "end": 1088, "text": "[37]", "ref_id": "BIBREF37"}], "ref_spans": []}, {"section": "Discussion", "text": "The perturbation in balance between gastro-protective mechanisms and gastrotoxicity of different agents is the basis of acute inflammation and secretion of several proinflammatory cytokines [38] . It is reported earlier that acute inflammation induced by ethanol is accompanied by neutrophils infiltration of gastric wall mucus [39] . As shown in Figure 4 , our results demonstrated that submucosal infiltration was effectively suppressed by pre-treatment of rats with CPRHE. An extensive generation of ROS and free radicals causes metabolic impairments and irreversible cell damages in the human body [40] . As such, protecting the gastric tissue from oxidative damages can provide successful treatment approaches by natural products against ulcer formation [41] . Superoxide dismutase by converting the superoxide to hydrogen peroxide has a critical role in this protecting effect [42] . Superoxide radical anions such as ROS are generated by neutrophils, which results in the reaction with cellular lipids and the production of lipid peroxides [43] . An effective indicator of oxidative stress and mucosal injuries by ROS is malondialdehyde (MDA), which is a major metabolite of lipid peroxidation [44] . This is the first study to show that oral administration of CPRHE could protect against gastric ulceration by elevating superoxide dismutase activity, which is reflected by decreased MDA production.", "cite_spans": [{"start": 190, "end": 194, "text": "[38]", "ref_id": "BIBREF38"}, {"start": 328, "end": 332, "text": "[39]", "ref_id": "BIBREF39"}, {"start": 602, "end": 606, "text": "[40]", "ref_id": "BIBREF40"}, {"start": 759, "end": 763, "text": "[41]", "ref_id": "BIBREF41"}, {"start": 883, "end": 887, "text": "[42]", "ref_id": "BIBREF42"}, {"start": 1047, "end": 1051, "text": "[43]", "ref_id": "BIBREF43"}, {"start": 1201, "end": 1205, "text": "[44]", "ref_id": "BIBREF44"}], "ref_spans": [{"start": 347, "end": 355, "text": "Figure 4", "ref_id": "FIGREF3"}]}, {"section": "Discussion", "text": "In our study, the NO level is significantly increased after pre-treatment with CPRHE. The important role of NO synthesis for the gastroprotective system and effectiveness of anti-ulcer agents has been elucidated earlier [45] . It has been shown that suppression of NO pathway by L-NAME markedly inhibited the gastroprotective activity of several anti-ulcer medications. Furthermore, formation of ethanol-induced gastric lesions is remarkably abolished by NO-stimulating drugs. Meanwhile, reduction in NO synthesis can increase the susceptibility of the gastric mucosa to the destructive effects of ethanol [46, 47] . Therefore, increasing NO level by CPRHE treatment is beneficial in alleviating ethanol-induced gastric wall destruction as shown in this study. Our findings showed that administration of CPRHE to rats induced the up-regulation of Hsp70 protein associated with down-regulation of Bax protein. Hsp70 is a 70 kDa protein which belongs to the heat shock protein family. This protein is abundantly produced in response to various forms of stress, such as toxic agents, oxidative stress, infection and heat shock [48] . It is well known that the ethanol-triggered generation of ROS could suppress Hsp70 expression and intensifies the oxidative damages [49] . Hence, natural products with the ability to induce the over-expression of Hsp70 may provide higher threshold of protection against gastric lesions [50] . Previous studies have demonstrated that the suppression of Bax expression or its dysfunction can protect cells against programmed cell death through prevention of cytochrome c release from mitochondria to cytosol. A variety of stimuli, including heat, radiation and excessive production of ROS cause the dimerization of Bax protein and translocation to the outer mitochondrial membrane, which trigger cytochrome c release [51] [52] [53] . In our study, suppression of ROS production induced by CPRHE seems to be the reason for the attenuation of Bax expression.", "cite_spans": [{"start": 220, "end": 224, "text": "[45]", "ref_id": "BIBREF45"}, {"start": 606, "end": 610, "text": "[46,", "ref_id": "BIBREF46"}, {"start": 611, "end": 614, "text": "47]", "ref_id": "BIBREF47"}, {"start": 1124, "end": 1128, "text": "[48]", "ref_id": "BIBREF48"}, {"start": 1263, "end": 1267, "text": "[49]", "ref_id": "BIBREF49"}, {"start": 1417, "end": 1421, "text": "[50]", "ref_id": "BIBREF50"}, {"start": 1846, "end": 1850, "text": "[51]", "ref_id": "BIBREF51"}, {"start": 1851, "end": 1855, "text": "[52]", "ref_id": "BIBREF52"}, {"start": 1856, "end": 1860, "text": "[53]", "ref_id": "BIBREF53"}], "ref_spans": []}, {"section": "Discussion", "text": "Previous study done using Curcuma longa showed that hexane soluble fraction of the rhizome was effective against HCl-induced peptic ulcer, while the hexane non-soluble fraction was inactive [54] . Therefore, in this study, the hexane extract was used to investigate the anti-ulcer potential of C. purpurascens rhizome. Furthermore, gas chromatography profile of CPRHE suggested the presence of turmerone as the major active compound. Turmerone is an active constituent with powerful antioxidant activity, which has been previously isolated from other Curcuma species [55] . A previous clinical trial suggested that turmerone is responsible for the anti-ulcer effect of C. longa [12] . However, insufficient research studies on the photochemistry of this spice could not provide enough evidence to confirm the major role of turmerone for the observed anti-ulcer effect.", "cite_spans": [{"start": 190, "end": 194, "text": "[54]", "ref_id": "BIBREF54"}, {"start": 567, "end": 571, "text": "[55]", "ref_id": "BIBREF55"}, {"start": 678, "end": 682, "text": "[12]", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "Conclusions", "text": "The present study elucidated the anti-ulcer effect of C. purpurascens rhizome against ethanol-induced gastric lesions. The gastroprotective mechanism of CPRHE was achieved by increasing SOD and NO levels, which in turn suppressed gastric acidity and prevented the destruction of the gastric mucus wall. Immunohistochemistry analysis of gastric homogenate elicited the critical role of Bax down-regulation and Hsp70 up-regulation. In addition, the acute toxicity test of CPRHE provided useful information regarding the safety of this traditional medicinal plant. Further investigation on the active phytochemical constituents contributing to the gastroprotective activity is undergoing in our laboratory to identify potential anti-ulcer agent in CPRHE. 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The chromatogram showed the chemical constituents of C. purpurascens hexane extract.", "type": "figure"}, "FIGREF1": {"text": "Gross evaluation. Results demonstrated that the rodents pre-treated with (C) omeprazole and CPRHE at doses of (D) 200 mg/kg and (E) 400 mg/kg had conspicuously decreased area of gastric ulcer formation compared to (B) ulcer control. (A) Normal control group demonstrated no gastric lesion formation.", "type": "figure"}, "FIGREF2": {"text": "Immunohistochemical examination of Hsp70 (first row) and Bax (second row). The results depicted the down-regulation of Bax and up-regulation of Hsp70 proteins in rats pre-treated with (C) omeprazole and CPRHE at the doses of (D) 200 mg/kg and (E) 400 mg/kg compared to the (B) lesion control group. (A) Normal control group demonstrated normal Immunohistochemical structure.", "type": "figure"}, "FIGREF3": {"text": "Histological evaluation. Histopathology of rodents pre-treated with (C) omeprazole or CPRHE at the doses of (D) 200 mg/kg and (E) 400 mg/kg compared to the (B) lesion control group. (A) Normal control group demonstrated normal histological structure. (H and E stain10\u00d7).", "type": "figure"}, "TABREF0": {"text": "The experimental design and specifications of the animal study", "type": "table"}, "TABREF1": {"text": "The major bioactive compounds of C. purpurascens hexane extract as characterized using GC-MS-TOF analysis", "type": "table"}, "TABREF2": {"text": "Serum biochemical analysis of rats. Effect of CPRHE on (a) renal function test, (b) liver function test and (c) hematology analysis of the rodents", "type": "table"}, "TABREF3": {"text": "Gastroprotective effect of CPRHE against ethanol-induced gastric injury All values are expressed as mean \u00b1 SD. *indicates (P <0.05) compared to the (B) lesion control group. CPRHE: C. purpurascens rhizome hexane extract.", "type": "table"}}}
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{"paper_id": "18989984", "_pdf_hash": "b618589ef72484f6c9411042dfa5aafc17d6db91", "abstract": [], "body_text": [{"section": "", "text": "Most previous reports on endocrine disorders in children with shunted hydrocephalus describe individual cases of sexual precocity.'", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Close to 10% of the children with shunted hydrocephalus studied by Kaiser et al (8/90 patients) developed sexual precocity.4 Precocious puberty has especially been observed in patients with meningomyelocele, but Mayer and Landau found that 52 patients out of 79 with this disease had associated hydrocephalus' and 6% of these had precocious puberty (3/52), raised basal oestradiol and testosterone, and raised peak luteinising hormone (LH) and follicle stimulating hormone (FSH) responses to gonadotrophin releasing hormone (GnRH). The prevalence of cryptorchidism among boys with meningomyelocele was observed to be 15% (7/45) . In another survey all 45 patients with meningomyelocele had hydrocephalus, 6 and the various stages of puberty were reached earlier than expected, indicating that puberty advances more rapidly in children with this disease. Precocious puberty was observed in 4% of the patients (2/45) and cryptorchidism in one quarter of the boys. The age at menarche varied from 9.4 to 11.9 years (n=4).", "cite_spans": [{"start": 705, "end": 706, "text": "6", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "", "text": "Since most previous reports on precocious puberty in children with hydrocephalus concern mainly meningomyelocele patients, there is a lack of information on the average timetable of sexual maturation in hydrocephalic children and adolescents with an aetiology other than meningomyelocele. We report here on pubertal development, age at menarche, and gonadotrophin and sex hormone concentrations in 114 patients with shunted hydrocephalus in comparison with 73 healthy controls.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "SUBJECTS", "text": "The initial series comprised 212 Lopponen, Saukkonen, Serlo, Tapanainen, Ruokonen, Knip their controls, except that the male prepubertal patients had an increased waist-hip ratio. The pubertal patients were shorter than their controls, had an increased relative weight, especially the females, and an increased waisthip ratio and body fat mass. The pubertal female patients had also a higher BMI than the control girls. Gonadal development occurred on an average earlier in the hydrocephalic males than in the controls (Tanner G2-5), the same trend being seen for pubic hair (Tanner PH2-6) (fig 1) Only two male patients (3.2%; 2/62) were between the two groups was not significant found with a unilateral undescended testis, one (4.3 U/I (1.9 to 6.6) v 2.9 U/I (-0.9 to 6.8); of whom was a 6 year old boy with meningo-p=0.08). SHBG concentrations tended to be myelocele, who had congenital anorchia on the lower in the pubertal and postpubertal girls other side. Another 5 year old boy with menin-with hydrocephalus than in the controls, while gomyelocele also had unilateral anorchia. Thus the FAI tended to be higher. There were no the prevalence of congenital anorchia among differences in oestradiol or testosterone conthe males with meningomyelocele was 33.3% centrations between the patients and controls, (2/6) . A third male patient had a unilaterally nor were there any statistically significant hypoplastic testis. None of the control boys differences in gonadotrophin, sex hormone, or (n=38) had undescended testes or anorchia. SHBG concentrations between the pubertal Two hydrocephalic boys who had been and postpubertal boys with hydrocephalus and shunted at under 1 year of age (aged 10.8 and their controls. 15.9 years at the final evaluation) had commuBased on retrospective data there were five nicating hydrocele diagnosed for the first time patients with true precocious puberty in this at this clinical examination and subsequently population (table 6), giving a frequency of treated surgically. Both of them had a ventricu-4.4% (5/114). Two of these were boys. loperitoneal shunt.", "cite_spans": [], "ref_spans": [{"start": 590, "end": 597, "text": "(fig 1)", "ref_id": "FIGREF0"}]}, {"section": "SUBJECTS", "text": "The prepubertal girls with hydrocephalus Discussion had significantly higher basal FSH, LH, and The relation between pubertal development SHBG concentrations than the control girls and chronological age has been evaluated pre-(table 4), while the prepubertal boys had viously in hydrocephalic patients with meninsignificantly higher LH concentrations than gomyelocele,6 but not in subjects with hydrothe control boys but no other statistically cephalus of other aetiologies. We observed in significant differences in endocrine variables.", "cite_spans": [], "ref_spans": []}, {"section": "SUBJECTS", "text": "this cross sectional study that pubic hair develBasal FSH in pubertal and postpubertal oped significantly earlier in the hydrocephalic hydrocephalic girls was significantly higher patients than in the controls and that genital than in control girls (table 5). The female development in the males also occurred signifipatients had increased FSH concentrations, cantly earlier. The age at menarche varied from 9.4 to 11.9 years in the girls with meningomyelocele examined by Greene et al,6 but the number of menstruating girls in that series was smallonly four. Dalton and Dalton studied the mean age at menarche in 37 girls with neural tube defects20 and obtained a figure of 10.5 years, but there is no information on how many of these girls had hydrocephalus as well. The other groups of girls included were ones with asthma, cerebral palsy, epilepsy, retinoblastoma, and other chronic diseases, and their mean ages at menarche varied from 10.8 to 13.5 years. Thus it was the girls with neural tube defects who had the youngest mean age at menarche in that survey.", "cite_spans": [], "ref_spans": []}, {"section": "SUBJECTS", "text": "The mean age at menarche among Finnish girls in general in 1982 was 13.3 years, while that of their mothers had been 13.6 years.2' There has been a secular trend towards an earlier menarche over the past century, with a decrease of about 3-4 months per decade, and the average age at menarche in the United Kingdom, for example, is currently 12.8 years.22 The present hydrocephalic girls, however, experienced their menarche an average of 1.5 years earlier than the control girls and 1.5 years earlier than their mothers, confirming that factors other than genetic ones are responsible for the earlier manifestation of the menarche in girls with hydrocephalus.", "cite_spans": [], "ref_spans": []}, {"section": "SUBJECTS", "text": "What factors determine the age at menarche? Numerous phenomena act in combination, including genetic influences, socioeconomic conditions, general health and wellbeing, nutritional status, and regular, intensive physical exercise, since athletics, gymnastics, and ballet, for instance, have been associated with delayed maturation and menarcheal age.22 The genetic impact does not seem to be crucial in the present series, and the same general health and wellbeing may be said to apply to both the patients and the controls. Likewise, there were no subjects in either group who took part in competitive sports. In terms of nutritional status, the pubertal hydrocephalic girls had a significantly greater relative weight than the control girls.2' Adipose tissue is an important source of oestrogen, and its amount has an influence on oestrogen metabolism. There is a hypothesis concerning a threshold weight for height and a critical proportion of body fat required before the 22 menarche can occur. A change in body composition is known to occur during the adolescent growth spurt, so that the ratio of lean body weight to fat is on an average 5:1 at the initiation of the growth spurt and decreases to 3:1 before the menarche, when about 22% of the body weight is fat. We calculated the ratio of lean body weight to fat in the prepubertal hydrocephalic girls relative to that in the controls and could not detect any differences in this or in age, weight, or relative weight, whereas the pubertal and postpubertal hydrocephalic girls had a higher absolute and relative weight2\" and their lean body weight ratio to fat was lower, although their mean age did not differ from that of the control girls. Overweight becomes more severe later in puberty, however, and accordingly it can hardly explain the younger age at menarche alone.", "cite_spans": [], "ref_spans": []}, {"section": "SUBJECTS", "text": "Previous reports on pubertal development in patients with hydrocephalus concern mainly girls, but the present series also included boys and compared them with age matched controls, upon which the patients were found to have significantly larger relative testicular volumes. The number of male patients with anorchia, hypoplastic testis, cryptorchidism, and communicating hydrocele indicates that the genitalia of boys with hydrocephalus should be examined initially at diagnosis and subsequently at regular intervals, especially in cases with ventriculoperitoneal shunts.", "cite_spans": [], "ref_spans": []}, {"section": "SUBJECTS", "text": "An increase in pulsatile LH secretion plays a crucial role in the induction of puberty, and circulating LH concentrations are a sensitive indicator of pubertal development. 24 The emergence of regular daytime LH pulses is closely related to the onset of breast development in girls25 and there is also an increase in LH pulse frequency associated with the initiation of puberty in boys. 25 The present prepubertal children with hydrocephalus were found to have higher basal gonadotropin concentrations, particularly LH levels, than the controls, indicating a central stimulus before any clinical sign of puberty can be detected. Pubertal female patients had increased FSH concentrations, especially in the postovulatory period.", "cite_spans": [{"start": 173, "end": 175, "text": "24", "ref_id": "BIBREF26"}, {"start": 387, "end": 389, "text": "25", "ref_id": "BIBREF27"}], "ref_spans": []}, {"section": "SUBJECTS", "text": "Neely et al have shown in a recent study2\" that spontaneous serum gonadotropin concentrations are more specific for the evaluation of precocious puberty than stimulated LH and FSH concentrations.", "cite_spans": [], "ref_spans": []}, {"section": "SUBJECTS", "text": "Gonadotropin releasing hormone (GnRH) is secreted mainly from the medial basal hypothalamus in episodic bursts into the hypothalamic-pituitary portal system and thereby to the anterior pituitary. The variation in the frequency of its pulsatile secretion affects the amount of LH and FSH released. The postnatal decrease in gonadotropin secretion during childhood before the onset of puberty, the juvenile pause, appears to be mediated by the central nervous system (CNS). Damage to the CNS may release the inhibition and bring about premature pubertal development. 28 The reasons for the increased gonadotropin secretion in the prepubertal patients with hydrocephalus remain to be defined, but one can assume that it may be due to increased intracranial pressure or unphysiological variations in this pressure. There was a significant correlation between the number of shunt revisions and relative testicular volume in hydrocephalic males. The relative testicular volume was also larger in those prepubertal male patients who had shunt revisions associated with increased intracranial pressure, and the enlargement of the testes is the first sign of puberty in males.", "cite_spans": [{"start": 565, "end": 567, "text": "28", "ref_id": "BIBREF30"}], "ref_spans": []}, {"section": "SUBJECTS", "text": "Although SHBG concentrations were higher in the prepubertal patients with hydrocephalus than in the controls, the present data do not provide information on whether this is a primary phenomenon or secondary to enhanced gonadotropin secretion. In the latter case they would reflect an attempt to counter-act the effects of increased peripheral gonadotropin concentrations by reducing the circulating concentrations of free sex hormones.29 If primary, the high SHBG in combination with decreased free sex hormone concentrations may stimulate pituitary gonadotropin release and by that mechanism contribute to the induction of early puberty. Accelerated sexual maturation would then result in decreased concentrations of SHBG in pubertal subjects with hydrocephalus. Another factor contributing to low SHBG in such subjects is the increased frequency of obesity among them. 23 The prevalence of precocious puberty observed here was of the same magnitude as in previous reports.1 -5 In addition, several patients were identified with early puberty that did not fulfil the criteria of true precocious puberty.", "cite_spans": [{"start": 871, "end": 873, "text": "23", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "SUBJECTS", "text": "The results show that patients with hydrocephalus experience early puberty, which is reflected in an early menarche in girls and an increased testicular volume in boys. This accelerated physical maturation does not seem to be due to genetic factors. Based on our observations, one can speculate that the increased gonadotropin concentrations observed especially in prepubertal patients may be a consequence of unphysiological increases or decreases'0 in intracranial pressure.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "This work was supported by the Sigrid Juselius Foundation, Helsinki, Finland (TL,MK), the Alma and K A Snelhman Foundation, Oulu, Finland (TL), the Arvo and Lea Ylppo Foundation, Helsinki, Finland (TL), and the Foundation for Paediatric Research in Finland (TL)", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF1": {"title": "Endocrine expression of hydrocephalus. 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Patients with tumours (n=24) or achondroplasia (n=3) were ex- cluded, as were patients with an intelligence quotient (IQ) below 50 (n=26), since factors other than the hydrocephalus itself may haveFourteen patients had moved to another university hospital district and 30 had died. One patient refused to participate. Thus the final population comprised 114 patients (52 females, 62 males), including 17 with spina bifida (11 females, six males) and 97 without (41 females, 56 males). Thirty eight children without spina bifida (15 females, 23 males) were prepubertal, while 59 (26 females, 33 males) were pubertal (n=54) or postpubertal (n=5). Six of the 17 subjects with spina bifida were prepubertal and 11 pubertal or postpu- bertal. The clinical evaluation was carried out at the Department of Paediatrics, University Central Hospital, Oulu, Finland. Informed consent was obtained from the subjects or their parents or both. The research was conducted accord- ing to the Declaration of Helsinki. The mean age of the patients at the final evaluation was 11.8 years (range 5.0 to 19.9 years) and that of the controls 12.0 years (range 5.1 to 19.7 years). The median age of the hydrocephalic patients at the first operation had been 0.5 years (range 0.0 to 14.2 years), the females having been operated on earlier than the males (median 0.2 years (range 0.0 to 8.6 years) v 0.7 years (range 0.0-14.2 years); p < 0.03). The mean duration of the shunting period had been 10.0 years (range 1.3 to 19.8 years). Most of the shunts involved in the final evaluation were of the Hakim-Cordis type (n=74), but Orbis- Sigma shunts had been used more often recently (n=26). There were still some patients operated on earlier who had received a Pudenz shunt (n= 14). Most of the shunts were ventriculoperitoneal (n=90) and a minority ventriculoatrial (n=24). An antisiphon device had been installed in 46 patients. The median number of shunt revisions was two per patient (range 0 to 14). The aetiology was assessed according to a modification of the classification proposed by Amacher and Wellington, excluding neoplastic tumours as a possible aetiological condition.7 Magnetic resonance imaging was performed on a subgroup of 61 patients at the final evalu- ation and their aetiological diagnosis was based on these findings.'0 The aetiology was congeni- tal in 76 cases (66.7%), with the following sub-mm with a Harpenden wall mounted stadi- ometer and weight to an accuracy of 0.1 kg with an electronic scale. The relative height and the relative weight were assessed from Finnish growth charts.\" The body mass index (BMI) represents the ratio between weight (kg) and height squared (m'). The waist and the hip were measured to the next succeeding 1.0 mm with a metallic tape measure.'2 The biceps, tri- ceps, and subscapular skinfolds were measured to an accuracy of 0.1 mm with a Harpenden skinfold caliper (John Bull, British Indicators Ltd, St Albans, Herts, UK).\" Body density was calculated from the combined results of triceps and subscapular skinfold thickness according to Parizkova.\"4 The percentage of body fat was calculated by the method described by KeysThe stage of puberty was assessed according to Tanner and Whitehouse.'6 If there were no signs of puberty (GIPHI or BiPHi), the sub- jects were classified as prepubertal. SubjectsAnthropometric measurements in prepubertal and pubertal male patients with hydrocephalus and their controls; values are mean (95% confidence interval)", "type": "table"}, "TABREF1": {"text": "The mean value for both testicles was used, but Data on the age of the mothers at menarche in the case of anorchia or an undescended tes-was collected by means of a questionnaire. tis the volume of the only measurable testis was Bone age was evaluated from an x ray of the left hand and wrist by the method of Greulich andanalysed with time resolved fluoroimmunoas- says using commercial reagents from Wallac I l (Turku, Finland). Serum testosterone and 3o 00 oestradiol-17,B concentrations were quantifiedWhitney U test in the case of a skewed distribution or ordinal variables. The relation between the number of shunt revisions and signs of early puberty was evaluated with the Spearman non-parametric correlation analysis (r). The Mantel-Haenszel X2 for trends was used when comparing the distribu- tion of specific age groups by stage of puberty. The results are expressed as means (95% con- fidence intervals) unless otherwise indicated.", "type": "table"}, "TABREF2": {"text": "Mean age", "type": "table"}, "TABREF4": {"text": ". In the age group from 12 to 14 years two thirds of thewas also significantly lower than that of their \u00a3[w%0 ai C o\u00b0m others at that stage (11.7 years v 13.2 years;", "type": "table"}, "TABREF5": {"text": "", "type": "table"}, "TABREF6": {"text": "Patients with precocious puberty", "type": "table"}}}
{"paper_id": "199662043", "_pdf_hash": "dcb477dcbb3f56b96b755e19fea19a8e5c980aa1", "abstract": [{"section": "Abstract", "text": "Cell lines and bacterial strains. Vero cells (African green monkey kidney cells, ATCC) were cultured in Dulbecco's modified Eagle's medium (DMEM, Gibco) supplemented with 10% heatinactivated fetal bovine serum (HI-FBS) at 37\u00b0C in a 5% CO2 atmosphere. E. coli DH5\u03b1 and XL-1 were grown in Luria-Bertani Miller broth (Difco) at 37\u00b0C, supplemented with ampicillin (100 \u00b5g\u00b7ml -1 ), rifampin (20 \u00b5g\u00b7ml -1 ), or chloramphenicol (20 \u00b5g\u00b7ml -1 ) where appropriate. P. vulgaris OX2 (ATCC 7829), P. vulgaris OX19 (ATCC 6898), and P. mirabilis OXK (ATCC 15146) strains were grown in Luria-Bertani Miller broth (Difco) at 37\u00b0C. Rickettsia rickettsii Sheila Smith (Rocky Mountain Laboratory, Dr. Ted Hackstadt), R. conorii Malish 7 (ATCC VR-613) and kkaebi variants were grown in Vero cells in the presence of rifampin (0.2 \u00b5g\u00b7ml -1 ) and/or chloramphenicol (0.3 \u00b5g\u00b7ml -1 ) where appropriate. Rickettsiae were purified from Vero cells by differential centrifugation through 33% MD-76R solution (816 mM meglumine diatrizoate, 157 mM sodium diatrizoate hydrate, 1 mM NaH2PO4, pH 7.0; 21,000 \u00d7 g, 4\u00b0C, 20 min) and stored at -80\u00b0C in SPG buffer (218 mM sucrose, 3.8 mM KH2PO4, 7.2 mM K2HPO4, 4.9 mM L-glutamate, pH 7.2).", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Genomic and plasmid DNA purification. Rickettsial genomic DNA (gDNA) and plasmid vectors were extracted using commercially available kits (PureLink genomic DNA extraction kit and QIAGEN plasmid kits) following the manufacturers' instructions.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Plasmid construction. Plasmids were constructed using the primers and restriction enzymes indicated in SI appendix, Table S3 . pHTRL1 and pHTRL2 were sequentially constructed by directional cloning of polymerase chain reaction (PCR) amplified transcription promoter (PrompB) and terminator (TrompB) of R. rickettsii rompB into the multiple cloning sites (MCS) of the pMOD-2<MCS> transposon construction vector (Epicentre). The sequence of the cat gene was", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "codon-optimized for use in R. conorii, synthesized by Integrated DNA Technologies, Inc and PCR cloned into pHTRL2, creating the kkaebi mini-transposon flanked by 19-bp Tn5 inverse repeat (IR) sequences in pHTRL3. The R. prowazekii-optimized arr2 rifampin resistance cassette, derived from pRAM18dRGA (kindly provided by Dr. Ulrike Munderloh, University of Minnesota) (1) , was inserted into pHTRL2, generating pHTRL5. The 1.6 kbp fragment, which was created by overlap extension PCR of colE1 origin of replication and PrompB-cat-TrompB, was used for generation of a R. conorii-E. coli shuttle vector (pHTRL4) by ligating with a 5.6 kbp fragment containing a multiple cloning site, dnaA and parA derived from pRAM18dRGA.", "cite_spans": [{"start": 367, "end": 370, "text": "(1)", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "", "text": "Another shuttle vector (pHTRL6) was constructed by replacing the cat gene with another antibiotic cassette, arr2, from pHTRL5. For pHTRL7, a gene coding for green fluorescent protein (GFPUV) driven by the rompA promoter (PrompA) was cloned into pHTRL6. A gene fragment containing R. conorii Rc0457-Rc0460 was PCR amplified from R. conorii template DNA and cloned into MCS of pHTRL7.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Inverse PCR. Transposon insertion sites were identified by inverse PCR (iPCR). Chromosomal DNA samples, isolated from kkaebi variants, were digested with NdeI at 37\u00b0C for one hour, followed by heat-inactivation at 65\u00b0C for 20 min and then self-ligated with T4 DNA ligase (NEB) at 16\u00b0C for 16 hours. Following ligation, the plasmid DNA was isolated with a PCR purification kit (Qiagen) and used as a template in an iPCR (iPCRF, 5'-GCTGTAATATCAAGCTGAACAGTCTGG-3'; iPCRR, 5'-CAAGGTGATAAGGTATTAATGCCACTTG-3'). DNA sequencing of the obtained PCR fragments revealed the kkaebi insertion sites within the chromosome of R. conorii (GenBank Accession no. NC_003103.1).", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "RNA extraction and cDNA synthesis. Three independent cultures of the R. conorii wild-type, HK2 pHTRL7, and HK2 pHTRL8 variants were grown on Vero cells at 34\u00b0C with 5% CO2 for 2 days. Vero cells were mechanically disrupted with 3 mm glass beads. After host cell debris was removed by centrifugation (1,000 \uf0b4g, 4\u00b0C, 5 min), the supernatant containing R. conorii was treated with RNAprotect Bacteria Reagent (Qiagen). Total RNA was extracted using RNeasy Mini Kit (Qiagen) with on-column DNase I digestion, according to the manufacturer's instructions. 100 ng of total RNA was used for cDNA synthesis with random hexamers (iScript cDNA synthesis kit, Bio-Rad). Primers used for PCR amplification of Rc0459 is listed in SI appendix, Table S3 .", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Growth and plaque assay. Growth curves were generated by infecting wild-type R. conorii and kkaebi variants into monolayers of Vero cells in 6-well plates at a multiplicity of infection of 0.01. At 2-day intervals, Vero cells in each well were dislodged with 3 mm glass beads and lysed by vortexing with 3 mm glass beads. R. conorii infectious titer was determined by infecting monolayers of Vero cells with 10-fold serial dilutions of lysates containing Rickettsia in DMEM supplemented with 5% HI-FBS. Upon infection, Vero cells were incubated at 34\u00b0C with 5% CO2 for 60 min to allow attachment and overlaid with DMEM containing 5% HI-FBS and 0.5% agarose. Antibiotics were added six hours post-infection and incubation continued at 34\u00b0C for four-five days prior to isolation or direct enumeration of plaques with MTT staining (Acros).", "cite_spans": [], "ref_spans": []}, {"section": "Microscopy analyses. Cytopathology in Vero cell cultures was analyzed by microscopy. On day 3 post-infection, differential interference contrast (DIC) images of Vero cells infected with R.", "text": "conorii variants in multiple fields of 6-well plates were captured with a charge-coupled device camera, contrast adjusted, and pseudo-colored using Affinity Photo. Areas of cytopathic Vero cells were assessed by NIH ImageJ software. For electron microscopic studies, Vero cells infected with R. conorii variants for three days were fixed with 2% glutaraldehyde and 4% paraformaldehyde in 0.1 M sodium cacodylate buffer, embedded in epoxy, and thin sectioned (Advanced Electron Microscopy Facility, University of Chicago). Sections were stained with uranyl acetate and viewed using a Tecnai F30 (Philips/FEI) transmission electron microscope (field emission gun, 300 kV accelerating voltage, and magnification of \u00d7 25,000) and a highperformance charge-coupled device camera with 4,000-by-4,000 resolution. Images were acquired using Gatan Digital Micrograph software, contrast adjusted, and processed using Affinity Photo. Rickettsial cell width and length were measured using NIH ImageJ software.", "cite_spans": [], "ref_spans": []}, {"section": "Microscopy analyses. Cytopathology in Vero cell cultures was analyzed by microscopy. On day 3 post-infection, differential interference contrast (DIC) images of Vero cells infected with R.", "text": "Transformation. Approximately 5\uf0b410 8 PFU of purified R. conorii were electroporated with 5 \u00b5g of plasmids, immediately plated onto Vero cell monolayers, and then allowed to infect Vero cells for 60 min at 34\u00b0C, after which the medium was removed and replaced with fresh DMEM containing 5% HI-FBS and 0.5% agarose. Six hours post-infection, medium containing antibiotics was added for the selection of transformants. Individual plaques isolated and expanded in Vero cell monolayers in the presence of antibiotics. Typical yields for plasmid transformation are shown in SI Appendix, Table S4 . Rifampin 53 (\u00b120) pHTRL4", "cite_spans": [], "ref_spans": [{"start": 581, "end": 589, "text": "Table S4", "ref_id": "TABREF1"}]}, {"section": "Microscopy analyses. Cytopathology in Vero cell cultures was analyzed by microscopy. On day 3 post-infection, differential interference contrast (DIC) images of Vero cells infected with R.", "text": "Chloramphenicol 287 (\u00b121) a R. conorii Malish 7 was electroporated with 5 \u00b5g of pHTRL4 or pHTRL6 in 100 \u00b5l SPG buffer in 0. ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Development of shuttle vectors for transformation of diverse Rickettsia species", "authors": [{"first": "N", "middle": ["Y"], "last": "Burkhardt", "suffix": ""}], "year": 2011, "venue": "PLoS One", "link": "3135590"}, "BIBREF1": {"title": "Rickettsia conorii infection of C3H/HeN mice. A model of endothelial-target rickettsiosis", "authors": [{"first": "D", "middle": ["H"], "last": "Walker", "suffix": ""}, {"first": "V", "middle": ["L"], "last": "Popov", "suffix": ""}, {"first": "J", "middle": [], "last": "Wen", "suffix": ""}, {"first": "H", "middle": ["M"], "last": "Feng", "suffix": ""}], "year": 1994, "venue": "Lab. Invest", "link": "23118764"}}, "ref_entries": {"FIGREF0": {"text": "Rabbit immunization. Affinity purified LPS samples (10 U per injection) were emulsified with complete Freund's adjuvant (Difco) and injected subcutaneously into New Zealand white rabbits (Charles River Laboratories). At 21-day intervals, rabbits received booster immunizations of LPS emulsified with incomplete Freund's adjuvant (Difco). Mouse model of R. conorii systemic infection. C3H/HeN mice (male, 6-week, N=10 per group, Charles River Laboratories) were infected by intravenous retro-orbital injection with lethal (1 \u00d7 10 6 PFU) or sub-lethal (1 \u00d7 10 3 PFU) doses of R. conorii in 0.1 ml SPG buffer (2). Infected mice were monitored twice daily for signs of disease and daily for weight loss. Blood samples were collected on day 14 post-infection to determine serum antibody titers by western blot analyses against rickettsial antigens. Biosafety and biosecurity. Animal research was performed in accordance with institutional guidelines following experimental protocol review, approval, and supervision by the University of Chicago's Institutional Biosafety Committee (IBC) and the Institutional Animal Care and Use Committee (IACUC). Animals were managed by The University of Chicago Animal Resource Center, which is accredited by the American Association for Accreditation of Laboratory Animal Care and the Department of Health and Human Services (DHHS number A3523-01). Animals were maintained in accordance with the applicable portions of the Animal Welfare Act and the DHHS \"Guide for the Care and Use of Laboratory Animals\". Veterinary care was under the direction of full-time resident veterinarians boarded by the American College of Laboratory Animal Medicine. Experiments with Rickettsia were performed in biosafety level 3 (BSL3) or animal BSL3 (ABSL3) containment. The University of Chicago Institutional Biosafety Committee and National Institute of Health Recombinant DNA Advisory Committee reviewed and approved the use of a gene encoding chloramphenicol resistance for the selection of mutants with insertional lesions in R. conorii. Statistical analyses. All statistical analyses were performed using Prism software (GraphPad). The proportion of survival animals was analyzed using the two-tailed Log-rank test. Two-way ANOVA with Bonferroni post-tests was performed to analyze the statistical significance of body-weight change and R. conorii growth data. Measurements of R. conorii survival in plasma, cytopathogenic sizes, and relative transcription levels were analyzed for statistical significance using one-way ANOVA with Dunnett's multiple comparison test. Materials and data availability. The data and unique materials that support the findings of this study are available from the corresponding author upon request. Whole-genome-sequencing data (wild-type R. conorii Malish 7 and rifampin-resistant R. conorii) are deposited to the Sequence Read Archive database (Accession PRJNA513326). SI Tables.", "type": "figure"}, "FIGREF1": {"text": "1 cm-gap sterile cuvettes at 3.0 kV, 200 ohms, 25 \u03bcF, 5 ms using a Gene Pulser (Bio-Rad). b Vero cells infected with R. conorii transformants in the presence of rifampin (0.2 \u00b5g\u00b7ml -1 ) or chloramphenicol (0.3 \u00b5g\u00b7ml -1 ). c Data are the mean plaque forming units (PFU, \u00b1SEM) of R. conorii propagated on Vero cells (N=3).", "type": "figure"}, "FIGREF2": {"text": "Generation of kkaebi variants and identification of HK2 and HK15. (A) Schematic overview of kkaebi-mutagenesis. (B) PCR amplification of the kkaebi-transposon from the genomic DNA of R. conorii variants. (C) Inverse PCR analysis to identify kkaebi insertion sites in the chromosome of R. conorii variants. (D) PCR amplification of Rc0457 and Rc0459 from genomic DNA of R. conorii wild-type (WT), HK2, and HK15.", "type": "figure"}, "FIGREF3": {"text": "The N-acetyl-L-quinovosamine (L-QuiNAc) biosynthesis gene cluster in R. conorii. (A) Diagram of three conserved genes in R. conorii (NC_003103.1), P. vulgaris (JPIX01000008.1) and V. cholerae (AF390573.1). (B) Percent identity of amino acid sequences. (C) Proposed pathway for UDP-L-QuiNAc biosynthesis.", "type": "figure"}, "FIGREF4": {"text": "Plasmid complementation analysis with R. conorii HK2. (A) Maps of pHTRL7 encoding codon-optimized arr2 and (B) pHTRL8 carrying Rc0457-Rc0460. (C) Relative transcription level of Rc0459 in R. conorii variants isolated from Vero cells at 2 days post inoculation (N=3). (D) Quantification of plaque forming units (PFU) in Vero cell cultures inoculated for variable incubation times with R. conorii WT, HK2 (pHTRL7) or HK2 (pHTRL8) (N=3). Immunoblot analyses of affinity purified LPS from R. conorii wild-type (WT) or the pso mutants HK2 and HK15 with (E) human immune serum from individuals convalescent from R. conorii infection (\u03b1-RcHu) or (F) rabbit serum raised against purified wild-type R. conorii LPS (\u03b1-LPSWT). (G) Coomassie-stained SDS-PAGE analysis of outer membrane fractions from R. conorii WT, HK2 (pHTRL7) or HK2 (pHTRL8). Data are the mean (\u00b1SEM) of three independent determinations. Statistical significances for Rc0459 transcription levels and rickettsial growth were analyzed with one-way ANOVA with Dunnett's multiple comparison test and two-way ANOVA with Bonferroni post-tests, respectively. *, P<0.05; **, P<0.0001.", "type": "figure"}, "FIGREF5": {"text": "Size measurements of R. conorii variants. (A) Bacterial widths and (B) lengths were determined using transmission electron microscopic images from Vero cells infected for three days with R. conorii wild-type (WT), HK2, or HK15. One-way ANOVA with Dunnett's posttest was used to identify statistically significant differences (N=34 for WT, N=31 for HK2, and N=32 for HK15; P>0.05; center line, median; box limits, upper and lower quartiles; whiskers, minimum and maximum values).", "type": "figure"}, "TABREF0": {"text": "", "type": "table"}, "TABREF1": {"text": "Selecting for R. conorii plasmid transformants", "type": "table"}}}
{"paper_id": "199662061", "_pdf_hash": "3bae7443316673573711eb08610930d6a317a19d", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "What are the possible moir\u00e9 patterns of graphene on hexagonally packed surfaces? Universal solution for hexagonal coincidence lattices, derived by a geometric construction", "authors": [{"first": "P", "middle": [], "last": "Zeller", "suffix": ""}, {"first": "S", "middle": [], "last": "G\u00fcnther", "suffix": ""}], "year": 2014, "venue": "New J. Phys", "link": "173818"}, "BIBREF1": {"title": "Indexing moir\u00e9 patterns of metal-supported graphene and related systems: strategies and pitfalls", "authors": [{"first": "P", "middle": [], "last": "Zeller", "suffix": ""}, {"first": "X", "middle": [], "last": "Ma", "suffix": ""}, {"first": "S", "middle": [], "last": "G\u00fcnther", "suffix": ""}], "year": 2017, "venue": "New J. Phys", "link": "197469815"}, "BIBREF2": {"title": "On Designing Moir\u00e9 Patterns", "authors": [{"first": "G", "middle": [], "last": "Lebanon", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Bruckstein", "suffix": ""}, {"first": "V", "middle": [], "last": "Cantoni", "suffix": ""}, {"first": "M", "middle": [], "last": "Marinaro", "suffix": ""}, {"first": "A", "middle": [], "last": "Petrosino", "suffix": ""}], "year": 2002, "venue": "Visual Attention Mechanisms", "link": "118824976"}, "BIBREF3": {"title": "Variational approach to moir\u00e9 pattern synthesis", "authors": [{"first": "G", "middle": [], "last": "Lebanon", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Bruckstein", "suffix": ""}], "year": 2001, "venue": "JOSA A", "link": "2985950"}, "BIBREF4": {"title": "Analytical Transmission Electron Microscopy: An Introduction for Operators", "authors": [{"first": "J", "middle": [], "last": "Thomas", "suffix": ""}, {"first": "T", "middle": [], "last": "Gemming", "suffix": ""}], "year": 2014, "venue": "", "link": "118203765"}, "BIBREF5": {"title": "Atomic and electronic reconstruction at the van der Waals interface in twisted bilayer graphene", "authors": [{"first": "H", "middle": [], "last": "Yoo", "suffix": ""}], "year": 2019, "venue": "Nat. Mater", "link": "117715384"}, "BIBREF6": {"title": "Moir\u00e9 structures in twisted bilayer graphene studied by transmission electron microscopy", "authors": [{"first": "T", "middle": [], "last": "Latychevskaia", "suffix": ""}, {"first": "C", "middle": [], "last": "Escher", "suffix": ""}, {"first": "H.-W", "middle": [], "last": "Fink", "suffix": ""}], "year": 2019, "venue": "Ultramicroscopy", "link": "54168962"}, "BIBREF7": {"title": "Direct and Scalable Deposition of Atomically Thin Low-Noise MoS2 Membranes on Apertures", "authors": [{"first": "P", "middle": [], "last": "Waduge", "suffix": ""}], "year": 2015, "venue": "ACS Nano", "link": "5579907"}, "BIBREF8": {"title": "Electron Diffraction Using Transmission Electron Microscopy", "authors": [{"first": "L", "middle": ["A"], "last": "Bendersky", "suffix": ""}, {"first": "F", "middle": ["W"], "last": "Gayle", "suffix": ""}], "year": 2001, "venue": "J. Res. Natl. Inst. Stand. Technol", "link": "5741826"}, "BIBREF9": {"title": "The Bonding Electron Density in Aluminum", "authors": [{"first": "P", "middle": ["N H"], "last": "Nakashima", "suffix": ""}, {"first": "A", "middle": ["E"], "last": "Smith", "suffix": ""}, {"first": "J", "middle": [], "last": "Etheridge", "suffix": ""}, {"first": "B", "middle": ["C"], "last": "Muddle", "suffix": ""}], "year": 2011, "venue": "Science", "link": "1948896"}, "BIBREF10": {"title": "X-ray electron density investigation of chemical bonding in van der Waals materials", "authors": [{"first": "H", "middle": [], "last": "Kasai", "suffix": ""}], "year": 2018, "venue": "Nat. Mater", "link": "205565329"}, "BIBREF11": {"title": "Oxygen-Induced In-Situ Manipulation of the Interlayer Coupling and Exciton Recombination in Bi2Se3/MoS2 2D Heterostructures", "authors": [{"first": "Z", "middle": [], "last": "Hennighausen", "suffix": ""}], "year": 2019, "venue": "ACS Appl. Mater. Interfaces", "link": "104296041"}, "BIBREF12": {"title": "Tightly bound trions in monolayer MoS2", "authors": [{"first": "K", "middle": ["F"], "last": "Mak", "suffix": ""}], "year": 2013, "venue": "Nat. Mater", "link": "205408065"}, "BIBREF13": {"title": "Tunable and laser-reconfigurable 2D heterocrystals obtained by epitaxial stacking of crystallographically incommensurate Bi2Se3 and MoS2 atomic layers", "authors": [{"first": "A", "middle": [], "last": "Vargas", "suffix": ""}], "year": 2017, "venue": "Sci. Adv", "link": "215005543"}}, "ref_entries": {}}
{"paper_id": "199662777", "_pdf_hash": "c1cf56343b58c9f4df2e2483086ef2cb1b02b34a", "abstract": [{"section": "Abstract", "text": "The majority of current visual-algorithmic architecture is constricted to specific parameters that are gradient related, keeping their parts' relation fixed within the algorithm, far away from a truly parametric modeling with a flexible topology. Recent findings around genetics and certain genes capable of shape conditioning (development) have succeeded in recovering the science of embryology as a valid field that connects and affects the evolutionary ecosystem, showing the existence of universal mechanisms that are present in living species, thus describing powerful strategies for generation and emergence. Therefore, a new dual discipline is justified: Evolutionary developmental biology science. Authors propose the convergence of genetics algorithms and simulated features from evolutionary developmental biology into a single data-flow that will prove itself capable of generating great diversity through a simple and flexible structure of data, commands, and polygonal geometry. For that matter, a case study through visual-algorithmic software deals with the hypothesis that for obtaining a greater emergence and design space, a simpler and more flexible approach might only be required, prioritizing hierarchical levels over complex and detailed operations.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Definition and Evolution of Architectural Design Through Computational Heuristics", "text": "The development of algorithmic-aided design (AAD) [1] , or visual programming, is one of the elements responsible for the digital momentum within the architectural discipline, where its accessibility is as important as its potential. Easy-to-use tools available to non-mathematical experts are always part of the discussion of the architectural identity, as the designer is granted new abilities while being simultaneously constrained to them.", "cite_spans": [{"start": 50, "end": 53, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Definition and Evolution of Architectural Design Through Computational Heuristics", "text": "Evolutionary algorithms (EAs) have had an amazing impact in the design workflow. By the mid-20th century, Fogel's 'evolutionary programming', Holland's 'genetic algorithm' and Rechenberg and Schwefel's 'evolutionary strategies' were already developed [2] .", "cite_spans": [{"start": 251, "end": 254, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Definition and Evolution of Architectural Design Through Computational Heuristics", "text": "Despite their independent research, a series of evolutionary algorithm conferences in the 1990s allowed beneficial interactions to set the digital evolutionary background, especially within the field of architecture and design. Making such complex algorithms available for non-computational experts through tools linked to visual programming representation allows an exponential growth of the design disciplines regarding the complexity they allow to reach and analyze.", "cite_spans": [], "ref_spans": []}, {"section": "Definition and Evolution of Architectural Design Through Computational Heuristics", "text": "Research on the relationship between evolutionary computation and design has also grown over the last decade. Designers, as Herbert stated already in the 1990s, are trying to improve our understanding by simulating, as imitation is possible because distinct physical systems can be organized to exhibit nearly identical behavior.", "cite_spans": [], "ref_spans": []}, {"section": "Definition and Evolution of Architectural Design Through Computational Heuristics", "text": "as distinct but complementary disciplines, officially merged in 1999 when evolutionary developmental biology, evo-devo, was granted its own division in the Society for Integrative and Comparative Biology (SICB) [7] .", "cite_spans": [{"start": 211, "end": 214, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Definition and Evolution of Architectural Design Through Computational Heuristics", "text": "However, evo-devo has not been implemented yet in the digital simulation of evolutionary algorithms, which lack many of the geometrical properties related to gene regulation (to be listed and explained later on): Body plan, homeobox genes, genetic switches, and allometric grow [8] .", "cite_spans": [{"start": 278, "end": 281, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Definition and Evolution of Architectural Design Through Computational Heuristics", "text": "Authors propose the convergence of evolutionary algorithms and evo-devo strategies into a single data-flow that will be proven capable of generating great diversity through a simple and flexible structure of data, commands, and polygonal geometry. To maintain accessibility, the strategy can be incorporated into any optimization algorithm (evolutionary or not) to perform design variety and optimization without the need of coding or additional software.", "cite_spans": [], "ref_spans": []}, {"section": "Algorithms and Computation in Architecture", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Evolution, Emergence, Complexity, and Environment Responsiveness in Architecture", "text": "The theory of transformational linguistics and the information-processing theory of cognition were born in the same matrix, produced by the development of the modern digital computer.", "cite_spans": [], "ref_spans": []}, {"section": "Evolution, Emergence, Complexity, and Environment Responsiveness in Architecture", "text": "MIT Architecture Machine Group was founded in October 1967 by professor Nicholas Negroponte and was operative until 1985. Creating an \"architecture machine\" that would help architects design buildings was the very first description of their aim.", "cite_spans": [], "ref_spans": []}, {"section": "Evolution, Emergence, Complexity, and Environment Responsiveness in Architecture", "text": "Already in 1970, in an article published by Scientific American [9] , Conway's game of life was proposing complexity through a series of simple rules for behavioral relationships. Subsequently, this led to the controversial proposal stated by Stephen Wolfram [10] .", "cite_spans": [{"start": 64, "end": 67, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 259, "end": 263, "text": "[10]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Evolution, Emergence, Complexity, and Environment Responsiveness in Architecture", "text": "Similarly, Herbert in 1996 dealt with the idea of an \"Artifact\" as an interface between the inner and outer environment. The author pointed out that the first advantage of distinguishing two environments was that with just minimal assumptions about the inner environment, we would be able to predict behavior from the knowledge of the system goals and its outer environment. He understood then the outer environment as the one that determines the conditions for goal attainment, while the inner environment as the organization of natural phenomena capable of attaining goals in some ranges of environment.", "cite_spans": [], "ref_spans": []}, {"section": "Evolution, Emergence, Complexity, and Environment Responsiveness in Architecture", "text": "In this context, the proposals developed at the Architectural Association by John Frazer [11] are taken as special architectural reference. One of the main worries that stands out from Frazer's evolutionary architecture is the environment analysis, meaning to develop a responsive architecture that is altered by it, aim that led his interest towards cybernetics.", "cite_spans": [{"start": 89, "end": 93, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Evolution, Emergence, Complexity, and Environment Responsiveness in Architecture", "text": "Picking up the witness, Michael Weinstock emphasizes the biological character of the evolutionary process through projects such as parametric and evolutionary development of urban tissues [12] , which serve as precursors to the work later exhibited in this article.", "cite_spans": [{"start": 188, "end": 192, "text": "[12]", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "Evolution, Emergence, Complexity, and Environment Responsiveness in Architecture", "text": "Negroponte also coincides with this aspect:", "cite_spans": [], "ref_spans": []}, {"section": "Evolution, Emergence, Complexity, and Environment Responsiveness in Architecture", "text": "\" . . . responsive means that the environment which has an active role, initiating to a greater or lesser degree changes as a result and function of complex or simple computations.\" [13] It can be stated that complexity often takes the form of hierarchy, as hierarchic systems have some common properties independent of their content [3] . How complex a structure is depends a lot on the way we describe it. Since much of design, particularly architectural and engineering design, is concerned with objects or arrangements in real Euclidean two-dimensional (2D) or three-dimensional (3D) space, the representation of space and things in space should be a central topic of research. To achieve simplification, a proper representation must be found. And so, constructing a non-trivial theory of complex systems is by way a theory of hierarchy. Also like this, a large proportion of complex systems observed in nature are hierarchic: The natural world is one where complexity evolves from simplicity. The notion of substituting a process description for a state description of nature played a central role in the development of modern science. The correlation between state/process descriptions are basic for the survival of an adaptive organism, to its capacity of acting to the environment [3] .", "cite_spans": [{"start": 334, "end": 337, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 1289, "end": 1292, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "State of Computational Genetic Algorithms (GAs) Research in Architecture", "text": "Although genetic algorithms (GAs) have been well established and adapted, architects continue to seek strategies for integrating the design philosophy into a functional framework for the evolutionary algorithm. These strategies, understood as autonomous processes, explore architecture without prejudices or constrains, free from subjective judgements; searching for new relations in the design space to find unexpected constructions or different workflows.", "cite_spans": [], "ref_spans": []}, {"section": "State of Computational Genetic Algorithms (GAs) Research in Architecture", "text": "\"It is precisely the notion of loose control that can be postulated as a possible new authorial model, pitted against the totalizing normativity of current computational design methods.\" [14] Despite all the virtues of GAs, the majority of current visual-algorithmic architecture deals with changing parameters that are related to specific characteristics. For this reason, the algorithms produce gradients inside those specific characteristic-variable changes within a range.", "cite_spans": [{"start": 187, "end": 191, "text": "[14]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "State of Computational Genetic Algorithms (GAs) Research in Architecture", "text": "In that sense, neither their position inside of the algorithm nor the relation between the components changes; the topology stays the same, leading to an algorithm that is not really parametric itself but, rather, fixed.", "cite_spans": [], "ref_spans": []}, {"section": "State of Computational Genetic Algorithms (GAs) Research in Architecture", "text": "Results then can be endless and very adaptable, but, rarely unexpected. Resultant geometries tend to share distinguishing features once the definition has been set. In other words, there are not great leaps in terms of shape grammar inside of the same design. This situation has also led to a detriment in the value of parametric design and the quality of its projects [15] .", "cite_spans": [{"start": 369, "end": 373, "text": "[15]", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "State of Computational Genetic Algorithms (GAs) Research in Architecture", "text": "Crosses between evo-devo and evolutionary algorithm in design have been studied by some researchers for the last 10 years. In 2008, Sprecher and Kalnit, arguing about the tremendous implications that evo-devo could have in design processes, presented research in ACADIA, introducing the idea of recombining switches and shape annealing methods [16] . Researchers were focused on creating a computational structure that was based on a series of subsystems acting as switches, arguing that switch-regulated combinations of subsystems were able to produce a wide variety of morphologies.", "cite_spans": [{"start": 344, "end": 348, "text": "[16]", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "State of Computational Genetic Algorithms (GAs) Research in Architecture", "text": "From the 2010s, MIT researchers like Neri Oxman or Skylar Tibbits stated that programmable matter was a feasible future if the intricacies of natural systems investigations were focused properly.", "cite_spans": [], "ref_spans": []}, {"section": "State of Computational Genetic Algorithms (GAs) Research in Architecture", "text": "Sidefx Houdini, which combines VDM (Visual Dataflow Modeling) in a procedural generation software, was proposed by Jansen and Chen in 2011 as a possible solution for overcoming the main issues (skills and speed) that used to appear when trying to implement evo-devo design methods. Its main limitation, computer grid accessibility, was proposed to be solved by the EDITS (evo-devo in the sky) method proposed by Jansen in 2013 [17] . This method was supposed to address these three limitations by proposing a system based on Dexen, a distributed execution environment proposed by the author in 2011, a workflow system and a set of computer aided design based design tools.", "cite_spans": [{"start": 427, "end": 431, "text": "[17]", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "State of Computational Genetic Algorithms (GAs) Research in Architecture", "text": "Nimish Biloria and Jia-Rey Chang developed HyperCell at TU Delft within Hyperbody Lab in 2012 [18] . Tackling existing architectural spaces as a way of investigating how to solve future massive human population growth, they proposed evo-devo as the basis for their Hypercell three main basic ideas: Simple-complexity, geometry rules, and switching/triggering. It was aimed to go beyond structural issues, studying adaptability through space organizations using the idea of the evo-devo's fate maps.", "cite_spans": [{"start": 94, "end": 98, "text": "[18]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "Research Hypothesis", "text": "As John Frazer stated as far back as 1995, we, as architects, are evolving the rules for generating form, rather than the forms themselves.", "cite_spans": [], "ref_spans": []}, {"section": "Research Hypothesis", "text": "As previously mentioned, this research deals with the hypothesis that, for obtaining a greater emergence and variety of the design space, a simpler and more flexible approach might be required, prioritizing hierarchical levels over complex and defined operations.", "cite_spans": [], "ref_spans": []}, {"section": "Research Hypothesis", "text": "A specialized algorithm can only handle the task it has been set to, reducing then variation and unpredictability. In addition, introducing changes later on will be more difficult in reconfiguring the statement [19] .", "cite_spans": [{"start": 211, "end": 215, "text": "[19]", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Research Hypothesis", "text": "It is evident that communication with the esthetical or philosophical aspect of design is still lacking. A deep gap exists between design's non-linear approach and the strictly-defined structures of GAs. Moreover, the algorithm remains constrained to the associative topology of the model anchored to the initial design of the architect's proposal [20] .", "cite_spans": [{"start": 348, "end": 352, "text": "[20]", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Research Hypothesis", "text": "For this reason, new ways to improve the framework are still being investigated. For instance, recent researches added shape recognition-form diversity-for phenotype evaluation in post-optimization articulation in the genetic process [21] . The addition of dynamic modular frameworks has also been proposed, addressing context for the population-environment, goals, user, etc. [22] -as well as the use of Cartesian genetic programming for modifying the topology of the model [20] , or the implementation of interactive cluster-oriented frameworks parallel to the genetic process [23] .", "cite_spans": [{"start": 234, "end": 238, "text": "[21]", "ref_id": "BIBREF22"}, {"start": 377, "end": 381, "text": "[22]", "ref_id": "BIBREF23"}, {"start": 475, "end": 479, "text": "[20]", "ref_id": "BIBREF21"}, {"start": 579, "end": 583, "text": "[23]", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "Research Hypothesis", "text": "Authors have tackled, within the brief of a previous research [24] , embodied color patterns to translate data, and have used Grasshopper's path grammar to build a model's structure in prior articles.", "cite_spans": [{"start": 62, "end": 66, "text": "[24]", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "Research Hypothesis", "text": "Following latest AAD trends, this article will focus on the Grasshopper plug-in, based on McNeel's Rhinoceros3D. Nonetheless, the behavior of visual/graphical/diagrammatic programming or \"node editing\" can be found in other 3D products such as Dinamo, Maya, Blender, or Houdini.", "cite_spans": [], "ref_spans": []}, {"section": "Research Hypothesis", "text": "The purpose of this article is to set the data flow and methodology in visual algorithmic software (such as Grasshopper), in order to incorporate simulated features from evo-devo, allowing great geometric and architectonic diversity in a rather simple algorithm-that is, avoiding the use of scripting or added complexity through external pieces of software (add-ons).", "cite_spans": [], "ref_spans": []}, {"section": "Digital Abstraction of Evo-Devo: Basic Concept Definitions for Implementation", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Bio-Logics of Evo-Devo", "text": "From a biological perspective, Darwin's evolutionary proposal has been constantly updated. The \"modern synthesis\" theory should be highlighted, which integrates Charles Darwin's theory on natural selection, Gregor Mendel's theory on genetic inheritance, mutations, and population genetics [25] , along with other compendiums and improvements based on latest discoveries [26] .", "cite_spans": [{"start": 289, "end": 293, "text": "[25]", "ref_id": "BIBREF28"}, {"start": 370, "end": 374, "text": "[26]", "ref_id": "BIBREF30"}], "ref_spans": []}, {"section": "Bio-Logics of Evo-Devo", "text": "Current GAs are clearly influenced by the evolutionary theory and have incorporated gene strategy as strings that exchange characters-crossover-mutations to improve the search space and elitism selection through generations. However, they rarely introduce development (shape and change) as a process embodied in the evolutionary search.", "cite_spans": [], "ref_spans": []}, {"section": "Bio-Logics of Evo-Devo", "text": "Evo-devo also emphasizes more the field of mutations, being one of the elements that puts both evolution and development in common [27] . In spite of negative consequences regarding the efficiency of the search, mutations suppose a great help to transcend \"local optima\" and to enlarge the \"design space\". Pieces of software like Octopus or Wallacei (both add-ons for Grasshopper) include more detailed settings about mutation rate and strength.", "cite_spans": [{"start": 131, "end": 135, "text": "[27]", "ref_id": "BIBREF31"}], "ref_spans": []}, {"section": "Homeobox Genes", "text": "Findings around genetics include certain genes capable of shape conditioning (development) that have succeeded in recovering the science of embryology as a valid field that connects and affects the evolutionary ecosystem. They show the existence of universal mechanisms that are present in any living specie, thus describing powerful strategies for generation and emergence. They help to justify the tandem: Evolutionary developmental biology science [6] .", "cite_spans": [{"start": 451, "end": 454, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Homeobox Genes", "text": "The importance of evo-devo is notable. Firstly, for continuing the synthesis of the theory of evolution through embryology and integrating molecular genetics. Secondly, for facilitating the understanding of evolution through the drama of form, illustrating changes and formal diversity [6] .", "cite_spans": [{"start": 286, "end": 289, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Homeobox Genes", "text": "Embryology also explains the natural processes which develop a single-cell into complex multi-cellular organisms. Within DNA, 3% is regulatory. In that percentage, two relevant groups of control can be distinguished: \"What\" and \"where\". Respectively, these are the Homeobox genes and the genetic switches.", "cite_spans": [], "ref_spans": []}, {"section": "Homeobox Genes", "text": "Homeoboxes are genes assigned to purposes, to functionality, directly related to the phenotype; while switches create overlapping patterns that turn those genes on and off. Biologically, there can be up to 10 switches regulating a single gene, from which a functional overlap of patterns can be deduced. This is based then on the concept of emergence and complexity: There are not so many complex tools, but different ways of combining them [28] .", "cite_spans": [{"start": 441, "end": 445, "text": "[28]", "ref_id": "BIBREF32"}], "ref_spans": []}, {"section": "Homeobox Genes", "text": "As Leroi describes, despite the obvious differences between biology and computation language, these genes work in a way that can be clearly understood [27] : This mechanism structures and identifies the different parts of the body, allowing self-signaling to interpret the cell's situation. That is, the body plan can be thought of as the geometric abstraction of the phenotype, a map to order and dispatch the successive transformations, the recursive subdivision in which the switches operate.", "cite_spans": [{"start": 151, "end": 155, "text": "[27]", "ref_id": "BIBREF31"}], "ref_spans": []}, {"section": "Homeobox Genes", "text": "When talking about evolutionary jumps, huge changes are justified through multitasking [29] . For this situation to occur, there must be repetitive elements that appear, precisely, because of the body plan. Two different organs might serve to the same purpose, allowing one of them to be specified or changed. Or the other way around, the same organ can be used for two things, as redundancy in the system provides new opportunities ( Figure 1 ).", "cite_spans": [{"start": 87, "end": 91, "text": "[29]", "ref_id": "BIBREF33"}], "ref_spans": [{"start": 435, "end": 443, "text": "Figure 1", "ref_id": "FIGREF2"}]}, {"section": "Allometry", "text": "The third tool within the development process is the allometry [30] . Defined as the characteristic which refers to changes in relative size of body parts correlated with changes in overall size, allometry allows organisms with the same topology to end up, for example, with complementary nostrils: A horn versus a blowing hole at the top. However, a thorough analysis will reveal that the topology of the shapes is consistent.", "cite_spans": [{"start": 63, "end": 67, "text": "[30]", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "Allometry", "text": "Allometry allows geometric changes within the same topology, causing a new cycle of modifications on the phenotype, also referred to as \"an additional fourth spatial dimension\", with strong proportions related to efficiency, surface areas, and growing patterns [31] .", "cite_spans": [{"start": 261, "end": 265, "text": "[31]", "ref_id": "BIBREF35"}], "ref_spans": []}, {"section": "Allometry", "text": "In architecture, allometry can be used to speak about scale and proportions, to embed non-linear changes that could be established by the body plan. This would allow adaptation to specific contexts without compromising the topology of the project and its relations.", "cite_spans": [], "ref_spans": []}, {"section": "Allometry", "text": "Digitally, the strength of allometric changes can be applied through lists of boosters/enhancers that resemble typical sliders (numeric ranges) and scale commands. Considering the evolutive analogy, the manifestation of allometry is better related to sliders in the GAs (gene pools) than it is currently to genes. subdivision in which the switches operate.", "cite_spans": [], "ref_spans": []}, {"section": "Allometry", "text": "When talking about evolutionary jumps, huge changes are justified through multitasking [29] . For this situation to occur, there must be repetitive elements that appear, precisely, because of the body plan. Two different organs might serve to the same purpose, allowing one of them to be specified or changed. Or the other way around, the same organ can be used for two things, as redundancy in the system provides new opportunities (Figure 1 ). ", "cite_spans": [{"start": 87, "end": 91, "text": "[29]", "ref_id": "BIBREF33"}], "ref_spans": [{"start": 433, "end": 442, "text": "(Figure 1", "ref_id": "FIGREF2"}]}, {"section": "Geometry Interoperability, 3D Meshes, and Phenotypes", "text": "After a conscientious look at the mechanics of evo-devo, some of its similarities with the digital field seem obvious and easily reproducible, such as patterns and Boolean logics.", "cite_spans": [], "ref_spans": []}, {"section": "Geometry Interoperability, 3D Meshes, and Phenotypes", "text": "From all of them, the most fascinating is the construction and development of embryos, the body plan. Architects will find the geometric functioning of the embryo really comfortable since it is based on orientation, subdivision, symmetry, and polarity.", "cite_spans": [], "ref_spans": []}, {"section": "Geometry Interoperability, 3D Meshes, and Phenotypes", "text": "Together with subdivision, tessellation becomes a notable way to understand inner structures or approach cell aggregation. Whether it be faces, cells, pixels, voxels, or maxels [32] , a system that can be subdivided to incorporate hierarchical levels is fundamental to properly simulate the biological aspects.", "cite_spans": [{"start": 177, "end": 181, "text": "[32]", "ref_id": "BIBREF36"}], "ref_spans": []}, {"section": "Geometry Interoperability, 3D Meshes, and Phenotypes", "text": "In that sense, the 3D modeling of polygon meshes seems to be a firm candidate capable of dealing with the needs of the proposed abstraction. Not only because the embryo's diagram looks surprisingly similar, but because of its advantages over other models such as splines. Mesh lightness and flexibility have been well documented and are currently applied to most software for simulation and analysis: Finite elements, raytracing, collisions, structural models, energy, aerodynamics, 3D printing, etc. Even when it comes to complex surfaces, where NURBS (non-uniform rational B-spline) stand out, meshes are still used in organic modeling due to their subdivision capability.", "cite_spans": [], "ref_spans": []}, {"section": "Geometry Interoperability, 3D Meshes, and Phenotypes", "text": "Therefore, polygon meshes have become increasingly popular in recent years and have great impact in computer graphics and geometry processing. Proof of their versatility is their application to different areas such as neuroscience, mechanical engineering, astrophysics, entertainment, cultural heritage, geo-exploration, architecture, and urban modeling [33] .", "cite_spans": [{"start": 354, "end": 358, "text": "[33]", "ref_id": "BIBREF37"}], "ref_spans": []}, {"section": "Geometry Interoperability, 3D Meshes, and Phenotypes", "text": "In that regard, polygon meshes can be valued because of two main advantages with several implications:", "cite_spans": [], "ref_spans": []}, {"section": "Geometry Interoperability, 3D Meshes, and Phenotypes", "text": "\u2022 Conceptual simplicity (vertex-edge-face).", "cite_spans": [], "ref_spans": []}, {"section": "Geometry Interoperability, 3D Meshes, and Phenotypes", "text": "Efficiency for complex systems. Better performance for repetitive tasks (such as GAs).", "cite_spans": [], "ref_spans": []}, {"section": "Geometry Interoperability, 3D Meshes, and Phenotypes", "text": "\u2022 Topologic flexibility (associative relations). Constant subdivision (for organic or hierarchic purposes). Relaxation and remeshing. Low constrains for geometry modification. Fractal properties, since change can apply in different levels.", "cite_spans": [], "ref_spans": []}, {"section": "Geometry Interoperability, 3D Meshes, and Phenotypes", "text": "It is also worth mentioning the universal character of the meshes and a remarkable effort to turn it into a digital raw material. So that, the basic principles and theories keep being updated to perform inside new software such as Grasshopper: Half-edge system [34] , implicit surfaces [35, 36] or marching cubes [37] , are proof of this. In that sense, the Plankton library has special relevance for the Grasshopper community [38] .", "cite_spans": [{"start": 261, "end": 265, "text": "[34]", "ref_id": "BIBREF38"}, {"start": 286, "end": 290, "text": "[35,", "ref_id": "BIBREF39"}, {"start": 291, "end": 294, "text": "36]", "ref_id": "BIBREF40"}, {"start": 313, "end": 317, "text": "[37]", "ref_id": "BIBREF41"}, {"start": 427, "end": 431, "text": "[38]", "ref_id": "BIBREF42"}], "ref_spans": []}, {"section": "Geometry Interoperability, 3D Meshes, and Phenotypes", "text": "For all these reasons, the prototype of the case study will rely on meshes, combining data patterns with Boolean logics while modifying them in different levels of their mesh topology.", "cite_spans": [], "ref_spans": []}, {"section": "Case Study", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Objectives and Setting", "text": "The main objective of the case study is to test the viability of building an associative model capable of incorporating the characteristics of evo-devo described above to solve the deficiencies exposed. The definition is designed to resemble a simple path of data, logic and consequent as expected in a digital environment.", "cite_spans": [], "ref_spans": []}, {"section": "Objectives and Setting", "text": "The prototype (from now on, individual/s) is formed by a body plan consisting of four to six parts, originally a matrix of 2 \u00d7 3 cubes.", "cite_spans": [], "ref_spans": []}, {"section": "Objectives and Setting", "text": "At the same time, new genes with switches and boosters are introduced, ensuring that they can be applied in any of its parts with no repetition limit. That is to say, in some individuals, the same gene can manifest in all its parts. These genes are fully interchangeable and configurable to function in any situation posed by a polygonal mesh.", "cite_spans": [], "ref_spans": []}, {"section": "Objectives and Setting", "text": "Phases of the experiment are as follows, adding complexity incrementally:", "cite_spans": [], "ref_spans": []}, {"section": "Objectives and Setting", "text": "1.", "cite_spans": [], "ref_spans": []}, {"section": "Objectives and Setting", "text": "To treat merely the deformations of the parts (allometry), putting major interest in ensuring that the system works and genes can express freely (switches).", "cite_spans": [], "ref_spans": []}, {"section": "2.", "text": "Include enhancers (boosters) in those genes through lists, and introduce adaptability criteria to analyze and check their correct evolution. 3.", "cite_spans": [], "ref_spans": []}, {"section": "2.", "text": "Add modifiers to allow shape changing of the parts, i.e., alter the 'body plan', combined with previous phases. 4.", "cite_spans": [], "ref_spans": []}, {"section": "2.", "text": "Introduce new genes as homeobox (through meshes modifiers) that are expressed in different phases, on top of inner and outer references to the GAs process.", "cite_spans": [], "ref_spans": []}, {"section": "2.", "text": "The individuals run through a multi-objective genetic algorithm (MOGA) to better foresee the feasible extremes and possibilities of the definition. Multi-objective algorithms evolve the population in multiple directions (fitness). Three properties are chosen to both maximize and minimize: Area, volume, and number of faces. There are then six fitness criteria that should be contradicting enough to search for different solutions all along the Pareto front.", "cite_spans": [], "ref_spans": []}, {"section": "2.", "text": "In that regard, the MOGA is set to 20 generations with a population of 200 individuals, using the default settings established by the plug-in Octopus (SPEA-2): Elitism 0.5, mutation probability 0.2, mutation rate 0.9, and crossover rate 0.8.", "cite_spans": [], "ref_spans": []}, {"section": "2.", "text": "Last population after GA implementation is shown as a result of the different phases. Individuals are colored based on their relative properties to better understand their differences and characteristics, better distinguishing the individuals within the population. The coloring system is based on their fitness values, by building an RGB color for each of them: Green (area), blue (volume), and red (faces). Minimized values have darker colors (30, 30, 30) , while maximized values tend to be white (255, 255, 255). Pure colors arise with specialized individuals (Figure 2 ", "cite_spans": [{"start": 445, "end": 449, "text": "(30,", "ref_id": "BIBREF34"}, {"start": 450, "end": 453, "text": "30,", "ref_id": "BIBREF34"}, {"start": 454, "end": 457, "text": "30)", "ref_id": "BIBREF34"}], "ref_spans": [{"start": 564, "end": 573, "text": "(Figure 2", "ref_id": "FIGREF4"}]}, {"section": "Grasshopper Implementation and Initial Results", "text": "The first attempts quickly reveal the first problem: If there is only one flow of data-a typical feature in visual programming-no repetitions of genes can be created (because the component only exists once). Therefore, a path must be created for each part of the individual-up to 6.", "cite_spans": [], "ref_spans": []}, {"section": "Grasshopper Implementation and Initial Results", "text": "To achieve the objective of the experiment, the definition requires that each of the six parts is susceptible to \"suffering\" each of the genes.", "cite_spans": [], "ref_spans": []}, {"section": "Grasshopper Implementation and Initial Results", "text": "For this reason, the inclusion of 'clusters' is called for. Clusters are components that incorporate other Grasshopper definitions inside. Each of these clusters incorporates each and every one of the genes. By means of a numerical list indicating which gene has to be expressed, the input geometric information (one of the six parts of the body) is validated only for a single gene, the rest of them resulting in null geometry and producing a null value, non-existent (scheme 1).", "cite_spans": [], "ref_spans": []}, {"section": "Grasshopper Implementation and Initial Results", "text": "Thus, a model that works exactly as genetic switches is built: Genes are present in all the body, but they only express based on the switch data. There is no restriction on any gene. Therefore, any hypothetical definition must agglutinate all existing genes into a cluster that will replicate as many times as parts make up the body-plan. There may be fewer parts than the total due to mutations or random elements, but no more, as that would generate an existing but blank information flux. It should be remembered that the modification gene must be universal, i.e., they must be susceptible to be applied anywhere and anytime, otherwise there would be an error in the information flux. As so, the use of meshes in this experiment has one extra justification added.", "cite_spans": [], "ref_spans": []}, {"section": "Grasshopper Implementation and Initial Results", "text": "Regarding other Grasshopper implementations, the definition is based on three simple groups of information. These types will be explained in depth in the following chapters and approached by the different steps of the experiment. Definitions of genes and which would be the most suitable for architectural construction are left out of the article responsibility, where the most basic ones have been chosen. The case study is meant to remain abstract in order to focus on data flow and component relations. However, it is advisable to consult the pioneer works of Frazer [11] , as well late case studies related to the fields of shape grammar [14, 38] and space syntax.", "cite_spans": [{"start": 570, "end": 574, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 642, "end": 646, "text": "[14,", "ref_id": "BIBREF14"}, {"start": 647, "end": 650, "text": "38]", "ref_id": "BIBREF42"}], "ref_spans": []}, {"section": "Grasshopper Implementation and Initial Results", "text": "To mention a few, most common objectives to be optimized in architecture are: Matter, structure, shadow projection, solar exposure, built area, volume/surface ratio, height, density, connections, or views. Choosing the right genes to influence these properties is key to developing a healthy population and a rich \"search space\".", "cite_spans": [], "ref_spans": []}, {"section": "Grasshopper Implementation and Initial Results", "text": "The first attempts quickly reveal the first problem: If there is only one flow of data-a typical feature in visual programming-no repetitions of genes can be created (because the component only exists once). Therefore, a path must be created for each part of the individual-up to 6.", "cite_spans": [], "ref_spans": []}, {"section": "Grasshopper Implementation and Initial Results", "text": "To achieve the objective of the experiment, the definition requires that each of the six parts is susceptible to \"suffering\" each of the genes.", "cite_spans": [], "ref_spans": []}, {"section": "Grasshopper Implementation and Initial Results", "text": "For this reason, the inclusion of 'clusters' is called for. Clusters are components that incorporate other Grasshopper definitions inside. Each of these clusters incorporates each and every one of the genes. By means of a numerical list indicating which gene has to be expressed, the input geometric information (one of the six parts of the body) is validated only for a single gene, the rest of them resulting in null geometry and producing a null value, non-existent (Scheme 1).", "cite_spans": [], "ref_spans": []}, {"section": "Grasshopper Implementation and Initial Results", "text": "Biomimetics 2019, 4, x FOR PEER REVIEW 9 of 18 views. Choosing the right genes to influence these properties is key to developing a healthy population and a rich \"search space\". ", "cite_spans": [], "ref_spans": []}, {"section": "Grasshopper Implementation and Initial Results", "text": "The first attempts quickly reveal the first problem: If there is only one flow of data-a typical feature in visual programming-no repetitions of genes can be created (because the component only exists once). Therefore, a path must be created for each part of the individual-up to 6.", "cite_spans": [], "ref_spans": []}, {"section": "Grasshopper Implementation and Initial Results", "text": "To achieve the objective of the experiment, the definition requires that each of the six parts is susceptible to \"suffering\" each of the genes.", "cite_spans": [], "ref_spans": []}, {"section": "Grasshopper Implementation and Initial Results", "text": "For this reason, the inclusion of 'clusters' is called for. Clusters are components that incorporate other Grasshopper definitions inside. Each of these clusters incorporates each and every one of the genes. By means of a numerical list indicating which gene has to be expressed, the input geometric information (one of the six parts of the body) is validated only for a single gene, the rest of them resulting in null geometry and producing a null value, non-existent (scheme 1). Thus, a model that works exactly as genetic switches is built: Genes are present in all the body, but they only express based on the switch data. There is no restriction on any gene. Therefore, any hypothetical definition must agglutinate all existing genes into a cluster that will replicate as many times as parts make up the body-plan. There may be fewer parts than the total due to mutations or random elements, but no more, as that would generate an existing but blank information flux. It should be remembered that the modification gene must be universal, i.e., they must be susceptible to be applied anywhere and anytime, otherwise there would be an error in the information flux. As so, the use of meshes in this experiment has one extra justification added.", "cite_spans": [], "ref_spans": []}, {"section": "Grasshopper Implementation and Initial Results", "text": "Regarding other Grasshopper implementations, the definition is based on three simple groups of information. These types will be explained in depth in the following chapters and approached by the different steps of the experiment. Thus, a model that works exactly as genetic switches is built: Genes are present in all the body, but they only express based on the switch data. There is no restriction on any gene. Therefore, any hypothetical definition must agglutinate all existing genes into a cluster that will replicate as many times as parts make up the body-plan. There may be fewer parts than the total due to mutations or random elements, but no more, as that would generate an existing but blank information flux. It should be remembered that the modification gene must be universal, i.e., they must be susceptible to be applied anywhere and anytime, otherwise there would be an error in the information flux. As so, the use of meshes in this experiment has one extra justification added.", "cite_spans": [], "ref_spans": []}, {"section": "Grasshopper Implementation and Initial Results", "text": "Regarding other Grasshopper implementations, the definition is based on three simple groups of information. These types will be explained in depth in the following chapters and approached by the different steps of the experiment.", "cite_spans": [], "ref_spans": []}, {"section": "1.", "text": "The phenotype: Expressed as a mesh, originated in the body plan, that gradually receives changes through genes. It is a list of four to seven meshes to allow independent interaction and modifications. 2.", "cite_spans": [], "ref_spans": []}, {"section": "1.", "text": "Genes: Composed by modifiers, meaning components that change meshes in different ways: Trimming, scaling (uniform or nonuniform), or remeshing (Mesh+). It is worth remembering that evolutionary algorithms usually consider number sliders as genes. This is not the case, and also the point of this research.", "cite_spans": [], "ref_spans": []}, {"section": "3.", "text": "Boosters and switches: Both exist as mere lists of data. To relate the genetic algorithm and the Grasshopper definition, these data are originated through a gene pool component (several number sliders grouped under the same constraints).", "cite_spans": [], "ref_spans": []}, {"section": "Steps", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "To Check Parts Deformation to Ensure that Any Gene Can Be Applied to Any of the Parts", "text": "From this point onwards, because of the need to duplicate information, clusters containing gene information are used throughout the algorithm.", "cite_spans": [], "ref_spans": []}, {"section": "To Check Parts Deformation to Ensure that Any Gene Can Be Applied to Any of the Parts", "text": "Initial genes only consider scalar changes in different axis, becoming the allometry part of the model. The body plan is still simple and only orthogonal changes are allowed. The Grasshopper's components for these changes are: Scale, nonuniform scale (Y, Z, and YZ axis), and movement (X axis) (Figure 3 ). 1. The phenotype: Expressed as a mesh, originated in the body plan, that gradually receives changes through genes. It is a list of four to seven meshes to allow independent interaction and modifications. 2. Genes: Composed by modifiers, meaning components that change meshes in different ways:", "cite_spans": [], "ref_spans": [{"start": 294, "end": 303, "text": "(Figure 3", "ref_id": "FIGREF11"}]}, {"section": "To Check Parts Deformation to Ensure that Any Gene Can Be Applied to Any of the Parts", "text": "Trimming, scaling (uniform or nonuniform), or remeshing (Mesh+). It is worth remembering that evolutionary algorithms usually consider number sliders as genes. This is not the case, and also the point of this research. 3. Boosters and switches: Both exist as mere lists of data. To relate the genetic algorithm and the Grasshopper definition, these data are originated through a gene pool component (several number sliders grouped under the same constraints).", "cite_spans": [], "ref_spans": []}, {"section": "Steps", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "To Check Parts Deformation to Ensure that Any Gene Can Be Applied to Any of the Parts", "text": "From this point onwards, because of the need to duplicate information, clusters containing gene information are used throughout the algorithm.", "cite_spans": [], "ref_spans": []}, {"section": "To Check Parts Deformation to Ensure that Any Gene Can Be Applied to Any of the Parts", "text": "Initial genes only consider scalar changes in different axis, becoming the allometry part of the model. The body plan is still simple and only orthogonal changes are allowed. The Grasshopper's components for these changes are: Scale, nonuniform scale (Y, Z, and YZ axis), and movement (X axis) (Figure 3) . ", "cite_spans": [], "ref_spans": [{"start": 294, "end": 304, "text": "(Figure 3)", "ref_id": "FIGREF11"}]}, {"section": "Addition of Boosters for the Genes Through Lists of Data and Analysis Criteria", "text": "The use of numeric lists as parallel information to generate data flow allows to exponentially change possible outcomes of the aforementioned genes. To check the correct behavior of this part of the experiment, an evolutionary algorithm is implemented in the definition (first Galapagos, then Octopus).", "cite_spans": [], "ref_spans": []}, {"section": "Addition of Boosters for the Genes Through Lists of Data and Analysis Criteria", "text": "As previously mentioned, these lists are based on gene pool components. To improve the search ", "cite_spans": [], "ref_spans": []}, {"section": "Addition of Boosters for the Genes Through Lists of Data and Analysis Criteria", "text": "The use of numeric lists as parallel information to generate data flow allows to exponentially change possible outcomes of the aforementioned genes. To check the correct behavior of this part of the experiment, an evolutionary algorithm is implemented in the definition (first Galapagos, then Octopus).", "cite_spans": [], "ref_spans": []}, {"section": "Addition of Boosters for the Genes Through Lists of Data and Analysis Criteria", "text": "As previously mentioned, these lists are based on gene pool components. To improve the search and reduce the design space, these lists include multipliers, i.e., the number of elements within the range borders is reduced: For 0 to 1 there are only five positions, instead of 10 (0.0-0.2-0.4-0.8-1.0).", "cite_spans": [], "ref_spans": []}, {"section": "Addition of Boosters for the Genes Through Lists of Data and Analysis Criteria", "text": "The individuals produced (phenotypes) soon reach extreme typologies, thanks to the drastic shapes that boosters allow [39] . The diversity found in the Pareto front announces the correct behavior of both body plan and boosters.", "cite_spans": [{"start": 118, "end": 122, "text": "[39]", "ref_id": "BIBREF43"}], "ref_spans": []}, {"section": "Addition of Boosters for the Genes Through Lists of Data and Analysis Criteria", "text": "Although evolution criteria or settings for the fitness search are not relevant for the final purpose of the experiment, they do confirm basic necessary points for any similar task:", "cite_spans": [], "ref_spans": []}, {"section": "Addition of Boosters for the Genes Through Lists of Data and Analysis Criteria", "text": "\u2022 To observe the extremes and diversity of the population.", "cite_spans": [], "ref_spans": []}, {"section": "\u2022", "text": "To check that geometry and its values are understood at all times by the GAs.", "cite_spans": [], "ref_spans": []}, {"section": "Addition of Modifiers to Change the Body Plan", "text": "To greatly increase the diversity of shapes produced by the definition, the original grid is substituted by a system of moving and rotating planes. These planes divide the basic genotype (an abstract rectangle) in an unknown quantity of parts to be split and extruded as a mesh (ranging from 4 to 7) (Figures 4 and 5) .", "cite_spans": [], "ref_spans": [{"start": 300, "end": 317, "text": "(Figures 4 and 5)", "ref_id": "FIGREF14"}]}, {"section": "Addition of Modifiers to Change the Body Plan", "text": "To better compare the generations, the original rectangle is kept at 2 \u00d7 4 \u00d7 6 units. However, introducing genes and clusters in the body plan would also have a positive impact in the richness of the design space. Although evolution criteria or settings for the fitness search are not relevant for the final purpose of the experiment, they do confirm basic necessary points for any similar task:", "cite_spans": [], "ref_spans": []}, {"section": "Addition of Modifiers to Change the Body Plan", "text": "\u2022 To observe the extremes and diversity of the population.", "cite_spans": [], "ref_spans": []}, {"section": "\u2022", "text": "To check that geometry and its values are understood at all times by the GAs.", "cite_spans": [], "ref_spans": []}, {"section": "Addition of Modifiers to Change the Body Plan", "text": "To greatly increase the diversity of shapes produced by the definition, the original grid is substituted by a system of moving and rotating planes. These planes divide the basic genotype (an abstract rectangle) in an unknown quantity of parts to be split and extruded as a mesh (ranging from 4 to 7) (Figures 4 and 5) .", "cite_spans": [], "ref_spans": [{"start": 300, "end": 317, "text": "(Figures 4 and 5)", "ref_id": "FIGREF14"}]}, {"section": "Addition of Modifiers to Change the Body Plan", "text": "To better compare the generations, the original rectangle is kept at 2 \u00d7 4 \u00d7 6 units. However, introducing genes and clusters in the body plan would also have a positive impact in the richness of the design space. ", "cite_spans": [], "ref_spans": []}, {"section": "Addition of New Genes for Mesh Modification and Their Activation Based on Different Criteria", "text": "In this phase, a new toolkit of genes is introduced to change the topology of the parts in the individuals. These mesh modifiers subdivide the mesh and change its geometry by adding, deleting, or connecting their faces. As previously mentioned, there are six homeotic genes that change the phenotype appearance (extracted from Mesh + plug-in): Node, Antisub, Pinch, Hair, Peel, and Polyp. Their only purpose is being able to distinguish the different genes and giving the algorithm more options (Figure 6 ). In this phase, a new toolkit of genes is introduced to change the topology of the parts in the individuals. These mesh modifiers subdivide the mesh and change its geometry by adding, deleting, or connecting their faces. As previously mentioned, there are six homeotic genes that change the phenotype appearance (extracted from Mesh + plug-in): Node, Antisub, Pinch, Hair, Peel, and Polyp. Their only purpose is being able to distinguish the different genes and giving the algorithm more options (Figure 6 ). As a second addition to this last chapter, inner and outer references have been introduced to establish different relations to the self-developing system (Figure 7 ):", "cite_spans": [], "ref_spans": [{"start": 495, "end": 504, "text": "(Figure 6", "ref_id": "FIGREF20"}, {"start": 1003, "end": 1012, "text": "(Figure 6", "ref_id": "FIGREF20"}, {"start": 1170, "end": 1179, "text": "(Figure 7", "ref_id": "FIGREF22"}]}, {"section": "Addition of New Genes for Mesh Modification and Their Activation Based on Different Criteria", "text": "\u2022 Inner relation has been set within the cluster. When one of the parts has a volume greater than the established number (29 u 3 ), the mesh subdivides itself. These should establish a tendency to have biggest parts with more faces.", "cite_spans": [], "ref_spans": []}, {"section": "Addition of New Genes for Mesh Modification and Their Activation Based on Different Criteria", "text": "\u2022 Outer relation as a random factor that can influence the individual [11] . To simulate, in a simple way, the environment influence on the phenotype, a probability graph with conditional gates has been set to change the mesh in three ways:", "cite_spans": [{"start": 70, "end": 74, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Addition of New Genes for Mesh Modification and Their Activation Based on Different Criteria", "text": "o No changes. 80% probability.", "cite_spans": [], "ref_spans": []}, {"section": "Addition of New Genes for Mesh Modification and Their Activation Based on Different Criteria", "text": "o Catmull-Clark subdivision. 10% probability (subdivision to organic).", "cite_spans": [], "ref_spans": []}, {"section": "Addition of New Genes for Mesh Modification and Their Activation Based on Different Criteria", "text": "o Picture frame. 10% probability (holes in the mesh). As a second addition to this last chapter, inner and outer references have been introduced to establish different relations to the self-developing system (Figure 7 ):", "cite_spans": [], "ref_spans": [{"start": 208, "end": 217, "text": "(Figure 7", "ref_id": "FIGREF22"}]}, {"section": "Addition of New Genes for Mesh Modification and Their Activation Based on Different Criteria", "text": "\u2022 Inner relation has been set within the cluster. When one of the parts has a volume greater than the established number (29 u 3 ), the mesh subdivides itself. These should establish a tendency to have biggest parts with more faces.", "cite_spans": [], "ref_spans": []}, {"section": "Addition of New Genes for Mesh Modification and Their Activation Based on Different Criteria", "text": "\u2022 Outer relation as a random factor that can influence the individual [11] . To simulate, in a simple way, the environment influence on the phenotype, a probability graph with conditional gates has been set to change the mesh in three ways:", "cite_spans": [{"start": 70, "end": 74, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Addition of New Genes for Mesh Modification and Their Activation Based on Different Criteria", "text": "No changes. 80% probability. Catmull-Clark subdivision. 10% probability (subdivision to organic). Picture frame. 10% probability (holes in the mesh).", "cite_spans": [], "ref_spans": []}, {"section": "Addition of New Genes for Mesh Modification and Their Activation Based on Different Criteria", "text": "\u2022 Outer relation as a random factor that can influence the individual [11] . To simulate, in a simple way, the environment influence on the phenotype, a probability graph with conditional gates has been set to change the mesh in three ways:", "cite_spans": [{"start": 70, "end": 74, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Addition of New Genes for Mesh Modification and Their Activation Based on Different Criteria", "text": "o No changes. 80% probability.", "cite_spans": [], "ref_spans": []}, {"section": "Addition of New Genes for Mesh Modification and Their Activation Based on Different Criteria", "text": "o Catmull-Clark subdivision. 10% probability (subdivision to organic).", "cite_spans": [], "ref_spans": []}, {"section": "Addition of New Genes for Mesh Modification and Their Activation Based on Different Criteria", "text": "o Picture frame. 10% probability (holes in the mesh). ", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "The use of clusters and universal modifiers ensures fast changes through the parametric model and greatly decreases the size and complexity of the definition. So that, nesting the definition in a hierarchical way has proven useful and a flexible tool.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "Thus, the data flow to simulate evo-devo proposed by the authors after the case study is the following (Scheme 2):", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "Biomimetics 2019, 4, x FOR PEER REVIEW 13 of 18", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "The use of clusters and universal modifiers ensures fast changes through the parametric model and greatly decreases the size and complexity of the definition. So that, nesting the definition in a hierarchical way has proven useful and a flexible tool.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "Thus, the data flow to simulate evo-devo proposed by the authors after the case study is the following (scheme 2): Scheme 2. Proposed data flow to parametrize evo-devo within the digital genetic algorithm (GA) framework in visual programming. Source: Authors.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "As a result, only two lists of data (gene pools) are needed per gene type: Switch and booster. This procedure allows to stack many levels of genes for different purposes, while the only worry should be that input and output work as a mesh (Figure 8) .", "cite_spans": [], "ref_spans": [{"start": 239, "end": 249, "text": "(Figure 8)", "ref_id": "FIGREF24"}]}, {"section": "Results", "text": "It is advised to constrain gradients of booster's lists to low quantities with significant steps between them. Doing the opposite will add unnecessary combinations and slow down the algorithmic search/optimization. Scheme 2. Proposed data flow to parametrize evo-devo within the digital genetic algorithm (GA) framework in visual programming. Source: Authors.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "As a result, only two lists of data (gene pools) are needed per gene type: Switch and booster. This procedure allows to stack many levels of genes for different purposes, while the only worry should be that input and output work as a mesh ( Figure 8 ).", "cite_spans": [], "ref_spans": [{"start": 241, "end": 249, "text": "Figure 8", "ref_id": "FIGREF24"}]}, {"section": "Results", "text": "As a result, only two lists of data (gene pools) are needed per gene type: Switch and booster. This procedure allows to stack many levels of genes for different purposes, while the only worry should be that input and output work as a mesh (Figure 8) .", "cite_spans": [], "ref_spans": [{"start": 239, "end": 249, "text": "(Figure 8)", "ref_id": "FIGREF24"}]}, {"section": "Results", "text": "It is advised to constrain gradients of booster's lists to low quantities with significant steps between them. Doing the opposite will add unnecessary combinations and slow down the algorithmic search/optimization. The gradient of colors through the phases and additions to the algorithm enhance significative differences. The design space boundaries keep changing, and thus the population tends toward specific hues, some of the colors cannot be reached anymore. Remarkable evaluations from color analysis might be ( Figure 9 ):", "cite_spans": [], "ref_spans": [{"start": 518, "end": 526, "text": "Figure 9", "ref_id": "FIGREF27"}]}, {"section": "Results", "text": "\u2022 First phase (Section 5.3.1) was able to better optimize geometries related to warm colors, while the last (Section 5.3.4) generation did to cold.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "\u2022 Phase three (Section 5.3.3), due to the increment of the design space, started to present fewer extreme individuals with a tendency to green (area optimization). It is advised to constrain gradients of booster's lists to low quantities with significant steps between them, doing the opposite will add unnecessary combinations and slow down the algorithmic search/optimization.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "The gradient of colors through the phases and additions to the algorithm enhance significative differences. The design space boundaries keep changing, and thus the population tends toward specific hues, some of the colors cannot be reached anymore. Remarkable evaluations from color analysis might be ( Figure 9 ):", "cite_spans": [], "ref_spans": [{"start": 303, "end": 311, "text": "Figure 9", "ref_id": "FIGREF27"}]}, {"section": "Results", "text": "\u2022 First phase (Section 5.3.1) was able to better optimize geometries related to warm colors, while the last (Section 5. The evolution in the color scheme makes sense due to the added complexity in the model. Because of this, the algorithm finds it difficult to create individuals with a high amount of faces without increasing areas or volume.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "Three histogram charts ( Figure 10 ) have been arranged to describe the data produced by the last generation of the following combinations. All of them include boosters and MOGA's optimization. All data in the chart have been normalized to 0-1 in the horizontal axis, while the vertical axis is logarithmic to better describe that very same data.", "cite_spans": [], "ref_spans": [{"start": 25, "end": 34, "text": "Figure 10", "ref_id": "FIGREF2"}]}, {"section": "Results", "text": "1. Simple body plan plus allometry (blue). 2. Rotation planes to the body plan plus allometry (red). 3. Mesh modifiers with environment inputs plus allometry and rotation planes (yellow).", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "Area and volume charts follow the same behavior. It is observable that the successive additions The evolution in the color scheme makes sense due to the added complexity in the model. Because of this, the algorithm finds it difficult to create individuals with a high amount of faces without increasing areas or volume.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "Three histogram charts ( Figure 10 ) have been arranged to describe the data produced by the last generation of the following combinations. All of them include boosters and MOGA's optimization. All data in the chart have been normalized to 0-1 in the horizontal axis, while the vertical axis is logarithmic to better describe that very same data.", "cite_spans": [], "ref_spans": [{"start": 25, "end": 34, "text": "Figure 10", "ref_id": "FIGREF2"}]}, {"section": "1.", "text": "Simple body plan plus allometry (blue).", "cite_spans": [], "ref_spans": []}, {"section": "2.", "text": "Rotation planes to the body plan plus allometry (red).", "cite_spans": [], "ref_spans": []}, {"section": "3.", "text": "Mesh modifiers with environment inputs plus allometry and rotation planes (yellow). Figure 10 . Chart distribution based on data produced by the last generation. Source: Authors.", "cite_spans": [], "ref_spans": [{"start": 84, "end": 93, "text": "Figure 10", "ref_id": "FIGREF2"}]}, {"section": "Discussion", "text": "As architects under the influence of computing, we continue to inquire into its language and the ability of its processes to generate architecture. We continue to explore design and push the limitations of the user interface, supporting that \"logic should be the new way\" as Leach stated in the 2000s [40] .", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Although the framework proposed is meant to be as abstract and flexible as possible, architects should always revisit their own understanding for approaching the project, accepting that designing the behavior of the body plan and defining its shape grammar should be part of their design process [41] .", "cite_spans": [{"start": 296, "end": 300, "text": "[41]", "ref_id": "BIBREF45"}], "ref_spans": []}, {"section": "Discussion", "text": "The case study has successfully demonstrated the possibility of seamlessly incorporating elements of evo-devo. Approach, strategies, and final design have been considerably influenced by EAs, and the simulation of biological processes allowed to deal with great complexity while keeping advantages and design flexibility.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "\"Simply stated, what we are evolving are the rules for generating form, rather than the forms themselves. We are describing processes, not components; ours is the packet-of-seeds as opposed to the bag-of-bricks approach.\" [11] .", "cite_spans": [{"start": 222, "end": 226, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Discussion", "text": "Including a cluster as the body plan was later discarded for a better comparison of the individuals. As in biology, if changes (usually due to mutations) occur in deeper steps of the development, they produce greater modifications. This is highly interesting for discovering new designs, but implementing it in the case study meant too much variance to be properly analyzed later on. Area and volume charts follow the same behavior. It is observable that the successive additions have made it possible to increase the extremes in the maxima while maintaining the minima. That is, design space is increased and repetition is reduced.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Adding complexity to the mesh (red and yellow) was expected to produce both area and volume augment: The first due to the rugosity of the faces, the second because that rugosity increases the bounding box space.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "The addition of rotation to the body plan building (red) greatly increased the boundaries, allowing complexity under a less constrained design strategy. The average also decreased, proving again that the population gets diverse.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "The third chart (faces) depicts a dramatic change between the mesh modifiers (yellow) and two previous phases. This is expected, as all mesh modifiers increased number of faces and, also, environment setting granted the option to duplicate them. In that sense, it would have been recommendable to introduce mesh modifiers that could reduce mesh face count. Once more, the addition of rotation planes unblocked (red) the capacity of the prototype, that was fixed until then to six-sided boxes.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "As architects under the influence of computing, we continue to inquire into its language and the ability of its processes to generate architecture. We continue to explore design and push the limitations of the user interface, supporting that \"logic should be the new way\" as Leach stated in the 2000s [40] .", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Although the framework proposed is meant to be as abstract and flexible as possible, architects should always revisit their own understanding for approaching the project, accepting that designing the behavior of the body plan and defining its shape grammar should be part of their design process [41] .", "cite_spans": [{"start": 296, "end": 300, "text": "[41]", "ref_id": "BIBREF45"}], "ref_spans": []}, {"section": "Discussion", "text": "The case study has successfully demonstrated the possibility of seamlessly incorporating elements of evo-devo. Approach, strategies, and final design have been considerably influenced by EAs, and the simulation of biological processes allowed to deal with great complexity while keeping advantages and design flexibility.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "\"Simply stated, what we are evolving are the rules for generating form, rather than the forms themselves. We are describing processes, not components; ours is the packet-of-seeds as opposed to the bag-of-bricks approach.\". [11] Including a cluster as the body plan was later discarded for a better comparison of the individuals. As in biology, if changes (usually due to mutations) occur in deeper steps of the development, they produce greater modifications. This is highly interesting for discovering new designs, but implementing it in the case study meant too much variance to be properly analyzed later on.", "cite_spans": [{"start": 223, "end": 227, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Discussion", "text": "For that matter, architects should always set the boundaries of the body plan within the range of feasibility to reduce unnecessary search through the fitness landscape. Avoiding over information through needless gradients of data will create meaningful genomes with phenotypes that are relevant and can make a difference in the fitness landscape.", "cite_spans": [], "ref_spans": []}, {"section": "Further Research", "text": "Final concerns of the case study were focused towards the implementation in the future of a critical feature from the biologic systems. Phenotypes depend on switches, the body plan, homeotic genes, and boosters [27] ; nevertheless, embryological modeling allows to eliminate size association and scaling problems by introducing indirect connections between genotype and phenotype, dramatically reducing computational load [42] . This is crucial in the GA environment, as thousands of individuals have to be expressed as phenotypes for them to be evaluated and selected. Being able to extrapolate from the raw data of the individual (the genome, as in DNA) would have a major impact in the design landscape, as the one calculated in this article, through the addition of evo-devo processes.", "cite_spans": [{"start": 211, "end": 215, "text": "[27]", "ref_id": "BIBREF31"}], "ref_spans": []}, {"section": "Further Research", "text": "The whole process gains special relevance due to the need of reducing the computational load, in the same way that DNA does, trying to avoid the explicit calculation of the phenotype.", "cite_spans": [], "ref_spans": []}, {"section": "Further Research", "text": "The appearance of Building Information Modelling (BIM) might have a great influence in that sense, as the expression of architectural form is generated digitally from information [43] . The study of the physical qualities of a gene has demonstrated, for example, that not every person with the same variation in their genes will physically show on his body a physical abnormality. Those genes out of the normal physical qualities (i.e., extra length on a particular gene) provoke, just in some cases, a physical change in the human body or brain. Because of this, study of the abnormal physical characteristics of the genes in individuals not showing phenotypes variations, confronted by the study of the ones that are indeed showing phenotype variations, has been demonstrated to be a really powerful tool for research on genetic disorders.", "cite_spans": [{"start": 179, "end": 183, "text": "[43]", "ref_id": "BIBREF47"}], "ref_spans": []}, {"section": "Further Research", "text": "The analysis of the physical properties of the genes themselves can be, in a similar way, very useful for analysis purposes when building physical characteristics-phenotype-defined by relevant information systems such as BIM.", "cite_spans": [], "ref_spans": []}, {"section": "Further Research", "text": "On the other hand, keeping a low complexity model of the phenotypes through mesh face memory [44] could help to improve analysis of \"architectonic embryos\" that would carry on and develop specific properties from basic levels to more detailed ones in the hierarchic structure. Mesh face memory could add inclusive and exclusive properties, or even sub-groups of genetic modifiers within the same parametric model. Also, as a last matter of further research, the possibility of a machine learning (ML) algorithm implementation has been considered. Once the Pareto front components have been defined, and through the inclusion of certain variables representing the particular requirements for a specific design, a ML algorithm can be taught as the one evaluating and choosing the most adequate element within the Pareto front elements to that very particular design brief. 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The Body Plan These regulatory genes are intrinsically related to a second characteristic of the biologic development: the body plan.", "type": "figure"}, "FIGREF2": {"text": "Figure 1. (Left) A worm's body plan. (Middle) Body plan comparison between different species and embryo subdivision's topology (source: Carroll, 2005). (Right) 3D mesh subdivision modeling (source: Authors).", "type": "figure"}, "FIGREF3": {"text": "Figure 1. (Left) A worm's body plan. (Middle) Body plan comparison between different species and embryo subdivision's topology (source: Carroll, 2005). (Right) 3D mesh subdivision modeling (source: Authors).", "type": "figure"}, "FIGREF4": {"text": "Figure 2. Analysis of individuals based on three fitness criteria both minimized and maximized. Colors applied are based on RGB channels: 30-255, 255 being the maximized value and 30 the minimized. Source: Authors.", "type": "figure"}, "FIGREF5": {"text": "Scheme 1. Cluster diagram and path selection through switch. Source: Authors.", "type": "figure"}, "FIGREF6": {"text": "Figure 2. Analysis of individuals based on three fitness criteria both minimized and maximized. Colors applied are based on RGB channels: 30-255, 255 being the maximized value and 30 the minimized. Source: Authors.", "type": "figure"}, "FIGREF7": {"text": "Figure 2. Analysis of individuals based on three fitness criteria both minimized and maximized. Colors applied are based on RGB channels: 30-255, 255 being the maximized value and 30 the minimized. Source: Authors.", "type": "figure"}, "FIGREF8": {"text": "Scheme 1. Cluster diagram and path selection through switch. Source: Authors.", "type": "figure"}, "FIGREF9": {"text": "Scheme 1. Cluster diagram and path selection through switch. Source: Authors.", "type": "figure"}, "FIGREF10": {"text": "2019, 4, x FOR PEER REVIEW 10 of 18", "type": "figure"}, "FIGREF11": {"text": "Figure 3. Genes as allometry introduced within a simple body plan. Checking genes repetition and data flow behavior. Source: Authors.", "type": "figure"}, "FIGREF12": {"text": "Figure 3. Genes as allometry introduced within a simple body plan. Checking genes repetition and data flow behavior. Source: Authors.", "type": "figure"}, "FIGREF14": {"text": "Figure 4. Position and rotation for planes to organize the body plan. Source: Authors. Figure 4. Position and rotation for planes to organize the body plan. Source: Authors.", "type": "figure"}, "FIGREF15": {"text": "Figure 4. Position and rotation for planes to organize the body plan. Source: Authors. Figure 4. Position and rotation for planes to organize the body plan. Source: Authors.", "type": "figure"}, "FIGREF16": {"text": "Figure 4. Position and rotation for planes to organize the body plan. Source: Authors.", "type": "figure"}, "FIGREF17": {"text": "Figure 5. Generation 20 though the test that mixes both allometric genes and non-orthogonal body plan modification. Source: Authors.", "type": "figure"}, "FIGREF18": {"text": "Figure 5. Generation 20 though the test that mixes both allometric genes and non-orthogonal body plan modification. Source: Authors.", "type": "figure"}, "FIGREF19": {"text": "Addition of New Genes for Mesh Modification and Their Activation Based on Different Criteria", "type": "figure"}, "FIGREF20": {"text": "Figure 6. Six different mesh modifiers applied in the last phase to change the topology. Isometric view. Source: Authors.", "type": "figure"}, "FIGREF21": {"text": "Figure 6. Six different mesh modifiers applied in the last phase to change the topology. Isometric view. Source: Authors.", "type": "figure"}, "FIGREF22": {"text": "Figure 7. Generation 20 in the last phase of the case study. Source: Authors. Figure 7. Generation 20 in the last phase of the case study. Source: Authors.", "type": "figure"}, "FIGREF23": {"text": "Figure 7. Generation 20 in the last phase of the case study. Source: Authors. Figure 7. Generation 20 in the last phase of the case study. Source: Authors.", "type": "figure"}, "FIGREF24": {"text": "Figure 8. Added complexity into the model (from left to right): Regular subdivision, orthogonal subdivision, non-orthogonal subdivision, allometric changes, application of mesh modifiers, and extra subdivision because environment requirements are met.", "type": "figure"}, "FIGREF25": {"text": "Figure 8. Added complexity into the model (from left to right): Regular subdivision, orthogonal subdivision, non-orthogonal subdivision, allometric changes, application of mesh modifiers, and extra subdivision because environment requirements are met.", "type": "figure"}, "FIGREF26": {"text": "3.4) generation did to cold. \u2022 Phase three (Section 5.3.3), due to the increment of the design space, started to present fewer extreme individuals with a tendency to green (area optimization). \u2022 Last phase (Section 5.3.4) achieved new colors that had not appeared in previous phases, like purple, but lost vivid warm colors. Biomimetics 2019, 4, x FOR PEER REVIEW 14 of 18 \u2022 Last phase (Section 5.3.4) achieved new colors that had not appeared in previous phases, like purple, but lost vivid warm colors.", "type": "figure"}, "FIGREF27": {"text": "Figure 9. Selection of extreme individuals within the Pareto front. Arrangement based on HUE, each row belongs to a different phase (from top to bottom: First phase, third phase, and last phase). Source: Authors.", "type": "figure"}, "FIGREF28": {"text": "Figure 9. Selection of extreme individuals within the Pareto front. Arrangement based on HUE, each row belongs to a different phase (from top to bottom: First phase, third phase, and last phase). Source: Authors.", "type": "figure"}, "FIGREF29": {"text": "Figure 10. Chart distribution based on data produced by the last generation. Source: Authors.", "type": "figure"}, "TABREF1": {"text": "Biomimetics 2019, 4, x FOR PEER REVIEW 15 of 18", "type": "table"}}}
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{"paper_id": "199664240", "_pdf_hash": "7b708069637b64cded8abbe1eb7ea469232ac419", "abstract": [{"section": "Abstract", "text": "The existing theoretical literature on mass customization maintains that customization reduces product differentiation and intensifies price competition. In contrast, operations management studies argue that customization serves primarily to differentiate a company from its competitors. Interactive involvement of the customer in product design creates an affective relationship with the firm, relaxing price competition. This paper provides a model that incorporates consumer involvement to explain the phenomena described in the operations management literature.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Two firms on the Hotelling line compete for a continuum of consumers with heterogeneous brand preferences. An exogenously given fraction of consumers is potentially interested in customization. Consumer benefits from customization are the rewards from a special shopping experience and the value of product customization (a better fitting product); these benefits are higher for consumers located closer to the customizing brand. When a consumer purchases a customized product, he/she incurs waiting costs. Each firm simultaneously decides whether to offer standard products, customized products, or both, and then engage in price competition. I show that customization increases product differentiation, leading to less intense price competition. Depending on the parameter values, in equilibrium either both firms offer customized products, one firm offers customized products and the other standard and customized products, or one firm offers customized products and the other standard products. I perform comparative statics analysis with respect to the fraction of consumers interested in customization, the waiting costs, and the fixed cost of customization.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Mass customization is the capability to produce individually tailored goods and services for a relatively large market with near mass production efficiency. 1 Advances in Internet-based information technologies and improvements in manufacturing flexibility have made customization a reality in many product categories. For example, Dell builds to order notebook and desktop computers; Nike and Adidas allow consumers to create their most preferred athletic pair of shoes; apparel vendor Lands' End offers custom-crafted pants and shirts; Timbuk2 customizes messenger bags and backpacks; MiniUSA.com provides a \"build a new MINI\" option where the consumer can construct a MINI Cooper car of his/her dreams.", "cite_spans": [{"start": 157, "end": 158, "text": "1", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Introduction", "text": "Theoretical studies of mass customization draw upon earlier literature in horizontal product differentiation. 2 Customization enables firms to take advantage of consumers' desires for ideal varieties, but reduces product differentiation and intensifies price competition ( Customization differs from the strategy of offering as many variants as possible. For true customization to take place, the customer must be involved in specifying the characteristics of his/her ideal product during the product design, fabrication, and assembly. 3 This important aspect of customization has never received direct attention in the theoretical literature.", "cite_spans": [{"start": 110, "end": 111, "text": "2", "ref_id": "BIBREF1"}, {"start": 536, "end": 537, "text": "3", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Introduction", "text": "Operations management and information system scholars, on the other hand, have thoroughly described the economic implications of consumer co-design activities. They argue that customization serves primarily to differentiate a company from its competitors. The interactive involvement of the customer in the product design process creates a stronger affective relationship with the firm that subsequently leads to firm loyalty. High loyalty, in turn, relaxes price-based competition (Gom-mans, Krishnan, and Scheffold, 2001, Broekhuizen and Alsem, 2002, Grewal, Iyer, Krishnan, and Sharma, 2003, Arora et al., 2008) , which is incompatible with the findings in the theoretical studies.", "cite_spans": [{"start": 595, "end": 614, "text": "Arora et al., 2008)", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Introduction", "text": "The present paper attempts to reconcile the conflicting implications of the theoretical and the qualitative operations management literatures regarding the effect of mass customization on the intensity of price competition. Namely, it formalizes the arguments put forth in the operations management literature and proposes a model that successfully captures the effect of relaxed price competition due to consumer interactive involvement.", "cite_spans": [], "ref_spans": []}, {"section": "Overview of the Model and Results", "text": "I adopt the standard Hotelling model with two firms competing for a continuum of consumers. Consumers are heterogeneous in two dimensions. First, each consumer is identified by a point on the unit interval that represents his/her brand preferences. Second, consumers differ in their \"readiness\" for customization. Specifically, I assume that a fraction of consumers never buys customized products for exogenous reasons like privacy, lack of computer literacy, or general resistance to change. The rest of the consumers are potentially interested in customization.", "cite_spans": [], "ref_spans": []}, {"section": "Overview of the Model and Results", "text": "If a firm chooses to offer customization, it must incur sunk costs associated with achieving high levels of manufacturing technology and flexibility (Broekhuizen and Alsem, 2002) . I also account for non-zero lead time. When a consumer purchases a customized product, he/she suffers the cost of waiting for the product to be assembled and delivered (Tu, Vonderembse, and Ragu-Nathan, 2001, Zipkin, 2001 ).", "cite_spans": [{"start": 149, "end": 178, "text": "(Broekhuizen and Alsem, 2002)", "ref_id": "BIBREF3"}, {"start": 390, "end": 402, "text": "Zipkin, 2001", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "Overview of the Model and Results", "text": "I assume a positive relationship between consumers' benefits from customization and their valuations of the brand. That is, consumers located \"closer\" to the brand gain more from customization. This central assumption finds strong support in the operations management literature. Customization benefits are the rewards from a special shopping experience such as satisfaction with the fulfilment of a co-design task M\u00fcller, 2004, Franke and ) and the value of product customization (i.e., the increment of utility a consumer gains from a product that fits better to his/her needs than the best standard product available). The rewards from an enjoyable shopping experience are, obviously, higher for consumers who are dedicated to the customizing firm. Also, consumers who favor a certain brand possess more knowledge of this brand. Knowledgeable consumers can more easily transfer their needs into appropriate characteristics of the brand than less knowledgeable ones, and the products they co-design better match their needs (Jiang, 2004, Piller, Schubert, Koch, and M\u00f6slein, 2005) . As a result, for these consumers the value of product customization is higher than for consumers located \"farther away\" from the brand.", "cite_spans": [{"start": 1068, "end": 1082, "text": "M\u00f6slein, 2005)", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Overview of the Model and Results", "text": "The timeline of the game is as follows. First, the firms simultaneously decide whether to offer standard products, customized products, or both. After the choices of product strategies are made, the firms engage in price competition. Consumers decide which products to purchase, and the profits are realized.", "cite_spans": [], "ref_spans": []}, {"section": "Overview of the Model and Results", "text": "The main driver of the equilibrium analysis results is that the firms' customized products are more differentiated than their standard products. I show that, depending on the parameter values, the following three scenarios can occur in equilibrium: (1) both firms offer customized products; (2) one firm offers customized products and the other firm offers standard and customized products; and (3) one firm offers customized products and the other firm offers standard products. In the first scenario the firms' customized products compete head-to-head (relaxed price competition), in the second and third scenarios the competition is between one firm's standard products and the other firm's customized products (moderate price competition). The scenario in which both firms offer standard and customized products cannot occur in equilibrium because it leads to intense price competition between the firms' standard products.", "cite_spans": [], "ref_spans": []}, {"section": "Overview of the Model and Results", "text": "Comparative static analysis with respect to the key parameters of the modelthe fraction of consumers potentially interested in customization, the waiting costs, and the fixed cost of customization -reveal some interesting results. For example, if scenario (2) obtains in equilibrium, then the higher the fraction of consumers potentially interested in customization is, the lower the firms' equilibrium prices and profits are. Another intriguing result is that scenario (1) can occur in equilibrium only if the waiting costs are sufficiently high.", "cite_spans": [], "ref_spans": []}, {"section": "Literature Review", "text": "I will briefly summarize the existing theoretical papers on mass customization competition and contrast them with the present study. Next, I will relate my model of customization to the advertising literature.", "cite_spans": [], "ref_spans": []}, {"section": "Literature Review", "text": "Consumers in Xia and Rajagopalan (2009), like in this paper, are heterogeneous in preferences for the two firms (brands). The firms decide which type of products, standard or customized, to offer and then a standard product firm chooses the product variety and a custom product firm chooses the lead time. Customization eliminates the loss in utility from getting a standard product that does not meet a consumer's needs exactly. Unlike the present study, in Xia and Rajagopalan (2009) consumers' benefits from customization are independent of their valuations of the brand. The authors develop an index that signifies the relative attractiveness of standardization and customization. They also identify the strategic roles of product variety and lead time.", "cite_spans": [{"start": 459, "end": 485, "text": "Xia and Rajagopalan (2009)", "ref_id": "BIBREF32"}], "ref_spans": []}, {"section": "Literature Review", "text": "Other papers that consider duopoly price competition in which the firms choose whether to customize their products, assume consumer heterogeneity in product -not brand -preferences. The firms' standard products are located at the end points of the unit interval representing the product space. 4 Customization reduces (Mendelson and Parlakt\u00fcrk, 2008b, Syam and Kumar, 2006) or eliminates (Syam, Ruan, and Hess, 2005, Loginova and Wang, 2011) a consumer's disutility of misfit -the distance from the consumer's ideal product to the firm's standard product. Hence, the closer the consumer is to the firm, the less he/she gains from purchasing a customized product of this firm. It follows that customization by one or both firms reduces product differentiation and intensifies price competition. This is diametrically opposite to the present study that shows that customization softens price competition. The difference in the findings can be traced to the differences in the underlying assumptions on the standard product offerings. The above papers assume that initially (before customization choices are made) each firm produces only one standard product that is maximally differentiated from its rival's standard product. In the present model each firm produces a number of standard products to target consumers of different tastes, and consumers can find a reasonably wellfitting product among them. That is, a consumer's disutilities of misfit at the two firms are negatively correlated in the aforementioned papers, but uncorrelated in my model.", "cite_spans": [{"start": 294, "end": 295, "text": "4", "ref_id": "BIBREF3"}, {"start": 318, "end": 332, "text": "(Mendelson and", "ref_id": "BIBREF17"}, {"start": 361, "end": 373, "text": "Kumar, 2006)", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "Literature Review", "text": "Out of the papers cited above only Syam and Kumar (2006) include offering both standard and customized products into the firms' strategy spaces. The authors show that when a firm offers customized products, it is always beneficial to offer standard products as well. In equilibrium either both firms offer standard and customized products, or one firm offers standard products and the other firm offers standard and customized products. These results are quite different from the present study, due to the differences in the modeling approaches.", "cite_spans": [{"start": 35, "end": 56, "text": "Syam and Kumar (2006)", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "Literature Review", "text": "The following studies do not allow firms to choose between mass production and customization, focusing instead on technological aspects of flexible manufacturing. Mendelson and Parlakt\u00fcrk (2008b) consider a traditional firm and a customizing firm. They model replenishment and inventory costs for the traditional firm and assume limited capacity for the customizing firm. In Bernhardt, Liu, and Serfes (2007) two customizing firms acquire information about each individual consumer to match his/her needs as much as they can. Given investments in information acquisition, the firms then compete in prices. The authors show that in equilibrium the firms make asymmetric investments in order to reduce price competition. In their extension a \"brand name\" dimension is added. When consumers differ enough on this dimension, then both firms make extensive investments in information acquisition technology. Dewan, Jing, and Seidmann (2003) consider two firms that choose their customization scopes simultaneously, sequentially, and in an incumbent plus entrant situation. They show that an early adopter may be able to keep out potential competitors by choosing its customization scope strategically.", "cite_spans": [], "ref_spans": []}, {"section": "Literature Review", "text": "The present study is broadly related to the literature on advertising and product differentiation. Of the two types of advertising, informative and persuasive, customization has much in common with the latter. 5 In the context of the Hotelling model, Von der Fehr and Stevik (1998) distinguish between three types of persuasive advertising. The first type enhances the value of a product in the eyes of consumers, the second type shifts the distribution of consumers in the direction of the firm's product, and the third type increases perceived product differences. Customization in my model, thus, combines the effects of both the first and the third types of persuasive advertising. The main finding of Von der Fehr and Stevik (1998) is that a positive relationship between the degree of (inherent) product substitutability and equilibrium levels of advertising is consistent only with the advertising that increases perceived product differences.", "cite_spans": [{"start": 210, "end": 211, "text": "5", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Literature Review", "text": "Despite the similarities between customization and persuasive advertising, my model does not have a close equivalent in the advertising literature. Bloch and Manceau (1999) and Tremblay and Polasky (2002) use the Hotelling line, but consider the second (in Von der Fehr and Stevik's terms) type of persuasive advertising. Johnson and Myatt (2006) allow for demand shifts (the first type) and rotations (the third type), but analyze the monopoly supply of a single product. They show that when consumers' valuations are relatively homogenous, the monopolist will choose to serve a large fraction of potential consumers. When consumers are heterogeneous, the monopolist will restrict sales to a relatively small niche of consumers.", "cite_spans": [{"start": 148, "end": 172, "text": "Bloch and Manceau (1999)", "ref_id": "BIBREF2"}, {"start": 177, "end": 204, "text": "Tremblay and Polasky (2002)", "ref_id": "BIBREF28"}], "ref_spans": []}, {"section": "Literature Review", "text": "The rest of the paper is organized as follows. In the next section I introduce the model. In Section 3 the pricing stage is analyzed. In Section 4 I study the firms' equilibrium choices of product strategies. Concluding remarks are provided in Section 5. Proofs of all lemmas propositions are relegated to the Appendix.", "cite_spans": [], "ref_spans": []}, {"section": "The Model", "text": "Two symmetric firms, A and B, compete for a continuum of heterogeneous consumers with a total mass of one. Firm A produces brand A and firm B produces brand B. Investing K \u2265 0 into manufacturing flexibility enables a firm to offer customization. In the spirit of mass customization's postulate of achieving near mass production efficiency, I assume that both standard and customized products are produced at the same constant marginal cost c. Without loss of generality, I normalize the marginal cost to zero.", "cite_spans": [], "ref_spans": []}, {"section": "The Model", "text": "Consumers are in the market to purchase at most one unit of the product. They are heterogeneous in two dimensions. First, each consumer is identified by a point x in the unit interval [0, 1] that represents his/her relative preference for brand A versus brand B. To keep the model tractable, I assume that consumers are uniformly distributed along this dimension. Second, independent of x, consumers differ in their levels of readiness for customization. Specifically, I assume that fraction 1 \u2212 \u03b1 of consumers never buys customized products for exogenous reasons like privacy, lack of computer literacy, or general resistance to change. The rest of consumers (fraction \u03b1) are potentially interested in customization. For the ease of exposition I will refer to the former as traditional consumers and to the latter as tech-savvy consumers.", "cite_spans": [], "ref_spans": []}, {"section": "The Model", "text": "Let p A and p B denote the prices charged by firm A and firm B for their standard products. For the consumer at location x, the payoff from purchasing firm A's standard product equals", "cite_spans": [], "ref_spans": []}, {"section": "The Model", "text": "Here v \u2212 tx is his/her valuation of brand A. Similarly, the consumer's payoff from purchasing firm B's standard product is", "cite_spans": [], "ref_spans": []}, {"section": "The Model", "text": "The term v \u2212 t(1 \u2212 x) is his/her valuation of brand B. Parameter t represents the intensity of consumers' relative preferences for the two brands. Letp A andp B denote the firms' prices for their customized products. (I use the overbar symbol to distinguish prices for the customized products from prices for the standard products.) For the consumer at location x, the payoff from purchasing firm A's customized product is", "cite_spans": [], "ref_spans": []}, {"section": "The Model", "text": "where \u2206 > 0 and w is the cost of waiting for the product to be assembled and delivered. Similarly, his/her payoff from purchasing firm B's customized product is", "cite_spans": [], "ref_spans": []}, {"section": "The Model", "text": "It follows from (1) through (4) that the consumer's benefits from customization are", "cite_spans": [], "ref_spans": []}, {"section": "The Model", "text": "if he/she purchases from firm A,", "cite_spans": [], "ref_spans": []}, {"section": "The Model", "text": "if he/she purchases from firm B. I believe that the positive relationship between the consumer's valuation of a given brand and his/her benefits from customization is the most realistic assumption. In support of this, let me reiterate some parts of the Introduction. Customization benefits for consumers are twofold:", "cite_spans": [], "ref_spans": []}, {"section": "The Model", "text": "(a) the rewards from a special shopping experience and satisfaction with the fulfillment of a co-design task, (b) the increment of utility a consumer gains from a product that fits better to his/her needs than the best standard product available.", "cite_spans": [], "ref_spans": []}, {"section": "The Model", "text": "The rewards from an enjoyable shopping experience (a) are, obviously, higher for consumers who are dedicated to the customizing firm. The same applies to (b). Indeed, consumers who favor a certain brand would, in general, possess more knowledge of this brand. Knowledgeable consumers can more easily transfer their needs into appropriate characteristics of the brand than less knowledgeable consumers, and thus the products they co-design better match their needs. Since the focus of this paper is on strategic effects of customization rather than customization technology, \u2206 and w are treated as exogenous parameters. In reality firms have some control over these variables. They can reduce the waiting costs w, for example, by expediting the production process and shipping by air. They can increase \u2206 by acquiring technologies that foster joint creativity during product design or reduce the difficulty of transferring customer needs into a concrete product specification.", "cite_spans": [], "ref_spans": []}, {"section": "The Model", "text": "The game unfolds in two stages. The first stage is the customization stage, in which each firm simultaneously chooses between offering the standard product (S), the customized product (C), or both standard and customized products (SC). 6 These decisions become observable after they are made. In the second stage the firms simultaneously choose prices. Consumers subsequently decide which products to purchase, and the firms' profits are realized. The equilibrium concept employed is subgame perfect Nash equilibrium.", "cite_spans": [{"start": 236, "end": 237, "text": "6", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Analysis of the Pricing Stage", "text": "In this section I investigate the firms' pricing decisions, taking as given their choices in the first stage of the game. There are nine subgames, but only six scenarios to consider: both firms choose S, both firms choose SC, both firms choose C, one firm chooses SC and the other firm S, one firm chooses C and the other firm S, and one firm chooses C and the other firm SC.", "cite_spans": [], "ref_spans": []}, {"section": "Analysis of the Pricing Stage", "text": "In subsequent analysis the following constraints will be placed on the parameters v, t, w, \u2206, and \u03b1. First, I assume that the benefits from customization exceed the waiting costs w at the aggregate level, but not uniformly. Algebraically,", "cite_spans": [], "ref_spans": []}, {"section": "Analysis of the Pricing Stage", "text": "The latter inequality simply means that \u2206(v \u2212 tx) > w fails to hold for consumers located further away from the customizing firm. The two inequalities can be combined into one constraint:", "cite_spans": [], "ref_spans": []}, {"section": "Analysis of the Pricing Stage", "text": "Second, I assume competitive environment. There is enough interest in customization on the part of consumers, i.e., \u03b1 is not too low:", "cite_spans": [], "ref_spans": []}, {"section": "Analysis of the Pricing Stage", "text": "Also, v is sufficiently high so that in equilibrium all consumers would buy a product from one of the two firms (with the exception of 1 \u2212 \u03b1 traditional consumers under the scenario in which both firms choose C):", "cite_spans": [], "ref_spans": []}, {"section": "Analysis of the Pricing Stage", "text": "These parameter constraints seem reasonable; they will keep the analysis of the model focused and the results tractable.", "cite_spans": [], "ref_spans": []}, {"section": "Subgames (S, S) and (C, C)", "text": "Subgames (S, S) and (C, C) are straightforward. When both firms offer the standard products, the equilibrium prices and profits are as in the Hotelling linear city model. That is, p", "cite_spans": [], "ref_spans": []}, {"section": "Subgames (S, S) and (C, C)", "text": "Now suppose both firms offer the customized products. Expressions (3) and (4) can be written as", "cite_spans": [], "ref_spans": []}, {"section": "Subgames (S, S) and (C, C)", "text": "It immediately follows that in subgame (C, C) the equilibrium prices and profits ar\u0113", "cite_spans": [], "ref_spans": []}, {"section": "Subgames (S, S) and (C, C)", "text": "As the firms' customized products are more differentiated than their standard products, price competition is less intense in subgame (C, C). Note that the profits of the firms in subgame (C, C) may be lower than in subgame (S, S), because fraction 1 \u2212 \u03b1 drops out from the pool of consumers.", "cite_spans": [], "ref_spans": []}, {"section": "Subgame (SC, SC)", "text": "Suppose each firm offers both standard and customized products. Consumers' optimal purchasing decisions are illustrated in Figure 1 . Tech-savvy consumers from interval [0,x A ] will purchase firm A's customized product and those from interval [x B , 1] will purchase firm B's customized product. The rest of the tech-savvy consumers will purchase firm A's and firm B's standard products (intervals [x A ,x] and [x,x B ], respectively). Traditional consumers from interval [0,x] will purchase firm A's standard product and those from interval [x, 1] will purchase firm B's standard product.", "cite_spans": [], "ref_spans": [{"start": 123, "end": 131, "text": "Figure 1", "ref_id": "FIGREF1"}]}, {"section": "Subgame (SC, SC)", "text": "Marginal typex A is indifferent between firm A's customized and standard products,", "cite_spans": [], "ref_spans": []}, {"section": "Subgame (SC, SC)", "text": "Similarly, marginal typex B is indifferent between firm B's customized and standard products, ", "cite_spans": [], "ref_spans": []}, {"section": "Subgame (SC, SC)", "text": "Finally, marginal typex is indifferent between firm A's and firm B's standard products,", "cite_spans": [], "ref_spans": []}, {"section": "Subgame (SC, SC)", "text": "The profit functions of the firms in subgame (SC, SC) are", "cite_spans": [], "ref_spans": []}, {"section": "Subgame (SC, SC)", "text": "and", "cite_spans": [], "ref_spans": []}, {"section": "Subgame (SC, SC)", "text": "Maximizing \u03a0 A with respect to p A andp A , and \u03a0 B with respect to p B andp B yields the equilibrium prices and profits, which are summarized in the following lemma.", "cite_spans": [], "ref_spans": []}, {"section": "Subgame (SC, SC)", "text": "Lemma 1 (Equilibrium prices and profits in subgame (SC, SC)). Suppose each firm offers both standard and customized products. The equilibrium prices and profits are p = t as in subgame (S, S). The firms' customized products are isolated from direct competition. 7 When setting a price for its customized product, each firm only considers the price for its standard product. Take, for example, firm A. The optimal choice ofp A maximizes what the firm makes on top ofxp A (if firm A offered only the standard product). That is, max", "cite_spans": [{"start": 262, "end": 263, "text": "7", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Subgame (SC, SC)", "text": "The first-order condition implies", "cite_spans": [], "ref_spans": []}, {"section": "Subgame (SC, S)", "text": "Suppose one of the firms (say, firm A) offers both standard and customized products, and firm B only the standard product. Consumers' optimal purchasing decisions are illustrated in ", "cite_spans": [], "ref_spans": []}, {"section": "Subgame (SC, S)", "text": "The profit functions of the firms in subgame (SC, S) are and", "cite_spans": [], "ref_spans": []}, {"section": "Subgame (SC, S)", "text": "Maximizing (11) with respect to p A andp A , and (12) with respect to p B yields the equilibrium prices and profits.", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 2 (Equilibrium prices and profits in subgame (SC, S)).", "text": "Suppose firm A offers both standard and customized products, and firm B offers the standard product. The equilibrium prices and profits are", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 2 (Equilibrium prices and profits in subgame (SC, S)).", "text": "The equilibrium prices in subgame (SC, C) are the same as in subgame (SC, SC). This is because in both subgames the firms compete with their standard products. As a result, in equilibrium the firms charge t for them. When setting a price for its customized product, firm A faces optimization problem (10) . Hence, p (SC,S) A = t + (\u2206v \u2212 w)/2.", "cite_spans": [{"start": 300, "end": 304, "text": "(10)", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Subgame (C, S)", "text": "Suppose one of the firms (say, firm A) offers the customized product and firm B the standard product. Tech-savvy consumers from interval [0,x] will purchase firm A's customized product, the rest will purchase firm B's standard product. All traditional consumers will purchase firm B's standard product. (See Figure 3. ) Marginal typex is indifferent between firm A's customized product and firm B's standard product,", "cite_spans": [], "ref_spans": [{"start": 308, "end": 317, "text": "Figure 3.", "ref_id": "FIGREF5"}]}, {"section": "Subgame (C, S)", "text": "The profit functions of the firms in subgame (C, S) are", "cite_spans": [], "ref_spans": []}, {"section": "Subgame (C, S)", "text": "and", "cite_spans": [], "ref_spans": []}, {"section": "Subgame (C, S)", "text": "Maximizing (14) with respect to p A and (15) with respect to p B leads to Lemma 3.", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 3 (Equilibrium prices and profits in subgame (C, S)).", "text": "Suppose firm A offers the customized product and firm B offers the standard product. The equilibrium prices and profits arep", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 3 (Equilibrium prices and profits in subgame (C, S)).", "text": "Firm A competes with its customized product and firm B with its standard product. These two products are more differentiated than the standard products in subgames (S, S), (SC, SC), or (SC, S), hence price competition is less intense. Indeed, it can be shown that for any \u03b1, w, and v satisfying (A1) through (A3), bothp In equilibrium firm A serves", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 3 (Equilibrium prices and profits in subgame (C, S)).", "text": "customers, and firm B serves the rest. It is easy to see that firm A's market share increases in \u03b1, implying that firm B's market share decreases in \u03b1. It follows that the profit of the non-customizing firm B decreases in the fraction of tech-savvy consumers. This result conforms with economic intuition. It is interesting that the profit of the customizing firm A also decreases in the fraction of tech-savvy consumers. (See the Appendix for the proof of this result.) The reason is that firm A's market share increases in \u03b1 at a slower rate thanp (C,S) A decreases.", "cite_spans": [], "ref_spans": []}, {"section": "Subgame (C, SC)", "text": "Suppose one of the firms (say, firm A) offers the customized product, and firm B both standard and customized products. Two different purchasing patterns arise in this subgame, depending on the value of the waiting costs w. Figure 4 illustrates consumers' optimal purchasing decisions when the waiting costs are high. Tech-savvy consumers from interval [0,x] will purchase firm A's customized product. The rest of the tech-savvy consumers will purchase firm B's standard and customized products (intervals [x,x B ] and [x B , 1], respectively). All traditional consumers will purchase firm B's standard product. (6) and (13), hencex", "cite_spans": [], "ref_spans": [{"start": 224, "end": 232, "text": "Figure 4", "ref_id": "FIGREF7"}]}, {"section": "Subgame (C, SC)", "text": "The profit functions of the firms are", "cite_spans": [], "ref_spans": []}, {"section": "Subgame (C, SC)", "text": "and", "cite_spans": [], "ref_spans": []}, {"section": "Subgame (C, SC)", "text": "Maximizing (16) with respect top A and (17) with respect to p B andp B yields the equilibrium prices and profits.", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 4 (Equilibrium prices and profits in subgame (C, SC) when w is high).", "text": "Suppose firm A offers the customized product, and firm B offers both standard and customized products. If the waiting costs are high, the equilibrium prices and profits arep ", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 4 (Equilibrium prices and profits in subgame (C, SC) when w is high).", "text": "It follows thatp are the same as in subgame (C, S). This is because when w is high, in subgames (C, SC) and (C, S) firm A competes with its customized product and firm B with its standard product. When setting a price for its customized product, firm B only considers the price for its standard product, hencep Figure 5 illustrates consumers' optimal purchasing decisions when the waiting costs are low. Tech-savvy consumers from interval [0,x] will purchase firm A's customized product. The rest of the tech-savvy consumers will purchase firm B's customized product. All traditional consumers will purchase firm B's standard product.", "cite_spans": [], "ref_spans": [{"start": 311, "end": 319, "text": "Figure 5", "ref_id": "FIGREF8"}]}, {"section": "Lemma 4 (Equilibrium prices and profits in subgame (C, SC) when w is high).", "text": "Marginal typex is indifferent between firm A's and firm B's customized products,", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 4 (Equilibrium prices and profits in subgame (C, SC) when w is high).", "text": "The profit functions of the firms are", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 4 (Equilibrium prices and profits in subgame (C, SC) when w is high).", "text": "and", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 4 (Equilibrium prices and profits in subgame (C, SC) when w is high).", "text": "Maximizing (18) and (19) leads to the following lemma.", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 5 (Equilibrium prices and profits in subgame (C, SC) when w is low).", "text": "Suppose firm A offers the customized product, and firm B offers both standard and customized products. If the waiting costs are low, the equilibrium prices and profits arep", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 5 (Equilibrium prices and profits in subgame (C, SC) when w is low).", "text": "and", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 5 (Equilibrium prices and profits in subgame (C, SC) when w is low).", "text": "The two firms compete with their customized products. As a result,p", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 5 (Equilibrium prices and profits in subgame (C, SC) when w is low).", "text": "= (1 + \u2206)t as in subgame (C, C). Firm B does not face any competition for its standard product, so it sets p (C,SC) B to v \u2212 t, extracting full surplus from the consumer located at 0.", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 5 (Equilibrium prices and profits in subgame (C, SC) when w is low).", "text": "Lemma 5 implies that firm A's profit increases in the fraction of tech-savvy consumers \u03b1, whereas firm B's profit decreases in \u03b1. This is different from the results obtained for high w.", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 5 (Equilibrium prices and profits in subgame (C, SC) when w is low).", "text": "Having derived the profit functions for the pricing stage, we move one step back to study the customization stage.", "cite_spans": [], "ref_spans": []}, {"section": "Equilibrium Choices of Product Strategies", "text": "In the customization stage each firm simultaneously decides whether to offer the standard product, the customized product, or both. The strategic form of this game is given by the following table:", "cite_spans": [], "ref_spans": []}, {"section": "Equilibrium Choices of Product Strategies", "text": "Here, K is the fixed cost of customization. To focus on competitive effects of customization, I will consider K = 0. I will relax this assumption in Subsection 4.3.", "cite_spans": [], "ref_spans": []}, {"section": "Equilibrium Choices of Product Strategies", "text": "It is easy to see that (S, S), (S, SC) and (SC, S) cannot occur in equilibrium. In all these subgames the firms compete with their standard products, sop A = p B = t. Whichever firm offers the standard product will benefit from offering the customized product as well. Indeed, a deviation from S to SC will not affect the competition between the firms' standard products, but will allow the deviating firm to sell the customized product to its most loyal customers at a higher price, resulting in \u03b1 \u2206t \u2206v \u2212 w 2 2 increase in profit. (See the discussion after Lemma 1.) In the spirit of constraint (A1), I will consider two values for the waiting costs, w = \u2206(v \u2212 t/2) and w = \u2206(v \u2212 t). The smaller the waiting costs, the more time efficient is the production of customized products. Thus, I will refer to w = \u2206(v \u2212 t/2) as the case of marginally efficient customization technology and to w = \u2206(v \u2212 t) as highly efficient customization technology.", "cite_spans": [], "ref_spans": []}, {"section": "Equilibrium Choices of Product Strategies", "text": "Another reason for considering these two values is that they lead to different purchasing patterns in subgames (C, SC) and (SC, C). Namely, Figure 4 and the results of Lemma 4 correspond to marginally efficient customization technology, whereas Figure 5 and the results of Lemma 5 to highly efficient customization technology.", "cite_spans": [], "ref_spans": [{"start": 140, "end": 148, "text": "Figure 4", "ref_id": "FIGREF7"}, {"start": 245, "end": 253, "text": "Figure 5", "ref_id": "FIGREF8"}]}, {"section": "Marginally Efficient Customization Technology", "text": "In this subsection we derive the firms' equilibrium choices of product strategies when w = \u2206(v \u2212 t/2).", "cite_spans": [], "ref_spans": []}, {"section": "Marginally Efficient Customization Technology", "text": "First note that (C, S) and (S, C) cannot occur in equilibrium, for the reason mentioned earlier: Whichever firm offers the standard product will benefit from offering the customized product as well. Consider, for example, subgame (C, S). Firm B's profit will increase by", "cite_spans": [], "ref_spans": []}, {"section": "Marginally Efficient Customization Technology", "text": "if it switches from S to SC, as such deviation will not affect the competition between firm A's customized product and firm B's standard product (see Lemmas 3 and 4). Straightforward calculations show that when w = \u2206(v \u2212 t/2), when w = \u2206(v \u2212 t/2). The inequality", "cite_spans": [], "ref_spans": []}, {"section": "Marginally Efficient Customization Technology", "text": "holds for \u03b1 = 1/2, but fails for \u03b1 = 1. Let \u03b1 * denote the critical value of \u03b1. Hence, we have the following proposition.", "cite_spans": [], "ref_spans": []}, {"section": "Marginally Efficient Customization Technology", "text": "Proposition 1 (Equilibrium choices of product strategies when w = \u2206(v \u2212 t/2)). In the case of marginally efficient customization technology, the pure-strategy Nash equilibrium is (C, SC) or (SC, C) if \u03b1 < \u03b1 * and (C, C) if \u03b1 > \u03b1 * .", "cite_spans": [], "ref_spans": []}, {"section": "Marginally Efficient Customization Technology", "text": "The explicit expression of \u03b1 * can be found in the Appendix.", "cite_spans": [], "ref_spans": []}, {"section": "Highly Efficient Customization Technology", "text": "In this subsection we derive the firms' equilibrium choices of product strategies in the case of highly efficient customization technology, w = \u2206(v \u2212 t).", "cite_spans": [], "ref_spans": []}, {"section": "Highly Efficient Customization Technology", "text": "Obviously, (C, C) cannot occur in equilibrium. Consider, for example, firm B. If firm B offers the standard product in addition to its customized products, the competition between the firms' customized products will not be affected (see the discussion after Lemma 5) . Firm B's profit will increase by (1 \u2212 \u03b1)(v \u2212 t) due to traditional customers. ", "cite_spans": [], "ref_spans": []}, {"section": "Highly Efficient Customization Technology", "text": "is equivalent to", "cite_spans": [], "ref_spans": []}, {"section": "Highly Efficient Customization Technology", "text": ", which holds for any \u03b1 and v satisfying (A2) and (A3). Therefore, (SC, SC) cannot occur in equilibrium.", "cite_spans": [], "ref_spans": []}, {"section": "Highly Efficient Customization Technology", "text": "Proposition 2 (Equilibrium choices of product strategies when w = \u2206(v \u2212 t)). In the case of highly efficient customization technology, the pure-strategy Nash equilibrium is (C, SC) or (SC, C).", "cite_spans": [], "ref_spans": []}, {"section": "Fixed Cost of Customization", "text": "In this subsection I consider K > 0. First note that (SC, SC) cannot occur in equilibrium for any value of K, since it was shown earlier that \u03a0", "cite_spans": [], "ref_spans": []}, {"section": "Fixed Cost of Customization", "text": "(SC, S) and (S, SC) cannot occur in equilibrium either: Straightforward calculations (see the Appendix) confirm that \u03a0", "cite_spans": [], "ref_spans": []}, {"section": "Fixed Cost of Customization", "text": "Therefore, in the case of marginally efficient customization technology and \u03b1 < \u03b1 * , or in the case of highly efficient technology we have (S, S) (C, S) or (S, C) (C, SC) or (SC, C)", "cite_spans": [], "ref_spans": []}, {"section": "Fixed Cost of Customization", "text": "In the case of marginally efficient technology and \u03b1 > \u03b1 * we have", "cite_spans": [], "ref_spans": []}, {"section": "Summary of the Results", "text": "Let me summarize the main results of the equilibrium analysis.", "cite_spans": [], "ref_spans": []}, {"section": "Summary of the Results", "text": "\u2022 When the waiting costs are high, the equilibrium changes from (C, SC) or (SC, C) to (C, C) as the fraction of tech-savvy consumers \u03b1 increases. The intuition behind this result is as follows. Consider, for example, subgame (C, SC). The competition is between firm A's customized product and firm B's standard product. When considering offering only the customized product, firm B faces the tradeoff between less intense price competition and losing traditional consumers as customers. The former overwhelms the latter when the fraction of tech-savvy consumers is high.", "cite_spans": [], "ref_spans": []}, {"section": "Summary of the Results", "text": "\u2022 When the waiting costs are low, the equilibrium is (C, SC) or (SC, C). (C, C) cannot occur in equilibrium. This is because in subgames (C, SC) and (SC, C) the competition is between the firms' customized products, and hence, is already relaxed. Whichever firm offers both products does not benefit from offering only the customized product, as it will lose traditional customers without affecting price competition.", "cite_spans": [], "ref_spans": []}, {"section": "Summary of the Results", "text": "\u2022 The result that (C, C) can occur in equilibrium when customization technology is marginally efficient, but cannot when it is highly efficient, is intriguing. What drives this result are two different purchasing patterns in subgame (C, SC) (as well as in subgame (SC, C)). When the waiting costs are high, not all tech-savvy consumers purchase customized products in equilibrium ( Figure  4) . Those who do not favor either of the brands (the middle segment) benefit less from customization; they find w too high, and hence purchase firm B's standard product. When the waiting costs are low, all tech-savvy consumers purchase customized products ( Figure 5 ). The latter pattern implies less intense price competition than the former.", "cite_spans": [], "ref_spans": [{"start": 382, "end": 392, "text": "Figure  4)", "ref_id": "FIGREF7"}, {"start": 649, "end": 657, "text": "Figure 5", "ref_id": "FIGREF8"}]}, {"section": "Summary of the Results", "text": "\u2022 Another interesting result is that (SC, SC) -the scenario in which both firms offer standard and customized products -does not arise in equilibrium. This is a consequence of firms avoiding head-on competition with their standard products.", "cite_spans": [], "ref_spans": []}, {"section": "Summary of the Results", "text": "\u2022 How does an increase in the fraction of tech-savvy consumers affect the firms' equilibrium prices and profits? If (C, C) obtains in equilibrium, the prices remain the same and the profits increase. If (C, SC) or (SC, C) obtains in equilibrium, the profit of the firm that offers both standard and customized product decreases, whereas the profit of the firm that offers only the customized product may decrease (in the case of marginally efficient customization technology) or increase (in the case of highly efficient customization technology).", "cite_spans": [], "ref_spans": []}, {"section": "Summary of the Results", "text": "As to the equilibrium prices, they decrease in the case of marginally efficient technology and remain the same in the case of highly efficient technology.", "cite_spans": [], "ref_spans": []}, {"section": "Summary of the Results", "text": "\u2022 If the fixed cost of customization K is substantial, but not prohibitive, then the equilibrium will be (C, S) or (S, C). In other words, only one firm will offer the customized product. Moreover, the customizing firm will not offer the standard product in addition to the customized product. This is because the competition in subgame (C, S) is less intense than in subgame (SC, S) (and the competition in subgame (S, C) is less intense than in subgame (S, SC)).", "cite_spans": [], "ref_spans": []}, {"section": "Concluding Remarks", "text": "The present paper is the first one to model consumer interactive involvement in product design. This aspect of mass customization has never been the focus of the theoretical literature. I incorporated benefits and drawbacks of customer co-design activities -enjoyable shopping experience, difficulties in transferring individual needs into appropriate product characteristics, waiting costs -into customization competition. The paper also views the standard product offerings in a manner different from most of the existing theoretical studies on customization. Each firm initially produces a range of standard products, so every consumer can find a reasonably wellfitting product to suit his/her individual needs. The competing firms may end up offering very similar standard products: The differences between Nike's and Adidas' running shoes are far smaller than the differences between running and basketball shoes made by Nike, and the differences between geometries of the 56-cm frames produced by Specialized and Trek bike manufacturers are smaller than the differences between the 56-cm and 48-cm frames made by Trek. At this point, the only distinction in the eye of the consumer is the brand name attached to these products. Therefore, in my model consumer heterogeneity on the Hotelling line is interpreted as variability in preferences for brand, rather than product attributes.", "cite_spans": [], "ref_spans": []}, {"section": "Concluding Remarks", "text": "The new modeling ideas were motivated by, and aimed at explaining, the pre-dominant findings in the operations management literature that customization softens price competition because affective bonds are formed between the firm and its customers as a result of consumer interactive involvement in co-design activities. These findings apparently contradict the theoretical literature that maintains that customization reduces product differentiation and intensifies price competition. The importance of the present study is that it provides a theoretical model consistent with the phenomena described in the operations management literature.", "cite_spans": [], "ref_spans": []}, {"section": "Concluding Remarks", "text": "Other findings of this paper may also be useful. As mass customization is an emerging business strategy, one might want to know how the level of consumer readiness for customization affects firms' customization choices and prices. I conducted a comparative statics analysis with respect to the key parameters of the model that revealed a number of interesting results.", "cite_spans": [], "ref_spans": []}, {"section": "Concluding Remarks", "text": "See the proof of Lemma 1 and the discussion following Lemma 2.", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Lemma 3:", "text": "The first-order conditions for (14) and (15) \u2202\u03a0 A \u2202p A = 0", "cite_spans": [{"start": 31, "end": 35, "text": "(14)", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Proof of Lemma 3:", "text": "yield the equilibrium prices and profits in Lemma 3.", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Lemma 3:", "text": "We need to check that the equilibrium value ofx is between 0 and 1. In fact, it can be shown thatx (C,S) \u2208 (1/2, 1). Indeed, by (A1), ", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Lemma 5:", "text": "The first-order conditions for (18) and (19) yield the equilibrium prices and profits in Lemma 5. The equilibrium value ofx isx (C,SC) = 1/2. We need to check that, if the waiting costs are low, the tech-savvy consumer located at 1/2 receives a higher payoff from purchasing firm A's customized product than firm B's standard product:", "cite_spans": [{"start": 31, "end": 35, "text": "(18)", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "Proof of Lemma 5:", "text": "Indeed, setting w to its lower bound \u2206(v \u2212 t) yields", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Lemma 5:", "text": "which holds by (A3).", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Proposition 1:", "text": "The discussion preceding Proposition 1 constitutes the proof. It is left to show that Since the left-hand side of the inequality decreases in \u03b1 and the right-hand side increases, it is sufficient to show that it holds for \u03b1 = 1:", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Proposition 1:", "text": "(2 + \u2206) .", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Proposition 2:", "text": "The discussion preceding Proposition 2 constitutes the proof.", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Proposition 2:", "text": "Proof of \u03a0 In the case of w = \u2206(v \u2212 t/2) the inequality becomes ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Putting One-to-one Marketing to Work: Personalization, Customization, and Choice", "authors": [{"first": "Neeraj", "middle": [], "last": "Arora", "suffix": ""}, {"first": "Xavier", "middle": [], "last": "Dreze", "suffix": ""}, {"first": "Anindya", "middle": [], "last": "Ghose", "suffix": ""}, {"first": "James", "middle": ["D"], "last": "Hess", "suffix": ""}, {"first": "Raghuram", "middle": [], "last": "Iyengar", "suffix": ""}, {"first": "Bing", "middle": [], "last": "Jing", "suffix": ""}, {"first": "Yogesh", "middle": [], "last": "Joshi", "suffix": ""}, {"first": "V", "middle": [], "last": "Kumar", "suffix": ""}, {"first": "Nicholas", "middle": [], "last": "Lurie", "suffix": ""}, {"first": "S", "middle": [], "last": "Scott Neslin", "suffix": ""}, {"first": "Meng", "middle": [], "last": "Sajeesh", "suffix": ""}, {"first": "Niladri", "middle": [], "last": "Su", "suffix": ""}, {"first": "Jacquelyn", "middle": [], "last": "Syam", "suffix": ""}, {"first": "Z. 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Indeed, if two or more firms offer a consumer the product that completely matches the consumer's tastes, then competition leads to marginal cost pricing.", "type": "figure"}, "FIGREF1": {"text": "Figure 1: Market shares in subgame (SC, SC)", "type": "figure"}, "FIGREF3": {"text": "Tech-savvy consumers from interval [0,x A ] will purchase firm A's customized product. The rest of the tech-savvy consumers will purchase firm A's and firm B's standard products (intervals [x A ,x] and [x, 1], respec- tively). Traditional consumers from interval [0,x] will purchase firm A's standard product and those from interval [x, 1] will purchase firm B's standard product. Marginal typesx A andx are determined by the same indifference conditions as in subgame (SC, SC) (equations 5 and 7), henc\u00ea", "type": "figure"}, "FIGREF4": {"text": "Figure 2: Market shares in subgame (SC, S)", "type": "figure"}, "FIGREF5": {"text": "Figure 3: Market shares in subgame (C, S)", "type": "figure"}, "FIGREF6": {"text": "How does \u03b1, the fraction of tech-savvy consumers, affect the firms' equilibrium prices and profits in subgame (C, S)? For comparison, recall that in subgame (SC, SC) the equilibrium prices do not depend on \u03b1 and the equilibrium profits increase in \u03b1. Lemma 3 implies that bothp\u03b1. The intuition is as follows. The firms compete with each other only for tech-savvy consumers of mass \u03b1. Traditional consumers of mass 1 \u2212 \u03b1 all purchase from firm B. The smaller the number of traditional consumers is, the more aggressively firm B competes with firm A for tech-savvy consumers, resulting in lower equilibrium prices.", "type": "figure"}, "FIGREF7": {"text": "Figure 4: Market shares in subgame (C, SC) when w is high", "type": "figure"}, "FIGREF8": {"text": "Figure 5: Market shares in subgame (C, SC) when w is low", "type": "figure"}, "FIGREF10": {"text": "\u2206v \u2212 w)/2 (see the discussion after Lemma 1). In the previous subsection it was shown that both \u03a0makes in subgame (C, SC) compared with subgame (C, S), \u03a0 (C,SC) B is still a decreasing function of \u03b1. (See the Appendix for the proof.)", "type": "figure"}, "FIGREF11": {"text": "16 holds for any \u03b1 satisfying (A2). (See the proof of Proposition 1 in the Appendix.) Hence, (SC, SC) cannot occur in equilibrium. The intuition behind this result is as follows. When firm A switches from SC to C, the competition becomes less intense. For firm A, the positive effect of less intense price competition overwhelms the negative effect of losing traditional consumers as customers. Finally, let us compare \u03a0", "type": "figure"}, "FIGREF12": {"text": "any \u03b1 and v satisfying (A2) and (A3). It follows that (C, S) cannot occur in equilibrium. The same applies to (S, C). Finally, we compare \u03a0 (C,SC) A with \u03a0 (SC,SC) A when w = \u2206(v \u2212 t). The inequality", "type": "figure"}, "FIGREF13": {"text": "Straightforward calculations verify that under assumptions (A1) through (A3) the traditional consumer located at 0 receives positive payoff in equilibrium.+(\u2206v\u2212w+t) 2 < \u2212(2+\u2206) 2 t 2 +(\u2206v\u2212\u2206(v\u2212t)+t) 2 = \u2212(3+2\u2206)t 2 < 0.", "type": "figure"}, "TABREF0": {"text": "Next, the critical value of \u03b1, \u03b1 * , is the solution to", "type": "table"}, "TABREF1": {"text": "In the case of w = \u2206(v \u2212 t) the inequality becomes", "type": "table"}}}
{"paper_id": "199664260", "_pdf_hash": "8c86d743b5ebdbabec2b54e25d38c21814f27c4d", "abstract": [{"section": "Abstract", "text": "Polyethylene glycol (PEG) conjugation technology has been successfully applied to improve the performance of protein drugs. In this study, L-asparaginase was N-terminal sitespecifi cally modifi ed by alkylating PEG with monomethoxy polyethylene glycol-propionaldehyde (mPEG-ALD 20000 ). The optimum reaction parameters were determined as pH 5.0, a molar ratio of mPEG-ALD 20000 to L-asparaginase of 10:1, a reaction time of 16 h and temperature of 25 \u00b0C. PEG-L-asparaginase (PEG-L-ASNase) was isolated and purifi ed with consecutive anion-exchange (XK, 16 \u00d7 20 cm, Q Sepharose FF) and gel-fi ltration (Tricorn, 10 \u00d7 600 cm, Sephacryl S-300 HR) chromatography, respectively. PEG-L-ASNase retained 43.5% of its activity and the N-terminal amino groups were modifi ed to an extent of 3.67%.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "L-Asparaginase (L-asparagine-amidohydrolase, E.C.3.5.1.1, L-ASNase), the enzyme that converts L-asparagine to L-aspartic acid and ammonia, has been a main component of treatment regiments for patients with acute lymphocytic, acute lymphoblastic leukaemia (ALL) and chronic myelogenous leukaemia (Narta et al., 2007) . The clinical action of this enzyme is attributed to the reduction of L-asparagine since tumour cells, unable to synthesize this amino acid, are selectively killed by L-asparagine deprivation (Kwon et al., 2009) . However, native L-ASNase is associated with a high incidence of allergic reactions, low stability, as well as short half-life due to rapid clearance in the body. Covalent attachment of polyethylene glycol (PEG) is one of the techniques currently employed to extend the circulation time of proteins in the blood (Kinstler et al., 1996; Park et al., 2010) . A great deal of interest has been generated in PEGylation since it prolongs the circulation time, increases resistance against proteolytic digestion in serum, reduces the immunogenicity, as well as lowers its cytotoxicity (Lee et al., 2003; Narta et al., 2007; Roberts et al., 2002; Veronese, 2001; Veronese and Harris, 2008) .", "cite_spans": [{"start": 295, "end": 315, "text": "(Narta et al., 2007)", "ref_id": "BIBREF10"}, {"start": 509, "end": 528, "text": "(Kwon et al., 2009)", "ref_id": "BIBREF5"}, {"start": 842, "end": 865, "text": "(Kinstler et al., 1996;", "ref_id": "BIBREF4"}, {"start": 866, "end": 884, "text": "Park et al., 2010)", "ref_id": "BIBREF11"}, {"start": 1109, "end": 1127, "text": "(Lee et al., 2003;", "ref_id": "BIBREF7"}, {"start": 1128, "end": 1147, "text": "Narta et al., 2007;", "ref_id": "BIBREF10"}, {"start": 1148, "end": 1169, "text": "Roberts et al., 2002;", "ref_id": "BIBREF13"}, {"start": 1170, "end": 1185, "text": "Veronese, 2001;", "ref_id": "BIBREF15"}, {"start": 1186, "end": 1212, "text": "Veronese and Harris, 2008)", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "Introduction", "text": "PEG-L-asparaginase (PEG-L-ASNase) has been developed since the early nineties and is used for the treatment of ALL in patients who are hypersensitive to native L-ASNase. PEG-L-ASNases, commercially available, are formed by non-specifi c random PEGylation of \u03b5-amino groups on the lysine residues of enzymes (Narta et al., 2007) . Although this type of conjugation has resulted in increased retention of the blood and hence circulation time, it can lead to steric hindrance of the specifi c binding of PEGylated proteins to their cellular receptors thus decreasing their bioactivity (Bailon and Berthold, 1998) . PEGylation strategies have been improved in recent years so as to introduce a reactive amino acid at a desired site of a protein to achieve site-specifi c PEGylation (Lee et al., 2003; Veronese and Pasut, 2005) . One such strategy available is alkylation, which maintains the positive charges of the starting amino groups required for retaining biological activity and solubility, rather than acylation (Veronese and Pasut, 2005) . These strate gies can also be utilized to achieve the mono-site-specifi c PEGylation by controlling the reaction conditions. It has been shown that alkylated PEGylation rhG-CSF could preserve the charges on the N-terminal amino groups thus retaining the biological activity (Kinstler et al., 1996) . In the present study, we conjugated the N-terminus of L-ASNase with monomethoxy polyethylene glycol-propionaldehyde (mPEG-ALD 20000 ) using the alkylation strategy. The optimum reaction parameters and the purifi cation strategies of bioconjugates have been assessed. ", "cite_spans": [{"start": 307, "end": 327, "text": "(Narta et al., 2007)", "ref_id": "BIBREF10"}, {"start": 582, "end": 609, "text": "(Bailon and Berthold, 1998)", "ref_id": "BIBREF0"}, {"start": 778, "end": 796, "text": "(Lee et al., 2003;", "ref_id": "BIBREF7"}, {"start": 797, "end": 822, "text": "Veronese and Pasut, 2005)", "ref_id": "BIBREF16"}, {"start": 1015, "end": 1041, "text": "(Veronese and Pasut, 2005)", "ref_id": "BIBREF16"}, {"start": 1318, "end": 1341, "text": "(Kinstler et al., 1996)", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Material and Methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Materials", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Preparation of PEG-L-ASNase bioconjugates", "text": "Five mg of L-ASNase were dissolved in 1 mL phosphate-buffered saline (PBS, 0.1 M, pH 5.0) and mixed with mPEG-ALD 20000 at a molar ratio of 1:10. Sodium cyanoborohydrate (20.4 \u03bcL, 1 M) was added, and the reaction mixture was diluted with PBS (0.1 M, pH 5.0) to provide a fi nal enzyme concentration of 0.02 M. The conjugation reaction was allowed to proceed for 16 h at 4 \u00b0C.", "cite_spans": [], "ref_spans": []}, {"section": "Reaction parameters", "text": "Optimum reaction conditions in terms of the molar ratio of the components of the mixture, pH value of the buffer, time, and temperature were investigated. L-ASNase and mPEG-ALD 20000 were mixed at the molar ratios of 1:1, 1:3, 1:5, 1:7, 1:9, 1:11, 1:13, and 1:15, respectively, in 0.1 M PBS (pH 5.0) and the conjugation reaction was run for 16 h at 4 \u00b0C. In order to fi nd the optimum pH, the reactions were carried out in buffers with different pH values (pH 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0) . We analysed the effect of time and temperature on the conjugation reaction by carrying it out for 8, 16, 24, 32, 40, 48, 56, 64 , and 72 h at 4 \u00b0C, 25 \u00b0C, and 37 \u00b0C, respectively.", "cite_spans": [], "ref_spans": []}, {"section": "Purifi cation of PEG-L-ASNase", "text": "For the best isolation and purifi cation of the bioconjugates, a two-step procedure involving anion-exchange and gel-fi ltration chromatography was used. The samples were pooled and applied to a Q Sepharose FF column (XK, 16 \u00d7 20 cm) equilibrated with buffer A (20 mM PBS, pH 7.0) and eluted with buffer B (20 mM PBS, 1 M NaCl, pH 7.0). Afterwards, samples were subjected to Sephacryl S-300 HR (Tricorn, 10 \u00d7 600 cm) gelfi ltration chromatography in 20 M PBS (15 mM NaCl, pH 7.2). The fl ow rate of buffers in both steps was 1 mL/min, and the samples were analysed at 214 nm with an \u00c4KTA Purifi er 10 (GE Healthcare, Piscataway, NJ, USA).", "cite_spans": [], "ref_spans": []}, {"section": "Sodium dodecylsulfate-polyacrylamide gel electrophoresis (SDS-PAGE)", "text": "SDS-PAGE analysis was performed according to the method of Laemmli (1970) using 12.5% polyacrylamide gel. The SDS-PAGE gels were stained with silver nitrate (Pritsa and Kyriakidis, 2001 ) and scanned by Quantity One software (Bio-Rad, Hercules, CA, USA). The percentage of modifi ed L-ASNase was analysed as follows: percentage of L-ASNase = (volume of modifi ed L-ASNase bands/total volume of L-ASNase bands) \u00b7 100%.", "cite_spans": [{"start": 59, "end": 73, "text": "Laemmli (1970)", "ref_id": "BIBREF6"}, {"start": 157, "end": 185, "text": "(Pritsa and Kyriakidis, 2001", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Protein determination", "text": "Protein was determined by the method of Bradford as modifi ed by Bearden (1978) , using bovine serum albumin as a standard.", "cite_spans": [{"start": 65, "end": 79, "text": "Bearden (1978)", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Determination of residual amino groups of the enzyme", "text": "The presence of unmodifi ed amino acids was determined as described by Stocks et al. (1986) . Briefl y, proteins were dissolved in a small volume of PBS (0.1 M, pH 8.0). The solutions were diluted to different concentrations (0, 1, 2, 3, 4, 5, 6 \u03bcg/mL) with the same buffer. To 1.5 mL solution, 0.3 mL fl uorescamine solution (0.3%, w/v, dissolved in acetone) was added. The fl uorescence intensity was measured after 7 min at 475 nm with a Shimadzu UV-visible spectrophotometer (Kyoto, Japan).", "cite_spans": [{"start": 71, "end": 91, "text": "Stocks et al. (1986)", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Determination of enzyme activity", "text": "L-ASNase activities were assayed according to the method previously described by Matsuyama et al. (1991) . In brief, 1.9 mL L-asparagine (0.33%, w/v) were added to 0.1 mL enzyme solution (5 mg/ mL in 0.1 M PBS, pH 8.0) and the mixture incubated at 37 \u00b0C for 3 min. The reaction was terminated with 0.5 mL 25% (w/w) trichloroacetic acid. The mixtures, 0.5 mL, were transferred into a new tube and treated with 1 mL Nessler's reagent and 7 mL double distilled water for 15 min at room temperature. The absorbance of the sample was then measured at 450 nm.", "cite_spans": [{"start": 81, "end": 104, "text": "Matsuyama et al. (1991)", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Effect of molar ratio on the rate of PEGylation", "text": "The molar concentration of modifying agents such as PEG has been shown to affect the extent of PEGylation (Harris et al., 2001) . Fig. 1 shows the effects of different molar ratios of mixtures on the rate of PEG-L-ASNase modifi cation. We observed that as the molar ratio of mPEG-ALD 20000 to L-ASNase increased from 1:1 to 15:1, the PEG-L-ASNase protein modifi cation rate increased by 43.1%, 46.7%, 48.5%, 51.7%, 54.3%, 55.3%, 54.6%, and 53.7%, respectively. The highest modifi cation rate of 55.3% was obtained with an 11:1 molar ratio of mPEG-ALD 20000 to L-ASNase. However, we also observed that a higher ratio resulted in increased polymorphism of PEGylation (Fig. 1, lanes 6 to 8) . In order to avoid polymorphism and rather achieve mono-modification, a molar ratio of 10:1 was chosen in the subsequent experiments.", "cite_spans": [{"start": 106, "end": 127, "text": "(Harris et al., 2001)", "ref_id": "BIBREF2"}], "ref_spans": [{"start": 130, "end": 136, "text": "Fig. 1", "ref_id": "FIGREF0"}, {"start": 665, "end": 687, "text": "(Fig. 1, lanes 6 to 8)", "ref_id": "FIGREF0"}]}, {"section": "Effect of pH value on the rate of PEGylation", "text": "The N-terminal PEGylation of L-ASNase is obtained by conjugating methoxy-PEG derivatives at acidic pH conditions (Kinstler et al., 1996) . We observed that the percentage of modifi ed enzyme changed with different pH values (Fig. 2) . We found that pH 5.0 gave the highest percentage of 59.1% before purifi cation. L-ASNase, isolated from E. coli, consists of two types of subunits (Fig. 2, lane 9) . As shown in Fig. 2 , bands of subunit B of the enzyme were not present in lane 1 to lane 4 (pH 4.0 to 5.5). This indicates that PEGylation was preferentially on subunit B of the enzyme.", "cite_spans": [{"start": 113, "end": 136, "text": "(Kinstler et al., 1996)", "ref_id": "BIBREF4"}], "ref_spans": [{"start": 224, "end": 232, "text": "(Fig. 2)", "ref_id": "FIGREF1"}, {"start": 382, "end": 398, "text": "(Fig. 2, lane 9)", "ref_id": "FIGREF1"}, {"start": 413, "end": 419, "text": "Fig. 2", "ref_id": "FIGREF1"}]}, {"section": "Effect of temperature on the rate of PEGylation", "text": "Time and temperature are two other parameters that affect the rate of the reaction. Comparing three different reaction temperatures, we observed that the reaction proceeded faster at 37 \u00b0C as compared to 25 \u00b0C and 4 \u00b0C (Fig. 3) . However, the percentage of modifi ed enzymes decreased rapidly at higher temperatures at longer reaction times (72 h).", "cite_spans": [], "ref_spans": [{"start": 219, "end": 227, "text": "(Fig. 3)", "ref_id": "FIGREF4"}]}, {"section": "Purifi cation of PEG-L-ASNase", "text": "Mono-PEGylated enzyme produced in the PEGylation reactions was separated from higher PEGylated enzyme and unreacted enzyme as well as free PEG or low-molecular weight impurities by anion-exchange chromatography. As shown in Fig. 4 , four peaks were obtained in the chromato- gram. These four peaks were collected and analysed as described in Materials and Methods. P1, the fraction of non-adsorbed material, contained no protein but only free PEG as detected by the iodine staining method (Nag et al., 1996) . P4 was also found to contain no protein but rather some low-molecular weight impurities. P2 and P3 contained both enzymes. SDS-PAGE analysis showed that P2 contained both PEGylated enzyme and unmodifi ed L-ASNase (Fig. 5, lane 1 and lane 2) , whereas P3 contained only unmodifi ed L-ASNase (Fig. 5, lane 3) . The tailing of P2 indicated that it had some unreacted L-ASNase. A sample of P2 was collected and further purifi ed by gel-fi ltration chromatography.", "cite_spans": [{"start": 489, "end": 507, "text": "(Nag et al., 1996)", "ref_id": "BIBREF9"}], "ref_spans": [{"start": 224, "end": 230, "text": "Fig. 4", "ref_id": "FIGREF3"}, {"start": 723, "end": 750, "text": "(Fig. 5, lane 1 and lane 2)", "ref_id": "FIGREF0"}, {"start": 800, "end": 816, "text": "(Fig. 5, lane 3)", "ref_id": "FIGREF4"}]}, {"section": "Purifi cation of PEG-L-ASNase", "text": "As shown in Fig. 6 , the retention time of P2 (PEG-L-ASNase) was 23.4 min (Fig. 6b) , while that of native L-ASNase was 30.1 min (Fig. 6a) . In size-exclusion chromatography (Fig. 6b) , the peak had a narrow and symmetrical shape. This indicated that the target purifi ed PEG-L-ASNase was of high purity and homogeneity. The purity of the sample was estimated to be in the range of 98% by comparison of the two peak areas. SDS-PAGE separated purifi ed PEG-L-ASNase into two bands (Fig. 5, lane 4) , likely indicating that some subunits of L-ASNase were not conjugated with PEG.", "cite_spans": [], "ref_spans": [{"start": 12, "end": 18, "text": "Fig. 6", "ref_id": "FIGREF6"}, {"start": 74, "end": 83, "text": "(Fig. 6b)", "ref_id": "FIGREF6"}, {"start": 129, "end": 138, "text": "(Fig. 6a)", "ref_id": "FIGREF6"}, {"start": 174, "end": 183, "text": "(Fig. 6b)", "ref_id": "FIGREF6"}, {"start": 480, "end": 496, "text": "(Fig. 5, lane 4)", "ref_id": "FIGREF3"}]}, {"section": "Determination of residual amino groups and enzyme activity of PEG-L-ASNase", "text": "From The activity retained in PEG-L-ASNase was determined according to the method of Matsuyama et al. (1991) . PEG-L-ASNase had an activity of 89.659 IU/mg, while native L-ASNase had 205.901 IU/mg. Thus 43.545% of the enzyme activity were retained in the PEGylated enzyme.", "cite_spans": [{"start": 85, "end": 108, "text": "Matsuyama et al. (1991)", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Isoelectric focusing electrophoresis (IFE) of PEG-L-ASNase", "text": "IFE is used to isolate and characterize molecules by their different PI value. According to the IFE (Fig. 8) , the PI of native L-ASNase was 4.88. The three bands of PI, 5.81 (main), 5.00, and 4.82, thus are from PEGylated enzyme.", "cite_spans": [], "ref_spans": [{"start": 100, "end": 108, "text": "(Fig. 8)", "ref_id": "FIGREF7"}]}, {"section": "Discussion", "text": "This work focuses on the preparation method and reaction parameters of N-terminal site-specifi c PEGylated L-ASNase retaining high enzymatic activity. The prolonged half-life of PEGylated proteins often compensates for the reduction of biologic activity in vivo, leading to an overall increase in their therapeutic effects (Yoshioka et al., 2004) . Alkylation, which is a convenient way for conjugation when the positive charge of the amino group is critical for the retention of biological activity, was chosen here to obtain mono-N-terminal site-specifi c PEGylated L-ASNase. However, the reaction rate of the formation of the Schiff base is relatively low and the pH value of the reaction mixture is critical for selective \u03b1-amino terminal modifi cation (Veronese, 2001) . It is crucial to fi nd optimum conditions for the modifi cation. Therefore, the reaction parameters, i.e. the molar ratio of alkylated PEG to enzyme, pH value, reaction time, and temperature, have been investigated in this study.", "cite_spans": [{"start": 323, "end": 346, "text": "(Yoshioka et al., 2004)", "ref_id": "BIBREF18"}, {"start": 757, "end": 773, "text": "(Veronese, 2001)", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "Discussion", "text": "The amount of PEG had signifi cant effects on the degree of modifi cation of the \u03b1-amino groups of the enzyme (Fig. 1) . It was highest at a ratio of 11:1. However, a higher molar ratio of mPEG-ALD 20000 to enzyme resulted in higher polymorphism (Fig. 1, lanes 5 to 8) . Thus, mono-PEGylation was obtained at a molar ratio of 10:1. It is well-known that the pH value of the reaction plays a critical role in the extent and site of PEGylation, especially by alkylation. Different from acylating PEGs, PEG-aldehyde does not modify the charge of amino residues but forms a Schiff base which is then reduced with cyanoborohyd ride. We observed in this study that mono-N-terminal PEGylation of LASNase was obtained by conjugating methoxy-PEG derivatives at acidic pH conditions, i.e. pH 5.0 (Fig. 2, lane 4) . Under acidic conditions, Nterminal \u03b1-amino groups are more reactive than the \u03b5-amine groups in lysine residues (Lee et al., 2003) . The pH value not only affected the extent of enzyme modifi cation but also reaction sites. As shown in Fig. 2 , the B-subunit of L-ASNase was selectively modifi ed. Thus, site-specifi c mono-PEGylation can be achieved by controlling the reaction conditions.", "cite_spans": [{"start": 916, "end": 934, "text": "(Lee et al., 2003)", "ref_id": "BIBREF7"}], "ref_spans": [{"start": 110, "end": 118, "text": "(Fig. 1)", "ref_id": "FIGREF0"}, {"start": 246, "end": 268, "text": "(Fig. 1, lanes 5 to 8)", "ref_id": "FIGREF0"}, {"start": 786, "end": 802, "text": "(Fig. 2, lane 4)", "ref_id": "FIGREF1"}, {"start": 1040, "end": 1046, "text": "Fig. 2", "ref_id": "FIGREF1"}]}, {"section": "Discussion", "text": "After PEGylation, the modifi ed enzyme must be separated from PEG, unreacted enzyme, and multiple PEGylated enzymes. Due to the molecular weights of L-ASNase (141 kDa) and mPEG-ALD 20000 (20 kDa), modifi ed enzyme was diffi cult to get well separated from native enzyme by molecular-size chromatography only. Besides, some physicochemical properties of the parent molecules such as surface charge and molecular morphology in solution are also changed by PEGylation (Lee et al., 2003) . Therefore, a twostep strategy of anion-exchange chromatography and molecular size-exclusion chromatography was utilized in the present study. In the anionexchange chromatography, we found that PEGylated enzymes are eluted in low-salt buffer. Mono-PEGylated enzyme was separated from higher PEGylated enzyme, unreacted enzyme, as well as free PEG or low-molecular weight impurities by anion-exchange chromatography (Fig. 4) . Native L-ASNase is a tetramer of four dimers. However, it can form hexamers in elution buffer (Pritsa and Kyriakidis, 2001 ). Due to the strong hydrophilici ty of mPEG-ALD 20000 , the apparent molecular weight is higher than the actual molecular weight in the mobile phase buffer (Jackson et al., 1987) . L-ASNase eluted later than PEGylated L-ASNase (Fig. 6) . Therefore, binding forces between enzymes conjugated with PEG and side chains of matrix were weakened in ion-exchange chromatography due to steric hindrance effects.", "cite_spans": [{"start": 465, "end": 483, "text": "(Lee et al., 2003)", "ref_id": "BIBREF7"}, {"start": 1005, "end": 1033, "text": "(Pritsa and Kyriakidis, 2001", "ref_id": "BIBREF12"}, {"start": 1191, "end": 1213, "text": "(Jackson et al., 1987)", "ref_id": "BIBREF3"}], "ref_spans": [{"start": 900, "end": 908, "text": "(Fig. 4)", "ref_id": "FIGREF3"}, {"start": 1262, "end": 1270, "text": "(Fig. 6)", "ref_id": "FIGREF6"}]}, {"section": "Discussion", "text": "IFE separates proteins by their specifi c PI values. Due to different PEGylation sites, PEGylation proteins with the same molecular weights may be resolved into several bands in IFE. We found that purifi ed PEG-L-ASNase consisted of three isomeric compounds in this study (Fig. 8) . In a typical protein PEGylation via modifi cation of lysine and N-terminal amino groups, respectively, PEG molecules attached to one of several potential sites on the protein, each attachment location defi ning a different isotype (Nag et al., 1996) . Thus, mono-PEGylated proteins may have more than one isomeric form and the different PEG isotypes have interesting implications in the drug development process.", "cite_spans": [{"start": 514, "end": 532, "text": "(Nag et al., 1996)", "ref_id": "BIBREF9"}], "ref_spans": [{"start": 272, "end": 280, "text": "(Fig. 8)", "ref_id": "FIGREF7"}]}, {"section": "Conclusions", "text": "The alkylating PEGylation of L-ASNase at the N-terminal \u03b1-amino groups was optimized. The reaction conditions were a pH value of 5.0, a molecular ratio of mPEG-ALD 20000 to LASNase of 10:1, a reaction time of 16 h, and a temperature of 25 \u00b0C. The two-step purifi cation procedure with anion-exchange (Q Sepharose FF) and gel-fi ltration (Sephacryl S-300 HR) chromatography can be utilized to purify PEG-L-ASNase. The retained enzyme activity was found to be 43.5%. This method of alkylating PEGylation and the purifi cation strategy may be useful in the further application of this enzyme.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Polyethylene glycolconjugated pharmaceutical proteins", "authors": [{"first": "P", "middle": [], "last": "Bailon", "suffix": ""}, {"first": "W", "middle": [], "last": "Berthold", "suffix": ""}], "year": 1998, "venue": "Pharm. Sci. Technol. Today", "link": null}, "BIBREF1": {"title": "Quantitation of submicrogram quantities of protein by an improved protein-dye binding assay", "authors": [{"first": "J", "middle": ["C"], "last": "Bearden", "suffix": ""}], "year": 1978, "venue": "Biochim. Biophys. 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Biophys. Res. Commun", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Fig. 1. SDS-PAGE analysis of the effect of the molar ratio of mPEG-ALD 20000 to L-ASNase on PEGylation of the enzyme. Lane 0, protein marker; lanes 1 -8, molar ratio of mPEG-ALD 20000 to L-ASNase was 1:1, 3:1, 5:1, 7:1, 9:1, 11:1, 13:1, and 15:1, respectively.", "type": "figure"}, "FIGREF1": {"text": "Fig. 2. SDS-PAGE analysis of the effect of pH value on the modifi cation of L-ASNase by mPEG-ALD 20000 . Lane 0, protein marker; lanes 1 -8, pH 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, and 7.5, respectively; lane 9, native L-ASNase.", "type": "figure"}, "FIGREF2": {"text": "in order to determine the percent- age of modifi ed enzymes, two equations were used: linear equation of purifi ed PEG-L-ASNase:percentage of modifi ed enzyme can be cal- culated as follows: percentage of PEG-L-ASNase = 1 -(linear slope of equation of PEG-L-ASNase/linear slope of equation of native L-ASNase) \u00b7 100% = 3.76%.", "type": "figure"}, "FIGREF3": {"text": "Fig. 4. Purifi cation of PEG-L-ASNase by XK Q Sepharose TM FF column chromatography.", "type": "figure"}, "FIGREF4": {"text": "Fig. 3. Effect of the reaction time and temperature on the modifi cation of mPEG-ALD 20000 to L-ASNase.", "type": "figure"}, "FIGREF5": {"text": "Fig. 5. SDS-PAGE of samples separated by XK Q Sepharose TM FF column chromatography. Lane 0, marker; lane 1, P2; lane 2, tailor of P2; lane 3, P3; lane 4, purifi ed PEG-L-ASNase.", "type": "figure"}, "FIGREF6": {"text": "Fig. 6. (a) Chromatography of native L-ASNase on a Tricorn Sephacryl S-300 HR column. (b) Chormatography of P2 on a Tricorn Sephacryl S-300 HR column.", "type": "figure"}, "FIGREF7": {"text": "Fig. 8. Isoelectric focusing electrophoresis of L-ASNase and PEG-L-ASNase. Lane 0, PI marker; lane 1, native L-ASNase; lane 2, PEG-L-ASNase. Fig. 7. Enzyme activity of PEG-L-ASNase and native L-ASNase as a function of enzyme concentration.", "type": "figure"}, "TABREF0": {"text": "A PEGylation Technology of L-Asparaginase with Monomethoxy Polyethylene Glycol-Propionaldehyde", "type": "table"}, "TABREF1": {"text": "St. Louis, MO, USA). All other chemicals used were of analytical reagent grade and were purchased from Sinopharm Chemical Reagent Co. Ltd. (Shanghai, China).", "type": "table"}}}
{"paper_id": "199664740", "_pdf_hash": "cd708125fa3f035a31bd61b30e88a4ceaa04c228", "abstract": [], "body_text": [{"section": "", "text": "cerned with Malory's Morte Darthur, \"the most comprehensive, coherent and consecutively-written single-author treatment of the Arthurian legend until the modern period\" (161). This review will concentrate on these four contributions for reasons that reflect my personal interest only. 3 The first two articles on the Morte Darthur, P. J. C. Field's \"Malory's SourceManuscript for the First Tale of Le Morte Darthur\" (111-119) and Linda Gowans' \"Malory's Sources -and Arthur's Sisters -Revisited\" (121-142) are obviously source studies. Field starts off with the three French Post-Vulgate texts of Merlin, two of which are possible sources for Malory's first tale. 4 These are Cambridge University Library, MS Additional 7071 and the so-called Huth MS, London, British Library, MS Additional 38117. The manuscripts are introduced briefly (112f.). Unfortunately, however, they are neither dated nor is there a stemma given that would reveal their relationship to each other. This may have seemed self-evident to the expert author, 5 but it might have helped the more uninformed reader's understanding of Field's train of thoughts. Central to the article is a discussion of two earlier contributions to the topic by Eug\u00e8ne Vinaver (1949 Vinaver ( & 1990 and Jonathan Passaro (2009) , the first preferring the Huth MS, the second the Cambridge MS as the source of the first tale. Field offers his own analysis (115ff.), including in his deliberations two Spanish printed editions of the 15th and 16th century respectively (112). With Field conceding that \"certainty is hard to find in textual criticism\" (119), the discussion is interesting but not very strong. He concludes that his examples \"make it unreasonable to suppose that Malory worked up his first tale from Cambridge Additional 7071\" (119).", "cite_spans": [{"start": 1220, "end": 1233, "text": "Vinaver (1949", "ref_id": "BIBREF6"}, {"start": 1264, "end": 1278, "text": "Passaro (2009)", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "", "text": "Gowans' is a complex article including well-devised comparisons of different versions of the earlier part of the Merlin story -e.g. she shows how a third daughter for the Duke of Cornwall came to life in some versions (123-128) -, giving quotes from an Italian and various French manuscripts. The article is skillfully written, explains relationships, disentangles the interrelations of several versions of the story and offers even more details in informed footnotes. The author's conclusion leaves space for further research: \"I suggest, therefore, that the number of lost Merlin manuscripts, the complexity of their cyclical composition, and the amount of transmission activity in England, were all greater than may have been envisaged\" (142).", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "This thread is not taken up by the next two articles on the Morte Darthur. Ryan Naughton is concerned with Sir Gareth (143-160), and Dorsey Armstrong links Malory's Morte closely to Cornwall (161-189). Naughton's \"Peace, Justice and Retinue-Building in Malory's 'The Tale of Sir Gareth of Orkney'\" is a wellstructured article consisting of four main parts. The author makes use of Paul Strohm's theory of the intended audience (cf. note 8) -logically, he assumes an intended knightly audience. Consequently, the tale is read as an exemplum for the benefit of this audience \"and not just [as] an idealized representation of knightly acumen\". By doing this \"readers can see how the youth's adventures suggest that historical knights should use any means [...] to subdue rebellious peers and subjects and thus (re)establish and maintain peace and justice\" (145). Gareth is depicted as defender of justice in the first part of the article (146-8). The second part focusses on the episode of the Red Knight and Lyonesse, and the perelyste knyght is unfavourably compared to Gareth (148-152). The third part pivots around the mercy Gareth shows towards the Red Knight (153-155), while the fourth part concentrates on an analysis of Gareth and his battles with the \"colour-coded knights\" (cf. note 4).", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Naughton shows how the hero broadens his retinue of followers (155-159), and this retinue-building is convincingly linked to bastard feudalism \"that reached its apogee during the Wars of the Roses\" and is defined as \"the disintegration of land-based feudal ties and the rise of service for pay that emerged in the High and Later Middle Ages\" (156). This was certainly viewed with negative feelings by the \"'natural' nobility\" (157), and maybe even led to a decline in knightly ideals -one need only think of the ambivalent characterisation of Chaucer's Knight in the General Prologue to his Canterbury Tales -or even to the disruption of social order. Yet Malory \"ensures that the chivalric community of the romance is not torn asunder with rival fractions\" by assimilating Gareth's knights \"into the Arthurian chivalric community\" (158), which means that Arthur becomes lord over all of them.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Naughton's main points are nicely summed up at the end of the paper (159f.). Throughout the article, the reader is carefully guided through the author's argumentation by a close reading of Malory's tale and a presentation of each argument according to the rulebook of academic writing. Somewhat redundantly, each part concludes with what the intended knightly audience was meant to deduce. Dorsey Armstrong's contribution is titled \"Mapping Malory's Morte: The (Physical) Place and (Narrative) Space of Cornwall\" (161-189). From beginning to end, her article is a good read. One can find a link to Naughton's preceding paper right at the beginning where Armstrong considers the topic of overlordship in the Morte Darthur and where the reader might catch a glimpse of an ideal knightly world from Malory's source, in contrast to his own version of the Arthurian legend (cf. 163).", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "The article's starting point is the conflict between Uther Pendragon, King of England, and the Duke of Cornwall though \"technically Cornwall should be considered part of 'Englond'\" -both in Malory's days and during the periods when most of his sources were composed (162). There we have a duke and a king but nevertheless we are left with unresolved questions of overlordship (162). Considering that the Morte begins and ends with the mention of 'matters of Cornwall', mostly problematic in nature, and that the middle third originates there (see below), Armstrong posits that \"in this light, understanding Cornwall would seem to be critically necessary to understanding Malory's text\" (162). Her theoretical tools to achieve this are postcolonial (163f.).", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "In part I, Armstrong explains the specific position of Cornwall on linguistic and geographical grounds. Though the region beyond the River Tamar officially belonged to Britain from the 7th century onwards -\"more or less\" (168) -it somehow evaded being part of it as well as it evaded open conflict with it. Part II turns from this Cornish/British microcosm to the macrocosm of medieval mappae mundi where Britain is habitually portrayed as being squeezed in on the edge of the known world. This was meant to heighten its position of uniqueness (170). 6 Thus, \"Cornwall was on the edge of the edge\" (170), in some maps it was even depicted as a real island separated completely from the mainland by the Tamar (cf. Figure 3 at 178). The focus of part III is on an historical account of Cornwall in relation to the rest of Britain (176ff.). Significantly, Cornwall was successful in separating itself in many respects. For instance, it played hardly any military role during the Wars of the Roses (179). The problematic aspect of this in relation to Malory and the Morte is obvious:", "cite_spans": [], "ref_spans": [{"start": 713, "end": 721, "text": "Figure 3", "ref_id": "FIGREF0"}]}, {"section": "", "text": "In 1327 Bishop Grandisson declared that Cornwall was not only \"the ends of the earth, but [...] the very end of the ends thereof\". And from this edge of Britain comes the ruler who unites, centralizes, and expands that entity known as 'Britain' -at least, writers like Malory seemed to wish to imagine that he had (180).", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Part IV changes the perspective: How did the Cornish view Arthur? Which claims did Cornwall lay on the legend? To answer these questions, Armstrong was helped by the fortuitous circumstance that a late medieval Cornish miracle \uf5f1\uf5f1 6 Here, Armstrong strongly relies on Lavezzo (2006) .", "cite_spans": [{"start": 267, "end": 281, "text": "Lavezzo (2006)", "ref_id": "BIBREF4"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Throughout the text, Arthur is unequivocally identified as a Cornishman (182): \"He may be King of Britain and/or England, but even as far away as Rome", "authors": [], "year": "", "venue": "Bewnans Ke, was unearthed in 2000 (180) and has hardly gained any criticism so far (note 55)", "link": null}, "BIBREF1": {"title": "Arthur's court can define itself against the Cornish \"other\". Structurally, \"the Cornish material makes the Morte Darthur\" (185) because Malory chose the French prose Tristan as his source, instead of the Vulgate or Post-Vulgate, whenever \"he needed to provide his massive opus with a centre\" (186). In Cornwall, key events find their origin that drive the story to its tragic end (187). The article closes with a look at Cornwall 500 years later and skillfully links modern matters of language policy to the Morte (part VI", "authors": [], "year": "", "venue": "Armstrong compares the Cornish court with Camelot: on a narrative level", "link": null}, "BIBREF2": {"title": "The Cambridge Companion to the Arthurian Legend", "authors": [], "year": 2009, "venue": "", "link": null}, "BIBREF3": {"title": "King Arthur in the Medieval Low Countries", "authors": [], "year": 2000, "venue": "Medievalia Lovaniensia", "link": "165436675"}, "BIBREF4": {"title": "Angels on the Edge of the World: Geography, Literature, and English Community", "authors": [{"first": "Kathy", "middle": [], "last": "Lavezzo", "suffix": ""}], "year": 2006, "venue": "", "link": null}, "BIBREF5": {"title": "Malory's Text of the Suite du Merlin", "authors": [{"first": "Jonathan", "middle": [], "last": "Passaro", "suffix": ""}], "year": 2009, "venue": "Arthurian Literature XXVI. Cambridge: Brewer", "link": null}, "BIBREF6": {"title": "Le Gen\u00e8se de la Suite de Merlin", "authors": [{"first": "Eug\u00e8ne", "middle": [], "last": "Vinaver", "suffix": ""}], "year": 1949, "venue": "M\u00e9langes de philologie romane et de litt\u00e9rature m\u00e9di\u00e9vale offerts \u00e0 Ernest Hoepffner. Paris: Belles Lettres", "link": null}, "BIBREF7": {"title": "The Works of Sir Thomas Malory", "authors": [], "year": 1990, "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "The other five contributions are: Christopher Berard, \"Edward III's Abandoned Order of the Round Table\" (1-40); Julian Luxford, \"King Arthur's Tomb at Glastonbury: The Relocation of 1368 in Context\" (41-51); Joshua Byron Smith, \"Benedict of Gloucester's Vita Sancti Dubricii: An Edition and Translation\" (53-100); Sjoerd Levelt, \"New Evidence for an Interest in Arthurian Literature in the Dutch Low Countries in the Fifteenth and Early Sixteenth Centuries\" (101- 110); Bart Besamusca and Jessica Quinlan, \"The Fringes of Arthurian Fiction\" (191-242). 4 For a comprehensive summary of Malory's sources see p. 111f. 5 Field's new edition of Malory's Morte Darthur is to be published in November 2013 by Boydell & Brewer.", "type": "figure"}}}
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{"paper_id": "199665838", "_pdf_hash": "d7c7215afeba31703559f90ad29139c63a777daf", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Big History: From the Big Bang until the Present", "authors": [{"first": "Cynthia", "middle": ["Stokes"], "last": "See", "suffix": ""}, {"first": "", "middle": [], "last": "Brown", "suffix": ""}], "year": 2007, "venue": "", "link": null}, "BIBREF1": {"title": "Maps of Time: An Introduction to Big History", "authors": [{"first": "David", "middle": [], "last": "Christian", "suffix": ""}, {"first": "William", "middle": ["H"], "last": "Mcneill", "suffix": ""}], "year": 2004, "venue": "", "link": "140568292"}, "BIBREF2": {"title": "The Structure of History: From the Big Bang until Today", "authors": [{"first": "Fred", "middle": [], "last": "Spier", "suffix": ""}], "year": 1996, "venue": "", "link": "117820803"}, "BIBREF3": {"title": "See also the forum on Big History at World History Connected", "authors": [{"first": "Fred", "middle": [], "last": "Spier", "suffix": ""}], "year": 2009, "venue": "Big History and the Future of Humanity", "link": null}, "BIBREF4": {"title": "Challenges and Opportunities: Reflections on Teaching Big History Discussion Sessions", "authors": [{"first": "Lauren Mcarthur", "middle": [], "last": "Harris", "suffix": ""}, {"first": "Sarah", "middle": [], "last": "Hamilton", "suffix": ""}], "year": 2009, "venue": "World History Connected", "link": null}, "BIBREF5": {"title": "Challenges and Opportunities", "authors": [{"first": "Mcarthur", "middle": [], "last": "Harris", "suffix": ""}, {"first": "Hamilton", "middle": [], "last": "", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF6": {"title": "For a historical excavation of the genealogy of the Anthropocene concept", "authors": [{"first": "J", "middle": [], "last": "Paul", "suffix": ""}, {"first": "Eugene", "middle": ["F"], "last": "Crutzen", "suffix": ""}, {"first": "", "middle": [], "last": "Stoermer", "suffix": ""}], "year": 2000, "venue": "Global Change Newsletter", "link": null}, "BIBREF7": {"title": "The Emergence of Multispecies Ethnography", "authors": [{"first": "Helmreich", "middle": [], "last": "Kirksey", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF8": {"title": "Again, see the useful review of this work in Kirksey and Helmreich", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF9": {"title": "The Emergence of Multispecies Ethnography", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF10": {"title": "Other authors have instead raised the specter of future rights for robots. This question has been posed not only as an abstract intellectual exercise but also as a feature of the \"futures research\" of some 62 For one such example, see Asher Seidel, Inhuman Thoughts: Philosophical Explorations of Posthumanity", "authors": [], "year": 1999, "venue": "Katherine Hayles, How We Became Posthuman: Virtual Bodies in Cybernetics, Literature, and Informatics", "link": null}, "BIBREF11": {"title": "Nick Bostrum distinguishes optimism about such new enhancement capacities as characteristic of \"transhumanism\" and pessimism about these capacities' dystopic possibilities as \"bioconservatism", "authors": [], "year": 2005, "venue": "Defence of Posthuman Dignity", "link": null}, "BIBREF12": {"title": "For an introduction to the debates, consult Samuel Moyn", "authors": [], "year": 2006, "venue": "History and Theory", "link": null}, "BIBREF13": {"title": "Advocating Dignity: Human Rights Mobilizations in Global Politics", "authors": [{"first": "Jean", "middle": ["H"], "last": "Quataert", "suffix": ""}], "year": 2010, "venue": "", "link": "152438779"}, "BIBREF14": {"title": "Human dignity in historical perspective: The contemporary and traditional paradigms", "authors": [{"first": "Oliver", "middle": [], "last": "Sensen", "suffix": ""}], "year": 2011, "venue": "European Journal of Political Theory", "link": "145655880"}, "BIBREF15": {"title": "Defence of Posthuman Dignity", "authors": [{"first": "Bostrum", "middle": [], "last": "Cited In", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF16": {"title": "In Defence of Posthuman Dignity", "authors": [{"first": "", "middle": [], "last": "Bostrum", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF17": {"title": "and the recent piece \"Robot ethics: morals and the machine", "authors": [{"first": "Sohail", "middle": [], "last": "Inayatullah", "suffix": ""}, {"first": "Phil", "middle": [], "last": "Mcnally", "suffix": ""}], "year": 2006, "venue": "The Rights of Robots: Technology, Culture and Law in the 21 st Century", "link": null}, "BIBREF18": {"title": "Go to the website for the American Society for the Prevention of", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF19": {"title": "Seriously, as an old Isaac Asimov fan, I must say this robot rights 'issue' is at best silly and at worst a smoke screen for an animal rights argument", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF20": {"title": "Whereas scholarship on human rights tends to focus on parsing either the human or rights, what is needed is a more unified approach that considers the entangled histories of \"humanity\" and \"rights", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF21": {"title": "Human Rights: A Thirty-Year Struggle: the Sustained Efforts to give Force of law to the Universal Declaration of Human Rights", "authors": [], "year": 1977, "venue": "United Nations Educational, Scientific, and Cultural Organization", "link": null}, "BIBREF22": {"title": "Missing the Green: Golf Course Ecology, Environmental Justice, and Local 'Fulfillment' of the Human Right to Water", "authors": [{"first": "Richard", "middle": [], "last": "Hiskes", "suffix": ""}], "year": 2010, "venue": "Human Rights Quarterly", "link": "145727254"}, "BIBREF23": {"title": "Missing the Green", "authors": [{"first": "", "middle": [], "last": "Hiskes", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF24": {"title": "Missing the Green", "authors": [{"first": "", "middle": [], "last": "Hiskes", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF25": {"title": "Missing the Green", "authors": [{"first": "", "middle": [], "last": "Hiskes", "suffix": ""}], "year": "", "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "199666531", "_pdf_hash": "753fc01a659dade2f775d165272fb2239011ffaf", "abstract": [], "body_text": [{"section": "Introduction", "text": "This article deals with possessives in four Romance languages: French, Italian, Spanish and Romanian. As is well known, these languages display many differences with respect to the distribution of their possessive forms, although all these forms derive etymologically from Latin. However, whereas in Latin the possessives are strong forms exhibiting a distribution similar to that of lexical adjectives, 2 this is not the case for most possessives in Romance languages. Although the strong forms found in the four languages display an adjectival morphology, their distribution does not match with that of lexical adjectives. Moreover, some of these languages, such as French and Spanish, have developed, in addition, a weak paradigm with determiner-like properties, which is in complementary distribution with the strong form.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The aim of my contribution is (i) to examine to what extent the possessive systems of the above mentioned four Romance languages are mutually divergent and (ii) to verify whether the observed differences can be regarded as the result of different grammaticalization paces. As all types of possessives -adjectival, pronominal or determiner-like -are basically grammatical forms, it may seem surprising to attempt to explain changes within the possessive paradigm through grammaticalization processes. After all, it is well known that grammaticalization typically involves the development of lexical forms into grammatical devices, for example lexical verbs turning into auxiliaries or inflectional affixes. However, grammaticalization may also be characterized as the development from grammatical to even more grammatical forms (see Kury\u0142owicz 1960) and it is this latter interpretation of the term which is adopted in this article.", "cite_spans": [{"start": 832, "end": 848, "text": "Kury\u0142owicz 1960)", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Introduction", "text": "As I show, all evolutions from Latin to Romance observed in the possessive system involve change of categorial status: pronouns are replaced by adjectives and adjectives change into determiners. I argue that these categorial changes are the result of grammaticalization and that this grammaticalization process is the most advanced in French, where neither of the two paradigms still displays adjectival properties. It is the least advanced in Italian, where possessives are still highly adjectival. As for Spanish, it has weak determiner forms for the prenominal possessives and strong adjectival forms for the postnominal forms, thus occupying an intermediate position between French and Italian. Finally, the Romanian system stands entirely apart since the possessive depends on the morpheme al, often called the 'possessive article' , which has no counterpart in the other languages.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "This article is structured as follows. Section 2 will provide a quick survey of the different types of possessives found in the four Romance languages under discussion and will show that these paradigms tend to eliminate pronominal possessives. Section 3 will examine how strong possessives have become clitic determiners in French and in Spanish. Section 4 will deal with the morphological and distributional properties of the strong forms in the four languages and will show that the French mien is the most deficient, having lost most of its adjectival properties. Table 1 provides a survey of the masculine possessive forms found in Latin and in the four Romance languages considered here. Eius (pl. eorum/earum) is in fact the genitive form of the demonstrative pronoun is, which is unmarked as to distance (see section 2.3). It has various pronominal uses. When it appears in the genitive in an adnominal position, it expresses a relation of possession. It has to be noted that in Latin the genitive of other pronouns, such as demonstratives (hic, iste, ille) or identity markers (cf. ipse, idem), can also be used as a possessive form.", "cite_spans": [], "ref_spans": [{"start": 568, "end": 575, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "From pronouns to adjectives", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Three types of possessive", "text": "As shown in various studies (see Cardinaletti 1998 , Schoorlemmer 1998 , Zribi-Hertz 1999 , Ihsane 2000 , Alexiadou 2004 ), these paradigms are heterogeneous in that they contain different types of possessives. Although these studies differ in their analyses of particular forms, they all agree in distinguishing the following three types of possessives, illustrated here by the most representative example found in the four languages:", "cite_spans": [{"start": 33, "end": 50, "text": "Cardinaletti 1998", "ref_id": "BIBREF5"}, {"start": 51, "end": 70, "text": ", Schoorlemmer 1998", "ref_id": "BIBREF22"}, {"start": 71, "end": 89, "text": ", Zribi-Hertz 1999", "ref_id": "BIBREF26"}, {"start": 90, "end": 103, "text": ", Ihsane 2000", "ref_id": "BIBREF15"}, {"start": 104, "end": 120, "text": ", Alexiadou 2004", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Three types of possessive", "text": "-The adjectival type, such as the Italian possessive mio (1msg), which exhibits an adjectival distribution in that it can occur as an attribute, either in prenominal or postnominal position, and as a predicate.", "cite_spans": [], "ref_spans": []}, {"section": "Three types of possessive", "text": "(1 ", "cite_spans": [], "ref_spans": []}, {"section": "Two agreement patterns", "text": "The heterogeneity of the possessive paradigm in one and the same language and its cross-linguistic variability can be explained by the double status of possessives. Syntactically they appear in an adnominal position, and tend therefore to behave either as adjuncts or specifiers. However, from a semantic and referential point of view they behave like pronouns, in that they refer to an entity, which I will call the possessor. As is the case with the referents of personal pronouns, too, this possessor can be identified either deictically or anaphorically. Furthermore, the third-person pronouns constitute the pronominal counterparts of lexical possessive PPs 3 (see 6) or genitive NPs in case languages. As shown in (7), possessives can be coordinated with lexical PPs in Italian and Spanish or with lexical genitives in Romanian. (Antrim 2003: 8) This double status of possessives, which are syntactically modifiers or specifiers and referentially pronouns, explains why they can be categorized either as adjectives/determiners or as pronouns. For possessives, the most salient difference between these categories is their agreement pattern: pronominal possessives inherit their features (person, gender, number) from their referent or antecedent, while adjectival or specifying possessives agree in gender and number with the head noun. However, all possessive forms exhibit person and number agreement with the possessor. As a consequence, the adjectival and determiner forms show a hybrid agreement pattern: with the possessor with respect to person and number; with the head noun with respect to number and gender.", "cite_spans": [], "ref_spans": []}, {"section": "Two agreement patterns", "text": "This double agreement pattern does not raise problems since the two patterns are expressed differently. The agreement with the possessor is expressed by the root of the possessive forms, hence lexically, and is therefore not grammatical agreement but referential concord. The agreement with the head noun is marked by inflectional morphemes and is triggered by grammatical relations only, as clearly appears from the glosses of the following Italian examples. Although all possessives are pronouns and are labelled so in most grammatical traditions, I will henceforth restrict the use of the term pronoun to the non agreeing forms.", "cite_spans": [], "ref_spans": []}, {"section": "Possessive pronouns in Romance", "text": "The existence of several types of possessives can already be observed in the Latin system, which contained two of them, the agreeing type (1msg meus, 1fsg mea, 1nsg meum) and the non agreeing one (3sg eius, 3mpl eorum, 3fpl earum), corresponding to the genitive case of the personal pronoun 3msg is. It is important to note that, in both Latin and Romance, the non agreeing forms occur only in the third person, singular and plural, and not in the deictic 1st-2nd persons. Furthermore, in Classical Latin the genitive pronoun occurred only in contexts of discourse anaphora, but not in those of bound anaphora, where the use of the reflexive suus was compulsory. We can thus infer that the use of the possessive pronoun was restricted to contexts giving rise to ambiguity in the identification of the antecedent and, hence, aimed at reducing this ambiguity through agreement of the pronoun with its antecedent. However, for referentially non ambiguous possessives, such as deictics or reflexive possessives, Latin had exclusively agreeing forms (1msg meus, 2msg tuus, 3msg suus).", "cite_spans": [], "ref_spans": []}, {"section": "Possessive pronouns in Romance", "text": "A glance at Table 1 shows that most possessive pronouns were lost in the evolution from Latin to Romance. Especially for the singular forms, three of the four languages have replaced the third-person-singular pronoun with the reflexive form, which has thus lost its reflexive use. As noted by Stotz (1998: 292-293) , this loss of reflexivity can be observed in Medieval Latin as well.", "cite_spans": [], "ref_spans": [{"start": 12, "end": 19, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Possessive pronouns in Romance", "text": "In the third-person singular, only Romanian still has genuine pronouns. However, 3msg lui and 3fsg ei derive from the dative pronouns illui (< ille) and ei (< is). In contemporary Romanian, these forms occur either as adnominal genitive or strong dative pronouns, as the Romanian case system shows syncretism between the genitive and the dative. (GLR 2005: 234) A further point of note is that the genitive possessive pronouns alternate with the agreeing form s\u0103u, derived from the reflexive suus. As in Medieval Latin and in the other Romance languages, s\u0103u has lost its reflexive use. It is generally used in written and rather formal language, the genitive pronoun being the most usual form in spoken language. 4 The survival of the genitive pronouns as possessives in Romanian can be explained by two factors. The first is that Romanian is still a case language and that, morphologically, the genitive pronouns display roughly the same inflection as other genitivemarked words. The second factor is that, in Romanian, definite determiners and determiner-like adjectives such as demonstratives and possessives are generally postposed to the head noun. The postposition of the genitive pronoun to the head noun yields a strong parallel with genitive NPs, with which the possessives can be coordinated, as already shown in example (7). However, the distribution of the genitive pronouns is somewhat different from that of genitive NPs. For instance, unlike the latter, genitive pronouns (as well as possessive adjectives) can occur before the noun when they follow an adjective bearing the enclitic definite article (or are preceded by the morpheme al, which will be commented below). As for the third-person-plural possessive form, the evolution of the possessives has been more diverse. As can be seen from Table 1 , the Latin genitive plural personal pronouns eorum/earum have not survived in Romance. Spanish has chosen the reflexive suus, which thus neutralizes not only the gender of the possessor, but also its number. The three other languages have replaced these personal pronouns with the genitive masculine plural demonstrative illorum, which tended to replace both the masculine eorum and the feminine earum in Late Latin (see Stotz 1998: 293) . In all three languages, the forms derived from illorum are also used as dative pronouns; that is, as a dative clitic pronoun in French, as a strong dative pronoun in Romanian and as a strong or weak form in Italian. Notice that whereas in Romanian lor is part of a paradigm of third-personpossessive pronouns, in modern Italian loro is an idiosyncratic pronoun within the possessive paradigm. However, in Old Italian, loro constituted a paradigm with the possessive pronouns 3msg lui and 3fsg lei, which have lost the oblique cases in contemporary Italian (see Rohlfs 1970 , Stefanini 1976 , Cardinaletti 1998 . As shown in (16c) this possessive use of the pronoun lui is attested in Italian until the nineteenth century, but was in competition with the much more frequent prepositional use il di lui N, a structure which is still used in modern Italian (see 16d; see also Salvi & Renzi 2010: 368 This shows that the pronoun loro is a remnant of a system of third-personpossessive pronouns, similar to the Romanian system. 5 5 Cardinaletti (1998) analyzes loro as a DP-internal weak pronoun, which contrasts with both the prenominal and the postnominal possessive adjectives, which are strong forms. However, the data on which this claim is based are controversial. According to Cardinaletti (1998) , loro cannot appear in predicative position, nor in isolation nor in certain elliptic NPs, and cannot be used without the article with kinship nouns (cf. ex. 25).", "cite_spans": [{"start": 2820, "end": 2831, "text": "Rohlfs 1970", "ref_id": "BIBREF20"}, {"start": 2832, "end": 2848, "text": ", Stefanini 1976", "ref_id": "BIBREF24"}, {"start": 2849, "end": 2868, "text": ", Cardinaletti 1998", "ref_id": "BIBREF5"}, {"start": 3286, "end": 3305, "text": "Cardinaletti (1998)", "ref_id": "BIBREF5"}, {"start": 3538, "end": 3557, "text": "Cardinaletti (1998)", "ref_id": "BIBREF5"}], "ref_spans": [{"start": 1810, "end": 1817, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Possessive pronouns in Romance", "text": "(i) Italian a. *Questo ritratto \u00e8 loro. vs b. Questo ritratto \u00e8 suo. (Cardinaletti 1998: 83) this portrait is theirs this portrait is his/hers 'This is his/her portrait. ' .", "cite_spans": [], "ref_spans": []}, {"section": "Possessive pronouns in Romance", "text": "(ii) a. Di chi \u00e8 questo libro? b. Suo./*Loro. (Cardinaletti 1998 : 84) of whom is this book his theirs 'Whose book is this ?' 'His/*theirs. ' (iii) a. Da-mmi quelli suoi.", "cite_spans": [{"start": 46, "end": 64, "text": "(Cardinaletti 1998", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Possessive pronouns in Romance", "text": "b. *Da-mmi quelli loro. (Cardinaletti 1998: 94) give-me these his/hers give-me these theirs 'Give me his/her ones. ' (iv) a. (*il) mio fratello b. *(il) loro fratello (Cardinaletti 1998 : 103) the mine brother the theirs brother 'my brother' Nevertheless the contrast between loro and possessive adjectives is not as clear-cut as We can thus summarize as follows: in the evolution from Latin to Romance languages, possessive pronouns tended to be replaced with agreeing forms, the only surviving pronouns being Italian 3pl loro and Romanian 3sg+pl lui/ei/lor. The question is whether this evolution can be described as a case of grammaticalization. At first glance, the answer to this question might seem to be negative, as pronouns are more grammatical than the basically lexical category of adjectives. However, given that the pronominal forms correspond more directly to their lexical counterparts, which are DPs, the replacement of pronouns with agreeing forms can be explained by the predominance of the syntactic position of the possessive within the NP over its referential function. From this respective, Spanish has the most advanced system, immediately followed by French, where the pronoun leur has turned into an agreeing form. Romanian is clearly the less evolved language in that it has a complete system of genuine pronouns for the third-person singular and plural, while Italian loro is an idiosyncratic possessive pronoun within an agreeing possessive paradigm.", "cite_spans": [{"start": 167, "end": 185, "text": "(Cardinaletti 1998", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "From strong adjectival forms to clitic determiners", "text": "As noted above, French and Spanish have two complete paradigms of possessives: a weak form (Fr. mon, Sp. mi) and a strong form (Fr. mien, Sp. m\u00edo). Both forms derive from the Latin accusative meum and display an adjectival agreement pattern in that they agree in number and gender with the head noun. However, these two paradigms do not alternate in the same syntactic positions. As shown by Cardinaletti (1998) , Schoorlemmer (1998 ), Zribi-Hertz (1999 , Ihsane (2000) , Antrim (2003) and Alexiadou (2004) , the weak type behaves syntactically like a determiner, while the behaviour of the strong form, albeit with many restrictions on context (see claimed by Cardinaletti. Examples such as (ia) are attested (see v), and (iiia) and (iiib), although considered both ungrammatical by some speakers of Italian, are attested, which shows that the use of loro differs less from that of the other possessives than argued by Cardinaletti. For further critical remarks on the claim of Cardinaletti, see Ihsane (2000) .", "cite_spans": [{"start": 392, "end": 411, "text": "Cardinaletti (1998)", "ref_id": "BIBREF5"}, {"start": 414, "end": 432, "text": "Schoorlemmer (1998", "ref_id": "BIBREF22"}, {"start": 433, "end": 453, "text": "), Zribi-Hertz (1999", "ref_id": "BIBREF26"}, {"start": 456, "end": 469, "text": "Ihsane (2000)", "ref_id": "BIBREF15"}, {"start": 472, "end": 485, "text": "Antrim (2003)", "ref_id": "BIBREF2"}, {"start": 490, "end": 506, "text": "Alexiadou (2004)", "ref_id": "BIBREF1"}, {"start": 997, "end": 1010, "text": "Ihsane (2000)", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "From strong adjectival forms to clitic determiners", "text": "(v) Italian i suoi libri, quelli di altri e quelli suoi, the his/hers books, those of others and those his/hers 'his/hers books, those of the others and his/hers' (Stampaquot -Corpus Coris) (vi) tra gli interessi nostri e quelli loro between the interests ours and those theirs 'between our interests and theirs' (Internet d) section 4), is closer to that of lexical adjectives. In this section, I will concentrate on the weak form and investigate the extent to which its distribution is similar to that of other determiners, such as articles.", "cite_spans": [], "ref_spans": []}, {"section": "Possessives as determiners", "text": "The possessive determiners of French and Spanish share three crucial properties with articles. First, contrary to their strong counterparts in all four languages, 6 they can license an NP. 6 In Italian and in Spanish, the strong forms can also appear without the article, thus giving rise to apparent counter-examples. However, the possessive NP appears in contexts allowing the absence of the article, such as predicates (ia), vocatives or exclamations (ib), indefinite plurals (ic, iia) and negative contexts (iib). Moreover, in some of these examples the strong possessive is postposed to the head noun, a position which is not accessible to determiners. (i) Italian a. Sar\u00f3 sempre tua amica. will.be always your friend 'I will always be your friend. ' (Cordin 1988: 607) Picallo & Rigau (1999: 977) , in Spanish the strong possessive does co-occur with the demonstrative, but only in formal language. They also observe that in several northern dialects of Spain, such as those spoken in Leon and Asturias, the prenominal possessive can also co-occur with the definite article (la mi casa, el mi pueblo). 8 Notice, though, that possessive determiners differ from articles in that they require the presence of a noun, while the definite article can license an NP with an empty noun. As shown by Picallo & Rigau (1999: 981) Evidently, as argued by Alexiadou (2004) for the possessives in French, English and German, the cliticization of possessive forms is a strong argument in favour of the grammaticalization of the possessive paradigm in French and in Spanish. As shown by Hopper & Traugott (1993: 7) , cliticization is the penultimate stage in the cline of grammaticality, which they present as follows: content word > grammatical word > clitic > inflectional affix In Spanish, the grammaticalization of the prenominal weak possessive is also confirmed by phonetic and morphological erosion, another clear symptom of both grammaticalization and cliticisation (cf. Antrim 2003) . Although Spanish has a rich morphology of the agglutinating type, separating gender and number morphemes (-o/-a for the gender distinction and -\u2205/-s for the number distinction, see (24)), the morphology of the possessive determiner is extremely reduced, neutralizing gender oppositions in the singular and in the third-person plural forms, as is demonstrated in Table 2 .", "cite_spans": [{"start": 1349, "end": 1365, "text": "Alexiadou (2004)", "ref_id": "BIBREF1"}, {"start": 1969, "end": 1981, "text": "Antrim 2003)", "ref_id": "BIBREF2"}], "ref_spans": [{"start": 2346, "end": 2353, "text": "Table 2", "ref_id": "TABREF10"}]}, {"section": "Possessives as determiners", "text": "While the morphology of the weak paradigm in French is richer than that of Spanish in that it shows gender distinctions in the singular (see Table 3 ), it displays two particularities which argue in favour of its grammaticalization. -the feminine singular is marked by the morpheme -a, just as for the definite article, while lexical adjectives take the feminine morpheme -e (cf. msg grand, fsg grande 'big'); -the first-and second-person plural forms exhibit an irregular morphology, which is not found anywhere else in French morphology.", "cite_spans": [], "ref_spans": []}, {"section": "Possessives as determiners", "text": "Some initial stages of cliticization and grammaticalization can also be found in Italian and in Romanian, where prenominal possessives can occur without the article when used with certain kinship nouns. In Italian, this article-less construction is compulsory with singular non-derived kinship nouns, but agrammatical with plural and derived kinship nouns. In Romanian it is restricted to a few singular kinship nouns in informal spoken language. According to Cardinaletti (1998) , the Italian possessive displays clitic behaviour in these uses, whereas in its prenominal position it behaves as a weak form and in postnominal uses as a strong form, although all these forms are homophonous. She justifies this claim by noting that, used with kinship nouns, they cannot occur alone, either in ellipsis (27a) or in isolation (27b), nor can they be contrasted (27c) or coordinated (27e). Conversely, it should be noted that in old French the clitic pronoun is compatible with articles, as is shown by the following example, taken from Buridant (2000: 155) . This construction has since been lost. This diachronic development may suggest that the evolution of possessives passes through two steps: first, strong forms become weak prenominal ones, used with another determiner; subsequently, the weak prenominal forms tend to occupy the determiner position and undergo cliticization. The observations made in this section confirm the conclusion reached in the preceding section. They show that both Spanish and French have the most grammaticalized possessive paradigm: both languages have completely eliminated the possessive pronouns and both have developed clitic determiners. By contrast, the Italian and Romanian paradigms still contain pronouns and exhibit few instances of cliticisation (see also Van Peteghem 2011).", "cite_spans": [{"start": 460, "end": 479, "text": "Cardinaletti (1998)", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "From genuine adjectives to deficient adjectives", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "The declension of strong possessives", "text": "Let us now concentrate on the analysis of the strong forms. All four languages have strong possessives, exhibiting the same number and gender morphemes as lexical adjectives.", "cite_spans": [], "ref_spans": []}, {"section": "The declension of strong possessives", "text": "Interestingly, the most complete paradigms can be found in Spanish (see Table 4 ), immediately followed by Italian (see Table 5 ), which displays the same oppositions as Spanish, with the exception of the third-personplural invariable pronoun loro, as discussed in section 2. As for French (see Table 6 ), the strong possessive has a reduced morphology: in the plural forms, the gender opposition is completely neutralized, and in the whole paradigm the number oppositions are marked only in the written forms. In the oral language they are marked by the definite article, with which the possessive is obligatorily used. It has to be noted that the declension of the plural forms, neutralizing gender and in oral speech also number, is consistent with the declension type found with lexical adjectives ending in -e, such as rustre.", "cite_spans": [], "ref_spans": [{"start": 72, "end": 79, "text": "Table 4", "ref_id": "TABREF13"}, {"start": 120, "end": 127, "text": "Table 5", "ref_id": "TABREF14"}, {"start": 295, "end": 302, "text": "Table 6", "ref_id": "TABREF15"}]}, {"section": "The declension of strong possessives", "text": "The most peculiar declension is found in Romanian. Although gender and number agreement with the head noun are systematically marked (except for the pronouns lui/ei/lor, as noted above), the typical adjectival morphology is found only with the first-and second-person plural forms (see Table 7 ). The other forms display a determiner-like morphology in the feminine, the morphemes being fsg -a, fpl -le, which contrast with the adjectival endings -\u0103/-e (see Table 8 ). The -a/-le opposition is mainly found with determiners such as the enclitic definite article, the demonstratives cel and acel and the so-called possessive article al, which will be discussed below. However, it appears also with a few lexical adjectives such as greu ('heavy' , 'difficult' , cf. greu, grea, grei, grele) . We can thus say that, morphologically, the strong possessive corresponds more to determiners than to adjectives in Romanian, and is therefore the least adjectival one.", "cite_spans": [], "ref_spans": [{"start": 286, "end": 293, "text": "Table 7", "ref_id": "TABREF16"}]}, {"section": "The distribution of strong possessives", "text": "A distributional analysis of the strong possessives in the four languages, however, leads to a completely different result, especially for French. The following data show that French mien no longer behaves as an adjective and is highly deficient from a distributional point of view. The same goes for Romanian, in contrast to Spanish and Italian, where the distribution of strong possessives is very similar to that of lexical adjectives. In what follows, I will argue in favour of the following deficiency scale for the strong possessives in the four languages under discussion:", "cite_spans": [], "ref_spans": []}, {"section": "The distribution of strong possessives", "text": "This scale is motivated by the following four observations. (1) In Italian, the strong possessive can occur either post-or pre-nominally, just like lexical adjectives (the postnominal use being limited to focalizing contexts), whereas in Spanish it is restricted to the postnominal position. In Romanian, where both lexical adjectives and definite determiner elements, such as definite articles and demonstratives, appear post-nominally, it is generally postposed to the noun bearing the so-called enclitic article - (u)l, -a, -i, -le 9 (see 31). However, in a literary register it can also precede the noun, in which case it requires the presence of the 'possessive' or 'genitive article' al (see 33b). This morpheme, which agrees in gender and number with the noun denoting the possessed item (msg al, fsg a, mpl ai, fpl ale), 10 appears whenever the possessive modifier is not immediately adjacent to the enclitic definite article. As further analysis of this morpheme is beyond the scope of this article, I will consider it here as a kind of substitute for the definite article.", "cite_spans": [], "ref_spans": []}, {"section": "The distribution of strong possessives", "text": "11 9 In the grammatical tradition of Romanian, this article is generally described as an enclitic element. However, as shown by Ortman & Popescu (2000) , it rather behaves as an affix. As this issue is not crucial here, we will not further discuss it. 10 Notice that this article is composed of a (deriving from the Latin preposition ad) + the enclitic definite article (-l, -a, -i, -le) . When the element to the right of the article is invariable, it appears in its basic form a.", "cite_spans": [], "ref_spans": []}, {"section": "The distribution of strong possessives", "text": "(i) autor-ul a unsprezece opere author-the.M A eleven operas 'the author of eleven operas' 11 The analysis of this al-form, which has no counterpart in other Romance languages, is controversial since it has both determiner-like and prepositional properties. It not only heads the possessive modifier, but also lexical genitive NPs whenever they are not immediately adjacent to the enclitic definite article; that is, (i) in indefinite or demonstrative NPs, in elliptic NPs, in definite NPs with an intervening postponed adjective, and also (ii) in anaphoric elliptic NPs.", "cite_spans": [], "ref_spans": []}, {"section": "The distribution of strong possessives", "text": "(i) O carte a mea Carte-a aceasta a mea Carte-a cea mai recent\u0103 a mea a book A mine book-the this A mine book-the CEL more recent A mine ' A book of mine' 'This book of mine' 'My latest book' (ii) Prieten-ul meu locuie\u015fte la Bucure\u015fti. Al t\u0103u locuie\u015fte la Bra\u015fov.", "cite_spans": [], "ref_spans": []}, {"section": "The distribution of strong possessives", "text": "friend-the mine lives at Bucharest AL yours lives at Brasov 'My friend lives in Bucharest. Yours lives in Brasov. ' In (i) it behaves as an agreeing preposition-like element and has therefore been considered a 'prepositional determiner' (see Stef\u0103nescu 1997) , while in (ii) it is more determiner-like. In various studies within the framework of Generative Grammar, it is analyzed as a case assigner (see Dobrovie-Sorin 1987 , Gro\u015fu 1988 , Cornilescu 1995 , D'hulst, Coene & Tasmowski 1997 , Ortman & Popescu 2000 . By contrast, in French the strong possessive mien cannot be used as an attribute, either pre-nominally or post-nominally, though it could occur in pre-nominal position in Old French, as noted by Buridant (2000: 153-155 (Roland, 2198; Buridant 2000: 153) . the mine death me makes so anguished 'My own death fills me with such anxiety. '", "cite_spans": [{"start": 242, "end": 258, "text": "Stef\u0103nescu 1997)", "ref_id": "BIBREF23"}, {"start": 405, "end": 424, "text": "Dobrovie-Sorin 1987", "ref_id": "BIBREF10"}, {"start": 438, "end": 455, "text": ", Cornilescu 1995", "ref_id": "BIBREF7"}, {"start": 456, "end": 489, "text": ", D'hulst, Coene & Tasmowski 1997", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "The distribution of strong possessives", "text": "(2) Another important difference between the four languages bears upon the predicative use of the possessive, which is possible with or without the article in Italian and Spanish, but generally requires the presence of the definite article in French and of the article al in Romanian. Again it has to be noted that the predicative use of mien was frequent in Old French (see Buridant 2000: 154-155) and is still possible in contemporary French, but only in a literary register and mostly in secondary predication constructions (cf. faire mien 'make mine'). (Ricoeur 1949; Frantext) (3) Another distributional criterion is provided by the compatibility of the strong possessive with determiner-like elements, such as the definite and indefinite articles, demonstratives, indefinites and numerals. This criterion yields a different picture for each of the four languages. The Italian possessive is the most compatible one in that it can combine with all determiners in prenominal as well as in postnominal position. The same goes for the Spanish possessive modifier, but only in postnominal position. As for Romanian, as noted above, it requires immediate adjacency either to the enclitic definite article or to its substitute al. Hence, al shows up whenever the possessive co-occurs with determiners other than the definite article. By contrast, the strong possessive in French, which only appears in elliptic NPs, does not combine with determiners other than the definite article. However, in Old French it was perfectly compatible within the NP with various determiners such as definite and indefinite articles and demonstratives, as shown by the examples in (37), taken from Buridant (2000: 154) . Furthermore, the Frantext corpus provides examples of co-occurrences of mine with the indefinite article up to the seventeenth century and with the demonstrative up to the eighteenth century. Both the attributive uses of mien and its compatibility with other determiners have been lost since the end of the seventeenth century, as a result of which it has become highly defective. In summary, we can say that there is a clear contrast between Italian and Spanish on the one hand, where the possessive combines with all determiners under certain conditions, and contemporary French and Romanian on the other hand, where the possessive adjective is always headed by a definite article in French or by its substitute al in Romanian.", "cite_spans": [], "ref_spans": []}, {"section": "The distribution of strong possessives", "text": "(4) My final argument in favour of the deficiency scale proposed above bears upon coordination. Whereas in all four languages strong possessives can be coordinated when preceded by the article (or the al form in Romanian) (see 40), in Italian and in Spanish only they can also be coordinated without the presence of the article (41). elliptic NPs). Clearly, the most 'adjectival' possessive is the Italian, which displays all the adjectival properties of adjectives. The Spanish strong possessive displays all but one, the exception being that it cannot appear in prenominal position, where the use of a determiner is compulsory. Finally, the Romanian possessive is always dependent either on the enclitic definite article or on the possessive article al.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions and perspectives", "text": "The above findings show that the possessive paradigm is, without any doubt, the most grammaticalized in French, for two crucial reasons: (i) it has developed a clitic determiner and (ii) its strong possessive form no longer displays an adjectival distribution. The least grammaticalized possessive paradigm is the Italian, because it is still highly adjectival. In Spanish, the possessive paradigm holds an intermediate position between these two languages in that it has a double system: a clitic determiner similar to the French, which is in an advanced stage on the grammaticalization scale, and a strong possessive, very similar to the Italian, which is less grammaticalized. As for Romanian, it exhibits a peculiar system, showing many divergences from the three other languages. These divergences are related to other grammatical differences of Romanian, such as the fact that it is a case language and that it postposes definite determiners. For this reason, it is difficult to position its possessive system on a grammaticalization scale. Nevertheless, it is clear that in this language the possessive displays fewer adjectival properties than in Italian or in the postnominal strong possessive in Spanish. However, with respect to the possessive determiner in French and Spanish and to French mien, we can only say that the possessive system has followed a totally different path in Romanian, which makes it impossible to \"measure\" its degree of grammaticalization. The hypothesis presented here needs to be tested by means of a comprehensive diachronic study of the development of possessives. Such a study is essential for a full understanding of the evolution of possessives in Romance. It would also be interesting to flesh out this analysis with a diatopic study taking into account dialectal data. Finally, a study of the interaction of adnominal possessives with other possessive devices, such as the verbal clitic pronouns (cf. the possessive dative in all four languages, and the clitic proforms en in French and ne in Italian) and possessive PPs or genitive NPs, may also shed light on the evolution of the expression of possession in the languages studied here. 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Art\u00edculos en homenaje a Eugeen Roegiest con motivo de su 65 cumplea\u00f1os", "authors": [{"first": "Peter", "middle": [], "last": "Stotz", "suffix": ""}, {"first": "", "middle": [], "last": "Formenlehre", "suffix": ""}, {"first": "", "middle": [], "last": "Syntax Und Stilistik", "suffix": ""}, {"first": "", "middle": ["H"], "last": "Munich: C", "suffix": ""}, {"first": "", "middle": [], "last": "Beck", "suffix": ""}], "year": 1998, "venue": "", "link": null}, "BIBREF26": {"title": "Le syst\u00e8me des possessifs en fran\u00e7ais standard moderne", "authors": [{"first": "Anne", "middle": [], "last": "Zribi-Hertz", "suffix": ""}], "year": 1999, "venue": "Langue Fran\u00e7aise", "link": "170160218"}}, "ref_entries": {"FIGREF1": {"text": "", "type": "figure"}, "FIGREF2": {"text": "book-the him-gen/her-gen/them-gen 'his/her/their book' b. carte-a b\u0103iat-ul-ui/ fete-i/ b\u0103ie\u0163i-l-or book-the boy-the-gen/girl-the.gen/boys-the-gen 'The boy's/girl's/boys' book'", "type": "figure"}, "FIGREF3": {"text": "Romanian a. mare-a ei iubire great-the hers love 'her great love' b. *mare-a Marie-i iubire great-the Mary-GEN love", "type": "figure"}, "FIGREF4": {"text": "French Par un son fils a il trop grand dehait. by a his son has he too big pain 'Because of one of his sons, he has too much pain. ' (Po\u00e8me; Buridant 155)", "type": "figure"}, "FIGREF6": {"text": "34) a. Italian Questo libro \u00e8 mio/il mio.", "type": "figure"}, "FIGREF7": {"text": "36) a. Italian il/ un/questo/qualche mio libro the/a/ this/ some mine book b. Spanish el/ un/este/algun libro m\u00edo the/a/ this/some book mine 'the/a/this/some book of mine' c. Romanian o carte a mea/ carte-a aceasta a mea/ c\u00e2teva c\u0103rti ale mele a book A mine/book-the this A mine/some books ALE mine 'a book of mine'/'this book of mine'/'some books of mine'", "type": "figure"}, "FIGREF8": {"text": "40) a. French Ces maisons valent plus cher que la mienne et la these houses are.worth more expensive than the mine and the tienne. yours 'These houses are worth more than mine and yours. ' b. Romanian casa mea \u015fi a ta house-the mine and A yours c. Italian la mia casa e la tua the mine house and the yours d. Spanish la casa m\u00eda y la tuya the house mine and the yours 'my house and yours' (41) a. Italian sotto la mia e tua sorveglianza (Rodolfo Tommasi; 1997) under the mine and yours supervision 'under my supervision and yours' b. Spanish la foto m\u00eda y tuya the picture mine and yours 'our picture'", "type": "figure"}, "TABREF0": {"text": "Possessives in Latin and Romance", "type": "table"}, "TABREF1": {"text": "-The determiner type, such as French mon and Spanish mi, whose distri- bution is determiner-like in that it can license an NP and does not combine with other determiners.him.dat have.1 given him.dat/her.dat a book 'I gave a book to him/to her. '", "type": "table"}, "TABREF2": {"text": "the yours and a team.gen-the.gen yours.gen 'your activity and the activity of your team' (Internet c) Moreover, third-person possessives display a pronominal-like behavior with respect to binding: like pronouns, they can be bound by a c-com- manding quantifier (see 8a) and are able to bind a reflexive (see 8b; see also Antrim 2003: 8).", "type": "table"}, "TABREF3": {"text": "him/her.cl.dat have given him/her.dat a book 'I have given a book to him/to her. ' Notice, though, that, in literary Romanian, dative clitics (third-person-sin- gular but mostly first-and second-person-singular clitics) can also be used as adnominal possessives. Therefore, the question arises as to whether the strong adnominal pronouns lui/ei are to be analyzed as genitive marked, or rather, as argued by Ortman & Popescu (2000), as dative marked. As this issue goes beyond the scope of this article, I will not discuss it here.stays in house-me.cl.dat and not pay rent 'He stays in my house and does not pay rent. '", "type": "table"}, "TABREF4": {"text": "However, from a morphological point of view, only Romanian lor and Italian loro still behave like genuine pronouns in that they do not agree with the head noun. French leur, on the other hand, exhibits number agreement which is audible in liaison contexts. We can thus conclude that this pronoun has been adjectivized in French.", "type": "table"}, "TABREF5": {"text": ").c. il lui padre era morto due anni innanzi. the him.gen/dat father was dead two years before 'His father died two years before. ' (Vittorio Alfieri, 1809) Modern Italian d. costringendo-lo per\u00f2 ad adottare il di lui nipote Germanico, forcing-him however to adopt the of him nephew Germanico 'but forcing him to adopt his nephew Germanico' (MON2001_04)", "type": "table"}, "TABREF7": {"text": "although -as we will see in section 4 -the conditions under which these combinations are possible differ from one language to another.Peter him.dat pleases your dress but not him.dat pleases mi/el mi. my/the my 7 However, as noted by", "type": "table"}, "TABREF8": {"text": "I acquainted to your mother to you.pol 'I got acquainted with your mother. ' (Benito P\u00e9rez Gald\u00f3s, Electra I, 9)", "type": "table"}, "TABREF9": {"text": ", in various Spanish dialects (Mexico, Andes), clitic doubling occurs even with lexical PPs.", "type": "table"}, "TABREF10": {"text": "Clitic determiner possessives in Spanish", "type": "table"}, "TABREF12": {"text": "mine brother will.come, the yours on.the.other.hand not 'My brother will come, while yours will not. ' b. Verr\u00e0 tuo fratello o il fratello di Gianni? *(Il) suo. will.come your brother or the brother of Gianni ? (the) his. 'Who will come, your brother or John's ? His.", "type": "table"}, "TABREF13": {"text": "Strong possessives in Spanish", "type": "table"}, "TABREF14": {"text": "Strong possessives in Italian", "type": "table"}, "TABREF15": {"text": "Strong possessives in French", "type": "table"}, "TABREF16": {"text": "First", "type": "table"}, "TABREF19": {"text": "'They say then, in accordance with human rights: this city is mine, this slave is mine, this house is mine. ' (Gratien, in Buridant 2000: 154) b. C' est une des rares certitudes maternelles que j' aie faites this is one of.the rare certainties maternal that I have made miennes. (Brisac 1996; Frantext) mine 'This is one of the few certainties that I have acquired as a mother. ' c. Cela suffit pour que je reconnaisse ces actions comme miennes . . . this suffices for that I recognize these actions as mine 'That is enough to let me recognize these actions as mine. '", "type": "table"}, "TABREF20": {"text": "Un mien ami, tant qu' il fut gar\u00e7on, produisoit chaque semaine a mine friend as.long as he was boy produces each week un volume de po\u00ebsies gaillardes. a volume of poems ribald ' A friend of mine, when he was young, wrote several ribald poems every week. ' (Charles Dufresny 1699; Frantext) b. Je vous demande excuse pour ce mien serviteur ; I you ask excuse for this mine servant 'I beg your pardon for this servant of mine. ' (Thomas Gueullette 1756; Frantext)", "type": "table"}, "TABREF21": {"text": "The distribution of possessives in the four languages Weak possessives Strong possessives Fr. mon Sp. mi Fr. mien Sp. m\u00edo It. mio Rom. mea", "type": "table"}, "TABREF22": {"text": "AL/A/AI/ALE forms of the posses- sive article in Romanian cl clitic dat dative fpl feminine plural", "type": "table"}}}
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{"paper_id": "199667929", "_pdf_hash": "924483988d61d4c5bb14d0d50af8fd1c622ebd41", "abstract": [{"section": "Abstract", "text": "Fourier transform infrared (FTIR) spectroscopic imaging of colon biopsy tissues in transmission combined with machine learning for the classification of different stages of colon malignancy was carried out in this study. Two different approaches, an optical and a computational one, were applied for the elimination of the scattering background during the measurements and compared with the results of the machine learning model without correction for the scattering. Several different data processing pathways were implemented in order to obtain a high accuracy of the prediction model. This study demonstrates, for the first time, that C-H stretching and amide I bands are of little to no significance in the classification of the colon malignancy, based on the Gini importance values by random forest (RF). The best prediction outcome is found when supervised RF classification was carried out in the fingerprint region of the spectral data between 1500 and 1000 cm \u22121 (excluding the contribution of amide I and II bands). An overall prediction accuracy higher than 90% is achieved through the RF. The results also show that dysplastic and hyperplastic tissues are well distinguished. This leads to the insight that the important differences between hyperplastic and dysplastic colon tissues lie within the fingerprint region of FTIR spectra. In this study, computational correction performed better than optical correction, but the findings show that the disease states of colon biopsies can be distinguished effectively without elimination of Mie scattering effect.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Open Access This article is distributed under the terms of the Creative Comm ons Attribution 4.0 International License (http:// creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Colon cancer is a disease in the large intestine in which abnormal cells divide uncontrollably. Most cases of the colon cancer begin as a small adenomatous polyp which lines the inner surface of the colon [38] . In the UK, colon cancer is the fourth most common cancer with 16,000 deaths every year, making it the second most common cause of cancer death in 2016 [11] . Early detection of colon cancer can help reduce mortality and morbidity. The current diagnostic approach for this disease includes biopsy collection followed by histopathology during colonoscopy or surgery. In recent years, FTIR spectroscopy has been shown as a promising technique to enhance the clinical diagnosis in a label-free way by investigating the chemical content of the biopsy samples [5, 19, 25, 27] .", "cite_spans": [{"start": 205, "end": 209, "text": "[38]", "ref_id": "BIBREF38"}, {"start": 766, "end": 769, "text": "[5,", "ref_id": "BIBREF4"}, {"start": 770, "end": 773, "text": "19,", "ref_id": "BIBREF18"}, {"start": 774, "end": 777, "text": "25,", "ref_id": "BIBREF24"}, {"start": 778, "end": 781, "text": "27]", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "Introduction", "text": "Although FTIR spectroscopy has the potential as a clinical prognostic tool, there are several challenges associated with it, most notably the reflection and scattering contribution ('dispersion artefact') that arise from the spatial inhomogeneity of the sample. In fact, the dispersion artefact is found to be largely dominated by resonant Mie scattering in pure transmission experiment, as opposed to measurement in transflection mode where the reflection artefact becomes significant [6] . The Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00216-019-02069-6) contains supplementary material, which is available to authorized users. scattering contribution can lead to spectral distortion, for example, a decrease in the absorbance of the amide I band, and to a greater extent, manifest itself as a derivative-like baseline at the high wavenumber side of the amide I band. It can also result in significant frequency shifting of spectral bands that are used extensively to classify biological specimens. To be able to interpret FTIR spectra correctly, it requires the correction of the dispersion artefact aforementioned. The origin of dispersion artefact and their subsequent effect is detailed in published articles [6, 7] .", "cite_spans": [{"start": 486, "end": 489, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 1268, "end": 1271, "text": "[6,", "ref_id": "BIBREF5"}, {"start": 1272, "end": 1274, "text": "7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Introduction", "text": "Resonant Mie scattering (RMieS) algorithm developed by Bassan et al. was proved to be successful at correcting the 'dispersion arterfact' [6] . This algorithm is used in this manuscript; however, the correction algorithm is computationally intensive and time consuming. In addition, physical alteration of imaging set-up for measurements in transmission by employing an additional lens on top of the window that forms pseudo-hemisphere has shown to be effective at producing aberration-free and high-quality spectra from tissues and from cells [14, 15, 20, 36] . The other challenge in FTIR spectroscopic measurements is the presence of spectral bands of water vapour in the sample spectra, which hampers the analysis of protein secondary structure in the amide I region (1700-1600 cm \u22121 ) [1, 2, 18] . This water vapour interference can be minimised by computational subtraction of the pure water vapour spectrum from the sample spectrum, with algorithm described by Brunn et al. [13] .", "cite_spans": [{"start": 138, "end": 141, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 544, "end": 548, "text": "[14,", "ref_id": "BIBREF13"}, {"start": 549, "end": 552, "text": "15,", "ref_id": "BIBREF14"}, {"start": 553, "end": 556, "text": "20,", "ref_id": "BIBREF19"}, {"start": 557, "end": 560, "text": "36]", "ref_id": "BIBREF35"}, {"start": 790, "end": 793, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 794, "end": 796, "text": "2,", "ref_id": "BIBREF1"}, {"start": 797, "end": 800, "text": "18]", "ref_id": "BIBREF17"}, {"start": 981, "end": 985, "text": "[13]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Introduction", "text": "FTIR spectra contain a wealth of information about the sample. As such, in analysis of spectra of biological systems, multivariate statistics and machine learning algorithms are frequently applied to extract the important information. The two main strategies in chemometrics used to analyse FTIR spectral data are unsupervised learning and supervised learning. The variety of the methods is detailed by Goodacre [17] . The aim of this paper is to utilise the well-established machine learning approach, random forest in this case, to examine the spectral ranges that could potentially contain the most important spectral biomarkers that distinguish between colon specimens of various degree of malignancy.", "cite_spans": [{"start": 412, "end": 416, "text": "[17]", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Materials and methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Sample preparation", "text": "The samples are formalin-fixed paraffin-embedded (FFPE) colon biopsies at different disease stages of malignancy (hyperplasia, dysplasia, and cancer), provided by St. Mary's Hospital (Imperial College London, UK), following standard clinical protocols. The samples were microtomed at 3 \u03bcm thickness from a specimen block and mounted onto a 2-mmthick CaF 2 window (Crystran Ltd., UK) for FTIR analysis. The adjacent section was mounted onto a glass slide, stained with haematoxylin and eosin (H&E) and assessed by a trained pathologist. The sections deposited on CaF 2 windows were deparaffinised as per the procedure described by Song et al. [34, 35] and stored with a desiccant before use.", "cite_spans": [{"start": 642, "end": 646, "text": "[34,", "ref_id": "BIBREF33"}, {"start": 647, "end": 650, "text": "35]", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "FTIR spectroscopic imaging measurements", "text": "The experiments were carried out in transmission mode at \u00d7 15 magnification (NA = 0.4), with a Hyperion 3000 FTIR microscope coupled to Tensor 27 FTIR spectrometer (Bruker Corp.). A liquid nitrogen cooled 64 \u00d7 64-pixel focal plane array (FPA), which has a field of view of 170 \u00d7 170 \u03bcm 2 , is used for simultaneous acquisition of FTIR spectral dataset. As imaging was combined with mapping, 3 \u00d7 3 individual images were stitched into one, resulting in a total measured area of 510 \u00d7 510 \u03bcm 2 for each tissue. The spectral images from 12 sample areas were acquired. A new background was recorded before measuring each individual image. All measurements were taken in the mid-IR range from 3900 to 900 cm \u22121 , at 4 cm \u22121 spectral resolution and with 521 co-added scans. An additional CaF 2 lens, which has been shown to significantly reduce Mie scattering [15] , was also employed for imaging of the exact same tissue areas. The design and set-up of the lens for combining imaging with mapping were described in details by Kimber et al. [21] . To put it briefly, the added lens is kept in focus with an external holder whilst the stage is shifted in x-and y-direction for different areas to be measured.", "cite_spans": [{"start": 854, "end": 858, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 1035, "end": 1039, "text": "[21]", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "FTIR spectroscopic imaging measurements", "text": "The additional lens implemented to correct for the chromatic aberration in infrared measurement is referred to as 'correcting lens' from this point onwards in this paper. To the authors' knowledge, the assessment of the performance of the correcting lens has not been closely examined with advanced machine learning approaches.", "cite_spans": [], "ref_spans": []}, {"section": "Data processing and chemometric analytical procedure", "text": "The spectral data were processed with MATLAB R2018b (The MathWorks, Inc.). The spectral data in the range of 1800-1000 cm \u22121 and 3000-2800 cm \u22121 were used for further analysis. The region between 2800 and 1800 cm \u22121 contains no important spectral information whilst the region > 3000 cm \u22121 is sensitive to water content within the tissues. Baseline correction and water vapour subtraction were not applied to the data. Second derivatives of the obtained spectra were calculated with Savitzky-Golay 9-point smoothing, which were then vector normalised. The spectra, second derivatives, and normalised second derivative data were then separately subjected to unsupervised machine learning, in this instance, the K-means clustering algorithm (tested for 2 to 6 clusters, each with 5 replicates and infinite iteration until the solution converges to a local minimum). A total of 2000 individual sample spectra were recorded and used for machine learning. Only eight chemical images of the different tissue sections are shown here for demonstration purpose. Training and test models were created, each made up of 500 random spectra sampled from each cluster without replacement, for tissue at the same disease stage. In other words, the model consists of 2000 spectral data (500 for healthy (H), 500 for hyperplastic polyps (HY), 500 for dysplastic polyps (D), and 500 for cancer sections (C)) which are identified by H&E staining. The models were from different individuals ensuring that the interpatient variability is included in the study. Employing machine learning to study imaging data has been demonstrated in previous works [10, 17] .", "cite_spans": [{"start": 1628, "end": 1632, "text": "[10,", "ref_id": "BIBREF9"}, {"start": 1633, "end": 1636, "text": "17]", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Data processing and chemometric analytical procedure", "text": "The training model, after undergoing data dimensionality reduction with PCA, was subsequently supplied to random forest (RF) classifier to generate a prediction model on the test model. RF operates by constructing multiple decision trees for classification on the data, gets prediction from each tree and thus outputs the class mode by means of voting. In this study, bootstrapping as well as a five-fold cross validation of the dataset is implemented [12] . Among various supervised machine learning classifiers, RF is preferable since it is faster and insensitive to over-fitting [16] . The prediction accuracy of the RF model is presented in the form of a confusion matrix. Intermodel predictability was carried out with independent training and test set. The size of training to test models was varied from 1:1 to 1:6. The analytical procedure is repeated with the measurement data obtained from the added correcting lens, as well as for no-lens data but corrected with RMieS algorithm (provided by Peter Gardner's Lab, University of Manchester) [6, 8, 22, 28] . The parameters of the RMieS algorithm are given in Electronic Supplementary Material (ESM) ( Table S1 ). Several machine learning parameters, namely the number of clusters, the spectral range for supervised and unsupervised classification, the size of training and test models, and the variance of retained PCA, have been tried and tested, to optimise the prediction model. The important features are selected from the Gini index-a score of the feature importance that is derived from the training of the RF classifier, which technically correlates to the optimal 'Gini impurity' split at each nodes within the binary trees [30] . Based on the selected features or spectral range, a flowsheet depicting all the different pathways to re-training machine leaning in categorising the different stages of the colon cancer is shown in Fig. 1 . The prediction accuracy of the test models was used as the criteria to cross-check the spectral range highlighted by the machine learning as the 'key biomarker' that can be utilised to understand different degree of malignancy of colon. Figure 1 shows all the pathways that are tested with unsupervised and supervised approach via training and re-testing of the spectral data based on Gini importance (see figure in section 'Gini index obtained from RF classifier'). The features in this study are not independent of one another; thus, important spectral range is discussed instead of the single features. The paper starts off by describing Mie scattering and the implementation of correcting lens on the FTIR spectra of colon tissue, followed by the unsupervised learning on the second derivative spectra without RMieS correction. With supervised classifier, the performance of both model with and without any RMieS correction is compared and discussed to establish a proof of concept that RMieS correction might not be necessary in this case study. On top of that, this paper serves to demonstrate that amide I band plays a very little role in the differences between specimens via feature selection in machine learning. The results are detailed as follows.", "cite_spans": [{"start": 452, "end": 456, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 582, "end": 586, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 1050, "end": 1053, "text": "[6,", "ref_id": "BIBREF5"}, {"start": 1054, "end": 1056, "text": "8,", "ref_id": "BIBREF7"}, {"start": 1057, "end": 1060, "text": "22,", "ref_id": "BIBREF21"}, {"start": 1061, "end": 1064, "text": "28]", "ref_id": "BIBREF27"}, {"start": 1691, "end": 1695, "text": "[30]", "ref_id": "BIBREF29"}], "ref_spans": [{"start": 1897, "end": 1903, "text": "Fig. 1", "ref_id": "FIGREF0"}, {"start": 2143, "end": 2151, "text": "Figure 1", "ref_id": "FIGREF0"}]}, {"section": "Results and discussion", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Physical and computational correction of Mie scattering effect", "text": "Mie scattering effect is significantly reduced at the edges of the tissues when correcting lens is added, shown in Fig. 2 , where increase in absorbance of the amide I band and reduction in the sharp derivative-like distortion to the spectra at1 710 cm \u22121 are observed. Correction with added lens slightly shifted the peak position of the amide I band by~1 cm \u22121 from 1652 to 1653 cm \u22121 . With the added lens, which acts like an immersion objective as reported by Kimber et al. [21] , the image has~40% increase in magnification (total area of 360 \u00d7 360 \u03bcm 2 compared with 510 \u00d7 510 \u03bcm 2 for image without lens) and is flipped due to the arrangement of the tissue during measurement whereby the tissue is placed facing downwards with the correcting lens added on top of it. Computation correction with RMieS algorithm was more efficient at recovering a flat baseline of the spectra (Fig. 3 ) compared with correction with the added lens but was more time consuming. The peak position of amide I band was corrected to where the peak is supposed to be at 1654 cm \u22121 with the computational method.", "cite_spans": [{"start": 478, "end": 482, "text": "[21]", "ref_id": "BIBREF20"}], "ref_spans": [{"start": 115, "end": 121, "text": "Fig. 2", "ref_id": "FIGREF1"}]}, {"section": "Data processing", "text": "Eight different tissue regions, which comprise of 4 training and 4 test models (as described in data processing procedure), are measured and analysed. The number of areas taken in total is 12 (four disease states for three patients). Chemical images showing the distribution of integrated absorbance, estimated with trapezoidal rule of integration, at the spectral bands of 1272-1184 cm \u22121 , 1712-1589 cm \u22121 , and 2944-2880 cm \u22121 , which are assigned to asymmetric phosphate stretching of nucleic acid, amide I, and CH stretching of lipid respectively [31] , are represented in Fig. 4 (top: training model; bottom: test model; only eight samples were selected for comparison here), alongside the H&E stain images, which were used by pathologists to assign the stage of tissue malignancy. The cumulative distribution curves of the pixel count of each integrated absorbance (with the data sorted into 100 bins) are also shown for easier comparison of the chemical images. Although the pixel count is by no means an accurate indicator of the specific variation between disease stages as it is dependent on the area of measurement, it provides a quantitative means for direct comparison of the chemical images which is not quite so distinct even after normalisation of the colour scale.", "cite_spans": [{"start": 552, "end": 556, "text": "[31]", "ref_id": "BIBREF30"}], "ref_spans": [{"start": 578, "end": 584, "text": "Fig. 4", "ref_id": "FIGREF2"}]}, {"section": "Data processing", "text": "As can be seen in the curves of pixel count Fig. 4 , the integrated absorbance of nucleic acid band at 1271-1184 cm \u22121 is lowest for healthy colon biopsy when a 95% confidence interval is taken, likewise for amide I band. The opposite is observed for the lipid spectral band within 2944-2880 cm \u22121 , whereby the lowest integrated absorbance is achieved in cancer tissues. This is in agreement with the high nucleic acid-to-cytoplasmic ratio observed in colon cancer tissues [26] as well as the loss of normal glandular architecture. The inner lining or mucosa of healthy colon is lined with columnar epithelium and large number of goblet cells, where numerous secretory vesicles containing mucus (glycoprotein) are present, in addition to the secreted mucin in the intestinal epithelial surface layer. Mucus is a complex biochemical layer made up of carbohydrates, antimicrobial peptides, immunoglobulins, electrolytes, and lipids [4] . For diseased tissue, however, the goblet cells are not differentiated well to perform its function; instead, they become highly metastasizing cells with high metabolic rate, which might progress to cancer (an aggregation of undifferentiated cells). The difference between different stages of cancer is also highlighted in the mean average spectrum obtained after taking their second derivatives. The evaluation of the variation is not very straightforward, thus the need for machine learning to perform the task of classification of colon disease. The interpretation of the second derivative spectra is not included in the main discussion as machine learning only requires the input of 'features', which is the absorbance at various wavenumbers, and 'label', the stage of disease. The second derivative spectral bands and their corresponding band assignment are, nonetheless, provided in ESM Fig. S4 and Table S2 to demonstrate the potential variation that might be picked up by the machine learning classification model. The most significant differences lie in the peak shift and the intensity of the trough of the second derivative data.", "cite_spans": [{"start": 474, "end": 478, "text": "[26]", "ref_id": "BIBREF25"}, {"start": 931, "end": 934, "text": "[4]", "ref_id": "BIBREF3"}], "ref_spans": [{"start": 44, "end": 50, "text": "Fig. 4", "ref_id": "FIGREF2"}, {"start": 1829, "end": 1836, "text": "Fig. S4", "ref_id": "FIGREF2"}]}, {"section": "Gini index obtained from RF classifier", "text": "The choice of spectral wavenumbers for classification, as mentioned earlier, is based on the Gini index (Fig. 5) . The results show that the fingerprint region (< 1500 cm \u22121 ) contains the most important features (greater than Gini index of 0.015). This was followed by the lipid region (3000-2800 cm \u22121 ) of secondary importance. Surprisingly, the best prediction accuracy is obtained when unsupervised training is applied on the spectral range of secondary importance, whilst the most important features are used for supervised training. A similar machine learning study was performed by Kuepper et al. on colon cancer; however, the spectral range used for the training is inclusive of the amide I band [23] . It should be realised that the amide I region shows no significant importance, based on the Gini values demonstrated here. Fig. 3 The raw spectra of 100 random pixels before and after RMieS correction, shown on the left and on the right respectively. Severe Mie scattering effect can be seen in the figure on the left prior to correction Unsupervised learning K-means clustering are used for intra-tissue classification, by maximising inter-distance variance between data within a tissue. It is important to recognise here that the optimum parameters for clustering in this study, after assessing the outcome of the supervised predictive model by comparing different spectral ranges and the number of clusters (results not shown), are based on the second derivative of the spectra between 3000 and 2800 cm \u22121 (introduced as the 'lipid region' henceforth, although strictly speaking, the spectral band within this region is not limited to lipid; it is assigned to the C-H stretching of methyl and methylene groups) [31] . The three clusters identified are considered sufficient in this study following these reasoning: first of all, the various tissue morphology categorised by the clusters are fed into supervised machine learning independently as a way of phasing out unnecessary regions of the tissue since not all morphology or clusters show essentially distinct spectra between different stages of colon disease; the highest performance is obtained with the spectra from high lipid region, which can be easily classified with just 3 clusters. Secondly, the higher the number of unsupervised clusters implemented, the higher the degree of similarity of the spectral data within each cluster; the lower the tolerance for dissimilarity of the test datasets, in other words, overfitting of data is introduced. In addition, since K-means is an unsupervised imaging approach, higher number of clusters have a tendency to cluster data that are close to each other which should have been treated as one (the sum of squared distances between each cluster decreases exponentially with increasing number of clusters). Besides, the main objective of this study is to assess the importance of lipid and amide bands in the prediction ability of the RF machine learning, the least number of clusters which can output a good predictive performance is desirable, in this case, three clusters for the intra-tissue differentiation can warrant a prediction outcome greater than 90% accuracy. Most importantly, higher category of classification (> 3 groups) is not needed as the lipid region is of secondary importance, as discussed before. Although the higher number of clusters are useful at exploration of the various histopathological architecture of colon adenocarcinoma, as analysed by Lasch et al. using similar multivariate imaging approaches [24] , the tissue morphology is not explored in this paper. The false colour images generated from K-means clustering and their corresponding second derivatives are shown in Fig. 6 .", "cite_spans": [{"start": 705, "end": 709, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 1726, "end": 1730, "text": "[31]", "ref_id": "BIBREF30"}, {"start": 3546, "end": 3550, "text": "[24]", "ref_id": "BIBREF23"}], "ref_spans": [{"start": 104, "end": 112, "text": "(Fig. 5)", "ref_id": "FIGREF3"}]}, {"section": "Gini index obtained from RF classifier", "text": "From the mean second derivative spectra by averaging all the pixels within the same cluster, the tissue regions are effectively classified into low and high lipid absorbance region (cluster 1 and cluster 2 respectively), which are fed into the supervised learning algorithm separately. This reinforces the findings by Song et al. [35] that spectral bands of lipid are still useful biomarkers for intra-tissue classification, despite the lower Gini importance index. The lipid spectral region contains a wealth of information. Bassan et al. has also demonstrated that the high wavenumber spectral range (O\u2212H, N \u2212H, and C\u2212H stretches occurring at ca. 3800-2500 cm \u22121 ) is useful for the generation of false colour classification image of breast tissue microarrays on glass substrate [9] . They are free from interference with the spectral bands of water vapour and Mie scattering, with the only possible variation coming from the deparaffinisation process on the formalin-fixed tissues. This variation is controlled and minimised by strictly adhering to the deparaffinisation protocol.", "cite_spans": [{"start": 330, "end": 334, "text": "[35]", "ref_id": "BIBREF34"}, {"start": 781, "end": 784, "text": "[9]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Gini index obtained from RF classifier", "text": "It is possible that the cancerous tissues are more susceptible to change during solvent-based removal of material, required prior to the paraffin embedding process. The FFPE process requires fixation of fresh tissue in formalin for 6 to 24 h, followed by multiple washes in ethanol/water with increasing ethanol concentration until water has been removed. Xylene, or possibly isopropanol, is then used to remove the ethanol, taking with it much of the fats within the natural tissue. Finally, the tissue is soaked in molten paraffin, usually at 60\u00b0C. Precautions were taken to conduct the de-waxing process in a closely controlled manner, so that each of the three samples were treated in the same way; however, the manner in which the FFPE was first conducted is out of our control, including the amount of fats and other materials that may have been removed in that process. That said, surprisingly, similar observations were made on prostate cancer tissues that are supplied by different pathologists but de-waxed with the same procedure [35] that this wavenumber region (3000-2800 cm \u22121 ) is different between normal and cancer samples. Thus, the explanation that tissues of different malignancy retain various amount of fats after deparaffinisation essentially still offers a different kind of 'key biomarker' for cancer differentiation in FTIR imaging study.", "cite_spans": [{"start": 1041, "end": 1045, "text": "[35]", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "Supervised machine learning", "text": "Random forest classifier was shown to be an efficient supervised machine learning technique for the classification of spectral data in previous studies [3, 17, 33] . In this study, second derivative data (for measurements with and without correcting lens) from various spectral ranges were used to train the algorithm-model 1, between 1800 and 1000 cm \u22121 and 3000-2800 cm \u22121 (all range); model 2, 1800-1000 cm \u22121 only (fingerprint region with amide bands); model 3, 1500-1000 cm \u22121 only (fingerprint region); and model 4, 3000-2800 cm \u22121 only (lipid region). To clarify, re-training and retesting of the RF models is still required after Gini selection to Fig. 6 Representative colour-coded K-means clustered images of healthy colon biopsy sections of a test and b training model. Cluster represented in light blue is for areas dominated by goblet cells (denoted as cluster 2), dark blue for basal membrane (denoted as cluster 1), and yellow for areas without tissue. c Average second derivative spectra of the corresponding clusters in the high wavenumber spectral region (3000-2800 cm \u22121 ), following the colour code in K-means cluster subjectively assess the prediction performance; hence, the results are organised in the way shown in the workflow (Fig. 1 ) in this manuscript.", "cite_spans": [{"start": 152, "end": 155, "text": "[3,", "ref_id": "BIBREF2"}, {"start": 156, "end": 159, "text": "17,", "ref_id": "BIBREF16"}, {"start": 160, "end": 163, "text": "33]", "ref_id": "BIBREF32"}], "ref_spans": [{"start": 1252, "end": 1259, "text": "(Fig. 1", "ref_id": "FIGREF0"}]}, {"section": "Supervised machine learning", "text": "The overall prediction accuracy for each model is shown in Fig. 7 . A typical fingerprint region of infrared measurement is loosely defined to be between~1600 and 1500 cm \u22121 to 500 cm \u22121 [1, 37] . To avoid confusion to readers, in this paper, the fingerprint region is referring to spectral range within 1500-1000 cm \u22121 inclusive. At this part of the analysis, no computational correction of Mie scattering is applied. Figure 7 shows that overall prediction accuracy is higher for data in cluster 2, region of higher lipid absorbance, than cluster 1. A comparison of the performance of measurements with and without correcting lens can be achieved by analysing cluster 2, which reveals that apart from model 1 and model 4, the measurements with correcting lens, despite its ability to minimise Mie scattering at the edges of the tissues, generally underperform compared with measurements without the added lens. The lowest accuracy of cluster 2 prediction is obtained from model 3 with added lens. This is because whilst the added lens approach removes the scattering effect and thus improves the quality of amide I band, the spectra collected in the range of 1100-1000 cm \u22121 suffer from enhanced noise, which is not an issue with computational approach. This happens because the additional stacking of lens on top of the CaF 2 substrate (from the way the correcting lens is set-up) reduces the throughput of light. Due to the lower photon counts that pass through the sample and the fact that CaF 2 has a cut-off at 900 cm \u22121 in transmission, the spectral quality in the low wavenumber region deteriorates significantly compared with the set-up without correcting lens.", "cite_spans": [{"start": 187, "end": 190, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 191, "end": 194, "text": "37]", "ref_id": "BIBREF36"}], "ref_spans": []}, {"section": "Supervised machine learning", "text": "Model 2 (with lens) gives a slightly better performance when amide bands are factored into consideration as added lens is shown to improve the absorbance of the spectral band of amide I. Model 4 which considers the data exclusively from the lipid region is undeterred by the noise introduced by the extra lens configuration and model 1 which takes into consideration all the spectral regions shows similar performance with and without additional lens, for reasons discussed above. Instead of CaF 2 , a pseudo-hemispherical ZnS lens with infrared cut-off at~700 cm \u22121 was suggested to improve the spectral quality [20] . However, Mie scattering correction does not play a significant role in optimising the performance of the supervised learning, reinforced by the finding that the highest prediction accuracy of 92.7% can be achieved with model 3 (fingerprint region). In other words, the second derivative spectral data within 1500-1000 cm \u22121 from cluster of high lipid absorbance region alone is sufficient to achieve effective discrimination of all the different grades of colon cancer as the fingerprint region is least affected by Mie scattering. The interference of the water vapour spectra within this region is also minimal (as shown in ESM Fig. S5 ). Therefore, removal of Mie scattering effect is not necessary as the amide spectral range (1700-1500 cm \u22121 ) does not need to be included in data analysis at all, as demonstrated here.", "cite_spans": [{"start": 613, "end": 617, "text": "[20]", "ref_id": "BIBREF19"}], "ref_spans": [{"start": 1249, "end": 1256, "text": "Fig. S5", "ref_id": "FIGREF3"}]}, {"section": "Supervised machine learning", "text": "On the other hand, model 4 gives the lowest prediction accuracy; this infers that lipid spectral region (or high wavenumber region) alone is not reliable for supervised training of the classification model in the study of colon biopsy. Nevertheless, the possibility of classifying between normal and cancer state of a biopsy, without classification of the stages of disease, based solely on the lipid region is not ruled Fig. 7 The bar chart shows the overall prediction accuracy in percentage of various models for measurement with and without correcting lens (and without computational correction for Mie scattering effect) for cluster 1 of low lipid absorbance and cluster 2 of high lipid absorbance out. For example, the study by Pilling et al. for different types of cancer (breast cancer) and using different substrates that rely on high wavenumber spectral range alone allows for rapid discrimination between normal epithelium, malignant epithelium, normal stroma, and cancer-associated stroma of breast biopsies with classification accuracy as high as 95% [32] . However, the categorisation of the different stages of breast cancer was not shown in their study. The breakdown of the true positive rates (or true negative rates for non-healthy tissue) of each cancer grade (measurement without additional lens) is shown for all models of cluster 2 in Fig. 8 .", "cite_spans": [{"start": 1064, "end": 1068, "text": "[32]", "ref_id": "BIBREF31"}], "ref_spans": []}, {"section": "Supervised machine learning", "text": "From these results, it is apparent that healthy and malignant tissues are easily distinguished from other stages of the disease, whereas dysplastic tissue is often misclassified as hyperplasia, if the correct spectral range is not implemented. Hyperplastic and dysplastic tissues rely heavily on differences within 1500-1000 cm \u22121 , possibly from the change in concentration of the nucleic acid and carbohydrates in the tissues [1] , and can be classified at a high accuracy when only the fingerprint region is used. Hyperplasia and dysplasia exhibit very similar spectral pattern above 1500 cm \u22121 ; hence, they are best differentiated from each other when the amide and lipid bands, which have higher absorbance and would dominate over the nucleic acid bands when no vector normalisation is carried out, are eliminated from the training dataset (model 3). The results from supervised learning give a significant insight into assessing the spectral biomarkers of colon cancer.", "cite_spans": [{"start": 428, "end": 431, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Supervised machine learning", "text": "It is important to note that a high intra-model prediction (prediction within the training model without test model) does not warrant a high inter-model prediction (prediction with the test model). In this case, inter-model prediction is employed as a better and more reliable guide to verify the efficiency of the machine learning and should be carried out where possible. The stability of the training model is confirmed by decreasing the ratio of the size of training to test models from 1:1 to 1:6; the error in the prediction accuracy is a mere \u00b1 2.0%. The optimum variance of PCA for the training of the model is found to be 99%; ca. 20% of the second derivative data within the fingerprint region contains useful information for data classification (see ESM Fig. S1 for results tested with variance of PCA retained ranging from 87 to 100%). The final best results of the prediction model summarised in a confusion matrix plot [29] and the corresponding receiving operator characteristic (ROC) curve of the random forest classifier are presented in Fig. 9 .", "cite_spans": [{"start": 933, "end": 937, "text": "[29]", "ref_id": "BIBREF28"}], "ref_spans": [{"start": 765, "end": 772, "text": "Fig. S1", "ref_id": "FIGREF0"}, {"start": 1055, "end": 1061, "text": "Fig. 9", "ref_id": "FIGREF4"}]}, {"section": "Supervised machine learning", "text": "The findings are reinforced by comparing the prediction outcome with that obtained from spectral data after correction with RMieS algorithm (and without the correcting lens). The performance of the fingerprint region with amide bands after RMieS correction shows significant improvement in the prediction accuracy compared with the second derivative data before correction (from 81 to 91% prediction accuracy), despite being slightly lower than that of the fingerprint region alone, due to the correction of the amide I band (92%). Correction with the RMieS algorithm is computational whilst correction with the added lens is a practical optical approach; thus, as expected, the RMieS algorithm provides a more precise solution which indeed yields a better overall prediction accuracy. The confusion matrices for both cases are provided in ESM Fig. S2 and Fig. S3 respectively. In this study, both correcting lens and RMieS correction are shown to be useful at correcting the scattering effect on amide I band but might not be necessary if classification of the stages of the colon adenocarcinoma via machine learning technique is the main objective as the training model without any correction for Mie scattering is sufficient to yield accuracy comparable with that after correction. Fig. 8 The bar chart shows the prediction accuracy of different stages of colon disease within each model of cluster 2 (high lipid absorbance area) for measurement without lens", "cite_spans": [], "ref_spans": [{"start": 844, "end": 863, "text": "Fig. S2 and Fig. S3", "ref_id": "FIGREF1"}]}, {"section": "Conclusion and outlook", "text": "Spectral data of colon biopsies obtained with a correcting lens for FTIR imaging show a significant reduction in spectral aberrations due to inhibiting Mie scattering, as was shown in our studies with other types of cancer tissues. Optical modification of the FTIR spectroscopic imaging with a CaF 2 correcting lens has the advantage that the Mie scattering correction algorithm does not need to be performed. However, for this study the correction effect was not as good compared to the computational method. Here, we report the insignificance of the role of amide I band in machine learning for the first time. Importantly, the findings show that the disease states can be distinguished without resorting to the correction of Mie scattering effect. By using K-means clustering and RF classifier with PCA reduction, our work has demonstrated that optimisation of the training model by refining the selected range of FTIR spectral data can alter the prediction outcome.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion and outlook", "text": "The novelty of this work showed that the best prediction outcome for the studied colon biopsy samples were obtained when unsupervised learning of the C-H stretching bands is coupled with supervised learning of the spectral region between 1500-1000 cm -1 . Hence, whilst the C-H stretching region is useful for intra-tissue segmentation, only the spectral range of 1500-1000 cm \u22121 is important for supervised machine learning. The amide I band can be excluded from data analysis altogether, as evidenced in the Gini indices obtained in this work. In addition, reliance on the C-H stretching spectral region (3000-2800 cm \u22121 ) alone in supervised learning gives the worst prediction. This exploratory study involving a manageable number of datasets successfully highlights the extraction of the most meaningful parts of the spectral data, which sets a framework for further validation of the predictive ability of a more sophisticated deep learning model in future work.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion and outlook", "text": "To summarise, further application of this method to an unknown colon biopsy sample is straightforward and potentially fully automated with simple programming. Initial K-means clustering (with the number of clusters set to two) on the C-H stretching bands alone will pick up regions of high lipid absorbance which will subsequently be fed into the already trained RF model that predicts the outcome of the malignancy stage of the specimen. The findings, though significant, are limited to FTIR spectroscopic imaging of the colon biopsy. Furthermore, Mie scattering is more pronounced in single-cell imaging than tissue; the results of this study are strictly limited to differentiation of disease progression in colon tissue specimens. The ROC curve illustrates the diagnostic ability of the classifier system. 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National Cancer Institute", "authors": [], "year": 2016, "venue": "", "link": null}, "BIBREF39": {"title": "Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations", "authors": [], "year": "", "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Schematic overview of the data processing and machine learning steps explored in this study. The best pathway leading to the optimised result is highlighted in grey", "type": "figure"}, "FIGREF1": {"text": "Top: false colour K-means cluster images of healthy colon tissue without the lens (left) and with the lens (right) obtained by mapping from nine stitched images. Each of the chemical images has a size of 510 \u00d7 510 \u03bcm 2 . Cluster represented in light blue shade (box) indicates the edges of the tissue. Bottom: the average measured spectra from the areas representing the edges of the tissue", "type": "figure"}, "FIGREF2": {"text": "FTIR spectroscopic images of the colon biopsy used in the training models (top) and test models (bottom), depicting the distribution of different components by evaluating the integrated absorbance at various spectral ranges, which are labelled at the top of each column. The first column gives the H&E-stained images identified by the pathologist. Each image has a size of 510 \u00d7 510 \u03bcm 2 .The colorscale of the images is normalised across each component (column-wise) for comparison of their absorbances.", "type": "figure"}, "FIGREF3": {"text": "Plot of Gini importance values obtained from RF prediction model against wavenumber of colon biopsy tissue, overlaid on the average FTIR spectrum of healthy colon tissues (normalised between 0 and 0.040) for clarification purpose", "type": "figure"}, "FIGREF4": {"text": "The confusion matrix plot (MATLAB R2018b) shows the best result that can be obtained from the fingerprint region of the spectral data with model 3 (C, cancer; D, dysplasia; H, healthy; HY, hyperplasia). The rows show the predicted class and the columns represent the true class. The diagonal cells correspond to correctly classified observations, whilst the off-diagonal cells correspond to observations that are incorrectly classified. Both the number of observations and the percentage of the total number of observations are shown in each cell. The column on the right of the plot shows the percentages of all the examples predicted to belong to each class that are correctly and incorrectly classified. The row at the bottom of the plot shows the percentages of all the examples belonging to each class that are correctly and incorrectly classified. Overall accuracy of the prediction of the classifier model is given in the cell in the bottom right of the plot. b", "type": "figure"}}}
{"paper_id": "199668059", "_pdf_hash": "20b263d33b18e2ca017829155a0de08fbb33a585", "abstract": [{"section": "Abstract", "text": "When a predator attacks a flock of starlings (Sturnus vulgaris), involving thousands of individuals, a typical collective escape response is the so-called agitation wave, consisting of one or more dark bands (pulses) propagating through the flock and moving away from the predator (usually a Peregrine falcon, Falco peregrinus). The mechanism underlying this collective behavior remains debated. A theoretical study has suggested that the individual motion underlying a pulse could be a skitter (in the form of a zigzag), that is copied by nearby neighbors, and causes us to temporarily observe a larger surface of the wing because the bird is banking during turning while zigzagging. It is not known, however, whether pulses during a wave event weaken over time. This is of interest, because whereas during the usual turning by an undisturbed flock the motion is copied completely without weakening, we may expect that pulses dampen during a wave event because individuals that are further away from a predator react less because of reduced fear. In the present paper, we show in empirical data that pulses during a wave event weaken over time. Our computational model, StarDisplay, reveals that this is most likely a consequence of a reduction of the maximum banking angle during the zigzag escape maneuver rather than by a reduced tendency to copy this maneuver with time. The response seems adaptive because of lowered danger at a larger distance to the location of attack.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Huge flocks of starlings display amazing patterns of collective escape when attacked by an avian predator, such as a Peregrine falcon. One of them is the \"agitation wave\" in which dark bands move away from the predator. Dark bands arise probably from the temporarily larger wing area, which is observed when birds perform a skitter escape motion (zigzag) while temporarily banking sideward. Whereas during regular flock turns birds copy each other's motion completely, it is unknown whether this happens during agitation waves, because individuals further away from the attack may be less frightened. Studying this both empirically at the group level only and in a computational model at both the level of the individual and the group, we show that pulses of waves fade out with time and that this is probably due to a reduced maximum banking angle during the zigzag maneuver rather than a lower tendency of copying. This seems an adaptive response.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "The study of collective motion of social animals, including humans, is an interdisciplinary field at the frontiers of science, which has greatly benefitted from combining empirical and modeling approaches (Camazine et al. 2003; Grimm et al. 2005; Sumpter et al. 2012; Ouellette 2019) . When starlings swirl above their roosting site in huge flocks of thousands of individuals, they perform even without a predator attacking them complex maneuvers involving sudden collective turns that change the shape and density of flocks remarkably. When the flocks are attacked by a predator, they display patterns of collective escape that are even more complex (Feare 1984; Ballerini et al. 2008a; Carere et al. 2009; Goodenough et al. 2017; Storms et al. 2019 ).", "cite_spans": [{"start": 205, "end": 227, "text": "(Camazine et al. 2003;", "ref_id": "BIBREF6"}, {"start": 228, "end": 246, "text": "Grimm et al. 2005;", "ref_id": "BIBREF12"}, {"start": 247, "end": 267, "text": "Sumpter et al. 2012;", "ref_id": "BIBREF24"}, {"start": 268, "end": 283, "text": "Ouellette 2019)", "ref_id": "BIBREF20"}, {"start": 651, "end": 663, "text": "(Feare 1984;", "ref_id": "BIBREF10"}, {"start": 664, "end": 687, "text": "Ballerini et al. 2008a;", "ref_id": "BIBREF2"}, {"start": 688, "end": 707, "text": "Carere et al. 2009;", "ref_id": "BIBREF7"}, {"start": 708, "end": 731, "text": "Goodenough et al. 2017;", "ref_id": "BIBREF11"}, {"start": 732, "end": 750, "text": "Storms et al. 2019", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Communicated by P. A. Bednekoff", "text": "Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00265-019-2734-4) contains supplementary material, which is available to authorized users.", "cite_spans": [], "ref_spans": []}, {"section": "Communicated by P. A. Bednekoff", "text": "One of the most common patterns of collective escape is the so-called \"wave of agitation,\" where one or more dark bands (here referred to as pulses) of an approximately fixed width originate close to the attacking predator and travel within a second over the flock away from it (Procaccini et al. 2011; Storms et al. 2019) ; thus, the wave is transferring information rapidly across many individuals (Gerlotto et al. 2006; Procaccini et al. 2011) . The function of this wave may be that it confuses the predator in whom to attack (Procaccini et al. 2011) . How individuals behave and transfer information to produce such pulses is still unknown. Information transmission in flocks of starlings has been studied empirically so far only during collective turning (Attanasi et al. 2014; Cavagna et al. 2015) . Based on detailed empirical data recorded with three cameras, it has been shown that once an individual had started a turn, others followed at approximately constant intervals, with an identical turning motion (Attanasi et al. 2014) . Whether during an agitation wave individuals copy and repeat escape maneuvers identically or weaken the maneuver over time, so that the pulse would fade out, remains unknown. This question is of interest, because in our recent analysis of reactions of a flock to a predator, we quantitatively showed that the patterns of collective response of starlings are fine tuned to the characteristics of hunting by a falcon (such as its speed and direction from which it attacks; Storms et al. 2019) . Similarly, weakening of a wave over time may be adaptive and reducing fear and responsiveness to a predator when it is further away is in line with theoretical predictions (Broom and Ruxton 2005) .", "cite_spans": [{"start": 278, "end": 302, "text": "(Procaccini et al. 2011;", "ref_id": "BIBREF22"}, {"start": 303, "end": 322, "text": "Storms et al. 2019)", "ref_id": "BIBREF23"}, {"start": 400, "end": 422, "text": "(Gerlotto et al. 2006;", "ref_id": "BIBREF10"}, {"start": 423, "end": 446, "text": "Procaccini et al. 2011)", "ref_id": "BIBREF22"}, {"start": 530, "end": 554, "text": "(Procaccini et al. 2011)", "ref_id": "BIBREF22"}, {"start": 761, "end": 783, "text": "(Attanasi et al. 2014;", "ref_id": "BIBREF0"}, {"start": 784, "end": 804, "text": "Cavagna et al. 2015)", "ref_id": "BIBREF9"}, {"start": 1017, "end": 1039, "text": "(Attanasi et al. 2014)", "ref_id": "BIBREF0"}, {"start": 1513, "end": 1532, "text": "Storms et al. 2019)", "ref_id": "BIBREF23"}, {"start": 1707, "end": 1730, "text": "(Broom and Ruxton 2005)", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Communicated by P. A. Bednekoff", "text": "In the present study, we investigate agitation waves both empirically and theoretically. Empirically, we analyze agitation waves elicited by avian predators (Peregrine falcon) and video-recorded above urban roosts in Rome, Italy. Empirical analysis can be done only at the group level because of the great distance between observers and the flocks. Theoretically, we use our earlier computational model, StarDisplay, in which flocks resemble empirical data in many ways (Hemelrijk and Hildenbrandt 2011; Hemelrijk and Hildenbrandt 2015a, b; Hemelrijk et al. 2015) . In it, we showed that individual motion underlying the wave of agitation was a skitter motion (zigzagging) resulting in an \"orientation wave\" rather than a motion of fleeing inward into the flock causing a density wave (in which individuals temporarily cluster closer together) (Hemelrijk et al. 2015) .The change of orientation of the wing towards the observer during the simultaneous skitter motion of several individuals caused the dark bands. We continue to investigate the skitter maneuver by studying what happens at the individual level in more detail, and producing in the model agitation waves that are either damped in their amplitude of regular variation of darkness or not.", "cite_spans": [{"start": 470, "end": 503, "text": "(Hemelrijk and Hildenbrandt 2011;", "ref_id": "BIBREF14"}, {"start": 541, "end": 563, "text": "Hemelrijk et al. 2015)", "ref_id": "BIBREF18"}, {"start": 844, "end": 867, "text": "(Hemelrijk et al. 2015)", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Communicated by P. A. Bednekoff", "text": "We posed the following questions: (1) Does the intensity of darkness of an agitation wave decrease with time as it progresses through the flock? (2) How does the regular variation of darkness in the model compare to that in real flocks in terms of decrease of darkness of pulses, if we assume in the model (a) a complete tendency to repeat the \"zigzag\" maneuver, (b) a reduced tendency to repeat it, and (c) a complete tendency to repeat it, but by banking to a smaller maximum angle?", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "We investigated whether pulses of agitation waves in empirical data of starling flocks under predation threat collected in Rome, Italy (Procaccini et al. 2011 ) fade out and compared this with pulses, which were generated in a computational model of starling flocks, StarDisplay (Hemelrijk et al. 2015) .", "cite_spans": [{"start": 135, "end": 158, "text": "(Procaccini et al. 2011", "ref_id": "BIBREF22"}, {"start": 279, "end": 302, "text": "(Hemelrijk et al. 2015)", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Empirical footage and its analysis", "text": "We collected data on 16 wave events including a total of 44 pulses from the footage of 5 starling flocks recorded in Rome across two winter seasons as described in a previous study (Procaccini et al. 2011) . We distinguish between wave events and pulses following the definition by Procaccini and coauthors (Procaccini et al. 2011) , whereby a wave event comprises a single pulse of darkness ( Figs. 1 and 2 ) or a series of pulses (Fig. 2b ) that travel in a given direction through the flock and a wave event is separated from the next one by an interval of 10 s. We identify a pulse in the plots of regular variation of luminance applying the following criteria: (a) there should be a decrease of luminance from a local maximum until a local minimum and (b) the regular variation of luminance of each specific pulse should be visible at its start location (red line in Fig. 2b ) before being visible at its end location (blue Figs. 2b and S1; Table S1 ). The wave ends by the last oscillation, thus where there is a last local maximum followed by a local minimum in both, the location at the beginning and end.", "cite_spans": [{"start": 181, "end": 205, "text": "(Procaccini et al. 2011)", "ref_id": "BIBREF22"}, {"start": 307, "end": 331, "text": "(Procaccini et al. 2011)", "ref_id": "BIBREF22"}], "ref_spans": [{"start": 394, "end": 407, "text": "Figs. 1 and 2", "ref_id": "FIGREF0"}]}, {"section": "Empirical footage and its analysis", "text": "We selected those videos with agitation waves in which flock and falcon were clearly visible, the shape of the flock was relatively undisturbed, and not deforming too much and in which the predator attacked at a single location in the flock without changing attack location during the wave event.", "cite_spans": [], "ref_spans": []}, {"section": "Empirical footage and its analysis", "text": "To determine whether the darkness of pulses decreases with time, we measure per wave event and per pulse the difference in amplitude of the regular variation of luminance at a location (so-called region of interest) close to where the wave starts (starting location) and at a location where the wave approximately ends (end location) (Figs. 1 and 2). Fading out of waves is indicated by a statistically positive difference over all waves between the amplitude at beginning minus that at its end for each wave event or pulse. For some wave events, we average values of maximally 3 measurements at the beginning and at the end of the pulse. To measure the amplitude at a specific location of the flock (namely at the start location and end location), we need to follow the location of this region over time ( Fig. 1 ). We designed a computer program for linearly interpolating these two positions of a specific region of interest over time. The amplitude of the luminance L(t) at a specific location is normalized by the average luminance of the background and computed per wave event and per pulse as max[", "cite_spans": [], "ref_spans": [{"start": 807, "end": 813, "text": "Fig. 1", "ref_id": "FIGREF0"}]}, {"section": "Empirical footage and its analysis", "text": ", whereby maximum and minimum are measured either over the complete wave or per pulse respectively. The average value of the normalized luminance in the region of interest is the value for Y from the YUV color space divided by 255, the maximum value of the Y channel. Here, Y stands for the luminance and U and V for the range of blue-yellow and redcyan colors respectively. A normalized luminance of 1 represents a plain, white area and 0 a plain, black area. We calculated amplitudes at the level of a wave event and at the level of pulses (as defined above) as follows (Fig. 2a, b) . At the level of the wave event, we measured the maximum amplitude at each of the two locations by subtracting the minimum of luminance from the maximum, at the location at the beginning and at the end (Fig. 2a) . At the level of the pulse, we measured the amplitude per pulse at both locations (Figs. 2b and S1 ).", "cite_spans": [], "ref_spans": [{"start": 881, "end": 897, "text": "(Figs. 2b and S1", "ref_id": "FIGREF0"}]}, {"section": "Empirical footage and its analysis", "text": "The amplitudes of regular variation of luminance were not normally distributed (Figs. 3a, b and S3) and sample size was small, so we used nonparametric tests only, namely the Wilcoxon matched-pairs signed-ranks test and Kendall rank correlations. Fig. 2 Measurement of amplitude of regular variation of luminance at two levels, more coarsely, a per wave event and more refined, b per pulse. a The amplitude of the luminance per wave event is measured over the whole wave event at the location at the beginning (red), namely as indicated in the discretized square in Fig. 1 and at the location at the end of the wave (blue) (see continued square in Fig. 1) , and in the background (black line) over time (in sec). b The amplitude is measured per pulse (subsequent pulses are indicated by increasing numbers) at both locations, beginning and end (see Fig. 1 ).", "cite_spans": [], "ref_spans": [{"start": 566, "end": 572, "text": "Fig. 1", "ref_id": "FIGREF0"}, {"start": 648, "end": 655, "text": "Fig. 1)", "ref_id": "FIGREF0"}, {"start": 849, "end": 855, "text": "Fig. 1", "ref_id": "FIGREF0"}]}, {"section": "Empirical footage and its analysis", "text": "Amplitudes of the beginning (in red) and end locations (blue) of each pulse are indicated and pulses are numbered consecutively (for pulses measured in all wave events; see Fig. S1 ). The amplitude per wave event and per pulse is measured in both cases as max[", "cite_spans": [], "ref_spans": [{"start": 173, "end": 180, "text": "Fig. S1", "ref_id": "FIGREF0"}]}, {"section": "Empirical footage and its analysis", "text": "where the maximum and minimum are calculated per wave or pulse respectively. Controlled for the average of the background over time (indicated as (avg[bg(t) ", "cite_spans": [], "ref_spans": []}, {"section": "Simulation experiments in the model StarDisplay", "text": "We use our model of collective motion of starling flocks, StarDisplay (Hildenbrandt et al. 2010; Hildenbrandt 2011, 2015a, b; Hemelrijk et al. 2015) , since its flocks resemble real flocks in many traits, including its agitation waves (Hemelrijk et al. 2015, see also \"Introduction\") . This model, parametrized to empirical data of real starlings (Table S2) , is based on coordination among birds, in which individuals are attracted to others, align with them, avoid collisions with them, and fly following a simplified version of flying behavior based on fixed wing aerodynamics (Hildenbrandt et al. 2010; Hemelrijk and Hildenbrandt 2011 , 2015a Hemelrijk et al. 2015) . Following empirical findings, in the model, individuals are attracted to staying above the area for sleeping (the roosting site) and coordinate with only their 7 closest neighbors (Ballerini et al. 2008b ). For more detail on the basic model, see supplementary material. Here, we focus on details of modeling the agitation wave in flocks of 2000 individuals. Birds are represented as black delta-shaped objects and waves are initiated by a single bird at the border of the flock that supposedly detects a predator. The escape maneuver is a skitter motion, in the form of a \"zigzag\" (Table S3 ). Here, a bird follows a bend path in which it rolls (banks) temporarily in one direction and rolls back again. In the original model (Hemelrijk et al. 2015) , the neighbors nearby copy this motion exactly, which causes dark bands to propagate over the flock. In the present study, we have adjusted the copying of the escape maneuver in two ways: (1) we reduce the chance that neighbors copy it, and Fig. S7 ). c Difference in amplitude of the modulating luminance in the model at the location at the beginning and end of a wave for a decreasing probability to copy the escape maneuver. d Same difference in amplitude in the model against a decreasing angle of banking during the escape maneuver of zigzagging. The differences in amplitudes of luminance between the locations at the beginning and end were mostly not distributed normally: Shapiro-Wilk normality test in empirical data: n = 16 wave events, W = 0.89, p = 0.07 two-tailed; n = 44 pulses, W = 0.96, p = 0.10 two-tailed; modeling results of probability of copying: n = 13, W = 0.96, p = 0.70 two-tailed and thus followed up by nonparametric tests; apart from the differences for reduced depth of banking: n = 17, W = 0.88, p = 0.04 two-tailed, which were normally distributed and subsequently tested parametrically. a, b The amplitude of luminance is on average larger at the location at the beginning than at its end: Wilcoxon matched-pairs signed-ranks test: at level of wave events: n = 16, W = 108, p = 0.007 two-tailed; at level of pulses: n = 44, W = 677.5, p = 0.014 two-tailed. c Decreasing the tendency to copy in the model has a non-significant effect (Kendall rank correlation: n = 13, tau = \u2212 0.23, p = 0.31 two-tailed). d If individuals copy the zigzag with a decreasing maximum banking angle, the wave fades out (Pearson product-moment correlation: df = 15, r = 0.67, p = 0.0003 two-tailed). For the decrease in angle of banking, see Fig. S2 , and for normalized luminance at both locations over time with decreasing banking angles, see Fig. S8 (2) we make the neighbors roll less deep (but as long) at each event of copying the escape maneuver. We have studied the effect of various parameters in a single wave event where individuals were copying (or not) the escape maneuver from the 7 closest neighbors. The parameter range of the probability of copying was limited between 1.00 and 0.4 with decrements of 0.5, thus, 1.00, 0.95, 0.9, etcetera, in order to keep individuals together in the flock despite their difference in motion. The parameters of the reduction of the maximum angle of tilting with subsequent events of copying ranged from 0 to 0.04, with increments of 0.0025, meaning that the maximum angle of tilting was reduced by that fraction (0%, 0.25%, 0.5%, 0.75%, 1%, etcetera). Here, we reduced the angle of banking (called CopyDecay in Fig. S6 ) by a fraction while keeping the same time interval of banking.", "cite_spans": [{"start": 70, "end": 96, "text": "(Hildenbrandt et al. 2010;", "ref_id": "BIBREF19"}, {"start": 126, "end": 148, "text": "Hemelrijk et al. 2015)", "ref_id": "BIBREF18"}, {"start": 580, "end": 606, "text": "(Hildenbrandt et al. 2010;", "ref_id": "BIBREF19"}, {"start": 607, "end": 638, "text": "Hemelrijk and Hildenbrandt 2011", "ref_id": "BIBREF14"}, {"start": 639, "end": 646, "text": ", 2015a", "ref_id": "BIBREF16"}, {"start": 647, "end": 669, "text": "Hemelrijk et al. 2015)", "ref_id": "BIBREF18"}, {"start": 852, "end": 875, "text": "(Ballerini et al. 2008b", "ref_id": "BIBREF3"}, {"start": 1399, "end": 1422, "text": "(Hemelrijk et al. 2015)", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Simulation experiments in the model StarDisplay", "text": "We generate two-dimensional images of the flock on a white background by making the observer (or camera) move parallel to the flock in the same direction as the flock and pointing to the center of gravity of the flock (at an almost fixed angle) so that it perceives maximal changes in wing surface. The amplitude of regular variations of luminance of the flock is measured in the same way as in the empirical footage.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "In videos of real flocks, we analyzed 16 wave events that comprised one to 6 pulses of darkness traveling through the flock (a total of 44 pulses; Table S1 ).", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "The results show that the amplitude of the regular variation of luminance is on average larger at the location at the beginning than the location at its end ( Fig. 3a, b ; for both methods, see Fig. 2a, b; for the difference in amplitude at location at beginning and end of a pulse for each pulse per wave, see Fig.  S7 and for separate pulses, see Fig. S1 ). This means that empirically a pulse fades out.", "cite_spans": [], "ref_spans": [{"start": 159, "end": 169, "text": "Fig. 3a, b", "ref_id": "FIGREF1"}, {"start": 349, "end": 356, "text": "Fig. S1", "ref_id": "FIGREF0"}]}, {"section": "Results", "text": "In our computational model, StarDisplay, we represent the weakening of pulses in two ways by decreasing (a) the tendency to copy over time, and (b) the maximum angle of tilting during a skitter-like escape maneuver (the zigzag). In the model, we see that decreasing the tendency to copy has no significant effect on the amplitude at the end position (Fig. 3c ). Yet, if individuals copy the zigzag with a decreasing maximum banking angle, the pulse in our model weakens like in empirical data (Figs. 3d and S8 ).", "cite_spans": [], "ref_spans": [{"start": 350, "end": 358, "text": "(Fig. 3c", "ref_id": "FIGREF1"}, {"start": 493, "end": 509, "text": "(Figs. 3d and S8", "ref_id": "FIGREF1"}]}, {"section": "Discussion", "text": "The empirical data from attacks by falcons on real flocks of starlings show that agitation waves and their pulses significantly decrease in intensity and thereby, transmission of information about a threat decreases with time. To produce a decay in a wave in our computational model, StarDisplay, individuals need to repeat the zigzag-like escape maneuver while reducing its prominence over time, meaning that individuals are banking to a maximum angle that is smaller with each subsequent event of copying. Decay in intensity of the pulses happens neither if individuals copy the escape maneuver completely from their nearby neighbors nor if they reduce their tendency to copy it. Thus, our study suggests that in real flocks, waves and pulses fade out due to decreasing the maximum exposure of the surface of the wings to the observer during copying the zigzag escape maneuvers over time.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "This extends our former results when using StarDisplay for studying what underlies agitation waves (Hemelrijk et al. 2015) . Here, we suggested that waves either reflected a change of density of individuals in the flock (Axelsen et al. 2001; Procaccini et al. 2011) or their orientation (Buchanan et al. 1988; Potts 1984) or both (Hemelrijk et al. 2015) . We showed that only when the wave through the flock comprised a zigzag escape maneuver, our visual system observed indeed a dark band moving along the flock, not when the escape maneuver involved individuals fleeing fast forward into the flock. The orientation wave (skitter wave by zigzagging) in the model moved away from the predator at a speed similar to that in empirical data of the agitation wave of real flocks (Procaccini et al. 2011) . The information transmission during copying in the model was complete, and therefore, individuals were always repeating a zigzag when at least one of their influential neighbors performed it and were repeating it in exactly the same way as they observed it. Our present findings show that our earlier model of agitation waves differs from empirical data in its lack of decay in amplitude of regular variation of luminance with time (Hemelrijk et al. 2015) .", "cite_spans": [{"start": 99, "end": 122, "text": "(Hemelrijk et al. 2015)", "ref_id": "BIBREF18"}, {"start": 220, "end": 241, "text": "(Axelsen et al. 2001;", "ref_id": "BIBREF1"}, {"start": 242, "end": 265, "text": "Procaccini et al. 2011)", "ref_id": "BIBREF22"}, {"start": 287, "end": 309, "text": "(Buchanan et al. 1988;", "ref_id": "BIBREF5"}, {"start": 310, "end": 321, "text": "Potts 1984)", "ref_id": "BIBREF21"}, {"start": 330, "end": 353, "text": "(Hemelrijk et al. 2015)", "ref_id": "BIBREF18"}, {"start": 775, "end": 799, "text": "(Procaccini et al. 2011)", "ref_id": "BIBREF22"}, {"start": 1234, "end": 1257, "text": "(Hemelrijk et al. 2015)", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Discussion", "text": "Our findings seem to warrant the use of the model StarDisplay for testing different hypotheses, because it adds an extra pattern (of damping of waves) to several other emergent properties of modeled flocks that resemble empirical data outside the context of predation. These are the flocks' relative proportions of height, width, and length; their similar density at front and back; collective turning over equal radii, which produces changes of shape during turning; the scale free correlation between collective heading and flock size, and the degree of diffusion in the flock (Hemelrijk and Hildenbrandt 2008 , 2015a Hildenbrandt et al. 2010; Hemelrijk et al. 2015) .", "cite_spans": [{"start": 579, "end": 611, "text": "(Hemelrijk and Hildenbrandt 2008", "ref_id": "BIBREF13"}, {"start": 612, "end": 619, "text": ", 2015a", "ref_id": "BIBREF16"}, {"start": 620, "end": 645, "text": "Hildenbrandt et al. 2010;", "ref_id": "BIBREF19"}, {"start": 646, "end": 668, "text": "Hemelrijk et al. 2015)", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Discussion", "text": "As a possible limitation of our study, we acknowledge that our empirical data are based on events in which flocks reacted to a single predator, even though waves were sometimes generated by more than one predator. We omitted these few episodes because they were too complex for our analysis. Besides, we also ignored waves generated by a non-predator passing by (such as a gull), because these waves are weaker and die out sooner. Although we expect our explanation to hold here also, this needs further study.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "A decreasing maximum banking angle when copying a maneuver of turning while zigzagging differs from what is empirically observed in starling flocks during \"regular\" collective turning in the absence of a negative stimulus such as a predator. During regular turning when the group is undisturbed, individuals appear all to be turning over the same angle (Attanasi et al. 2014) . The fading out of the turning in the zigzag-skitter motion with each subsequent event of copying may be a consequence of decreasing fearfulness of birds the larger their distance to the predator. Such decrease in responsiveness could be adaptive in terms of energy expenditure, because at a larger distance from the predator, the chance to be caught is smaller (Broom and Ruxton 2005) . Individual starlings are sensitive to subtle cues of predation risk and rapidly resume normal behavior, e.g., foraging, if these cues are gone (Carter et al. 2008) .", "cite_spans": [{"start": 353, "end": 375, "text": "(Attanasi et al. 2014)", "ref_id": "BIBREF0"}, {"start": 739, "end": 762, "text": "(Broom and Ruxton 2005)", "ref_id": "BIBREF4"}, {"start": 908, "end": 928, "text": "(Carter et al. 2008)", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Discussion", "text": "Future studies based on filming at closer proximity (possibly with the help of drones) are needed to explore in detail how fading out of skitter motions during escape maneuvers compare to the individual behavior during undisturbed turns of the flock.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Acknowledgments The video material for this project was gathered during a NEST program (STREP project \"StarFlag\" no. 12682) aimed at studying animal group movements where CKH and HH coordinated the unit on flocking models, and Enrico Alleva and Daniela Santucci, the unit collecting field data. Field video recording was carried out by CC and Francesca Zoratto. We thank the Self-Organization Lab for helpful discussions, particularly Rolf Storms and Kim Kiekebos for initial work on the analyses.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Author contributions CKH and HH conceived the idea of this paper; CKH wrote the main part of the manuscript and contributed to the statistical analysis. HH supervised the analysis of empirical data, did the computational modeling and the analysis of the modeling data, made some Figs, and contributed to the writing. CA analyzed the empirical data, made most of the Figs, and wrote part of the methods. CC collected the data, contributed to discussions, and participated in the writing.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Funding information This work is financed by the Netherlands Organisation for Scientific Research (NWO), the Open Technology Programme (OTP) Preventing bird strikes: Developing RoboFalcons to deter bird flocks, project number 14723, awarded to CKH. Cooperation with CC was funded by two visitor grants from NWO (040.11.468 and 040.11.573/1798) to CKH.", "cite_spans": [], "ref_spans": []}, {"section": "Data availability", "text": "The datasets generated and/or analyzed during the current study are available in the Figshare https://doi.org/10.6084/m9. figshare.8104724.", "cite_spans": [], "ref_spans": []}, {"section": "Compliance with ethical standards", "text": "Conflict of interests The authors declare that they have no conflict of interest.", "cite_spans": [], "ref_spans": []}, {"section": "Compliance with ethical standards", "text": "Ethical approval This study is purely observational and did not involve captive animals or experimental manipulations, only analyses of video material. The video recordings of the flocks and falcons were taken from hundreds of meters distance in an urban environment and did not cause any disturbance to the birds.", "cite_spans": [], "ref_spans": []}, {"section": "Compliance with ethical standards", "text": "Open Access This article is distributed under the terms of the Creative Comm ons Attribution 4.0 International License (http:// creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Information transfer and behavioural inertia in starling flocks", "authors": [{"first": "A", "middle": [], "last": "Attanasi", "suffix": ""}, {"first": "A", "middle": [], "last": "Cavagna", "suffix": ""}, {"first": "Del", "middle": [], "last": "Castello", 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and end location (square indicated with continuous line). The dotted lines indicate the period of 1 s over which frames are interpolated during the motion of the region of interest. The arrow shows the direction of motion of the pulse over the flock", "type": "figure"}, "FIGREF1": {"text": "Fig. 3 Amplitudes of the modulating luminance normalized by the average luminance of the background at the location at the beginning and end of a 16 wave events and b 44 pulses in 16 wave events in 5 real flocks (see supplementary Fig. S7). c Difference in amplitude of the modulating luminance in the model at the location at the beginning and end of a wave for a decreasing probability to copy the escape maneuver. d Same difference in amplitude in the model against a decreasing angle of banking during the escape maneuver of zigzagging. The differences in amplitudes of luminance between the locations at the beginning and end were mostly not distributed normally: Shapiro-Wilk normality test in empirical data: n = 16 wave events, W = 0.89, p = 0.07 two-tailed; n = 44 pulses, W = 0.96, p = 0.10 two-tailed; modeling results of probability of copying: n = 13, W = 0.96, p = 0.70 two-tailed and thus followed up by", "type": "figure"}}}
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{"paper_id": "199668397", "_pdf_hash": "fe70d808b8244bc86df66ab5c6af58acdd4e04a5", "abstract": [{"section": "Abstract", "text": "Phosphonates are rare and unusually bioactive natural products. However, most bacterial phosphonate biosynthetic capacity is dedicated to tailoring cell surfaces with molecules like 2-aminoethylphosphonate (AEP). Although phosphoenolpyruvate mutase (Ppm)-catalyzed installation of C-P bonds is known, subsequent phosphonyl tailoring (Pnt) pathway steps remain enigmatic. Here we identify nucleotidyltransferases in over two-thirds of phosphonate biosynthetic gene clusters, including direct fusions to~60% of Ppm enzymes. We characterize two putative phosphonyl tailoring cytidylyltransferases (PntCs) that prefer AEP over phosphocholine (P-Cho) -a similar substrate used by the related enzyme LicC, which is a virulence factor in Streptococcus pneumoniae. PntC structural analyses reveal steric discrimination against phosphocholine. These findings highlight nucleotidyl activation as a predominant chemical logic in phosphonate biosynthesis and set the stage for probing diverse phosphonyl tailoring pathways.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "W ith stability and bioactivity imparted by a characteristic carbon-phosphorus bond, phosphonates are unusual and relatively unexplored biological molecules. Since the discovery of 2-aminoethylphosphonate (AEP) in nature six decades ago 1 , phosphonates and phosphinates have gained recognition as a small but commercially successful class of natural products exemplified by the antibiotic fosfomycin and the herbicide phosphinothricin (Fig. 1a) 2, 3 . Although exploration of these molecules and their biosynthesis is still in its infancy, bioinformatic analyses have revealed widespread genetic capacity to produce chemically diverse phosphonates [4] [5] [6] . For example, 5% of sampled microbes encode phosphoenolpyruvate mutase (Ppm) 4 , which catalyzes rearrangement of phosphoenolpyruvate (PEP) to the C-P bond-containing product phosphonopyruvate (PnPy) (Fig. 1b) 7 . Despite this predicted ubiquity, natural product classes like polyketides and nonribosomal peptides have been far more intensively investigated, and the relative dearth of characterized phosphonates partly reflects technical challenges associated with high polarity and lack of chromophores 8 . However, the few phosphonate biosynthetic gene clusters that have been characterized have revealed unusual enzymes catalyzing unprecedented chemical transformations 9 . These findings highlight the gap between current biosynthetic knowledge and future discovery potential, and motivate continued investigation of biological phosphonates.", "cite_spans": [{"start": 446, "end": 448, "text": "2,", "ref_id": "BIBREF1"}, {"start": 649, "end": 652, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 653, "end": 656, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 657, "end": 660, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "", "text": "Even more overlooked than freely diffusible small molecule phosphonates are those that modify, or tailor, cell surfaces. Comprehensive bioinformatic analysis of microbial ppm gene distribution predicted that most putative phosphonate biosynthetic gene clusters encode cell wall phosphonoglycans and phosphonolipids 4 . Although a handful of phosphonylated glycans and lipids have been structurally identified-such as the AEP-modified capsular polysaccharide from Bacteroides fragilis 10 (Fig. 1c) -almost nothing is known about their biosynthesis or biological roles. Modulating biological function by adding or removing small molecules on cell surface materials has long been recognized as a key mechanism of bacterial adaptation and virulence. Common cell surface modifications include the addition of acetyl 11 , pyruvyl 12 , phosphoethanolamine 13, 14 , and phosphocholine (P-Cho) [15] [16] [17] groups to lipids and glycans. Indeed, P-Cho is a virulence factor encoded by the Lic pathway in pathogens, such as Streptococcus pneumoniae 15, 18 , and lic gene disruption impedes P-Cho decoration of teichoic acids and attenuates S. pneumoniae virulence [19] [20] [21] . Understanding the biosynthetic logic of these modifications therefore represents an important goal with therapeutic implications, as phosphonates may similarly modulate virulence.", "cite_spans": [{"start": 849, "end": 852, "text": "13,", "ref_id": "BIBREF12"}, {"start": 885, "end": 889, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 890, "end": 894, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 895, "end": 899, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 1040, "end": 1043, "text": "15,", "ref_id": "BIBREF14"}, {"start": 1155, "end": 1159, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 1160, "end": 1164, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 1165, "end": 1169, "text": "[21]", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "", "text": "To address the gap between bioinformatic prediction and biosynthetic knowledge, we are characterizing several biosynthetic gene clusters predicted to encode cell wall phosphonoglycans or phosphonolipids. For instance, guided by the presence of ppm genes, we previously identified gene expression and/or phosphonate production from anaerobic bacteria Atopobium rimae, Treponema denticola, and Olsenella uli 22 , each of which have been associated with disease of the human oral cavity [23] [24] [25] . Commonly associated with ppm and found in these gene clusters are ppd and aept, which respectively, encode PnPy decarboxylase (Ppd) and AEP transaminase (AEPT) to generate AEP (Fig. 1b) 26, 27 . Unfortunately, additional genes commonly found in predicted phosphonyl tailoring gene clusters have not been described, and the biosynthetic steps leading to phosphonyl modifications remain unknown (Fig. 1) . Herein we reveal widespread occurrence of nucleotidyltransferase-encoding genes in phosphonate biosynthesis and characterize two representative enzymes as phosphonatespecific cytidylyltransferases from the Gram-positive actinobacterium A. rimae and the Gram-negative spirochete T. denticola. These enzymes efficiently activate AEP, presumably for subsequent capture by carbohydrate or lipid nucleophiles. We propose the phosphonyl tailoring (pnt) nomenclature for these gene clusters, and specifically use PntC for AEP cytidylyltransferase based on its sequence and biosynthetic similarity to LicC of the P-Cho tailoring (Lic) pathway. Indeed, in contrast to PntC, LicC from S. pneumoniae (Spn-LicC) strongly prefers PCho over AEP as a substrate for cytidylyl activation. Structure determination of PntC from T. denticola (Tde-PntC) and molecular dynamics analyses indicate that PntC selectivity for the smaller AEP substrate is primarily driven by active site steric constraints. Overall, identifying this remarkably widespread family of phosphonate-specific PntC cytidylyltransferases sets the stage for deciphering the biosynthetic roles of CMP-phosphonate conjugates and the biological consequences of this underexplored cell surface chemistry.", "cite_spans": [{"start": 484, "end": 488, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 489, "end": 493, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 494, "end": 498, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 687, "end": 690, "text": "26,", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "Results", "text": "Nucleotidyltransferases are enriched in phosphonate biosynthesis. To identify enzymes commonly associated with Ppm, we assessed Ppm protein sequences for the presence of fused domains. Precedent for active Ppm fusion proteins was", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "Fosfomycin Phosphinothricin AEP PnAA PnPy PEP ? Pnt enzymes Fig. 1 Phosphonates in nature. a Small molecule bioactive natural products fosfomycin and phosphinothricin. b Biosynthesis of the common phosphonate AEP from phosphoenolpyruvate (PEP) via the intermediacy of phosphonopyruvate (PnPy) and phosphonoacetaldehyde (PnAA). Cofactors in parentheses are thiamine pyrophosphate (TPP) and pyridoxal 5\u2032-phosphate (PLP). Unknown phosphonyl tailoring (Pnt) biosynthetic steps lead from AEP to c, cell surface phosphonoglycans like that isolated from Bacteroides fragilis recently established in the Streptomyces wedmorensis fosfomycin biosynthetic pathway. The Ppm enzyme Fom1 possesses an N-terminally fused cytidylyltransferase (CyTase) domain catalyzing cytidylyltransfer from CTP to hydroxyethylphosphonate (HEP) to generate CMP-HEP 28 . Inspired by this example of a biosynthetically relevant Ppm-fused domain, we generated a Ppm fusion inventory (Fig. 2) . From the NCBI refSeq database containing 113,086 genomes we identified 146,399 proteins in 72,350 genomes matching the hidden Markov model (HMM) for the Ppm/isocitrate lyase Pfam family (PF13714). After filtering out identical sequences we were left with 27,716 non-redundant protein sequences matching PF13714, of which only 905 (3.3%) were fused to another Pfam domain (Fig. 2a) . Of the 27,716 total sequences, only 1485 possessed the Ppm-specific EDKXXXXXNS motif 4 . Surprisingly, almost all fusions (883 out of 905) possessed this motif, indicating that the majority of Ppm enzymes (59.5%) are fused to other domains (Fig. 2a) Fig. 2b ). PF12804 is exemplified by Spn-LicC 29 , and PF01467 by the Fom1 CyTase 28 . This predominance of nucleotidyltransferase domains fused to Ppm enzymes was unexpected and supports a co-evolutionary trajectory of the two catalytic activities. In bacteria, co-evolution of functionally related genes is generally observed as colocalization, or clustering, on the chromosome 30 . A compilation of calculated distances, in number of genes, between ppm and the nearest gene encoding either PF12804 or PF01467 clearly illustrated a tendency for these genes to be in close proximity (Fig. 2c) . For instance, 59 .3% of all nearest nucleotidyltransferases were fused to ppm (distance = 0 genes). The next most frequent distance was two genes away, and about two-thirds (67.7%) of nucleotidyltransferases were within five genes of ppm (Fig. 2c  inset) . Note that these calculations identify only the nearest nucleotidyltransferase in a given gene cluster and therefore do not account for gene clusters possessing more than one nucleotidyltransferase. For example, the gene clusters in Fig. 3c possess nucleotidyltransferases that are both ppm-fused as well as one or two genes away. In these cases only the nearest nucleotidyltransferase would be tabulated, which for all three would be the fused domain at a distance of zero. In summary, this proximity bias indicates a functional relationship between Ppm and nucleotidyltransferases, and strongly implies an important role for the latter in phosphonate biosynthesis.", "cite_spans": [], "ref_spans": [{"start": 949, "end": 957, "text": "(Fig. 2)", "ref_id": "FIGREF0"}, {"start": 1331, "end": 1340, "text": "(Fig. 2a)", "ref_id": "FIGREF0"}, {"start": 1583, "end": 1592, "text": "(Fig. 2a)", "ref_id": "FIGREF0"}, {"start": 1593, "end": 1600, "text": "Fig. 2b", "ref_id": "FIGREF0"}, {"start": 2177, "end": 2186, "text": "(Fig. 2c)", "ref_id": "FIGREF0"}, {"start": 2427, "end": 2443, "text": "(Fig. 2c  inset)", "ref_id": "FIGREF0"}, {"start": 2678, "end": 2685, "text": "Fig. 3c", "ref_id": "FIGREF1"}]}, {"section": "Results", "text": "Interestingly, many ppm-associated nucleotidyltransferases are annotated as LicC-like cytidylyltransferases, which provides an important clue regarding possible biosynthetic function. The lic (lipopolysaccharide core) operon catalyzes choline import, phosphorylation and attachment of P-Cho to a glycan substrate destined for the cell wall 18, 31 . Mirroring the chemical logic of the eukaryotic Kennedy pathway, a LicC cytidylyltransferase catalyzes formation of CDP-choline from CTP and P-Cho (Fig. 3b) . LicC from S. pneumoniae (Spn-LicC) has been structurally and biochemically characterized 29, 32, 33 , and gene disruption attenuated virulence in a mouse model 21 . Overall, the similarities between P-Cho and AEP and genomic proximity of ppm and licC-like genes suggested that phosphonates may be activated as CMP-conjugates in a manner analogous to P-Cho activation by LicC (Fig. 3a) .", "cite_spans": [{"start": 340, "end": 343, "text": "18,", "ref_id": "BIBREF17"}, {"start": 596, "end": 599, "text": "29,", "ref_id": "BIBREF28"}, {"start": 600, "end": 603, "text": "32,", "ref_id": "BIBREF31"}], "ref_spans": [{"start": 495, "end": 504, "text": "(Fig. 3b)", "ref_id": "FIGREF1"}, {"start": 882, "end": 891, "text": "(Fig. 3a)", "ref_id": "FIGREF1"}]}, {"section": "Results", "text": "PntC enzymes preferentially activate AEP. Intrigued by the genomic proximity of ppm and licC-like cytidylyltransferases, we sought to characterize the putative phosphonate-specific nucleotidyltransferases Oul593, Ari1348 and Tde1415. We observed transcription of oul593 and ari1348 in pure cultures (Supplementary Fig. 1 ), and previously reported chemical shifts consistent with phosphonates via solid-state 31 P NMR analysis of T. denticola and O. uli whole cells 22 . Furthermore, each genomic neighborhood encodes AEP production and biosynthetic machinery associated with cell wall glycans, such as LicD-like phosphotransferases or glycosyltransferases (Fig. 3c) . In fact, both A. rimae and O. uli possess lic genes relatively nearby on the chromosome. The Ppm protein sequences also phylogenetically cluster into phosphonoglycan/lipid clades 4, 22 , which further suggests that these phosphonates are directed to the cell surface. To evaluate the substrate preference of putative phosphonate nucleotidyltransferases relative to Spn-LicC, we expressed and purified Ari1348, Tde1415, and Spn-LicC, but Oul593 was insoluble ( Supplementary Fig. 2 ). Dynamic light scattering (DLS) analysis indicated monomeric quaternary structures for Spn-LicC and Ari1348 ( Supplementary Fig. 3 ), as previously observed for Spn-LicC 33 . In contrast, Tde1415 has a predicted monomeric molecular weight of~70 kDa with DLS data indicating a dimer of 146 kDa. Cytidylyltransferase activity detected using an HPLC assay revealed time-dependent formation of CDP-choline (CDP-Cho) and CMP-AEP by Spn-LicC and Ari1348, respectively (Fig. 4a) . CDP-Cho was verified by comparison to commercially sourced authentic standard and high-resolution mass spectrometry (expected mass, 488.1073; observed, 488.1071). CMP-AEP was identified based on high-resolution mass spectrometry and . Overall, these results clearly demonstrated Ari1348-catalyzed formation of CMP-AEP and imply shared biosynthetic logic for P-Cho and phosphonate tailoring pathways (Fig. 3 ).", "cite_spans": [{"start": 848, "end": 850, "text": "4,", "ref_id": "BIBREF3"}], "ref_spans": [{"start": 657, "end": 666, "text": "(Fig. 3c)", "ref_id": "FIGREF1"}, {"start": 1129, "end": 1149, "text": "Supplementary Fig. 2", "ref_id": "FIGREF0"}, {"start": 1262, "end": 1282, "text": "Supplementary Fig. 3", "ref_id": "FIGREF1"}, {"start": 1614, "end": 1623, "text": "(Fig. 4a)", "ref_id": "FIGREF2"}, {"start": 2025, "end": 2032, "text": "(Fig. 3", "ref_id": "FIGREF1"}]}, {"section": "Results", "text": "Although activity was observed for each enzyme with its proposed substrate, a comparison of substrate preference further supported our cognate substrate assignments and prompted the adoption of new nomenclature to describe this class of phosphonate-specific enzyme. Previous work revealed a 2700-fold higher specificity constant for Spn-LicC towards P-Cho relative to phosphoethanolamine (Table 1) , but activity towards phosphonate substrates was not examined 33 . Our HPLC assays revealed poor cross-reactivity with non-cognate substrates (Fig. 4b) . Specifically, Ari1348 clearly preferred AEP over PCho under the same conditions, signifying phosphonate cytidylyltransferase activity. In addition, both Ari1348 and Tde1415 exhibited strong activity towards CTP, limited activity towards ATP, and no activity detected for GTP ( Supplementary Fig. 8 ). Similar limited reactivity towards ATP was previously observed in the Fom1 CyTase domain 28 and Spn-LicC 32, 33 . Based on phosphonate preference and functional analogy to LicC, we propose phosphonyl tailoring cytidylyltransferase (PntC) terminology to distinguish these enzymes from P-Cho-specific LicC cytidylyltransferases (Fig. 3) . The strict substrate specificity implied by the HPLC analyses of Fig. 4b prompted quantitative investigation via steady-state kinetic analysis. Using a coupled assay to detect pyrophosphate release 34, 35 , our initial rate measurements of Spn-LicC towards P-Cho with saturating concentrations of CTP revealed a k cat of 1.06 \u00b1 0.04 s \u22121 and K M of 2.36 \u00b1 0.65 \u00b5M, affording a k cat /K M comparable to previous reports 29, 32, 33 (Table 1, Supplementary  Fig. 9 ). In contrast, AEP as a substrate yielded k cat and K M values of 0.723 \u00b1 0.054 s \u22121 and 318 \u00b1 129 \u00b5M, respectively, revealing a 200-fold preference for P-Cho over AEP. Ari-PntC (Ari1348) exhibited the opposite preference, with a 440-fold higher specificity constant for AEP versus P-Cho (Table 1 , Supplementary Fig. 9) . Similarly, Tde-PntC (Tde1415) was not sufficiently active towards P-Cho to obtain steady-state kinetic data, but activity towards AEP was similar to Ari-PntC (Table 1) . Overall, clear preference for AEP as a substrate supports assignment of these enzymes as phosphonate-specific cytidylyltransferases, or PntCs.", "cite_spans": [{"start": 959, "end": 962, "text": "32,", "ref_id": "BIBREF31"}, {"start": 1389, "end": 1392, "text": "34,", "ref_id": "BIBREF33"}, {"start": 1610, "end": 1613, "text": "29,", "ref_id": "BIBREF28"}, {"start": 1614, "end": 1617, "text": "32,", "ref_id": "BIBREF31"}], "ref_spans": [{"start": 388, "end": 397, "text": "(Table 1)", "ref_id": "TABREF2"}, {"start": 541, "end": 550, "text": "(Fig. 4b)", "ref_id": "FIGREF2"}, {"start": 1180, "end": 1188, "text": "(Fig. 3)", "ref_id": "FIGREF1"}, {"start": 1256, "end": 1263, "text": "Fig. 4b", "ref_id": "FIGREF2"}, {"start": 1621, "end": 1630, "text": "(Table 1,", "ref_id": "TABREF2"}, {"start": 1942, "end": 1950, "text": "(Table 1", "ref_id": "TABREF2"}, {"start": 2135, "end": 2144, "text": "(Table 1)", "ref_id": "TABREF2"}]}, {"section": "Results", "text": "Molecular determinants of specificity are primarily steric. Structural studies were undertaken to understand PntC substrate selectivity for AEP versus P-Cho. In contrast to Ari-PntC, the larger two-domain protein Tde1415 was readily crystallized to afford a 2.72 \u00c5 structure of the apo enzyme and a 1.95 \u00c5 structure of the product complex obtained in the presence of CTP and AEP substrates (Supplementary Table 1 ). As predicted from gene annotations (Fig. 3c) , the overall structure of the enzyme included an N-terminal PntC connected to a C-terminal AEPT domain ( Supplementary Fig. 10 ). The classic type I aminotransferase fold of the AEPT domain is very similar to AEPT from Salmonella typhimurium, which is the only other AEPT structure known 36 . Interestingly, neither of these structures possesses a covalently linked pyridoxal 5\u2032-phosphate (PLP) cofactor, and the colorless Tde1415 solution was consistent with a missing internal aldimine chromophore. To our knowledge, these two enzymes and the alanine-glyoxylate aminotransferase from Anabaena 37 are the only crystallographic examples of non-covalently bound PLP. Nonetheless, aminotransferase activity was detected as 31 P NMR chemical shifts consistent with the transformation of AEP to phosphonoacetaldehyde (PnAA, Supplementary Fig. 11 ) and confirmed by mass spectrometry (Supplementary Fig. 12 ). The AEPT domain of Tde1415 possesses PLP and the requisite active site features to support classical aminotransferase catalysis ( Supplementary Fig. 13 ).", "cite_spans": [], "ref_spans": [{"start": 405, "end": 412, "text": "Table 1", "ref_id": "TABREF2"}, {"start": 451, "end": 460, "text": "(Fig. 3c)", "ref_id": "FIGREF1"}, {"start": 1341, "end": 1363, "text": "(Supplementary Fig. 12", "ref_id": "FIGREF0"}, {"start": 1497, "end": 1518, "text": "Supplementary Fig. 13", "ref_id": "FIGREF1"}]}, {"section": "Results", "text": "The crystal structure of the PntC domain of Tde1415 in complex with the CMP-AEP product possesses a binding orientation reminiscent of the previously reported Spn-LicC: CDP-Cho structure (PDB 1JYL, Fig. 5 ) 29 . Strikingly, the presence of two adjacent magnesium ions in the Tde-PntC active site contrasts with the single ion observed in the Spn-LicC complex, and each apo-enzyme has one less metal ion. Consistent with our assignment of the metals as magnesium ions, the temperature factors increased from 31.3 to 62.7 \u00c5 2 when Zn 2+ was included in crystallographic refinements. In addition, EDTA treatment inactivated Tde1415, but activity was restored by the addition of Mg 2+ or Zn 2+ but not Ca 2+ (Supplementary Fig. 14) . Varying metal ion content is well established among phosphate-processing enzymes. For example, a two-magnesium mechanism is favored for CMP-Kdo synthetase (KdsB) 38, 39 , FomD employs two metals for cytidylyl (S)-2-hydroxypropoylphosphonate hydrolysis 40 , DNA polymerases commonly employ a two-metal ion mechanism with evidence for an additional third divalent metal ion 41 , and terpene synthases require three metal ions 42 . Overall, in contrast to Spn-LicC, which loses a salt bridge between Arg129 and a metal-coordinating residue Glu216, the metal coordination sphere of Tde-PntC does not undergo major changes upon ligand binding (Supplementary Fig. 10 ).", "cite_spans": [{"start": 892, "end": 895, "text": "38,", "ref_id": "BIBREF37"}], "ref_spans": [{"start": 198, "end": 204, "text": "Fig. 5", "ref_id": "FIGREF3"}, {"start": 704, "end": 727, "text": "(Supplementary Fig. 14)", "ref_id": "FIGREF2"}]}, {"section": "Results", "text": "The crystal structures of Spn-LicC 29 and Tde-PntC provide an opportunity to probe the selectivity determinants for respective cognate substrates P-Cho and AEP, which are present in the active sites as CMP-conjugate products. The two substrates clearly differ in size, and possibly in charge; the positive charge of the quaternary amine of P-Cho does not necessarily occur at the primary amine of AEP. Although primary amines are typically positively charged (pK a~1 0) 43 , active site pK a perturbations could occur 44 to neutralize AEP. However, few clues exist from the TdePntC crystal structure, which reveals water, Glu196, and Glu104 positioned to interact with the primary amine of AEP via hydrogen bonds. Intriguingly, the equivalent positions in SpnLicC (D192 and D105) are occupied by smaller Asp side chains (Fig. 5) , which may provide more room to accommodate the larger P-Cho substrate. In addition, Spn-LicC possesses a composite aromatic box for binding the choline quaternary amine via cation-\u03c0 interactions (Fig. 5) 45 . Notably, Ari-PntC also possesses the equivalent aromatic residues, suggesting that charge may not be a key determinant of P-Cho versus AEP selectivity, and highlighting that Ari-PntC is more closely related to SpnLicC than Tde-PntC ( Supplementary Fig. 15 ). Therefore, protein cavity volumes were calculated 46 to evaluate the effects of steric restriction against the larger P-Cho substrate in the Tde-PntC active site. The larger pocket volume of Spn-LicC (~381 \u00c5 3 ) compared to Tde-PntC (~287 \u00c5 3 ) (Fig. 5 ) corresponds to the difference of~64 \u00c5 3 in molecular volume between CDP-Cho and CMP-AEP, or the~75 \u00c5 3 volume of the choline trimethylamine moiety 47 .", "cite_spans": [], "ref_spans": [{"start": 820, "end": 828, "text": "(Fig. 5)", "ref_id": "FIGREF3"}, {"start": 1026, "end": 1034, "text": "(Fig. 5)", "ref_id": "FIGREF3"}, {"start": 1274, "end": 1295, "text": "Supplementary Fig. 15", "ref_id": "FIGREF3"}, {"start": 1544, "end": 1551, "text": "(Fig. 5", "ref_id": "FIGREF3"}]}, {"section": "Results", "text": "To further probe the effects of steric constraint on substrate selectivity, we pursued molecular dynamics simulations. In addition to the enzyme:product crystal structures of Spn-LicC: CDP-Cho and Tde-PntC:CMP-AEP, we also modeled noncognate enzyme:product pairs Spn-LicC:CMP-AEP and TdePntC:CDP-Cho using 10 \u00d7 150 ps independent trajectories (1.5 ns in total) for each complex (Fig. 5) . Notably, the Tde-PntC active site did not readily accommodate the additional volume of CDPCho, and significant conformational changes in the ligand occurred immediately during the simulations. Specifically, the choline moiety was forced towards cytidine, with a concomitant shift in the phosphate backbone enabled by rotation about the ribose C5\u2032-O5\u2032 bond. The distribution of this dihedral angle during the Tde-PntC simulations indicates: (i) the magnitude of this shift for the non-cognate ligand CDP-Cho, and (ii) the comparatively narrow distribution of dihedral angles accessed by the cognate ligand CMP-AEP (Fig. 5c) . Similar results were obtained for Spn-LicC, characterized by a narrow distribution for the cognate ligand CDP-Cho and a broad bimodal distribution of dihedral angles for the non-cognate CMP-AEP. Insofar as dihedral angle distributions represent movement of the ligand, the narrow distribution of cognate ligand conformations may reflect a more tightly bound ternary complex. Although not observed in the crystal structure, it is possible that a proportion of the LicC:ligand complex in solution would carry an additional Mg 2+ ion, similar to the observed Tde-PntC:CMP-AEP complex. We therefore also performed simulations with a second Mg 2+ for both Spn-LicC product complexes, revealing a bimodal distribution of the dihedral for CDP-Cho with a second peak around -150\u00b0 (Supplementary Fig. 16 ) and a narrower distribution for CMP-AEP. This may explain why Spn-LicC can accept the noncognate substrate (e.g. with two Mg 2+ bound), albeit with increased K M (Table 1) due to the limited interactions of the primary amine in the LicC choline-binding pocket. Overall, the molecular dynamics simulations provided further support for the influence of steric effects on enzyme selectivity.", "cite_spans": [], "ref_spans": [{"start": 378, "end": 386, "text": "(Fig. 5)", "ref_id": "FIGREF3"}, {"start": 1002, "end": 1011, "text": "(Fig. 5c)", "ref_id": "FIGREF3"}, {"start": 1786, "end": 1808, "text": "(Supplementary Fig. 16", "ref_id": "FIGREF4"}]}, {"section": "Results", "text": "Mechanistic insight from structural data. The crystal structures determined in apo form (PDB 6PD1) and in the presence of CTP and AEP (PDB 6PD2) provide additional mechanistic insight. Electron density outlines the CMP-AEP product (Fig. 6a) with partial density at the expected location of the pyrophosphate (PP i ) leaving group. This PP i pocket was also detected by the Roll algorithm in both Spn-LicC and TdePntC 46 (Fig. 5a, b) . The PP i site is defined by the first five residues of the GXG(T/S)RX 4-8 PK nucleotidyltransferase consensus sequence (boxed region, Supplementary Fig. 15 ) 32 , which provides stabilizing positive charge via backbone amide protons and the conserved residue Arg15. The terminal Lys25 of the consensus sequence is positioned to interact most strongly with the magnesium-coordinated \u03b1-phosphate of CTP, and alanine substitution of this highly conserved residue abolished cytidylyltransferase activity in the related enzymes FrbH (K38A) and YgbP (K27A) 48, 49 . Similar to the Spn-LicC structure, Lys25 appears positioned to accept additional negative charge arising during a pentacoordinate transition state, which would result from nucleophilic attack of AEP in an associative mechanism (Fig. 6b) . The partially conserved residue Lys153 may guide attack by interacting with phosphonate oxygen. This mechanistic trajectory was also proposed based on a similar crystallographic orientation of Lys27 in the MEP cytidylyltransferase YgbP 49 . Indeed, we observed markedly diminished activities (<10% of wildtype) when alanine was substituted at Arg15, Lys25, and Lys153 of Tde-PntC ( Supplementary Fig. 17 ), lending support to the mechanism proposed in Fig. 6b . Although detailed kinetic analysis was beyond the scope of this study, we expect that PntC enzymes will employ ordered sequential binding. Previous substrate and product inhibition analyses of Spn-LicC favored CTP as the leading substrate and CDP-Cho as the final product off the enzyme 29 , and initial CTP binding was concluded from pulse chase analysis of YgbP 49 .", "cite_spans": [{"start": 986, "end": 989, "text": "48,", "ref_id": "BIBREF47"}], "ref_spans": [{"start": 231, "end": 240, "text": "(Fig. 6a)", "ref_id": "FIGREF4"}, {"start": 420, "end": 432, "text": "(Fig. 5a, b)", "ref_id": "FIGREF3"}, {"start": 569, "end": 590, "text": "Supplementary Fig. 15", "ref_id": "FIGREF3"}, {"start": 1222, "end": 1231, "text": "(Fig. 6b)", "ref_id": "FIGREF4"}, {"start": 1686, "end": 1693, "text": "Fig. 6b", "ref_id": "FIGREF4"}]}, {"section": "Discussion", "text": "We have identified nucleotidyltransferase Pfam families in about two-thirds of phosphonate biosynthetic gene clusters. Surprisingly, about 60% of all Ppm enzymes are fused to one or both of two Pfams, with MobA-like NTP transferase (PF12804) as the most commonly fused domain. Only one member of this family was previously known to act on a phosphonate substrate; FrbH catalyzes cytidylyltransfer to L-2-amino-4-phosphonobutyrate during FR-900098 biosynthesis 48 . The other commonly fused domain is cytidylyltransferase-like (PF01467), which includes the PhpF phosphonoformate cytidylyltransferase functioning in phosphinothricin biosynthesis 50 and the Fom1 HEP cytidylyltransferase from the fosfomycin biosynthetic pathway 28 . In demonstrating AEP-specific cytidylyltransferase activity for two PF12804 enzymes, we have expanded the catalytic repertoire of this family to include phosphonyl tailoring cytidylyltransferases (PntCs) involved in putative cell surface tailoring pathways. Cytidylyl activation has been well documented in the biosynthesis of cell surface glycans and phospholipids, but is rare in natural product biosynthesis. Indeed, we are not aware of examples beyond small molecule phosphonates and the MEP pathway (e.g. YgbP of the IspD family) for terpenoid biosynthesis.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "In contrast, CMP-activated sialic, legionaminic, pseudaminic acids, as well as CMP-Kdo, exemplify common intermediates in cell surface glycan biosynthesis 38, 51 . Similarly, CMP-conjugates facilitate phospholipid biosynthesis, including CDP-diacylglycerol and the aforementioned CDP-choline 52, 53 . The significance of cytidylyltransferase-enrichment in phosphonate biosynthesis is unclear, but may simply reflect that most phosphonates occur on cell surface glycans and lipids.", "cite_spans": [{"start": 155, "end": 158, "text": "38,", "ref_id": "BIBREF37"}, {"start": 292, "end": 295, "text": "52,", "ref_id": "BIBREF51"}], "ref_spans": []}, {"section": "Discussion", "text": "We expect that PntC enzymes will activate a variety of phosphonates to furnish a mosaic of cell surface phosphonate chemistry. Identifying CMP-conjugates will enable discovery of new phosphonyl modifications and elucidation of their biological roles. Further examples of related chemical logic in biosynthetic pathways, such as AEP and the virulence factor P-Cho, will present opportunities to understand and manipulate enzyme selectivity for developing biocatalysts and selective antivirulence agents.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "General. CTP was purchased from Thermo Fisher Scientific (Mississauga, ON, Canada). Chelex 100 sodium form (50-100 mesh), AEP, P-Cho, and CDP-Cho were purchased from Sigma-Aldrich (Oakville, ON, Canada). P-Cho was treated with Chelex 100 resin as previously described prior to use in order to remove calcium, which inhibits the enzyme 32 . All other chemicals were used without further purification. DNA sequencing was performed at The Centre for Applied Genomics at the Hospital for Sick Children (Toronto, ON, Canada). HR-ESI-MS was performed at the Alberta Glycomics Centre (Edmonton, AB, Canada). HPLC analysis was performed using a Prominence LC-20AT system equipped with a diode array detector (Shimadzu, Kyoto, Japan). FPLC purifications were performed using an NGC\u2122 Chromatography System (Bio-Rad, Mississauga, ON). NMR spectra were recorded on an Agilent DD2 operating at 400 MHz for 1 H and 100 MHz for 13 C. A Varian Unity Inova operating at 121 MHz was used to record 31 P NMR spectra. 54, 55 . The GA (gathering) score thresholds were applied for determining matches, which is considered a reliable curated threshold for defining family membership 55 .", "cite_spans": [{"start": 998, "end": 1001, "text": "54,", "ref_id": "BIBREF53"}], "ref_spans": []}, {"section": "Methods", "text": "Retrieving Ppm and PntC homologs from HMMs. HMMs matching the retrieved Ppm and PntC mentioned above (for Ppm: PF13714; for PntC: PF12804, PF00483, PF01129) were used to scan collectively annotated protein sequences from the NCBI Refseq genome databases 56 of complete genomes (n = 8582), genome scaffolds (n = 41,568), and contigs (n = 60,795), using HMMscan. After potential homologs were thus identified, a Python script was written and used to narrow the results into homologs sharing alignment to at least one of the HMMs for PntC and the single HMM retrieved for Ppm. To improve accuracy of the search, results were filtered to ensure that only sequences with \u226560% alignment to the HMMs were included. Ppm homologs were further screened to ensure the presence of the conserved catalytic motif EDKXXXXXNS, which distinguishes PEP mutase from other members of the isocitrate lyase family 4 .", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "Inventory of Ppm fusion domains. Protein sequences were retrieved for all identified Ppm homologs from NCBI RefSeq genome databases and scanned for HMMs using the HMMER software suite to establish an inventory of fusion domains. The GA (gathering score) threshold was once again applied for determining family membership. A Perl script was applied to account for overlapping domains. In the case of overlapping domains, only the domain with the highest score was included in analysis. Results were also filtered with \u226560% alignment to the HMMs as described above.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "Distribution of distances between ppm and pntC genes. A Python script was written to calculate distances, in number of genes, between ppm and pntC homologs (after filtering for \u226560% HMM alignment and presence of Ppm motif) in complete, contig, and scaffold NCBI RefSeq genome databases. If multiple ppm or pntC were present in one genome/contig, only the closest distance was tabulated.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "To further limit the results to non-redundant genomes (one per species), the genome database was filtered using tri-nucleotide DNA signatures as reported previously 57 . The genomes were filtered at a distance delta = 0.03, which roughly corresponds to species.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "Sequence alignment and homology modeling. The following amino acid sequences were retrieved from NCBI and submitted to the Clustal Omega website for alignment: 58 Bfr-PntC from B. fragilis 638R (CBW22390); Tde-PntC from T. denticola ATCC 35405 (NP_992021); Cj1416 from Campylobacter jejuni (CAI38904); Oul-PntC from O. uli DSM 7084 (ADK67708); Ari-PntC from A. rimae ATCC 49626 (ZP_03568201); Spn-LicC from S. pneumoniae R36A (AAK94072); Hin-LicC from Haemophilus influenzae C486 (AJO89865). Homology models were generated via amino acid sequence submission to the I-TASSER server 59 . Protein pocket sizes were calculated using the Roll algorithm of the webbased POCASA program after deleting the CMP-conjugate ligand but not metal cofactor(s) 46 .", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "Molecular dynamics simulations. The crystal structures of 1JYL (chain D) and 6PD2 (focusing on the chain B active site of the BD dimer) were used with experimental coordinates for cognate substrates CDP-Cho and CMP-AEP, respectively. Non-cognate substrates (i.e. 1JYL:CMP-AEP and 6PD2:CDP-Cho) were built in PyMOL 60 . The Enlighten plugin for PyMOL was used to execute protocols using AmberTools14 software for ligand parameterization with GAFF 61 , hydrogen and solvent addition (PREP protocol), structure relaxation and minimization (STRUCT protocol), and molecular dynamics (MD at 300 K; DYNAM protocol) 62 . All simulated active site residues were in their standard protonation states; Tde1415 histidines within the solvated simulation sphere were protonated as follows: HIE57, HID186, HIE187, HIE197, and HIE226. For each of the four complexes, 10 independent 150 ps MD simulations were run using a 20 \u00c5 solvent shell surrounding P A atom (equivalent of CTP \u03b1-phosphate P) of the substrate. From the 1500 ps of simulation data for each complex, dihedral angles were measured every 1 ps using the cpptraj program included in AmberTools 63 . The simulation data was clustered using cpptraj (hierarchical agglomerative clustering on the RMSD of the substrate, with \u03b5 = 0.85 for all complexes except for Tde-PntC: P-Cho complex, which used \u03b5 = 1.1) to identify centroid conformations that were representative of most common conformations observed.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "Bacterial strains and media. Escherichia coli BL21(DE3) and E. coli DH5\u03b1 (Supplementary Table 2 ) from Life Technologies (Carlsbad, CA) were used for protein production and cloning, respectively, and were cultured in standard LB broth. The spn-licC gene was purchased from BioBasic Canada (Markham, ON) in the pET57 vector to include the N-terminal sequence MGSSH 6 SSGLVPRGSH prior to the N-terminal methionine residue and preserve the exact sequence of the previously characterized enzyme 29, 33 . The synthetic spn-licC gene was directly cloned as an NdeI/XhoI fragment into pET29 to afford pGH1000. The ari1348 gene was purchased codon-optimized for E. coli from BioBasic in the pET28a vector and subcloned as an NdeI/NotI fragment into pET29. The resulting pGH2000 expression construct is designed to generate C-terminal His 6 -tagged Ari-PntC protein.", "cite_spans": [{"start": 491, "end": 494, "text": "29,", "ref_id": "BIBREF28"}], "ref_spans": []}, {"section": "Methods", "text": "The tde1415 gene was purchased from BioBasic in pET28a and subcloned without its stop codon as a NdeI/NotI fragment into pET21b to afford pGH3000 for producing C-terminal histidine-tagged protein. RT-PCR analysis. Gene transcription was monitored with primers outlined in Supplementary Table 4 . RNA extraction from bacteria was performed using the Ribopure RNA isolation kit (Invitrogen, Carlsbad, CA). Any remaining genomic DNA that may have been carried through the RNA extraction process was removed with a 1 h DNaseI treatment step, which was included in the kit. Following RNA extraction and DNaseI treatment, a DNA-based PCR was always performed to detect undigested DNA. The lack of amplification products confirmed the absence of contaminating genomic DNA. RT-PCR was carried out using the OneStep RT-PCR kit (Qiagen) according to the manufacturer's recommendations. Briefly, each reaction setup consisted of 2 \u00b5l of dNTP mix (400 \u00b5M of each dNTP in a reaction), 0.6 \u00b5M of each primer, 2 \u00b5l of polymerase mix and 2 \u00b5l of specific RNA templates. The thermal cycling protocol was performed with the iCycler iQ multicolor realtime detection system (Bio-Rad, Hercules, CA) and contained an initial reverse transcription step of 50\u00b0C for 30 min followed by PCR activation at 95\u00b0C for 15 min. Subsequent steps in the protocol contained 40 cycles of amplification (94\u00b0C for 45 s, 55\u00b0C for 45 s, 72\u00b0C for 1 min) and a concluding step at 72\u00b0C for 10 min. Amplified products were analyzed on 1.8% (w/v) agarose gels stained with 0.5 \u00b5g/ml ethidium bromide and imaged with a VersaDocTM 4000 MP (BioRad).", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "Site-directed mutagenesis and analysis of mutants. Tde1415 enzyme variants R15A, K25A, and K153 were generated by overlap extension PCR mutagenesis using primers listed in Supplementary Table 4 . All mutants were verified by sequencing and proteins expressed in pET21b. Activity of enzyme variants was monitored by 31 P NMR after 2 h incubation at room temperature in 50 mM Tris-Cl pH 8.0 containing 7.0 mM CTP, 3 mM AEP, 10 \u00b5M Tde1415, and 7.0 mM of MgCl 2 . Phosphonoacetic acid at 6.0 mM was added as an internal standard immediately prior to 31 P NMR spectral acquisition.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "Protein production. Plasmids were transformed into E. coli BL21(DE3) and plated on the LB agar plates containing the appropriate antibiotic. Single colonies were picked into~5 ml and grown overnight at 37\u00b0C in LB supplemented with antibiotic, 1 ml of which was then transferred to 50 ml LB supplemented with antibiotic. After overnight growth at 37\u00b0C, 1 l batches of fresh LB were inoculated with 10 ml of the overnight culture and incubated at 37\u00b0C and 220 rpm. At OD 600~0 .5, cultures were cooled on ice to~18\u00b0C, supplemented with 0.1 mM IPTG, and then incubated overnight at 18\u00b0C. Cells were harvested by 15 min centrifugation at 4\u00b0C and 4000\u00d7g and subsequent steps were performed on ice. From 1 L of culture, the resulting pellet was resuspended in cell lysis buffer (50 ml, 0.73 M sucrose, 50 mM Tris-Cl, pH 8.0) and supplemented with 4 mM dithiothreitol (DTT, Amresco, Solon, OH). Egg white lysozyme (1 mg, Amresco) was added and stirred for 10 min, after which deoxycholate solution (50 ml) was added and the solution was using MWCO 3500 dialysis tubing, and then run over a HiTrap Q FF anion exchange column (GE Healthcare, Chicago, IL) attached to an NGC FPLC system (Bio-Rad, Hercules, CA). After isocratic flow in 50 mM Tris-Cl (pH 8.0) for 2.5 column volumes, a linear gradient from 0 to 700 mM NaCl was performed over 18 column volumes. Tde1415 eluted at~120 mM NaCl, and Ari1348 eluted at 250 mM NaCl, consistent with the respective predicted pI values of 5.7 and 5.0 as calculated using the ProtParam tool on the ExPASy web server 64 . Pooled FPLC fractions were concentrated to~2 ml by ultrafiltration using 10 kDa MWCO centrifugation filters (Pall Corporation, Port Washington, NY), then desalted into Tris-Cl pH 8.0 buffer using PD-10 columns (GE Healthcare). The desalted protein was concentrated to~200 \u00b5l by ultrafiltration, then either used immediately or frozen as beads in liquid nitrogen for storage at \u221280\u00b0C until further use.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "Protein analysis. Protein concentrations were estimated using the Bradford assay 65 , and purity was assessed using SDS-PAGE. Oligomeric structure was evaluated using size-exclusion chromatography and DLS. The former was performed on a Bio-Rad NGC FPLC system equipped with a Superdex 75 10/300 GL column from GE Healthcare, eluted using an isocratic flow (0.5 ml/min) of 50 mM Tris-Cl and 150 mM MgCl 2 at pH 8.0. DLS was performed on 20 \u00b5l of freshly purified protein (8 mg/ml) at 20\u00b0C using a DynaPro NanoStar (Wyatt Technology, Santa Barbara, CA).", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "HPLC enzyme assays. Reactions containing 50 nM enzyme, 1 mM of either AEP or P-Cho, 4 mM CTP, 7 mM MgCl 2 , and 50 mM Tris-Cl pH 7.8 were allowed to proceed for 30 min prior to quenching a 10 \u00b5l aliquot with an equal volume of cold methanol (containing 0.1% TFA). The quenched reaction was centrifuged for 5 min prior to injecting 1 \u00b5l on an HPLC equipped with a Luna NH2 column (3 \u00b5m, 100 \u00c5, 100 \u00d7 4.6 mm, Phenomenex, Torrance CA, USA) using an isocratic elution at 1 ml/min in a mobile phase of 20 mM ammonium acetate, pH 10.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "Aminotransferase activity assays. The AEPT activity was observed by combining 1.5 mM AEP, 6 mM pyruvate, 30 \u00b5M pyridoxal-5\u2032-phosphate (PLP) in 50 mM Tris-Cl buffer containing 50 mM MgCl 2 , pH 8.0. The reaction was initiated by adding 1 \u00b5M of Tde1415 enzyme, which was missing in the no-enzyme negative control. The reaction was either monitored directly via 31 P NMR as shown in Supplementary Fig. 11 or allowed to proceed at room temperature for 2 h prior to removal of enzyme by ultrafiltration using a Vivaspin 5000 Da MWCO membrane centrifugation device (Sartorius, Goettingen, Germany). Filtrate was stored frozen at \u221220\u00b0C prior to mass spectrometric analysis at the Mass Spectrometry Facility at the University of Guelph (Supplementary Fig. 12 ).", "cite_spans": [], "ref_spans": [{"start": 728, "end": 750, "text": "(Supplementary Fig. 12", "ref_id": "FIGREF0"}]}, {"section": "Methods", "text": "Metal use assays. 140 \u00b5l of 400 \u00b5M recombinant wildtype Tde1415 was diluted to a volume of 3.0 ml with 50 mM EDTA, 50 mM Tris-HCl, pH 8.0 buffer. The protein solution was applied to an Econo-Pac 10DG desalting column (Bio-Rad) and exchanged into 50 mM EDTA, 50 mM Tris-Cl, pH 8.0 buffer. The eluted protein was concentrated using a 5 kDa MWCO ultracentrifuge device (Sartorius) and then desalted a second time into 50 mM Tris-Cl, pH 8.0. The de-metalated protein was again concentrated to 2.0 ml by ultracentrifugation and stored at 4 o C. PntC activity was monitored by 31 P NMR after 2 h incubation at room temperature in 50 mM Tris-Cl pH 8.0 containing 7.0 mM CTP, 3 mM AEP, 5.5 \u00b5M Tde1415, and 7.0 mM of divalent metal (MgCl 2 , CaCl 2 , or ZnCl 2 ). Phosphonoacetic acid at 6.0 mM was added as an internal standard immediately prior to 31 P NMR spectral acquisition.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "Colorimetric coupled enzyme assays. The EnzCheck \u00ae Pyrophosphate Assay Kit (Molecular Probes, Inc., Eugene, OR, USA) was used to determine the activity of Spn-LicC, Ari-PntC, and Tde1415. Each reaction was kept to a total volume of 100 \u00b5l and performed in triplicate. The reaction components were split between two wells, one well contained the substrate and enzyme, while the other well contained CTP. Well 1 contained 0.5 \u00b5l (1U) PNP, 0.5 \u00b5l (0.03U) IPP, 10 \u00b5l (0.2 mM) MESG, 2.5 \u00b5l 20X reaction buffer, 16 \u00b5l (4 mM) CTP, and 20.5 \u00b5l of water, making a total of 50 \u00b5l. Well 2 contained 0.5 \u00b5l (1U) PNP, 0.5 \u00b5l (0.03U) IPP, 10 \u00b5l (0.2 mM) MESG, 2.5 \u00b5l 20X reaction buffer, 12 \u00b5l (7 mM) MgCl 2 , enzyme (variable), substrate (variable), and H 2 O to fill to a final volume of 50 \u00b5l. A control with either no enzyme or substrate was made for each trial. The separate wells were incubated for 30 min at room temperature. After 30 min, well 2 was combined to well 1, and absorbance was recorded every 30 s at 360 nm for 30 min. Initial velocities (<10% substrate turnover) for each substrate concentration were exported to Excel and Michaelis-Menten and substrate inhibition equations were fit by non-linear regression using the R software 66 .", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "Purification of CMP-AEP. 5 ml reactions containing 1 \u00b5M Ari-PntC, 1 mM of AEP, 2 mM CTP, 7 mM MgCl 2 , and 50 mM Tris-Cl pH 8 were allowed to proceed for 1 h at room temperature prior to removing the enzyme through centrifugation in a 5 kDa ultracentrifugation tube. The flow-through was injected on the FPLC over a 5 ml GE Hi-Trap\u2122 Q FF anion exchange column into the mobile phase A (25 mM ammonium bicarbonate pH 9) and eluted using a linear gradient of 0-70% mobile phase B (25 mM ammonium bicarbonate + 1 M NaCl pH 9). Peak fractions pertaining to the CMP-AEP product were collected and lyophilized to a dry solid.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "20-25 mg of the lyophilized product was dissolved into 600 \u00b5l of D 2 O before subsequent 1 H, 13 C, and 31 P experiments were performed. Phosphonoacetic acid was added as an internal standard for the 31 P experiments.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "Protein crystallization. Purified Tde1415 in 50 mM Tris-Cl, pH 8.0 and 240 mM NaCl, were concentrated to 20 mg/ml with and without presence of 5 mM CTP/5 mM AEP. Tde1415 was initially screened against commercially available sparce-matrix screens in a 1:1 ratio, 1 \u03bcL final volume using an ARI Crystal Gryphon (Art Robins Instruments). The microplates were sealed, incubated at 18 o C, and conditions in which crystal growth was observed were used to design hanging-drop vapor diffusion expansion crystal plates. The ligand-free structure was determined by crystals grown against a crystallization solution composed of 0.01 M nickel II chloride hexahydrate, 0.1 M Tris-Cl, pH 8.5, 1.0 M lithium sulfate monohydrate and cryoprotected with an equivalent solution supplemented with 30% (v/v) glycerol. The product complex was determined from a crystal grown against a crystallization solution composed of 0.2 M magnesium acetate tetrahydrate, 0.1 M sodium cacodylate trihydrate pH 6.5, 20% (w/v) polyethylene glycol 8000 cryoprotected with an equivalent solution supplemented with 30% (v/v) glycerol.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "X-ray data collection and processing. Protein crystals were retrieved, briefly introduced in cryoprotectant, and snap-frozen in liquid nitrogen. Data analysis was performed at the Advanced Photon Source (APS) at Argonne National Laboratory (Argonne, Illinois, Illinois & Michigan Canal State Trail, 9700 Cass Ave, Lemont, IL 60439, USA) and the Canadian Light Source (CLS) at the University of Saskatchewan (Saskatoon, Saskatchewan, Canadian Light Source Inc., 44 Innovation Boulevard, SK S7N 2V3, Canada). At the APS, X-ray diffraction data was collected at beamline 17-ID of the Argonne National Laboratory Synchrotron Facility. At the CLS, X-ray diffraction data was collected at beamline CLS-08-ID. In both cases images were collected using 0.25 oscillations at a temperature of 100 K and wavelength of 0.9795 nm. Data were indexed and scaled using AutoProcess in the space group P2 1 and data processed to 2.72 \u00c5 resolution. Note that while both datasets belong to the P2 1 space group, the unit cell dimensions were different. The \"apo\" structure of Tde1415 was solved via molecular replacement using the program PHASER 67 searching for four copies of PDB coordinates 1JYK 29 and 1VJO 37 which are the cytidyltransferase LicC from S. pneumoniae and an alanineglyoxylate aminotransferase from Anabaena [Nostoc.] sp. PCC 7120, respectively. Cycles of iterative model building, structure refinement, and density modification were performed with PHENIX 68 and were interspersed with inspection and manual building with COOT 69 . Restraints for CDP-Cho were generated via the Grade Web Server (http://grade.globalphasing.org). Ramachandran analysis of the apo structure revealed: 2288 (94.1%) torsion angles in the preferred region, 119 (4.9%) allowed, and 25 (1.0%) disallowed; for the Tde1415:CMP-AEP complex: 2325 (95.1%) preferred, 98 (4.0%) allowed, 21 (0.9%) disallowed.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "Reporting summary. 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Right: After filtering for the presence of the characteristic Ppm motif (EDKXXXXXNS), 26,231 presumed non-Ppm sequences were removed. Only 22 of these removed sequences were fused to other domains. b Summary of the remaining 1485 predicted Ppm proteins and inventory of fusion status: Ppm alone (red, 40.5%); PF12804, MobA-like NTP transferase (NTP_transf_3; gray, 32.9%); PF01467, Cytidylyltransferase-like (CTP_transf_like; orange, 23.6%); not visible are two genes matching PF02775 and PF02776 (both TPP-binding domains), which corresponds to 0.1% of non-redundant Ppm proteins. The blue slice represents 42 triple fusion proteins (2.8% of all Ppm proteins) with Ppm fused to both PF12804 and PF01467. c Distribution of genomic distances (in genes) between ppm and the nearest of either PF12804 or PF01467. Blue dots represent logarithm of the number of genes counted for each distance (corresponding to left y-axis), and the line represents the cumulative fraction of genomic distances (right y-axis); 59.3% of nearest nucleotidyltransferase genes (those closest to ppm) are fused to ppm (distance = 0), and only single counts occur at distances greater than~350 genes. Inset: Number of genes for each distance up to 20, illustrating that two-thirds of nucleotidyltransferase genes are within~5 genes of ppm", "type": "figure"}, "FIGREF1": {"text": "Fig. 3 Bacterial cell surface modifications employing cytidylyl activation. a Proposed phosphonyl tailoring (Pnt) pathway logic based on its similarity to b the lipopolysaccharide core (Lic) pathway. c Putative gene clusters for three oral anaerobes under study, highlighting relevant genes for phosphocholine (P-Cho) and phosphonate tailoring. Black-colored genes are proposed to encode phosphonate-tailoring cytidyltransferases (PntCs) when located near ppm genes (red), and P-Cho cytidyltransferases (LicC) when located near other lic genes (e.g. those encoding LicA shown in yellow). For clarity, annotations for uncolored genes are not included", "type": "figure"}, "FIGREF2": {"text": "Fig. 4 HPLC chromatograms of reactions catalyzed by Spn-LicC and Ari-PntC (Ari1348). a Time-resolved reaction of CTP (open circle) with: I, P-Cho and Spn-LicC to make CDP-Cho (filled circle), and II, AEP and Ari-PntC to generate CMP-AEP (open square). b Spn-LicC more readily produces CDP-Cho (panel II) than CMP-AEP (panel III); in contrast, Ari-PntC preferentially generates CMP-AEP (panel IV) compared to CDP-Cho (panel V) after 30 min of reaction time. All reactions contained 50 nM enzyme, 1 mM of either AEP or P-Cho, 4 mM CTP, and 7 mM MgCl 2 in 50 mM Tris-Cl, pH 8.0", "type": "figure"}, "FIGREF3": {"text": "Fig. 5 Molecular dynamics simulations of Tde-PntC (top) and Spn-LicC (bottom). a Representative conformations of the Tde-PntC active site with cognate ligand CMP-AEP and Mg 2+ ions colored teal; non-cognate ligand CDP-Cho and Mg 2+ ions are magenta. The transparent gray surface representation denotes the 287 \u00c5 3 cavity calculated from the crystal structure (minus CMP-AEP) using the Roll algorithm of POCASA 42 . b Representative conformations of the Spn-LicC active site showing the cognate ligand CDP-Cho and Mg 2+ ion colored magenta; non-cognate ligand CMP-AEP and Mg 2+ are colored teal. Transparent gray surface outlines the 381 \u00c5 3 cavity calculated from the 1JYL crystal structure coordinates after removing CDP-Cho (26). c Histogram of C4\u2032-C5\u2032-O5\u2032-PA dihedral angles sampled during 10 \u00d7 150 ps independent simulations for each protein:ligand pair, using the same color scheme for each ligand (CMP-AEP = teal; CDP-Cho = magenta). Dotted lines represent crystallographically observed dihedral angles", "type": "figure"}, "FIGREF4": {"text": "Fig. 6 Proposed mechanism of PntC. a CMP-AEP electron density (gray mesh: Fo-Fc omit map contoured at 3.5 sigma; blue mesh: 2Fo-Fc map contoured at 5.0 sigma highlighting the heavier Mg and P atoms) for the Tde-PntC:CMP-AEP complex. b Mechanistic interpretation of the crystallographic data. The proposed ternary complex structure (top) with extensive interactions stabilizing the PPi leaving group of CTP (blue). Nucleophilic attack of AEP (teal) generates a pentacoordinate phosphate intermediate or transition state possessing additional negative charge stabilized by Lys25 (middle). In the absence of obvious candidate general base residues, we propose that active site pK a perturbations may result in the deprotonated AEP substrate shown. Loss of PPi generates the CMP-AEP product bound in the active site (bottom) as seen in the crystal structure in a", "type": "figure"}, "FIGREF5": {"text": "stirred until it became viscous (~10 min). The deoxycholate solution contained 24 mM deoxycholate sodium salt (BioBasic, Markham, ON), 0.5% v/v Triton X-100 (BioBasic), 20 mM Tris-Cl, pH 8.0, 0.3 M NaCl. A solution of 1 M MgCl 2 (500 \u00b5l) was added together with deoxyribonuclease I from bovine pancreas (Sigma- Aldrich) and stirred at room temperature until the solution became less viscous. The solution was then centrifuged at high speed (14,000\u00d7g) for 20 min at 4\u00b0C to afford clarified supernatant raw extract. Protein purification. To each 50 ml of raw extract was added 2 ml of Ni-NTA agarose affinity resin (QIAGEN, Hilden, Germany) and gently shaken at 4\u00b0C and 120 rpm for 40 min. The resin was then washed and eluted with 20 and 250 mM imidazole, respectively, in 50 mM Tris-Cl buffer pH 8.0 containing 300 mM NaCl. Eluted protein (10 ml) was dialyzed overnight at 4\u00b0C in 50 mM Tris-Cl,| (2019) 10:3698 | https://doi.org/10.1038/s41467-019-11627-6 | www.nature.com/naturecommunications", "type": "figure"}, "TABREF0": {"text": "in what represents an unu- sual and potentially distinguishing feature of the Ppm enzyme family. Indeed, only 40.5% of Ppm enzymes were 'stand-alone' proteins not fused to any other domain, and most Ppm enzymes", "type": "table"}, "TABREF1": {"text": "a Left: 27,716 non-redundant Ppm protein sequences were identified in NCBI's refSeq prokaryotic genome database that matched the PF13714 HMM, of which 905 were fused to other domains. Right: After filtering for the presence of the characteristic Ppm motif (EDKXXXXXNS), 26,231 presumed non-Ppm sequences were removed. Only 22 of these removed sequences were fused to other domains. b Summary of the remaining 1485 predicted Ppm proteins and inventory of fusion status:8% of all Ppm proteins) with Ppm fused to both PF12804 and PF01467. c Distribution of genomic distances (in genes) between ppm and the nearest of either PF12804 or PF01467. Blue dots represent logarithm of the number of genes counted for each distance (corresponding to left y-axis), and the line represents the cumulative fraction of genomic distances (right y-axis); 59.3% of nearest nucleotidyltransferase genes (those closest to ppm) are fused to ppm (distance = 0), and only single counts occur at distances greater than~350 genes.", "type": "table"}, "TABREF2": {"text": "Steady-state kinetic constants of cytidylyltransferases aPEtn phosphoethanolamine a Standard errors are included for data generated in this work b Ratio of specificity constants (k cat /K M ) for ChoP:AEP (or PEtn) c Substrate inhibition observed with K S = 4 \u00b1 1 mM d Substrate inhibition observed with K S = 6.4 \u00b1 0.9 mM e ND, not determined due to low activity", "type": "table"}, "TABREF3": {"text": "). Nucleophilic attack of AEP (teal) generates a pentacoordinate phosphate intermediate or transition state possessing additional negative charge stabilized by Lys25 (middle). In the absence of obvious candidate general base residues, we propose that active site pK a perturbations may result in the deprotonated AEP substrate shown. Loss of PPi generates the CMP-AEP product bound in the active site (bottom) as seen in the crystal structure in a", "type": "table"}}}
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{"paper_id": "199668868", "_pdf_hash": "0b492ed474f1e659583b3f9b70861dedbd072c01", "abstract": [{"section": "Abstract", "text": "Abstract. We investigate the Jordan-H\u00f6lder property (JHP) in exact categories. First we introduce a new invariant of exact categories, the Grothendieck monoids, and show that (JHP) holds if and only if the Grothendieck monoid is free. Moreover, we give a criterion for this which only uses the Grothendieck group and the number of simple objects. Next we apply these results to the representation theory of artin algebras. For a large class of exact categories including functorially finite torsion(-free) classes, (JHP) holds precisely when the number of projectives is equal to that of simples. We study torsion-free classes in type A quiver in detail using the combinatorics of symmetric groups. In particular, we show that simples correspond to Bruhat inversions of a c-sortable element, and give the combinatorial criterion for (JHP).", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "To begin with, let us recall the Jordan-H\u00f6lder theorem for modules. This classical theorem says that the ways in which M can be built up from simple modules are essentially unique.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Theorem (the Jordan-H\u00f6lder theorem). Let \u039b be a ring and M a \u039b-module of finite length. Then every composition series of M are equivalent. In particular, composition factors of M together with their multiplicities are uniquely determined by M .", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Let us express this situation as follows: the category of \u039b-modules of finite length satisfies the Jordan-H\u00f6lder property, abbreviated by (JHP). The aim of this paper is to investigate to what extent this property is valid for various settings, especially those arising in the representation theory of algebras. It is known that an abelian category satisfies (JHP) if every object has finite length (e.g. [St, p.92] ), so the abelian case is rather trivial. In this paper, we study (JHP) in the context of Quillen's exact categories, which generalize abelian categories and serve as a useful categorical framework for studying various subcategories of module categories.", "cite_spans": [{"start": 405, "end": 409, "text": "[St,", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "", "text": "As in the case of module categories, we can define a poset of admissible subobjects of an object of an exact category, and classical notions like simple objects, composition series and (JHP) make sense in this setting (see Section 2). Typical examples of exact categories are extension-closed subcategories of mod \u039b for an artin algebra \u039b, and in this case, all objects have at least one composition series. However, it turns out that there exist many categories which do not satisfy (JHP), as well as those which do. Here are some examples (we refer to Section 8.2 for more examples).", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Example A (c.f. [BHLR, Example 6.9] ). Let k be a field and define E as the category of finitedimensional k-vector spaces whose dimensions are not equal to 1. Then obviously E is closed under extensions in mod k, thus an exact category, and k 2 and k 3 are simple objects in E. However, we have the following two different decompositions of k 6 into these simples:", "cite_spans": [{"start": 16, "end": 22, "text": "[BHLR,", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "", "text": "Thus composition series (and lengths) are not unique.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "The next examples are torsion-free classes of a module category, which have been studied in the representation theory of algebras. See Section 6 for the detailed explanation of this example.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Example B (c.f. Example 6.17 (1)). Let Q be a quiver 1 \u2192 2 \u2190 3 and consider the path algebra kQ. Then the Auslander-Reiten quiver of mod kQ is given as follows:", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Consider the subcategory E 1 := add{S 2 , P 1 , P 3 , I 2 , S 3 } of mod \u039b, which corresponds to the light gray region. Then it is checked that S 2 , P 1 , S 3 are simples of E 1 , and E 1 satisfies (JHP). For example, P 3 decomposes into S 2 and S 3 , and I 2 decomposes into P 1 and S 3 .", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "On the other hand, consider E 2 := add{S 2 , P 1 , P 3 , I 2 }, which corresponds to the dark gray region. Then (JHP) fails in E 2 : in fact, all four indecomposables are simple in E 2 , but we have two exact sequences 0 \u2192 P 1 \u2192 P 1 \u2295 P 3 \u2192 P 3 \u2192 0 (a split sequence), and 0 \u2192 S 2 \u2192 P 1 \u2295 P 3 \u2192 I 2 \u2192 0 (an almost split sequence), which implies that P 1 \u2295 P 3 has two different decomposition: one into P 1 and P 3 and the other into S 2 and I 2 . Thus composition factors of P 1 \u2295 P 3 are not unique.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "To explorer (JHP), we introduce a new invariant of exact categories, a Grothendieck monoid. First let us make some observation on the Grothendieck group K 0 (E) of E. If E satisfies (JHP), then we can easily check that K 0 (E) is a free abelian group, since simple objects form a free basis of K 0 (E) by (JHP). Thus (JHP) implies the freeness of K 0 (E). However, the converse is not true:", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "3 holds for i = 1, 2 in Example B but (JHP) fails in E 2 . Therefore, we need a more sophisticated invariant of exact categories than Grothendieck groups. To this purpose, we propose to study Grothendieck monoid M(E) of an exact category E, which is a monoid defined by the same universal property as the Grothendieck group. In the representation theory of algebras, this monoid is closely related to the monoid of dimension vectors (see Corollary 5.9).", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "By using this monoid, we obtain the following simple characterization of (JHP):", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Theorem C (= Theorem 4.12). Let E be a skeletally small exact category. Then the following are equivalent:", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "(1) E satisfies (JHP).", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "(2) M(E) is a free monoid.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "(3) K 0 (E) is a free abelian group, and the images of non-isomorphic simple objects in K 0 (E) form a basis of K 0 (E).", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "The computation of M(E) is rather hard compared to K 0 (E), and the following gives easier criterion for (JHP) which can be useful in actual situations.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Theorem D (= Theorem 4.13). Let E be a skeletally small exact category. Suppose that K 0 (E) is finitely generated. Then the following are equivalent:", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "(1) E satisfies (JHP).", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "(2) K 0 (E) is a free abelian group, and rank K 0 (E) is equal to the number of non-isomorphic simple objects in E.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "We apply these results to the context of the representation theory of artin algebras. In many cases, the Grothendieck group turns out to be free of finite rank, whose rank is equal to the number of non-isomorphic indecomposable projective objects (Proposition 5.8) . Thus Theorem D tells us that all we have to do to check (JHP) is to count the number of simple objects in E, and then to compare it to that of projectives. In particular, we can give a criterion whether a functorially finite torsion(-free) class satisfies (JHP) using the language of \u03c4 -tilting theory (Corollary 5.15) . As an easy application of this theorem, we show the following result on Nakayama algebras.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Corollary E (= Corollary 5.19). Let \u039b be a Nakayama algebra. Then every torsion-free class of mod \u039b satisfies (JHP).", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Finally, we discuss simple objects in torsion-free classes of the category mod kQ for a type A quiver Q. Torsion-free classes of mod kQ are classified in [IT, AIRT, Tho] : they are in bijection with c Q -sortable elements in the symmetric group S n+1 . Let F (w) be the torsion-free class of mod kQ corresponding to a c Q -sortable element w. Then it is natural to expect that we can describe simples in F (w) and the validity of (JHP) by using the combinatorics of S n+1 . We obtain the following result along this line.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Theorem F (= Theorem 6.14, Corollary 6.15). Let Q be a quiver of type A n and w \u2208 S n+1 a c Q -sortable element. Consider the corresponding torsion-free class F (w) of mod kQ. Then we have the following:", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "(1) Simple objects in F (w) are in bijection with Bruhat inversions of w.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "(2) F (w) satisfies (JHP) if and only if the number of supports of w is equal to that of Bruhat inversions of w.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Here Bruhat inversions are inversions of w which give rise to covering relations in the Bruhat order of S n+1 (see Definition 6.2). In a forthcoming paper [Eno3] , it will be shown that this holds for other Dynkin types (see Remark 6.19).", "cite_spans": [{"start": 155, "end": 161, "text": "[Eno3]", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "", "text": "1.1. Organization. This paper is divided into two parts and an appendix. In Part 1, we develop the general theory of posets of admissible subobjects, (JHP) and Grothendieck monoids of exact categories. In Part 2, we apply results in Part 1 to the representation theory of artin algebras, and give some examples of computations. In Appendix A, we collect basic properties on monoids which we need in the body part.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "The content of each section is as follows. In Section 2, we study posets of admissible subobjects of objects in exact categories, and give several basic definitions which we use throughout this paper, such as (JHP). In the latter part of Section 2, we give some categorical conditions which ensure that subobject posets are (modular) lattices. In Section 3, we define the Grothendieck monoid of an exact category, and study its basic properties as a monoid. In Section 4, we give characterizations of (JHP) in terms of Grothendieck monoids or groups (Theorems C and D) .", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "In Section 5, we apply the general results to the representation theory of artin algebras. We mainly consider good extension-closed subcategories of module categories (see Assumption 5.6), and study (JHP) for this class of categories. In Section 6, we consider torsion-free classes of mod kQ where Q is a type A quiver and prove Theorem F. In Section 7, we give examples of computations of the Grothendieck monoids. In Section 8, we collect counter-examples on various conditions which we have investigated. In Section 9, some open problems are discussed.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "1.2. Conventions and notation. Throughout this paper, we assume that all categories are skeletally small, that is, the isomorphism classes of objects form a set. In addition, all subcategories are assumed to be full and closed under isomorphisms. For a category E, we denote by Iso E the set of all isomorphism classes of objects in E. For an object X in E, the isomorphism class of X is denoted by [X] \u2208 Iso E.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "For a set of object C of an additive category E, we denote by add C the subcategory of E consisting of direct summands of finite direct sums of objects in C.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "For a Krull-Schmidt category E, we denote by ind E the set of isomorphism classes of indecomposable objects in E. We denote by |X| the number of non-isomorphic indecomposable direct summands of X.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "By a module we always mean right modules unless otherwise stated. For a noetherian ring \u039b, we denote by mod \u039b (resp. by proj \u039b) the category of finitely generated right \u039b-modules (resp. finitely generated projective right \u039b-modules).", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "As for exact categories, we use the terminologies inflations, deflations and conflations. We refer the reader to [B\u00fch] for the basics of exact categories. For an inflation A X in an exact category, we denote by X \u0589 X/A the cokernel of A X. We say that an exact category E has a progenerator P (resp. an injective cogenerator I) if P is projective (resp. I is injective) and every objects in E admits a deflation from a finite direct sum of P (resp. an inflation into a finite direct sum of I). For a Krull-Schmidt exact category E, we denote by P(E) (resp. I(E)) the category consisting of all projective (resp. injective) objects in E.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Let A be an abelian category and E a subcategory of A. We say that E is extension-closed if for every short exact sequence 0 \u2192 X \u2192 Y \u2192 Z \u2192 0 in A, we have that Y belongs to E whenever both X and Z belong to E. In such a case, unless otherwise stated, we regard E as an exact category with the natural exact structure, namely, conflations are precisely short exact sequences of A whose terms all belong to E.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "For a poset P and two elements a, b \u2208 P with a \u2264 b, we denote by [a, b] the interval poset [a, b] := {x \u2208 P | a \u2264 x \u2264 b} with the obvious partial order.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "By a monoid M we mean a commutative semigroup with a unit, and we always use an additive notation: the operation is denoted by +, and the unit of addition is always denoted by 0. A homomorphism between monoids is a map which preserves the addition and 0.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "We denote by N the monoid of non-negative integers: N = {0, 1, 2, \u00b7 \u00b7 \u00b7 } with the addition +.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "For a set A, we denote by #A the cardinality of A.", "cite_spans": [], "ref_spans": []}, {"section": "Part 1. General theory", "text": "In this part, we develop the general theory of posets of admissible subobjects, (JHP) and Grothendieck monoids of exact categories.", "cite_spans": [], "ref_spans": []}, {"section": "Posets of admissible subobjects", "text": "To study the Jordan-H\u00f6lder property (JHP) on exact categories, one has to define what (JHP) exactly means, which we will do in this section. The contents of this section are natural generalizations of the corresponding ones in module categories or abelian categories.", "cite_spans": [], "ref_spans": []}, {"section": "Posets of admissible subobjects", "text": "2.1. Basic properties. First we collect some basic definitions on the poset of admissible subobjects, which we use throughout this paper.", "cite_spans": [], "ref_spans": []}, {"section": "Posets of admissible subobjects", "text": "Definition 2.1. Let E be a skeletally small exact category and X an object of E.", "cite_spans": [], "ref_spans": []}, {"section": "Posets of admissible subobjects", "text": "\u2022 We call an inflation A X an admissible subobject of X. We often call A an admissible subobject of X in this case.", "cite_spans": [], "ref_spans": []}, {"section": "Posets of admissible subobjects", "text": "\u2022 Two subobjects A, B of X are called equivalent if there exists an isomorphism A \u223c \u2212 \u2192 B which makes the following diagram commutes:", "cite_spans": [], "ref_spans": []}, {"section": "Posets of admissible subobjects", "text": "We denote by P(X) the equivalence class of admissible subobjects of X. When we would like to emphasize the ambient category E, we write P E (X).", "cite_spans": [], "ref_spans": []}, {"section": "Posets of admissible subobjects", "text": "\u2022 We define a partial order on P(X) as follows: We write A \u2264 B for A, B \u2208 P(X) if there exists an inflation A B which makes the following diagram commutes:", "cite_spans": [], "ref_spans": []}, {"section": "Posets of admissible subobjects", "text": "It is easily checked that this relation actually gives a partial order on P(X).", "cite_spans": [], "ref_spans": []}, {"section": "Posets of admissible subobjects", "text": "We remark that P(X) always has the greatest element X and the smallest element 0.", "cite_spans": [], "ref_spans": []}, {"section": "Posets of admissible subobjects", "text": "Example 2.2. Let A be an abelian category and E an extension-closed subcategory of A. Then for an object X \u2208 E, we have that", "cite_spans": [], "ref_spans": []}, {"section": "Posets of admissible subobjects", "text": "In other words, a usual subobject A of X with A \u2208 E is admissible precisely when X/A \u2208 E holds.", "cite_spans": [], "ref_spans": []}, {"section": "Posets of admissible subobjects", "text": "Although we assume that there exists an inflation A B in order to have A \u2264 B, if E is weakly idempotent complete, then this condition is not necessary. We refer to [B\u00fch, Section 7] for weakly idempotent completeness. Lemma 2.3. Let E be an exact category which is weakly idempotent complete. Then for an object X and two subobjects A, B \u2208 P(X) of X, the following are equivalent:", "cite_spans": [{"start": 164, "end": 169, "text": "[B\u00fch,", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Posets of admissible subobjects", "text": "(1) A \u2264 B holds in P(X).", "cite_spans": [], "ref_spans": []}, {"section": "Posets of admissible subobjects", "text": "(2) There exists a morphism \u03d5 : A \u2192 B which makes the following diagram commutes:", "cite_spans": [], "ref_spans": []}, {"section": "Posets of admissible subobjects", "text": "(2) \u21d2 (1): It is enough to check that \u03d5 is an inflation. This follows from that \u03b9\u03d5 is an inflation and E is weakly idempotent complete, see [B\u00fch, Proposition 7 .6] for example.", "cite_spans": [{"start": 140, "end": 145, "text": "[B\u00fch,", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Posets of admissible subobjects", "text": "Example 2.4. Let A be an abelian category and E an extension-closed subcategory of A. Suppose that E is closed under direct summands, that is, if A \u2295 B belongs to E then so do A and B. Then E is idempotent complete, thus weakly idempotent complete. Many important exact categories investigated in the representation theory of algebras arise in this way.", "cite_spans": [], "ref_spans": []}, {"section": "Posets of admissible subobjects", "text": "The next proposition ensures that for any interval [A, B] in P(X), we have an isomorphism of posets [A, B] \u223c = P(B/A), as in the case of abelian categories.", "cite_spans": [], "ref_spans": []}, {"section": "Posets of admissible subobjects", "text": "Proposition 2.5. Let E be an exact category and X an object of E. Then the following hold, where all the intervals are considered in P(X).", "cite_spans": [], "ref_spans": []}, {"section": "Posets of admissible subobjects", "text": "(1) For a subobject A \u2208 P(X) of X, we have an isomorphism of posets [0, A] \u223c = P(A).", "cite_spans": [], "ref_spans": []}, {"section": "Posets of admissible subobjects", "text": "(2) For a subobject A \u2208 P(X) of X, we have an isomorphism of posets (\u2212)/A : [A, X] \u223c = P(X/A). Moreover, X/B \u223c = (X/A)/(B/A) holds for any B in [A, X]. (3) For two subobjects A, B \u2208 P(X) with A \u2264 B, we have an isomorphism of posets (\u2212)/A :", "cite_spans": [], "ref_spans": []}, {"section": "Posets of admissible subobjects", "text": "[A, B] \u223c = P(B/A). Moreover, for any X 1 , X 2 in P(X) with A \u2264 X 1 \u2264 X 2 \u2264 B, we have that", "cite_spans": [], "ref_spans": []}, {"section": "Posets of admissible subobjects", "text": ", there is an inflation B A since B \u2264 A holds. Thus B \u2208 P(A) holds. On the other hand, let B \u2208 P(A). Then we have an inflation B A. Since inflations are closed under compositions, it follows that the composition B A X is an inflation, hence B is a subobject of X. Consequently we have B \u2208 P(X), and clearly B \u2208 [0, A] holds. These assignments are easily shown to be mutually inverse isomorphisms of posets between [0, A] and P(A).", "cite_spans": [], "ref_spans": []}, {"section": "Posets of admissible subobjects", "text": "(2) For an element B \u2208 [A, X], we have inflations A B X. Then we obtain the following commutative diagram", "cite_spans": [], "ref_spans": []}, {"section": "Posets of admissible subobjects", "text": "in E (see [B\u00fch, Lemma 3.5] ). Thus the assignment B \u2192 B/A gives a morphism of poset (\u2212)/A : [A, X] \u2192 P(X/A). Moreover, by the above sequence, X/B \u223c = (X/A)/(B/A) holds.", "cite_spans": [{"start": 10, "end": 15, "text": "[B\u00fch,", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Posets of admissible subobjects", "text": "Conversely, let M X/A a subobject of X/A. By taking the pullback of X \u0589 X/A along M X/A, we obtain the following diagram", "cite_spans": [], "ref_spans": []}, {"section": "Posets of admissible subobjects", "text": "in E where all rows and columns are conflations (see [B\u00fch, Proposition 2.15] ). Since A \u2264 B holds in P(X), the assignment M \u2192 B gives a morphism of poset P(X/A) \u2192 [A, X]. These maps are easily seen to be mutually inverse to each other. (3) This follows from (1) and (2), since we have the following chain of isomorphisms of posets", "cite_spans": [{"start": 53, "end": 58, "text": "[B\u00fch,", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Posets of admissible subobjects", "text": "where the middle interval is considered in P(B) and the two right intervals are considered in P(A).", "cite_spans": [], "ref_spans": []}, {"section": "Posets of admissible subobjects", "text": "Now we introduce simple objects in exact categories, that is, objects which cannot be decomposed into small pieces with respect to conflations. This objects plays a central role throughout this paper, and to determine simple objects in a given exact category is an essential (and difficult) task when we check (JHP).", "cite_spans": [], "ref_spans": []}, {"section": "Posets of admissible subobjects", "text": "Definition 2.6. Let E be an exact category and X an object of X. We say that X is simple if the poset P(X) of admissible subobjects of X has exactly two distinct elements 0 and X. This is equivalent to that X is not zero and there is no conflation of the form L X \u0589 N in E with L, N = 0. We denote by sim E the set of isomorphism classes of simple objects in E.", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "In module categories, submodule series (a chain of submodules) serves as a basic tool when we consider composition series and the Jordan-H\u00f6lder theorem. It is natural to introduce the corresponding notion, inflation series, in the context of exact categories. Here are the definitions of it and related notions, including (JHP).", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "First recall some notions from poset theory. A chain of a poset P is a totally ordered subset of P . A chain T of P is called maximal if there exists no chain of P which properly contains T . A chain T is called finite if T is a finite set. Such a chain is of the form x 0 < x 1 < \u00b7 \u00b7 \u00b7 < x n , and we say that this chain has length n in this case.", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "Let E be a skeletally small exact category.", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "\u2022 For X in E, an inflation series of X is a finite sequence of inflations 0 = X 0 X 1 \u00b7 \u00b7 \u00b7 X n = X. We often identify it with a weakly increasing sequence 0 = X 0 \u2264 X 1 \u2264 \u00b7 \u00b7 \u00b7 \u2264 X n = X in P(X).", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "\u2022 We say that an inflation series 0 = X 0 X 1 \u00b7 \u00b7 \u00b7 X n = X of X is a proper inflation series if none of X i X i+1 is an isomorphism, or equivalently, X 0 < X 1 < \u00b7 \u00b7 \u00b7 < X n holds in P(X). In this case, we say that this inflation series has length n. We often identify proper inflation series with finite chains of P(X) which contain 0 and X.", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "\u2022 Let X and Y be objects in E, and let 0 = X 0 X 1 \u00b7 \u00b7 \u00b7 X n = X and 0 = Y 0 Y 1 \u00b7 \u00b7 \u00b7 Y m = Y be two inflation series of X and Y respectively. Then these inflation series are called isomorphic if m = n and there exists a permutation \u03c3 of the set {1, 2, \u00b7 \u00b7 \u00b7 n} such that X i /X i\u22121 and Y \u03c3(i) /Y \u03c3(i)\u22121 are isomorphic in E for all i. In this case, we say that X and Y have isomorphic inflation series.", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "\u2022 An inflation series 0 = X 0 X 1 \u00b7 \u00b7 \u00b7 X n = X of X is called a composition series if X 0 < X 1 < \u00b7 \u00b7 \u00b7 < X n is a maximal chain in P(X), or equivalently, each quotient X i /X i\u22121 is a simple object for all i (this follows from Proposition 2.5). We often identify composition series with finite maximal chains of P(X).", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "\u2022 E is called a length exact category if every object X in E, the set of lengths of proper inflation series of X has an upper bound, or equivalently, the set of lengths of finite chains of P(X) has an upper bound.", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "\u2022 A length exact category E satisfies the unique length property if any composition series of X have the same length for every object X in E.", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "\u2022 A length exact category E satisfies the Jordan-H\u00f6lder property, abbreviated by (JHP), if any composition series of X are isomorphic to each other for every object X in E. First we prove some properties of length exact categories which easily follow from definitions. Actually the proof only uses the general theory of posets.", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "Proposition 2.7. For a length exact category E and an object X in E, the following holds:", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "(1) Every chain of P(X) is finite.", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "(2) Composition series of X are precisely maximal chains of P(X).", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "(3) Every proper inflation series of X can be refined to a composition series.", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "(4) X has at least one composition series.", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "Proof.", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "(1) Suppose that P(X) has a chain T consisting of infinitely many elements. Then by choosing a finite subset of T , we can obtain a finite chain of P(X) with an arbitrary large length, which is a contradiction.", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "(2) This follows from (1) and the definition of compositions series.", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "(3) Suppose that a proper chain 0 = X 0 < X 1 < \u00b7 \u00b7 \u00b7 < X n = X of P(X) is given. If this chain is maximal, then we have nothing to do. Suppose that this is not the case. If [X i\u22121 , X i ] = {X i\u22121 , X i } for every i, then this chain is clearly maximal. Thus there exist some i and Y \u2208 P(X) with X i\u22121 < Y < X i . Consequently, we obtain a chain X 0 < X 1 < \u00b7 \u00b7 \u00b7 < X i\u22121 < Y < X i < \u00b7 \u00b7 \u00b7 < X n of P(X) with length n + 1, which is a refinement of the original chain. By iterating this process, we will eventually obtain a finite maximal chain, since lengths of finite chains of P(X) have an upper bound.", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "(4) We may assume that X = 0. Then (4) follows by applying (3) to a chain 0 < X of P(X).", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "Remark 2.8. Let E be an exact category and suppose that for every X \u2208 E there exists at least one composition series of X. Even so, E may not be a length exact category, since lengths of finite chains of P(X) may be arbitrary large (unfortunately the author does not know such an example). However, if E is an abelian category (or more generally, an exact category such that every subobject poset is a modular lattice), then E is a length exact category. This follows from Theorem 2.17.", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "By definition, (JHP) implies the unique length property for length exact categories. For concrete (counter-)examples concerning (JHP) and the unique length property, we refer the reader to Section 8.2.", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "In the remaining part of this section, we give a sufficient condition for the unique length property by using the theory of modular lattices.", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "2.3. Quasi-abelian implies lattice. Recall that a lattice L is a poset such that for every two elements a, b \u2208 L, there exist the meet a \u2227 b, the greatest lower bound, and the join a \u2228 b, the least upper bound. In abelian categories, it is classical that the subobject poset P(X) is always a lattice by considering sum and intersection of subobjects. However, this does not hold in general, even if we consider pre-abelian categories (see Examples 8.1 and 8.2). In this subsection, we will show that P(X) is a lattice when we consider torsion(-free) classes of abelian categories, or more generally, quasi-abelian categories.", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "First we recall the definition of quasi-abelian categories.", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "Definition 2.9. Let E be an additive category.", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "(1) E is pre-abelian if every morphism in E has a kernel and a cokernel. It is well-known that pre-abelian category has all pullbacks and pushouts. (2) A pre-abelian category E is quasi-abelian if the class of kernel morphisms is closed under pushouts and the class of cokernel morphisms is closed under pullbacks.", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "Quasi-abelian categories in the above sense are sometimes called almost abelian [Rum1, Rum2] , or semi-abelian [Ra\u020b] . See Historical remark in [Rum3, Section 2] for the somewhat involved history of quasi-abelian categories.", "cite_spans": [{"start": 80, "end": 86, "text": "[Rum1,", "ref_id": "BIBREF31"}, {"start": 87, "end": 92, "text": "Rum2]", "ref_id": "BIBREF32"}, {"start": 144, "end": 150, "text": "[Rum3,", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "Every quasi-abelian category has the natural greatest exact structure, and we always consider this greatest exact structure in what follows. More precisely, the following proposition holds. We refer to [B\u00fch, Proposition 4.4] for the proof.", "cite_spans": [{"start": 202, "end": 207, "text": "[B\u00fch,", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "Proposition 2.10. Let E be a quasi-abelian category. Then E has the greatest exact structure, in which conflations, inflations and deflations are precisely kernel-cokernel pairs, kernel morphisms and cokernel morphisms respectively. By this proposition, for an object X in a quasi-abelian category E, an inflation A X is nothing but a kernel morphism in E. Moreover, for two subobject \u03b9 A : A X and \u03b9 B : B X, we have that A \u2264 B holds in P(X) if and only if \u03b9 A factors through \u03b9 B . This follows from Proposition 2.3 since every pre-abelian category is idempotent complete.", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "A typical example of quasi-abelian categories are torsion(-free) classes of abelian categories.", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "Definition 2.11. Let A be an abelian category.", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "(1) Let T and F be subcategories of A. We say that a pair (T , F ) is a torsion pair in A if it satisfies the following conditions: (a) A(T , F ) = 0 holds, that is, A(T, F ) = 0 holds for every T \u2208 T and F \u2208 F . (b) For every object X \u2208 A, there exists a short exact sequences", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "in A with T X \u2208 T and F X \u2208 F . In this case, we say that T is a torsion class and F is a torsion-free class.", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "(2) We say that a torsion pair (T , F ) is hereditary if T is closed under subobjects in A. In this case, we say that F is a hereditary torsion-free class.", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "For a torsion pair (T , F ) on an abelian category, it is easily checked that T is closed under quotients and extensions, and that F is closed under subobjects and extensions. Hence we can regard T and F as exact categories.", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "The next proposition is classical, e.g. [Rum2, Theorem 2] . For the convenience of the reader, we give a simple proof which makes use of the exact structure.", "cite_spans": [{"start": 40, "end": 46, "text": "[Rum2,", "ref_id": "BIBREF32"}], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "Proposition 2.12. Let (T , F ) be a torsion pair in an abelian category A. Then T and F are both quasi-abelian.", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "Proof. We only show that F is quasi-abelian. Since F is closed under extensions in A, we have that F has the natural exact structure, where conflations are short exact sequences with all terms in F . By the axiom of exact categories, inflations are closed under pushouts and deflations are closed under pullbacks. Thus it suffices to show that E is pre-abelian, that every kernel morphism in F is an inflation and that every cokernel morphism in F is a deflation.", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "First we show that every morphism has a kernel, and every kernel morphism is an inflation. Let f : X \u2192 Y be an arbitrary morphism in F . Then we have the following commutative diagram in A with exact rows:", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "Since F is closed under subobjects in A, we have K, Im f \u2208 F . Therefore \u03b9 : K \u2192 X is a kernel of f in F , and this is actually an inflation in F since the bottom row is a conflation in F . Next we show that every morphism in F has a cokernel and every cokernel morphism is a deflation in F . Let f : X \u2192 Y be an arbitrary morphism in F and denote by C the cokernel of f in A. Then we have the following commutative diagram in A with exact rows and columns", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "where T C \u2208 T and F C \u2208 F . Then K \u2208 F holds since F is closed under subobjects, and it is straightforward to see that \u03c0 is a cokernel of f in F . It follows that the middle row is a conflation in F and that \u03c0 is actually a deflation in F .", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "We omit the following lemma, which can be checked straightforwardly.", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "Lemma 2.13. Let E be an additive category and suppose that we have the commutative diagram", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "such that the left square is pullback and i is a kernel of f . Then i \u2032 is a kernel of f g. In particular, kernel morphisms are closed under pullbacks if exists. Now we can prove that quasi-abelian implies lattice property.", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "Proposition 2.14. Let E be a quasi-abelian category with the greatest exact structure and X an object of E. Then P(X) is a lattice.", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "Proof. Let A, B \u2208 P(X) be two admissible subobjects of X.", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "We first construct the meet A \u2229 B. Note that since E is pre-abelian, E has pullbacks. Now we take the following pullback:", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "Then by Lemma 2.13, the above morphisms A \u2229 B \u2192 A and A \u2229 B \u2192 B are kernel morphisms, hence inflations. Thus the composition A \u2229 B A X is an inflation, so it is an admissible subobject of X. Hence we have A \u2229 B \u2208 P(X) and that A \u2229 B \u2264 A, B. Suppose that W \u2208 P(X) satisfies W \u2264 A and W \u2264 B. Then by the universal property of the pullback, we have a morphism W \u2192 A \u2229 B such that the composition W \u2192 A \u2229 B X is an inflation. Note that E is idempotent complete because E is pre-abelian. Then Lemma 2.3 shows that W \u2264 A \u2229 B holds in P(X). Therefore A \u2229 B is the meet of A and B in the poset P(X). Next we will show the existence of the join A + B \u2208 P(X). Here we shall give two constructions.", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "(First Construction): This construction is in fact the dual of the previous one, but we include it here for the completeness. Since E is pre-abelian, it has pushouts. Now we take the following pushout:", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "Then by the dual of Lemma 2.13, we have that the above morphism X/A \u2192 C is a cokernel morphism, hence a deflation. It follows that the composition X \u0589 X/A \u0589 C is a deflation, so C can be written as C = X/(A + B) for some A + B \u2208 P(X). Now we leave it the reader to verify that A + B is actually a join of A and B in P(X).", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "(Second Construction): The second construction is similar to the usual construction of the join in abelian categories: the join A + B is obtained by taking the image of the map A \u2295 B \u2192 X. Moreover, we will use this construction later to show the modular property of the lattice. To state the construction, we use the following basic property on quasi-abelian categories.", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "Lemma 2.15 ( [B\u00fch, Proposition 4.8] ). Every morphism f in a quasi-abelian category admits a factorization f = \u03b9p such that \u03b9 is a kernel morphism and p is an epimorphism. Clearly \u03b9 A and \u03b9 B factors through \u03b9, so A, B \u2264 A + B holds by Proposition 2.3. On the other hand, suppose that \u03b9 C : C X satisfies A, B \u2264 C. Then since \u03b9 A , \u03b9 B factors through \u03b9 C , the universal property of A \u2295 B yield a morphism \u03d5 : A \u2295 B \u2192 C which makes the following diagram commutes, where the bottom row is a conflation.", "cite_spans": [{"start": 13, "end": 18, "text": "[B\u00fch,", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "It follows that \u03c0 C \u03b9p = 0, and since p is an epimorphism, we have that \u03c0 C \u03b9 = 0. Thus \u03b9 factors through \u03b9 C , so A + B \u2264 C holds in P(X) by Proposition 2.3.", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "Remark 2.16. Proposition 2.14 can be checked explicitly when E is a torsion-free class of an abelian category as follows. Let (T , F ) be a torsion pair in an abelian category A and X an object of F . We give a construction of a meet and a join of A, B \u2208 P F (X).", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "\u2022 A meet A \u2229 B is the usual meet of subobjects in an abelian category A. We only observe that A \u2229 B is actually admissible, that is, X/(A \u2229 B) belongs to F . We have the following exact sequence in A:", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "Since F is closed under direct sums and subobjects, it follows that X/(A \u2229 B) belongs to F , that is, A \u2229 B is an admissible subobject of X.", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "\u2022 A join of A and B in P F (X) is in general different from the usual join A + B of subobjects in an abelian category A. The problem is that A + B is not necessarily admissible, that is, X/(A + B) may not belong to F . However, we have the following exact sequence", "cite_spans": [], "ref_spans": []}, {"section": "Basic definitions on inflation series, composition series and (JHP).", "text": "with the left term in T and the right term in F , and let us define A + B \u2208 P F (X) by the isomorphism X/(A + B) \u223c = F (X/(A + B)). We leave it to the reader to check that A + B is indeed a join of A and B in P F (X).", "cite_spans": [], "ref_spans": []}, {"section": "2.4.", "text": "Integral quasi-abelian implies modularity and the unique length property. It is known that a submodule lattice, or more generally, a subobject lattice in an abelian category, is a modular lattice (see e.g. [St, Proposition IV.5.3] ", "cite_spans": [{"start": 206, "end": 210, "text": "[St,", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "2.4.", "text": "Modularity is an useful tool to study composition series, since we have the following Jordan-H\u00f6lder theorem for modular lattices. For the proof, we refer the reader to [St, Corollary 3.2, Proposition 3.3] .", "cite_spans": [{"start": 168, "end": 172, "text": "[St,", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "2.4.", "text": "Theorem 2.17 (The Jordan-H\u00f6lder theorem for modular lattices). Let L be a modular lattice with the least element 0 and the greatest element 1. Suppose that L has at least one finite maximal chain. Then the following holds:", "cite_spans": [], "ref_spans": []}, {"section": "2.4.", "text": "(1) Every chain of L must be finite.", "cite_spans": [], "ref_spans": []}, {"section": "2.4.", "text": "(2) Every maximal chain of L has the same length.", "cite_spans": [], "ref_spans": []}, {"section": "2.4.", "text": "(3) Every chain can be refined to some maximal chain, thus the set of lengths of chains of L has an upper bound.", "cite_spans": [], "ref_spans": []}, {"section": "2.4.", "text": "Moreover, we have some kind of uniqueness of composition series: for two maximal chains 0 = x 0 < x 1 < \u00b7 \u00b7 \u00b7 < x l = 1 and 0 = y 0 < y 1 < \u00b7 \u00b7 \u00b7 < y l = 1, each intervals [x i\u22121 , x i ] and [y j\u22121 , y j ] are \"isomorphic\" up to permutations (strictly speaking, isomorphic here means projective in lattice theory, see e.g. [St, III. Section 2] for the detail). Actually, the Jordan-H\u00f6lder theorem for length abelian categories are proved by using the above lattice-theoretic one (see [St, p.92] for example).", "cite_spans": [{"start": 484, "end": 488, "text": "[St,", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "2.4.", "text": "However, in the case of exact categories, modularity of subobject lattices does not imply (JHP) in general because \"isomorphic\" above may not induce an isomorphism. Even so, modularity clearly does imply the unique length property. Thus we have the following corollary.", "cite_spans": [], "ref_spans": []}, {"section": "2.4.", "text": "Corollary 2.18. Let E be an exact category. Suppose that for every object X \u2208 E, the poset P(X) is a modular lattice and that at least one composition series of X exists. Then E is a length exact category and satisfies the unique length property.", "cite_spans": [], "ref_spans": []}, {"section": "2.4.", "text": "In the rest of this section, we will show that integral quasi-abelian categories are exact categories in which the above situation occurs.", "cite_spans": [], "ref_spans": []}, {"section": "2.4.", "text": "Definition 2.19. A quasi-abelian category E is called integral quasi-abelian if the class of epimorphisms is closed under pullbacks and the class of monomorphisms is closed under pushouts.", "cite_spans": [], "ref_spans": []}, {"section": "2.4.", "text": "The typical example is a hereditary torsion-free class of abelian categories (Definition 2.11), see e.g. [Rum1, Lemma 6] for the proof.", "cite_spans": [{"start": 105, "end": 111, "text": "[Rum1,", "ref_id": "BIBREF31"}], "ref_spans": []}, {"section": "2.4.", "text": "To show modularity, we need the following lemma of integral quasi-abelian category, which asserts that a regular morphism is so called an essential epimorphism.", "cite_spans": [], "ref_spans": []}, {"section": "2.4.", "text": "Lemma 2.20. Let E be an integral quasi-abelian category. Suppose that we have morphisms A f \u2212 \u2192 B g \u2212 \u2192 C in E which satisfies the following conditions: (1) g is a monomorphism and an epimorphism (that is, g is regular).", "cite_spans": [], "ref_spans": []}, {"section": "2.4.", "text": "(2) gf is an epimorphism. Then f is an epimorphism.", "cite_spans": [], "ref_spans": []}, {"section": "2.4.", "text": "Proof. Consider the following commutative diagram in E:", "cite_spans": [], "ref_spans": []}, {"section": "2.4.", "text": "Then we have that \u03c0 \u2032 gf = g \u2032 \u03c0f = 0, and since gf is an epimorphism, \u03c0 \u2032 = 0. Thus g \u2032 \u03c0 = 0 holds. On the other hand, since monomorphisms are stable under pushouts and g is a monomorphism, so is g \u2032 . Therefore \u03c0 = 0 holds, so f is an epimorphism.", "cite_spans": [], "ref_spans": []}, {"section": "2.4.", "text": "To prove modularity, the following criterion is quite useful.", "cite_spans": [], "ref_spans": []}, {"section": "2.4.", "text": "Lemma 2.21 ( [St, Proposition III.2.3] ). Let L be a lattice. Then the following are equivalent:", "cite_spans": [{"start": 13, "end": 17, "text": "[St,", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "2.4.", "text": "(1) L is a modular lattice.", "cite_spans": [], "ref_spans": []}, {"section": "2.4.", "text": "(2) Take any a, b \u2208 L with a \u2264 b, and take x, c, c Proposition 2.22. Let E be an integral quasi-abelian category with the greatest exact structure and X an object of E. Then P(X) is a modular lattice.", "cite_spans": [], "ref_spans": []}, {"section": "2.4.", "text": "Proof. For a subobjects A and B of X, we denote by A \u2229 B (resp. A + B) the meet (resp. join) of them constructed in Proposition 2.14. We would like to use Lemma 2.21. By Proposition 2.5, every interval of P(X) is isomorphic to P(Y ) for some object Y of E. Thus it suffices to show the following claim:", "cite_spans": [], "ref_spans": []}, {"section": "2.4.", "text": "Let \u03b9 A , \u03b9 B1 and \u03b9 B2 be the inflations corresponding to A, B 1 and B 2 respectively. By the construction of the meet given by Proposition 2.14, we have the following pullback diagram for each i = 1, 2.", "cite_spans": [], "ref_spans": []}, {"section": "2.4.", "text": "On the other hand, by the second construction of the join given in Proposition 2.14, we have the following factorization on the join A + B i for each i:", "cite_spans": [], "ref_spans": []}, {"section": "2.4.", "text": "We have shown that r i is both a monomorphism and an epimorphism for each i. Let \u03b9 : B 1 B 2 be the inflation corresponding to B 1 \u2264 B 2 . Then we have the following commutative diagram:", "cite_spans": [], "ref_spans": []}, {"section": "2.4.", "text": "Since r 2 is a monomorphism and an epimorphism and r 1 is an epimorphism, it follows that", "cite_spans": [], "ref_spans": []}, {"section": "2.4.", "text": "is an epimorphism by Lemma 2.20. However, [ 1 0 0 \u03b9 ] is a kernel morphism, so it must be an isomorphism. Thus \u03b9 also is an isomorphism by matrix calculation.", "cite_spans": [], "ref_spans": []}, {"section": "2.4.", "text": "Corollary 2.23. Let E be an integral quasi-abelian category which is length as an exact category (for example, a hereditary torsion-free class of length abelian category). Then E satisfies the unique length property.", "cite_spans": [], "ref_spans": []}, {"section": "2.4.", "text": "Proof. This immediately follows from Proposition 2.22 and Corollary 2.18.", "cite_spans": [], "ref_spans": []}, {"section": "2.4.", "text": "We refer the reader to Example 8.5 for concrete examples which satisfy the unique length property.", "cite_spans": [], "ref_spans": []}, {"section": "Grothendieck monoid of an exact category", "text": "To an exact category E, we can associate the abelian group K 0 (E), called the Grothendieck group, which is defined by the universal property with respect to conflations. The investigation and calculation of this group is a very classical topic in the various area of mathematics. However, much less attention has been paid to the monoid version of the Grothendieck group, the Grothendieck monoid M(E), which we introduce in this section.", "cite_spans": [], "ref_spans": []}, {"section": "Grothendieck monoid of an exact category", "text": "Remark 3.1. Grothendieck monoids of exact categories in our sense were defined independently in [BeGr] and used to study Hall algebras. Also Brookfield studied the structure of the Grothendieck monoid of the category of noetherian modules in [Bro1, Bro2, Bro3] .", "cite_spans": [{"start": 242, "end": 248, "text": "[Bro1,", "ref_id": "BIBREF8"}, {"start": 249, "end": 254, "text": "Bro2,", "ref_id": "BIBREF9"}, {"start": 255, "end": 260, "text": "Bro3]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Grothendieck monoid of an exact category", "text": "3.1. Construction and basic properties of the Grothendieck monoid. Note that monoids are assumed to be commutative in our convention. First we give the definition of Grothendieck monoids and study their basic properties as monoids. We refer to Appendix A for some unexplained notions on monoids.", "cite_spans": [], "ref_spans": []}, {"section": "Grothendieck monoid of an exact category", "text": "Definition 3.2. Let E be a skeletally small exact category.", "cite_spans": [], "ref_spans": []}, {"section": "Grothendieck monoid of an exact category", "text": "(1) A map f : Iso E \u2192 M to a monoid M is said to respect conflations if it satisfies the following conditions:", "cite_spans": [], "ref_spans": []}, {"section": "Grothendieck monoid of an exact category", "text": "which satisfies the following universal property: (a) \u03c0 respects conflations in E.", "cite_spans": [], "ref_spans": []}, {"section": "Grothendieck monoid of an exact category", "text": "(b) Every map f : Iso E \u2192 M to an monoid M which respects conflations in E uniquely factors through \u03c0, that is, there exists a unique monoid homomorphism f :", "cite_spans": [], "ref_spans": []}, {"section": "By abuse of notation, we often write \u03c0[X] = [X] to represent an element in M(E).", "text": "First of all, we must show that the Grothendieck monoid actually exists. . Now let us define a monoid congruence \u223c on Iso E which is generated by the following relations (see Proposition A.6):", "cite_spans": [], "ref_spans": []}, {"section": "By abuse of notation, we often write \u03c0[X] = [X] to represent an element in M(E).", "text": "Using this, we obtain a monoid M(E) := Iso E/ \u223c. Now it is clear from the construction that M(E) enjoys the required universal property of the Grothendieck monoid.", "cite_spans": [], "ref_spans": []}, {"section": "By abuse of notation, we often write \u03c0[X] = [X] to represent an element in M(E).", "text": "The following is a more direct characterization whether", "cite_spans": [], "ref_spans": []}, {"section": "By abuse of notation, we often write \u03c0[X] = [X] to represent an element in M(E).", "text": "Proposition 3.4. Let E be a skeletally small exact category and X, Y two objects of E. Then", "cite_spans": [], "ref_spans": []}, {"section": "By abuse of notation, we often write \u03c0[X] = [X] to represent an element in M(E).", "text": "Proof. We freely use the construction of", "cite_spans": [], "ref_spans": []}, {"section": "By abuse of notation, we often write \u03c0[X] = [X] to represent an element in M(E).", "text": "have isomorphic inflation series for each i. It is clear that \u2248 is an equivalence relation on Iso E, and it suffices to show that \u2248 and \u223c coincides.", "cite_spans": [], "ref_spans": []}, {"section": "By abuse of notation, we often write \u03c0[X] = [X] to represent an element in M(E).", "text": "First we show that \u2248 is a monoid congruence on Iso E. It is enough to show that for every object A in E, if X and Y have isomorphic inflation series, then so do", "cite_spans": [], "ref_spans": []}, {"section": "By abuse of notation, we often write \u03c0[X] = [X] to represent an element in M(E).", "text": "where the last inflations are the inclusion into direct summands. Therefore \u2248 is a monoid congruence on Iso E.", "cite_spans": [], "ref_spans": []}, {"section": "By abuse of notation, we often write \u03c0[X] = [X] to represent an element in M(E).", "text": "Next we will prove that \u2248 coincides with \u223c. From the argument above this proposition, we", "cite_spans": [], "ref_spans": []}, {"section": "By abuse of notation, we often write \u03c0[X] = [X] to represent an element in M(E).", "text": ". To show the converse implication, it suffices to show that for every conflation X Y \u0589 Z, we have that", "cite_spans": [], "ref_spans": []}, {"section": "By abuse of notation, we often write \u03c0[X] = [X] to represent an element in M(E).", "text": ". This is clear since we have inflation series 0 X Y of Y and 0 X X \u2295 Z of X \u2295 Z which are isomorphic since Y /X \u223c = Z.", "cite_spans": [], "ref_spans": []}, {"section": "By abuse of notation, we often write \u03c0[X] = [X] to represent an element in M(E).", "text": "Using this description of the Grothendieck monoid, we can prove some properties of it.", "cite_spans": [], "ref_spans": []}, {"section": "By abuse of notation, we often write \u03c0[X] = [X] to represent an element in M(E).", "text": "Proposition 3.5. Let E be a skeletally small exact category. then the following hold.", "cite_spans": [], "ref_spans": []}, {"section": "By abuse of notation, we often write \u03c0[X] = [X] to represent an element in M(E).", "text": "(1) For an object X in E, we have that", "cite_spans": [], "ref_spans": []}, {"section": "By abuse of notation, we often write \u03c0[X] = [X] to represent an element in M(E).", "text": "Proof.", "cite_spans": [], "ref_spans": []}, {"section": "By abuse of notation, we often write \u03c0[X] = [X] to represent an element in M(E).", "text": "(1) This follows immediately from Proposition 3.4 since if 0 and X has isomorphic inflation series, then clearly X \u223c = 0 holds.", "cite_spans": [], "ref_spans": []}, {"section": "By abuse of notation, we often write \u03c0[X] = [X] to represent an element in M(E).", "text": ". Therefore both X and Y must be isomorphic to 0 in E. Thus M(E) is reduced.", "cite_spans": [], "ref_spans": []}, {"section": "By abuse of notation, we often write \u03c0[X] = [X] to represent an element in M(E).", "text": "We can prove that non-isomorphic simples in E are distinct in M(E), and in fact they are in bijection with atoms. This property is remarkable compared to the Grothendieck group, since non-isomorphic simples may represent the same element in the Grothendieck group K 0 (E) (see Section 8.3.1). We refer the reader to Definition A.8 for the notion of atoms.", "cite_spans": [], "ref_spans": []}, {"section": "By abuse of notation, we often write \u03c0[X] = [X] to represent an element in M(E).", "text": "Proposition 3.6. Let E be a skeletally small exact category. then the following hold.", "cite_spans": [], "ref_spans": []}, {"section": "By abuse of notation, we often write \u03c0[X] = [X] to represent an element in M(E).", "text": "(1) Let S and X be two objects in E.", "cite_spans": [], "ref_spans": []}, {"section": "By abuse of notation, we often write \u03c0[X] = [X] to represent an element in M(E).", "text": "between the set sim E of isomorphism classes of simple objects in E and the set Atom M(E) of atoms in M(E).", "cite_spans": [], "ref_spans": []}, {"section": "By abuse of notation, we often write \u03c0[X] = [X] to represent an element in M(E).", "text": "Proof.", "cite_spans": [], "ref_spans": []}, {"section": "By abuse of notation, we often write \u03c0[X] = [X] to represent an element in M(E).", "text": "(1) Suppose that S and Y has isomorphic inflation series for Y \u2208 E and a simple object S in E. Then it is clear that S \u223c = Y holds, since possible inflation series of S is of the form 0 \u00b7 \u00b7 \u00b7 0 S = \u00b7 \u00b7 \u00b7 = S. Now the assertion of (1) inductively follows from Proposition 3.4.", "cite_spans": [], "ref_spans": []}, {"section": "By abuse of notation, we often write \u03c0[X] = [X] to represent an element in M(E).", "text": "(2) This is obvious from (1). Conversely, suppose that [X] is not simple. We may assume that X = 0, so we have a nontrivial conflation", "cite_spans": [], "ref_spans": []}, {"section": "By abuse of notation, we often write \u03c0[X] = [X] to represent an element in M(E).", "text": "Now we have proved that atoms in M(E) are precisely those coming from simple objects. Then the remaining claim follows immediately from (2).", "cite_spans": [], "ref_spans": []}, {"section": "By abuse of notation, we often write \u03c0[X] = [X] to represent an element in M(E).", "text": "For later use, we show another necessary condition for Proposition 3.7. Let E be a skeletally small exact category and X, Y two objects of E. Suppose that X belongs to a Serre subcategory D of E and that", "cite_spans": [], "ref_spans": []}, {"section": "By abuse of notation, we often write \u03c0[X] = [X] to represent an element in M(E).", "text": "Proof. By Proposition 3.4, it suffices to show the assertion when X and Y have isomorphic inflation series. Take inflation series 0 3.2. Grothendieck monoid and positive part of Grothendieck group. The Grothendieck group of an exact category is a classical object, which is defined by the similar universal property as the Grothendieck monoid. In this section, we will recall the Grothendieck group and investigate the relation between the Grothendieck monoid.", "cite_spans": [], "ref_spans": []}, {"section": "By abuse of notation, we often write \u03c0[X] = [X] to represent an element in M(E).", "text": "Definition 3.8. Let E be a skeletally small exact category.", "cite_spans": [], "ref_spans": []}, {"section": "By abuse of notation, we often write \u03c0[X] = [X] to represent an element in M(E).", "text": "(1) A map f : Iso E \u2192 G to an abelian group G is said to respect conflations if it satisfies", "cite_spans": [], "ref_spans": []}, {"section": "By abuse of notation, we often write \u03c0[X] = [X] to represent an element in M(E).", "text": "with a map \u03c0 : Iso E \u2192 K 0 (E) which satisfies the following universal property: (a) \u03c0 respects conflations in E.", "cite_spans": [], "ref_spans": []}, {"section": "By abuse of notation, we often write \u03c0[X] = [X] to represent an element in M(E).", "text": "(b) Every map f : Iso E \u2192 G to an abelian group G which respects conflations in E uniquely factors through \u03c0, that is, there exists a unique group homomorphism", "cite_spans": [], "ref_spans": []}, {"section": "By abuse of notation, we often write \u03c0[X] = [X] to represent an element in M(E).", "text": "By abuse of notation, we often write", "cite_spans": [], "ref_spans": []}, {"section": "By abuse of notation, we often write \u03c0[X] = [X] to represent an element in M(E).", "text": "By the defining properties of the Grothendieck monoid and the Grothendieck group, it is clear that the latter is obtained from the former by taking the group completion, as the following proposition claims. We refer the reader to Appendix A for this notion.", "cite_spans": [], "ref_spans": []}, {"section": "By abuse of notation, we often write \u03c0[X] = [X] to represent an element in M(E).", "text": "Proposition 3.9. Let E be a skeletally small exact category. Then the Grothendieck group K 0 (E) exists, and it is realized as the group completion gp M(E) of the Grothendieck monoid M(E).", "cite_spans": [], "ref_spans": []}, {"section": "By abuse of notation, we often write \u03c0[X] = [X] to represent an element in M(E).", "text": "In what follows, we always identify gp M(E) with K 0 (E) and we denote by \u03b9 :", "cite_spans": [], "ref_spans": []}, {"section": "By abuse of notation, we often write \u03c0[X] = [X] to represent an element in M(E).", "text": "Definition 3.10. Let E be a skeletally small exact category. We denote by K + 0 (E) the image of the natural map \u03b9 :", "cite_spans": [], "ref_spans": []}, {"section": "By abuse of notation, we often write \u03c0[X] = [X] to represent an element in M(E).", "text": "It follows from Proposition A.15 that \u03b9 :", "cite_spans": [], "ref_spans": []}, {"section": "By abuse of notation, we often write \u03c0[X] = [X] to represent an element in M(E).", "text": ", where M(E) can is the universal largest cancellative quotient of M(E). Thus the positive part has lost information on non-cancellative part compared to the Grothendieck monoid. Even so, K + 0 (E) is a more sophisticated invariant of E than K 0 (E). Note that we have many examples in which the Grothendieck monoids are not cancellative, see Section 8.3.", "cite_spans": [], "ref_spans": []}, {"section": "By abuse of notation, we often write \u03c0[X] = [X] to represent an element in M(E).", "text": "We shall see later in Corollary 5.9 that for a large class of exact categories E arising in the representation theory of artin algebras, including functorially finite torsion-free classes, we can identify K + 0 (E) with the monoid of dimension vectors of modules in E.", "cite_spans": [], "ref_spans": []}, {"section": "Characterization of (JHP)", "text": "We will show the basic relationship between structures of exact categories and combinatorial properties of the Grothendieck monoids.", "cite_spans": [], "ref_spans": []}, {"section": "Characterization of (JHP)", "text": "4.1. Length-like functions and length exact categories. First we give an analogue of dimension or length of the module category, which characterizes length exact categories.", "cite_spans": [], "ref_spans": []}, {"section": "Characterization of (JHP)", "text": "Definition 4.1. Let E be a skeletally small exact category. We say that a map \u03bd : Iso E \u2192 N is a weakly length-like function if it satisfies the following conditions:", "cite_spans": [], "ref_spans": []}, {"section": "Characterization of (JHP)", "text": "(", "cite_spans": [], "ref_spans": []}, {"section": "Characterization of (JHP)", "text": "(2) \u03bd[X] = 0 implies X \u223c = 0 for every X \u2208 E. We say that \u03bd is a length-like function if it satisfies (2) and the following: Note that (weakly) length-like functions are far from being unique (for example, any positive multiple of a length-like function is a length-like function). First, we observe that a weakly lengthlike function gives an upper bound for lengths of X.", "cite_spans": [], "ref_spans": []}, {"section": "Characterization of (JHP)", "text": "Lemma 4.3. Let E be a skeletally small exact category with a weakly length-like function \u03bd. For every X \u2208 E and proper inflation series 0 = X 0 < X 1 < \u00b7 \u00b7 \u00b7 < X n = X of X (considered in P(X)), we have n \u2264 \u03bd[X]. In particular, E is a length exact category.", "cite_spans": [], "ref_spans": []}, {"section": "Characterization of (JHP)", "text": "Proof. Since \u03bd is weakly length-like, we have inductively", "cite_spans": [], "ref_spans": []}, {"section": "Characterization of (JHP)", "text": "This means that the set of lengths of finite chains of P(X) has an upper bound \u03bd[X] for every X \u2208 E, thus E is a length exact category.", "cite_spans": [], "ref_spans": []}, {"section": "Characterization of (JHP)", "text": "Theorem 4.4. Let E be a skeletally small exact category. Then the following are equivalent:", "cite_spans": [], "ref_spans": []}, {"section": "Characterization of (JHP)", "text": "(1) E has a weakly length-like function.", "cite_spans": [], "ref_spans": []}, {"section": "Characterization of (JHP)", "text": "(2) E is a length exact category.", "cite_spans": [], "ref_spans": []}, {"section": "Characterization of (JHP)", "text": "Proof.", "cite_spans": [], "ref_spans": []}, {"section": "Characterization of (JHP)", "text": "(1) \u21d2 (2): This is Lemma 4.3.", "cite_spans": [], "ref_spans": []}, {"section": "Characterization of (JHP)", "text": "(2) \u21d2 (1): For an object X \u2208 E, the lengths of chains of P(X) has an upper bound, thus we can define \u03bd[X] by the following: \u03bd[X] := max{l | there exists a chain of P(X) with length l}.", "cite_spans": [], "ref_spans": []}, {"section": "Characterization of (JHP)", "text": "We will show that \u03bd : Iso E \u2192 N is a weakly length-like function. If \u03bd[X] = 0, then X \u223c = 0 holds since otherwise we have a chain 0 < X of length one.", "cite_spans": [], "ref_spans": []}, {"section": "Characterization of (JHP)", "text": "Suppose that we have a conflation X Y \u0589 Z in E and put m := \u03bd[X] and n := \u03bd[Z]. We have chains 0 = X 0 < X 1 < \u00b7 \u00b7 \u00b7 < X n = X of P(X) and 0 = Z 0 < Z 1 < \u00b7 \u00b7 \u00b7 < Z m = Z of P(Z). By Proposition 2.5, we have an isomorphism of posets [X, Y ] \u223c = P(Z), so we have a chain", "cite_spans": [], "ref_spans": []}, {"section": "Characterization of (JHP)", "text": "Remark 4.5. The weakly length-like function constructed in the proof of (2) \u21d2 (1) is the same as the length given in [BHLR, Section 6] .", "cite_spans": [{"start": 117, "end": 123, "text": "[BHLR,", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Characterization of (JHP)", "text": "Using this theorem, we obtain numerous examples of length exact categories.", "cite_spans": [], "ref_spans": []}, {"section": "Characterization of (JHP)", "text": "Example 4.6. The typical example in the representation theory of artin algebra is as follows. Let \u039b be an artin algebra, and let E be an extension-closed subcategory of mod \u039b. The assignment X \u2192 l(X), where l(X) denotes the (usual) length of X as a \u039b-module, gives a length-like function on E. It is clear that the same argument holds for any extension-closed subcategory of a length abelian category.", "cite_spans": [], "ref_spans": []}, {"section": "Characterization of (JHP)", "text": "Remark 4.7. It can be showed that the category of maximal Cohen-Macaulay modules CM R over a commutative Cohen-Macaulay ring R (or more generally, CM \u039b for an R-order \u039b) has a length-like function. It is an interesting problem to study these categories satisfy (JHP).", "cite_spans": [], "ref_spans": []}, {"section": "Characterization of (JHP)", "text": "The following gives the criterion for the Grothendieck monoid to be finitely generated.", "cite_spans": [], "ref_spans": []}, {"section": "Characterization of (JHP)", "text": "Proposition 4.8. Let E be a skeletally small exact category. Suppose that E is a length exact category. Then M(E) is atomic, and the following are equivalent:", "cite_spans": [], "ref_spans": []}, {"section": "Characterization of (JHP)", "text": "(1) sim E is a finite set.", "cite_spans": [], "ref_spans": []}, {"section": "Characterization of (JHP)", "text": "(2) Atom M(E) is a finite set.", "cite_spans": [], "ref_spans": []}, {"section": "Characterization of (JHP)", "text": "(3) M(E) is a finitely generated.", "cite_spans": [], "ref_spans": []}, {"section": "Characterization of (JHP)", "text": "Proof. Since E is a length exact category, each object X of E admits a composition series 0 = X 0 X 1 \u00b7 \u00b7 \u00b7 X n , and", "cite_spans": [], "ref_spans": []}, {"section": "Characterization of (JHP)", "text": ", and Proposition 3.6 implies that each [X i /X i\u22121 ] is an atom in M(E). Thus M(E) is atomic. Proposition 3.6 shows that (1) is equivalent to (2). On the other hand, Proposition A.9 (2) shows that (2) is equivalent to (3).", "cite_spans": [], "ref_spans": []}, {"section": "Freeness of monoids and (JHP)", "text": ". Now we can prove the characterization of (JHP) for an exact category in terms of its Grothendieck monoid.", "cite_spans": [], "ref_spans": []}, {"section": "Freeness of monoids and (JHP)", "text": "Theorem 4.9. Let E be a skeletally small exact category. Then the following are equivalent:", "cite_spans": [], "ref_spans": []}, {"section": "Freeness of monoids and (JHP)", "text": "(1) E is a length exact category and satisfies (JHP).", "cite_spans": [], "ref_spans": []}, {"section": "Freeness of monoids and (JHP)", "text": "(2) M(E) is a free monoid, or equivalently, a factorial monoid. If these conditions are satisfied, then", "cite_spans": [], "ref_spans": []}, {"section": "Freeness of monoids and (JHP)", "text": "Proof. Recall that we have an equality Atom M(E) = {[S] | S \u2208 sim E} by Proposition 3.6. Also note that the conditions in (2) are equivalent by Proposition A.9 (5) and Proposition 3.5.", "cite_spans": [], "ref_spans": []}, {"section": "Freeness of monoids and (JHP)", "text": "(1) \u21d2 (2): Let us denote by F the free monoid with basis Atom M(E). Then we have a natural monoid morphism \u03d5 :", "cite_spans": [], "ref_spans": []}, {"section": "Freeness of monoids and (JHP)", "text": "We shall construct the inverse of this map.", "cite_spans": [], "ref_spans": []}, {"section": "Freeness of monoids and (JHP)", "text": "For [X] in Iso E, take a composition series 0", "cite_spans": [], "ref_spans": []}, {"section": "Freeness of monoids and (JHP)", "text": "This map does not depend on the choice of composition series by (JHP). We show that this map respects conflations in E.", "cite_spans": [], "ref_spans": []}, {"section": "Freeness of monoids and (JHP)", "text": "Suppose that we have a conflation X Y \u0589 Z in E and that we have composition series 0 = X 0 < X 1 < \u00b7 \u00b7 \u00b7 < X n = X in P(X) and 0 = Z 0 < Z 1 < \u00b7 \u00b7 \u00b7 < Z m = Z in P(Z). By Proposition 2.5 (2), we have an isomorphism of posets [X, Y ] \u223c = P(Z), so we have a chain", "cite_spans": [], "ref_spans": []}, {"section": "Freeness of monoids and (JHP)", "text": "is a composition series of Y . Now it is obvious that the map Iso E \u2192 F constructed above respects conflations. Thus we obtain a monoid homomorphism \u03c8 :", "cite_spans": [], "ref_spans": []}, {"section": "Freeness of monoids and (JHP)", "text": "We show that \u03d5 and \u03c8 are mutually inverse to each other.", "cite_spans": [], "ref_spans": []}, {"section": "Freeness of monoids and (JHP)", "text": "(\u03c8\u03d5 = id F ): Since F is generated by [S] with S being simple in E, it suffices to show that \u03c8\u03d5[S] = [S] holds. This is obvious since \u03d5[S] = [S], and S has the composition series 0 < S.", "cite_spans": [], "ref_spans": []}, {"section": "Freeness of monoids and (JHP)", "text": "(\u03d5\u03c8 = id M(E) ): Let X be an object with a composition series 0", "cite_spans": [], "ref_spans": []}, {"section": "Freeness of monoids and (JHP)", "text": "On the other hand, we have inductively", "cite_spans": [], "ref_spans": []}, {"section": "Freeness of monoids and (JHP)", "text": "(2) \u21d2 (1): First we show that E is a length exact category. By Lemma A.18, we have that M(E) has a length-like function. Thus E has a length-like function, thus it is a length exact category by Proposition 4.4.", "cite_spans": [], "ref_spans": []}, {"section": "Freeness of monoids and (JHP)", "text": "Next we will show that E satisfies (JHP). Let X be an object of E and let 0 = X 0 < X 1 < \u00b7 \u00b7 \u00b7 < X m = X and 0 = Y 0 < Y 1 < \u00b7 \u00b7 \u00b7 < Y m = X be two composition series of X. Then we have", "cite_spans": [], "ref_spans": []}, {"section": "Freeness of monoids and (JHP)", "text": "is free on Atom M(E) by Proposition A.9 (3), it follows that m = n holds and there exists a permutation \u03c3 of the set {1, 2, \u00b7 \u00b7 \u00b7 , n} such that", "cite_spans": [], "ref_spans": []}, {"section": "Freeness of monoids and (JHP)", "text": "by Proposition 3.6 (2). Thus these two composition series are isomorphic.", "cite_spans": [], "ref_spans": []}, {"section": "Freeness of monoids and (JHP)", "text": "The remaining assertions follow from Proposition A.9 (3) and Example A.11.", "cite_spans": [], "ref_spans": []}, {"section": "Freeness of monoids and (JHP)", "text": "The trivial and classical example in which (JHP) holds is, as stated in the introduction, a length abelian category. Recall that an abelian category is called a length abelian category if it is a length exact category as an exact category, that is, every object has a composition series (see Remark 2.8).", "cite_spans": [], "ref_spans": []}, {"section": "Freeness of monoids and (JHP)", "text": "Corollary 4.10. Let A be a length abelian category. Then M(A) is a free monoid with basis {[S] | S \u2208 sim A}. In particular, K 0 (A) is a free abelian group with the same basis.", "cite_spans": [], "ref_spans": []}, {"section": "Freeness of monoids and (JHP)", "text": "Proof. This follows from the Jordan-H\u00f6lder theorem for length abelian categories (see e.g. [St, p.92] ) and Theorem 4.9.", "cite_spans": [{"start": 91, "end": 95, "text": "[St,", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "Grothendieck groups and (JHP).", "text": "We have shown that (JHP) can be checked by the freeness of the Grothendieck monoid, but the computation of it is rather hard. In this subsection, we give a criterion for (JHP) using the Grothendieck group, which is easier to compute than the Grothendieck monoid. All contents of this subsection is just a formal consequence of the general theory of monoids, that is, the general criterion for a monoid to be free (Theorem A.20 and Corollary A.21 ).", "cite_spans": [], "ref_spans": []}, {"section": "Grothendieck groups and (JHP).", "text": "Before we state this, we will make an observation on the Grothendieck groups. Let E be a length exact category. If E satisfies (JHP), then by Theorem 4.9, its Grothendieck monoid M(E) is free, thus K 0 (E) is a free abelian group. Conversely, under this assumption we have the following inequality.", "cite_spans": [], "ref_spans": []}, {"section": "Grothendieck groups and (JHP).", "text": "Proposition 4.11. Let E be a skeletally small exact category. Suppose that K 0 (E) is a free abelian group. Then the following inequality holds:", "cite_spans": [], "ref_spans": []}, {"section": "Grothendieck groups and (JHP).", "text": "Proof. This follows from the corresponding statement on monoids, Proposition A.19. Now let us state our main characterizations of (JHP) in terms of the Grothendieck group.", "cite_spans": [], "ref_spans": []}, {"section": "Grothendieck groups and (JHP).", "text": "Theorem 4.12. Let E be a skeletally small exact category. Then the following are equivalent:", "cite_spans": [], "ref_spans": []}, {"section": "Grothendieck groups and (JHP).", "text": "(1) E is a length exact category and satisfies (JHP).", "cite_spans": [], "ref_spans": []}, {"section": "Grothendieck groups and (JHP).", "text": "(2) M(E) is free.", "cite_spans": [], "ref_spans": []}, {"section": "Grothendieck groups and (JHP).", "text": "(3) E is a length exact category, and K 0 (E) is a free abelian group of basis {[S] | S \u2208 sim E}. (4) E is a length exact category, and all elements [S] \u2208 K 0 (E) with S \u2208 sim E are linearly independent over Z in K 0 (E).", "cite_spans": [], "ref_spans": []}, {"section": "Grothendieck groups and (JHP).", "text": "Proof. This immediately follows from Theorems 4.9 and A.20 once we recall the following:", "cite_spans": [], "ref_spans": []}, {"section": "Grothendieck groups and (JHP).", "text": "\u2022 E has a length-like function if and only if M(E) has a length-like function (Definition 4.1).", "cite_spans": [], "ref_spans": []}, {"section": "Grothendieck groups and (JHP).", "text": "\u2022 M(E) is reduced (Proposition 3.5).", "cite_spans": [], "ref_spans": []}, {"section": "Grothendieck groups and (JHP).", "text": "\u2022 If E is a length exact category, then M(E) is atomic (Proposition 4.8).", "cite_spans": [], "ref_spans": []}, {"section": "Grothendieck groups and (JHP).", "text": "If the Grothendieck group is known to be free of finite rank, then we have a more convenient characterization: we only have to count the number of simples and compare it to the rank. Theorem 4.13. Let E be a skeletally small exact category. Then the following are equivalent:", "cite_spans": [], "ref_spans": []}, {"section": "Grothendieck groups and (JHP).", "text": "(1) E is a length exact category satisfying (JHP) and # sim E is finite.", "cite_spans": [], "ref_spans": []}, {"section": "Grothendieck groups and (JHP).", "text": "(2) M(E) is free and # sim E is finite.", "cite_spans": [], "ref_spans": []}, {"section": "Grothendieck groups and (JHP).", "text": "(3) M(E) is a finitely generated free monoid.", "cite_spans": [], "ref_spans": []}, {"section": "Grothendieck groups and (JHP).", "text": "(4) E is a length exact category, # sim E is finite and K 0 (E) is a free abelian group with basis", "cite_spans": [], "ref_spans": []}, {"section": "Grothendieck groups and (JHP).", "text": "The following conditions hold:", "cite_spans": [], "ref_spans": []}, {"section": "Grothendieck groups and (JHP).", "text": "Proof. This immediately follows from Theorems 4.9 and A.20, as in the proof of Theorem 4.12.", "cite_spans": [], "ref_spans": []}, {"section": "Grothendieck groups and (JHP).", "text": "This characterization has lots of applications in Part 2, since Grothendieck groups of various exact categories arising in the representation theory of algebras are turned out to be free of finite rank (see Proposition 5.12).", "cite_spans": [], "ref_spans": []}, {"section": "Grothendieck groups and (JHP).", "text": "4.4. Half-factoriality of monoids and the unique length property. In this subsection, we will give a characterization of the unique length property in terms of Grothendieck monoids. As we have seen in Theorem 4.9, (JHP) corresponds to freeness, or equivalently, factoriality of monoids. We will see that the unique length property corresponds to half-factoriality. This is natural since both two properties are about the uniqueness of length of factorizations. We refer the reader to Definition A.8 for the notion of half-factorial monoids.", "cite_spans": [], "ref_spans": []}, {"section": "Grothendieck groups and (JHP).", "text": "Theorem 4.14. Let E be a skeletally small exact category. Then the following are equivalent:", "cite_spans": [], "ref_spans": []}, {"section": "Grothendieck groups and (JHP).", "text": "(1) E is a length exact category and satisfies the unique length property.", "cite_spans": [], "ref_spans": []}, {"section": "Grothendieck groups and (JHP).", "text": "(2) E has a length like function l satisfying l[S] = 1 for every simple object S in E.", "cite_spans": [], "ref_spans": []}, {"section": "Grothendieck groups and (JHP).", "text": "Proof. The proof is similar to that of Theorem 4.9, and actually is easier.", "cite_spans": [], "ref_spans": []}, {"section": "Grothendieck groups and (JHP).", "text": "(1) \u21d2 (2): We will construct a length-like function l : Iso E \u2192 N. Let X be an object of E. Since E satisfies the unique length property, X has at least one composition series, and every composition series of X has the same length n. We define l[X] := n. Then l is a length-like function by the similar argument to the proof of Theorem 4.4. Moreover, clearly l[S] = 1 holds for every simple object S in E.", "cite_spans": [], "ref_spans": []}, {"section": "Grothendieck groups and (JHP).", "text": "(2) \u21d4 (3): By Remark 4.2, we can identify a length-like function on E with that of M(E). Moreover, we have an equality Atom M(E) = {[S] | S \u2208 sim E} by Proposition 3.6. Thus this equivalence follows from Lemma A.18.", "cite_spans": [], "ref_spans": []}, {"section": "Grothendieck groups and (JHP).", "text": "(2) \u21d2 (1): By Proposition 4.4, our category E is a length exact category. Let X be an object of E. Then it is easily checked that the length of any composition series of X is equal to l [X] . Thus E satisfies the unique length property.", "cite_spans": [], "ref_spans": []}, {"section": "Part 2. Applications to artin algebras", "text": "In this part, we investigate several properties on exact categories arising in the representation theory of artin algebras, by using the results in the previous part.", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "In this section, we investigate (JHP) for subcategories of module categories of artin algebras. In the rest of this paper, we fix a commutative artinian ring R. An R-algebra \u039b is called an artin R-algebra if \u039b is finitely generated as an R-module. We often omit the base ring R and call \u039b an artin algebra. For an artin R-algebra \u039b, we denote by D : mod \u039b \u2192 mod \u039b op the standard Matlis duality.", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "5.1. Basic properties on Grothendieck monoids. First we collect some basic properties on the Grothendieck monoid, which immediately follows from the general observations we have made. In particular, our exact category always becomes a length exact category.", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "Proposition 5.1. Let \u039b be an artin algebra and E an extension-closed subcategory of mod \u039b. Then the following hold.", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "(1) The assignment X \u2192 l(X), where l(X) denotes the usual length of X as a \u039b-module, induces a length-like function on E. (2) E is a length exact category. Proof. These follow from Example 4.6 (1), Theorem 4.4 and Proposition 4.8.", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "The most simple example is the case E = mod \u039b, so let us compute M(mod \u039b) and K 0 (mod \u039b).", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "Proposition 5.2. Let \u039b be an artin algebra, and let S 1 , \u00b7 \u00b7 \u00b7 , S n be a complete set of simple right \u039b-modules up to isomorphism. Then M(mod \u039b) is free with basis [S 1 ], \u00b7 \u00b7 \u00b7 , [S n ]. In particular, K 0 (mod \u039b) is a free abelian group with the same basis. Moreover, |\u039b| = # ind P(mod \u039b) = # sim(mod \u039b) = n holds.", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "Proof. All the assertions except the last follow form Corollary 4.10. The last one holds because there is a bijection between non-isomorphic indecomposable projective \u039b-modules and nonisomorphic simple \u039b-modules.", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "By this, the Grothendieck group K 0 (mod \u039b) is often identified with Z n , where n is the number of simples. This is what is called dimension vectors of modules.", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "Definition 5.3. Let \u039b be an artin algebra, and fix a complete set of non-isomorphic simple \u039b-", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "Then we denote by dim : mod \u039b \u2192 Z n the assignment which sends X to (a 1 , \u00b7 \u00b7 \u00b7 , a n ), where a i is the Jordan-H\u00f6lder multiplicity of S i in X. This induces an isomorphism", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "For a \u039b-module X, we call dim X the dimension vector of X.", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "A typical example of extension-closed subcategories is an Ext-perpendicular category with respect to a given module.", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "Definition 5.4. Let \u039b be an artin algebra and U \u2208 mod \u039b a \u039b-module. We denote by \u22a5 U the subcategory of mod \u039b which consists of X \u2208 mod \u039b such that Ext", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "\u22a5 U is an extension-closed subcategory of mod \u039b, and we always regard it as an exact category from now on.", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "Exact categories arising in this way have nice homological properties as follows. These can be checked directly, so we omit the proofs.", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "Proposition 5.5. Let \u039b be an artin algebra, U \u2208 mod \u039b a \u039b-module and E := \u22a5 U . then the following hold.", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "(1) For any short exact sequence 0 \u2192 X \u2192 Y \u2192 Z \u2192 0 in mod \u039b, if Y and Z belong to E, then so does X. (2) E is closed under direct summands, thus it is idempotent complete. (3) proj \u039b \u2282 E holds. (4) E is an exact category with a progenerator \u039b.", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "5.2. Ext-perpendicular categories of modules with finite injective dimension. To check whether (JHP) holds or not, it is easier to deal with the case where the Grothendieck group is free of finite rank. Let us introduce an assumption which ensures this.", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "Assumption 5.6. There exists an artin algebra \u039b and a \u039b-module U \u2208 mod \u039b with finite injective dimension such that E is exact equivalent to \u22a5 U .", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "We give examples of such E later in Example 5.13.", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "Lemma 5.7. Let E, \u039b and U be as in Assumption 5.6. Then the following hold.", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "(1) Put n := id(U \u039b ). For every module X \u2208 mod \u039b, there exists an exact sequence", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "in mod \u039b such that each P i is finitely generated projective and \u2126 n X belongs to E. (2) The natural inclusion E \u0592\u2192 mod \u039b induces an isomorphism of the Grothendieck groups", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "Proof.", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "(1) By taking a projective resolution of X, obviously there exists a short exact sequence of the form (5.1) such that each P i is finitely generated projective. Thus it suffices to show that \u2126 n X \u2208 \u22a5 U . This is because Ext", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "This follows from (1) and Quillen's Resolution Theorem [Qui, \u00a74] on algebraic K-theory. We give an elementary proof here, which is similar as given in [Yos, Lemma 13.2] .", "cite_spans": [{"start": 55, "end": 60, "text": "[Qui,", "ref_id": "BIBREF28"}, {"start": 151, "end": 156, "text": "[Yos,", "ref_id": "BIBREF35"}], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "We shall construct the inverse of the natural homomorphism K 0 (E) \u2192 K 0 (mod \u039b). For a module X \u2208 mod \u039b, take an exact sequence of the form (5.1). Then consider the assignment X \u2192 0\u2264i<n (\u22121)", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": ". This assignment does not depend on the choice of exact sequences of the form (5.1) by the Schanuel lemma, and it respects short exact sequences by the Horseshoe lemma. Thus we obtain the map K 0 (mod \u039b) \u2192 K 0 (E). This is the desired inverse, and we leave it the reader to check the details.", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "To sum up, our exact category has the following nice properties.", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "Proposition 5.8. Let E be as in Assumption 5.6. Then the following hold.", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "(1) E is a length exact category with a progenerator.", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "(2) K 0 (E) is free of finite rank.", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "(3) rank K 0 (E) = # ind P(E) = |P | holds, where P is a progenerator of E.", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "Proof.", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "(1) follows from Propositions 5.1 (2) and 5.5 (4). (2) and (3) follows directly from Lemma 5.7 and Proposition 5.2.", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "In this situation, the positive part of the Grothendieck group of E can be identified with the set of dimension vectors of modules which belong to E.", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "Corollary 5.9. Let \u039b and E be as in Assumption 5.6, and fix a complete set of simple \u039b-modules", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "n induces an isomorphism of monoids between M(E) can \u223c = K + 0 (E) and the monoid of dimension vectors of modules in", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "Proof. This is immediate from Proposition A.15, the definition of", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "shown in Proposition 5.5 and the definition of the dimension vector. Now our previous characterization of (JHP) has rather simple consequence in this situation.", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "Theorem 5.10. Let E be an exact category which satisfies Assumption 5.6. Then E satisfies (JHP) if and only if # sim E = # ind P(E) holds, that is, the number of non-isomorphic simples in E is equal to that of non-isomorphic indecomposable projectives in E.", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "Proof. Immediately follow from Proposition 5.8 and Theorem 4.13.", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "Actually most exact categories which have been investigated in the representation theory of artin algebras satisfy Assumption 5.6. Among them, those arising from cotilting modules have been attracted an attention.", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "Definition 5.11. Let \u039b be an artin algebra. We say that a \u039b-module U \u2208 mod \u039b is cotilting if it satisfies the following conditions:", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "(1) The injective dimension of U is finite. ", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "in mod \u039b for some n such that U i \u2208 add U for each i.", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "The simplest example of cotilting modules is D\u039b. In this case, the perpendicular category \u22a5 (D\u039b) coincides with the module category mod \u039b. For a general cotilting module, though its perpendicular category \u22a5 U is not abelian, it has nice properties.", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "Proposition 5.12. Let \u039b be an artin algebra and U a cotilting \u039b-module. Put E := \u22a5 U . Then the following hold:", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "(1) E has a progenerator \u039b and an injective cogenerator U .", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "(2) K 0 (E) is a free abelian group of finite rank.", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "Proof.", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "(1) By Proposition 5.5, the exact category E has a progenerator \u039b. We refer to [AR3, Theorem 5.4] for the proof of the fact that U is an injective cogenerator of E.", "cite_spans": [{"start": 79, "end": 84, "text": "[AR3,", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "(2) This follows from Propositions 5.5 and 5.2. (3) By Propositions 5.5 and 5.2, we only have to show that # ind I(E) = |U | is equal to # ind P(E) = |\u039b|. This follows from tilting theory, e.g. [Hap] .", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "In particular, it says the number of indecomposable projectives and injectives in E coincide. In the case of mod \u039b, this number is also equal to the number of simples. Thus Theorem 5.10 says that the violation of this coincidence is nothing but an obstruction for (JHP).", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "Example 5.13. The following exact categories E satisfy Assumption 5.6, hence Theorem 5.10 holds for them.", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "(1) E := \u22a5 U for a cotilting \u039b-module U over an artin algebra \u039b. Note that # ind P(E) = # ind I(E) holds in this case, by Proposition 5.12.", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "(2) E = GP \u039b for an Iwanaga-Gorenstein artin algebra \u039b. Here \u039b is called Iwanaga-Gorenstein if id \u039b \u039b and id \u039b \u039b are both finite, and in this case, we denote by GP \u039b the category \u22a5 \u039b, called the category of Gorenstein-projective modules. (3) Functorially finite torsion-classes and torsion-free classes of mod \u039b for an artin algebra \u039b.", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "This classes of categories has been attracted an attention, since \u03c4 -tilting theory gives a powerful combinatorial tool to investigate them, e.g. [AIR] .", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "Proof.", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "(1) and (2) follow from definition. (3) is well-known to experts (e.g. see [Iya, Proposition 1.2 .1]), but we give a sketch here for the convenience of the reader. We show that a functorially finite torsion-free class F is a special case of (1). By factoring out the annihilator, we may assume that F is faithful torsion-free class of \u039b, that is, the intersection of annihilators of modules in F is zero. Then it can be shown that \u039b \u039b \u2208 F holds. The well-known characterizations on classical (co)-tilting modules tells us that F = \u22a5 U holds for a cotilting module U with id U \u2264 1.", "cite_spans": [{"start": 75, "end": 80, "text": "[Iya,", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "For a functorially finite torsion class T , the similar argument shows that T comes from the classical tilting module. Now the Brenner-Butler theorem tells us that T is exact equivalent to the torsion-free class over another algebra which is induced by some classical cotilting module. Thus T is also a special case of (1).", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "For those familiar with \u03c4 -tilting theory, we will state a consequence of our result in \u03c4 -tiltingtheoretical language. We omit the related definitions and notation, see [AIR] for the detail.", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "Corollary 5.14. Let \u039b be an artin algebra and F = Sub U a functorially finite torsion-free class of mod \u039b where U is a support \u03c4 \u2212 -tilting module. Then the following are equivalent:", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "(1) F satisfies (JHP).", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "(2) The number of non-isomorphic simple objects is equal to |U |.", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "Dually we obtain the \u03c4 -tilting and torsion-class version:", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "Corollary 5.15. Let \u039b be an artin algebra and T = Fac T a functorially finite torsion class of mod \u039b where T is a support \u03c4 -tilting. Then the following are equivalent:", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "(1) F satisfies (JHP).", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "(2) The number of non-isomorphic simple objects is equal to |T |.", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "In the case of functorially finite torsion-free classes, we obtain the following finiteness result on the positive cone M(F ) can \u223c = K + 0 (F ). Note that M(F ) itself is not in general finitely generated (see Section 8.3.1 for example).", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "Proposition 5.16. Let \u039b be an artin algebra and F a torsion-free class of mod \u039b such that F is the smallest torsion-free class which contains some \u039b-module U (for example, F is functorially finite). Then K + 0 (F ) is isomorphic to a finitely generated submonoid of N n for some n.", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "Proof. This follows from the following fact: F is described as the category of modules which have finite filtrations such that each successive quotient is a submodule of U (see [MS, Lemma 3 .1]). It follows that M(F ) is generated by {[V ] | V is a submodule of U }. By Corollary 5.9, we may identify K + 0 (F ) with the set of dimension vectors of modules in F , which is generated by the set of dimension vectors of submodules of U . This set is obviously finite, so K + 0 (F ) is finitely generated.", "cite_spans": [{"start": 177, "end": 181, "text": "[MS,", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "5.3. Torsion-free classes over Nakayama algebras. We investigate torsion-free classes over Nakayama algebras. In particular, we will show that any such categories satisfy (JHP).", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "First we recall the notion of Nakayama algebras. For an artin algebra \u039b, we say that a \u039b-module M is uniserial if the set of submodules of M is totally ordered by inclusion. An artin algebra \u039b is called Nakayama if every indecomposable right and left projective \u039b-module is uniserial. We will use the following description of indecomposable modules over Nakayama algebras (see e.g. [ASS, Chapter V] for the detail).", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "Proposition 5.17. We have the following for a Nakayama algebra \u039b.", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "(1) Every indecomposable modules in mod \u039b is uniserial.", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "(2) M \u2208 ind(mod \u039b) is uniquely determined by the following data: (a) The simple module S :", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": ", the length of M as a \u039b-module.", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "In particular, \u039b is of finite representation type. We denote this module by S (m) . We will investigate simple objects in a torsion-free class of mod \u039b for a Nakayama algebra. Note that since mod \u039b has finitely many indecomposables, every torsion-free class of mod \u039b is functorially finite, so it satisfies Assumption 5.6 by Example 5.13 (3).", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "Theorem 5.18. Let \u039b be a Nakayama algebra and F a torsion-free class of mod \u039b. Then there exists bijections between the following sets:", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "(1) top F , the set of isomorphism classes of simple modules top M for M \u2208 ind F . (2) sim F , the set of isomorphism classes of simple objects in F .", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "(3) ind P(F ), the set of isomorphism classes of indecomposable projective objects in F . The maps from (2) and (3) to (1) are given by M \u2192 top M . On the other hand, for a simple module S \u2208 top F in (1), the corresponding objects are given by S (m) in (2) and S (n) in (3), where", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "and n := max{i | S (i) \u2208 F }.", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "Proof. Let ind P(F ) denote the set of isomorphism classes of indecomposable projective objects in F , and let us denote by top : ind F \u2192 top F the map which sends M to top M . This induces maps sim F \u2192 top F and ind P(F ) \u2192 top F . We will show that these maps are bijections.", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "(top : sim F \u2192 top F is a bijection): First we show that this map is a surjection. For S \u2208 top F , put m := min{i | S (i) \u2208 F }. We claim that S (m) is a simple object in F . Suppose this is not the case. Then there exists a short exact sequence", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": ", it has top S. But this contradicts the minimality of m because 0 < l(M ) < l(S (m) ) = m holds. Thus S (m) belongs to sim F . Hence the map sim F \u2192 top F is a surjection.", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "Next we will show that this map is an injection. Suppose that this is not the case. Then there exist a simple module S and 0 < i < j such that both S (i) and S (j) are simple in F . Then we have a short exact sequence", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "in mod \u039b by Proposition 5.17 (3), and K = 0 since i = j. However, K belongs to F since F is closed under submodules. Thus the above is a conflation in F , which shows that S (j) is not a simple object in F . This is a contradiction, so sim F \u2192 top F is an injection.", "cite_spans": [], "ref_spans": []}, {"section": "(JHP) for extension-closed subcategories of module categories", "text": "It is clear from the above argument that the inverse of the map top : sim F \u2192 top F is given by S \u2192 S (m) as claimed. (ind P(F ) \u2192 top F is a bijection): First we show that this map is a surjection. Let M be an indecomposable object in F and put S := top M . Since F satisfies Assumption 5.6, it has enough projectives by Proposition 5.8", "cite_spans": [], "ref_spans": []}, {"section": "1", "text": ". Thus there exists a deflation", "cite_spans": [], "ref_spans": []}, {"section": "1", "text": "in F , where P i \u2208 ind P(F ) for each i. This map is a surjection in mod \u039b, so it induces a surjection", "cite_spans": [], "ref_spans": []}, {"section": "1", "text": "It follows that top P i = S holds for some i. This means that the map ind P(F ) \u2192 top F is surjective.", "cite_spans": [], "ref_spans": []}, {"section": "1", "text": "Next we will show that this map is an injection. Suppose that this is not the case. Then there exists a simple module S and 0 < i < j such that both S (i) and S (j) are projective objects in F . Now Proposition 5.17 (3) implies that there exists a short exact sequence", "cite_spans": [], "ref_spans": []}, {"section": "1", "text": "Since F is closed under submodules, this is a conflation in F , and since i < j, we have K = 0. However, the projectivity of S (i) implies that the above sequence splits. This is a contradiction since S (j) is indecomposable. This completes the proof that top : ind P(F ) \u2192 top F is a bijection.", "cite_spans": [], "ref_spans": []}, {"section": "1", "text": "Finally, we shall describe the inverse of top : ind P(F ) \u2192 top F . For an object S \u2208 top F , put n := max{i | S (i) \u2208 F }, and we claim that the map S \u2192 S (n) is the inverse. Suppose that 1 \u2264 i < n and S (i) belongs to F . Then as in the proof of injectivity, we have a conflation in F", "cite_spans": [], "ref_spans": []}, {"section": "1", "text": "with K = 0 and this sequence does not split since S (n) is indecomposable. Thus S (i) cannot be projective in F . By this fact and the fact that top : ind P(F ) \u2192 top F is surjective, we must have that the inverse of this map is given by S \u2192 S (n) .", "cite_spans": [], "ref_spans": []}, {"section": "1", "text": "As an immediate corollary, we obtain the following result.", "cite_spans": [], "ref_spans": []}, {"section": "1", "text": "Corollary 5.19. Let \u039b be a Nakayama algebra and F a torsion-free class of mod \u039b. Then F satisfy (JHP).", "cite_spans": [], "ref_spans": []}, {"section": "1", "text": "Proof. By Theorem 5.10, it suffices to show that # sim F = # ind P(F ) holds. This follows from Theorem 5.18.", "cite_spans": [], "ref_spans": []}, {"section": "Torsion-free classes of Type A and Bruhat inversion", "text": "In this section, we investigate simple objects in a torsion-free class of the category of representation of type A quiver by using the combinatorics of the symmetric group. For a quiver Q, we denote by kQ the path algebra of Q over a field k. As usual, we identify representations of Q with right kQ-modules.", "cite_spans": [], "ref_spans": []}, {"section": "Torsion-free classes of Type A and Bruhat inversion", "text": "For an acyclic quiver Q, a classification of torsion-free classes of mod kQ with finitely many indecomposables is known: they are in bijection with so called c-sortable elements of the Coxeter group of Q ( [IT] for a Dynkin quiver and [AIRT, Tho] for a general quiver). For a type A quiver, the corresponding Coxeter group is just a symmetric group, and we can describe all indecomposable kQ-modules in a quite explicit way. In this section, we freely use these description particular to type A, but in a forthcoming paper [Eno3] , we will show that the results are valid in other Dynkin types, or more generally, preprojective algebras of Dynkin types (see Remark 6.19).", "cite_spans": [{"start": 523, "end": 529, "text": "[Eno3]", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Torsion-free classes of Type A and Bruhat inversion", "text": "6.1. Bruhat inversions of elements in the symmetric group. First we recall combinatorial notions on the symmetric groups we need later. These notions are well-studied in the context of Coxeter groups, but we give explicit description for type A case here for the convenience of the reader. The standard reference is [BB] .", "cite_spans": [], "ref_spans": []}, {"section": "Torsion-free classes of Type A and Bruhat inversion", "text": "We denote by S n+1 the symmetric group which acts on the set {1, 2, \u00b7 \u00b7 \u00b7 , n, n + 1} from left. We often use the one-line notation to represent elements of S n+1 , that is, we write w = w(1)w(2) \u00b7 \u00b7 \u00b7 w(n + 1) for w \u2208 S n+1 . We denote by (i j) for 1 \u2264 i, j \u2264 n + 1 the transposition of the letters i and j, and write T for the set of all transpositions in S n+1 . Then S n+1 is generated by the simple reflections s i := (i i + 1) for 1 \u2264 i \u2264 n. We write S for the set of all simple reflections. For example, we have s 2 s 1 s 3 s 2 = 3412 in S 4 .", "cite_spans": [], "ref_spans": []}, {"section": "Torsion-free classes of Type A and Bruhat inversion", "text": "Note that for a transposition t = (i j) and w \u2208 S n+1 , the element tw is obtained by interchanging two letters i and j in the one-line notation for w, e.g. we have (3 4) \u00b7 3412 = 4312.", "cite_spans": [], "ref_spans": []}, {"section": "Torsion-free classes of Type A and Bruhat inversion", "text": "Each element w \u2208 S n+1 can be written as a product of simple reflections:", "cite_spans": [], "ref_spans": []}, {"section": "Torsion-free classes of Type A and Bruhat inversion", "text": "This expression of w is called reduced if l is the minimal among all such expressions. In this case, l is called the length of w and we write \u2113(w) := l.", "cite_spans": [], "ref_spans": []}, {"section": "Torsion-free classes of Type A and Bruhat inversion", "text": "For an element w \u2208 S n+1 , a transposition t \u2208 T is called an inversion of w if \u2113(tw) < \u2113(w) holds, and we denote by inv(w) the set of all inversions of w. It is known that a transposition (i j) with i < j is an inversion of w if and only if j precedes i in the one-line notation for w, that is,", "cite_spans": [], "ref_spans": []}, {"section": "Torsion-free classes of Type A and Bruhat inversion", "text": "It is well-known that \u2113(w) = # inv(w) holds. The following class of inversions plays an important role in this paper, since we shall see that this corresponds to simple objects in a torsion-free class. Definition 6.2. We say that an inversion t of an element w \u2208 S n+1 is a Bruhat inversion of w if it satisfies \u2113(tw) = \u2113(w) \u2212 1. We denote by Binv(w) the set of Bruhat inversions of w.", "cite_spans": [], "ref_spans": []}, {"section": "Torsion-free classes of Type A and Bruhat inversion", "text": "We can interpret Bruhat inversions in terms of the cover relation of the Bruhat order. Recall that the Bruhat order on S n+1 is a partial order \u2264 generated by the following relation: for every t \u2208 T and w \u2208 S n+1 with \u2113(tw) < \u2113(w), we have that tw < w holds. In what follows, we always denote by \u2264 (and <) the Bruhat order on S n+1 .", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 6.3 ([BB, Lemma 2.1.4]).", "text": "For a transposition t = (i j) \u2208 T with i < j and an element w \u2208 S n+1 , the following are equivalent:", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 6.3 ([BB, Lemma 2.1.4]).", "text": "(1) t is a Bruhat inversion of w.", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 6.3 ([BB, Lemma 2.1.4]).", "text": "(2) tw is covered by w in the Bruhat order, that is, tw < w holds and there exists no element u \u2208 S n+1 satisfying tw < u < w. (3) In the one-line notation for w, the letter j precedes i, and there exists no l with i < l < j such that the letter l appears between j and i. (4) (i j) \u2208 inv(w) and there exists no l with i < l < j satisfying (i l), (l j) \u2208 inv(w). (1) For w 1 = 45231 we have:", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 6.3 ([BB, Lemma 2.1.4]).", "text": "Binv(w 1 ) = {(1 2), (1 3), (2 4), (2 5), (3 4), (3 5)}.", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 6.3 ([BB, Lemma 2.1.4]).", "text": "(2) For w 2 = 54213 we have:", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 6.3 ([BB, Lemma 2.1.4]).", "text": "Binv(w 2 ) = {(1 2), (2 4), (3 4), (4 5)} Note that # inv(w 1 ) = # inv(w 2 ) = 8 but Binv(w 1 ) = 6 > 4 = Binv(w 2 ).", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 6.3 ([BB, Lemma 2.1.4]).", "text": "We will use the notion of support of elements in S n+1 .", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 6.3 ([BB, Lemma 2.1.4]).", "text": "Definition 6.5. Let w be an element of S n+1 . Then i \u2208 {1, \u00b7 \u00b7 \u00b7 , n} is called a support of w if there exists some reduced expression of w which contains s i . We denote by supp(w) the set of all supports of w. We say that w has full support if supp(w) = {1, 2, \u00b7 \u00b7 \u00b7 , n}.", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 6.3 ([BB, Lemma 2.1.4]).", "text": "In fact, if i is in supp(w), then any reduced expression of w contains s i ( [BB, Corollary 1.4.8] ). We will use the following characterization of the support later.", "cite_spans": [{"start": 77, "end": 81, "text": "[BB,", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Lemma 6.3 ([BB, Lemma 2.1.4]).", "text": "Lemma 6.6. For w \u2208 S n+1 and i \u2208 {1, \u00b7 \u00b7 \u00b7 , n}, the following are equivalent:", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 6.3 ([BB, Lemma 2.1.4]).", "text": "(1) i \u2208 supp(w).", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 6.3 ([BB, Lemma 2.1.4]).", "text": "(2) There exists some j with 1 \u2264 j \u2264 i such that w \u22121 (j) > i, that is, j does not appear in the initial segment of length i in the one-line notation for w. (3) There exists some j with 1 \u2264 j \u2264 i such that w(j) > i. (4) There exists some l with i < l such that l appears in the initial segment of length i in the one-line notation for w.", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 6.3 ([BB, Lemma 2.1.4]).", "text": "For example, by Using this criterion, we can easily check that supp(45231) = {1, 2, 3, 4, 5}, supp(21543) = {1, 3, 4}, and supp(12543) = {3, 4}.", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 6.3 ([BB, Lemma 2.1.4]).", "text": "6.2. Coxeter element, c-sortable elements and torsion-free classes. We will recall the Ingalls-Thomas bijection [IT] between sortable elements and torsion-free classes in the case of type A quiver, following [Tho] . In what follows, Q is a quiver of type A with n vertices, whose underlying graph is the following:", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 6.3 ([BB, Lemma 2.1.4]).", "text": "As usual, we identify right kQ-modules over the path algebra Q and representations of Q. For a kQ-module M and a vertex i of Q, we denote by M i the vector space attached to i. A Coxeter element of S n+1 is an element c \u2208 S n+1 obtained as the product of all simple reflections s 1 , \u00b7 \u00b7 \u00b7 , s n \u2208 S in some order, or equivalently, an element with length n which has full support. We say that a Coxeter element c is associated to Q if s i appears before s j in c whenever there is an arrow i \u2190 j in Q. It is known that Coxeter elements are in bijection with orientations of edges in the underlying graph of Q.", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 6.3 ([BB, Lemma 2.1.4]).", "text": "Example 6.7. We give an example of the correspondence between Coxeter elements in S 4 and orientations of A 3 quiver.", "cite_spans": [], "ref_spans": []}, {"section": "Orientations of", "text": "In what follows, we adopt the following convention:", "cite_spans": [], "ref_spans": []}, {"section": "Orientations of", "text": "Assumption 6.8. Q is a quiver of type A with n vertices, whose underlying graph is given by 1 2 \u00b7 \u00b7 \u00b7 n and c is the Coxeter element of S n+1 associated with Q.", "cite_spans": [], "ref_spans": []}, {"section": "Orientations of", "text": "Torsion-free classes of mod kQ are classified by the combinatorial notion called c-sortable elements, which was introduced by Reading [Rea] .", "cite_spans": [], "ref_spans": []}, {"section": "Orientations of", "text": "Definition 6.9. Let c be a Coxeter element of S n+1 . We say that an element w of S n+1 is c-sortable if there exists a reduced expression of the form w = c", "cite_spans": [], "ref_spans": []}, {"section": "Orientations of", "text": "Now we can state the correspondence between c-sortable elements and torsion-free classes. First let us observe that ind(mod kQ) is parametrized by transpositions. Here a support of a module M \u2208 mod kQ is a vertex i with M i = 0, and we denote by [i, j) the set of elements l \u2208 {1, 2, \u00b7 \u00b7 \u00b7 , n} with i \u2264 l < j. The following is just a restatement of the well-known classification of indecomposable representations of type A quiver.", "cite_spans": [], "ref_spans": []}, {"section": "Orientations of", "text": "Proposition 6.10. Let Q be a quiver as in Assumption 6.8. For a transposition (i j) \u2208 T with i < j, there exists a unique indecomposable module M := M [i,j) in mod kQ with its support [i, j). This module is a representation of Q defined by the following:", "cite_spans": [], "ref_spans": []}, {"section": "Orientations of", "text": "\u2022 For vertices, Example 6.11. Let Q be the quiver Q = 1 \u2192 2 \u2190 3. Then the Auslander-Reiten quiver of mod kQ is as follows, where indecomposables are labelled according to Proposition 6.10.", "cite_spans": [], "ref_spans": []}, {"section": "Orientations of", "text": "Now torsion-free classes of mod kQ are classified as follows. Here a support of a subcategory F of mod kQ is the union of supports of modules in F .", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 6.12 ([Tho, Theorem 4.2])", "text": ". Let Q and c be as in Assumption 6.8. For w \u2208 S n+1 , define the subcategory F (w) of mod kQ by", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 6.12 ([Tho, Theorem 4.2])", "text": "then the following hold.", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 6.12 ([Tho, Theorem 4.2])", "text": "(1) If w is c-sortable, then F (w) is a torsion-free class of mod kQ, and the bijection T", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 6.12 ([Tho, Theorem 4.2])", "text": "(2) The map w \u2192 F (w) gives a bijection between c-sortable elements of S n+1 and torsion-free classes of mod kQ. (3) Let w be a c-sortable element. Then supp(w) coincides with the support of F (w), and the equality # supp(w) = # ind P(F (w)) = # ind I(F (w)) holds.", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 6.12 ([Tho, Theorem 4.2])", "text": "Proof. The proof is essentially contained in other references such as [Tho] , but we will clarify the relation between our convention and others, which use the language of root systems. We freely use basics of the root system. Let \u03a6 be a root system of type A n whose Dynkin graph is as in Assumption 6.8, and let e 1 , \u00b7 \u00b7 \u00b7 , e n be set of simple roots corresponding to vertices 1, \u00b7 \u00b7 \u00b7 , n. We identify S n+1 with the Weyl group W of \u03a6 as usual. Under this identification, a transposition (i j) of S n+1 corresponds to a reflection with respect to a positive root \u03b1 [i,j) := l\u2208[i,j) e l . By this, the set of transpositions are in bijection with the set of positive roots.", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 6.12 ([Tho, Theorem 4.2])", "text": "For a kQ-module M , we define the dimension vector dim M by dim M : and M [i,j) corresponds to a positive root", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 6.12 ([Tho, Theorem 4.2])", "text": "The following description of inv(w) is well-known, see e.g. [BB, Proposition 4.4.6 ", "cite_spans": [{"start": 60, "end": 64, "text": "[BB,", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "]:", "text": "Lemma 6.13. Let t \u2208 S n+1 = W be a transposition, \u03b1 \u2208 \u03a6 the positive root corresponding to t and w = s i1 s i2 \u00b7 \u00b7 \u00b7 s ir a reduced expression of arbitrary w \u2208 W . Then t \u2208 inv(w) if and only if \u03b1 = s i1 s i2 \u00b7 \u00b7 \u00b7 s i l\u22121 (e i l ) for some 1 \u2264 l \u2264 r. Now return to our proof. (1) and (2) follow from [Tho, Theorem 4 .2] and our above identification. Let us prove (3).", "cite_spans": [{"start": 301, "end": 306, "text": "[Tho,", "ref_id": "BIBREF27"}], "ref_spans": []}, {"section": "]:", "text": "Let w be a c-sortable element. By Example 5.13, the equality # ind P(F (w)) = # ind I(F (w)) holds. On the other hand, the number of supports of F (w) is equal to # ind I(F (w)) by the general theory of support (\u03c4 -)tilting theory, see e.g. [IT, Proposition 2.5(4) , Lemma 2.9] or [AIR, Theorem 2.7] . Thus it suffices to show that the number of supports of F (w) is equal to # supp(w).", "cite_spans": [{"start": 281, "end": 286, "text": "[AIR,", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "]:", "text": "Take a reduced expression", "cite_spans": [], "ref_spans": []}, {"section": "]:", "text": "is a subword of c and satisfies (m) ). First suppose that l \u2208 supp(w), which means that s l appears in the word c (0) . Then we can write the reduced expression of c (0) as c (0) = c \u2032 s l c \u2032\u2032 such that c \u2032 (and c \u2032\u2032 ) does not contain the letter s l . Let (i j) be a transposition which corresponds to a positive root \u03b1 := c \u2032 (e l ), then it belongs to inv(w) by Lemma 6.13. Clearly the e l -component of \u03b1 is equal to 1, thus l is a support of", "cite_spans": [], "ref_spans": []}, {"section": "]:", "text": "Conversely, suppose that l is a support of M := M [i,j) for some (i j) \u2208 inv(w). Take a positive root which corresponds to (i j). Then we have dim M = \u03b1, thus the e l -component of \u03b1 is strictly positive. On the other hand, Lemma 6.13 shows that l must be appear in a reduced expression of w, thus l \u2208 supp(w).", "cite_spans": [], "ref_spans": []}, {"section": "]:", "text": "6.3. Bruhat inversions and simples. Our main result in this section is the following, which establishes a bijection between simples in F (w) and Bruhat inversions of w.", "cite_spans": [], "ref_spans": []}, {"section": "]:", "text": "Theorem 6.14. Let Q and c be as in Assumption 6.8 and w a c-sortable element of S n+1 . Then the natural bijection inv(w) \u223c \u2212 \u2192 ind F (w) restricts to a bijection Binv(w) \u2192 sim F (w). In other words, for (i j) \u2208 inv(w) with i < j, the object M [i,j) is simple in F (w) if and only if (i j) is a Bruhat inversion of w.", "cite_spans": [], "ref_spans": []}, {"section": "]:", "text": "Before we give a proof, let us state the immediate consequence of this, which characterizes (JHP) in a purely combinatorial way. See Example 6.17 for the actual example of Theorem 6.14 and Corollary 6.15. Proof. Theorem 6.14 implies that # sim F (w) = # Binv(w) holds. On the other hand, Theorem 6.12 implies that # ind P(F (w)) = # supp(w) holds. Thus our assertion follows from Theorem 5.10.", "cite_spans": [], "ref_spans": []}, {"section": "]:", "text": "To prove Theorem 6.14, we use the following explicit exact sequences in mod kQ.", "cite_spans": [], "ref_spans": []}, {"section": "]:", "text": "Lemma 6.16. Let (i j) be a transposition in S n+1 with i < j and consider the kQ-module M [i,j) given by Proposition 6.10. Then the following hold.", "cite_spans": [], "ref_spans": []}, {"section": "]:", "text": "(1) For each l with i < l < j, exactly one of the following two exact sequences exists:", "cite_spans": [], "ref_spans": []}, {"section": "]:", "text": ", and there exists an exact sequence", "cite_spans": [], "ref_spans": []}, {"section": "]:", "text": "Moreover, there exists two exact sequences:", "cite_spans": [], "ref_spans": []}, {"section": "]:", "text": "Here we put M [a,a) = 0.", "cite_spans": [], "ref_spans": []}, {"section": "]:", "text": "Proof.", "cite_spans": [], "ref_spans": []}, {"section": "]:", "text": "(1) Consider the orientation of the edge between l \u2212 1 and l in Q. Suppose that we have l \u2212 1 \u2190 l in Q. Then we claim that a subspace M [i,l) is a submodule of M [i,j) . This M [i,l) is closed under the action of Q in M [i,j) because there exists no path which starts from one of [i, l) and ends at one of [l, j) . Now the existence of (6.1) is clear. By the same reason, if we have l \u2212 1 \u2192 l in Q, then we have (6.2).", "cite_spans": [], "ref_spans": []}, {"section": "]:", "text": ", and it is easily checked that the action of kQ on this quotient coincides with that on", "cite_spans": [], "ref_spans": []}, {"section": "]:", "text": "Thus we obtain (6.3). Moreover, since", "cite_spans": [], "ref_spans": []}, {"section": "]:", "text": ", we must have that either i = l or l \u2212 1 \u2192 l in Q holds, and that either l \u2032 = j or l \u2032 \u2212 1 \u2190 l \u2032 in Q holds. Thus the existence of two exact sequences (6.4) and (6.5) follows from the proof of (1).", "cite_spans": [], "ref_spans": []}, {"section": "]:", "text": "Proof of Theorem 6.14. Let (i j) with i < j is an inversion of w. Since any simple object is indecomposable, it suffices to show that (i j) is a Bruhat inversion of w if and only if M [i,j) is simple in F (w).", "cite_spans": [], "ref_spans": []}, {"section": "]:", "text": "First, suppose that (i j) is not a Bruhat inversion of w. Then by Proposition 6.3, there exists some l with i < l < j such that both (i l) and (l j) belong to inv(w). Thus both M [i,l) and M [l,j) belong to F (w). Now we have an exact sequence (6.1) or (6.2) by Lemma 6.16. In either case, this gives a conflation in F (w), and since M [i,l) and M [l,j) ", "cite_spans": [], "ref_spans": []}, {"section": "]:", "text": "Conversely, suppose that M [i,j) is not a simple object in F (w). Then we have a non-isomorphic inflation N M [i,j) in F (w) for some object 0 = N of F (w). Take an indecomposable direct summand", "cite_spans": [], "ref_spans": []}, {"section": "]:", "text": "\u0592\u2192 N is an inflation and inflations are closed under compositions. Now Lemma 6.16 (2) tells us that [l,", "cite_spans": [], "ref_spans": []}, {"section": "]:", "text": "is not an isomorphism, we have i < l < j or i < l \u2032 < j. Suppose we have the former. Then since M [i,l) \u2208 F (w), the transposition (i l) is an inversion of w. On the other hand, the exact sequence (6.5) of Lemma 6.16 implies that M [l,j) belongs to F (w), since F (w) is closed under submodules. Thus (l j) is also an inversion of w. This implies that (i j) is not a Bruhat inversion by Lemma 6.3. The case i < l \u2032 < j is completely similar, except we use (6.4) instead of (6.5).", "cite_spans": [], "ref_spans": []}, {"section": "]:", "text": "Example 6.17. Let us look at several examples.", "cite_spans": [], "ref_spans": []}, {"section": "]:", "text": "(1) Let Q be the quiver Q = 1 \u2192 2 \u2190 3. Then the Coxeter element associated with Q is c = s 2 s 1 s 3 = 3142 \u2208 S 4 . In Table 1 , we list all c-sortable elements and the corresponding inversions, Bruhat inversions and torsion-free classes. The black vertices indicate simple objects in F (w) and the white ones indicate the rest of indecomposables in F (w). According to this table, we conclude that F (w) satisfies (JHP) except for the case w = 3412. (2) Let Q be the quiver Q = 1 \u2190 2 \u2192 3 \u2190 4. The associated Coxeter element is c = s 1 s 3 s 2 s 4 = 24153 \u2208 S 5 . The Auslander-Reiten quiver of mod kQ is as follows:", "cite_spans": [], "ref_spans": []}, {"section": "]:", "text": "In Table 2 , we list all faithful torsion-free classes of mod kQ, which corresponds to csortable elements with full support. Here as in (1), the black vertices indicate simple objects in F (w) and the white the rest. From this table, for example, we can check that the number of faithful torsion-free classes satisfying (JHP) is 8. By using the computer program, we can calculate that the number of all torsion-free classes is 42, which is the Catalan number, and 34 ones among them satisfy (JHP).", "cite_spans": [], "ref_spans": []}, {"section": "]:", "text": "As an application of Corollary 6.15, we obtain the following result on a linearly oriented quiver. The proof is purely combinatorial. Note that this follows also from Corollary 5.19, since kQ in this case is a Nakayama algebra.", "cite_spans": [], "ref_spans": []}, {"section": "]:", "text": "Corollary 6.18. Let Q be a linearly oriented quiver of type A. Then every torsion-free classes F of mod kQ satisfies (JHP). Table 1 . Example of Theorem 6.14 for Q = 1 \u2192 2 \u2190 3 c-sortable elements w supp(w) inv(w) Binv(w) Proof. We may assume that Q is 1 \u2192 2 \u2192 \u00b7 \u00b7 \u00b7 \u2192 n, so c = s n \u00b7 \u00b7 \u00b7 s 2 s 1 . To prove the assertion, we use the combinatorial characterization of c-sortable elements given in [Rea, Theorem 4.12] : an element w \u2208 S n+1 is c-sortable if it is 231-avoiding, that is, there exists no i < l < j such that l appears before j and j appears before i in the one-line notation for w. Then according to Corollary 6.15, the assertion amounts to the following purely combinatorial lemma (or equivalently, this lemma follows from two categorical statements: Corollaries 6.15 and 5.19).", "cite_spans": [{"start": 396, "end": 401, "text": "[Rea,", "ref_id": "BIBREF30"}], "ref_spans": []}, {"section": "]:", "text": "Lemma. For every 231-avoiding element w of S n+1 , we have # Binv(w) = # supp(w).", "cite_spans": [], "ref_spans": []}, {"section": "]:", "text": "To prove this lemma, we will construct an explicit bijection Binv(w)", "cite_spans": [], "ref_spans": []}, {"section": "]:", "text": "In what follows, we will work on the one-line notation for w. Table 2 . Example of Theorem 6.14 for faithful torsion-free classes over Let (i j) be a Bruhat inversion of w with i < j. We claim that i \u2208 supp(w) holds. If this is not the case, then the initial segment of length i contains exactly 1, 2, \u00b7 \u00b7 \u00b7 , i by Lemma 6.6. This is a contradiction since j(> i) appears before i by (i j) \u2208 inv(w). Thus i \u2208 supp(w) holds, and we obtain a map Binv(w) \u2192 supp(w) by (i j) \u2192 i.", "cite_spans": [], "ref_spans": []}, {"section": "]:", "text": "We will show that this map is an injection. Suppose (i j 1 ) and (i j 2 ) are two different Bruhat inversion of w with i < j 1 < j 2 , so j 1 and j 2 appears before i. Then j 1 must appear before j 2 , since otherwise (i j 2 ) would not be a Bruhat inversion. Thus w looks like \u00b7 \u00b7 \u00b7 j 1 \u00b7 \u00b7 \u00b7 j 2 \u00b7 \u00b7 \u00b7 i \u00b7 \u00b7 \u00b7 , which contradicts to that w is 231-avoiding. Thus this map is an injection.", "cite_spans": [], "ref_spans": []}, {"section": "]:", "text": "Next we will show that this map is a surjection. Let i be a support of w. We claim that there exists some letter j such that i < j and j appears before i. By Lemma 6.6, there exists some l with l > i such that l appears in the initial segment of length i. Suppose that any letters left to i are less than i, that is, there is no j as in the above claim. Then in particular i belongs to the initial segment of length i, and is left to l. Also by Lemma 6.6 (2), there exists a letter i \u2032 with i \u2032 \u2264 i such that i \u2032 does not appear in the initial segment of length i. However we have i \u2032 = i holds thus i \u2032 < i, since i appears in the initial segment of length i. Now we have i \u2032 < i < l and w looks like\u00b7 \u00b7 \u00b7 i \u00b7 \u00b7 \u00b7 l \u00b7 \u00b7 \u00b7 i \u2032 \u00b7 \u00b7 \u00b7 , which contradicts to that w is 231-avoiding. Thus the claim follows, that is, there exists some letter j such that i < j and j appears before i. Take the rightmost letter j with this property. Then (i j) is clearly a Bruhat inversion. Thus the map Binv(w) \u2192 supp(w) is surjective.", "cite_spans": [], "ref_spans": []}, {"section": "]:", "text": "Remark 6.19. In a forthcoming paper [Eno3] , we will show that the natural analogue for Theorem 6.14 holds for mod kQ with an arbitrary Dynkin quiver Q, or more generally, for mod \u03a0 for a preprojective algebra \u03a0 of an arbitrary Dynkin type.", "cite_spans": [{"start": 36, "end": 42, "text": "[Eno3]", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "So far, we do not know any method to compute the Grothendieck monoid M(E) for a given length exact category E in general, except the following information:", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "\u2022 M(E) is just a free monoid if E turns out to satisfy (JHP) (Theorem 4.9).", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "\u2022 The cancellative quotient M(E) can , which is isomorphic to the positive part K + 0 (E) of the Grothendieck group (Proposition A.15), is nothing but the monoid of dimension vectors of modules belonging to E under mild assumption (Corollary 5.9).", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "Thus the problem is: we do not know how to check whether M(E) is cancellative or not (if M(E) is cancellative, then M(E) can be calculated in principle by the above), and the calculation seems to be rather difficult if M(E) is not cancellative.", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "In this section, we will show (a bit artificial) examples of calculations of M(E) such that M(E) is not cancellative. 7.1. A category of modules with a designated set of dimension vectors. We will convince the reader that lots of monoids can appear as the Grothendieck monoids of exact categories. First we consider the case of split exact categories.", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "Proposition 7.1. Let E be a split exact category, that is, every conflation splits. Then M(E) is isomorphic to Iso E (with addition given by \u2295) as monoids.", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "Proof. This follows from the construction given in Proposition 3.3, or one can show this by checking the universal property directly. The details are left to the reader.", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "Using this, we can realize any submonoids of N n as Grothendieck monoids.", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "Proposition 7.2. Let M be a submonoid of N n for some n \u2265 0. Then there exists a split exact category E such that M(E) \u223c = M holds.", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "Proof. Let k be a field and consider a semisimple k-algebra \u039b := k n . Then \u039b has n non-isomorphic simple modules, and we denote by dim X \u2208 N n for X \u2208 mod \u039b the dimension vector of X, see Definition 5.3. Define the full subcategory E of mod \u039b by the following:", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "This is an extension-closed subcategory of mod \u039b, and we claim that M(E) \u223c = M holds. First observe that every short exact sequence in mod \u039b splits, so E is a split exact category. Thus it suffices to show that Iso E \u223c = M as monoids by Proposition 7.1. It is easy to see that Iso(mod \u039b) \u223c = N n holds by the map X \u2192 dim X, and by construction, this map restricts an isomorphism Iso E \u223c = M .", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "If E is a full subcategory of a module category, then by regarding E as an exact category with a split exact structure, Proposition 7.1 shows that our monoid M(E) only concerns with direct sum decompositions of modules. In this case, M(E) is free if and only if the uniqueness of direct sum decompositions holds (e.g. Krull-Schmidt categories), thus the combinatorial property of the monoid M(E) encodes information on the non-unique direct sum factorizations of modules. This has been studied by several authors (e.g. [Fac1, Fac2, BaGe] ), and we refer the reader to the recent article [BaGe] and references therein for more information on this direction.", "cite_spans": [{"start": 519, "end": 525, "text": "[Fac1,", "ref_id": "BIBREF17"}, {"start": 526, "end": 531, "text": "Fac2,", "ref_id": "BIBREF18"}, {"start": 532, "end": 537, "text": "BaGe]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "In a similar way to the construction of E above, we can attach extension-closed subcategories of module categories to any submonoids of K 0 (mod \u039b) for an artin algebra \u039b.", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "Definition 7.3. Let \u039b be an artin algebra with n non-isomorphic simple modules. For a submonoid M of N n , we define the subcategory E M of mod \u039b by the following:", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "Then it is an extension-closed subcategory of mod \u039b, thus an exact category.", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "By the universal property of M(E M ), we have a monoid homomorphism M(E M ) \u2192 M induced by dim. It seems that M(E M ) is somewhat closer to M , and the next proposition shows that M(E M ) is a thickening of M by some non-cancellative part:", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "Proposition 7.4. Let \u039b be an artin algebra with n non-isomorphic simple modules and M a submonoid of N n . Then dim :", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "Proof. Let us introduce some notation. Write E := E M for simplicity. Let S i denote the simple \u039b-module with dim S i = e i for 1 \u2264 i \u2264 n, where e i is the standard basis of N n . For an element d \u2208 N n , we denote by S d the unique semisimple \u039b-module satisfying dim", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "Thus, to prove M(E) can \u223c = M , it suffices to show that for two objects X, Y \u2208 E, we have [X] \u223c can [Y ] in M(E) if and only if dim X = dim Y holds (see Proposition A.15). The \"only if\" part is clear since N n (or M ) is cancellative, so we will prove the \"if\" part. Suppose that X, Y \u2208 E satisfy dim X = dim Y , and put d :", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "Let l max (X) be the maximum of lengths of indecomposable direct summands of X, and we show [X] \u223c can [S d ] by induction on l := l max (X). If l = 1, then X is semisimple and X \u223c = S d holds. Suppose l > 1, and take a direct summand X 1 of X with l(X 1 ) = l. We have X = X 1 \u2295 X/X 1 , and take a simple submodule S of X 1 . Note that S is a direct summand of S d since S is a composition factor of X. Thus there are two exact sequences in mod \u039b:", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "where the second one is just a split exact sequence. By taking direct sum of these two sequences, we obtain the following exact sequence.", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "The dimension vectors of terms of this exact sequence is d, 2d and d respectively, so this is a conflation of E. Therefore, we have", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "holds, where X \u2032 = S \u2295 X 1 /S \u2295 X/X 1 . Thus we can replace the direct summand X 1 of X with S \u2295 X 1 /S. By iterating this process to all direct summands of X with length l, we obtain an object Z in E such that l max (Z) < l and [X] \u223c can [Z] . Thus the claim follows from induction.", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "Thus our category E M has a monoid M as a cancellative quotient of its Grothendieck monoid M(E M ), but M(E M ) is not cancellative in general. In the next subsection, we give an example of computation of M(E M ).", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "7.2. The case of A 2 quiver and monoids with one generator. Throughout this subsection, we denote by k a field and by Q a quiver 1 \u2190 2, and put \u039b := kQ. Although the structure of the category mod \u039b seems to be completely understood, this category has lots of extension-closed subcategories, and the computation of their Grothendieck monoids is rather hard as we shall see in this subsection.", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "First we recall basic properties of the category mod \u039b. We have the complete list of indecomposable objects in mod \u039b: two simple modules S 1 and S 2 , which are supported at vertices 1 and 2 respectively, and one non-simple projective injective module P . The Grothendieck group K 0 (mod \u039b) is a free abelian group with basis {[S 1 ], [S 2 ]}, and we identify it with Z 2 . Now we apply the construction E M defined in the previous subsection to this case, where M is a submonoid of N 2 . We will compute the monoid M(E M ) in the case that M is generated by one element. In such a case, by Proposition 7.4, M(E M ) can \u223c = N holds, thus M(E M ) is a thickening of N in some sense.", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "To present the monoid structure, we will use the Cayley quiver, which is a monoid version of the Cayley graph of a group.", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "Definition 7.5. Let M be a monoid with a set of generators A \u2282 M . Then the Cayley quiver of M with respect to A is a quiver defined as follows:", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "\u2022 The vertex set is M .", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "\u2022 For each a \u2208 A and m \u2208 M , we draw a (labelled) arrow m a \u2212 \u2192 m + a.", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "For an atomic monoid M , the natural choice of A above is the set Atom M of all atoms of M . Now we can state our computation.", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "Proposition 7.6. Let M := N(m, n) be a submonoid of N 2 generated by (m, n) \u2208 N 2 with (m, n) = (0, 0). Consider the exact category E := E M as in Definition 7.3. Then the following hold, where we set l := min{m, n}.", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "(1) E has exactly l + 1 distinct simple objects A 0 , \u00b7 \u00b7 \u00b7 , A l , where", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "which are precisely the atoms of M(E). Then the Cayley quiver of M(E) with respect to Atom M(E) is given as follows, where we draw arrows \u0589 to represent l + 1 arrows a 0 , \u00b7 \u00b7 \u00b7 , a l .", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "\u2022 (Case 1) The case m = n:", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "an an an an", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "Here non-labelled usual arrows \u2192 represent n arrows a 0 , \u00b7 \u00b7 \u00b7 , a n\u22121 .", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "Proof. For simplicity, put E := E M .", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "(1) It is clear that each A i is a simple object in E since dim A i = (m, n), and that A i \u223c = A j holds if and only if i = j. On the other hand, we claim that every object in E is a direct sum of A i 's, which clearly implies the assertion. In fact, take an object X \u2208 E with dim X = (N m, N n) for N > 0. Then X is isomorphic to", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "for some 0 \u2264 i \u2264 N l. Take any integers i 1 , i 2 , \u00b7 \u00b7 \u00b7 , i N such that 0 \u2264 i j \u2264 l for each j and i = i 1 + \u00b7 \u00b7 \u00b7 + i N . Then it is straightforward to see that X \u223c = A i1 \u2295 \u00b7 \u00b7 \u00b7 \u2295 A iN holds.", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "(2) By Proposition 3.6, we have that Atom M(E) = {a 0 , a 1 , \u00b7 \u00b7 \u00b7 , a l } holds for a i := [A i ], and all of them are distinct. On the other hand, we have a map \u03d5 : M(E) \u2192 N which sends an object X with dim X = (N m, N n) to N for N \u2208 N. This map is clearly a surjection (and actually this is the universal cancellative quotient of M(E) by Proposition 7.4, but this fact is not needed here). Denote by M(E) N the inverse image \u03d5 \u22121 (N ), and our strategy to compute", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "Moreover, since every object of E is a direct sum of A i 's, we have x \u2208 M(E) N if and only if there exist integers 0 \u2264 i 1 , \u00b7 \u00b7 \u00b7 , i N \u2264 l satisfying x = a i1 + \u00b7 \u00b7 \u00b7 + a iN . The key part of our computation is to show the following equality in M(E):", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "(Claim 1): For 1 \u2264 i \u2264 l and 0 \u2264 j \u2264 l, we have the equality a i + a j = a i\u22121 + a j in M(E), except the case j = m = n.", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "Proof of Claim 1. First, note that we have the following exact sequence in mod \u039b.", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "Suppose that the equality j = m = n does not hold, then one can easily check that either j \u2264 m\u22121 or j \u2264 n \u2212 1 (or both) holds. Suppose the former, and consider a split exact sequence below", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "By taking direct sum of the above two exact sequences, one obtains a conflation in E:", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "Thus a i + a j = a i\u22121 + a j holds in M(E). Similarly, suppose that j \u2264 n \u2212 1 holds. Then by considering the following split sequence", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "as in the previous case, we obtain a conflation", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "which shows a i + a j = a i\u22121 + a j as well. This finishes the proof of Claim 1. In what follows, we consider two cases.", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "(Case 1): The case m = n. For every i, j with 0 \u2264 i \u2264 l and 0 \u2264 j \u2264 l, we have a i + a j = a i\u22121 + a j = \u00b7 \u00b7 \u00b7 = a 0 + a j = a 0 + a j\u22121 = \u00b7 \u00b7 \u00b7 = a 0 + a 0 = 2a 0 by Claim 1. Thus M(E) 2 = {2a 0 } holds. We claim inductively that M(E) N = {N a 0 } for N \u2265 2. This is because every element x in M(E) N +1 can be written as x = a i + y for some 0 \u2264 i \u2264 l and y \u2208 M(E) N , thus x = a i + N a 0 = (a i + a 0 ) + (N \u2212 1)a 0 = 2a 0 + (N \u2212 1)a 0 = (N + 1)a 0 . Now that M(E) N has been computed for all N \u2265 0, the description of the Cayley quiver of M(E) easily follows.", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "(Case 2): The case m = n. Note that l = m = n in this case, so we only use the letter n. For every i, j with 0 \u2264 i \u2264 n and 0 \u2264 j \u2264 n, if j = n, then a i + a j = a i\u22121 + a j = \u00b7 \u00b7 \u00b7 = a 0 + a j = a 0 + a j\u22121 = \u00b7 \u00b7 \u00b7 = 2a 0 by Claim 1. Thus M(E) 2 = {2a 0 , 2a n } holds (and later we will show 2a 0 = 2a n ). The same inductive argument as in (Case 1) shows that M(E) N = {N a 0 , N a n } holds for N \u2265 2, and it suffices to show that N a 0 = N a n in M(E) for N \u2265 2.", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "Suppose that N a 0 = N a n holds in", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "Denote by E P the full subcategory of E consisting of direct sums of A n = P n , or equivalently, the subcategory of E consisting of projective kQ-modules. Note that A N n \u2208 E P holds. Then the following claim holds: (Claim 2): In (Case 2), for every conflation", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "we have that Y \u2208 E P holds if and only if both X \u2208 E P and Z \u2208 E P hold (in other words, E P is a Serre subcategory of E). Proof of Claim 2. If X \u2208 E P and Z \u2208 E P hold, then the above sequence splits since Z is projective, thus Y \u223c = X \u2295 Z \u2208 E P holds. Conversely, suppose that Y \u2208 E P holds. Since \u03c0 induces a surjection top Y \u0589 top Z, and top Y is a direct sum of top P = S 2 , we have that so is top Z. However, top A i contains S 1 as a direct summand if i < n. Therefore, Z, which is a direct sum of appropriate A i 's, must be isomorphic to a direct sum of A n . Thus Z \u2208 E P holds. Moreover, the above sequence splits since Z is projective, thus Y \u223c = X \u2295 Z. Clearly E P is closed under direct summands in E, so X belongs to E P .", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "Let us return to our situation, that is, [A", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Grothendieck monoids", "text": "Since E P is a Serre subcategory of E by Claim 2 and A N n belongs to E P , Proposition 3.7 implies that A N 0 belongs to E P . This is a contradiction since A 0 is not projective. Therefore, we have N a 0 = N a n , which completes the proof.", "cite_spans": [], "ref_spans": []}, {"section": "Counter-examples", "text": "In this section, we give examples of bad behavior of exact categories on several topics which we have studied in the previous sections.", "cite_spans": [], "ref_spans": []}, {"section": "Counter-examples", "text": "8.1. On the poset of admissible subobjects. In this subsection, we collect some counterexamples on the poset P(X) (see Section 2.1 for the detail) 8.1.1. Subobject posets which are not lattices. The following example shows that P(X) is not necessarily a lattice.", "cite_spans": [], "ref_spans": []}, {"section": "Counter-examples", "text": "Example 8.1. Let k be a field and E a category of k-vector spaces whose dimensions are not equal to 1 and 3. Then E is an extension-closed subcategory of mod k, thus an exact category. Denote by X the 6-dimensional vector space with basis x 1 , \u00b7 \u00b7 \u00b7 , x 6 , and put A := x 1 , x 2 , x 3 , x 4 and B := x 1 , x 2 , x 3 , x 5 . Then since X/A and X/B has dimension 2, both A and B are admissible subobjects of X. Now the set-theoretic intersection of A and B is a 3-dimensional subspace C spanned by x 1 , x 2 , x 3 (which does not belong to E), and lower bounds of A and B in P E (X) are subspaces of C whose dimensions are exactly two or zero. Then A and B do not have the greatest lower bound, since there are many two-dimensional subspaces of C.", "cite_spans": [], "ref_spans": []}, {"section": "Counter-examples", "text": "The following is also an example in which P(X) is not a lattice, although the ambient category is pre-abelian.", "cite_spans": [], "ref_spans": []}, {"section": "Counter-examples", "text": "Example 8.2. Let k be a field and consider an algebra \u039b := k(1 \u03b1 \u2190 \u2212 2 \u03b2 \u2190 \u2212 3)/(\u03b2\u03b1). Put E := proj \u039b, then E has the natural exact structure induced from mod \u039b, and every conflation splits in E. It follows that a morphism \u03b9 : A \u2192 B in E is an inflation if and only if \u03b9 is a section, that is, a split monomorphism. Moreover, since gl.dim \u039b = 2 holds, kernels of morphisms between projective modules are projective, thus E is pre-abelian.", "cite_spans": [], "ref_spans": []}, {"section": "Counter-examples", "text": "We claim that P E (M ) is not a lattice for M := \u039b \u039b . By the previous argument, we can identify P E (M ) with the poset of submodules of M consisting of direct summands of M . We can write M = \u039b in the following way:", "cite_spans": [], "ref_spans": []}, {"section": "Counter-examples", "text": "where P i := e i \u039b for the primitive idempotent e i corresponding to the vertex i. In the rightmost part, we write composition series of modules, and the numbers correspond to k-basis. Consider the following two maps:", "cite_spans": [], "ref_spans": []}, {"section": "Counter-examples", "text": "Here \u03b2 : P 2 \u2192 P 3 denotes the multiplication map \u03b2 \u00b7 (\u2212). We can check by matrix elimination that these maps are sections, thus N i := Im \u03b9 i belongs to P E (M ) for each i. In the rightmost notation of M , N i looks like the following:", "cite_spans": [], "ref_spans": []}, {"section": "Counter-examples", "text": "We claim that N 1 and N 2 do not have the greatest lower bound in P E (M ). Let N be a lower bound for N 1 and N 2 in P E (M ). Then N must be contained in the set-theoretic intersection N 1 \u2229 N 2 :", "cite_spans": [], "ref_spans": []}, {"section": "Counter-examples", "text": "c , 0 0 ) \u2208 P 1 \u2295 P 2 \u2295 P 3 | a, c \u2208 k}, which is a two-dimensional vector space spanned by e 1 and \u03b1. Here (a, 0 c , 0 0 ) in the above notation corresponds to ae 1 + c\u03b1. Consider the quotient module \u039b/N 1 \u2229 N 2 :", "cite_spans": [], "ref_spans": []}, {"section": "Counter-examples", "text": "This is not projective, thus we have N 1 \u2229 N 2 / \u2208 P E (M ). Hence we have N N 1 \u2229 N 2 , so dim N = 0 or dim N = 1 holds. Therefore, to show that the meet of N 1 and N 2 does not exist in P E (M ), it suffices to show that there exist two distinct several one-dimensional submodules of N 1 \u2229 N 2 which belong to P E (M ). To show this, consider the following two maps:", "cite_spans": [], "ref_spans": []}, {"section": "Counter-examples", "text": "The images of these maps are one-dimensional submodules generated by e 1 and e 1 +\u03b1 respectively. By matrix elimination, we can show that these are direct summands of M , thus both belong to P E (M ). Therefore P E (M ) is not a lattice. 8.1.2. Subobject posets are lattices but not modular lattices. Recall from Proposition 2.14 that if E is a quasi-abelian category with the maximal exact structure, subobject posets are in fact lattices. However, there exist examples which are quasi-abelian but these lattices are not necessarily modular. For such examples, we refer the reader to Section 8.2.1, since the modularity implies the unique length property (Corollary 2.18).", "cite_spans": [], "ref_spans": []}, {"section": "8.2.", "text": "(JHP) and the unique length property. Next let us see some counter-examples on the unique factorization properties on exact categories. 8.2.1. Lengths are not unique. We collect some examples in which the unique length property fails (see Section 2.2). Example A in the introduction is one of such example, but is rather artificial and not idempotent complete. We give several idempotent complete examples (actually torsion-free classes, so quasi-abelian) which do not satisfy the unique length property. Actually we can obtain more examples in type A quiver by using the results in Section 6. Example 8.3. Let Q be a quiver 1 \u2190 2 \u2190 3 \u2192 4. Then the Auslander-Reiten quiver of mod kQ is as follows. Here we use the notation introduced in Proposition 6.10.", "cite_spans": [], "ref_spans": []}, {"section": "8.2.", "text": ": E : simple objects in E Define E as the additive subcategory of mod kQ corresponding to the gray region, then it is closed under extensions (and actually a torsion-free class) in mod kQ. We can check that E has 5 simples indicated by circles: sim E = {M [1, 2) , M [2, 3) , M [3, 5) , M [4, 5) , M [1,4) }. Now consider an object X := M [1, 5) . Roughly speaking, the gray region below X looks like a module category of an A 3 quiver, thus X seems to have length 3, and the gray region above X looks like a module category of an A 2 quiver, thus X seems to have length 2. In fact, we have the following two composition series of X:", "cite_spans": [], "ref_spans": []}, {"section": "8.2.", "text": "Thus lengths of X are not unique.", "cite_spans": [], "ref_spans": []}, {"section": "8.2.", "text": "Here is another example, which we have already encountered.", "cite_spans": [], "ref_spans": []}, {"section": "8.2.", "text": "Example 8.4. Consider Example 6.17 and let w be the fourth one in Table 2 , that is, w = 42513. Then F (w) is the additive subcategory corresponding to {A, B, C, D, E, F } depicted as follows:", "cite_spans": [], "ref_spans": []}, {"section": "8.2.", "text": "shows that C has length 2, hence X = C \u2295 D has length 3. On the other hand, a conflation B X \u0589 F implies that X has length 2. Thus lengths of X are not unique. 8.2.2. Length are unique but (JHP) fails. Here is an example of an exact category which satisfies the unique length property, but does not satisfy (JHP).", "cite_spans": [], "ref_spans": []}, {"section": "8.2.", "text": "Example 8.5. Let F be a hereditary torsion-free class of length abelian categories. Then F satisfies the unique length property by Corollary 2.23. Typically, F arises in the following way: Take any artin algebra \u039b and chose any set of simple modules S = {S 1 , \u00b7 \u00b7 \u00b7 , S l }. Define F as follows:", "cite_spans": [], "ref_spans": []}, {"section": "8.2.", "text": "Then F is a torsion-free class, and the corresponding torsion class is the smallest Serre subcategory which contains S. Thus F is a hereditary torsion-free class.", "cite_spans": [], "ref_spans": []}, {"section": "8.2.", "text": "We have already encountered such examples which do not satisfy (JHP): E 1 in Example B, and F (c 2 ) and F (c 2 s 1 ) in Example 6.17.", "cite_spans": [], "ref_spans": []}, {"section": "Examples which satisfy (JHP)", "text": ". Finally, we collect examples which satisfy (JHP) for the convenience of the reader.", "cite_spans": [], "ref_spans": []}, {"section": "Examples which satisfy (JHP)", "text": "Example 8.6. The following examples satisfy (JHP).", "cite_spans": [], "ref_spans": []}, {"section": "Examples which satisfy (JHP)", "text": "(1) Krull-Schmidt categories together with the split exact structure. This follows by Proposition 7.1 and the fact that the uniqueness of direct sum decomposition holds. (2) Length abelian categories. This is because the Jordan-H\u00f6lder theorem holds in any abelian categories, see e.g. [St, p.92] . (3) Torsion(-free) classes of mod \u039b for a Nakayama algebra \u039b (Corollary 5.19). (4) Torsion-free classes of mod kQ for a type A quiver Q which satisfies the condition given in Corollary 6.15. Explicit examples are given in Example 6.17 and E 1 in Example B. (5) The category F (\u2206) of modules with \u2206-filtrations over a quasi-hereditary algebra, or more generally, over a standardly stratified algebra (see e.g. [PR, Proposition 1.2] ). Simple objects in F (\u2206) are precisely standard modules.", "cite_spans": [{"start": 285, "end": 289, "text": "[St,", "ref_id": "BIBREF34"}, {"start": 707, "end": 711, "text": "[PR,", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "Examples which satisfy (JHP)", "text": "8.3. Non-cancellative Grothendieck monoids. In this subsection, we will give some examples in which the Grothendieck monoids are not finitely generated or not cancellative.", "cite_spans": [], "ref_spans": []}, {"section": "Examples which satisfy (JHP)", "text": "8.3.1. Functorially finite torsion-free class, but neither finitely generated nor cancellative. In a length exact category, its Grothendieck monoid is atomic, thus it is not finitely generated as a monoid if and only if there exists infinitely many non-isomorphic simple objects (Proposition 4.8).", "cite_spans": [], "ref_spans": []}, {"section": "Examples which satisfy (JHP)", "text": "We will give such an example. Let k be an algebraically closed field and Q a Kronecker quiver, namely, Q : 1 \u21d4 2. We refer the reader to [ARS, Section VIII.7] for the structure of mod kQ. We denote by E the subcategory of mod kQ consisting of modules which does not contain S 2 (simple modules supported at 2) as a direct summand. Then E is closed under extensions, thus an exact category. Actually, E is a torsion-free class associated with an APR cotilting module I 1 \u2295 \u03c4 S 2 , thus it is a functorially finite torsion-free class (with infinitely many indecomposables).", "cite_spans": [{"start": 137, "end": 142, "text": "[ARS,", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Examples which satisfy (JHP)", "text": "Recall that for each element x = [x 1 : x 2 ] \u2208 P 1 (k) in the projective line P 1 (k), we have a regular module R x with dimension vector (1, 1), or more explicitly, R x is the following representation of Q.", "cite_spans": [], "ref_spans": []}, {"section": "Examples which satisfy (JHP)", "text": "This assignment is injective, that is, we have R x \u223c = R y if and only if x = y in P 1 (k). Now we claim the following:", "cite_spans": [], "ref_spans": []}, {"section": "Examples which satisfy (JHP)", "text": "Actually, for any indecomposable preprojective module X except S 1 , it can be shown by explicit calculation that there exists an exact sequence", "cite_spans": [], "ref_spans": []}, {"section": "Examples which satisfy (JHP)", "text": "such that R is a non-zero regular module. Thus such X is not simple in E. Moreover, any indecomposable regular module is known to be written as a finite extension of R x for some x. Therefore, indecomposable modules except S 1 and R x 's are not simple. On the other hand, by considering dimension vectors, each R x must be simple object, because dim R x = (1, 1) is an atom of dim E. Thus R x is simple in E for each x \u2208 P 1 (k). Therefore, M(E) has infinitely many atoms (since k is an infinite field), so it is not finitely generated. Moreover, we will see that M(E) is not cancellative. In fact, for each x = [x 1 : x 2 ] \u2208 P 1 (k), we have an exact sequence", "cite_spans": [], "ref_spans": []}, {"section": "Examples which satisfy (JHP)", "text": "where the left map is an embedding of S 1 into the socle S 1 \u2295S 1 of P 2 . This shows that [", "cite_spans": [], "ref_spans": []}, {"section": "Examples which satisfy (JHP)", "text": "Moreover, this gives an example such that non-isomorphic simples may represent the same element in the Grothendieck group. In this example, by Proposition 5.9, we can identify K 0 (E) \u223c = Z 2 by taking dimension vectors. Thus for each x, y \u2208 P 1 (k), we have that", "cite_spans": [], "ref_spans": []}, {"section": "Examples which satisfy (JHP)", "text": "8.3.2. Only finitely many indecomposables, but not cancellative. In the previous example, the category we considered has infinitely many indecomposable objects. If an exact category E has finitely many indecomposables, then M(E) is finitely generated by a trivial reason, but it may not be cancellative as we shall see. Let \u039b be the following algebra:", "cite_spans": [], "ref_spans": []}, {"section": "Examples which satisfy (JHP)", "text": "Then the Auslander-Reiten quiver of mod \u039b is as follows:", "cite_spans": [], "ref_spans": []}, {"section": "Examples which satisfy (JHP)", "text": "where we write composition factors of modules, and", "cite_spans": [], "ref_spans": []}, {"section": "Examples which satisfy (JHP)", "text": "and M := 1 2 1 . Let E denote the additive subcategory of mod \u039b corresponding to these gray regions: ind E = {P 1 , P 2 , I 1 , M }. Then E is shown to be closed under extensions in mod \u039b 2 , and the AuslanderReiten quiver of the exact category E is as follows:", "cite_spans": [], "ref_spans": []}, {"section": "Examples which satisfy (JHP)", "text": "By checking subobjects, it can be shown that all 4 indecomposable objects in E are simple objects in E. However, by the Auslander-Reiten quiver of mod \u039b, it can be checked that we have the following conflations in E:", "cite_spans": [], "ref_spans": []}, {"section": "Examples which satisfy (JHP)", "text": "This implies the equality", "cite_spans": [], "ref_spans": []}, {"section": "Examples which satisfy (JHP)", "text": "by Proposition 3.6, we must have that M(E) is not cancellative.", "cite_spans": [], "ref_spans": []}, {"section": "Problems", "text": "In this section, we collect some open problems on several topics in this paper.", "cite_spans": [], "ref_spans": []}, {"section": "Problems", "text": "As we saw in Section 7, the computation of the Grothendieck monoid is rather difficult if it is not cancellative.", "cite_spans": [], "ref_spans": []}, {"section": "Problems", "text": "Problem 9.1. Let E be an exact category. Is there any criterion to check that M(E) is cancellative?", "cite_spans": [], "ref_spans": []}, {"section": "Problems", "text": "This leads to the following question.", "cite_spans": [], "ref_spans": []}, {"section": "Problems", "text": "Problem 9.2. Is there an example of E which satisfies:", "cite_spans": [], "ref_spans": []}, {"section": "Problems", "text": "(1) E has finitely many indecomposables up to isomorphisms.", "cite_spans": [], "ref_spans": []}, {"section": "Problems", "text": "(2) E = \u22a5 U for a cotilting module U over an artin algebra \u039b, or more strongly, E is a torsionfree class of mod \u039b. (3) M(E) is not cancellative.", "cite_spans": [], "ref_spans": []}, {"section": "Problems", "text": "If we drop (1) or (2), then we have such an example (Section 8.3.1 and 8.3.2 respectively). In what follows, let F be a functorially finite torsion-free class of mod \u039b for an artin algebra \u039b. The most general (and thus difficult) problem is the following: Problem 9.3. Compute the Grothendieck monoid M(F ), more precisely, draw the Cayley quiver as we did in Proposition 7.6.", "cite_spans": [], "ref_spans": []}, {"section": "Problems", "text": "As a first approximation to M(F ), the following problem naturally occurs, which is of interest in its own right.", "cite_spans": [], "ref_spans": []}, {"section": "Problems", "text": "Problem 9.4. For a given torsion-free class F , classify (or count) simple objects in F .", "cite_spans": [], "ref_spans": []}, {"section": "Problems", "text": "Of course, we cannot expect the general classification of simples, but it may be done when \u039b and F are given explicitly.", "cite_spans": [], "ref_spans": []}, {"section": "Problems", "text": "The cancellative quotient M(F ) can is easier to handle with by Corollary 5.9: it is nothing but the monoid of dimension vectors dim F . Moreover, it is a finitely generated submonoid of N n by Proposition 5.16. Such a monoid is called a positive affine monoid, and this class is investigated in the theory of combinatorial commutative algebra and toric geometry via its monoid algebra. We refer the reader to [BrGu] for the details on affine monoids and affine monoid algebras.", "cite_spans": [], "ref_spans": []}, {"section": "Problems", "text": "Problem 9.5. For a given torsion-free class F , investigate the combinatorial property of the affine monoid dim F , the monoid of dimension vectors of modules in F . In particular,", "cite_spans": [], "ref_spans": []}, {"section": "Problems", "text": "\u2022 Is this monoid normal?", "cite_spans": [], "ref_spans": []}, {"section": "Problems", "text": "\u2022 Describe the minimal generating set of it (this is related to simple objects in F ).", "cite_spans": [], "ref_spans": []}, {"section": "Problems", "text": "\u2022 When does this monoid homogeneous (this is related to the unique length property of F )?", "cite_spans": [], "ref_spans": []}, {"section": "Problems", "text": "\u2022 Compute invariants of this monoid, such as extreme rays, the class group, support hyperplanes, and so on.", "cite_spans": [], "ref_spans": []}, {"section": "Problems", "text": "Finally, we consider topics in Section 7. Let Q be a quiver of type A (or more generally, any Dynkin type, see Remark 6.19). Theorem 6.12 gives an explicit description of torsion-free classes of mod kQ. Thus it is reasonable to expect that Problems 9.3 and 9.5 may be easier in this case.", "cite_spans": [], "ref_spans": []}, {"section": "Problems", "text": "In addition, the author does not know when the uniqueness of lengths holds, except Example 8.5. Problem 9.6. In the situation of Theorem 6.12, is there a combinatorial criterion for w to check when F (w) has the unique length property?", "cite_spans": [], "ref_spans": []}, {"section": "Problems", "text": "Also the following (purely combinatorial) problem is of interest.", "cite_spans": [], "ref_spans": []}, {"section": "Problems", "text": "Problem 9.7. For a Coxeter element c, is there any closed formula which gives the number of torsion-free classes satisfying (JHP), or equivalently, the number of c-sortable elements w such that # supp(w) = Binv(w) holds?", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "We collect some basic definitions and properties on monoids needed in this paper. We recall that monoids are always assumed to be a commutative monoid with a unit, and that we use an additive notation with unit 0.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "A.1. Basic definitions. First, we collect some basic definitions on monoids, which we shall need throughout this paper.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "Definition A.1. Let M be a monoid.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "(1) M is reduced if a + b = 0 implies a = b = 0 for any elements a, b in M .", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "(2) M is cancellative if a + x = a + y implies x = y for a, x, y \u2208 M .", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "There is a natural pre-order \u2264 on any monoid.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "Definition A.2. Let M be a monoid. We define x \u2264 y if there exists some a \u2208 M such that y = x + a.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "It can be checked that x \u2264 y if and only if y \u2208 x + M if and only if y + M \u2282 x + M . This preorder is sometimes called Green's pre-order in semigroup theory, e.g. [Gri1, Gri2] , or divisibility pre-order in the multiplicative structure theory of integral domains, e.g. [GHK] . Definition A.3. A monoid M is called naturally partially ordered if the pre-order \u2264 on M is a partial order, that is, x \u2264 y and y \u2264 x implies x = y.", "cite_spans": [{"start": 163, "end": 169, "text": "[Gri1,", "ref_id": "BIBREF20"}, {"start": 170, "end": 175, "text": "Gri2]", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "The following properties can be easily checked.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "Proposition A.4. Let M be a monoid. Then M is reduced if and only if 0 \u2264 x \u2264 0 implies x = 0 for every x in M . In particular, a naturally partially ordered monoid is reduced.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "Although we cannot naively take quotients of monoids as in abelian groups since there may not exist additive inverses, we can obtain some kind of quotient monoids by considering quotient sets with respect to monoid congruences, which are the appropriate equivalence relations on monoids defined as follows.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "Definition A.5. Let M be a monoid. The equivalence relation \u223c is called a (monoid) congruence if x \u223c y implies a + x \u223c a + y for every a, x, y \u2208 M . In this case, the quotient set M/ \u223c of equivalence classes naturally has the structure of a monoid.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "We often use the smallest monoid congruence generated by some binary relation. See e.g. [Gri1, Propositions I.4.1, I.4 .2] for the detail.", "cite_spans": [{"start": 88, "end": 94, "text": "[Gri1,", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "Proposition A.6. Let M be a monoid and \u223c an arbitrary (not necessarily equivalence) binary relation on M . Then there exists the smallest monoid congruence \u2248 which contains \u223c, that is, x \u223c y implies x \u2248 y for x, y \u2208 M .", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "A.2. Factorization properties on monoids. Let us define several notions on unique factorization property on monoids. We refer the reader to [GHK] for the details in this subsection (please be aware that monoids in [GHK] are assumed to be cancellative, but contents in this subsection hold in non-cancellative monoids). The most typical one is the freeness of monoids, which are closely related to (JHP) for exact categories.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "Definition A.7. Let M be a monoid.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "(1) We say that a monoid is finitely generated if there exists a finite subset of M which generates M . (2) For a subset A of M , we say that M is free on A if every element x of M can be written as a finite sum of elements of A in a unique way up to permutations. A monoid is called free if it is free on some subset of M .", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "For a set A, we denote by N (A) the submonoid a\u2208A Na of the free abelian group Z (A) := a\u2208A Za with basis A, which consists of finite sums of non-negative linear combinations of elements in A. It is easy to see that N (A) is free on A and that a monoid is free if and only if it is isomorphic to N (A) for some set A. If A is a finite set, then we often write N A = N (A) and Z A = Z (A) . Now let us consider elements of a monoid which cannot be decomposed into smaller ones. Here, for simplicity, we only consider reduced monoids (this is a reasonable assumption since Grothendieck monoids are reduced by Proposition 3.5).", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "Definition A.8. Let M be a reduced monoid.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "(1) A non-zero element x of M is called an atom if x = y + z implies either y = 0 or z = 0 for y, z \u2208 M . We denote by Atom M the set of all atoms in M . (2) M is called atomic if Atom M generates M , that is, every element of M is a finite sum of atoms. (3) M is called factorial if every element can be expressed as a finite sum of atoms, and this expression is unique up to permutations. (4) M is called half-factorial if it is atomic, and for every element x and expressions x = a 1 + \u00b7 \u00b7 \u00b7 + a n with a i \u2208 Atom M , the number n depends only on x.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "The following observations can be proved directly from the definitions.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "Proposition A.9. Let M be a reduced monoid. then the following hold.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "(1) If M is generated by a subset A, then Atom M \u2282 A holds. In particular, Atom M is a finite set for a finitely generated monoid M . (2) M is finitely generated and atomic if and only if M is atomic and Atom M is a finite set. A.3. Group completion. For a given monoid M , there is the universal construction which transforms M into a group. We call it a group completion in this paper.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "Definition A.10. Let M be a monoid. Then the group completion gp M is an abelian group gp M together with a map \u03b9 : M \u2192 gp M which satisfies the following universal properties.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "(1) \u03b9 is a monoid homomorphism.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "(2) Every monoid homomorphism f : M \u2192 G into a group G factors uniquely \u03b9, that is, there exists a unique group homomorphism f : gp M \u2192 G which satisfies f = \u03b9f .", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "Example A.11. Let M be a monoid which is free on A. Then gp M is a free abelian group with basis A, that is, gp(N (A) ) = Z (A) . The original basis A can be reconstructed from M since A = Atom M , but this information is lost when taking the group completion, since bases of the free abelian group is far from unique. This is one advantage that we consider monoids, not groups.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "The explicit construction of the group completion is given as follows.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "Proposition A.12. Let M be a monoid. Define an equivalence relation \u223c on the set M \u00d7 M by (x 1 , y 1 ) \u223c (x 2 , y 2 ) :\u21d4 there exists an element a \u2208 M such that x 1 + y 2 + a = x 2 + y 1 + a.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "Then the quotient set (M \u00d7 M )/ \u223c is a group completion of M with a map M \u2192 (M \u00d7 M )/ \u223c given by x \u2192 (x, 0).", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "The cancellation property are related to the group completion as follows.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "Proposition A.13. Let M be a monoid. Then it is cancellative if and only if the natural map \u03b9 : M \u2192 gp M is an injection if and only if there is an injective monoid homomorphism into some group. In this case, every injective monoid homomorphism \u03d5 : M \u2192 G such that \u03d5(M ) generates G is automatically a group completion of M .", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "It follows that the image of the group completion is always cancellative. One of the difficulty of dealing with a monoid M is that M may not be cancellative. Thus this image is much easier to deal with than M , and it has more information on its group completion gp M . This corresponds to the positive part of the Grothendieck group, see Section 3.2.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "Definition A.14. Let M be a monoid. We denote by M can the image of the group completion \u03b9 : M \u2192 gp M , and call the cancellative quotient of M .", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "We leave it the reader to check M can is actually the largest cancellative quotient of M : Proposition A.15. Let M be a monoid and define an equivalence relation \u223c can on M by x \u223c can y :\u21d4 there exists an element a \u2208 M such that x + a = y + a.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "Then \u223c can is a monoid congruence on M , and we have an isomorphism of monoids M can \u223c = M/ \u223c can . Consequently, for every monoid homomorphism \u03d5 : M \u2192 N to a cancellative monoid N , there exists a unique monoid homomorphism \u03d5 : M can \u2192 N such that \u03d5 = \u03d5\u03b9.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "A.4. Length-like functions on monoids. We will introduce a kind of length on monoids, which corresponds to length-like functions on exact categories introduced in Definition 4.1. Definition A.16. Let M be a monoid. A length-like function on M is a monoid homomorphism \u03bd : M \u2192 N such that \u03bd(x) = 0 implies that x = 0.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "The existence of a length-like function implies some properties.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "Proposition A.17. Let M be a monoid and suppose that there exists a length-like function \u03bd : M \u2192 N on M . Then the following hold.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "(1) M is naturally partially ordered, hence reduced.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "(2) M is atomic.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "(3) \u03bd induces a length-like function on M can . Thus M can is also naturally partially ordered, reduced and atomic.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "Proof.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "(1) Suppose that x \u2264 y \u2264 x holds for x, y \u2208 M . Since \u03bd is a monoid homomorphism, it follows immediately that \u03bd(x) \u2264 \u03bd(y) \u2264 \u03bd(x) holds, thus \u03bd(x) = \u03bd(y). On the other hand, we have y = x + a for some a \u2208 M by x \u2264 y. Thus \u03bd(y) = \u03bd(x) + \u03bd(a), which implies that \u03bd(a) = 0. Since \u03bd is a length-like function, a = 0 holds, hence x = y. Thus M is naturally partially ordered, so it is reduced by Proposition A.4.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "(2) Suppose that M is not atomic. Then take an element x such that:", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "(a) x = 0. (b) x cannot be expressed as a finite sum of atoms.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "(c) \u03bd(x) is minimal among those x which satisfy (a) and (b).", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "Obviously x is not an atom by (b). Thus there is a decomposition x = y + z with y, z = 0. If both y and z satisfy (b), then so does x. Thus we may assume that y satisfies (b). However, we have \u03bd(x) = \u03bd(y) + \u03bd(z) with \u03bd(y), \u03bd(z) = 0 since \u03bd is a length-like function. Therefore \u03bd(y) < \u03bd(x) and y satisfies (a) and (b). This contradicts the minimality of x. (3) Since N is a cancellative monoid, \u03bd induces a monoid homomorphism \u03bd : M can \u2192 N. Recall that M can is the image of the group completion \u03b9 : M \u2192 gp M . Suppose that \u03bd(\u03b9x) = 0 holds for x \u2208 M . Then \u03bd(x) = (\u03bd\u03b9)(x) = 0, so x = 0 holds in M since \u03bd is a length-like function on M . Thus \u03b9x = 0 holds, therefore \u03bd is a length-like function on M can .", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "For later use, we show the following characterization of half-factorial monoids in terms of lengthlike functions.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "Lemma A.18. Let M be a half-factorial monoid (e.g. a free monoid). Then M has a length-like function. Moreover, the following are equivalent:", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "(1) M is a half-factorial monoid.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "(2) There exists a length-like function \u03bd : M \u2192 N such that \u03bd(a) = 1 for every atom a \u2208 Atom M .", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "Proof.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "(1) \u21d2 (2) Suppose that M is half-factorial. We define a monoid homomorphism l : M \u2192 N as follows: For every x in E, we can write x = l i=1 a i in M(E) with a i \u2208 Atom M for each i since M is atomic. We set l(x) := l. Since M is half-factorial, l does not depend on the choice of expressions, thus this map is well-defined. Furthermore, it is obvious that x = 0 whenever l(x) = 0, and that l(a) = 1 for every a \u2208 Atom M .", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "(2) \u21d2 (1): First observe that M is reduced and atomic by Proposition A.17 (2). Let x be an element of M . Consider any expression x = a 1 + \u00b7 \u00b7 \u00b7 + a n with a i \u2208 Atom M . Then by (2), we have that \u03bd(x) = \u03bd(a 1 ) + \u00b7 \u00b7 \u00b7 + \u03bd(a n ) = n. Therefore, the number n depends only on x, so M is half-factorial.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "A.5. Characterizations of free monoids. In what follows, we give a criterion for a given monoid to be free. We use this results to check (JHP) in Section 4, since (JHP) is characterized by the freeness of the Grothendieck monoid.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "If a monoid M is free, then it has a length-like function (Lemma A.18), its group completion is also free, and its rank coincides with the number of atoms. In general, we have the following inequality.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "Proposition A.19. Let M be a reduced atomic monoid and suppose that gp M is a free abelian group. Then the following inequality holds. rank(gp M ) \u2264 # Atom M Proof. Let \u03b9 : M \u2192 gp M denote the group completion. As an abelian group, gp M is generated by \u03b9M , so it is generated by \u03b9(Atom M ). Thus rank(gp M ) \u2264 # Atom M holds.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix A. Preliminaries on monoids", "text": "The following gives a kind of converse of this. This is an important characterization of free monoids, which is very useful to our setting.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Reiten, \u03c4 -tilting theory", "authors": [{"first": "T", "middle": [], "last": "Adachi", "suffix": ""}, {"first": "O", "middle": [], "last": "Iyama", "suffix": ""}, {"first": "I", "middle": [], "last": "", "suffix": ""}], "year": 2014, "venue": "Compos. 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Soc", "link": "121832427"}, "BIBREF34": {"title": "Rings of quotients: An introduction to methods of ring theory", "authors": [{"first": "B", "middle": [], "last": "Stenstr\u00f6m", "suffix": ""}], "year": 1975, "venue": "", "link": "122405718"}, "BIBREF35": {"title": "Cohen-Macaulay modules over Cohen-Macaulay rings", "authors": [{"first": "Y", "middle": [], "last": "Yoshino", "suffix": ""}], "year": 1990, "venue": "London Mathematical Society Lecture Note Series", "link": "5566454"}, "BIBREF36": {"title": "Chikusa-ku, Nagoya. 464-8602, Japan E-mail address: m16009t@math", "authors": [], "year": "", "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "20 5. (JHP) for extension-closed subcategories of module categories 20 5.1. Basic properties on Grothendieck monoids 20 5.2. Ext-perpendicular categories of modules with finite injective dimension 21 5.3. Torsion-free classes over Nakayama algebras 24 6. Torsion-free classes of Type A and Bruhat inversion 25 6.1. Bruhat inversions of elements in the symmetric group 26 6.2. Coxeter element, c-sortable elements and torsion-", "type": "figure"}, "FIGREF1": {"text": "Now for subobjects \u03b9 A : A X and \u03b9 B : B Y , consider the induced morphism [\u03b9 A , \u03b9 B ] : A \u2295 B \u2192 X. By the above lemma, there exists an object A + B and morphisms A \u2295 B p \u2212 \u2192 A + B \u03b9 \u2212 \u2192 X such that [\u03b9 A , \u03b9 B ] = \u03b9p holds, p is an epimorphism and \u03b9 is a kernel morphism. We claim that \u03b9 : A + B X is a join of A and B.", "type": "figure"}, "FIGREF2": {"text": "is, c and c \u2032 are complements of x in [a, b]), and that c \u2264 c \u2032 holds. Then we have c = c \u2032 .", "type": "figure"}, "FIGREF3": {"text": "For a skeletally small exact category E, its Grothendieck monoid M(E) exists. Proof. Define the operation + on Iso E by [A] + [B] := [A \u2295 B], then clearly Iso E is a monoid with an additive unit [0]", "type": "figure"}, "FIGREF4": {"text": "We first show that [S] is an atom in the monoid M(E). Suppose that [S] = [X] + [Y ]. Then we have that [S] = [X \u2295 Y ], so (1) implies that S \u223c = X \u2295 Y . Since simple objects are indecomposable, it follows that X \u223c = 0 or Y \u223c = 0 holds, that is, [X] = 0 or [Y ] = 0. Therefore [S] is an atom.", "type": "figure"}, "FIGREF5": {"text": "we have that Y \u2208 D holds if and only if both X \u2208 D and Z \u2208 D hold.", "type": "figure"}, "FIGREF6": {"text": "and D is closed under subquotients, X i /X i\u22121 belongs to D, thus so does Y i /Y i\u22121 for each i. Now Y can be obtained from Y i /Y i\u22121 by taking extensions, and since D is closed under extensions, it follows that Y \u2208 D holds.", "type": "figure"}, "FIGREF7": {"text": "M(E) is atomic.", "type": "figure"}, "FIGREF8": {"text": "M(E) is finitely generated if and only if sim E is a finite set.", "type": "figure"}, "FIGREF9": {"text": "(U, U ) = 0 holds. (3) There exists an exact sequence", "type": "figure"}, "FIGREF10": {"text": "If two indecomposable modules M and N in mod \u039b satisfy top M \u223c = top N and l(M ) \u2265 l(N ), then there exists a surjection M \u0589 N .", "type": "figure"}, "FIGREF11": {"text": "The following are examples of inversions in S 5 . (1) For w 1 = s 1 s 3 s 2 s 4 s 1 s 3 s 2 s 4 = 45231 we have:For w 2 = s 1 s 3 s 2 s 4 s 1 s 3 s 2 s 1 = 54213 we have:", "type": "figure"}, "FIGREF12": {"text": "The following are examples of Bruhat inversions in S 5 .", "type": "figure"}, "FIGREF13": {"text": "and 0 otherwise. Moreover, this give a bijection M [ ) : T \u223c \u2212 \u2192 ind(mod kQ) which restricts to S \u223c \u2212 \u2192 sim(mod \u039b).", "type": "figure"}, "FIGREF14": {"text": "Let Q and c be as in Assumption 6.8 and w a c-sortable element of S n+1 . Then F (w) satisfies (JHP) if and only if # supp(w) = # Binv(w) holds.", "type": "figure"}, "FIGREF15": {"text": "", "type": "figure"}, "FIGREF16": {"text": "", "type": "figure"}, "FIGREF17": {"text": "If M is free on a subset A of M , then A = Atom M holds. (4) If M is free, then it is atomic, cancellative, reduced and factorial. (5) M is free if and only if M is factorial.", "type": "figure"}, "TABREF1": {"text": "Remark 4.2. Obviously, a length-like function is weakly length-like. It is clear that we can identify a length-like function with a length-like function on the monoid M(E) by Proposition 3.5 (1), see Definition A.16.", "type": "table"}}}
{"paper_id": "199668948", "_pdf_hash": "5eeb511cb1eb9816ebf57b70dcdd874736ff3d01", "abstract": [{"section": "Abstract", "text": "Humans are able to conceive physical reality by jointly learning different facets thereof. To every pair of notions related to a perceived reality may correspond a mutual relation, which is a notion on its own, but one-level higher. Thus, we may have a description of perceived reality on at least two levels and the translation map between them is in general, due to their different content corpus, one-to-many. Following success of the unsupervised neural machine translation models, which are essentially one-toone mappings trained separately on monolingual corpora, we examine further capabilities of the unsupervised deep learning methods used there and apply some of these methods to sets of notions of different level and measure. Using the graph and word embedding-like techniques, we build one-to-many map without parallel data in order to establish a unified vector representation of the outer world by combining notions of different kind into a unique conceptual framework. Due to their latent similarity, by aligning the two embedding spaces in purely unsupervised way, one obtains a geometric relation between objects of cognition on the two levels, making it possible to express a natural knowledge using one description in the context of the other. * Author names are given in alphabetical order.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "Abstract Humans are able to conceive physical reality by jointly learning different facets thereof. To every pair of notions related to a perceived reality may correspond a mutual relation, which is a notion on its own, but one-level higher. Thus, we may have a description of perceived reality on at least two levels and the translation map between them is in general, due to their different content corpus, one-to-many. Following success of the unsupervised neural machine translation models, which are essentially one-toone mappings trained separately on monolingual corpora, we examine further capabilities of the unsupervised deep learning methods used there and apply some of these methods to sets of notions of different level and measure. Using the graph and word embedding-like techniques, we build one-to-many map without parallel data in order to establish a unified vector representation of the outer world by combining notions of different kind into a unique conceptual framework. Due to their latent similarity, by aligning the two embedding spaces in purely unsupervised way, one obtains a geometric relation between objects of cognition on the two levels, making it possible to express a natural knowledge using one description in the context of the other. * Author names are given in alphabetical order.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "It has been shown recently that it is possible to build a bilingual dictionary for a pair of languages in an unsupervised way [6, 1] with very high accuracy. These models even outperform their supervised counterparts on certain tasks. Building neural translator based on this approach proved to be successful [21, 22] .", "cite_spans": [{"start": 126, "end": 129, "text": "[6,", "ref_id": "BIBREF5"}, {"start": 130, "end": 132, "text": "1]", "ref_id": "BIBREF0"}, {"start": 309, "end": 313, "text": "[21,", "ref_id": "BIBREF21"}, {"start": 314, "end": 317, "text": "22]", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "Introduction", "text": "The mentioned models are based on the distributional similarity between the word embeddings, i.e. representations of words in finitedimensional linear vector space, with usually up to 300, and sometimes even more dimensions. The best-known word embedding model is Word2Vec, made by Mikolov et al. [25] . It is constructed by taking into account statistical measure of the co-occurrence of words in a given text corpus. The words which have similar meaning are represented by vectors which are closer in higher-dimensional linear vector space and vice versa. It turned out soon that there was similarity between distributions of words in a word embedding for different languages, even for distant families of languages [24] . Following this, Conneau et al. [6] successfully learned how to relate the word embedding distributions for language pairs, enabling the same words in different languages to match approximately in a common embedding space. The translation consists roughly in identifying them as nearest neighbours. This method is grosso modo a combination of the adversarial training, which approximately aligns the distributions in the em-bedding space, and the linear transformation called orthogonal Procrustes which then refines this mapping.", "cite_spans": [{"start": 297, "end": 301, "text": "[25]", "ref_id": "BIBREF25"}, {"start": 718, "end": 722, "text": "[24]", "ref_id": "BIBREF24"}, {"start": 756, "end": 759, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Introduction", "text": "Described method suffices for alignment of two sets of embedded vectors, which have approximately the same measure so that, up to the synonyms, the mapping between different languages is almost one-to-one. This is a consequence of the semantic similarity between the language corpora in their entirety. Following just mentioned approach we would like to examine the possibility of simultaneous learning and aligning semantically similar structures which describe the same physical system on two different levels, using two sets of data, but with the different measure. The resulting correspondence will not be one-to-one, as in the case of languages, but rather many-to-one (or one-tomany). Our aim is to mimic a mental representation of a set of objects and a set of metaobjects which are of different size and to relate them into unique semantically meaningful cognitive picture. To every two physical states which are causally connected, there is one transition law which enables transition between the states and describes this relation. Thus, we conjecture a similarity of the embedding spaces for the states and transition laws, which will, after we align the distributions of the two vector representations in a common embedding space, reveal this relational structure. This should augment the general knowledge about the given physical system. The agent will learn by analogy to relate two unrelated sets of notions into a unique notional picture.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "There is a plethora of the two-level systems of interest for task-specific artificial intelligence. Firstly, we can combine different monolingual embedding spaces and try to align word embeddings with phrase embeddings or sentence embeddings [5] . Here, every sentence is related to several words. So far, one can combine pictures with texts, jointly learn visual and verbal content [23] , caption images, or even generate one from the other [30] , where to every picture correspond several other textual or notional inputs. All those tasks are specific. We are interested here primarily in notional unification on the most general and primitive level, based solely on statistics, where all learning is inductive, starting from tabula rasa. In this way we want to imitate a very early developmental phase of the human and build a learning agent capable of understanding the basic relations, independent on their content.", "cite_spans": [{"start": 242, "end": 245, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 383, "end": 387, "text": "[23]", "ref_id": "BIBREF23"}, {"start": 442, "end": 446, "text": "[30]", "ref_id": "BIBREF30"}], "ref_spans": []}, {"section": "Introduction", "text": "In order to generate an outer world which could have two possible and equivalent descriptions we will use the graph model of physical system. This will result essentially in graph embedding. So far, there is an increasing interest in exploring the graph embeddings based on analogy with Word2Vec or similar methods [11] . The resulting vector spaces may be equipped with the rich algebraic structure which then enables different manipulation which is easier and at lower computational cost in several cases. On the other hand, vector embedding is lowerdimensional dense representation, compared to adjacency matrices in case of graphs (or onehot-encoding in case of words). Our method resembles DeepWalk [28] and Node2Vec [12] , with the difference that we have a fixed graph and do not really use random walk, although there is some randomness in certain transitions. Additionally, we use both node and edge embeddings (Sec. 3).", "cite_spans": [{"start": 315, "end": 319, "text": "[11]", "ref_id": "BIBREF11"}, {"start": 704, "end": 708, "text": "[28]", "ref_id": "BIBREF28"}, {"start": 722, "end": 726, "text": "[12]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Introduction", "text": "The plan of this paper is following. 1 First, in section 2 we will build a model which represents a physical system that can be described at two levels. One level is a pure sequence of physical states appearing as system evolves, and the other is a sequence of relations between physical states which plays a role of physical laws of transition applied in the course of the evolution of the system. We will construct this model in such a way that Kinematical notions \u2190\u2192 Dynamical notions relation is not one-to-one, but rather one-tomany. To every physical state correspond more state transition laws. Kinematics of the system will be described in terms of sequence of physical states, whereas the dynamics as the sequence of transition laws. We will further in section 3 try to attach the meaning to objects of the system by constructing the embedding vector space using Word2Vec model. This should mirror the semantic structure of the sequences obtained during the evolution, based solely on the co-occurrence of the states and laws. As a consequence, it should contain the information on the background causal structure of the system. The possibility of description of a physical system is thus twofold and we will build two embedding vector representations independently for each level of description. Further, in section 4, by relating the two vector representations, we will build a unified vector representation of the system. This should in geometrical terms give semantic relation between these twolevels of description. To this end, we will investigate the capabilities of the mentioned orthogonal Procrustes method to build sensible common embedding space for the representation of physical states and transition laws. After that in section 5, we present quantitative analysis of the model. In the section 6, we discuss our results and outlooks.", "cite_spans": [], "ref_spans": []}, {"section": "Graph representation of a physical system", "text": "In order to test our conjecture we will investigate a following setup. Our learning agent learns about some outer system of objects from physical world by perceiving their physical states. We will call an ensemble of possible physical states a system of physical states, S. The system allows for transition between physical states according to some rules. Henceforth, we will call the set of these possible transitions the set of transition laws. The states \u03c3 of the system S are denoted by ordinary numbers \u03c3 = 1, 2, 3, . . . , n, while the transitions \u03c4 between the states are denoted by the number of first and second state with a letter s between the numbers. This notation is chosen in order to make easier keeping track of relational structure of this two-level system. For example, the transition of the state \u03c3 1 to the state \u03c3 2 is denoted by \u03c3 1 s \u03c3 2 . The set of all transition laws will be denoted as L(S).", "cite_spans": [], "ref_spans": []}, {"section": "Graph representation of a physical system", "text": "The evolution of the physical system can be represented using an oriented graph. In that case, the transition from the state \u03c3 1 to the state \u03c3 2 has the form", "cite_spans": [], "ref_spans": []}, {"section": "Graph representation of a physical system", "text": "We will also allow for bidirectional transitions of the type", "cite_spans": [], "ref_spans": []}, {"section": "Graph representation of a physical system", "text": "which could happen in case of an isolated system spontaneously exchanging two states, as a consequence of some conservation law. In the expanded form, this can be denoted as", "cite_spans": [], "ref_spans": []}, {"section": "Graph representation of a physical system", "text": "Furthermore, we will enable some noise in the system such that it is possible for a state to go into several different states if it is allowed by the given transition laws. In our analysis, we use the simplest possible case, equal probabilities for transition if the transition laws allow it. For example, if there are allowed transitions", "cite_spans": [], "ref_spans": []}, {"section": "Graph representation of a physical system", "text": "all those transitions are possible with equal probability. Using this, we construct a randomly generated graph G(S) 2 , which represents a simple system of physical states and the corresponding transition laws, (Fig. 1 ). Our final goal is to allow our learning agent to form latent mental representation about her interaction with the physical system S. To probe the system we will let her interact with a randomly chosen state \u03c3 i \u2208 S and follow the evolution of states of the system, which results in a sequences of states. For example, for a given graph 2, 8, 6, 6, 3, 4, 9, 10,", "cite_spans": [], "ref_spans": []}, {"section": "Graph representation of a physical system", "text": "1, 3, 2, 10,", "cite_spans": [], "ref_spans": []}, {"section": "Graph representation of a physical system", "text": "where she randomly chooses the length of a sequence, with maximal length of 20, for the analyzed graph. The corresponding laws are 2s8, 8s6,", "cite_spans": [], "ref_spans": []}, {"section": "Graph representation of a physical system", "text": "1s3, 3s2, 2s10,", "cite_spans": [], "ref_spans": []}, {"section": "\u00b7 \u00b7 \u00b7", "text": "One may notice that the second and the third sequence here terminate in the state 10, which in this case plays a role of an equilibrium state.", "cite_spans": [], "ref_spans": []}, {"section": "\u00b7 \u00b7 \u00b7", "text": "When the system enters this state it stays there for a long time, because there is no way out.", "cite_spans": [], "ref_spans": []}, {"section": "\u00b7 \u00b7 \u00b7", "text": "Edges here describe the higher level notions. For instance, if a state \u03c3 1 represented by node corresponds to a cold temperature in the room, Figure 1 : Graph G(S), represents a system of physical states \u03c3 \u2208 S and corresponding state transition laws L(S). Nodes of the graph are physical states 1, . . . , n \u2208 S and arrows represent transition laws. In this specific example, the number of the nodes is n = 10. If our learning agent perceives the state 1, she can go to the next states 4 and 6, while she cannot reach directly the state 10, since nodes 1 and 10 are not directly connected. This can be described using transition laws 1s4 and 1s6. Notation is not commutative since the graph is oriented and from this graph it is clear that the transition 9s1 exists, while 1s9 is not possible. Due to a present noise, all these transitions are with equal probability. Since there are two directions of transition 4 to 5, there is a possibility of a loop 4 \u2190\u2192 5.", "cite_spans": [], "ref_spans": []}, {"section": "\u00b7 \u00b7 \u00b7", "text": "while a state \u03c3 2 corresponds to a warm temperature, then the edge \u03c4 1 = \u03c3 1 s \u03c3 2 can be related to heating the room and \u03c4 2 = \u03c3 2 s \u03c3 1 to cooling, and so on. We may say that temperature in the room is cold and then warm, or we may say that the temperature in the room rises, which is higher-level, relational description. In this way we established the two descriptions of a given environment and its evolution, each of which requires different number of notions. We assert here that these two ways of describing are equivalent, which in this case means that we need more higher-level notions. At the same time, using higher-level description results in shorter sequences.", "cite_spans": [], "ref_spans": []}, {"section": "\u00b7 \u00b7 \u00b7", "text": "The sequence of physical states obtained by following this oriented graph is pure kinematic description. On the other hand, the oriented edges of the graph, which represent transition laws, are consequence of the underlying physical laws. Therefore, we can interpret the sequences of transition laws as part of the dynamics of the system. They can be viewed as either differ-ent physical laws, or projection of one physical law onto the pair (an element of the product space) of the corresponding physical states. The dynamics of the system is here a higherorder description than the kinematics. On the other hand, if the physical states are just positions, the transitions could correspond to velocities, which are higher level kinematical notions; if the states are points in the phase space, transition laws might represent acceleration, which on the classical level might correspond to a force or another dynamical quantity.", "cite_spans": [], "ref_spans": []}, {"section": "\u00b7 \u00b7 \u00b7", "text": "distributional hypothesis of Harris [14] , which states that all words that have similar meaning appear in similar contexts. This reasoning can be extended in our case to the graph based physical system G(S), where a learning subject establishes a causal relation between physical states that occur in similar contexts. The treatment here will be exclusively statistical, since we want to investigate capability of an agent to learn about outer world in purely unsupervised way. An agent should build a latent vector representation of physical states. The states are not characterized by any other quality but their number. They are given as pure objects of cognition.", "cite_spans": [{"start": 36, "end": 40, "text": "[14]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "\u00b7 \u00b7 \u00b7", "text": "Representing words as vectors which form continuous linear vector space is relatively old idea [16] , but it gained momentum with the deep learning based CBOW and skip-gram Word2Vec model by Mikolov et al. [25] . This model is purely unsupervised, since it does not need labeled data. By applying this model on a text corpus, one obtains a vector representation which in certain sense reflects semantically relevant properties of the words. The resulting distribution is a latent vector representation which comes from the hidden layer of a neural network of Word2Vec model and at the first glance might not have a direct meaning to us. Nevertheless, it turns out that proximity of states reflects some semantic (causal) relations between the states. Vectors representing words which are causally similar are close in the resulting vector space and vice versa. The very idea of giving the geometric form to some semantic set is powerful since it allows algebraic treatment of semantic objects. Moreover, recent research suggests that it has some roots in physiology [3] .", "cite_spans": [{"start": 95, "end": 99, "text": "[16]", "ref_id": "BIBREF16"}, {"start": 206, "end": 210, "text": "[25]", "ref_id": "BIBREF25"}, {"start": 1066, "end": 1069, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "\u00b7 \u00b7 \u00b7", "text": "Beside Word2Vec there are several other newer and in certain sense more advanced methods to make word embedding like GloVe, [27] and FastText [4, 18] . Nevertheless, we do not need to take into account the internal or syntactical structure of words to learn word representation, which can be done with FastText, for instance. Instead, we have here a primitive or pure cognition of a physical system, defined in an abstract way, which could correspond more to the case of pre-lingual knowledge, thereby Word2Vec is sufficient for our needs.", "cite_spans": [{"start": 124, "end": 128, "text": "[27]", "ref_id": "BIBREF27"}, {"start": 142, "end": 145, "text": "[4,", "ref_id": "BIBREF3"}, {"start": 146, "end": 149, "text": "18]", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "\u00b7 \u00b7 \u00b7", "text": "Henceforth, except otherwise stated, everything we discuss will refer to the graph exam-ple from the previous section. Using skip-gram Word2Vec method with the windows size of 5 from the Gensim library [31] , we build two separate embedding vector spaces using sequences of physical states (5) and sequences of physical laws (6) . We train our model using 10000 randomly initialized sequences in both cases. Here we choose a relatively small number of dimensions in order to present our results graphically. For visualization we use principal component analysis (PCA), a statistically based dimensionality reduction technique [36] , from Scikit-learn [26] . It can distort some relations when projecting from higher-dimensional space when the number of dimensions is too high. Our choice for the number of embedding dimensions therefore is relatively low, d = 10.", "cite_spans": [{"start": 202, "end": 206, "text": "[31]", "ref_id": "BIBREF31"}, {"start": 325, "end": 328, "text": "(6)", "ref_id": "BIBREF5"}, {"start": 626, "end": 630, "text": "[36]", "ref_id": "BIBREF36"}, {"start": 651, "end": 655, "text": "[26]", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "\u00b7 \u00b7 \u00b7", "text": "After applying Word2Vec on sequences of states and laws, we obtain two embedding spaces. The embedding vectors for states \u03c3, are d-dimensional vectors \u03c3 and they belong to the embedding vector space E(S). There are n = 10 such vectors and we can collect them into a single matrix X of the dimension d \u00d7 n. Similarly, the vector encoding for m = 21 transition laws results in d \u00d7 m matrix Y , where we collected vectors \u03c4 for the embedding of transition laws E(L). From now on, we will refer to X \u2208 E(S) and Y \u2208 E(L) as to embedding vectors. The resulting 10-dimensional embedding spaces have some distribution of vectors which reflects latent semantic structure, like similarities and dissimilarities between the corresponding physical states and transition laws (Fig. 2) . In this way we represented our synthetic example of a physical world, using two levels of description with different measure, which was our aim. With this choice of density of graph edges pro node, we have = 2.1 times more transition laws than states. This can be viewed as interaction of agent with a system where she perceives the sequences of states she experiences and then goes to read the textbook which describes the evolution of the given physical system in terms of corresponding transition laws. We want to examine her capability to form a unique mental representation which could comprise both the instances of her direct experience of physical states and relational mental objects expressed in terms of transition laws.", "cite_spans": [], "ref_spans": [{"start": 763, "end": 771, "text": "(Fig. 2)", "ref_id": "FIGREF0"}]}, {"section": "\u00b7 \u00b7 \u00b7", "text": "This two-level description is based on the word embedding techniques, but it can also be related to some generic embedding. Especially if the laws can be stated in terms of sentences or phrases, some very advanced embedding models can be taken into account, like the universal sentence encoder [5] , where the whole sentences are embedded in a vector space of a very high dimensionality. In this case the position of a sentence reflects latent semantic property of a sentence.", "cite_spans": [{"start": 294, "end": 297, "text": "[5]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Building a unique representation space", "text": "In this section we want to build a unique latent vector representation for the set of physical states and related transition laws. We will refer to it as to the mental representation of a learning agent, due to the existence of underlying semantic structure and causality. We conjectured that aligning distributions of the vectors in the embedding representation space built independently for the states E(S) and laws E(L) should result in some sensible result, since it describes two aspects of the same physical reality.", "cite_spans": [], "ref_spans": []}, {"section": "Building a unique representation space", "text": "When we put together these independently trained embedding representations in a common 10-dimensional space we obtain two separated and non-related distributions like in Fig.  3 . This result is expected since the two sets of sequences, one for physical states and the other for transition laws have fully different statistics. Yet, they should posses certain latent similarity properties. One way to relate the distribution of obtained embedding vectors of physical laws Y \u2208 E(L) to the vectors of physical states X \u2208 E(S) in a common embedding space is called orthogonal Procrustes algorithm. We follow the approach of [32, 19] where this method is elaborated and used. The point is to apply linear mapping \u2126 : E(S) \u2192 E(L), where \u2126 is orthogonal, i.e., \u2126 T \u2126 = I, which minimizes the difference in Frobenius norm of the mapping \u03c9 = argmin \u2126 ||X \u2212 \u2126Y ||.", "cite_spans": [{"start": 621, "end": 625, "text": "[32,", "ref_id": "BIBREF32"}, {"start": 626, "end": 629, "text": "19]", "ref_id": "BIBREF19"}], "ref_spans": [{"start": 170, "end": 177, "text": "Fig.  3", "ref_id": "FIGREF1"}]}, {"section": "Building a unique representation space", "text": "The applied orthogonal mapping \u2126 acts on the vectors from Y \u2208 E(L) by performing rotations and reflections. The minimization of the norm in the equation (7) results in \u2126 which makes the mutual distance between the whole distributions in 10-dimensional space minimal. This problem has solution in terms of singular value decomposition (SVD) of the form", "cite_spans": [], "ref_spans": []}, {"section": "Building a unique representation space", "text": "where the SVD of the matrix XY T can be written in the form", "cite_spans": [], "ref_spans": []}, {"section": "Building a unique representation space", "text": "Here, the orthogonal matrices U and V correspond to rotations and reflections, while \u03a3, which is a diagonal matrix of eigenvalues of XY T , corresponds to scaling transformations. Thus, from the equation (8), it follows that this transformation consists of rotations and reflections. For the orthogonal Procrustes algorithm (7) to work X and Y should be of the same shape. Since there are more laws than states (n states and m laws), we have to somehow restrict the number of transition laws taken into account. Our choice is to restrict the vector Y to only the n most commonly applied transition laws before trying to align the two distributions. The restricted Y vector is the\u00f1", "cite_spans": [{"start": 324, "end": 327, "text": "(7)", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Building a unique representation space", "text": "Following this restriction, the usual SVD can be applied in order to learn the d \u00d7 d matrix \u2126 which maps\u1ef8 to X. Thereafter, we apply the matrix\u03a9 to the whole vector Y in order to align the distribution of laws from vector Y to the distribution of states, represented by the vector X", "cite_spans": [], "ref_spans": []}, {"section": "Building a unique representation space", "text": "Together, vectors X and \u03a5 belong to the common 10-dimensional embedding space E(C).", "cite_spans": [], "ref_spans": []}, {"section": "Building a unique representation space", "text": "The obtained result 3 in the common embedding space is visualized using PCA dimensional reduction in the Fig. 4 . The result suggests that there are some regularities in the geometric picture we obtained. Certain laws are placed somewhere between the corresponding states, belonging to the neighbours of the middle-point between the corresponding states in this 10dimensional space. Resulting alignment of the two distributions allows us to see clearly that the law 3s2 is placed near the half-way between the states 3 and 2. Similarly holds for 9s1, 3s5, 3s7, 9s10, etc. This regularity may be expressed in the form", "cite_spans": [], "ref_spans": [{"start": 105, "end": 111, "text": "Fig. 4", "ref_id": "FIGREF2"}]}, {"section": "Building a unique representation space", "text": "where \u03c4 is the vector representation of the transition law \u03c4 = \u03c3 1 s \u03c3 2 and \u03c3 1 and \u03c3 2 are vector representations of the corresponding states. The approximation sign correspond to the the vector at minimal distance, that is the nearest neighbour. This is expressed in Euclidean metric, but may be as well stated in terms of cosine distance, in which case the nearest neighbour correspond to maximum of the projection", "cite_spans": [], "ref_spans": []}, {"section": "Building a unique representation space", "text": "where we have a usual Euclidean dot product and the Euclidean L 1 norm. In most cases the vectors of transition laws are distorted from the nearest neighbours of a geometric middle-point for the corresponding states, making similar triangles. In these cases there are approximate analogies, for instance 5, 6 \u2194 5s6 \u223c 7, 6, \u2194 7s6, 5, 9 \u2194 5s9 \u223c 2, 9, \u2194 2s9, 5, 4 \u2194 5s4 \u223c 7, 4, \u2194 7s4, which can be expressed as", "cite_spans": [], "ref_spans": []}, {"section": "Building a unique representation space", "text": "where \u03c4 1 = \u03c3s \u03c3 1 and \u03c4 2 = \u03c3s \u03c3 2 . This suggests us that there is additional alignment needed in order to obtain full interpolation. The deviation from the interpolation equation (12) suggests that orthogonal Procrustes is maybe is not enough to fully prove our conjecture. Nevertheless, this is enough strong sign of distributional similarity between the two embeddings, since the regularities defined by the equations (12, 14) are present in nearly 60% of transition laws in this simple example.", "cite_spans": [{"start": 423, "end": 427, "text": "(12,", "ref_id": "BIBREF12"}, {"start": 428, "end": 431, "text": "14)", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Building a unique representation space", "text": "The two regularities can be expressed as more general statement that vector of transition law \u03c4 , where \u03c4 = \u03c3 1 s \u03c3 2 , and the corresponding states vectors \u03c3 1 and \u03c3 2 form isosceles triangles, or", "cite_spans": [], "ref_spans": []}, {"section": "Building a unique representation space", "text": "This means that the vector of transition laws populate regions between the corresponding states preserving the triangular structural relation with the states.", "cite_spans": [], "ref_spans": []}, {"section": "Building a unique representation space", "text": "Additionally, we can see that transition laws 4s5 and 5s4 are near neighbours and that they are placed somewhere between the states 4 and 5. The distinction between the given twodirectional laws interestingly defines a latent ordering. We will comment the ordering problem in the discussion section.", "cite_spans": [], "ref_spans": []}, {"section": "Building a unique representation space", "text": "Contrary to the obtained distribution alignments, if we just shrink random rotate and translate the whole distribution from Fig. 3 by hand so that the centroids of the distributions match, we do not obtain any sensible result (Table 2).", "cite_spans": [], "ref_spans": [{"start": 124, "end": 130, "text": "Fig. 3", "ref_id": "FIGREF1"}]}, {"section": "Experiments", "text": "In order to support our claims from the previous section, we apply the equation (16) in such a way that we keep first \u03c4 , \u03c3 1 and \u03c3 2 , and iterate through all transition laws vectors \u03c5 \u2208 \u03a5 in d = 10 dimensional space in order to find the corresponding nearest neighbour according to", "cite_spans": [{"start": 80, "end": 84, "text": "(16)", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Experiments", "text": "The embedding vectors are normalized and we use Euclidean L 1 norm for the results that follow. The statistics we apply here is the following: Top 10% is the percent of all cases when the \u03c5 is among 10% nearest neighbours for given \u03c4 . Similarly, we use Top 30% and Top 50%. For all iterations of \u03c5 \u2208 \u03a5 we also take the average placement of the right answer Avg, in the set of all iterations. We use percents rather than actual average placement due to the different choices of the number of states and transition laws. This means that if Avg is 30%, the correct answer is on average at the 30th place as the nearest neighbour in the case when there are 100 transition laws.", "cite_spans": [], "ref_spans": []}, {"section": "Experiments", "text": "For the example from the previous section with 10 states and 21 corresponding transition laws, i. e. density of = 2.1 laws pro state, we randomly generated 1000 graphs. The obtained statistics shows pretty good stability with standard deviations \u03c3 Top10% = 5%, \u03c3 Top30% = 8%, \u03c3 Top50% = 15% and \u03c3 Avg = 5%. Results are given in the Table 1 . On the contrary, if we shuffle the transition laws by randomly swapping their vectors, we get the results as in the Table 2 , which shows the absence of any regularity. In ideal case, the statistics for complete randomness of distribution is: Top 10% = 10%, Top 10% Top 30% Top 50% Avg 31 52 80 29 Top 30% = 30%, Top 50% = 50% and Avg = 50%.", "cite_spans": [], "ref_spans": [{"start": 332, "end": 339, "text": "Table 1", "ref_id": "TABREF0"}, {"start": 458, "end": 465, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "Experiments", "text": "We introduced the discrete set of states and transition laws. It is very important to see how this system behaves when we add the intermediate states connected with additional laws. In order to mimic the augmented resolution of the physical system, we only slightly increase the number of the connections of the given state with the another arbitrary state. This allows us to keep the ratio = 2.1 fixed. For the unchanged number of embedding dimensions d = 10, the results remain stable up to 10 4 states. For 1000 states and corresponding 2100 laws we get: Top 10% = 29%, Top 30% = 63%, Top 50% = 80% and Avg = 27%. The stability of the result is necessary condition if we want to have a good convergence towards the continuous limit and surprisingly, up to the increment of the order 10 3 , the model does not require a higher-dimensional embedding space to keep the results unchanged. This is possibly the consequence of the fact that in d-dimensional space, there is d(d \u2212 1)/2 independent basic rotations (45 in this case where d = 10), which is obviously enough to align the given distributions.", "cite_spans": [], "ref_spans": []}, {"section": "Experiments", "text": "A significant obstacle in obtaining better results are the outlier states and laws vectors of the embedding (the state 6 in Fig. 4 ), because they can displace the the whole distribution, which then fails to align properly. When Top 10% Top 30% Top 50% Avg 60 80 95 14 Table 3 : Scores in percent for the case when the outliers are removed.", "cite_spans": [], "ref_spans": [{"start": 124, "end": 130, "text": "Fig. 4", "ref_id": "FIGREF2"}]}, {"section": "Experiments", "text": "we remove the outliers by hand before orthogonal Procrustes, the results improve significantly (Table 3) . Similar results follow from the translation of the laws vector distribution toward the outlier of the states distribution so that the two distributions match better.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Our final goal is task-invariant way of acquiring natural knowledge, which is in line with attempts to obtain general (task-independent) artificial intelligence. Here we made first steps towards conceptual generalization on the most basic level. If we have two orders of description of a system, one primitive and one of a higher order, based on the former, we showed one way to put the second-order description into the context of the first-order description. This resulted in unified knowledge representation which could, for instance, allow the learning agent to infer dynamics of the system from kinematical inputs.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "One example, where analogous form of learning is present, is the eye-hand coordination at the early stages of human development. Infants take several months to make connections of simultaneous visual, and auditory stimuli with motor activity [9, 35] . Similarly, humans are able to identify the underlying dynamics of motion, taking into account kinematic information only [9, 29] . This is in direct correlation with our two-level graph representation, where two types of sequences correspond to kinematics and dynamics of the system.", "cite_spans": [{"start": 242, "end": 245, "text": "[9,", "ref_id": "BIBREF8"}, {"start": 246, "end": 249, "text": "35]", "ref_id": "BIBREF35"}, {"start": 373, "end": 376, "text": "[9,", "ref_id": "BIBREF8"}, {"start": 377, "end": 380, "text": "29]", "ref_id": "BIBREF29"}], "ref_spans": []}, {"section": "Discussion", "text": "Our results suggest that this method or its extensions could be applied to relate two 'languages' of different measure for description of the same physical reality. The co-occurrence of the events on different level amounts to establish causal relations and obtain a clearer picture of the outer world, based solely on the statistics. It refers to any kind of thought representations when there is a possibility to relate objects of cognition with the corresponding metaobjects, based on similar statistics. Instead of the conjectured interpolation, we obtained the triangular structure which might suggest that additional translation has to be applied.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Although this method allows us to establish geometrically based concept formation picture in certain sense, there are several possibilities for refinement. We only used the linear Procrustes transformation. The two distributions of the embedding vectors are only rotated and reflected, but not translated. The analysis from the previous section shows that additional translation remedies the result significantly. This refinement can be achieved by applying additional neural training which could result in translation prior to, or after rotations. We also tried to obtain alignment using simple generative adversarial network (GAN) [10] , but with a limited success. The generator was trained to mimic the distribution of X from the distribution of Y . The resulting distribution is similar to the distribution of X, but the points of Y tend rather to match and group near to the points of X, then to interpolate. Additionally, the stopping criterion should be better understood. One possible way to overcome this problem is the domainadversarial training [7] which is used in the case of unsupervised machine translation models.", "cite_spans": [{"start": 633, "end": 637, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 1057, "end": 1060, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Discussion", "text": "At this stage we did not take into account spatio-temporal relations between the events, but only mutual ordering relation. As we mentioned earlier, up to a slight hint of noncommutativity, there is an open question of ordering too. Namely, the language and thoughts are in general non-commutative (time-ordered) and the word embedding-like representations are basically commutative bags, which are thus not enough for communicating thoughts. Therefore we tried also neural machine translation using Seq2Seq architecture [34] , with or without teacher forcing [20] or the attention mechanism [2] to order and translate states into laws and conversely. These neural architectures essentially work very well when they are trained on the exact sequences of states and laws. Nevertheless, they only translate without semantic insight, and for the sequences of the states which are not allowed by the given laws, they usually spell nonsensical results. One direction of research would be to train Seq2Seq, not on exact sequences, but rather on environments of given sequences in the embedding space taking into account latent relations of states and transition laws. The other direction could be to apply Memory networks [38, 33] , with specially prepared datasets or to apply ordering in the form of some sort of positional encoding as in the case of the transformer architecture [37] .", "cite_spans": [{"start": 521, "end": 525, "text": "[34]", "ref_id": "BIBREF34"}, {"start": 560, "end": 564, "text": "[20]", "ref_id": "BIBREF20"}, {"start": 592, "end": 595, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 1221, "end": 1224, "text": "33]", "ref_id": "BIBREF33"}, {"start": 1376, "end": 1380, "text": "[37]", "ref_id": "BIBREF37"}], "ref_spans": []}, {"section": "Discussion", "text": "The extension of this result can be also interesting in cases of natural supervision [23] , where there is possibility of simultaneous learning visual concepts, words and sentences. Similarly, it could fit into the framework of the so called the thousand brains theory of intelligence [15] , which states that brain does not make only one model of the world but many models on different levels, while the resulting concept is the consensus of the votes.", "cite_spans": [{"start": 85, "end": 89, "text": "[23]", "ref_id": "BIBREF23"}, {"start": 285, "end": 289, "text": "[15]", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "Discussion", "text": "Objects (physical states) and meta-objects (transition laws) in our model are inspired by the concept formation formalism of G\u00e4rdenfors, [8, 9] . In this cognitive theory of semantics, notions and meanings can be represented geometrically as convex regions of the so called conceptual space. The underlying idea is to equip the representation space with topological structure, resulting in the existence of the notional domains. The topology is in this context based on convexity, i.e. interpolation (betweenness). Our result may be interpreted from this point of view as follows: if notions \u03c3 a and \u03c3 b belong to some category (convex domain of space), then the notion \u03c3 a s \u03c3 b which relates notions \u03c3 a and \u03c3 b belongs to the same notional category. In our case the notion of convexity is replaced by the triangular structure. G\u00e4rdenfors builds a self-contained semantic theory following this assumption, which then explains in-depth the constraints on how words related to their notional dynamical or kinematical nature acquire their syntactic function. 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The vector embedding representation E(S) for physical states (left) mirrors certain contextual similarities between physical states. Similarly for the transition laws embedding E(L) (right).", "type": "figure"}, "FIGREF1": {"text": "PCA projection of common embedding space for states and transition laws before orthogonal Procrustes.", "type": "figure"}, "FIGREF2": {"text": "PCA projection after applying orthogonal Procrustes on the set of transition laws. We obtain a unified interrelated representation of physical states (blue) and physical laws (red). Transition laws in certain cases interpolate between the corresponding physical states.", "type": "figure"}, "TABREF0": {"text": "Scores in percent for transition laws after orthogonal Procrustes.", "type": "table"}, "TABREF1": {"text": "Scores in percent for randomly shuffled transition laws.", "type": "table"}}}
{"paper_id": "2870167", "_pdf_hash": "7e23408c13945f1c656ecc7db53e24109f003744", "abstract": [{"section": "Abstract", "text": "Background: The clinical presentations of pertussis infection have considerable variation. Many infections and illnesses can cause prolonged repetitive paroxysmal cough that could be confused with Bordetella pertussis infection. Aim: This retrospective study was designed to compare the clinico-laboratory findings between two groups of hospitalized infants with confirmed, and those who have clinical pertussis disease; to identify the possible additional diagnostic clues \"for the diagnosis of confirmed pertussis disease\". Subjects and Methods: The study population consisted of infants \u226412 months of age with clinical diagnosis of pertussis that fulfilled the World Health Organization definition for pertussis or those diagnosed by physicians. Clinico-laboratory findings were compared between two groups of patients (confirmed vs. clinical cases). Results: From a total of 118 infants admitted with a clinical diagnosis of pertussis, 16% (19/118) were confirmed by laboratory to have confirmed pertussis. Twelve of 19 (63%) and 71.99% of confirmed and clinical cases were younger than 6 months of age, respectively. For most patients, the duration of symptoms before hospitalization was <14 days. There were no significant differences between two groups of patients for paroxysmal cough and facial discoloration. However, whoop and apnea were more common among confirmed pertussis cases: P = 0.01, and P = 0.02, respectively. Leukocytosis (\u226516,000/ml) (P = 0.01) and lymphocytosis (\u226511,000) (P = 0.02) were reported significantly more frequently in confirmed pertussis cases. Conclusion: Given the unavailability of a highly sensitive diagnostic test, in every afebrile patient with paroxysmal cough lasting for \u22657 days associated with whoop and/or apnea, particularly if accompanied by leukocytosis/lymphocytosis, pertussis disease should be considered. In this situation, prompt administration of empiric treatment for cases, and providing control measures to prevent infection transmission to contacts are recommended.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "The clinical presentation of Bordetella pertussis infection has considerable variation [1, 2] that depends on the age of patients, [3, 4] previous immunization or infection, [4] [5] [6] [7] [8] co-infection with other respiratory microbes, [9] [10] [11] [12] [13] [14] the presence of passively acquired antibodies, [15] [16] [17] and perhaps other factors related to the host and organism. [1] The classic manifestations of pertussis in unvaccinated susceptible subjects are described as the presence of repetitive paroxysmal coughing episodes, inspiratory whoop, posttussive vomiting, and cough lasting for \u22652 weeks. [1, 2, 18, 19] Mild and atypical presentations of pertussis are common, [1, 2, 20] particularly in young infants, [3, 4, 15] and previously immune individual. [4] [5] [6] [7] [8] Therefore, illnesses caused by other respiratory microbes are often confused with pertussis. [9] [10] [11] [12] [13] [14] An accurate diagnosis of pertussis cannot be made by clinical symptoms alone, and the laboratory confirmation of a clinical pertussis illness is required. [1, 18, 20] The challenge is for most countries to provide basic laboratory facilities for the diagnosis of pertussis. In this regard, the World", "cite_spans": [{"start": 87, "end": 90, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 91, "end": 93, "text": "2]", "ref_id": "BIBREF1"}, {"start": 131, "end": 134, "text": "[3,", "ref_id": "BIBREF2"}, {"start": 135, "end": 137, "text": "4]", "ref_id": "BIBREF3"}, {"start": 174, "end": 177, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 178, "end": 181, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 182, "end": 185, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 186, "end": 189, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 190, "end": 193, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 240, "end": 243, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 244, "end": 248, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 249, "end": 253, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 254, "end": 258, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 259, "end": 263, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 264, "end": 268, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 316, "end": 320, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 321, "end": 325, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 326, "end": 330, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 391, "end": 394, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 619, "end": 622, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 623, "end": 625, "text": "2,", "ref_id": "BIBREF1"}, {"start": 630, "end": 633, "text": "19]", "ref_id": "BIBREF18"}, {"start": 691, "end": 694, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 695, "end": 697, "text": "2,", "ref_id": "BIBREF1"}, {"start": 698, "end": 701, "text": "20]", "ref_id": "BIBREF19"}, {"start": 733, "end": 736, "text": "[3,", "ref_id": "BIBREF2"}, {"start": 737, "end": 739, "text": "4,", "ref_id": "BIBREF3"}, {"start": 740, "end": 743, "text": "15]", "ref_id": "BIBREF14"}, {"start": 778, "end": 781, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 782, "end": 785, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 786, "end": 789, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 790, "end": 793, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 794, "end": 797, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 891, "end": 894, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 895, "end": 899, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 900, "end": 904, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 905, "end": 909, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 910, "end": 914, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 915, "end": 919, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 1075, "end": 1078, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 1083, "end": 1086, "text": "20]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "Clinical and Laboratory Features of Pertussis in Hospitalized Infants with Confirmed Versus Probable Pertussis Cases", "text": "Health Organization (WHO) [19] and the Centers for Diseases Control and Prevention (CDC) [20] developed a case definition for pertussis for the epidemiological purpose. If purely standard clinical criteria were used to diagnose pertussis, this would result in considerably over-or under-diagnosis of pertussis. [20] During 2008-2011, Iran and Mazandaran province experienced a pertussis epidemic. [21] The aim of the present study was to compare the clinico-laboratory findings among two groups of patients younger than 12 months of age, who were hospitalized and treated as probable pertussis cases, and those confirmed by laboratory tests, to identify the possible additional diagnostic clues to support the clinical diagnosis of pertussis, particularly for regions with limited access to diagnostic laboratory services.", "cite_spans": [{"start": 26, "end": 30, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 89, "end": 93, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 311, "end": 315, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 397, "end": 401, "text": "[21]", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Subjects and Methods", "text": "Until the year 2007, the annual incidence rate of pertussis reported to the Iranian CDC (Ir-CDC) was very low (<0.2/100,000 population). [8, 22] From that, the number of clinical pertussis cases reported to Ir-CDC increased sharply, and continued for >3 years. This pattern was more prominent in Mazandaran, North of Iran and resulted in more hospitalization rate among children in the region. [23] To identify the possible additional diagnostics clues, this study was designed to compare the clinical features, laboratory and radiologic findings, and hospitals courses of pertussis disease between two groups of patients with confirmed versus probable pertussis cases. We reviewed the medical records of the infants younger than 12 months of age who were hospitalized, treated, and discharged with: Probable pertussis disease, whooping cough, pertussis syndrome, pertussis-link cough illness in Bouali Sina Hospital affiliated to the Mazandaran University of Medical Sciences during the period March 2008 to April 2012 in Sari, North of Iran. The clinical (probable) pertussis case definition was based on the Ir-CDC [22] and the WHO [19] criteria. The clinical case definition for pertussis to report a case consisted of an acute cough illness lasting \u226514-days with at least one pertussis associated symptom; paroxysmal cough, inspiratory whoop, and posttussive vomiting without any obvious cause. Furthermore, for this study, any afebrile coughing illness lasting \u22657-days and associated with paroxysm, whoop, facial discoloration during coughing episodes, or apnea as a presenting symptom or as a postparoxysmal event (irrespective of its duration) in infants <6 months of age was considered as a probable pertussis case. A confirmed case was defined as a probable case that was culture or polymerase chain reaction (PCR) positive. ", "cite_spans": [{"start": 137, "end": 140, "text": "[8,", "ref_id": "BIBREF7"}, {"start": 141, "end": 144, "text": "22]", "ref_id": "BIBREF21"}, {"start": 394, "end": 398, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 1118, "end": 1122, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 1135, "end": 1139, "text": "[19]", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Results", "text": "During the 4-year study period, 174 hospitalized patients (age range: 15 days to 13 years) met the criteria and were identified. Of the 174 cases, 13.2% (23/174) were confirmed by culture and/or PCR. PCR was performed in nearly all cases. From the 174 cases identified, 118 (68%) were younger than 12 months of age and included in the analysis. Of the 118 patients, 19 (16%) cases were confirmed to have pertussis by the laboratory. Nearly, 63% (12 of 19) of the confirmed pertussis and 71.7% (71 of 99) of clinical cases were younger than 6 months of age. There were no significant differences according to the sex: Male ratio 47.3 versus 49.5% (P = not significant [NS]), the mean duration of symptoms before the day of admission was 9.8 (3.4) days versus 10.7 (2.8) days; (P = NS) and the frequency of physician visits before hospitalization (73.7% vs. 72.9%) (P = NS) between the confirmed cases and patients with clinical pertussis, respectively. However, the duration of hospital stay was significantly longer in confirmed than probable cases; P = 0.04, and those requiring PICU care P < 0.001, respectively. The clinical signs and symptoms before the day of admission were available for the entire hospitalized patients (confirmed and probable cases) [ Table 1 ]. There were no significant differences for paroxysms, facial discoloration during coughing episodes, and posttussive vomiting between the confirmed versus the clinical pertussis cases. However, whooping and apnea (as a presenting compliant or as a postcoughing event) were significantly more frequent among the confirmed than the probable cases (P = 0.01 and P = 0.02), respectively [ ) were significantly more frequent in confirmed cases than those with clinical pertussis P = 0.02 and P = 0.01, respectively [ Table 1 ]. During the hospitalization, one 5-week-old and 9-week-old infants with confirmed pertussis developed seizures and aspiration pneumonia, respectively. All patients in both groups were treated with a macrolide and a bronchodilator. Five of the 19 (26%) of confirmed pertussis and 27 of the 99 (27%) of clinical cases were treated by an antibacterial agents other than a macrolide antibiotic. Fortunately, no mortality was reported.", "cite_spans": [], "ref_spans": [{"start": 1260, "end": 1267, "text": "Table 1", "ref_id": "TABREF1"}, {"start": 1782, "end": 1789, "text": "Table 1", "ref_id": "TABREF1"}]}, {"section": "Discussion", "text": "Bordetella pertussis infection has a wide-spectrum of clinical expression. Paroxysmal cough, facial discoloration during coughing episodes, and posttussive vomiting are the primary symptoms in the clinical diagnosis of pertussis and the mainstay of the WHO [19] and the Ir-CDC [21] case definition for B. pertussis infection. In this study, the typical symptoms of pertussis were observed in the majority of hospitalized patients. Whoop and apnea were two symptoms which were observed significantly more frequently in patients with confirmed pertussis than clinical pertussis. Whoop, a forceful inspiration of air through a narrow glottis, usually develops after a paroxysmal cough, and is a characteristic of pertussis disease. Its presence in infant represents true pertussis particularly during an outbreak, although in some occasions, other diseases may mimic whooping cough and result in confusion. [1, 2] These symptoms may be absent in neonate, [1, 3, 15] or older children with pertussis. [4, 6, 7] Otherwise, the frequency of apnea in patients with pertussis as presenting symptoms or as a sign of postparoxysm exhaustion is variable and depends on patient's age: Higher rates were reported in younger infants. A similar clinical presentation was reported in several other studies worldwide. [24] [25] [26] [27] [28] In a large multicenter study: Report of the active immunization monitoring program among hospitalized children <2 years of age conducted by Halperin et al. in the Canada; [24] a total of 1082 pertussis cases requiring hospitalization was reported. Most cases (91.9%) were infants <12 months of age, and 79.1% were <6 months of age. Virtually, all hospitalized children (93.7%) had a history of paroxysmal cough, and more than 58% who had vomiting and cyanosis were observed in 64.4% of cases. [24] Furthermore, whoop and apnea were reported in 43.9% and 26.2% of infants less than 6 months of age, 46.9% and 6.4% of infant older than 6 months, respectively. During a national active surveillance of pertussis among infants in Australia, [25] 140 hospitalized infants with pertussis disease (73% confirmed) were detected. Of those, 96% had paroxysmal cough and 67% cyanosis during coughing. Whooping and apnea were reported in 47% and 41% of cases, respectively. As part of a large vaccine efficacy trial, to describe the clinical presentations of culture-confirmed pertussis in children and their contacts with cough illness lasting \u22657 days in an outpatients setting, a study was designed and conducted by Heininger et al. in Germany, [26] 3629 samples were submitted, and B. pertussis was isolated in 601 (16.1%) cases 7.6% of cases were fully vaccinated. A total of 2079 out of 3629 (57.3%) was reported to have paroxysm during the course of their illness. Of the 601 culture positive, 68.1% had paroxysms, whereas 1670 of 3028 (55.2%) of culture-negative patients also had paroxysms. The frequency of whooping is was 90.1% in those with positive culture versus 45% in cases that were culture negative. However, the rate of apnea reported in their study was much lower than those reported by Halperin et al. and was 15.9% in infants less than 6 months of age and 1% in the older ones.", "cite_spans": [{"start": 257, "end": 261, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 277, "end": 281, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 904, "end": 907, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 908, "end": 910, "text": "2]", "ref_id": "BIBREF1"}, {"start": 952, "end": 955, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 956, "end": 958, "text": "3,", "ref_id": "BIBREF2"}, {"start": 959, "end": 962, "text": "15]", "ref_id": "BIBREF14"}, {"start": 997, "end": 1000, "text": "[4,", "ref_id": "BIBREF3"}, {"start": 1001, "end": 1003, "text": "6,", "ref_id": "BIBREF5"}, {"start": 1004, "end": 1006, "text": "7]", "ref_id": "BIBREF6"}, {"start": 1301, "end": 1305, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 1306, "end": 1310, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 1311, "end": 1315, "text": "[26]", "ref_id": "BIBREF25"}, {"start": 1316, "end": 1320, "text": "[27]", "ref_id": "BIBREF26"}, {"start": 1321, "end": 1325, "text": "[28]", "ref_id": "BIBREF27"}, {"start": 1497, "end": 1501, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 1819, "end": 1823, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 2063, "end": 2067, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 2561, "end": 2565, "text": "[26]", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "Discussion", "text": "It has been suggested previously that many other infections and illnesses [9] [10] [11] [12] [13] 28] can cause prolonged repetitive paroxysmal cough that can be confused with B. pertussis infection and would have fulfilled the WHO clinical criteria for pertussis diagnosis. In a serologic study, in children who coughed for more than 7-days and had no evidence of B. pertussis infection, [9] adenoviruses were the most frequent pathogen found, followed by the parainfluenza viruses, mycoplasma pneumonia, and respiratory syncytial virus (RSV). [9] The authors concluded that the differential diagnosis of pertussis-like cough illness by laboratory methods should include these infections. In a study by Korppi and Hiltunen, [14] B. pertussis etiology was studied in infants <6 months of age who were hospitalized for lower respiratory tract illnesses accompanied by cough during an RSV epidemic. B. pertussis was found as a co-infection in 8% of cases. In their retrospective study, RSV alone and mixed RSV-B. Pertussis cases could not be separated by clinical characteristics. The authors concluded that to avoid under-diagnosis, pertussis should be considered in all nonvaccinated infants with lower respiratory tract illnesses, also an RSV diagnosis does not exclude pertussis. [14] In a recent study on infants <6 months of age with lower respiratory *All confirmed and probable cases were treated with a macrolide and bronchodilator, **WBC: white blood cell counts \u226516,000 and lymphocytosis \u226511,000 cell/ml. NS: Not significant tract illness requiring PICU care for their illness, 20% had pertussis and 7% were mixed infection with RSV. The infants with pertussis suffered from cough, apnea, and whooping more often than infants without pertussis. [29] For this study, it was not possible to determine the relative roles of other respiratory microbes causing pertussis-like cough illness, and is a limitation of our study.", "cite_spans": [{"start": 74, "end": 77, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 78, "end": 82, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 83, "end": 87, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 88, "end": 92, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 93, "end": 97, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 98, "end": 101, "text": "28]", "ref_id": "BIBREF27"}, {"start": 389, "end": 392, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 545, "end": 548, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 725, "end": 729, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 1282, "end": 1286, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 1754, "end": 1758, "text": "[29]", "ref_id": "BIBREF28"}], "ref_spans": []}, {"section": "Discussion", "text": "Leukocytosis due to ALC was recognized as a hallmark of pertussis infection 100 years ago, and is usually present at the beginning of paroxysmal cough and persists for 3-4 weeks. Adolescents and young adults, partial immune subjects, and occasionally young infants have less impressive lymphocytosis. [1, 2] Most viral respiratory infections can cause relative lymphocytosis, however, this is not associated with leukocytosis and/or ALC. In this study, the statistically significant numbers of confirmed pertussis versus clinical cases showed leukocytosis and/or ALC. Similar to this, pattern was reported by Heinninger et al. in a large prospective vaccine efficacy trial in Germany. [26] Although ALC with/or without leukocytosis is not a confirmatory laboratory test, its presence in patients with clinical case definition for pertussis disease may support in diagnosing B. pertussis infection.", "cite_spans": [{"start": 301, "end": 304, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 305, "end": 307, "text": "2]", "ref_id": "BIBREF1"}, {"start": 685, "end": 689, "text": "[26]", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "Discussion", "text": "The laboratory diagnosis of pertussis is challenging, culture is highly specific, however, sensitivity can be low, require a long incubation, and result is influenced by several factors including: Time between cough beginning and sampling, patient age, earlier immunity (vaccinal/infection), receipt of a macrolide, and sampling methods. Rapid, highly sensitive, and specific PCR assays have been developed to detect B. pertussis infection. Factors that have negative effects on culture sensitivity have less impressive influence on PCR results. [20] In this retrospective study, pertussis infection was confirmed in 19 of 118 (16%) of cases. From a worldwide prospective, the challenge is for all countries to be able to provide basic laboratory diagnostic services. New laboratory diagnostic tests for the rapid and reliable detection of B. pertussis are required. Furthermore, providing facilities capable to evaluate relative roles of other agents causing pertussis-like coughing are recommended. These methods can aid to identify true pertussis and nonpertussis cases more readily, and may lead to more efficient patient-contact medical management care.", "cite_spans": [{"start": 546, "end": 550, "text": "[20]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "Discussion", "text": "In this study, more than two-thirds of cases in both groups were infants younger than 6 months; age group with the most severe disease and the higher complications. [1] [2] [3] 15, 18] Strategies to protect these groups of infants from pertussis disease and build immunity provided by active immunization, such as: Universal adolescents immunization \"adolescents act as the main source of infection for transmitting to young infants\", [30] neonatal immunization, [31] immunization of the mother before [32] or during pregnancy [33, 34] are recommended.", "cite_spans": [{"start": 165, "end": 168, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 169, "end": 172, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 173, "end": 176, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 177, "end": 180, "text": "15,", "ref_id": "BIBREF14"}, {"start": 435, "end": 439, "text": "[30]", "ref_id": "BIBREF29"}, {"start": 463, "end": 467, "text": "[31]", "ref_id": "BIBREF30"}, {"start": 502, "end": 506, "text": "[32]", "ref_id": "BIBREF31"}, {"start": 527, "end": 531, "text": "[33,", "ref_id": "BIBREF32"}, {"start": 532, "end": 535, "text": "34]", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "Discussion", "text": "In the most of our patients, the total duration of cough before hospitalization was <2 weeks, thus not fulfilling the clinical part of the WHO and Ir-CDC case definition for pertussis. Similar observations were reported also by others. [24] Although the WHO and Ir-CDC case definition played an important role in improving the sensitivity of pertussis diagnosis in epidemiological surveys, if these criteria are used purely clinically to select pertussis cases for confirmation, this may result in considerable under-diagnosis of pertussis. To improve pertussis case selection, a new case definition and strategy is required. [35] We recognize some limitations of this retrospective study. Although significant differences were noted between pertussis cases and control subjects, our analysis was limited by a small sample size. Furthermore, there were no diagnostic facilities to assess the relative roles of other microbes causing pertussis-like symptoms in the patients, which are the main limitations of the study.", "cite_spans": [{"start": 236, "end": 240, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 626, "end": 630, "text": "[35]", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "Conclusions", "text": "According to our study findings, in the case of afebrile infant with lower respiratory tract symptoms and paroxysmal cough for \u22657-days associated with whoop and/or apnea, particularly if it was accompanied by leukocytosis and/or absolute lymphocytosis, pertussis disease should be strongly considered. In this situation, especially in the lack of diagnostic laboratory facilities, empirical treatment of such suspected cases along with other control measures are recommended. 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{"paper_id": "2870562", "_pdf_hash": "a6f178bad86b0db256e35f64feb3a895f3622009", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Rock-Forming Minerals", "authors": [{"first": "W", "middle": ["A"], "last": "Deer", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Howie", "suffix": ""}, {"first": "J", "middle": [], "last": "Zussman", "suffix": ""}], "year": 1962, "venue": "", "link": null}, "BIBREF1": {"title": "On the structure-planes of corurlLdtm", "authors": [{"first": "J", "middle": ["W"], "last": "Judd", "suffix": ""}], "year": "", "venue": "Mineral. Mag", "link": null}, "BIBREF2": {"title": "Dana's System of Mineraloglt", "authors": [{"first": "C", "middle": [], "last": "Palache", "suffix": ""}, {"first": "H", "middle": [], "last": "Berman", "suffix": ""}, {"first": "C", "middle": [], "last": "Frondel", "suffix": ""}], "year": 1944, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "2870659", "_pdf_hash": "1b96636fe8ca57d52aea1e37f16bad6930a0744c", "abstract": [], "body_text": [{"section": "", "text": "Introduction by G. W. Black andJ. Foster.-The forward movement of orthoptic technique between 1925 and 1935 depended on a re-appreciation of the importance of anomalous retinal correspondence, measured by the improved synoptophores then available. Before this, many patients had been wasting their time on unsupervised divergence exercises.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "In this decade Ciippers's discovery of the high percentage of amblyopic eyes with eccentric fixation which are detectable by the Visuscope and undetectable by the synoptophore, is likely to have a similar effect on the occlusion treatment of amblyopia.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "The collaboration of Miss R. Downey (Orthoptist) and Mr. G. Brockbank (Ophthalmic Optician) at the Leeds General Infirmary has produced a subjective method which will (when applicable) detect an even smaller degree of eccentric fixation, and is, we think, of importance in view of the enormous effort that pleoptic treatment requires both from patient and therapist.", "cite_spans": [], "ref_spans": []}, {"section": "Eccentric Fixation", "text": "The pleoptic treatment of deep amblyopia, especially that of eccentric fixation, was introduced into Great Britain nearly 2 years ago. The methods of treatment were described first by Dr. A. Bangerter of St. Gallen, Switzerland, and later by Dr. C. Ciippers of Giessen, Germany. Strictly speaking, the word \"pleoptics\" referred to Bangerter's method rather than that of Clippers, which was entirely different in its physiological conception. These two methods are at present the subject of experiment in London, Manchester, and Leeds, but very few statistics are yet available.", "cite_spans": [], "ref_spans": []}, {"section": "Eccentric Fixation", "text": "At Leeds we have treated eccentric fixation experimentally by Ciippers's method, the instruments principally used were the Visuscope, the Euthyscope, and the Co-ordinator.", "cite_spans": [], "ref_spans": []}, {"section": "Eccentric Fixation", "text": "The Visuscope is an ophthalmoscope in which there is, amongst other discs, one containing a black star. This can be focused onto the fundus by allowing for the patient's refractive error, and when the patient is fixing the star, the point where it appears on the retina indicates to the observer the principal direction of gaze of that eye. During an examination with the Visuscope it -is necessary to occlude the non-fixing eye to avoid the influence of anomalous retinal correspondence.", "cite_spans": [], "ref_spans": []}, {"section": "Eccentric Fixation", "text": "The Euthyscope is used to create a negative after-image, which is an essential part of Ciippers's treatment of eccentric fixation and inhibition.", "cite_spans": [], "ref_spans": []}, {"section": "Eccentric Fixation", "text": "This instrument is a large ophthalmoscope with a special system of lenses permitting a high illumination of approximately 300 of the retina. Either of two central black spots may be selected to allow protection of 50 or 30 of the retina. An enormous ring-shaped after-image is thus formed by illuminating the posterior pole of the eye, the macula being protected by one of the black spots. A positive after-image, it will be appreciated, still maintains the amblyopic state; so a negative after-image is sought (a dark ring with clear centre) by projecting it on to an illuminated screen from 1 to 6 metres distant. The patient's attention is drawn to the central disc of this negative after-image which is a real object in space characterizing the fovea.", "cite_spans": [], "ref_spans": []}, {"section": "Eccentric Fixation", "text": "The Co-ordinator uses Haidinger's brushes as a subjective control for macular fixation. Its basis is an entoptic phenomenon recognized when plane or moderately elliptically polarized light enters the normal eye, and depends entirely upon regional variations in the brightness of the blue component of the incident light. The two brush-like objects seen are the visual residue of the absorption of the polarized component of the sky light by the double-refracting yellow lutein pigment of the macula. Like other entoptic phenomena; the bluish pattern fades rapidly if a fixed region of the retina is stimulated and so in this instrument the polarizer is made to rotate continuously.", "cite_spans": [], "ref_spans": []}, {"section": "Eccentric Fixation", "text": "In order to appreciate the significance of our precise measurement of eccentric fixation, which we describe later, a brief resume of Ciippers's method may be helpful. It is essential to analyse the prognosis of a case of eccentric fixation carefully before embarking on the treatment. The success of the treatment does not depend on the estimation of the visual acuity and the type of fixation only, as many other factors have to be taken into account. To ensure a perfect and enduring result the possibilities of attaining either binocular single vision or definite alternation should be envisaged.", "cite_spans": [], "ref_spans": []}, {"section": "Diagnosis and Prognosis", "text": "Depending on the age of the patient, the prognosis may be determined by the following procedures.", "cite_spans": [], "ref_spans": []}, {"section": "Diagnosis and Prognosis", "text": "Ciippers considers that the point of fixation is shown by the retinal point which bears the principal visual direction according to the results of the various investigations in each particular case. The eccentric fixation is not necessarily the point used for fixing the star of the Visuscope as this may be a point on the border of a scotoma. This is clearly demonstrated in patients who have previously had the fixing eye occluded and who fix eccentrically in this waybecause for them this point on the retina has a higher resolving power.", "cite_spans": [], "ref_spans": []}, {"section": "Diagnosis and Prognosis", "text": "Ciippers insists on this definition because otherwise, during treatment, when use is made of monocular diplopia, the attention will be drawn to the wrong image. (1) The spatial projection of the two after-images created at the maculae of the two eyes;", "cite_spans": [], "ref_spans": []}, {"section": "Diagnosis and Prognosis", "text": "(2) Measurement of the objective and subjective angles of strabismus using the Maddox scale with an after-image before the non-fixing eye and a special dark red filter before the fixing eye; (3) The Visuscope in a binocular examination; (4) The major amblyoscope-measuring (i) The objective and subjective angles by use of after-images, Haidinger's brushes, and real objects; (ii) The density and extent of the suppression by use of the Bjerrum screen. Therapy", "cite_spans": [], "ref_spans": []}, {"section": "Diagnosis and Prognosis", "text": "Treatment, based on conclusions drawn from the preceding examinations, may be carried out as follows. It must be remembered that differentiation is difficult as all the symptoms are intimately connected. New Method During our experiments with Ciippers's methods it soon became evident that it would be an advantage if we could find a method which would determine the exact position in degrees of an eccentric fixation. Initially we depicted eccentric fixation in our notes by marking-approximately the position of the Visuscope star on a conventional stamped drawing of the fundus. We decided that any method we adopted must allow us to measure the relationship between three points on the fundus: It would also be convenient if we continued to use the stamped outline of the fundus, which was so essential for marking the result of the usual Visuscope examination. These diagrams could then be given precise measurements and angles when necessary. Our method was to use the Two-Metre Bjerrum Screen and to measure the distances and angles between the points in degrees with a rotary tangent rule (Sinclair's Rule for the TwoMetre Screen).", "cite_spans": [], "ref_spans": []}, {"section": "Diagnosis and Prognosis", "text": "We seated the patient on an adjusted chair before the screen, with his chin fitted firmly yet comfortably in the chin-rest opposite the fixation spot in the centre of the screen at exactly 2 metres. First we occluded the eccentric fixing eye and carefully plotted the blind spot of the normal fixing eye; using the rotary tangent rule we measured the angle between the fixing macula and the centre of this normal blind spot. Then, covering the normal fixing eye, the patient looked at the fixation target with his eccentrically fixing eye. We then again charted the blind spot and also plotted the scotoma due to the non-functioning macula, measuring with the scale and rule the distances and angles between the three points (centre of the blind spot, centre of the macula scotoma, and the fixation spot). We found it necessary to examine each child several times depending on his ability to co-operate. With younger children it was always easier if one of us sat near the child to give encouragement during the examination and to make sure that the fixation on the fixation spot was steady, while the other worker moved the targets and inserted the pins in the Bjerrum screen. Provided the child grasped what was required and we were able to mark out the blind spot of the sound eye, a satisfactory plot was also obtainable with the other eye, even in children as young as 5 years old.", "cite_spans": [], "ref_spans": []}, {"section": "Diagnosis and Prognosis", "text": "In our calculations we assumed that the angle between the macula and the centre of the blind spot was similar in right and left eyes of the same patient. It is true that the relationship of the blind spot and the macula are affected by the Angle Alpha, but this itself is rarely asymmetrical. We have checked on the Bjerrum screen the angle between disc and macula in a number of patients who had normal fixation, including some with large degrees of anisometropia both hypermetropic and myopic, and the difference was usually less than 10. Traquair (1949) states that \"The distance of the blind spot from the fixation point is increased in hypermetropia and diminished in myopia in accordance with the difference in the length of the eye\". It is of course agreed that, if the length of the eye only was increased or diminished in myopia and hypermetropia, our assumption and calculation would be proportionately incorrect as the anisometropia varied. Many cases do not show purely axial anomalies, and in patients who have normal eyes except for refractive error and in whom the size of the two eyes varies, the increase or decrease in length is accompanied by increase and decrease in diameter of the globe, so that the whole eye is larger or smaller. Differences in the diameter of the globe vary the distance of the blind spot from the fixation point contrary to similar alterations in length. Therefore, in by far the greater number of cases, we can assume that the angle between the macula and the centre of the blind spot is similar in the two eyes of the same patient. On the following day, when the patient's pupils had contracted, we plotted the blind spot of the right eye on the Bjerrum screen. As the child was only 6 years old we had to do this several times before we obtained full co-operation. Using the rotary tangent rule, we measured the angle between the fixing macula and the centre of the normal blind spot which was 16-50. The axis at which this angle struck the screen was slightly below the horizontal. Applying the standard notation, this was on axis 1700 produced below the horizontal. This we have called minus 1700 (-1700). (Fig. 2A) .", "cite_spans": [], "ref_spans": []}, {"section": "Diagnosis and Prognosis", "text": "Covering the right eye we were able to chart the blind spot of the left eccentrically fixing eye, and we found and plotted the scotoma formed by the non-functioning macula. Using the same measurements as with the right eye, we measured the angle on the tangent scale between the fixation spot and the centre of the blind spot, which was 10-50, axis 1800.", "cite_spans": [], "ref_spans": []}, {"section": "Diagnosis and Prognosis", "text": "The angle between the centre of the macular scotoma and the centre of the blind spot was 16-50. The axis at which this angle struck the screen was -200. This was measured by placing the centre of the rotary scale at the centre of the macular scotoma and noting the angle of depression between the rule and the centre of the blind spot.. It will be noticed (Fig. 2B ) that the angle between the centre of the blind spot and the fixing macula of the right eye is the same as that between the centre of the blind spot and the centre of the macular scotoma of the left eye, 16.5, axis -20\u00b0. To transfer our findings to the stamped outline of the fundus it is necessary to imagine that our patient was able to focus the fixation spot with the left macula. Fig. 3 The angle between the macular scotoma and the eccentric fixation (Fig. 2B ) was 8 5\u00b0, axis + 300; it follows that, when the macula was in a normal primary position in the centre of the fundus diagram, the eccentric fixation would still be 8.50 distant from the macula, but its position on the axis would be moved from + 300 to -30\u00b0 (Fig. 3) . In Fig. 2B the angle between the macular scotoma and the blind spot was 16-50, axis -20\u00b0.", "cite_spans": [], "ref_spans": []}, {"section": "Diagnosis and Prognosis", "text": "When this axis -20\u00b0is applied to Fig. 3 and compared with the same angle and axis of the right eye ( Fig. 2A) , the blind spot of the left eye is 100 lower than that of the right eye.", "cite_spans": [], "ref_spans": []}, {"section": "Diagnosis and Prognosis", "text": "We have measured many cases and in only a few have we noted a slight torsion of the eccentric eye when fixing. In this case we made a careful examination with the Euthyscope and we were of the opinion that when the left eye was fixing, the disc was a little higher in relation to its macula than when the right eye was examined.", "cite_spans": [], "ref_spans": []}, {"section": "Diagnosis and Prognosis", "text": "In Fig. lA and Fig. lB the stamped diagrams of the fundi assumed the regular pattern of the macula and disc. Therefore it was necessary to readjust the axes in the few cases in which torsion of the eccentric fixing eye was demonstrated. In this particular case, the torsion was 100. Any adjustment of the disc and macular angle axis would need a similar movement of the macular eccentric fixation axis so that our three point measurements remained in the same relationship. In most of the cases we examined, there was no torsion, and the diagrams of Fig. 2B moved to Fig. 3 merely by changing the signs of the axes at which these angles subtended from the eye. Therefore the final position of the angle between fixation and the macula of this left eye, in space, was 8 5\u00b0, axis -20\u00b0, and the blind spot macula was at 16.50, axis -100 (Fig. 4) .", "cite_spans": [], "ref_spans": []}, {"section": "Diagnosis and Prognosis", "text": "We have plotted the macular scotoma in space on the Bjerrum screen and we have demonstrated the position of the eccentric fixation in relation to this macula. We must now imagine the position of these points on the fundus. Any point below and nasal to the macula projects itself above and temporally. This complete reversal of points only applies when both the fundus and the screen are viewed from the same direction; in this case as viewed by the patient in space (Fig. 4) , and as these points appear on the patient's fundus (Fig. 5) . group.bmj.com on October 13, 2017 -Published by http://bjo.bmj.com/ Downloaded from When observed, as from the patient's point of view, the position of the eccentric fixation on the fundus with the eye in its normal position, because of the reversal of points in space as on the fundus, was in the same relationship as the macular scotoma in space with the eye fixing with its eccentric fixation. Therefore the macular scotoma as demonstrated on the Bjerrum screen also demonstrates the position of the eccentric fixation on the fundus, both viewed as by the patient. It is, however, the usual practice to show the fundus as the observer sees it and to show field defects as the patient sees them. As Fig. 5 shows the positions of the blind spot and the eccentric fixation from the patient's viewpoint, then these positions must be laterally reversed to conform with the established practice of presenting fundus pictures as seen directly by the observer. The diagram (Fig. 6) Therefore, if the macular scotoma is plotted on the Bjerrum screen, this position laterally reversed is the position of the eccentric fixation as viewed by the Visuscope. In our illustration the macular scotoma was 8.50, axis +200, and laterally reversed this makes the eccentric fixation on the fundus as seen by the Visuscope 8.50, axis + 1600.", "cite_spans": [], "ref_spans": [{"start": 528, "end": 536, "text": "(Fig. 5)", "ref_id": "FIGREF3"}, {"start": 1237, "end": 1246, "text": "As Fig. 5", "ref_id": "FIGREF3"}]}, {"section": "Diagnosis and Prognosis", "text": "On occasions the macular scotoma was quite large and it was more convenient to measure the difference in the angles between the fixation and the centre of the blind spot in each eye. In practice this was found to be a quick and accurate method of measuring both large and small degrees of eccentric fixation. A small degree of eccentric fixation was effectively demonstrated in Case 2.", "cite_spans": [], "ref_spans": []}, {"section": "Diagnosis and Prognosis", "text": "Case 2, a man aged 29, had had his left (good) eye excised after a motor accident 6 months before starting treatment.", "cite_spans": [], "ref_spans": []}, {"section": "Diagnosis and Prognosis", "text": "Refraction.-Visual acuity in the right eye with -3 D sph., -2-5 D cyl., axis 15\u00b0, was 5/60.", "cite_spans": [], "ref_spans": []}, {"section": "Diagnosis and Prognosis", "text": "He showed an eccentric fixation with the Visuscope slightly nasal and inferior to the fovea.", "cite_spans": [], "ref_spans": []}, {"section": "Diagnosis and Prognosis", "text": "Treatment.-Ciippers's method was used and the visual acuity of the right eye improved to 6/36 with foveal fixation of the Visuscope star. Monocular diplopia was appreciated after 6 weeks' treatment, the visual acuity of the image to the left eye being 6/36 and that to the right 4/60.", "cite_spans": [], "ref_spans": []}, {"section": "Diagnosis and Prognosis", "text": "It was decided to measure the separation of these two images and to try to establish on which image the patient must now concentrate. It was assumed that the remaining eye was anatomically normal and the angle between the 6/36 fixation and the centre of the blind spot on the Bjerrum screen was compared with the angle between the 4/60 fixation and the centre of the blind spot. The angle with the 4/60 fixation coincided with the measurement of a normal adult eye. The difference between the two fixations as measured by the 2-metre Bjerrum screen was 30, and we were thus able to confirm that the image seen to the right was the image of the principal foveal direction in space.", "cite_spans": [], "ref_spans": []}, {"section": "Diagnosis and Prognosis", "text": "A further example of the diagnosis of small degrees of eccentric spatial localization was found in the following case.", "cite_spans": [], "ref_spans": []}, {"section": "Diagnosis and Prognosis", "text": "Case 3, a girl aged 6 years, had angular visual acuity of 12, and cortical visual acuity of 6/24 in the right eye with + 1 D sph., and visual acuity 6/6 in the left eye with + 0-5 D sph.", "cite_spans": [], "ref_spans": []}, {"section": "Diagnosis and Prognosis", "text": "Between the ages of 2 and 6 years she had received intermittent total and partial occlusion of the left eye. On diagnosis with the Visuscope the right fixation was found to be juxta-foveolar. Localization of Haidinger's brushes and an after-image appeared to be central. Binocularly on the synoptophore she showed an unharmonious anomalous retinal correspondence with an angle of anomaly of 50, but in space at 2 metres it was harmonious.", "cite_spans": [], "ref_spans": []}, {"section": "Diagnosis and Prognosis", "text": "Treatment.-This was attempted by Cuppers's method, monocularly and binocularly, and although the visual acuity in the right eye improved to 6/18 with foveolar fixation to the Visuscope star, the anomalous retinal correspondence remained intractable. Alternation was not achieved even after 3 months of total occlusion of the fixing eye. On examination of the central field a 1 to 2\u00b0eccentricity was discovered in the spatial localization of the right eye.", "cite_spans": [], "ref_spans": []}, {"section": "Diagnosis and Prognosis", "text": "In conclusion, it is suggested that, by the use of the Bjerrum screen, it is possible to determine the precise degree of the eccentricity in space, and that this enables small degrees of eccentric localization (undiscoverable by any other means) to be identified.", "cite_spans": [], "ref_spans": []}, {"section": "Diagnosis and Prognosis", "text": "At the beginning of this paper, we pointed out the difficulties attendant on various symptoms arising from eccentric fixation and their diagnosis. This added subjective examination may help in many cases to clarify the diagnosis and the possibilities of therapy. In measuring the macular scotoma by using known sizes of scotoma targets, large and small, it is possible to demonstrate the extent of the inhibition. Definition of the eccentric fixation in degrees keeps the notes compact and is convenient for transferring the details of the case to another clinic-if required.", "cite_spans": [], "ref_spans": []}, {"section": "Summary", "text": "Until Cuippers invented the Visuscope, which projects a black star on to the area of retina used by the patient to fix it, eccentric fixation was identified by the synoptophore and believed to be rare in monocular amblyopia.", "cite_spans": [], "ref_spans": []}, {"section": "Summary", "text": "group.bmj.com on October 13, 2017 -Published by http://bjo.bmj.com/ Downloaded from As occlusion of the better eye produces no improvement in an eye with eccentric fixation, the discovery that eccentric fixation was relatively frequent was of great practical importance.", "cite_spans": [], "ref_spans": []}, {"section": "Summary", "text": "The authors present an alternative method of detecting eccentric fixation by scotometry, which they believe to be more accurate than visuscopy though less easy to apply. Lateral reversal of the scotoma chart of the affected eye .reproduces the position of the eccentric fixation as determined by visuscopy on a fundus drawing.", "cite_spans": [], "ref_spans": []}, {"section": "Summary", "text": "Assuming that the eyes are automatically symmetrical, as appears to be justified in most cases, comparison of the co-ordinates of the centre of the blind spot and the fixation point in the two eyes, suggests that monocular amblyopia is rare without some degree of eccentric fixation.", "cite_spans": [], "ref_spans": []}, {"section": "Summary", "text": "We should like to thank Mr. G. W. Black and Mr. John Foster of Leeds for permission to describe their cases. REFERENCE TRAQUAIR, H. M. (1949) . \"Clinical Perimetry\", 2nd. ed., p. 12. Kimpton, London.", "cite_spans": [], "ref_spans": []}], "bib_entries": {}, "ref_entries": {"FIGREF0": {"text": "co-ordination of the eye and the extremities (especially the hand) when foveal fixation is assured by: (a) After-image created by the Euthyscope using the hand; (b) Haidinger's brushes using the hand. (3) Elimination of inhibition when foveal fixation is assured by: (a) After-image created by the Euthyscope; (b) Major amblyoscope. (4a) Elimination of difficulties of separation, which arise from rivalry of the spatial values monocularly and binocularly by: (a) After-image and Haidinger's brushes combined with real objects projected in space and on the major amblyoscope; (b) Attainment of binocular single vision with fusion amplitude. (4b) Disturbances of the cerebral cortex (Gestalt Auffassung) by: (a) Bangerter's pleoptic methods; (b) Attainment of binocular single vision with fusion amplitude.", "type": "figure"}, "FIGREF1": {"text": "(a) The centre of the macula; (b) The eccentric fixation point; (c) The centre of the blind spot.", "type": "figure"}, "FIGREF2": {"text": ". 2.-Normal right eye (A) and affected left eye (B) showing eccentric fixation of left eye as shown on Bjerrum screen.", "type": "figure"}, "FIGREF3": {"text": "FIG. 5.aEccentric fixation point as it appears on the patient's fundus.", "type": "figure"}, "TABREF0": {"text": "The localization of the principal visual direction may differ according as to whether the test is carried out with an after-image, Haidinger's brushes, or the star of the Visuscope. Of the tests mentioned, the star of the Visuscope resembles most nearly the fixation of an object in free space. Furthermore, Ciuppers holds the opinion that the defects arising from eccen- tric fixation are similar to those found in anomalous retinal correspondence. It has been demonstrated that the eccentric fixation either coincides with or is less than the angle of anomaly, but is never greater.", "type": "table"}, "TABREF1": {"text": "Case 1, a boy aged 6. Visual acuity 6/9 in the right eye with + 3 D sph., and 3/60 (angular and cortical) in the left eye with + 5 D sph. (i) Synoptophore.-Left convergent strabismus fixing right eye objective angle+ 100, subjective + 4\u00b0. (ii) Visuscope and Maddox Scale.-Angle of anomaly fixing right eye + 2 A\\ L/R 4A. (iii) After-Image and Maddox Scale.-Fixing right eye + 60 objectively OA L/R 4/A subjectively.Both eyes were dilated with Cyclogyl 1-0 per cent. and the fixation of each eye when viewed with the Visuscope showed a normal fixation at the macula for the right eye (Fig. 1A) and an eccentric fixation for the left eye, situated superior and nasal to the macula (Fig. iB).Normal right eye and affected left eye, showing fixation points as seen with the Visuscope.", "type": "table"}, "TABREF2": {"text": "would then demonstrate the projected positions of our three points (the eccentric fixation, the macula, and the centre of the blind spot).", "type": "table"}, "TABREF3": {"text": "shows the three positions, assumed in the stamped outline of the fundus.", "type": "table"}}}
{"paper_id": "2870666", "_pdf_hash": "3079c76a6f941e9def7d4f948934c0199eabff4d", "abstract": [{"section": "Abstract", "text": "Abstract-Traditional fingerprint matching has slow speed and low probability in search rate under large-scale and unstructured database background. In order to solve this problem, an advanced searching method based on Grover's search algorithm is proposed. It improves the Oracle operator in Grover's algorithm and transforms the database one into four registers: index register, quantum bit register which includes target fingerprint's matching value, data register, 1 qubit register. Database two is transformed into including all the records of the matching value between input fingerprint and template fingerprints. Compared with traditional algorithm, this improved method decreases the number of repetitions and raise the probability of success, thus it can effectively improve the search speed and accuracy.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Index Terms-quantum parallelism, Grover's searching algorithm, fingerprint matching, Oracle operator", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "I. INTRODUCTION", "text": "Confirmation of personal identity and authority is a very important part of life, especially with the networked era, people have become increasingly demanding security. However, more complicated set of passwords has become a big problem to people, in order to achieve higher security, more complex and more convenient to use a password is a popular choice. Each person's fingerprint pattern is different and unique in patterns, in other words, is the only and the same. Depend on this uniqueness and stability, so a person's fingerprints can be complying with himself. Through comparing his fingerprints with his fingerprints stored in advance we can verify the authenticity of his identity [1] . But for large-scale fingerprint database matching system, classical matching algorithm can only search from the template fingerprint database which includes N fingerprints one by one until you find the one which is matched with the input fingerprint. This algorithm needs to find the result continues for 2 N times, the probability of success is 2 1 . So for large-scale database, this classical matching algorithm will appears to the problem of lower recognition rate and the more difficult problems [2] . In 1996, Grover proposed the quantum quick search algorithm [3, 4] , because N quantum bits is in the state of it's superposition, such intervention operation only need to repeat N times, the chance to obtain the correct answer is close to 1, so it solves the problem of the classical matching algorithm which is inefficient and difficult. Compared with traditional algorithm, Grover algorithm has the square acceleration effect. Applying classical Grover algorithm to search in a structured database has been researched and got good results. For example, classical Grover algorithm has been correctly applied in the field of communication and got excellent outcome [5, 6] . However, applying the Grover's algorithm to the fingerprint matching is an issue of searching for a specific solution in unstructured database [5] , the study of original Grover's algorithm in solving these problems has not been reported recently.", "cite_spans": [{"start": 691, "end": 694, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 1002, "end": 1003, "text": "2", "ref_id": "BIBREF1"}, {"start": 1198, "end": 1201, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 1264, "end": 1267, "text": "[3,", "ref_id": "BIBREF2"}, {"start": 1268, "end": 1270, "text": "4]", "ref_id": "BIBREF3"}, {"start": 1870, "end": 1873, "text": "[5,", "ref_id": "BIBREF4"}, {"start": 1874, "end": 1876, "text": "6]", "ref_id": "BIBREF5"}, {"start": 2022, "end": 2025, "text": "[5]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "This article presented the method of improving the Oracle operator in original Grover's algorithm. We can calculate N numbers of match-score values by using the quantum parallelism only through a single quantum circuit compared to N times of calculation in traditional method. Next we use the improved Grover's searching method to get the location of the target fingerprint which just need to apply N times of operation compared to N times of calculation in traditional method. The experiment results show that the improved Grover's algorithm can effectively improve the search speed and accuracy. The layout of the article is as follows. In Section II, we introduce the quantum parallel algorithm and classical Grover's quantum search algorithm. In Section III, we discuss the traditional fingerprint matching method based on ridge line calibration. In Section IV, we present the fingerprint matching method based on Grover's quantum algorithm which includes the background of design program and the design project of this method. In Section V, we carry out the simulation experiments with the FVC finger data and give the evaluation results between our method and traditional method. Our concluding remarks appear in Section VI. Figure 1 . Circuit for the Grover iteration, G.", "cite_spans": [], "ref_spans": []}, {"section": "II. GROVER'S SEARCH ALGORITHM", "text": "x x x f ) ( ) 1 (\u2212 \u2192 n H \u2297 x x \u2212 \u2192 \u2192 0 0 0 > x n H \u2297", "cite_spans": [], "ref_spans": []}, {"section": "A. Quantum Bits", "text": "The bit is the fundamental concept of classical computation and classical information. A classical bit has a state-either 0 or 1-a qubit also has a state. Two possible states for a qubit are the states 0 and 1 , which as you might guess correspond to the states 0 and 1 for a classical bit. Notation like '", "cite_spans": [], "ref_spans": []}, {"section": "A. Quantum Bits", "text": "'is called the Dirac notation, and we'll be seeing it often, as it's the standard notation for states in quantum mechanics. The difference between bits and qubits is that a qubit can be in a state other than 0 or 1 . It is also possible to form Linear combinations of states, often called super-positions:", "cite_spans": [], "ref_spans": []}, {"section": "A. Quantum Bits", "text": "The number \u03b1 and \u03b2 are complex numbers, although for many purposes not much is lost by thinking of them as real numbers. Put another way, the state of a qubit is a vector in a two-dimensional complex vector space. The special states 0 and 1 are known as computational basis states, and form an orthonormal basis for this vector space.", "cite_spans": [], "ref_spans": []}, {"section": "B. Single Qubit Gates", "text": "Classical computer circuits consist of wires and logic gates. The wires are used to carry information around the circuit, while the logic gates perform manipulations of the information, converting it from one form to another. So we can define an analogous quantum NOT gate for qubits.", "cite_spans": [], "ref_spans": []}, {"section": "B. Single Qubit Gates", "text": "The quantum NOT gate acts linearly, that is, it takes the state [6, 7] .", "cite_spans": [{"start": 64, "end": 67, "text": "[6,", "ref_id": "BIBREF5"}, {"start": 68, "end": 70, "text": "7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "B. Single Qubit Gates", "text": "There is a convenient way of representing the quantum NOT gate in matrix form, which follows directly from the linearity of quantum gates. Suppose we define a matrix X to represent the quantum NOT gate as follows:", "cite_spans": [], "ref_spans": []}, {"section": "B. Single Qubit Gates", "text": "If the quantum state With the top entry corresponding to the amplitude for 0 and the bottom entry the amplitude for 1 , then the corresponding output from the quantum NOT gate is:", "cite_spans": [], "ref_spans": []}, {"section": "B. Single Qubit Gates", "text": "Notice that the action of the NOT gate is to take the state 0 and replace it by the gate corresponding to the first column of the matrix X . Similarly, the state 1 is replaced by the state corresponding to the second column of the matrix X .", "cite_spans": [], "ref_spans": []}, {"section": "C. Quantum Parallel Algorithm", "text": "The quantum parallelism is an essential feature of many quantum algorithms, it can make quantum computer evaluate the function", "cite_spans": [], "ref_spans": []}, {"section": "C. Quantum Parallel Algorithm", "text": "at many different value x at the same time, its basic principle is [8] : let", "cite_spans": [{"start": 67, "end": 70, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "C. Quantum Parallel Algorithm", "text": "is a functions of 1 qubit domain and range. In a quantum computer, a simple approach of calculating the function is to consider the quantum computer whose initial state is two quantum bits. Through the appropriate sequence of logic gates this state can operate as follows:", "cite_spans": [], "ref_spans": []}, {"section": "C. Quantum Parallel Algorithm", "text": "The symbol \u2295 here indicates addition modulo 2, the first register called 'data' register, the second is called the 'target' register, the transformation defined by the map circuit is employed to evaluate the function for multiple value of x simultaneously, by exploiting the ability of a quantum computer to be in superposition of different states.", "cite_spans": [], "ref_spans": []}, {"section": "C. Quantum Parallel Algorithm", "text": "More generally, the result of performing the Hadamard transform on n quantum bits initially in the all 0 state is:", "cite_spans": [], "ref_spans": []}, {"section": "C. Quantum Parallel Algorithm", "text": "That is, the Hadamard can transform produces an equal superposition of all computational basis states, moreover, it does this extremely efficiently, producing a superposition of n 2 states using just n gates.", "cite_spans": [], "ref_spans": []}, {"section": "D. Grover's Quantum Search Algorithm", "text": "The Grover's algorithm begins with the computer in the state", "cite_spans": [], "ref_spans": []}, {"section": "D. Grover's Quantum Search Algorithm", "text": ", the Hadamard transform is used to put the computer in the equal superposition state:", "cite_spans": [], "ref_spans": []}, {"section": "D. Grover's Quantum Search Algorithm", "text": "The quantum search algorithm then consists of repeated application of a quantum subroutine, know as the Grover iteration or Grover operator, the Grover iteration, whose quantum circuit is illustrated in Figure 1 , can be broken up into four steps [9] :", "cite_spans": [], "ref_spans": []}, {"section": "D. Grover's Quantum Search Algorithm", "text": "First, apply the Oracle O;", "cite_spans": [], "ref_spans": []}, {"section": "D. Grover's Quantum Search Algorithm", "text": "Second, apply the Hadamard transformation n H \u2297 ; Third, perform a conditional phase shift on the computer, with every computational basis state except 0 receiving a phase shift of -1:", "cite_spans": [], "ref_spans": []}, {"section": "D. Grover's Quantum Search Algorithm", "text": "Fourth, apply the Hadamard transformation n H \u2297 .", "cite_spans": [], "ref_spans": []}, {"section": "III. MINUTIA MATCHING ALGORITHM BASED ON RIDGE LINE CALIBRATION", "text": "Before fingerprint pattern match, we should finish the process which includes the fingerprint acquisition, preprocessing and minutiae extraction [10] [11] [12] . Next, find a reference point to determine whether this fingerprint which needs to be matched has singular points or not, these singular points are the central and triangular points showed in Figure If it has singular point, we select the nearest ridge line near the singular points, decide if the ridge lines corresponding to these two fingerprints which are needed to be matched are similar, we use these selected singular points as the reference point corresponding to those fingerprints for the next matching step when they are similar. There is the other situation, it does not have any singular points, and then we need to find another point as a reference point. We define two point sets, M and N , where the point set N denotes the L numbers of minutiae extracted from the input fingerprint, another point set M denotes the H numbers of minutiae extracted from the template fingerprints. Respectively expressing as two point sets:", "cite_spans": [{"start": 145, "end": 149, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 150, "end": 154, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 155, "end": 159, "text": "[12]", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "III. MINUTIA MATCHING ALGORITHM BASED ON RIDGE LINE CALIBRATION", "text": "are respectively recorded three pieces of information which are the i th and j th feature points of point sets M and N , three pieces of information are X coordinates, Y coordinates and direction.", "cite_spans": [], "ref_spans": []}, {"section": "III. MINUTIA MATCHING ALGORITHM BASED ON RIDGE LINE CALIBRATION", "text": "We need to set two reference points respectively from the template minutia set and the input minutia set as origins of the corresponding polar coordinates, so we can convert minutiae into polar coordinates [13] . Because we do not know the corresponding relationship between the template minutia set and the input minutia set in advance, we will consider all possible pairs of reference points.", "cite_spans": [{"start": 206, "end": 210, "text": "[13]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "III. MINUTIA MATCHING ALGORITHM BASED ON RIDGE LINE CALIBRATION", "text": "Each point of the template point set is", "cite_spans": [], "ref_spans": []}, {"section": "III. MINUTIA MATCHING ALGORITHM BASED ON RIDGE LINE CALIBRATION", "text": "and each point from the input point set is (14) where in We got the reference points of template and input minutia set in advance, we will set the rest of the feature points in template set N and input set M transiting to the polar with treating i N and i M as origin. The former records the transforming template minutia coordinates, the reference point coordinates, minutia representation in polar coordinates; the latter one, records entering minutia coordinates, entering reference coordinates, minutia representation in polar coordinates, at the same time, draw rotation angle of the entered reference minutia which relative to template reference minutia [14, 15] .", "cite_spans": [{"start": 43, "end": 47, "text": "(14)", "ref_id": "BIBREF13"}, {"start": 660, "end": 664, "text": "[14,", "ref_id": "BIBREF13"}, {"start": 665, "end": 668, "text": "15]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "III. MINUTIA MATCHING ALGORITHM BASED ON RIDGE LINE CALIBRATION", "text": "Set an matching score match-score whose initial value is 0, the matching condition to determining the y th input fingerprints minutia and the i th template fingerprints minutia is: give three thresholds, a r , a e , a \u03b8 . Two minutiae should be satisfied with the following relationship: ", "cite_spans": [], "ref_spans": []}, {"section": "IV. FINGERPRINT MATCHING METHOD BASED ON GROVER'S QUANTUM ALGORITHM", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "A . Background of Design Program", "text": "Since quantum state has a high degree of parallelism calculation property, it can generate n 2 numbers of operation results at one time equate to n 2 times conventional computer operations. Grover's quantum algorithm is the quantum which can fully reflect the quantum parallelism and effectively solve the complexity problem of classical computing theory. Therefore, this chapter presents an assumption based on quantum parallelism calculation characteristic and fingerprint matching algorithm by using improved Grover's algorithm, this assumption reduces the computational complexity of the fingerprint matching algorithm effectively [16] .", "cite_spans": [{"start": 635, "end": 639, "text": "[16]", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "A . Background of Design Program", "text": "According to the analysis of previous chapter, we classical know that fingerprint minutia matching algorithm based on ridge line correction is used to match between the minutia of input fingerprint and template fingerprint database. Finally, we get the total numbers of matching minutia, match-score, and then search in template fingerprints to find out which one has the bigger minutia matching numbers than a certain threshold. We can say that the input fingerprint and this template fingerprint are from the same finger. In this article we will extract a fingerprint A from template as the input fingerprint B , after getting all the numbers of match-score between fingerprint A and all the template fingerprints, search the minutia number of all the fingerprints in template, whose minutia number are the same with match-score is fingerprint A , then we can extract the fingerprint A from template database. This is a quantum searching algorithm in non-structure database, unlike the previous case that the database is structured. Structure database issue is to detect the sending sequence in modern communication and data in this kind of database is stored in the form of disorder but whole arrangement. When we calculate the Oracle operator we can constitute a corresponding relationship between the k 2 numbers of quantum registers and n 2 numbers of sending sequences. Next we can use an effective algorithm to detect the minimum judgment value and get the sending sequence. But the problem in this paper we are going to solve is that n 2 numbers of selected fingerprints can't form a corresponding relationship with k 2 quantum registers. Because what we has extracted is the minutiae from n 2 numbers of fingerprints, each fingerprint's minutia is different, if the qubit of the maximum minutia number has whole arranged, it may certainly contain many qubit sequence of fingerprints minutia numbers which is not belong to the template fingerprint database. If applying the previous Oracle operator which is used in modern communications in striking the sending signal sequence to this study, it may detect out the fingerprint which is not included in the template fingerprint database, resulting in an error.", "cite_spans": [], "ref_spans": []}, {"section": "B. Unstructured Fingerprint Database Matching Method", "text": "This chapter presents an assumption based on quantum parallelism calculation characteristic and fingerprint matching algorithm by using improved Grover's algorithm, The principle diagram of this assumption is showed in Figure 4 .", "cite_spans": [], "ref_spans": []}, {"section": "B. Unstructured Fingerprint Database Matching Method", "text": "The working principle of the system are described as:", "cite_spans": [], "ref_spans": []}, {"section": "B. Unstructured Fingerprint Database Matching Method", "text": "Figure4. Principle diagram based on the quantum parallelism and quantum Grover algorithm fingerprint database search methods.", "cite_spans": [], "ref_spans": []}, {"section": "B. Unstructured Fingerprint Database Matching Method", "text": "For the two qubit input and single-bit output ) ( x f function of quantum computing parallelism, it can be implemented by using a quantum circuit as Figure  5 . The same way in quantum parallel compute of n qubits input x for single-bit output ) ( x f function can be used to achieve the following quantum circuit as Figure 6 . , we apparently only evaluated f and get all the match-scores between input and template fingerprint. Where", "cite_spans": [], "ref_spans": []}, {"section": "B. Unstructured Fingerprint Database Matching Method", "text": "is equivalent to the classical method of striking match-score between the input fingerprint and one of the template fingerprint, unlike classical parallelism whose each multiple circuits built to compute match-score are executed simultaneously, to seek out all of the match-score between template fingerprint and input fingerprints need to loop n 2 times, but here, use quantum algorithm's ability to strike a match-score of a single line in different states of superposition state, it is used to simultaneously calculate x 's multiple value of match-score, using quantum lines shown above to strike, we can find out all the value, so it can speed up the computational efficiency. Implemented flow chart is showed in Figure 7 . There are n 2 numbers of match-score have been calculated above, establish a matching scores database including these match-score values, then we can use quantum parallelism principle and quantum quick search algorithm to get the template fingerprint which is matched with the input fingerprint.", "cite_spans": [], "ref_spans": [{"start": 717, "end": 725, "text": "Figure 7", "ref_id": "FIGREF7"}]}, {"section": "B. Unstructured Fingerprint Database Matching Method", "text": "The total numbers of template fingerprints are n N 2 = , we extract a fingerprint from them as an input fingerprint, so we can find only one in template fingerprint database which is the same with this input fingerprint, what's more, the list of template fingerprints is not ordered in any obvious way. we get every binary strings of all the matchscore, let the maximum one's length is l bits, the whole number of the input fingerprint minutiae is represented as a binary string S , these N numbers of template fingerprints are labeled from 1 to N , all these matchscore we have obtained from the input fingerprint can be expressed as", "cite_spans": [], "ref_spans": []}, {"section": "B. Unstructured Fingerprint Database Matching Method", "text": ", we need to construct two databases:", "cite_spans": [], "ref_spans": []}, {"section": "B. Unstructured Fingerprint Database Matching Method", "text": "Database one contains four registers: 1) An n qubit 'index' register initialized to 0 ; We know that for the single bit case, the quantum ground state are 0 and 1 , but this quantum qubit not only has that two states 0 and 1 but also has continuous state which falls between 0 and 1 , this state is a linear combination of those two states called superposition, like follows: ", "cite_spans": [], "ref_spans": []}, {"section": "B. Unstructured Fingerprint Database Matching Method", "text": "Symbol x is in a superposition of multiple value, we can index many value at one time, so it can increase the search speed.", "cite_spans": [], "ref_spans": []}, {"section": "B. Unstructured Fingerprint Database Matching Method", "text": "2) An l qubit register initialized to s and remaining in that state for the entire computation;", "cite_spans": [], "ref_spans": []}, {"section": "B. Unstructured Fingerprint Database Matching Method", "text": "3) An l qubit 'data' register initialized to 0 ; 4) A 1 qubit register initialized to numbers of matchscore calculated in advance, the template fingerprint whose match-score is the same with the number of input fingerprint minutiae is the match fingerprint which we are searching for.", "cite_spans": [], "ref_spans": []}, {"section": "B. Unstructured Fingerprint Database Matching Method", "text": "The key part of implementing the quantum searching algorithm is realization of the Oracle, which must flip the phase of the index which locates S in the memory. Suppose the first database is in the state:", "cite_spans": [], "ref_spans": []}, {"section": "B. Unstructured Fingerprint Database Matching Method", "text": "Now the index register is in the state x , this state is the superposition of each ground state, the data register is in the state 0 , then the contents x d of the x th memory cell are added to the data register:", "cite_spans": [], "ref_spans": []}, {"section": "B. Unstructured Fingerprint Database Matching Method", "text": ", where the addition \u2295 is done bitwise, modulo 2. That is to say the data register state at this time is:", "cite_spans": [], "ref_spans": []}, {"section": "B. Unstructured Fingerprint Database Matching Method", "text": "The state of second register in the first database is s , the state of the third register is x d , compare with second and third registers, if they are the same value, then a qubit flip is applied to register 4; otherwise nothing is changed. The effect of the operation is Then we add the contain x d of the x th register in the second database to the data register:", "cite_spans": [], "ref_spans": []}, {"section": "B. Unstructured Fingerprint Database Matching Method", "text": ", we can see that the date register of the first database is restored to the state 0 . We can use quantum search algorithm to determine the position of s in the database, where this operation has used only ) ( N O times in adding the content of database to the data register, but the classical way with the control need this operation N times. After those steps above, the overall effect is that, if s x d = , the state of register one is changed from x to x \u2212 , and to leave the register alone otherwise. Thus the first step Oracle operator in Grover's algorithm has been achieved. The total action of the Oracle thus leaves registers 2, 3 and 4 unaffected and unentangled with register 1, the location of these N states and in front of the establishment of a database match scores correspond to position.", "cite_spans": [], "ref_spans": []}, {"section": "B. Unstructured Fingerprint Database Matching Method", "text": "Use an operation known as Hadamard transform on the N states of register 1 unitary transform, by using matrix D on the probability amplitude vector of all states in registers 1 have a unitary transformation, rotating average value of all the states to greatly reduce the probability of finding out the target range of quantum states. Enlarge the probability of quantum state amplitude, matrix D is defined as: Finally, the index register can be measured on the location of the target quantum state, thus the location of the target fingerprint can be searched.", "cite_spans": [], "ref_spans": []}, {"section": "V. EXPERIMENT RESULTS AND ANALYSIS", "text": "In this section, we compare our fingerprint matching method based on Grover's quantum algorithm with traditional fingerprint recognition method.", "cite_spans": [], "ref_spans": []}, {"section": "V. EXPERIMENT RESULTS AND ANALYSIS", "text": "We use the recognition rate to performance evaluation of an automated fingerprint identification algorithm. The performance evaluation has two indexes. The FRR is false reject rate and the FAR is false accepted rate. Calculation formula is shown below / ( ) 100% FAR falsenum correctnum falsenum", "cite_spans": [], "ref_spans": []}, {"section": "V. EXPERIMENT RESULTS AND ANALYSIS", "text": "FRR is defined as the ratio of false rejects to total attempts at verification, which is how many times you have a mismatch when you should have match. While FAR is defined as the ratio of false rejects to total attempts at verification, which is the number of times you get match (with some else's fingerprint) when you should not be matched. These test results allow us to calculate the FRR and FAR, and based on these assess the quality of different algorithms. In this paper, all algorithms are programmed in MATLAB. We use the FVC fingerprint data to verify the effectiveness of our algorithm. We extract 256 fingerprint images to create a fingerprint template database. A fingerprint is selected from the template database as the identifying one. Our experiment purpose is to find out the location of this fingerprint in database. The experiment result is given bellow.", "cite_spans": [], "ref_spans": []}, {"section": "V. EXPERIMENT RESULTS AND ANALYSIS", "text": "The results in table I shows the different matching results between our algorithm and traditional algorithm. We can see that the improved Grover matching method has lower matching numbers and the square root of the traditional algorithm matching numbers. Moreover, our matching time has an obvious advantage on efficiency which just needs almost the a half of traditional matching time. At the same time, the matching accuracy is improved by using our algorithm.", "cite_spans": [], "ref_spans": []}, {"section": "VI. CONCLUSION", "text": "Quantum computation and quantum information has taught us to think physically about computation, and this approach yields many new and exciting capabilities for information processing and image processing, information theorists and MCS specialist have been gifted with a new and rich paradigm for exploration. I propose a improved Grover's search algorithm, the issue of applying this algorithm to fingerprint search is the problem of applying quantum computation to image search. By improving the Oracle operator of Grover's algorithm and combining with classical algorithm we can solve unstructured fingerprint matching problem. The next step is to use this improved Grover's algorithm to solve other image problem and apply it to the image search on the Internet. ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "On latent fingerprint enhancement", "authors": [{"first": "S", "middle": [], "last": "Yoon", "suffix": ""}, {"first": "J", "middle": [], "last": "Feng", "suffix": ""}, {"first": "A", "middle": ["K"], "last": "Jain", "suffix": ""}], "year": 2010, "venue": "Proc. 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Psych", "link": null}, "BIBREF9": {"title": "Polynomial-time algorithms for jprime factorization and discrete logarithms on a quantum computer", "authors": [{"first": "P", "middle": [], "last": "Shor", "suffix": ""}], "year": 1997, "venue": "Slam Joumal on Computing", "link": "204204426"}, "BIBREF10": {"title": "A fast quantum mechanical algorithm for estimating the median", "authors": [{"first": "L", "middle": ["K"], "last": "Grover", "suffix": ""}], "year": 1996, "venue": "", "link": "26617022"}, "BIBREF11": {"title": "An effective algorithm for fingerprint image enhancement based on wavelet transform", "authors": [{"first": "C", "middle": ["T"], "last": "Hsieh", "suffix": ""}, {"first": "E", "middle": [], "last": "Lai", "suffix": ""}, {"first": "Y", "middle": ["C"], "last": "Wang", "suffix": ""}], "year": 2003, "venue": "Pattern Recognition", "link": "19438573"}, "BIBREF12": {"title": "Fingerprint minutiae extraction based on binary image", "authors": [{"first": "", "middle": [], "last": "Jingguang", "suffix": ""}, {"first": "", "middle": [], "last": "Fu", "suffix": ""}, {"first": "", "middle": [], "last": "Gang", "suffix": ""}, {"first": "", "middle": [], "last": "Xu", "suffix": ""}, {"first": "", "middle": [], "last": "Yuguo", "suffix": ""}], "year": 2004, "venue": "Journal of Computer Research and Development", "link": null}, "BIBREF13": {"title": "Probabilistic Multimodality Fusion for Event Based Home Photo Clustering", "authors": [{"first": "Tao", "middle": [], "last": "Mei", "suffix": ""}, {"first": "Bin", "middle": [], "last": "Wang", "suffix": ""}, {"first": "Xiangsheng", "middle": [], "last": "Hua", "suffix": ""}, {"first": "Heqin", "middle": [], "last": "Zhou", "suffix": ""}, {"first": "Shipen", "middle": [], "last": "Li", "suffix": ""}], "year": 2006, "venue": "Canada", "link": "12657091"}, "BIBREF14": {"title": "Minutiae extraction by adaptive tracing the gray level ridge of the fingerprint image", "authors": [{"first": "", "middle": [], "last": "Jiang", "suffix": ""}, {"first": "Yau", "middle": [], "last": "Xudong", "suffix": ""}, {"first": "", "middle": [], "last": "Weiyun", "suffix": ""}, {"first": "", "middle": [], "last": "Wee", "suffix": ""}, {"first": "", "middle": [], "last": "Ser", "suffix": ""}], "year": 1999, "venue": "IEEE 6th International Conference on Image Processing", "link": "5962064"}, "BIBREF15": {"title": "Recent advances in fingerpint verificartion", "authors": [{"first": "A", "middle": ["K"], "last": "Jain", "suffix": ""}, {"first": "S", "middle": [], "last": "Pankanti", "suffix": ""}, {"first": "S", "middle": [], "last": "Prabhakar", "suffix": ""}], "year": "", "venue": "Proc. 3 rd Int'l Conf", "link": null}, "BIBREF16": {"title": "Based Biometric Person Authentication", "authors": [{"first": "-", "middle": [], "last": "Audio", "suffix": ""}, {"first": "", "middle": [], "last": "Video", "suffix": ""}], "year": 2001, "venue": "Lecture Notes in Computer Science", "link": null}, "BIBREF17": {"title": "Direct pore matching for fingerprint recognition", "authors": [{"first": "Q", "middle": [], "last": "Zhao", "suffix": ""}, {"first": "L", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "D", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "N", "middle": [], "last": "Luo", "suffix": ""}], "year": 2009, "venue": "Proceedings of ICB'09", "link": "9552131"}, "BIBREF18": {"title": "An evaluation of direct attacks using fake fingers generated from iso templates", "authors": [{"first": "J", "middle": [], "last": "Galbally", "suffix": ""}, {"first": "R", "middle": [], "last": "Cappelli", "suffix": ""}, {"first": "A", "middle": [], "last": "Lumini", "suffix": ""}, {"first": "G", "middle": ["G"], "last": "De Rivera", "suffix": ""}, {"first": "D", "middle": [], "last": "Maltoni", "suffix": ""}, {"first": "J", "middle": [], "last": "Fierrez", "suffix": ""}, {"first": "J", "middle": [], "last": "Ortega-Garcia", "suffix": ""}, {"first": "D", "middle": [], "last": "Maio", "suffix": ""}], "year": 2010, "venue": "Pattern Recognit. Lett", "link": null}}, "ref_entries": {"FIGREF2": {"text": "Figure2. The Central Points and Triangular Points.", "type": "figure"}, "FIGREF3": {"text": "connection of j N and i M with the first sampling point and the horizontal direction.", "type": "figure"}, "FIGREF4": {"text": "Figure3. Classical matching algorithm flow chart.", "type": "figure"}, "FIGREF5": {"text": "Figure 5. Quantum circuits for both compute ) 0 ( f and ) 1 ( f", "type": "figure"}, "FIGREF6": {"text": "Figure6. Quantum circuits both compute ) 0 ( f and ) 1 2 ( \u2212 n f", "type": "figure"}, "FIGREF7": {"text": "Figure 7. Improved to flow chart of striking match-score(j).", "type": "figure"}, "FIGREF11": {"text": "ACKNOWLEDGMENT This work is supported by the National Nature Science Foundation of China (No. 41074090), Henan Science and", "type": "figure"}, "TABREF0": {"text": "and it is easy to prove that it is unitary.", "type": "table"}, "TABREF1": {"text": "Rrotate is defined as the rotation angle from input image to template image when we treat i M and j N as reference points. If i M and j N can be considered as a pair of corresponding points, that is to say, their corresponding ridge line are similar to a certain extent, thenNext, determine the similarity of ridge line. Ridge line corresponding to minutiae i M is defined as T , Ridge line corresponding to minutiae i N is defined as t . Then determine weather t and T are matched, with the following formula to calculate the difference between the two ridge lines:", "type": "table"}, "TABREF2": {"text": "Where s is recorded number of points in ridgerespectively mean the distance from point i on ridge line T and t to the corresponding minutiae,T \u03b1 expresses the angle between that two lines, one of these two lines is the connection between point i on the ridge line T and the associated minutia, the other one is the connection between previous sample and corresponding minutia.is the expression of the angle between two lines, one of these two lines is the connection between point i on the ridge line t and the associated minutia, the other is the connection between", "type": "table"}, "TABREF3": {"text": "Multi-qubit is like the assumption of the above n qubit, its ground state of the quantum system arein database two needed to be structured, these N numbers of value can be addressed by an index x . The quantum state can load in this ground state's superposition state, so x can be in a superposition of multiple value. n Hadamard gates act in parallel on n qubit whose initial state is 0 . The parallel action of n Hadamard gates is denoted as", "type": "table"}, "TABREF4": {"text": "EXPERIMENTAL RESULTS OF TRADITIONAL ALGORITHM AND OUR ALGORITHMTechnology key project (No. 092102210360) and the Fifth Graduate Innovation Fund of Henan Polytechnic University and Doctorate Program of Henan Polytechnic University (No. B2009-27).", "type": "table"}}}
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{"paper_id": "2871396", "_pdf_hash": "db2a13ed3371ae5dc8086223097902694de3dadc", "abstract": [{"section": "Abstract", "text": "Abstract. The Green-Kubo representation of the shear viscosity of a dilute gas of inelastic hard disks derived from the Boltzmann equation is evaluated by means of the direct simulation Monte Carlo method. The relationship between the oneparticle dynamics of the original expression and the N-particle dynamics needed for the simulation is analyzed. The presence of velocity correlations in the latter is identified and their possible implications are discussed.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION", "text": "The prototypical model for granular gases is an ensemble of smooth inelastic hard spheres or disks with a constant coefficient of normal restitution \u03b1. For this model, the methods of kinetic theory have been applied and, in particular, the Boltzmann equation has been extended [1, 2] . Then, by using a modification of the Chapmann-Enskog procedure, hydrodynamic equations have been derived [3, 4] . As the reference state, the isotropic and homogeneous cooling state (HCS) of a granular system is used. Due to the energy dissipation, the HCS is not stationary, but its energy decreases monotonically. Hydrodynamics has been employed with success to describe the behavior of granular flows.", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "As for molecular systems, the Chapmann-Enskog method leads to complicated differential equations that have to be solved in some approximations. It has been shown that the aforementioned equations are equivalent to a representation of the transport coefficients that has a similar structure to the Green-Kubo relations for elastic systems, although with significant differences [5] . Equivalent expressions have been derived by identifying the hydrodynamic part of the spectrum of the linearized Boltzmann equation and assuming it dominates for long long times and wavelengths [6, 7] .", "cite_spans": [{"start": 576, "end": 579, "text": "[6,", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "Here, an evaluation of the Green-Kubo relation for the shear viscosity by means of N-particle simulations, namely the direct simulation Monte Carlo (DSMC) method [8] , is presented. This requires going from the one-particle effective dynamics, as defined by a linearized Boltzmann operator, to a supposed equivalent N-particle dynamics. The relationship between both descriptions will turn out to be important for the analysis of the results. The existence an exact mapping of the HCS onto a steady state will be exploited as the basis of the simulation method [9, 10] .", "cite_spans": [{"start": 162, "end": 165, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "THE GREEN-KUBO EXPRESSION FOR THE SHEAR VISCOSITY", "text": "By using the Chapman-Enskog method or eigenfunctions expansions [5, 6] , the shear viscosity \u03b7 of a dilute granular gas of N smooth inelastic hard disks (d = 2) or spheres (d = 3) of mass m and diameter \u03c3 can be expressed in the form", "cite_spans": [{"start": 68, "end": 70, "text": "6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "THE GREEN-KUBO EXPRESSION FOR THE SHEAR VISCOSITY", "text": "Here n is the density, T the temperature, v 0 (T ) = (2k B T /m) 1/2 with k B the Boltzmann constant, = (n\u03c3 d\u22121 ) \u22121 , and", "cite_spans": [], "ref_spans": []}, {"section": "THE GREEN-KUBO EXPRESSION FOR THE SHEAR VISCOSITY", "text": "The function \u03c7 HCS (c 1 ) is defined from the solution of the Boltzmann equation describing the HCS, f HCS (v 1 ,t), as [1] f HCS (v 1 ,t) = nv and it is an isotropic function of the vector c 1 . Finally, the time dependence of \u2206 xy is given by", "cite_spans": [], "ref_spans": []}, {"section": "THE GREEN-KUBO EXPRESSION FOR THE SHEAR VISCOSITY", "text": "where c 12 = c 1 \u2212 c 2 , \u0398 is the Heaviside step function, \u03c3 is the unit vector pointing from the center of particle 2 to the center of particle 1 at contact, the operator P 12 interchanges the subindexes 1 and 2 to its right, and b \u03c3 (c 1 , c 2 ) is an operator replacing all the velocities c 1 and c 2 appearing to its right by the postcollisional values c 1 and c 2 given by", "cite_spans": [], "ref_spans": []}, {"section": "THE GREEN-KUBO EXPRESSION FOR THE SHEAR VISCOSITY", "text": "The last term on the right hand side of Eq. (5) contains the time-independent reduced cooling rate of the HCS, \u03b6 0 , defining the evolution of the temperature in that state,", "cite_spans": [], "ref_spans": []}, {"section": "THE GREEN-KUBO EXPRESSION FOR THE SHEAR VISCOSITY", "text": "Equation (1) differs from the standard Green-Kubo expression for dilute molecular systems in several aspects:", "cite_spans": [], "ref_spans": []}, {"section": "THE GREEN-KUBO EXPRESSION FOR THE SHEAR VISCOSITY", "text": "\u2022 The average is taken over the velocity distribution of the HCS and not over the Maxwellian characterizing the equilibrium state. Both differ for \u03b1 < 1.", "cite_spans": [], "ref_spans": []}, {"section": "THE GREEN-KUBO EXPRESSION FOR THE SHEAR VISCOSITY", "text": "\u2022 The time correlation function couples the transversal momentum flux \u2206 xy and a \"modified flux\" \u03a6 2,xy .", "cite_spans": [], "ref_spans": []}, {"section": "THE GREEN-KUBO EXPRESSION FOR THE SHEAR VISCOSITY", "text": "\u2022 The dynamics includes an accelerating streaming between collisions.", "cite_spans": [], "ref_spans": []}, {"section": "THE GREEN-KUBO EXPRESSION FOR THE SHEAR VISCOSITY", "text": "\u2022 The time integral contains, in addition to the correlation function, an exponentially decreasing in time factor.", "cite_spans": [], "ref_spans": []}, {"section": "THE GREEN-KUBO EXPRESSION FOR THE SHEAR VISCOSITY", "text": "To render Eq. (1) suitable for evaluation by means of N-particle simulations, some issues must be addressed. First, it presents the technical difficulty that \u039b c involves the cooling rate \u03b6 0 that, therefore, must be known a priori. Consequently, it is useful to make a change of scale [9, 10] ,", "cite_spans": [], "ref_spans": []}, {"section": "THE GREEN-KUBO EXPRESSION FOR THE SHEAR VISCOSITY", "text": "with \u03c9 0 being an arbitrary time-independent dimensionless frequency. Then, Eq. (1) transforms into", "cite_spans": [], "ref_spans": []}, {"section": "THE GREEN-KUBO EXPRESSION FOR THE SHEAR VISCOSITY", "text": "Here, we have renamed the time and velocity variables, v 0,st \u2261 (2k B T st /m) 1/2 where", "cite_spans": [], "ref_spans": []}, {"section": "THE GREEN-KUBO EXPRESSION FOR THE SHEAR VISCOSITY", "text": "and the angular brackets denote average defined by", "cite_spans": [], "ref_spans": []}, {"section": "THE GREEN-KUBO EXPRESSION FOR THE SHEAR VISCOSITY", "text": "Moreover, the time dependence is now given by", "cite_spans": [], "ref_spans": []}, {"section": "THE GREEN-KUBO EXPRESSION FOR THE SHEAR VISCOSITY", "text": "with\u039b", "cite_spans": [], "ref_spans": []}, {"section": "THE GREEN-KUBO EXPRESSION FOR THE SHEAR VISCOSITY", "text": "In Eq. (9), the dynamics is defined by means of the linear operator \u039b st . Before computating it by N-particle simulation methods, it must be rewritten in terms of a well defined particle dynamics. The structure of \u039b st suggests to introduce an acceleration streaming between collisions,", "cite_spans": [], "ref_spans": []}, {"section": "THE GREEN-KUBO EXPRESSION FOR THE SHEAR VISCOSITY", "text": "while the effect of a collision between particles i and j is to instantaneously modify their velocities accordingly with the same rules as in the original dynamics and given in Eqs. (6), i.e.", "cite_spans": [], "ref_spans": []}, {"section": "THE GREEN-KUBO EXPRESSION FOR THE SHEAR VISCOSITY", "text": "For this dynamics, the Liouville equation can be obtained. Then, by means of any of the standard procedures, the Boltzmann equation can be derived in the low density limit. It has the form", "cite_spans": [], "ref_spans": []}, {"section": "THE GREEN-KUBO EXPRESSION FOR THE SHEAR VISCOSITY", "text": "where J[ f , f ] is the same Boltzmann collision operator as in the original dynamics. It is now easily verified that f st (v) is a steady solution of this equation [10] . Let us assume that the Liouville equation has a stationary solution \u03c1 st (\u0393), where \u0393 denotes a point in phase space. A sufficient condition for this is that the distribution function of the HCS in the actual, original dynamics has the scaling property", "cite_spans": [], "ref_spans": []}, {"section": "THE GREEN-KUBO EXPRESSION FOR THE SHEAR VISCOSITY", "text": "Consider time correlation functions of the form", "cite_spans": [], "ref_spans": []}, {"section": "THE GREEN-KUBO EXPRESSION FOR THE SHEAR VISCOSITY", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "THE GREEN-KUBO EXPRESSION FOR THE SHEAR VISCOSITY", "text": "with", "cite_spans": [], "ref_spans": []}, {"section": "The dynamical variable A(\u0393,t) \u2261 A[\u0393(t)]", "text": "is generated from A(\u0393) through the dynamics defined above. The low density limit of C AB,st can be obtained by using the same procedures as for molecular systems [10] . The hypothesis needed are the same as those required to derive the Boltzmann equation [11] , plus the additional assumption that velocity correlations are negligible in the HCS at low densities. Then, it is found that C AB,st is given by Eq. (11). This provides a direct way of evaluating the latter expression, and therefore the shear viscosity, by means of N-particle simulations, since the dynamics defined by Eqs. (14) and (15) is easily implemented. Of course, the equality", "cite_spans": [], "ref_spans": []}, {"section": "The dynamical variable A(\u0393,t) \u2261 A[\u0393(t)]", "text": "only holds at low enough densities and as long as velocity correlations effects are negligible in the HCS. The DSMC method is a very useful tool to generate the low density dynamics of a system [8, 12] . This method is designed as a real N-particle dynamics simulation of a low density gas, consequently providing its complete dynamical description. ", "cite_spans": [{"start": 194, "end": 197, "text": "[8,", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "SIMULATION RESULTS", "text": "We have performed DSMC simulations of a system of N = 10 4 inelastic hard disks. Since we are dealing with position independent quantities in a homogeneous state, it is enough to consider one cell in configuration space. This allows to increase the statistics and also avoids that the system spontaneously develops spatial inhomogeneities. This is important since the HCS is unstable with respect to spatial long wavelength perturbations [13, 14] . We introduce a dimensionless reduced shear viscosity \u03b7 * by scaling the viscosity with its elastic limit in the first Sonine approximation \u03b7 0 ,", "cite_spans": [], "ref_spans": []}, {"section": "SIMULATION RESULTS", "text": "Then, Eq. (9) yields", "cite_spans": [], "ref_spans": []}, {"section": "SIMULATION RESULTS", "text": "with", "cite_spans": [], "ref_spans": []}, {"section": "SIMULATION RESULTS", "text": "Let us remind that what is actually computed in the N-particle description is", "cite_spans": [], "ref_spans": []}, {"section": "SIMULATION RESULTS", "text": "The simulations show that the system reaches, after a transient period, a stationary state with a temperature T st . Then, we measured the velocity function \u2202 ln \u03c7 HCS (c)/\u2202 c, c = v/ v 0,st , to determine the modified flux \u03a6 2,xy (c), defined in Eq. (2) . For this, the range of v was partitioned into small non-overlapping bins and the frequency distribution was built. Afterwards, the numerical derivative was computed. An example of the results, for \u03b1 = 0.6, is given in Fig. 1 . Here and in the following, the unit of mass is m, the unit of length is = (n\u03c3 ) \u22121 , and the unit of time is [2k B T (0)/m] \u22121/2 , where T (0) is the initial temperature. Moreover, we set k B = 1, implying that in our units it is T (0) = 1/2. For large velocities, \u2202 ln \u03c7 HCS (c)/\u2202 c tends to a constant, reflecting the exponential decay of \u03c7 HCS (c) [15] .", "cite_spans": [], "ref_spans": [{"start": 475, "end": 481, "text": "Fig. 1", "ref_id": "FIGREF0"}]}, {"section": "SIMULATION RESULTS", "text": "Once the function \u03a6 2,xy has been determined for each of the values of \u03b1 considered, the correlation function J \u03b7 (t) has been measured. It is seen to decay exponentially in time, at least over more than two decades, for all the values of the restitution coefficient [16] . Then, J \u03b7 (t) was fitted to an exponential, J \u03b7 (t) = J \u03b7 (0)e \u2212\u03bb \u03b7 t , and the fitted parameters J \u03b7 (0) and \u03bb \u03b7 were determined. In terms of them, Eq. (24) reads", "cite_spans": [], "ref_spans": []}, {"section": "SIMULATION RESULTS", "text": "The values of \u03b7 * obtained in this way are shown in Fig. 2 . A good agreement is observed with the results obtained in the first Sonine approximation [17] , although a slightly different behavior is also clearly identified. It is interesting to consider the initial value of J \u03b7 (t) and decompose it in the form", "cite_spans": [{"start": 150, "end": 154, "text": "[17]", "ref_id": "BIBREF16"}], "ref_spans": [{"start": 52, "end": 58, "text": "Fig. 2", "ref_id": "FIGREF1"}]}, {"section": "SIMULATION RESULTS", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "SIMULATION RESULTS", "text": "The first component, J (1) \u03b7 (0) is identically the same as J \u03b7 (0), where J \u03b7 (t) was defined in Eq. (25). It is independent of the velocity correlations present in the system. In fact, its exact value can be easily obtained, and for the choice of \u03c9 0 used in the simulations and the units we are employing, it is J (1) \u03b7 (0) = J \u03b7 (0) = 1/2 for all \u03b1 [16] . The other part, J (2) \u03b7 (0), contains the effect of velocity correlations and was assumed to be negligible. The simulation results for J \u03b7 (0) are plotted in Fig. 3 . For \u03b1 < 0.6, contributions from J (2) \u03b7 become significant, indicating the presence of velocity correlations in the system. This result raises some fundamental questions. Are the observed correlations an artifact of the DSMC method? We believe they are not, since velocity correlations in the HCS also have been recently observed and measured in molecular dynamics simulations [18] . Why there is such a good agreement between the first Sonine approximation predictions and the simulation results for the shear viscosity, even from strong dissipation? A possible answer is that the Sonine expansion is introduced, and truncated, both in the initial conditions and in the dynamics of the fluxes, leading to some kind of compensation. For small values of \u03b1, which Green-Kubo expression is the right one, that with J \u03b7 (t) or that with J \u03b7 (t)?, or are both wrong? And, finally, can it be concluded from these results that the Boltzmann equation should be somehow revised for strong inelasticity? All these points clearly deserve further analysis.", "cite_spans": [], "ref_spans": [{"start": 518, "end": 524, "text": "Fig. 3", "ref_id": "FIGREF2"}]}, {"section": "SIMULATION RESULTS", "text": "Although in this paper we have restricted ourselves to the shear viscosity, the Green-Kubo expressions for the other two transport coefficients, associated with the heat flux, can be computed in a similar way. For not too strong dissipation, the simulation results agree quite well with the first Sonine approximation predictions. Nevertheless, the discrepancies grow rather fast as \u03b1 decreases below \u03b1 \u2248 0.7. This might be, at least partially, due to the presence of velocity correlations in the DSMC results. A detailed discussion of these transport coefficients will be published elsewhere [16] .", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF5": {"title": "Linearized Boltzmann Equation and Hydrodynamics for Granular gases", "authors": [{"first": "J", "middle": ["J"], "last": "Brey", "suffix": ""}, {"first": "J", "middle": ["W"], "last": "Dufty", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Ruiz-Montero", "suffix": ""}], "year": 2003, "venue": "Granular Gas Dynamics", "link": "118662026"}, "BIBREF7": {"title": "Molecular gas Dynamics and the Direct Simulation of Gas Flows", "authors": [{"first": "G", "middle": [], "last": "Bird", "suffix": ""}], "year": 1994, "venue": "", "link": "92471512"}, "BIBREF16": {"title": "Hydrodynamic Tranport Coefficients of Granular Gases", "authors": [{"first": "J", "middle": ["J"], "last": "Brey", "suffix": ""}, {"first": "D", "middle": [], "last": "Cubero", "suffix": ""}], "year": 2001, "venue": "Granular Gases", "link": null}}, "ref_entries": {"FIGREF0": {"text": "FIGURE 1. Plot of (ln X ) \u2261 \u2202 ln \u03c7 HCS /\u2202 c as a function of c = v/ v 0,st for \u03b1 = 0.6. The circles are the numerical derivative of the simulation results and the solid line the fitted function. The velocity is measured in the units defined in the text.", "type": "figure"}, "FIGREF1": {"text": "FIGURE 2. The reduced coefficient of shear viscosity \u03b7 * for a system of inelastic disks as a function of the coefficient of normal restitution \u03b1. The symbols are from the DSMC method and the solid line is the first Sonine approximation.", "type": "figure"}, "FIGREF2": {"text": "FIGURE 3. DSMC results for the correlation function J \u03b7 (0) (filled circles) and its diagonal part J (1) \u03b7 (0) (empty circles).", "type": "figure"}}}
{"paper_id": "2871701", "_pdf_hash": "4fc8284e21ccbfc3bc764c80ea49674eae21d85f", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "2871958", "_pdf_hash": "fe25125d8ef245ea2f32ad01b498eea2acb0c3e0", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Analysis of the Cyber Attack on the Ukrainian Power Grid, tech. report", "authors": [{"first": "R", "middle": ["M"], "last": "Lee", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Assante", "suffix": ""}, {"first": "T", "middle": [], "last": "Conway", "suffix": ""}], "year": 2016, "venue": "", "link": null}, "BIBREF1": {"title": "SCADA Systems: Challenges for Forensic Investigators", "authors": [{"first": "I", "middle": [], "last": "Ahmed", "suffix": ""}], "year": 2012, "venue": "Computer", "link": "11743854"}, "BIBREF2": {"title": "A Taxonomy of Attacks on the DNP3 Protocol", "authors": [{"first": "S", "middle": [], "last": "East", "suffix": ""}], "year": 2009, "venue": "Critical Infrastructure Protection, IFIP Advances in Information and Communication Technology", "link": null}, "BIBREF3": {"title": "Protecting Industrial Control Systems from Electronic Threats", "authors": [{"first": "J", "middle": [], "last": "Weiss", "suffix": ""}], "year": 2010, "venue": "", "link": "106954236"}, "BIBREF4": {"title": "Implementing Attacks for Modbus/TCP Protocol in a Real-Time Cyber Physical System Test Bed", "authors": [{"first": "B", "middle": [], "last": "Chen", "suffix": ""}], "year": 2015, "venue": "IEEE Int'l Workshop Technical Committee on Communications Quality and Reliability (CQR 15", "link": "26975587"}, "BIBREF5": {"title": "Attack Taxonomies for the Modbus Protocols", "authors": [{"first": "P", "middle": [], "last": "Huitsing", "suffix": ""}], "year": 2008, "venue": "Int'l J. Critical Infrastructure Protection", "link": "15539229"}, "BIBREF6": {"title": "Industrial Control System Cyber Attacks", "authors": [{"first": "T", "middle": ["H"], "last": "Morris", "suffix": ""}, {"first": "W", "middle": [], "last": "Gao", "suffix": ""}], "year": 2013, "venue": "Proc. 1st Int'l Symp. ICS and SCADA Cyber Security Research (ICS-CSR 13", "link": "18397010"}, "BIBREF7": {"title": "Combating Memory Corruption Attacks on SCADA Devices", "authors": [{"first": "C", "middle": [], "last": "Bellettini", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Rrushi", "suffix": ""}], "year": 2008, "venue": "Proc. 2nd. Ann. IFIP Int'l Conf. Critical Infrastructure Protection (IFIP 08), revised papers", "link": "11492655"}, "BIBREF8": {"title": "Hey, My Malware Knows Physics! Attacking PLCs with Physical Model Aware Rootkit", "authors": [{"first": "L", "middle": [], "last": "Garcia", "suffix": ""}], "year": 2017, "venue": "Proc. 24th Ann. Network and Distributed System Security Symp", "link": "41405752"}, "BIBREF9": {"title": "Detecting Industrial Control Malware Using Automated PLC Code Analytics", "authors": [{"first": "S", "middle": ["A"], "last": "Zonouz", "suffix": ""}], "year": 2014, "venue": "IEEE Security & Privacy", "link": "15641337"}, "BIBREF10": {"title": "SCADA Network Forensics of the PCCC Protocol", "authors": [{"first": "S", "middle": [], "last": "Senthivel", "suffix": ""}, {"first": "I", "middle": [], "last": "Ahmed", "suffix": ""}, {"first": "V", "middle": [], "last": "Roussev", "suffix": ""}], "year": 2017, "venue": "Proc. 7th Ann. Digital Forensics Research Conf. (DFRWS 17", "link": "10424870"}, "BIBREF11": {"title": "PLC Forensics Based on Control Program Logic Change Detection Works", "authors": [{"first": "K", "middle": [], "last": "Yau", "suffix": ""}, {"first": "K.-P", "middle": [], "last": "Chow", "suffix": ""}], "year": 2015, "venue": "J. Digital Forensics, Security and Law", "link": "4112762"}, "BIBREF12": {"title": "Forensic Analysis of SCADA Systems and Networks", "authors": [{"first": "T", "middle": [], "last": "Kilpatrick", "suffix": ""}], "year": 2008, "venue": "Int'l J. Security and Networks", "link": null}, "BIBREF13": {"title": "Snort IDS for SCADA Networks", "authors": [{"first": "C", "middle": [], "last": "Valli", "suffix": ""}], "year": 2009, "venue": "Proc", "link": "34271942"}, "BIBREF14": {"title": "Security and Management (SAM 09", "authors": [], "year": 2009, "venue": "", "link": null}, "BIBREF15": {"title": "Accurate Modeling of the Siemens S7 SCADA Protocol for Intrusion Detection and Digital Forensics", "authors": [{"first": "A", "middle": [], "last": "Kleinmann", "suffix": ""}, {"first": "A", "middle": [], "last": "Wool", "suffix": ""}], "year": 2014, "venue": "J. Digital Forensics, Security and Law", "link": null}, "BIBREF16": {"title": "A Firmware Verification Tool for Programmable Logic Controllers", "authors": [{"first": "L", "middle": [], "last": "Mcminn", "suffix": ""}, {"first": "J", "middle": [], "last": "Butts", "suffix": ""}], "year": 2012, "venue": "Critical Infrastructure Protection, of IFIP Advances in Information and Communication Technology", "link": "15980353"}}, "ref_entries": {}}
{"paper_id": "2872128", "_pdf_hash": "4420f2f1a8d23bc6b29efb5558689f4193869551", "abstract": [{"section": "Abstract", "text": "Oxidized low-density lipoproteins (LDLs) play an important role during the development of atherosclerosis characterized by intimal inflammation and macrophage accumulation. A key component of LDL is lysophosphatidylcholine (lysoPC). LysoPC is a strong proinflammatory mediator, and its mechanism is uncertain, but it has been suggested to be mediated via the platelet activating factor (PAF) receptor. Here, we report that PAF triggers a pertussis toxin-(PTX-) sensitive intracellular signaling pathway leading to sequential activation of sPLA 2 , PLD, cPLA 2 , and AA release in human-derived monocytes. In contrast, lysoPC initiates two signaling pathways, one sequentially activating PLD and cPLA 2 , and a second parallel PTX-sensitive pathway activating cPLA 2 with concomitant activation of sPLA 2 , all leading to AA release. In conclusion, lysoPC and PAF stimulate AA release by divergent pathways suggesting involvement of independent receptors. Elucidation of monocyte lysoPC-specific signaling mechanisms will aid in the development of novel strategies for atherosclerosis prevention, diagnosis, and therapy.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Lysophosphatidylcholine (lysoPC) is found at elevated levels in atherosclerotic lesions [1] and has been postulated to be an important causal agent in inflammation and atherosclerosis. It is a prominent phospholipid component of oxidized lowdensity lipoproteins (oxLDL), and we have earlier shown that secretory phospholipase A 2 -(sPLA 2 -) modified LDL [2] and lysoPC alone [3] can induce proinflammatory activation of human-derived monocytes by increased release of arachidonic acid (AA). LysoPC may be responsible for various cellular processes such as regulation of monocyte adhesion molecule expression [4] , chemoattractant properties [5] , and monocyte proinflammatory cytokine secretion [6] . Some of the intracellular signaling events initiated by lysoPC are the activation of phospholipase D (PLD) [7, 8] and stimulation of p38 and p42/44 mitogen-activated protein kinases (MAPKs) through G i /G o proteins [9] . Nevertheless, the signaling mechanisms regulating specific cellular processes of lysoPC are not completely understood.", "cite_spans": [{"start": 88, "end": 91, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 355, "end": 358, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 376, "end": 379, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 609, "end": 612, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 642, "end": 645, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 696, "end": 699, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 809, "end": 812, "text": "[7,", "ref_id": "BIBREF6"}, {"start": 813, "end": 815, "text": "8]", "ref_id": "BIBREF7"}, {"start": 918, "end": 921, "text": "[9]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Introduction", "text": "It has been argued that lysoPC triggers cellular signaling through G-protein-coupled receptors. To our knowledge, three different receptors have been suggested as lysoPC responsive receptors. First, evidence was presented showing that lysoPC initiates intracellular signaling through the platelet-activating factor (PAF) receptor [6, 8, 10] , and it was hypothesized that both lysoPC and PAF-induced common signaling pathways through the PAF receptor. Later, two new G-protein-coupled receptors specific to lysoPC, G2A and GPR4, were described [11, 12] . However, the data showing direct binding of lysoPC to these receptors have been retracted due to their irreproducibility [13] . In spite of this, there is still evidence of a functional relationship between lysoPC and the G2A receptor [14] [15] [16] [17] . In addition, lysoPC has been reported to activate G \u03b1s -proteins and induce apoptosis through the G2A receptor in primary lymphocytes [17] , which indicates that the G2A receptor is a G \u03b1s -receptor. Hence, there is still uncertainty if and how lysoPC induces intracellular signaling.", "cite_spans": [{"start": 330, "end": 333, "text": "[6,", "ref_id": "BIBREF5"}, {"start": 334, "end": 336, "text": "8,", "ref_id": "BIBREF7"}, {"start": 337, "end": 340, "text": "10]", "ref_id": "BIBREF9"}, {"start": 544, "end": 548, "text": "[11,", "ref_id": "BIBREF10"}, {"start": 549, "end": 552, "text": "12]", "ref_id": "BIBREF11"}, {"start": 676, "end": 680, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 790, "end": 794, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 795, "end": 799, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 800, "end": 804, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 805, "end": 809, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 946, "end": 950, "text": "[17]", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Introduction", "text": "PAF plays important roles in inflammation-mediating cell-cell interactions in models of acute and chronic inflammation in virtually all organs and induces cellular responses through the G-protein-coupled PAF receptor [18] . Compared to lysoPC, the intracellular signaling of PAF has been extensively studied, and PAF is known to activate both PLD and p38 MAPK through its receptor [19] [20] [21] [22] . Additionally, a protein kinase C-dependent PAF-induced pathway that releases AA has been suggested [23] . PAF-induced cPLA 2 activity is inhibited by pertussis toxin (PTX), suggesting G \u03b1i -protein involvement [24] .", "cite_spans": [{"start": 217, "end": 221, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 381, "end": 385, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 386, "end": 390, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 391, "end": 395, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 396, "end": 400, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 502, "end": 506, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 526, "end": 527, "text": "2", "ref_id": "BIBREF1"}, {"start": 613, "end": 617, "text": "[24]", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Introduction", "text": "Enzymes that can mediate AA release are the PLA 2 enzymes that hydrolyze fatty acids from the sn-2 position in membrane phospholipids. This results in the generation of biologically active lipids, such as free fatty acids and lysophospholipids, all of which regulate inflammation. PLA 2 enzymes comprise a large family that is diverse in structure, biological function, mechanism, localization, and regulation, and the isoenzymes are classified thereby [25] . cPLA 2 is preferentially arachidonyl selective and requires submicromolar amounts of Ca 2+ for activity [26, 27] . In a variety of cell types, phosphorylation and activation of cPLA 2 is brought about by MAPK [28] [29] [30] . Extracellular PLA 2 , also referred to as sPLA 2 , is secreted by cells in response to inflammatory stimuli, and is thought to augment the inflammatory process by catalyzing the production of lipid mediators. sPLA 2 has been associated with many physiological and pathophysiological processes such as rheumatoid arthritis, sepsis, psoriasis, and atherosclerosis [31] [32] [33] .", "cite_spans": [{"start": 453, "end": 457, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 564, "end": 568, "text": "[26,", "ref_id": "BIBREF25"}, {"start": 569, "end": 572, "text": "27]", "ref_id": "BIBREF26"}, {"start": 669, "end": 673, "text": "[28]", "ref_id": "BIBREF27"}, {"start": 674, "end": 678, "text": "[29]", "ref_id": "BIBREF28"}, {"start": 679, "end": 683, "text": "[30]", "ref_id": "BIBREF29"}, {"start": 1048, "end": 1052, "text": "[31]", "ref_id": "BIBREF30"}, {"start": 1053, "end": 1057, "text": "[32]", "ref_id": "BIBREF31"}, {"start": 1058, "end": 1062, "text": "[33]", "ref_id": "BIBREF32"}], "ref_spans": []}, {"section": "Introduction", "text": "In order to examine if lysoPC intracellular signaling is induced by an independent G-protein-coupled receptor, we compared lysoPC-and PAF-induced intracellular signaling components leading to AA release. Our results suggest that PAF triggers a PTX-sensitive pathway leading to sequential activation of sPLA 2 , PLD, and cPLA 2 and AA release. In contrast, lysoPC initiates two pathways, where one sequentially activates PLD and cPLA 2 , and a second PTX-sensitive pathway that activates cPLA 2 with the simultaneous activation of sPLA 2 , all leading to AA release initiated from independent receptors. In conclusion, our results suggest that lysoPC indeed induces AA release via different signaling pathways compared to PAF. This supports the hypothesis of divergent signalling pathways for the two lipids based on their binding to unique receptors. . Briefly, cells were lysed and homogenized using Trizol reagent. Chloroform was added before centrifuging for phase separation. The aqueous phase with RNA was transferred to a new tube, and RNA was precipitated by mixing the aqueous phase with isopropyl alcohol. RNA was pelleted by centrifuging and washed with ethanol before it was air-dried and suspended in DEPC-treated water. RNA concentration was determined by spectrophotometry at A 260 .", "cite_spans": [], "ref_spans": []}, {"section": "Materials and Methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "RT-PCR Detection of Different PLD Isoforms.", "text": "Total RNA was reverse-transcribed and amplified by PCR as previously described [3] . Conditions for RT-PCR were hPLD1a and hPLD1b, 94", "cite_spans": [{"start": 79, "end": 82, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "RT-PCR Detection of Different PLD Isoforms.", "text": "\u2022 C for 30 sec, 60", "cite_spans": [], "ref_spans": []}, {"section": "RT-PCR Detection of Different PLD Isoforms.", "text": "\u2022 C for 1 min, and 72", "cite_spans": [], "ref_spans": []}, {"section": "RT-PCR Detection of Different PLD Isoforms.", "text": "\u2022 C for 1 min for 27 cycles and for hPLD2, 94", "cite_spans": [], "ref_spans": []}, {"section": "RT-PCR Detection of Different PLD Isoforms.", "text": "\u2022 C for 1 min, 56", "cite_spans": [], "ref_spans": []}, {"section": "RT-PCR Detection of Different PLD Isoforms.", "text": "\u2022 C for 1.5 min and 72", "cite_spans": [], "ref_spans": []}, {"section": "RT-PCR Detection of Different PLD Isoforms.", "text": "\u2022 C for 2 min for 30 cycles. hPLD1a and hPLD1b are transcript variants of the same gene and primers were designed to distinguish the two transcript variants, which results in products of 638 bp (hPLD1a) and 533 bp (hPLD1b) [34] . Primers used for amplification were synthesized as follows: hPLD1a and hPLD1b fwd 5 -TGG-GCTCACCATGAGAA-3 (nucleotides 1475-1491) and rew 5 -GTCATGCCAGGGCATCCGGGG-3 (nucleotides 2133-2113) and hPLD2 fwd 5 -TCCATCCAGGCCATTCTGCAC-3 (nucleotides 2802-2778) and rew 5 -CTATGTCCACAT-TTCTAGGGGGAT-3 (nucleotides 2802-2778). All PCR reactions were performed with water as the negative control both for the RT reaction and PCR reaction (not shown). 2 In Vitro Assay. cPLA 2 activity was measured as described previously [35] . In brief, THP-1 cells were seeded (2 \u00d7 10 6 cells/well) and starved (0,5% v/v FCS, 18 h) before stimulation with lysoPC (40 \u03bcM, 10 min) or PAF (40 \u03bcM, 5 min). Preincubations with inhibitors were done under the same conditions as for AA-release. The cells were lysed in lysis buffer and protein concentrations were measured by BioRad protein reagent. 100 \u03bcg lysate was incubated with [ 14 C]-L-3 phosphatidylcholine, 1 steroyl-2-arachidonyl-micelles (100 \u03bcM) at 37", "cite_spans": [{"start": 223, "end": 227, "text": "[34]", "ref_id": "BIBREF33"}, {"start": 671, "end": 672, "text": "2", "ref_id": "BIBREF1"}, {"start": 742, "end": 746, "text": "[35]", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "PLD Choline", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "cPLA", "text": "\u2022 centigrade for 30 min before lipid extraction by the Bligh and Dyer method [36] . Free AA was separated from other phospholipids by TLC on aluminum silica gel 60 sheets developed with ethyl acetate/isooctane/ acetic acid/water (55/75/8/100, v/v/v/v). The amount of produced AA was detected by Phosphor-Imager and the cPLA2 activity was expressed as a percentage relative to total amount of phospholipids. In experiments with inhibitors, results are shown as percent inhibition of lysoPC or PAFinduced cells. Percent inhibition is calculated with data retracted from the background noise. Results shown are representative of three independent experiments.", "cite_spans": [{"start": 77, "end": 81, "text": "[36]", "ref_id": "BIBREF35"}], "ref_spans": []}, {"section": "MTT Cytotoxicity Assay.", "text": "LysoPC and different chemical inhibitors were tested for cytotoxicity by MTT assay as previously described [37] . The MTT assay reflects the mitochondrial dehydrogenase activity, and the absorbance at 580 nm was used as an index of cell viability.", "cite_spans": [{"start": 107, "end": 111, "text": "[37]", "ref_id": "BIBREF36"}], "ref_spans": []}, {"section": "Statistics.", "text": "The data are shown as means \u00b1 SD of separate experiments each containing 3 parallels (arachidonate and PLD assay) or 2 parallels (cPLA2 assay). For the arachidonate and PLD assay, the data of three independent experiments were compared with the Kruskal-Wallis test for random samples, and those at P < 0.05 were considered significant. Each set of experiments was repeated three times. [3] . In order to achieve a more detailed understanding of the mechanism of the lysoPC-induced pathway and, additionally, to distinguish it from pathways induced by other lysolipid analogues, we tested analogues such as lysophosphatidic acid, sphingosylphosphorylcholine (conc. ranging from 20 to 100 \u03bcM and stimulation time varying from 10 to 120 min, results not shown), and PAF for their ability to trigger AA release. Among the analogues tested, only PAF could induce significant AA release (Figure 1 ). PAF-stimulated [ 3 H]AA release in a dose-and time-dependent manner with a maximal release after five minutes (Figure 1(a) ) at an optimal concentration of 35 \u03bcM PAF (Figure 1(b) ). Comparatively, lysoPC stimulated AA release with a maximum after ten minutes at an optimal concentration of 40 \u03bcM [3] . Hence, we observed that PAF elicits AA release with slightly more rapid kinetics compared to lysoPC.", "cite_spans": [{"start": 386, "end": 389, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 1190, "end": 1193, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": [{"start": 881, "end": 890, "text": "(Figure 1", "ref_id": "FIGREF1"}, {"start": 1004, "end": 1016, "text": "(Figure 1(a)", "ref_id": "FIGREF1"}, {"start": 1060, "end": 1072, "text": "(Figure 1(b)", "ref_id": "FIGREF1"}]}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "LysoPC and PAF", "text": "It is difficult to define PAF's \"physiological concentration\", but the optimal concentrations of PAF and lysoPC were selected based on the criteria that the cells were viable, as measured by MTT assay [38] [39] [40] . To enhance the sensitivity of the AA assay, fatty acid-free BSA was added to the media. Hence, the final concentrations of free lipid in the stimulation media were less than the actual concentration used [41] . By stimulating THP-1 monocytes with 40 \u03bcM lysoPC for 10 min or 35 \u03bcM PAF for 5 min, we did get a fold increase in AA release between 3 to 12.", "cite_spans": [{"start": 201, "end": 205, "text": "[38]", "ref_id": "BIBREF37"}, {"start": 206, "end": 210, "text": "[39]", "ref_id": "BIBREF38"}, {"start": 211, "end": 215, "text": "[40]", "ref_id": "BIBREF39"}, {"start": 422, "end": 426, "text": "[41]", "ref_id": "BIBREF40"}], "ref_spans": []}, {"section": "LysoPC and PAF", "text": "In order to determine which PLA 2 enzymes contribute to AA release, different PLA 2 inhibitors were applied. The sPLA 2 inhibitor, SB203347, reduced PAF-stimulated AA release by 80% v/v (Figure 1(c) ), while the cPLA 2 /iPLA 2 inhibitor, MAFP, reduced AA release by 60% v/v (Figure 1(c) ). Consequently, our results suggest that PAF stimulate cPLA 2 or iPLA 2 activity; hence, the cPLA 2 activity assay is used later in this study to further assess cPLA 2 activation. Our results suggest that PAF-stimulated AA release is mediated by sPLA 2 and cPLA 2 or iPLA 2 in THP-1 cells, similar to the lysoPC-triggered response.", "cite_spans": [], "ref_spans": [{"start": 186, "end": 198, "text": "(Figure 1(c)", "ref_id": "FIGREF1"}, {"start": 274, "end": 286, "text": "(Figure 1(c)", "ref_id": "FIGREF1"}]}, {"section": "LysoPC and PAF Stimulate PLD Activity by Independent", "text": "Mechanisms. It has been shown that lysoPC [8] and PAF [19] stimulate PLD activity in mouse peritoneal macrophages. PLD is a widely expressed enzyme, of which there are three mammalian isoforms, PLD1a, PLD1b, and PLD2 [42] ; all three isoenzymes are expressed in human monocytes [43] . To our knowledge, the expression of PLD isoenzymes in THP-1 cells has not been analyzed. To assess which PLD enzymes were expressed, the PLD mRNA expression pattern was analyzed by RT-PCR. We did indeed find expression of PLD1a and PLD2 in both undifferentiated and differentiated THP-1 cells, while PLD1b was faintly expressed in undifferentiated cells and clearly upregulated in differentiated THP-1 cells (Figure 2 ). Since we use undifferentiated THP-1 cells in this study, any PLD activity we measure would be due mainly to PLD1a and/or PLD2. In order to determine if PLD is involved in lysoPC-and PAF-stimulated AA release in human-derived monocytes, [ 3 H]AA prelabeled THP-1 cells were preincubated with the primary alcohols 1-butanol and ethanol and with the secondary alcohol 2-butanol. The primary alcohols, but not the secondary alcohol 2-butanol, will attenuate signaling mediated by PLD, as they compete with water to be the hydroxyl donor in the hydrolysis of phospholipids by PLD. [ 3 H]AA release in response to lysoPC and PAF stimulation was partially inhibited by the two primary alcohols, 1-butanol and ethanol ( Figure 3 ) although ethanol was less effective in inhibiting [ 3 H]AA release by PAF than by lysoPC. As expected, the secondary alcohol, 2-butanol, did not inhibit [ 3 H]AA release ( Figure 3 ) because of its inability to be a hydroxyl donor. This suggests that the enzymatic product of PLD activity, phosphatidic acid (PA), regulates lysoPC-and/or PAFstimulated AA release in THP-1 cells.", "cite_spans": [{"start": 42, "end": 45, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 54, "end": 58, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 217, "end": 221, "text": "[42]", "ref_id": "BIBREF41"}, {"start": 278, "end": 282, "text": "[43]", "ref_id": "BIBREF42"}], "ref_spans": [{"start": 693, "end": 702, "text": "(Figure 2", "ref_id": "FIGREF2"}, {"start": 1418, "end": 1426, "text": "Figure 3", "ref_id": "FIGREF3"}, {"start": 1601, "end": 1609, "text": "Figure 3", "ref_id": "FIGREF3"}]}, {"section": "LysoPC and PAF Stimulate PLD Activity by Independent", "text": "To further assess if PLD is activated by lysoPC or PAF, PLD activity was analyzed by cellular release of [ 14 C]choline. Both lysoPC and PAF significantly increased [ 14 C]choline release, which is an indication of PLD activity (Figure 4(a) ). Optimal release was at 40 \u03bcM after 2 minutes for both lysoPC and PAF. This suggests that both lysoPC and PAF stimulate PLD activity.", "cite_spans": [], "ref_spans": [{"start": 228, "end": 240, "text": "(Figure 4(a)", "ref_id": "FIGREF4"}]}, {"section": "LysoPC and PAF Stimulate PLD Activity by Independent", "text": "PAF receptor is a G-protein coupled receptor and lysoPC is also believed to mediate intracellular signaling through G-protein-coupled receptors. To determine if different Gprotein coupled receptors were involved in PLD activation, we applied different inhibitors to the cells before stimulation of PLD activity. The PAF antagonist WEB2170 (10 \u03bcM) inhibited [ 14 C]choline release in response to lysoPC by 80% (Figure 4(b) ) and in response to PAF by 90% (Figure 4(c) ). The PAF receptor is regulated by G \u03b1i -proteins [24] . The G \u03b1i -protein inhibitor PTX inhibited lysoPC-induced PLD activation by about 30% (Figure 4(b) ) and PAF-induced PLD activation by 70% (Figure 4(c) ), suggesting that a G \u03b1i -protein is more central in the PAF-initiated stimulation of PLD compared to lysoPC.", "cite_spans": [{"start": 518, "end": 522, "text": "[24]", "ref_id": "BIBREF23"}], "ref_spans": [{"start": 409, "end": 421, "text": "(Figure 4(b)", "ref_id": "FIGREF4"}, {"start": 454, "end": 466, "text": "(Figure 4(c)", "ref_id": "FIGREF4"}, {"start": 610, "end": 622, "text": "(Figure 4(b)", "ref_id": "FIGREF4"}, {"start": 663, "end": 675, "text": "(Figure 4(c)", "ref_id": "FIGREF4"}]}, {"section": "LysoPC and PAF Stimulate PLD Activity by Independent", "text": "Since sPLA 2 involvement in the lysoPC and PAF signaling pathway is already suggested, we wanted to examine if sPLA 2 mediates PLD activity. In order to determine if sPLA2 activates PLD, the specific sPLA 2 inhibitor SB203347 was applied in the PLD experiment. SB203347 inhibited PAF-induced PLD activation by almost 100% (Figure 4(c) ), while lysoPC-induced PLD activation was inhibited only by 30% (Figure 4(b) ). This suggests that the PAF-induced pathway requires sPLA 2 for activation of PLD, while in the lysoPC pathway, sPLA 2 contributes poorly to PLD activation, which is in accordance with a study in HEK293 cells [44] . Additionally, involvement of G \u03b1i -proteins is more prominent in PAF-stimulated PLD activation compared to lysoPC-stimulated activation. Taken together, this suggests that divergent intracellular signaling pathways are initiated by lysoPC and PAF. ", "cite_spans": [{"start": 624, "end": 628, "text": "[44]", "ref_id": "BIBREF43"}], "ref_spans": [{"start": 322, "end": 334, "text": "(Figure 4(c)", "ref_id": "FIGREF4"}, {"start": 400, "end": 412, "text": "(Figure 4(b)", "ref_id": "FIGREF4"}]}, {"section": "cPLA 2 Activity Is Distinctively Stimulated in Response to", "text": "LysoPC and PAF. We have earlier shown that lysoPC stimulates cPLA 2 activity in human-derived monocytes [3] and that cPLA 2 is involved in PAF-mediated AA release by inhibition with MAFP (Figure 1(c) ). We examined cPLA 2 activation in an in vitro assay, and our results showed that cPLA 2 activity was significantly induced by both lysoPC and PAF ( Figure 5(a) ). LysoPC-induced responses are inhibited by PAF-receptor antagonists [6, 8, 10] , and it has been argued that lysoPC might act through the PAF receptor. To investigate if lysoPC-stimulated cPLA 2 activity is induced by PAF receptor, we applied the antagonist WEB2170 to the cells prior to analysis of cPLA 2 activity. LysoPC-and PAF-stimulated cPLA 2 activity was inhibited by WEB2170 by 40% ( Figure 5(b) ) and 95% ( Figure 5(c) ), respectively. This indicates that lysoPC acts partly through PAF receptor and partly thought another unidentified receptor.", "cite_spans": [{"start": 104, "end": 107, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 432, "end": 435, "text": "[6,", "ref_id": "BIBREF5"}, {"start": 436, "end": 438, "text": "8,", "ref_id": "BIBREF7"}, {"start": 439, "end": 442, "text": "10]", "ref_id": "BIBREF9"}], "ref_spans": [{"start": 187, "end": 199, "text": "(Figure 1(c)", "ref_id": "FIGREF1"}, {"start": 350, "end": 361, "text": "Figure 5(a)", "ref_id": "FIGREF5"}, {"start": 757, "end": 768, "text": "Figure 5(b)", "ref_id": "FIGREF5"}, {"start": 781, "end": 792, "text": "Figure 5(c)", "ref_id": "FIGREF5"}]}, {"section": "cPLA 2 Activity Is Distinctively Stimulated in Response to", "text": "Both lysoPC and PAF are reported to activate PLD in mouse peritoneal macrophages [8, 45] . In Figure 4 (a), we show that PLD is activated in human-derived monocytes by lysoPC or PAF. To analyze if PLD was involved in the pathway activating cPLA 2 , we applied 1-butanol to the cells before analysis of cPLA 2 activity. As shown by the cPLA 2 in vitro activity assay, LysoPC-or PAF-induced cPLA 2 activity was indeed inhibited by 1-butanol (0.25% v/v) by 70% ( Figure 5(a) ) and 95% ( Figure 5(b) ), which strongly suggests that PLD is involved in cPLA 2 activation although at a significantly higher degree in response to PAF compared to Journal of Lipids lysoPC stimulation. Again this suggests distinct signaling for PAF and lysoPC. We previously reported that sPLA 2 contributes to lysoPC-mediated AA release [3] , and above, we have shown for the first time that sPLA 2 also can contribute to PAFmediated AA release (Figure 1(c) ). To analyze if sPLA 2 regulates lysoPC-or PAF-induced cPLA 2 activity, we applied the sPLA 2 inhibitor SB203347. SB203347 inhibited PAF-stimulated cPLA 2 activity by 95% ( Figure 5(c) ), while lysoPC-induced stimulation was dramatically less sensitive to the inhibitor (15% reduction, Figure 5(b) ). These results indicate that PAF-mediated cPLA 2 activation is regulated by sPLA 2 ; however, lysoPC-mediated cPLA 2 activity is poorly regulated by sPLA 2 .", "cite_spans": [{"start": 81, "end": 84, "text": "[8,", "ref_id": "BIBREF7"}, {"start": 85, "end": 88, "text": "45]", "ref_id": "BIBREF44"}, {"start": 812, "end": 815, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 1388, "end": 1389, "text": "2", "ref_id": "BIBREF1"}], "ref_spans": [{"start": 94, "end": 102, "text": "Figure 4", "ref_id": "FIGREF4"}, {"start": 460, "end": 471, "text": "Figure 5(a)", "ref_id": "FIGREF5"}, {"start": 484, "end": 495, "text": "Figure 5(b)", "ref_id": "FIGREF5"}, {"start": 920, "end": 932, "text": "(Figure 1(c)", "ref_id": "FIGREF1"}, {"start": 1107, "end": 1118, "text": "Figure 5(c)", "ref_id": "FIGREF5"}, {"start": 1220, "end": 1231, "text": "Figure 5(b)", "ref_id": "FIGREF5"}]}, {"section": "cPLA 2 Activity Is Distinctively Stimulated in Response to", "text": "LysoPC has been reported to mediate signaling pathways through G \u03b1s -proteins [17] . In this study, we have used PTX, which is a G \u03b1i -protein inhibitor, in order to examine if G \u03b1i -proteins are involved in any of the pathways. PTX inhibited potently both lysoPC-( Figure 5(b) ) and PAF-( Figure 5(c) ) induced cPLA 2 activation by 100% and 68%, respectively, suggesting that cPLA 2 activity induced by lysoPC is regulated through G \u03b1i -proteins and to a lesser extent in the PAF-initiated pathway.", "cite_spans": [{"start": 78, "end": 82, "text": "[17]", "ref_id": "BIBREF16"}], "ref_spans": [{"start": 266, "end": 277, "text": "Figure 5(b)", "ref_id": "FIGREF5"}, {"start": 290, "end": 301, "text": "Figure 5(c)", "ref_id": "FIGREF5"}]}, {"section": "LysoPC and PAF-Stimulated [ 3 H]AA Release Is Partly", "text": "Blocked by the PAF Receptor Antagonist WEB2170. It has been reported that lysoPC may stimulate cells via the PAF receptor [6, 8, 10] . We compared the ability of the PAF receptor antagonist WEB2170 to inhibit AA release by lysoPC and PAF. WEB2170 inhibited both lysoPC-and PAF-stimulated [ 3 H]AA release by 40% (Figures 6(a) and 6(b) ) at 10 \u03bcM WEB2170, suggesting that lysoPC acts partly through PAF receptor and partly through another unidentified receptor. This is similar to what is observed in HL-60 cells [46] , regarding lysoPC and PAF's ability to initiate independent signaling mechanisms.", "cite_spans": [{"start": 122, "end": 125, "text": "[6,", "ref_id": "BIBREF5"}, {"start": 126, "end": 128, "text": "8,", "ref_id": "BIBREF7"}, {"start": 129, "end": 132, "text": "10]", "ref_id": "BIBREF9"}, {"start": 512, "end": 516, "text": "[46]", "ref_id": "BIBREF45"}], "ref_spans": [{"start": 312, "end": 334, "text": "(Figures 6(a) and 6(b)", "ref_id": "FIGREF6"}]}, {"section": "Discussion", "text": "Taken together, our results suggest that lysoPC and PAF differ in the way they stimulate PLD and cPLA 2 activation. PAF stimulates PLD and cPLA 2 activity in a sequential manner mediated by sPLA 2 . In contrast, lysoPC sPLA 2 -induced AA release appears to be in a very low extent dependent of PLD. Moreover, cPLA 2 is to a large extent regulated by G \u03b1i -proteins in the lysoPC pathway but to a lesser degree in the PAF pathway (as shown in Figure 7) .", "cite_spans": [], "ref_spans": [{"start": 442, "end": 451, "text": "Figure 7)", "ref_id": "FIGREF7"}]}, {"section": "Discussion", "text": "PLD is reported to be activated in response to lysoPC and PAF [10] [11] [12] 47] ; however, PLD has, to our knowledge, not been shown to be involved in lysoPC-or PAF-induced AA release. We have shown here that there is an important relationship between PLD, cPLA 2 , and consequently AA release. In addition, there is a striking difference upstream of PLD in the two pathways leading to AA release, where sPLA2 mediates PLD activation in response to PAF but partly in response to lysoPC. These results suggest two divergent pathways for lysoPC and PAF that earlier have been argued to share common signaling pathways.", "cite_spans": [{"start": 62, "end": 66, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 67, "end": 71, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 72, "end": 76, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 77, "end": 80, "text": "47]", "ref_id": "BIBREF46"}], "ref_spans": []}, {"section": "Discussion", "text": "Several possible mechanisms have been suggested in the literature about how PLD may affect AA release. Firstly, PLD may activate MAPK cascade that may contribute to phosphorylation of cPLA 2 and consequently activation of the enzyme [28, 48] . We are currently investigating if p38 may be an intermediate step between PLD and lysoPC induced AA release. Secondly, PLD generates PA, which may be a substrate for PLA 2 enzymes [49] . Third, sequential activation of PLD and phosphatidate phosphohydrolase results in DAG accumulation. This facilitates the interaction of cPLA2 with its substrate [50] . Thus, our results indicate that PLD is not only important in generation of the key mediator PA but also in activation of other enzymes such as cPLA 2 . Taken together, PLD seems to be important in order to differentiate between the lysoPC-and PAF-induced intracellular signaling pathways.", "cite_spans": [{"start": 189, "end": 190, "text": "2", "ref_id": "BIBREF1"}, {"start": 233, "end": 237, "text": "[28,", "ref_id": "BIBREF27"}, {"start": 238, "end": 241, "text": "48]", "ref_id": "BIBREF47"}, {"start": 424, "end": 428, "text": "[49]", "ref_id": "BIBREF48"}, {"start": 592, "end": 596, "text": "[50]", "ref_id": "BIBREF49"}, {"start": 747, "end": 748, "text": "2", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Discussion", "text": "Previously, both lysoPC and PAF have been shown to release AA in human-derived monocytes [3, 45] . Interestingly, our results suggest that the AA release is a result of two independent pathways, one initiated by PAF and a different pathway initiated by lysoPC. This novelty underscores lysoPC and PAF's ability to initiate and contribute to inflammation through the activation of PLA 2 enzymes and the consequent release of AA, which is a precursor for the proinflammatory hormones, the eicosanoids. Moreover, the two distinct pathways triggered by the two lipids suggest that AA release can be regulated by divergent pathways, mediating similar proinflammatory response. PAF-stimulated AA release has in cell systems other than monocytes been shown to be inhibited by the G \u03b1i -protein inhibitor, PTX, indicating that G \u03b1i -proteins are involved in PLA 2 activation [51] . It is known that lysoPC can mediate cellular responses through several G-proteins ( [17] and references herein). In our study, the PAF-mediated AA releasing pathway was clearly regulated by a G \u03b1i -protein. In contrast, G \u03b1i -proteins were important for cPLA 2 activation but not as much in regulating PLD activity in response to lysoPC. Thus, indicating a third pathway for AA release by lysoPC. Hence, our results suggest that the PAF pathway and in part the lysoPC pathway is triggered by G \u03b1i -protein coupled receptors.", "cite_spans": [{"start": 89, "end": 92, "text": "[3,", "ref_id": "BIBREF2"}, {"start": 93, "end": 96, "text": "45]", "ref_id": "BIBREF44"}, {"start": 867, "end": 871, "text": "[51]", "ref_id": "BIBREF50"}, {"start": 958, "end": 962, "text": "[17]", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Discussion", "text": "It is well known that PAF induces intracellular signaling through the G-protein coupled PAF receptor and that it is inhibited by different PAF antagonists such as WEB2170 [52] . In addition, it is reported that lysoPC-induced responses may be inhibited by PAF-receptor antagonists [6, 8, 10] , and previous authors suggest that this indicates cellular lysoPC-induced responses via the PAF receptor. We show here that both lysoPC-and PAF-stimulated cellular responses were inhibited by the PAF receptor antagonist, WEB2170 although the intracellular signaling pathways inhibited clearly were different. The literature opens for the existence of structurally related receptors effectuating lysoPC-or PAFstimulated responses, and further studies will be necessary to identify a specific receptor for lysoPC. Hence, our results strongly suggest that lysoPC and PAF stimulate independent signaling pathways leading to AA release are partly triggered by independent receptors, but we are uncertain as to the identity of the exact receptor responsible for the major lysoPC-induced intracellular signaling.", "cite_spans": [{"start": 171, "end": 175, "text": "[52]", "ref_id": "BIBREF51"}, {"start": 281, "end": 284, "text": "[6,", "ref_id": "BIBREF5"}, {"start": 285, "end": 287, "text": "8,", "ref_id": "BIBREF7"}, {"start": 288, "end": 291, "text": "10]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Discussion", "text": "In this study we come closer to resolving some of the molecular mechanisms regulating AA release in response to lysoPC in human-derived monocytes by comparing it to that of its analogue PAF. In conclusion, our results suggest separate pathways leading to AA release stimulated by PAF compared to lysoPC (Figure 7 ). PAF triggers a PTX sensitive pathway by sequentially activating sPLA 2 , PLD, and cPLA 2 , while lysoPC triggers one pathway by sequentially activating PLD and cPLA 2 , a second PTX sensitive pathway activating cPLA 2 and third pathway activating sPLA 2 . More detailed understanding of intracellular signaling mechanisms will allow for greater specificity in the design of future therapeutic strategies. ", "cite_spans": [], "ref_spans": [{"start": 303, "end": 312, "text": "(Figure 7", "ref_id": "FIGREF7"}]}, {"section": "Abbreviations", "text": "", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Lysophosphatidylcholine plays an essential role in the mitogenic effect of oxidized low density lipoprotein on murine macrophages", "authors": [{"first": "M", "middle": [], "last": "Sakai", "suffix": ""}, {"first": "A", "middle": [], "last": "Miyazaki", "suffix": ""}, {"first": "H", "middle": [], "last": "Hakamata", "suffix": ""}], "year": 1994, "venue": "Journal of Biological Chemistry", "link": "91439752"}, "BIBREF1": {"title": "Modification of LDL with human secretory phospholipase A or sphingomyelinase promotes its arachidonic acid-releasing propensity", "authors": [{"first": "J", "middle": [], "last": "Oestvang", "suffix": ""}, {"first": "D", "middle": [], "last": "Bonnefont-Rousselot", "suffix": ""}, {"first": "E", "middle": [], "last": "Ninio", "suffix": ""}, 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THP-1 cells were starved in RPMI 1640 supplemented with 1 mg/mL BSA and [ 14 C]choline (0.6 \u03bcCi/mL) for 40 h with a cell density of 6.75 \u00d7 10 5 cells/ well. The cells were stimulated with lysoPC (40 \u03bcM, 2 min) or PAF (40 \u03bcM, 2 min) in RPMI 1640 with 1 mg/mL BSA. Prein- cubations with inhibitors were conducted under same condi- tions as for AA-release. To extract aqueous phase metabolites the medium was centrifuged to remove cells before ice-cold chloroform/methanol (1 : 2, v/v) was added. To the medium- chloroform/methanol solution, ice-cold chloroform and wa- ter was added to a final ratio of methanol/chloroform/water (2 : 2 : 1, v/v/v). The solution was mixed well and centrifuged (500 g, 5 min) to separate the organic phase from the water phase. The upper aqueous phase was evaporated to dryness in a vacuum dryer overnight and resolved in water/ethanol (1 : 1, v/v). Free choline was separated from phospho- choline by TLC on aluminum silica gel 60 sheet developed with 0.9% w/v NaCl/methanol/NH 4 OH (50 : 50 : 5,v/v/v). Released choline in the medium was measured by Phospho- Imager. 1 M NaOH were added to the cells and the radioac- tivity was measured by liquid scintillation counting to deter- mine total radioactivity in cells. Results are expressed as re- leased choline in the medium relative to total radioactivity and are normalized to show fold induction of treated relative to untreated cells. In experiments with inhibitors, results are shown as percent inhibition of lysoPC or PAF-induced cells. Percent inhibition is calculated with data retracted from the background noise. Results given are representative of three independent experiments.", "type": "figure"}, "FIGREF1": {"text": "Figure 1: PAF and [ 3 H]AA release in human monocytes. Prelabeled THP-1 cells were stimulated with PAF, and [ 3 H]AA release was measured by liquid scintillation counting. (a) The time course of PAF-(35 \u03bcM) mediated [ 3 H]AA. (b) PAF stimulation for 5 min mediates [ 3 H]AA release in a dose-dependent matter. (c) Shows inhibition of PAF-induced [ 3 H]AA by the sPLA 2 inhibitor SB203347 (10 \u03bcM) and the cPLA 2 inhibitor MAFP (10 \u03bcM). The PAF concentration used is 35 \u03bcM. Data are expressed as means \u00b1 SD of triplicate determinations within separate experiments. Asterisks indicate that values are statistically different from PAF-treated cells ( * ).", "type": "figure"}, "FIGREF2": {"text": "Figure 2: Expression of PLD isoforms in THP-1 cells. RT-PCR with primers specific for different PLD isoforms (PLD1a 638 bp, PLD1b 533 bp, and PLD2 710 bp) was performed on total RNA isolated from undifferentiated THP-1, THP-1 cells differentiated for 72 h and 120 h (lanes 2,3, and 4, resp.; lane 1 is the positive control). Band intensities were calculated using BioRad image analysis software and fold induction of PLD mRNAs (normalized to b-actin) relative to undifferentiated cells is shown in the lower panel.", "type": "figure"}, "FIGREF3": {"text": "Figure 3: LysoPC-and PAF-mediated [ 3 H]AA release is inhibited by different alcohols. Prelabeled THP-1 cells were preincubated with different alcohols 30 min before challenge with lysoPC (40 \u03bcM, 10 min) or PAF (35 \u03bcM, 5 min). [ 3 H]AA release in the medium was measured by liquid scintillation counting. Data are expressed as means \u00b1 SD of triplicate determinations within separate experiments. Asterisks indicate that values are statistically different from PAF-or lysoPC-treated cells ( * ).", "type": "figure"}, "FIGREF4": {"text": "Figure 4: LysoPC and PAF stimulate PLD activity. (a) [ 14 C]choline prelabeled THP-1 cells were stimulated with lysoPC or PAF for two minutes, and [ 14 C]choline released in the medium was measured after TLC separation. (b) and (c) [ 14 C]choline prelabeled THP-1 cells were preincubated with WEB2170, SB203347, or PTX before (b) lysoPC or (c) PAF challenge. Data are expressed as means \u00b1 SD of triplicate determinations within separate experiments. Asterisks indicate that values are statistically different from PAF-or lysoPC-treated cells ( * ).", "type": "figure"}, "FIGREF5": {"text": "Figure 5: cPLA2 activity is differentially regulated by lysoPC and PAF. (a) cPLA 2 enzyme assays were done on cell lysates treated with lysoPC or PAF. (b) and (c) cPLA 2 activity was determined in lysates from THP-1 monocytes treated with different chemical inhibitors before stimulation with (b) lysoPC or (c) PAF. Data are expressed as means \u00b1 SD of duplicate determinations within separate experiments. Data shown are one representative of three independent experiments.", "type": "figure"}, "FIGREF6": {"text": "Figure 6: LysoPC-mediated [ 3 H]AA release is inhibited by the PAF-receptor antagonist WEB2170. Prelabeled THP-1 cells were preincubated with WEB2170, stimulated with (a) lysoPC (40 \u03bcM, 10 min.) or (b) PAF (35 \u03bcM, 5 min) and [ 3 H]AA release in the medium was measured by liquid scintillation counting. Data are expressed as means \u00b1 SD of triplicate determinations within separate experiments. Asterisks indicate that values are statistically different from PAF-or lysoPC-treated cells ( * ).", "type": "figure"}, "FIGREF7": {"text": "Figure 7: Proposed main molecular mechanisms of intracellular signaling mediated by (a) PAF receptor and (b) unidentified lysoPCsensitive receptor. The figure shows enzymes in bold/italic and inhibitors in small letters with the sign \"-|\".", "type": "figure"}, "TABREF0": {"text": "MTT), PTX, Triton-X100, EDTA, EGTA, PMSF, and fatty acid-free bovine serum albumin (BSA) were purchased from Sigma Chemical Co. (St. Louis, USA). Fetal calf serum was obtained from Integro b.v. (Holland) and WEB2170 from Boehringer Ingelheim (Germany). [ 3 H]AA and [ 14 C]-L-3 phosphatidylcholine, 1 stearoyl-2- arachidonyl were purchased from NEN (Boston, USA) and methyl[ 14 C]choline from Amersham LIFE SCIENCE (Buck- inghamshire, England). Biologically active PAF C:16 and methyl arachidonyl fluorophosphonate (MAFP) were pur- chased from Cayman Chemical (USA). NaOH, methanol, HCl, NaCl, NH 4 OH, 1-butanol, aluminium sheets silica gel 60 TLC plates, and chloroform were purchased from Merck (Darmstadt, Germany). L-glutamine was obtained from Gibco BRL (Life Technologies, Grand Island, NY, USA). Leupeptin and pepstatin were obtained from Roche Diag- nostics GmbH (Mannheim, Germany) and Bio-Rad reagent was from Bio-Rad Laboratories (Hercules, USA). Group IIA sPLA 2 inhibitor, SB203347, was generously donated by James Winkler, Smith Kline Beecham (Pharmaceuticals, Pa, USA).The THP-1 monocytes were when indicated differentiated with 160 nM PMA for 24 h. Differentiation from monocytes to macrophages was monitored by changes in morphology and adherent capacity. The THP-1 cell line was bought from ATCC and regularly checked for mycoplas- ma contamination.PAF for indicated concentrations and time periods in RPMI 1640 containing 1 mg/mL BSA. In experiments using antagonists and inhibitors, WEB2170 was incubated for 15 min, alcohols and MAFP for 30 min, SB203347 for 1 h, and PTX for 2 h prior to stimulation. Results are given as released [ 3 H]AA in the supernatant relative to [ 3 H]AA incorporated in the cells and are normalized to show fold induction of treated relative to untreated cells. In experi- ments with inhibitors, results are shown as percent inhibi- tion of lysoPC of PAF-induced cells. Results shown are repre- sentative of three independent experiments. 2.4. RNA Isolation. Total cellular RNA was isolated by TRIzol extraction according to the manufacturer's instructions (Gibco BRL, Life Technologies Inc., Grand Island, NY, USA)", "type": "table"}, "TABREF1": {"text": "Stimulate [ 3 H]AA Release in THP-1 Cells. We have earlier shown that lysoPC stimulates [ 3 H]AA and [ 14 C]OA release in the human-derived monocytic cell line, THP-1, mediated both by sPLA 2 and cPLA 2", "type": "table"}, "TABREF2": {"text": "Pertussis toxin MAFP: Methyl arachidonyl fluorophosphonate. inhibitor SB203347. This work was supported by a fellowship from the Norwegian University of Science and Technology no. 123641/310 (to M. W. Anthonsen), and grants from the Norwegian Public Health Programme, Project no. 1997/68 (to J. Oestvang) and 6228 (to B. Johansen).", "type": "table"}}}
{"paper_id": "2872249", "_pdf_hash": "4f4c7d71815ffdd86208f16fb5b1b57013162bbe", "abstract": [{"section": "Abstract", "text": "Background-Guidelines on patient selection for lung cancer resection identify a predicted postoperative forced expiratory volume in 1 second (ppoFEV 1 ) of <40% as a predictor of high risk. Experience with lung volume reduction surgery suggests that ppoFEV 1 may be underestimated in those with concomitant emphysema. Methods-Anatomical lobectomy was performed in 29 patients with a resectable lung cancer within a poorly perfused, hyperinflated emphysematous lobe identified by radionuclide perfusion scintigraphy and computed tomographic scanning. Perioperative changes in spirometric parameters at 3 months were compared in 14 patients (group A) of mean age 69 years (range 48-78) with ppoFEV 1 <40% (mean (SD) 31.4 (7)%) and 15 patients (group B) with ppoFEV 1 >40% (mean (SD) 47 (5)%). The correlation between predicted and actual postoperative FEV 1 was also assessed. Results-In group B there was a significant perioperative reduction in FEV 1 (p=0.01) but in group A FEV 1 did not change significantly after lobectomy (p=0.87); mean diVerence in perioperative change between groups A and B 331 ml (95% CI 150 to 510). Despite the diVerence in ppoFEV 1 between the groups, there was no diVerence in actual FEV 1 at 3 months. In-hospital mortality was 14% in group A and zero in group B, but at a median follow up of 12 (range 6-40) months there was no diVerence in survival between the groups. Conclusions-Selection for lung cancer resection in patients with emphysema using standard calculations of ppoFEV 1 may be misleading. The eVect of lobar volume reduction allows for an extension of the selection criteria. (Thorax 2001;56:791-795) Keywords: lobar volume reduction surgery; lung cancer; patient selection", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Increasing the resection rate is fundamental to improving outcome in non-small cell lung cancer (NSCLC). The suboptimal resection rate in the UK, currently around 10%, 1 2 may be partly attributed to the assessment of inoperability in the large number of patients who have both lung cancer and concomitant emphysema. Prediction of postoperative respiratory function has been found to be a predictor of pulmonary complications, 4 with a predicted postoperative forced expiratory volume in 1 second (ppoFEV 1 ) measurement of less than 40% predicted associated with an unacceptable risk of postoperative morbidity.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "5 These values have previously guided our patient selection. However, increased understanding of lung volume reduction surgery (LVRS) has shown that resection of relatively functionless emphysematous lung may actually improve lung function. We have therefore applied the principles of selection for LVRS to those patients presenting with resectable NSCLC and moderate to severe emphysema. We report our initial experience with this cohort of patients undergoing lobectomy for NSCLC who, as a result, eVectively have undergone LVRS. Our objectives were to assess whether lung function changes uniformly with lobectomy in all patients, whether the currently used predictive methods are accurate in all cases, and whether the cut oV point of 40% ppoFEV 1 is clinically binding.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "All patients were referred primarily for resection of a newly diagnosed NSCLC rather than for treatment of emphysema. Resectability was confirmed by computed tomographic (CT) scanning and, where indicated, cervical mediastinoscopy. Simple spirometric measurements of FEV 1 and forced vital capacity (FVC) were made as part of an assessment of operability. Patients did not undergo routine plethysmography.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "The preoperative COPD index 8 was derived for each patient using the following formula:", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "COPD index = FEV 1 (% predicted) + (FEV 1 /FVC (lit)) Predicted postoperative FEV 1 (ppoFEV 1 ) was also derived for each patient using the following formula estimating the number of pulmonary segments to be resected 9 : ppoFEV 1 = preoperative FEV 1 \u00d7 [1 \u2212 (b \u2212 n)]/(42 \u2212 n) where b = number of segments to be resected and n = number of obstructed segments of that lobe.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "In patients whose ppoFEV 1 was less than 60% predicted, quantitative radionuclide scintigraphy was performed to estimate the function of emphysematous areas of the lung. These were correlated with anatomical findings on the CT scan.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Lung resection was only attempted in patients with a ppoFEV 1 of less than 40% predicted if the tumour was resectable by lobectomy, the target lobe was emphysematous and contributed less than 10% of overall Thorax 2001;56:791-795 791", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "Increasing the resection rate is fundamental to improving outcome in non-small cell lung cancer (NSCLC). The suboptimal resection rate in the UK, currently around 10%, 1 2 may be partly attributed to the assessment of inoperability in the large number of patients who have both lung cancer and concomitant emphysema. 3 Prediction of postoperative respiratory function has been found to be a predictor of pulmonary complications, 4 with a predicted postoperative forced expiratory volume in 1 second (ppoFEV 1 ) measurement of less than 40% predicted associated with an unacceptable risk of postoperative morbidity. 5 These values have previously guided our patient selection. However, increased understanding of lung volume reduction surgery (LVRS) has shown that resection of relatively functionless emphysematous lung may actually improve lung function. 6 7 We have therefore applied the principles of selection for LVRS to those patients presenting with resectable NSCLC and moderate to severe emphysema. We report our initial experience with this cohort of patients undergoing lobectomy for NSCLC who, as a result, eVectively have undergone LVRS. Our objectives were to assess whether lung function changes uniformly with lobectomy in all patients, whether the currently used predictive methods are accurate in all cases, and whether the cut oV point of 40% ppoFEV 1 is clinically binding.", "cite_spans": [{"start": 317, "end": 318, "text": "3", "ref_id": "BIBREF2"}, {"start": 429, "end": 430, "text": "4", "ref_id": "BIBREF3"}, {"start": 507, "end": 508, "text": "1", "ref_id": "BIBREF0"}, {"start": 615, "end": 616, "text": "5", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Methods", "text": "All patients were referred primarily for resection of a newly diagnosed NSCLC rather than for treatment of emphysema. Resectability was confirmed by computed tomographic (CT) scanning and, where indicated, cervical mediastinoscopy. Simple spirometric measurements of FEV 1 and forced vital capacity (FVC) were made as part of an assessment of operability. Patients did not undergo routine plethysmography.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "The preoperative COPD index 8 was derived for each patient using the following formula:", "cite_spans": [{"start": 28, "end": 29, "text": "8", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Methods", "text": "Predicted postoperative FEV 1 (ppoFEV 1 ) was also derived for each patient using the following formula estimating the number of pulmonary segments to be resected 9 :", "cite_spans": [{"start": 163, "end": 164, "text": "9", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Methods", "text": "where b = number of segments to be resected and n = number of obstructed segments of that lobe.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "In patients whose ppoFEV 1 was less than 60% predicted, quantitative radionuclide scintigraphy was performed to estimate the function of emphysematous areas of the lung. These were correlated with anatomical findings on the CT scan.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "Lung resection was only attempted in patients with a ppoFEV 1 of less than 40% predicted if the tumour was resectable by lobectomy, the target lobe was emphysematous and contributed less than 10% of overall perfusion, and there was evidence of hyperinflation on radiological assessment.", "cite_spans": [], "ref_spans": []}, {"section": "PERIOPERATIVE MANAGEMENT", "text": "General anaesthesia was induced with intravenous propofol and fentanyl and maintained by a target controlled infusion of propofol. Neuromuscular blockade was maintained by intravenous vecuronium in increments as required. Ventilation was carried out via a double lumen endobronchial tube with 10 ml/kg oxygen in air. Before surgery a thoracic epidural tube was inserted between T5 and T8 and an infusion of fentanyl 5 \u00b5g/ml in bupivacaine 0.1% was commenced. During single lung ventilation, while resection was performed, tidal volumes were reduced to keep peak inflation pressures below 40 cm H 2 O and ventilation frequency was adjusted to keep end tidal carbon dioxide tensions below 6%. In the event of intraoperative arterial oxygen desaturation, oxygen was insuZated into the operative lung with the addition of continuous positive airway pressure if required. Surgical resection comprised anatomical lobectomy in all patients performed via muscle sparing posterolateral thoracotomy or by video assisted thoracoscopy 10 where possible. Systematic lymph node dissection 11 was employed and sleeve resections performed for hilar lymph node involvement of main bronchi. The endobronchial tube was removed in the operating theatre. Patients were than transferred to a high dependency unit via a recovery area, breathing spontaneously using a low volume mask delivering 40% inspired oxygen. Early postoperative mobilisation was facilitated by patient controlled epidural analgesia, early chest physiotherapy, and the early use of flutter valve drainage bags (Portex, Hythe, UK). 12 Patients were reviewed routinely at 2, 6, and 12 weeks and simple spirometric measurements of FEV 1 and FVC were performed.", "cite_spans": [{"start": 1023, "end": 1025, "text": "10", "ref_id": "BIBREF10"}, {"start": 1075, "end": 1077, "text": "11", "ref_id": "BIBREF11"}, {"start": 1580, "end": 1582, "text": "12", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "STATISTICAL ANALYSIS", "text": "The patients were arbitrarily analysed in two distinct groups: group A in whom ppoFEV 1 was less than 40% predicted and group B in whom ppoFEV 1 was greater than 40% predicted. Paired and independent sample t tests were used to compare perioperative changes in FEV 1 and diVerences between groups A and B. A Bland-Altman plot 13 was used to test the accuracy of the standard method of ppoFEV 1 calculation. Survival curves were estimated according to the Kaplan-Meier method and diVerences between groups assessed by log rank analysis. Intergroup diVerences in categorical variables were assessed by 2 analysis. The statistical software package SPSS for Windows 9.0 (SPSS Inc, Chicago, USA) was used for analysis.", "cite_spans": [{"start": 265, "end": 266, "text": "1", "ref_id": "BIBREF0"}, {"start": 326, "end": 328, "text": "13", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "PATIENT CHARACTERISTICS", "text": "There were no significant diVerences in the age/sex distributions of the two groups (table  1) . In all patients in whom radionuclide scintigraphy was performed, the tumour was situated in the zone of least perfusion. One lower lobectomy was performed and all other patients underwent upper lobectomy. Three lobectomies were performed thoracoscopically (one in group A, two in group B); all others were performed by thoracotomy including two sleeve resections (one in each group). There was no diVerence in postoperative hospital stay between the two groups. Major morbidity included respiratory complications (bronchopneumonia, empyema) which occurred in two patients in each group, and gastrointestinal perforation which occurred in two patients in group A. In-hospital mortality was higher in group A (two patients (14%) who were ventilated for postoperative bronchopneumonia). There was no diVerence in median survival. The overall pathological stage distribution was 15 patients in stage I, nine in stage II, four in stage IIIa, and one in stage IIIb (an ipsilateral satellite nodule). There was no significant diVerence in stage distribution between the two groups. All lobes removed showed histological evidence of centrilobular emphysema. Survival at 6 months was directly related to TNM stage (p=0.02) but not to preoperative FEV 1 (p=0.36). One year survival was found to be unrelated to either TNM stage (p=0.16), preoperative FEV 1 (p=0.27), or ppoFEV 1 (p=0.77).", "cite_spans": [], "ref_spans": [{"start": 84, "end": 94, "text": "(table  1)", "ref_id": "TABREF0"}]}, {"section": "PERIOPERATIVE CHANGES IN RESPIRATORY", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "FUNCTION", "text": "Overall, there was a significant perioperative decrease in FEV 1 (mean diVerence 116 ml, 95% CI 2 to 231, p=0.04; fig 1, table 2 ). In group B there was a significant perioperative group.bmj.com on May 2, 2017 -Published by http://thorax.bmj.com/ Downloaded from decrease in FEV 1 (mean diVerence 270 ml, 95% CI 170 to 380, p=0.001) and FVC (mean diVerence 440 ml, 95% CI 80 to 800, p=0.02), but not in group A where lobectomy resulted in no significant change in either FEV 1 (mean difference 60 ml, 95%CI -20 to 110) or FVC (mean diVerence 280 ml, 95% CI -140 to 700). There was a significant diVerence between groups A and B in the mean perioperative change in FEV 1 (mean diVerence 331 ml, 95% CI 150 to 510). Although there was a significantly lower mean FEV 1 in group A than in group B before surgery, at 3 months after lobectomy there was no significant diVerence in FEV 1 between the groups. There was a significant correlation between the perioperative change in FEV 1 and the preoperative COPD index (r=-0.53, p=0.01, fig 2) .", "cite_spans": [], "ref_spans": [{"start": 114, "end": 128, "text": "fig 1, table 2", "ref_id": "FIGREF0"}]}, {"section": "PREDICTION OF POSTOPERATIVE RESPIRATORY", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "FUNCTION", "text": "Predicted postoperative FEV 1 was significantly lower than the actual FEV 1 in group A (mean diVerence 10.3%, 95% CI 4.9 to 15.6, p=0.002), but there was no significant change in group B (mean diVerence -0.4%, 95% CI -3.7 to 4.5, fig 3) . A Bland-Altman plot (fig 4) shows that the mean discrepancy between actual and predicted FEV 1 was greater in group A. In only one patient in group A was the actual postoperative FEV 1 less than the ppoFEV 1 .", "cite_spans": [], "ref_spans": [{"start": 259, "end": 266, "text": "(fig 4)", "ref_id": "FIGREF2"}]}, {"section": "Discussion", "text": "We have found that lobectomy for NSCLC in patients with poor lung function secondary to emphysema is feasible. Although perioperative risk is increased, subsequent survival is not compromised. We would therefore contend that surgery is preferable to radical radiotherapy in this group of patients. Furthermore, in these patients anatomical lobectomy has been shown to have a therapeutic eVect on postoperative respiratory function.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Previous studies have also seen an improvement in pulmonary function in selected patients with severe emphysema undergoing lobectomy for lung cancer. 8 14 However, unlike our experience, there were few patients in these series with ppoFEV 1 less than 40% predicted. In a study of 13 patients a mean perioperative improvement of 3.7% was noted in predicted FEV 1 8 and a similar improvement in mean FEV 1 of 4% was found in another small series of 10 patients, 14 but again in patients with better preoperative respiratory function than ours. We have also demonstrated the use of a COPD index to predict perioperative change in FEV 1 . 8 While we are confident in attributing our demonstrated improvement to the eVects of surgery, we concede that a small proportion of the eVect is due to the optimising of medical treatment for COPD during hospitalisation. There may also be a psychological component to the eVect, secondary to increased motivation after successful removal of a lung cancer. To avoid the immediate detrimental eVects of surgery, assessment of spirometric parameters was not made before three postoperative months had elapsed. The estimation of perioperative risk in patients with respiratory dysfunction has focused on the calculation of ppoFEV 1 . 4 5 A value for ppoFEV 1 below 40% predicted has been proposed as the lower limit of acceptable risk and this is the reason for our arbitrary selection of this value to divide the patients into two groups. A hazard ratio of 1.46 for every 200 ml decrease in ppoFEV 1 below this value has been calculated. 4 The most simple method of ppoFEV 1 calculation is based on a reduction factor proportional to the number of bronchopulmonary segments to be resected. 15 However, this assumes the function of resected segments to be equivalent to the rest of the lung. It has been recognised that there is a possible source of underestimation if the tumour to be resected is obstructing the airway. A correction for this factor has been proposed. 9 In our series there were no obstructing tumours, although our calculations of predicted function did not take into account the eVect of deflation of the overexpanded thoracic cage, hence our underestimation of postoperative function in those patients with more severe emphysema. Quantitative radionuclide perfusion scintigraphy may give useful information regarding prediction of function after pneumonectomy, 16 but the information is not in suYcient anatomical detail to predict function after lobectomy.", "cite_spans": [{"start": 360, "end": 361, "text": "1", "ref_id": "BIBREF0"}, {"start": 460, "end": 462, "text": "14", "ref_id": "BIBREF14"}, {"start": 635, "end": 636, "text": "8", "ref_id": "BIBREF7"}, {"start": 1262, "end": 1263, "text": "1", "ref_id": "BIBREF0"}, {"start": 1571, "end": 1572, "text": "4", "ref_id": "BIBREF3"}, {"start": 1723, "end": 1725, "text": "15", "ref_id": "BIBREF15"}, {"start": 2002, "end": 2003, "text": "9", "ref_id": "BIBREF8"}, {"start": 2414, "end": 2416, "text": "16", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Discussion", "text": "Extrapolation of selection criteria for LVRS for emphysematous patients with concomitant lung cancer has suggested that both conditions can be treated simultaneously. In two series where malignant pulmonary nodules have been discovered during preoperative investigation for LVRS, subsequent simultaneous LVRS and contralateral lobectomy have been successful. 17 18 Furthermore, anatomical lobectomy has been used successfully for LVRS alone in patients without lung cancer. 19 The beneficial eVects on lung elastic recoil and chest wall mechanics 6 7 of resecting a hyperinflated tumour-containing lobe thus outweigh any loss of function, particularly if the lobe is poorly perfused. It is reasonable to assume that lobar LVRS would have a bilateral eVect on chest wall mechanics (and therefore a significant respiratory improvement) since some authors have found little diVerence in the comparative overall benefit of unilateral versus bilateral LVRS. 20 It is important to emphasise that in this study all patients underwent anatomical lobectomy and no patients underwent any form of sublobar \"lung shaving\" as is performed in LVRS.", "cite_spans": [{"start": 474, "end": 476, "text": "19", "ref_id": "BIBREF19"}, {"start": 953, "end": 955, "text": "20", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Discussion", "text": "The clinical implication of extending the selection criteria for lung cancer surgery is obviously an increase in the resection rate. In our unit we have operated on 14 patients with ppoFEV 1 less than 40% who would otherwise have been denied surgery. This equates to around 7% of all resections performed over this same time period. In the UK annually about 3000 resections are performed for NSCLC; thus, if our experience was applied nationally, over 200 more patients would undergo resection each year. While perioperative mortality would probably increase as a result of operating on more high risk patients, further work is required to analyse whether longer term overall survival from lung cancer would be improved. We have not found that 1 year survival from surgery in this series is worse in those with poorer preoperative lung function.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "In conclusion, consideration of fitness for surgery in lung cancer should acknowledge the eVect of lobar LVRS. Current methods of calculation may underestimate prediction of postoperative respiratory function and the cut oV point of 40% for ppoFEV 1 should not be clinically binding. Current guidelines 21 should include an acknowledgement of the eVects of surgery in heterogenous emphysema. Lung function does not change uniformly after lobectomy and these patients may even derive early benefit. Further study of durability and related health status changes is required. ", "cite_spans": [{"start": 248, "end": 249, "text": "1", "ref_id": "BIBREF0"}, {"start": 303, "end": 305, "text": "21", "ref_id": "BIBREF21"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Surgery for lung cancer", "authors": [{"first": "S", "middle": [], "last": "Fountain", "suffix": ""}], "year": 1998, "venue": "Thorax", "link": "5174896"}, "BIBREF1": {"title": "Improving surgical resection rate in lung cancer", "authors": [{"first": "C", "middle": [], "last": "Laroche", "suffix": ""}, {"first": "F", "middle": [], "last": "Wells", "suffix": ""}, {"first": "R", "middle": [], "last": "Coulden", "suffix": ""}], "year": 1998, "venue": "Thorax", "link": "2788202"}, "BIBREF2": {"title": "Clinical practice guidelines for the treatment of unresectable non-small-cell lung cancer", "authors": [{"first": "", "middle": [], "last": "Anonymous", "suffix": ""}], "year": 1997, "venue": "J Clin Oncol", "link": null}, "BIBREF3": {"title": "Assessment of operative risk in patients undergoing lung resection. 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{"paper_id": "2874050", "_pdf_hash": "0369be297ce4f27657caf7d7e12e5597a3c786ee", "abstract": [{"section": "Abstract", "text": "AbstractFor a connected graph, representing a sensor network, distributed algorithms for the Set Covering Problem can be employed to construct reasonably small subsets of the nodes, called k-SPR sets. Such a set can serve as a virtual backbone to facilitate shortest path routing, as introduced in [40] , [12] and [13] . When employed in a hierarchical fashion, together with a hybrid (partly proactive, partly reactive) strategy, the k-SPR set methods become highly scalable, resulting in guaranteed shortest path routing with comparatively little overhead.", "cite_spans": [{"start": 298, "end": 302, "text": "[40]", "ref_id": "BIBREF39"}, {"start": 305, "end": 309, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 314, "end": 318, "text": "[13]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Abstract", "text": "In this paper, we first discuss the notion of k-SPR sets, with the nodes of such a set functioning as routers for the network. These sets generalize our earlier k-SPR sets, which facilitated shortest path routing. We then introduce K-SPR sequences that are used for hierarchical routing. We propose a distributed greedy algorithm for construction of K-SPR sequences. The new sets facilitate minimal path routing, where \"minimal path\" here means \"shortest weighted path based on edge weights\".", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Finally, we introduce an efficient hybrid hierarchical routing strategy that is based on K-SPR sequences. Our approach is unique in the sense that although dominating sets have been used to construct virtual backbones in ad hoc and sensor networks, this is the first attempt to use k-hop connected k-dominating sets for hierarchical routing that is also minimal path routing.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "I. Introduction", "text": "Recent advances in micro-electro-mechanical systems (MEMS) and wireless research led to the development of sensor networks that show a lot of promise for future mobile applications [1] . Research efforts have been made to build low cost micro-sensors that possess processing capability as evidenced in the Smart Dust Project [21] , [45] , the PicoRadio Project [31] and WINS Project [32] , [47] . A large number of wireless sensor networks consist of portable mobile devices with limited battery power. In order to address this limitation, energy-efficient routing algorithms and protocols are a major focus of current research.", "cite_spans": [{"start": 181, "end": 184, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 325, "end": 329, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 332, "end": 336, "text": "[45]", "ref_id": "BIBREF44"}, {"start": 383, "end": 387, "text": "[32]", "ref_id": "BIBREF31"}], "ref_spans": []}, {"section": "I. Introduction", "text": "In our work, we model sensor networks by a connected weighted graph having bidirectional links. For the sake of simplicity, the network nodes are presumed to be identical in nature and to have the same transmission radii. Edge weights are used as a measurement of the impact on the network of using a given link. These weights will be referred to as \"costs\", and the exact details of how such costs are assigned will not be important in our discussion.", "cite_spans": [], "ref_spans": []}, {"section": "I. Introduction", "text": "It will simply be understood that the higher the cost of a link, the less desirable it is to transmit using this link. Costs might be a function of the minimal transmission energy required for the link, and/or the relative impact on the battery levels of the nodes involved in the link. The minimal transmission energy is of course a function of the proximity of the two nodes, as well as any interference. The relative impact on a node's battery energy level is additionally sensitive to the node's current battery level. Ideally, the links at a node with a weak battery should all have a high cost.", "cite_spans": [], "ref_spans": []}, {"section": "I. Introduction", "text": "Our contribution in this paper can be summarized as follows. We first discuss the notion of k-SPR sets, with the nodes of such a set functioning as routers for the network. These sets generalize our earlier k-SPR sets, which facilitated shortest path routing. We then introduce K-SPR sequences that will be used for hierarchical routing. We propose a distributed greedy algorithm for construction of K-SPR sequences. The new sets facilitate minimal path routing, where \"minimal paths\" in this paper means \"shortest weighted path based on edge weights\".", "cite_spans": [], "ref_spans": []}, {"section": "II. Our approach", "text": "Our routing strategy is based on special k-dominating sets of nodes, namely k-SPR sets, that generalize similar sets from our earlier work ( [12] , [13] , [14] , [40] , [39] ). The nodes in such a set serve as \"routers\" and play a central role in facilitating route requests. Moreover, the nature of a k-SPR set is such that this guarantees minimal path routing under reasonable assumptions.", "cite_spans": [{"start": 141, "end": 145, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 148, "end": 152, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 155, "end": 159, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 162, "end": 166, "text": "[40]", "ref_id": "BIBREF39"}, {"start": 169, "end": 173, "text": "[39]", "ref_id": "BIBREF38"}], "ref_spans": []}, {"section": "II. Our approach", "text": "k-SPR sets can be used in a hierarchical way, based on an increasing finite sequence of numbers k i , with one of these numbers corresponding to each of the levels of the hierarchy. This leads to an easily maintained and quite natural hybrid hierarchical routing strategy. It too guarantees minimal path routing. We supply detailed algorithms for forming such a hierarchy of k-SPR sets, which we call a K-SPR sequence.", "cite_spans": [], "ref_spans": []}, {"section": "II. Our approach", "text": "A reasonable choice for these numbers would be k i = k i , for some fixed integer k \u2265 2. Since the largest k i can be assumed not to exceed the diameter of G, the number of hierarchy levels in this case would be bounded by the logarithm of the diameter of G. Consequently, our hybrid routing strategy is highly scalable. Moreover, it is quite unique in its ability to also ensure minimal path routing.", "cite_spans": [], "ref_spans": []}, {"section": "III. Related work", "text": "Routing protocols for sensor networks are active areas of research and several researchers have proposed several protocols/heuristics in this regard. Here we only describe the ones that are closely related to our work.", "cite_spans": [], "ref_spans": []}, {"section": "III. Related work", "text": "Spin [17] is a flooding based protocol which has a broadcast system for data dissemination and works well for mobile sensors. It is also quite scalable and robust. The main drawback is nodes are always active and hence idle nodes consume energy.", "cite_spans": [{"start": 5, "end": 9, "text": "[17]", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "III. Related work", "text": "The directed diffusion data dissemination protocol proposed in [16] uses the sink to send out interest, which is a task description, to all sensors. Each sensor node then stores the interest entry in its cache. The interest entry contains a timestamp field and several gradient fields. As the interest is propagated throughout the sensor network, the gradients from the source back to the sink are set up. When the source has data for the interest, the source sends the data along the interest's gradient path. The interest and data propagation and aggregation are determined locally. Also, the sink must refresh and reinforce the interest when it starts to receive data from the source. Note that the directed diffusion is based on data-centric routing where the sink broadcasts the interest. The main drawbacks of this protocol are (a) the gradient setup phase is expensive and (b) it is not energy aware as the best paths might be used too often.", "cite_spans": [{"start": 63, "end": 67, "text": "[16]", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "A. Dominating-set-based routing", "text": "Since our framework for routing is based on minimum connected dominating set, we will here focus on only some of these, ones that are highly relevant to our own approach and that utilize a (k-)dominating set. The nodes in such a set provide a virtual backbone of router nodes, and in general, must be supplied with global routing information.", "cite_spans": [], "ref_spans": []}, {"section": "A. Dominating-set-based routing", "text": "The Connected Dominating Set (CDS) problem is described as follows: find a minimal subset D of nodes, such that the subgraph induced by D is connected and D is a dominating set, i.e. it is a set in which each node is either in D or adjacent to some node in D. Finding a minimum connected dominating set is known to be an NP-complete problem [15] . Several authors have proposed algorithms for obtaining approximately minimal connected dominating sets [15] .", "cite_spans": [{"start": 341, "end": 345, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 451, "end": 455, "text": "[15]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "A. Dominating-set-based routing", "text": "Span [6] is one of several ad hoc networking protocols based on the notion of a dominating set. In Span, \"coordinators\" -a group of nodes that form a connected dominating set over the network -do not sleep. Non-coordinator nodes follow a synchronized sleep/wake cycle, exchanging traffic using an algorithm based on the beaconing and traffic announcement methods of IEEE 802.11 IBSS power save. The routing protocol is integrated with the coordinator mechanism so that only coordinators forward packets, acting as a low latency routing backbone for network. Span is intended to maximize the amount of time nodes spend in the sleep state, while minimizing the impact of energy management on latency and capacity.", "cite_spans": [{"start": 5, "end": 8, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "A. Dominating-set-based routing", "text": "The algorithm of J. Wu and H. Li is a distributed algorithm [51] that is used to construct a connected dominating set in a connected graph of radius at least two. The set produced by their algorithm is used to form a virtual backbone of a wireless ad hoc network. Later, J. Wu, F. Dai, M. Gao and I. Stojmenovic [49] further extended the work of Wu and Li and proposed an algorithm for creating power aware connected dominating sets. Basically, the idea is to select nodes with higher energy level. When selecting a node in the dominating set, if there is a tie, they use the node ID to break the tie. They demonstrated that their method of selection of nodes increases the lifetime of the network.", "cite_spans": [{"start": 60, "end": 64, "text": "[51]", "ref_id": "BIBREF49"}, {"start": 312, "end": 316, "text": "[49]", "ref_id": "BIBREF47"}], "ref_spans": []}, {"section": "A. Dominating-set-based routing", "text": "In [40] , the authors generalized the Wu-Li algorithm so as to produce a k-hop connected k-dominating set that work as routers. (See Section IV for definitions.) One of the important aspect of their routing scheme was that it also guaranteed shortest path routing through the network along a path that was guaranteed at any point along the way, to encounter another router node within every k steps. Later the authors modified this algorithm and proposed a number of variations on it [12] , [13] . These were largely motivated by the following study into k-hop dominating sets.", "cite_spans": [{"start": 3, "end": 7, "text": "[40]", "ref_id": "BIBREF39"}, {"start": 484, "end": 488, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 491, "end": 495, "text": "[13]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "A. Dominating-set-based routing", "text": "In [24] , B. Liang and Z. J. Haas proposed a distributed greedy algorithm to produce a small k-dominating set. In order to do so, they reduced the problem to a special case of the Set Covering Problem. A similar but different reduction to this problem was also used in [12] . For a given value of k, though, the latter requires fewer steps than the Liang-Haas method. In addition it produces a set that is not only k-dominating, but is also k-hop connected, and has a special property to facilitate shortest path routing.", "cite_spans": [{"start": 3, "end": 7, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 269, "end": 273, "text": "[12]", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "B. Hierarchical routing", "text": "Hierarchical routing has gained special attention for sensor networks for their scalability and flexibility. Several hierarchical routing strategies for ad hoc networks based on dominating sets are discussed in [9] . In order to orchestrate hierarchical routing, various clustering algorithms have been developed for this purpose. Both deterministic and probabilistic distributed algorithms are used to construct clusters. The average communication costs in construction and maintenance of such hierarchies is shown to be logarithmic with the network size. However, all these clustering strategies do not guarantee shortest path routing.", "cite_spans": [{"start": 211, "end": 214, "text": "[9]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "B. Hierarchical routing", "text": "LEACH: Low-energy adaptive clustering hierarchy (LEACH) is a hierarchical-based protocol that minimizes energy dissipation in sensor networks [18] . The purpose of LEACH is to randomly select sensor nodes as cluster-heads, so the high energy dissipation in communicating with the base station is spread to all sensor nodes in the sensor network. Clusterhead selection is difficult to optimize in many situations.", "cite_spans": [{"start": 142, "end": 146, "text": "[18]", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "B. Hierarchical routing", "text": "PEGASIS & Hierarchical-PEGASIS: The Power-Efficient Gathering in Sensor Information Systems (PEGASIS) [27] is another hierarchical protocol that is an improvement of the LEACH protocol. As opposed to forming clusters like LEACH, PEGASIS first constructs chains consisting of sensor nodes so that each node transmits and receives from a neighbor and only one node is selected from that chain to transmit to the base station (sink). The data collected in this manner then moves from node to node, aggregated and eventually sent to the base station. The chain formation is done in a greedy way.", "cite_spans": [{"start": 102, "end": 106, "text": "[27]", "ref_id": "BIBREF27"}], "ref_spans": []}, {"section": "B. Hierarchical routing", "text": "Performance evaluation of PEGASIS indicates that it outperforms LEACH for different network sizes and topologies. However, one of the major drawback of PEGASIS is that it introduces excessive delay for distant node on the chain. Moreover, the single node acting as a leader of the chain can sometimes become a bottleneck.", "cite_spans": [], "ref_spans": []}, {"section": "B. Hierarchical routing", "text": "Hierarchical-PEGASIS [28] , which is an extension of PE-GASIS, is designed to addresses the delay incurred for packets during transmission to the base station. In order to improve the performance by reducing the delay in PE-GASIS, messages are transmitted simultaneously. There are two approaches to avoid collisions and possible signal interference among the sensors. The first one uses CDMA type signal coding techniques. The protocol with nodes having CDMA capability, constructs a chain of nodes and forms a tree like hierarchy. Each selected node in a particular level transmits data to the node in the upper level of the hierarchy. This method guarantees that data is transmitted in parallel and reduces the delay significantly. Since the tree constructed in this manner is balanced, the delay will be in O(log N ) where N is the number of nodes. The other approach (non-CDMA based) is quite different and allows only spatially separated nodes to transmit at the same time. Using this approach, a three-level hierarchy of the nodes is created first. The effects of interference is reduced by carefully scheduling simultaneous transmissions. The approach taken by PEGASIS avoids the clustering overhead of LEACH, but still requires dynamic topology adjustment since sensor's energy is not tracked. Hence every sensor must have the knowledge of its neighbor so that it knows where to route that data. So the topology needs adjustment and that can introduce significant overhead especially for networks with heavy traffic. TEEN and APTEEN: Threshold sensitive Energy Efficient sensor Network protocol (TEEN) [30] is another hierarchical protocol coupled with data centric approach that is designed to react to sudden changes in the sensing attributes such as weather conditions. The approach here is more proactive rather than reactive. This is particularly important for time-sensitive applications. The sensor network architecture is based on a hierarchical grouping where closer nodes form clusters and this process goes on the second level until base station (sink) is reached.", "cite_spans": [{"start": 21, "end": 25, "text": "[28]", "ref_id": "BIBREF28"}, {"start": 1611, "end": 1615, "text": "[30]", "ref_id": "BIBREF30"}], "ref_spans": []}, {"section": "B. Hierarchical routing", "text": "After the clusters are formed, the cluster head broadcasts the thresholds based on certain sensed attributes to the nodes. Once a node senses a value that exceeds the threshold value, it transmits data. However, TEEN is not suitable for applications where periodic data are required since the user may not get any data at all if the thresholds are not reached.", "cite_spans": [], "ref_spans": []}, {"section": "B. Hierarchical routing", "text": "The Adaptive Threshold sensitive Energy Efficient sensor Network protocol (APTEEN) [30] is a further extension of TEEN and designed to capture both periodic data collections and reacting to time-critical events. The architecture is similar to TEEN. First the base station forms the clusters. Then the cluster heads broadcast the attributes, the threshold values, and the transmission schedule to all nodes. In addition, the cluster heads also perform data aggregation. Performance evaluation of TEEN and APTEEN has indicated that they outperform LEACH [18] . The main drawbacks are the overhead and complexity of forming clusters in multiple levels, implementing threshold-based functions and dealing with attribute-based naming of queries.", "cite_spans": [{"start": 83, "end": 87, "text": "[30]", "ref_id": "BIBREF30"}, {"start": 552, "end": 556, "text": "[18]", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "IV. k-SPR sets and K-SPR sequences", "text": "The k-SPR sets to be presented are a straightforward generalization of the k-SPR sets defined in [12] (where they are called \"d-SPR sets\") and essentially introduced in [40] . The generalization is for the purpose of handling graphs that are equipped with link weights. After a discussion of k-SPR sets, sequences of such will be considered and ultimately used to facilitate hierarchical routing. Throughout this discussion, G will denote a finite connected graph representing a sensor network, with positive link weights referred to as \"costs\".", "cite_spans": [{"start": 97, "end": 101, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 169, "end": 173, "text": "[40]", "ref_id": "BIBREF39"}], "ref_spans": []}, {"section": "A. Basic definitions and a relationship between these", "text": "Given a path in G, the cost of the path is the sum of the costs of the links along the path. Given two nodes, u and v, the cost c(u, v) between these is the minimum of the costs of the paths connecting these two nodes. A path from u to v is said to be a minimal path if its cost is c(u, v). The radius of G is the largest number R \u2265 0 such that for each node u, there exists a node v satisfying c(u, v) \u2265 R. Let V denote the set of nodes of G. Let N = |V |.", "cite_spans": [], "ref_spans": []}, {"section": "A. Basic definitions and a relationship between these", "text": "Some fundamental definitions concerning subsets of V and claims about these required for the routing strategy to be described in the next section will now be presented.", "cite_spans": [], "ref_spans": []}, {"section": "A. Basic definitions and a relationship between these", "text": "Definition 1: Fix a positive number k. Fix a subset S of the set of nodes in V . (a) S is k-dominating if every node in V is within a cost k of some node in S. (b) S is k-hop connected if, given any two nodes u and v in S, there is a path in G from u to v such that the cost between consecutive elements of S along this path never exceeds k. (c) S is a k-SPR set if, given any two nodes u and v in V satisfying c(u, v) > k, there exists some node w in S such that w = u, w = v, and c(u, w) + c(w, v) = c(u, v).", "cite_spans": [], "ref_spans": []}, {"section": "A. Basic definitions and a relationship between these", "text": "The definition of a k-SPR set was formally introduced in [12] , and is a central concept in [40] as well. It essentially means that whenever two nodes are sufficiently far apart, there is certain to be at least one node from the k-SPR set lying between them along a minimal path. The three types of subsets of V are related via the following facts, which generalized [12, Theorem 1]:", "cite_spans": [{"start": 57, "end": 61, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 92, "end": 96, "text": "[40]", "ref_id": "BIBREF39"}], "ref_spans": []}, {"section": "A. Basic definitions and a relationship between these", "text": "Theorem 1: Assume that S is a k-SPR set for G. Then the following are true. (a) Given any two nodes u and v of G, there exists a minimal path connecting u to v such that the set of nodes along this path that are also in S \u222a {u, v} is k-hop connected.", "cite_spans": [], "ref_spans": []}, {"section": "A. Basic definitions and a relationship between these", "text": "Proof: The first claim will be proved by contradiction, so assume that it is false. Suppose that \u03bb \u2265 0 is as small as possible such that there exist nodes u and v with c(u, v) = \u03bb, but there is no path connecting u to v as described in part (a) of the theorem. Clearly \u03bb > k. Let p be any minimal path from u to v. So the cost of p is \u03bb. Let w be the first node along p whose cost from u exceeds k. Since c(u, w) > k, there is a node u in S, not equal to u or", "cite_spans": [], "ref_spans": []}, {"section": "A. Basic definitions and a relationship between these", "text": ", and hence c(u, v) = c(u, u ) + c(u , v), so that u must lie along a minimal path connecting u and v.", "cite_spans": [], "ref_spans": []}, {"section": "A. Basic definitions and a relationship between these", "text": "Since c(u , v) < \u03bb, by assumption there is a minimal path p from u to v, with the property described in the theorem (with u in place of u). Since u = w, c(u, u ) \u2264 k. So the concatenation of a minimal path from u to u followed by p is certainly a minimal path from u to v that has the property stated in the theorem, and so yields a contradiction. This establishes the first claim.", "cite_spans": [], "ref_spans": []}, {"section": "A. Basic definitions and a relationship between these", "text": "By choosing u and v arbitrarily from S, it now follows immediately from part (a) that S is k-hop connected. To show that it is k-dominating, consider any node x. Assuming now that G has radius exceeding k, there exists a node y with c(x, y) > k. Assume that y is as close to x as possible with this property. Since S is a k-SPR set, it contains a node z with c(x, z) + c(z, y) = c(x, y), and z is not equal to y. It follows that c(x, z) \u2264 k. Therefore, S is k-dominating.", "cite_spans": [], "ref_spans": []}, {"section": "B. Local views", "text": "When G represents an ad hoc network, [40] , [12] and [13] produce a k-SPR set to serve as a virtual backbone for routing purposes. To achieve practical distributed algorithms for finding such a k-SPR set, the following subgraphs of G need to be considered. These generalize similar subgraphs in [12] and [13] , but the terminology is altered slightly. A \"(d + 1)-local view\" there is called an \"extended d-local view\" here.", "cite_spans": [{"start": 37, "end": 41, "text": "[40]", "ref_id": "BIBREF39"}, {"start": 44, "end": 48, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 53, "end": 57, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 295, "end": 299, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 304, "end": 308, "text": "[13]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "B. Local views", "text": "Definition 2: Let v be a node of V . Let r \u2265 0. The rlocal view of v is the subgraph induced by all of the nodes within a cost r of v. The extended r-local view of v is the subgraph of G obtained by extending the r-local view of v by including also any nodes at a cost greater than r from v that are adjacent to a node in the r-local view, plus the links that realize these adjacencies.", "cite_spans": [], "ref_spans": []}, {"section": "It is", "text": "It is important for the purposes of shortest path routing to know when the cost between two nodes in some extended rlocal view agrees with the corresponding cost in the graph G as a whole. This issue is partly addressed in the first part of [12, Theorem 2] . A somewhat more general claim is the following.", "cite_spans": [{"start": 241, "end": 245, "text": "[12,", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "Lemma 1:", "text": "Next assume instead that c(v, x) + c(v, y) + c \u2264 2r. Clearly c(x, y) \u2264 c , so that this situation reduces to the prior one, and again it may be concluded that c = c(x, y).", "cite_spans": [], "ref_spans": []}, {"section": "C. A covering problem", "text": "Another common feature of the routing algorithms to be considered is that they all rely on a bipartite graph B = B(G), based on G, a portion of which is maintained in a data structure by each network node. The bipartite graph B is described as follows.", "cite_spans": [], "ref_spans": []}, {"section": "Definition 3:", "text": "The nodes of the bipartite graph B = B(G) constitute two sets V and P , each of which is an independent set in B. V is simply the set of all nodes of G. The elements of P are certain unordered pairs of nodes {x, y} of G. To describe which, first consider the setP of all such pairs satisfying c(x, y) > k. Partially orderP by taking {x , y } \u2264 {x, y} if (after possibly reordering x and y ) c(x, x ) + c(x , y ) + c(y , y) = c(x, y). (This means that x and y lie along some minimal path connecting x and y.) Now P is defined to be the subset ofP consisting of the minimal elements with respect to this partial order. The description of the bipartite graph B is completed by indicating that v \u2208 V is taken to be adjacent to {x, y} \u2208 P if and only if c(x, v) + c(v, y) = c(x, y), but v = x and v = y.", "cite_spans": [], "ref_spans": []}, {"section": "Definition 3:", "text": "When all the link costs are one, B is the same as the bipartite graph considered in [12] . The following claim is straightforward to check using Definition 2 and part (c) of", "cite_spans": [{"start": 84, "end": 88, "text": "[12]", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "Definition 3:", "text": "When this adjacency condition holds, we say that S covers P . The second part of [12, Theorem 2] may now be generalized to produce the following needed fact.", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 2: Let", "text": "e be an upper bound on the link costs of G. Suppose that u, v \u2208 V both cover the pair {x, y} \u2208 P . Then c(u, v) \u2264 k + e. Proof: 2c(u, v) \u2264 c(u, x) + c(x, v) + c(u, y) + c(y, v) = 2c(x, y). So c(u, v) \u2264 c(x, y) \u2264 k + e.", "cite_spans": [], "ref_spans": []}, {"section": "D. K-SPR sequences", "text": "The constructs presented in this subsection anticipates the hierarchical nature of the routing strategy to be introduced in the next section. Given a k-SPR set, it will be helpful to consider the following derived link-weighted graph.", "cite_spans": [], "ref_spans": []}, {"section": "Definition 4: Let S be a k-SPR set for G. Define the link-weighted graph G[S, k] as follows. The node set for the graph G[S, k] is S. Two elements u and v of S are made adjacent in G[S, k] if c(u, v) \u2264 k (in G). In this case, the link connecting u and v in G[S, k] is assigned the cost c(u, v).", "text": "By part (b) of Theorem 1, this graph is connected. Moreover, the cost between any two nodes in G[S, k] when measured in this graph agrees with the cost between them when measured in G. To accommodate a hierarchical version of k-SPR routing, this derived graph notion will now be used to introduce a generalization of the notion of a k-SPR set.", "cite_spans": [], "ref_spans": []}, {"section": "Definition 4: Let S be a k-SPR set for G. Define the link-weighted graph G[S, k] as follows. The node set for the graph G[S, k] is S. Two elements u and v of S are made adjacent in G[S, k] if c(u, v) \u2264 k (in G). In this case, the link connecting u and v in G[S, k] is assigned the cost c(u, v).", "text": "Definition 5: Fix a set of positive numbers K = {k 1 , ...., k l } with k 1 < k 2 < \u00b7 \u00b7 \u00b7 < k l . A K-SPR sequence for G is a collection S = {V 1 , ..., V l } of sets of nodes of G with the following property. Letting G 0 = G and V 0 = V , and letting", "cite_spans": [], "ref_spans": []}, {"section": "Definition 4: Let S be a k-SPR set for G. Define the link-weighted graph G[S, k] as follows. The node set for the graph G[S, k] is S. Two elements u and v of S are made adjacent in G[S, k] if c(u, v) \u2264 k (in G). In this case, the link connecting u and v in G[S, k] is assigned the cost c(u, v).", "text": ".., l, the set V i is required to be a k i -SPR set for the graph G i\u22121 , for i = 1, 2, ..., l. The following numbers will also be needed. Let r 0 = k 1 and for i > 0, let r i = k i+1 + 2k i + \u00b7 \u00b7 \u00b7 + 2k 1 .", "cite_spans": [], "ref_spans": []}, {"section": "Definition 4: Let S be a k-SPR set for G. Define the link-weighted graph G[S, k] as follows. The node set for the graph G[S, k] is S. Two elements u and v of S are made adjacent in G[S, k] if c(u, v) \u2264 k (in G). In this case, the link connecting u and v in G[S, k] is assigned the cost c(u, v).", "text": "Part (a) of Theorem 1 now generalizes as follows.", "cite_spans": [], "ref_spans": []}, {"section": "Definition 4: Let S be a k-SPR set for G. Define the link-weighted graph G[S, k] as follows. The node set for the graph G[S, k] is S. Two elements u and v of S are made adjacent in G[S, k] if c(u, v) \u2264 k (in G). In this case, the link connecting u and v in G[S, k] is assigned the cost c(u, v).", "text": "Theorem 3: Let K = {k 1 , ...., k l } be a set of positive numbers with k 1 < k 2 < \u00b7 \u00b7 \u00b7 < k l . Let S = {V 1 , ..., V l } be a K-SPR sequence for G. Given any two nodes u and v in V , there exists a minimal path p connecting u to v such that, for i = 1, 2, ..., l, the set of nodes consisting of the all the nodes along p and belonging to V", "cite_spans": [], "ref_spans": []}, {"section": "Proof:", "text": "If k = 1, then this reduces to part (a) of Theorem 1 since V 1 is by definition a k 1 -SPR set for G, and the minimal path p guaranteed by part (a) of Theorem 1 works here. u and v would be the first and last nodes along it that belong to V 0 . The argument for the general case can now be made using induction on k. To this end, fix some k > 1. We will show that the claim holds for any S of cost (size) k, assuming that it holds for shorter k-SPR sequences. Fix u, v \u2208 V . Let h be a minimal path from u to v that works as described in part (a) of Theorem 1 using V 1 for S. If h contains any nodes from V 1 , then let u and v denote the first and last such nodes, respectively. If no such nodes exist or if u = v , nothing more needs to be shown.", "cite_spans": [], "ref_spans": []}, {"section": "Proof:", "text": "Otherwise, let", "cite_spans": [], "ref_spans": []}, {"section": "Proof:", "text": ". By the induction hypothesis, applied to G 1 , there exists a minimal path in G 1 from u to v as described in Theorem 3, using the {k 2 , ..., k l }-SPR sequence {V 2 , ..., V l } in place of the K-SPR sequence S. This minimal path can be realized as a minimal path g from u to v in G by replacing each link of the minimal path in G 1 with a minimal path connecting its endpoints in G. Now define p to be the minimal path from u to v that first follows an initial portion of h from u to u , then follows g from u to v , and then follows a final portion of h from v to v. It is now straightforward to see that p fulfills the requirements of Theorem 3. The initial portion and final portion of h here each have cost at most k 1 . The fact that V i is an r i\u22121 -SPR set for G now follows by induction as well.", "cite_spans": [], "ref_spans": []}, {"section": "Proof:", "text": "E. An example Fig. 1. G and G 1 Consider the following example using k 1 = 3 and k 2 = 9. The graph on the left in Figure 1 is the original graph G. The dashed edges have cost one, while the solid edges have cost two. The dark vertices form a 3-SPR set V 1 for G. The graph on the right is then 3] . It has two types of edges. The dashed edges have cost two, while the solid edges have cost three. Here V 2 consists of the lone dark vertex in the figure. This is a 9-SPR for G 1 . Thus 9] ) would consist only of one vertex, and the process terminates. Now, in Theorem 3, consider the case where u and v are the top-left node and bottom-right node of G, respectively. There are several minimal paths connecting u and v, and we see that their cost is 15. One of these path starts at u, and repeatedly moves down one hop and then right one hop, zigzagging until arriving at v. Call this path p. Notice that it goes through the only node in V 2 , which we'll call w. Consider the claim in Theorem 3 when i = 2. The first and last nodes along p that belong to V 1 are u and v. The fact that {u, v, w} is 9-hop connected in G gives evidence in support of Theorem 3.", "cite_spans": [{"start": 295, "end": 297, "text": "3]", "ref_id": "BIBREF2"}, {"start": 486, "end": 488, "text": "9]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Proof:", "text": "Let's try a different choice for u and v, say by taking these to be the top-right node and the bottom-left node, respectively. Now the cost between u and v is only 10 and there is an evident unique minimal path connecting them. Let p now denote this path, which uses only edges of cost one, and which alternates between nodes in V 1 and nodes not in V 1 . Letting x and y denote the first and last nodes along the path that belong to V 1 , we see that c(x, y) = 8. There are no nodes from V 2 along p. So using i = 2 again, we now notice that {x, y} is 9-hop connected in G, as required.", "cite_spans": [], "ref_spans": []}, {"section": "V. Hierarchical routing via K-SPR sequences", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "A. Establishing a K-SPR sequence", "text": "Let k 0 be an upper bound on the link costs of G. Let K = {k 1 , ..., k l } be a set of positive numbers satisfying k 0 < k 1 < \u00b7 \u00b7 \u00b7 < k l . The distributed algorithms of [40] , [39] [12] and [13] , [14] can now be altered to handle graphs with weighted links. By iteratively applying such an algorithm, it then becomes straightforward to obtain a K-SPR sequence for G. Once this has been accomplished, the routing strategies described in the next section can be implemented.", "cite_spans": [{"start": 172, "end": 176, "text": "[40]", "ref_id": "BIBREF39"}, {"start": 179, "end": 183, "text": "[39]", "ref_id": "BIBREF38"}, {"start": 193, "end": 197, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 200, "end": 204, "text": "[14]", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "A. Establishing a K-SPR sequence", "text": "For example, the greedy algorithm approach in [12] is easily adapted to handle a graph with link costs, as will now be outlined. The following algorithm shows how this would proceed at level i, that is, when applied to the graph G i in order to find a k i+1 -SPR set for it. Note however that when i > 0, the processing at level i begins locally only after processing at level i \u2212 1 has completed locally. The distributed greedy algorithm used here, at each level, does not require strict synchronization though.", "cite_spans": [{"start": 46, "end": 50, "text": "[12]", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "A. Establishing a K-SPR sequence", "text": "Each node in the network has a unique ID number. Each node that becomes a level-i node (element of V i ) begins participating in the process of selecting level-(i + 1) nodes (elements of V i+1 ). Initially it is in the \"undecided\" state, but ultimately ends up in either the \"selected\" or \"not selected\" state after completing the algorithm. The selected nodes are of course the level-i nodes that are selected to become level-(i + 1) nodes, that is, the nodes of G i+1 . The distributed greedy algorithm is as follows.", "cite_spans": [], "ref_spans": []}, {"section": "Distributed greedy algorithm", "text": "Step 1: Each node v \u2208 V i gathers information about its r ilocal view of G i , which will henceforth be referred to as v's level-i view. This requires several rounds of passing local link-state information. Some nodes in this local view may still be actively participating in the greedy algorithm at a lower level. If this happens, then the level-i algorithm must stall until these nodes complete the lower level algorithms.", "cite_spans": [], "ref_spans": []}, {"section": "Distributed greedy algorithm", "text": "Step 2: v determines P v and C v , where these are defined as follows. P v denotes the set of all the nodes pairs {x, y} covered by v in the bipartite graph B. C v denotes the set of all the nodes that cover some node pair in P v . (v \u2208 C v , and by Lemma 2, v is able to \"see\" the elements of P v and C v . Actually, only a (k i+1 + k i )-local view is required for this.) v also computes its current covering number |C v | (the size of C v ).", "cite_spans": [], "ref_spans": []}, {"section": "Distributed greedy algorithm", "text": "Step 3: v multi-casts a message containing its covering number and its status (undecided, selected or not selected) to each node in C v . (Note that the first time this step is executed, v is undecided, and the last time it executes this step, it will be in one of the two decided states.)", "cite_spans": [], "ref_spans": []}, {"section": "Distributed greedy algorithm", "text": "Step 4: If v has entered one of the two decided states (selected or not selected), then it essentially terminates its participation in this algorithm (at the current level), except to help route messages between other nodes. Otherwise, if it is still undecided, then ....", "cite_spans": [], "ref_spans": []}, {"section": "Distributed greedy algorithm", "text": "Step 5: v waits until it receives messages as in Step 3 from each node in C v . For each such node u that has become decided, v removes u from C v , and if u has become selected, then v also removes any pairs from P v that u covers. Accordingly, v recomputes its covering number as necessary.", "cite_spans": [], "ref_spans": []}, {"section": "Distributed greedy algorithm", "text": "Step 6: If v's covering number is now zero, then v enters the \"not selected\" state, and loops back to Step 3. Otherwise....", "cite_spans": [], "ref_spans": []}, {"section": "Distributed greedy algorithm", "text": "Step 7: v checks to see if its own priority is the highest among all the nodes of C v . Priority here is defined to be the ordered pair (covering number, ID), lexicographically ordered (as in [19, Subsection 2.1]). If v has the highest priority, then v enters the \"selected\" state. In either case, it loops back to Step 3.", "cite_spans": [], "ref_spans": []}, {"section": "Remarks:", "text": "1. Once a selected node has terminated the greedy algorithm at level i, it can proceed to initiate its participation in the greedy algorithm at level i + 1, where it is of course initially undecided at this level.", "cite_spans": [], "ref_spans": []}, {"section": "In", "text": "Step 3, a node v is obliged to send a message to some of the nodes in its level-i view. This can be handled efficiently by means of \"optimal routing trees\" and lower level local routing. 3. It is also possible to let the ultimate number of levels be initially unspecified, perhaps until a level is reached consisting of a single node. The set K would then grow according to some formula, as new levels are constructed.", "cite_spans": [], "ref_spans": []}, {"section": "In", "text": "Other algorithms can be used in place of the greedy algorithm. For example, the probabilistic methods in [35] and [19] can easily be adapted to handle the covering problem associated with finding a k-SPR set, as opposed to the problem of just finding a k-dominating set. Also, it is possible to adapt the \"d-SPR-C method\" of [12] . Unlike the greedy algorithm, and assuming that link costs reflect transmission time delays, this algorithm completes in a time period that does not depend on the overall size of the network, but rather only depends on the maximum link cost and maximum node degree. The algorithm is as follows:", "cite_spans": [{"start": 105, "end": 109, "text": "[35]", "ref_id": "BIBREF34"}, {"start": 114, "end": 118, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 325, "end": 329, "text": "[12]", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "In", "text": "A faster algorithm", "cite_spans": [], "ref_spans": []}, {"section": "In", "text": "Step 1: Each node v gathers information about its r i -local view as in the greedy algorithm.", "cite_spans": [], "ref_spans": []}, {"section": "In", "text": "Step 2: v determines P v and C v as in the greedy algorithm.", "cite_spans": [], "ref_spans": []}, {"section": "In", "text": "Step 3: v sends its covering number |C v | to each member of C v .", "cite_spans": [], "ref_spans": []}, {"section": "In", "text": "Step 4: If v observes that there is a pair {x, y} \u2208 P v such that v has the highest priority (see Step 7 of the greedy algorithm) among all the nodes that cover {x, y}, then v becomes \"selected\". Otherwise, it becomes \"unselected\".", "cite_spans": [], "ref_spans": []}, {"section": "In", "text": "This algorithm clearly terminates after the four steps, and produces a k i+1 -SPR set by Theorem 3. In general though, this set is substantially bigger than the one produced by the greedy algorithm.", "cite_spans": [], "ref_spans": []}, {"section": "B. Local unicast routing at a given level", "text": "Once a K-SPR sequence has been established up to some level, say i, it is possible for a level-i node v to efficiently route a message to another level-i node u within its level-i view, as follows. Recall that if j < i, a level-i node is also a level-j node. Now v can easily discover a minimal path in the level-i view connecting it to u. Let u i\u22121 denote the first node on this minimal path after v. Since c(v, u i\u22121 ) \u2264 k i , the node u i\u22121 is visible to v in its level-(i \u2212 1) view. It can then find a minimal path connecting itself to u i\u22121 at this level. Let u i\u22122 be the node after v on this minimal path. And so forth, down to level zero.", "cite_spans": [], "ref_spans": []}, {"section": "B. Local unicast routing at a given level", "text": "Letting u i = u, v can append the sequence {u j } i j=1 as routing information to the message, before sending it to its neighbor (in G) u 0 . The level-zero views of the nodes along the way now aid to easily route the message to u 1 . By similar reasoning, requiring both level-one and levelzero views, the message can then delivered to u 2 . And so forth, until it ultimately arrives at u. Moreover, the path (in G) used to route the message from v to u is guaranteed to be a minimal path.", "cite_spans": [], "ref_spans": []}, {"section": "C. Special multicasting to routers", "text": "We now consider a very specific multicasting problem for a network with an established K-SPR sequence. This will be employed for both the proactive and reactive aspects of the hybrid routing scheme proposed in the next subsection. We will need the following definition and lemma. Thus a level-i router for v is a level-i node such that any shortest path connecting it to v contains no other level-i nodes.", "cite_spans": [], "ref_spans": []}, {"section": "Proof:", "text": "The claim can be seen by induction on i. Since the levelone nodes form a k 1 -SPR set, it clear that if v 1 is a level-one router for v, then c(v, v 1 ) \u2264 k 1 . Consider next a level-two router v 2 for v. Along a minimal path from v to v 2 , a level-one node v 1 (other than v 2 ) might occur. By altering the minimal path if necessary, it may be assumed that v 1 is a level-one router for v. Besides v 2 , the path cannot contain any other level-two nodes. But v 1 and v 2 and both in the graph G[V 1 , k 1 ] for which V 2 is a k 2 -SPR set. Here V 1 and V 2 denote the sets of level-one and level-two sets, respectively. Thus, c(", "cite_spans": [], "ref_spans": []}, {"section": "Proof:", "text": "And so forth.", "cite_spans": [], "ref_spans": []}, {"section": "Proof:", "text": "The goal now is to allow v to send a message to all of its routers, at all levels. In fact, this goal will be accomplished in such a way that forwarded messages always move along minimal paths, moving away from the source node v. Moreover, there will be no redundancy in the message forwarding, in the sense that no node will receive more than one copy of the message. That is, the message will move along a tree rooted at v, and each path from v in this tree will be a minimal path. This sort of \"multicasting to routers\" will provide a basis for the hybrid routing scheme described in the next subsection.", "cite_spans": [], "ref_spans": []}, {"section": "Proof:", "text": "To manage the proposed multicasting, it is necessary for a level-i router v i for v that receives the message along a given minimal path, to decide to which of the level-(i + 1) routers for v it must forward the message. As a technical detail, in order for v i to make this decision, it will be necessary that a list of all the level-i routers for v, along with their costs from v, be included in the header of the message that v i receives. Under reasonable conditions, this list will not be large. Before v i forwards the message to level-(i+1) the routers, it will likewise be necessary for it to append a list of all the level-(i + 1) routers for v, and their costs from v. However, the level-i router information can be removed from the header at this point. Now v i is within a cost k 1 + \u00b7 \u00b7 \u00b7 + k i of v, as are all of the level-i routers for v. Moreover, v i has received a list of these together with their costs from v. Let u denote one such level-i router. Consider a level-(i + 1) node w within a cost k i+1 of u. Such a node is potentially a level-(i + 1) router for v, and all level-(i+1) routers for v fit this description for some u. Now, with w fixed, it turns out that v i is able to determine which level-i routers u lie along a minimal path in G connecting v to w. In the first place, w is in the leveli view of v i , which can be seen by considering a shortest possible path from v i to v, and then to u, and then to w. The cost of this does not exceed r i , so c(v i , w) \u2264 r i . Also, c(v i , u) \u2264 2(k 1 + \u00b7 \u00b7 \u00b7 + k i ) and c(u, w) \u2264 k i+1 . It follows by Lemma 2 that v i is able to correctly compute c(u, w), using its level-i view (of level-i nodes within a cost r i ). It is now straightforward to see that v i is able to determine whether or not w is a level-(i + 1) router for v. If it is, then v i is also able to determine any level-i routers for v that lie along a minimal path connecting v and w.", "cite_spans": [], "ref_spans": []}, {"section": "Proof:", "text": "There is one last detail. In order to avoid redundant messages, for each level-(i + 1) router v i+1 for v, exactly one of the level-i routers for v lying between v and v i+1 along a minimal path should be selected to forward the message to v i+1 . Each of these routers is aware of the others and so some criterion can be used that they will all agree on in order to make the selection. For example, this decision could be made by using a simple criterion such as choosing the level-i router for v with the largest ID.", "cite_spans": [], "ref_spans": []}, {"section": "D. A hybrid hierarchical routing strategy", "text": "The routing strategy that will be developed here has the following theorem as its foundation. ", "cite_spans": [], "ref_spans": []}, {"section": "Proof:", "text": "Let i be as large as possible such that c(u, v) > k i . Some minimal path connecting u and v must contain a level-i node. By altering the initial and terminal portions of this path as necessary, it is straightforward to see that some minimal path connecting u and v must contain a level-i router u i for u as well as a level-i router", "cite_spans": [], "ref_spans": []}, {"section": "Proof:", "text": "During the process of establishing a K-SPR sequence in a sensor network, say by the greedy algorithm method, it is easy to arrange for each node v to be known to all of the nodes within a cost k 1 , as well as all of the level-one nodes that are within a cost k 2 of a level-one node that is within a cost k 1 of v, as well as all of the level-two nodes that are within a cost k 3 of a level-two node that is within a cost k 2 of a level-one node that is within a cost k 1 of v, and so forth. In fact, this does not require any additional messages, but rather only the inclusion of more information in the already required selection overhead messages.", "cite_spans": [], "ref_spans": []}, {"section": "Proof:", "text": "It j = 1, ..., i) . In addition, all level-i nodes within a cost k i+1 of one of the level-i routers v i of v will be made aware of v, and we may assume that these too have been provided with routing information to v. If the network is allowed to change dynamically, then any new node that joins the network later would be obliged to announce itself to its routers and to each level-i node within a cost k i+1 of one of its level-i routers. This could be managed using a variation of the multicasting to routers method discussed in the previous subsection. Now, after establishing the K-SPR sequence and the above routing information, suppose that a node u has a need to contact a node v, say to establish a virtual circuit in order to conduct an extended conversation with v. Suppose too that u is currently unaware of where v is in the network, and so has no routing information concerning it, other than the ID number of v or some other identifier such as a unique name. In particular, this would mean that c(u, v) > k 1 = r 0 .", "cite_spans": [], "ref_spans": []}, {"section": "Proof:", "text": "As a result of Theorem 3 and the assumptions we are making about the local information maintained by each node, at each level, the node u is able to find the node v as follows. u multicasts a request message to its routers, as described in the previous subsection. Eventually some node receiving the request will know about the existence of v, and will know a shortest path to it. This node can then reply by relaying this information back to u along with the information that describes a minimal path from itself to u. It does not need to forward the message to higher level routers. In this way, u learns a path to v, as well as its cost. At least one of the paths thus discovered will be a minimal path from u to v.", "cite_spans": [], "ref_spans": []}, {"section": "Proof:", "text": "Point-to-point communication between u and v can now be effected via routing information placed in the header. However, this only needs to involve a sequence u = u 0 , u 1 , \u00b7 \u00b7 \u00b7 u i , v i , \u00b7 \u00b7 \u00b7 v 1 , v 0 = v of nodes, where u j and v j are level-j routers for u and v, respectively (j = 1, ..., i) and c(u i , v i ) \u2264 k i+1 . The routing between these nodes can be managed by means of the appropriate local views of the various nodes along the way.", "cite_spans": [], "ref_spans": []}, {"section": "VI. Conclusion", "text": "In this paper, we first discuss the notion of k-SPR sets, with the nodes of such a set functioning as routers for the network. These sets generalize our earlier k-SPR sets, which facilitated shortest path routing. We then introduce k-SPR sequences that are used for hierarchical routing. We propose a distributed greedy algorithm for construction of k-SPR sequences. The new sets facilitate minimal path routing, where \"minimal paths\" here means \"shortest weighted path based on edge weights\".", "cite_spans": [], "ref_spans": []}, {"section": "VI. Conclusion", "text": "Finally, we introduce an efficient hybrid hierarchical routing strategy that is based on our approach of building k-SPR sequences. When the k-SPR sequence used consists of successive power of a fixed base (a reasonable choice), then the number of levels in the hierarchy is logarithmic dependent on the diameter of the network graph. This makes the strategy highly scalable. Our approach is unique in the sense that although dominating sets have been used to construct virtual backbones in ad hoc and sensor networks, this is the first attempt to use k-hop connected k-dominating sets for hierarchical routing that is also minimal path routing.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Wireless Sensor Networks: A Survey", "authors": [{"first": "I", "middle": ["F"], "last": "Akyildiz", "suffix": ""}, {"first": "W", "middle": [], "last": "Su", "suffix": ""}, {"first": "Y", "middle": [], "last": "Sankarasubramaniam", "suffix": ""}, {"first": "E", "middle": [], "last": "Cayirci", "suffix": ""}], "year": 2002, "venue": "Computer Networks", "link": "1230643"}, "BIBREF1": {"title": "New Distributed Algorithm for Connected Dominating Set in Wireless Ad Hoc Networks", "authors": [{"first": "K", "middle": ["M"], "last": "Alzoubi", "suffix": ""}, {"first": "P", "middle": [], "last": "Wan", "suffix": ""}, {"first": "O", "middle": [], "last": "Frieder", "suffix": ""}], "year": 2002, "venue": "Proc. 35th Hawaii Int. 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For i \u2265 1, a level-i node v i will be called a level-i router for v if the only level-i node u satisfying c(v, u)+c(u, v i ) = c(v, v i ) is u = v i .", "type": "figure"}, "FIGREF1": {"text": "Given any two nodes u and v, there exists a minimal path p connecting u and v, and a positive integer i, such that p contains a level-i router u i for u and a level-i router v i for v with c(", "type": "figure"}}}
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{"paper_id": "2875307", "_pdf_hash": "5651d966cb7055fd283a40d5077d7fb1a8f0f62d", "abstract": [], "body_text": [{"section": "INTRODUCTION", "text": "The replication of retroviruses and retrotransposons is inhibited by a diverse family of type I IFN-stimulated gene products commonly called restriction factors (Harris et al., 2012; Malim & Bieniasz, 2012; Zheng et al., 2012) . The replication of human immunodeficiency virus type 1 (HIV-1) is reduced by IFN treatment of cells in vitro (Ho et al., 1985; Yamamoto et al., 1986) and in vivo (Skillman et al., 1996) . At least some of the restriction factors that mediate the IFN-induced restriction of HIV-1 have been uncovered. For instance, the IFN-induced transmembrane proteins 2 and 3 (IFITM2 and IFITM3) can affect the entry or immediate post-entry steps of HIV-1 replication (Lu et al., 2011) . If the virus reaches the cytoplasm, it can then be inhibited by myxovirus resistance protein 2 (Mx2, also called MxB) (Goujon et al., 2013; Kane et al., 2013) . Mx2 binds capsid (CA) proteins that are part of the 'intact' (not-yet-disassembled) HIV-1 core and interferes with core disassembly (uncoating) Liu et al., 2013) . TRIM5a (tripartite motif protein 5, isoform a) is another IFN-inducible factor that intercepts incoming retroviruses in the cytoplasm of infected cells (Stremlau et al., 2004) . Restriction is host-and virus-specific, and HIV-1 is generally insensitive to human TRIM5a, as its CA is not recognized by the human version of the protein (Hatziioannou et al., 2004; Keckesova et al., 2004; Sebastian & Luban, 2005; Stremlau et al., 2004 Stremlau et al., , 2006 Yap et al., 2004) . However, HIV-1 is efficiently inhibited by TRIM5a expressed in several monkey species (up to~100-fold in single-cycle assays), including macaques and the African green monkey (Hatziioannou et al., 2003) . TRIM5a belongs to the tripartite motif (TRIM) family of proteins -a very large family (close to 100 members) of ubiquitin ligases that function in various pathways, including antiviral defence (Han et al., 2011; Reymond et al., 2001) . TRIM proteins contain, starting at the N-terminal domain, a RING domain, one or two B-boxes and a coiled-coil domain. Most of them also have an additional functional domain at the C terminus (Sardiello et al., 2008) ; in the case of TRIM5a, this additional domain is a PRYSPRY motif, also called SPRY or B30.2 (Song et al., 2005) . The PRYSPRY domain is responsible for the specificity of restriction, by mediating direct interactions with surface patches present in the N-terminal region of retroviral CA proteins (Biris et al., 2013; Sebastian & Luban, 2005; Yang et al., 2014) . In several independent instances, retrotransposition events have led to the insertion of the cyclophilin A (CypA)-coding sequence into the trim5 locus of New World or Old World primate species, leading to the expression of various TRIMCyp hybrid proteins. TRIMCyp expressed in the owl monkey (Aotus trivirgatus; omkTRIMCyp) very efficiently decreases HIV-1 infectivity (~100-to 500-fold in single-cycle assays) Sayah et al., 2004) . Amongst the other TRIMCyp hybrid proteins discovered, those expressed in pig-tailed macaques (Macaca nemestrina) and in some rhesus macaques (Macaca mulatta) do not restrict HIV-1, but target other lentiviruses such as HIV-2 (Brennan et al., 2008; Newman et al., 2008; Virgen et al., 2008; Wilson et al., 2008) .", "cite_spans": [{"start": 161, "end": 182, "text": "(Harris et al., 2012;", "ref_id": "BIBREF31"}, {"start": 183, "end": 206, "text": "Malim & Bieniasz, 2012;", "ref_id": "BIBREF55"}, {"start": 207, "end": 226, "text": "Zheng et al., 2012)", "ref_id": "BIBREF91"}, {"start": 338, "end": 355, "text": "(Ho et al., 1985;", "ref_id": "BIBREF37"}, {"start": 391, "end": 414, "text": "(Skillman et al., 1996)", "ref_id": "BIBREF76"}, {"start": 682, "end": 699, "text": "(Lu et al., 2011)", "ref_id": "BIBREF51"}, {"start": 820, "end": 841, "text": "(Goujon et al., 2013;", "ref_id": "BIBREF29"}, {"start": 842, "end": 860, "text": "Kane et al., 2013)", "ref_id": "BIBREF45"}, {"start": 1389, "end": 1412, "text": "Keckesova et al., 2004;", "ref_id": "BIBREF46"}, {"start": 1413, "end": 1437, "text": "Sebastian & Luban, 2005;", "ref_id": "BIBREF74"}, {"start": 1460, "end": 1483, "text": "Stremlau et al., , 2006", "ref_id": "BIBREF80"}, {"start": 1484, "end": 1501, "text": "Yap et al., 2004)", "ref_id": "BIBREF89"}, {"start": 1679, "end": 1706, "text": "(Hatziioannou et al., 2003)", "ref_id": "BIBREF81"}, {"start": 1902, "end": 1920, "text": "(Han et al., 2011;", "ref_id": "BIBREF30"}, {"start": 1921, "end": 1942, "text": "Reymond et al., 2001)", "ref_id": "BIBREF68"}, {"start": 2136, "end": 2160, "text": "(Sardiello et al., 2008)", "ref_id": "BIBREF69"}, {"start": 2255, "end": 2274, "text": "(Song et al., 2005)", "ref_id": "BIBREF77"}, {"start": 2481, "end": 2505, "text": "Sebastian & Luban, 2005;", "ref_id": "BIBREF74"}, {"start": 2506, "end": 2524, "text": "Yang et al., 2014)", "ref_id": "BIBREF88"}, {"start": 3185, "end": 3207, "text": "(Brennan et al., 2008;", "ref_id": "BIBREF11"}, {"start": 3208, "end": 3228, "text": "Newman et al., 2008;", "ref_id": "BIBREF61"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "Restriction of HIV-1 by omkTRIMCyp seems to occur by a mechanism similar to that of TRIM5a and is initiated by the direct binding of the CypA domain of TRIMCyp to CA proteins that are part of incoming cores (Black & Aiken, 2010; Price et al., 2009; Shi et al., 2013) . This interaction occurs relatively quickly, within 1 h following virus entry into the cytoplasm (Hulme et al., 2011) , and results in the destabilization of the retroviral core -a process sometimes referred to as premature decapsidation (B\u00e9rub\u00e9 et al., 2007; Diaz-Griffero et al., 2006b , 2007 . Overexpression of omkTRIMCyp in human cells results in an HIV-1 inhibition as potent as that observed in owl monkey cell lines such as owl monkey kidney (OMK) cells, showing that the HIV-1 restriction-null endogenous human TRIM5a does not interfere with restriction in this context (Berthoux et al., 2005a) . Interestingly, TRIM5 proteins are expressed at very low levels endogenously in the absence of IFN (Carthagena et al., 2008) , as illustrated by the difficulty in detecting them by immunoblotting or immunofluorescence microscopy. Moreover, restriction by TRIM5a or TRIMCyp involves their aggregation or multimerization on the targeted retroviral core, as seen in various imaging studies (Campbell et al., 2008; Ganser-Pornillos et al., 2011; Zhao et al., 2011) . Taken together, these observations raise an intriguing question: how can a sparsely expressed restriction factor quickly and efficiently intercept incoming retroviral cores in a process that may require hundreds or thousands of TRIM5 molecules? To address this question, we have hypothesized that TRIM5 proteins associate with cytoskeleton components used by retroviruses for their transport toward the nucleus, which would dramatically enhance the probability of successful interception. omkTRIMCyp, like TRIM5a, forms cytoplasmic bodies (CBs) whose sizes are dependent on expression levels (Perez-Caballero et al., 2005) . TRIM5a CBs co-localize with ubiquitin (Campbell et al., 2008) and proteasomal subunits (Danielson et al., 2012; Lukic et al., 2011) , which supports a functional role for CBs as the proteasome is involved in TRIM5a-mediated restriction . However, CBs and proteasome were found to be dispensable for HIV-1 restriction by omkTRIMCyp (PerezCaballero et al., 2005) , pointing to the possibility of differences between the precise mechanisms of action for these two restriction factors. TRIM5a CBs associate with microtubules (MTs) and their movements along these filaments have been reported (Campbell et al., 2007) . HIV-1 and other viruses are thought to recruit dynein motor complexes translocating on MTs for their retrograde transport (toward the nucleus) (reviewed by Dodding & Way, 2011; Hsieh et al., 2010; Mouland & Milev, 2012) . In a previous report, we showed that restriction of HIV-1 and N-tropic murine leukemia virus (N-MLV) by TRIM5a could be significantly attenuated by pharmacological treatments that affect the integrity and dynamics of MTs (Pawlica et al., 2014) . TRIM5a-mediated restriction was also inhibited by pharmacological or RNA interferencemediated disruption of dynein complexes (Pawlica et al., 2014) . Owing to the reported differences between TRIM5a and omkTRIMCyp in restricting HIV-1, we investigated whether the MT network and dynein complexes were relevant to omkTRIMCyp-mediated restriction.", "cite_spans": [{"start": 207, "end": 228, "text": "(Black & Aiken, 2010;", "ref_id": "BIBREF10"}, {"start": 229, "end": 248, "text": "Price et al., 2009;", "ref_id": "BIBREF67"}, {"start": 249, "end": 266, "text": "Shi et al., 2013)", "ref_id": "BIBREF75"}, {"start": 365, "end": 385, "text": "(Hulme et al., 2011)", "ref_id": "BIBREF42"}, {"start": 528, "end": 555, "text": "Diaz-Griffero et al., 2006b", "ref_id": "BIBREF22"}, {"start": 556, "end": 562, "text": ", 2007", "ref_id": "BIBREF24"}, {"start": 972, "end": 997, "text": "(Carthagena et al., 2008)", "ref_id": "BIBREF18"}, {"start": 1284, "end": 1314, "text": "Ganser-Pornillos et al., 2011;", "ref_id": "BIBREF27"}, {"start": 1315, "end": 1333, "text": "Zhao et al., 2011)", "ref_id": "BIBREF90"}, {"start": 1928, "end": 1958, "text": "(Perez-Caballero et al., 2005)", "ref_id": "BIBREF66"}, {"start": 2048, "end": 2072, "text": "(Danielson et al., 2012;", "ref_id": "BIBREF19"}, {"start": 2073, "end": 2092, "text": "Lukic et al., 2011)", "ref_id": "BIBREF53"}, {"start": 2549, "end": 2572, "text": "(Campbell et al., 2007)", "ref_id": "BIBREF14"}, {"start": 2731, "end": 2751, "text": "Dodding & Way, 2011;", "ref_id": "BIBREF25"}, {"start": 2752, "end": 2771, "text": "Hsieh et al., 2010;", "ref_id": "BIBREF41"}, {"start": 2772, "end": 2794, "text": "Mouland & Milev, 2012)", "ref_id": "BIBREF59"}, {"start": 3018, "end": 3040, "text": "(Pawlica et al., 2014)", "ref_id": "BIBREF63"}, {"start": 3168, "end": 3190, "text": "(Pawlica et al., 2014)", "ref_id": "BIBREF63"}], "ref_spans": []}, {"section": "RESULTS", "text": "Size and localization of TRIMCyp CBs are modulated by MTs and cytoplasmic dynein Previously, we showed that treatment of HeLa cells with nocodazole -a drug that inhibits MT polymerization (Luduena & Roach, 1991) -increased the size of TRIM5a CBs and caused them to localize closer to the nucleus, on average (Pawlica et al., 2014) . Depleting dynein heavy chain (DHC) also caused TRIM5a CBs to be larger and they were found to localize closer to the plasma membrane, on average (Pawlica et al., 2014) . We used the same approach to analyse the effect of these two interventions on omkTRIMCyp CBs. HeLa cells stably expressing omkTRIMCyp or transduced with the empty vector were stained with a monoclonal anti-FLAG antibody. Cells were treated with nocodazole at a concentration (2 mM) previously determined to result in efficient MT disassembly (Pawlica et al., 2014) or left untreated (Fig. 1a) . Alternatively, cells were transfected with a DHC small interfering RNA (siRNA) under conditions leading to an~85 % decrease in DHC protein expression levels (Pawlica et al., 2014) or were transfected with a control (luciferasetargeting) siRNA (Fig. 1b) . No staining was detected in the empty vector-transduced cells under the conditions used (Fig. 1a, b) . The size of omkTRIMCyp CBs, as represented by the area on the two-dimensional images recorded, was calculated, along with their relative localization, as described previously (Pawlica et al., 2014) . In the absence of drug and in the cells transfected with the luciferase-targeting siRNA, omkTRIMCyp CBs had a median area of~0.12 mm 2 , whilst the mean area was 0.13 mm 2 (Fig. 1c) . Treatment with nocodazole increased the median and mean size of CBs by 16.7 and 20.3 %, respectively (Fig. 1c, left panel) . DHC depletion increased the median size of omkTRIMCyp by 16.7 %, but had a bigger effect on their mean size, compared with the control siRNA (a 67.0 % increase, indicating that the effect was much more pronounced on a minority of CBs). The effect was significant in both experiments (P50.01 and P50.002, respectively), showing that the dynamics of TRIMCyp bodies are affected by treatments that disrupt MTs or interfere with cytoplasmic dynein function, similar to TRIM5a (Diaz-Griffero et al., 2006a; Pawlica et al., 2014) .", "cite_spans": [{"start": 188, "end": 211, "text": "(Luduena & Roach, 1991)", "ref_id": "BIBREF52"}, {"start": 308, "end": 330, "text": "(Pawlica et al., 2014)", "ref_id": "BIBREF63"}, {"start": 478, "end": 500, "text": "(Pawlica et al., 2014)", "ref_id": "BIBREF63"}, {"start": 845, "end": 867, "text": "(Pawlica et al., 2014)", "ref_id": "BIBREF63"}, {"start": 1055, "end": 1077, "text": "(Pawlica et al., 2014)", "ref_id": "BIBREF63"}, {"start": 1431, "end": 1453, "text": "(Pawlica et al., 2014)", "ref_id": "BIBREF63"}, {"start": 2237, "end": 2266, "text": "(Diaz-Griffero et al., 2006a;", "ref_id": "BIBREF21"}, {"start": 2267, "end": 2288, "text": "Pawlica et al., 2014)", "ref_id": "BIBREF63"}], "ref_spans": [{"start": 886, "end": 895, "text": "(Fig. 1a)", "ref_id": "FIGREF0"}, {"start": 1141, "end": 1150, "text": "(Fig. 1b)", "ref_id": "FIGREF0"}, {"start": 1241, "end": 1253, "text": "(Fig. 1a, b)", "ref_id": "FIGREF0"}, {"start": 1628, "end": 1637, "text": "(Fig. 1c)", "ref_id": "FIGREF0"}, {"start": 1741, "end": 1762, "text": "(Fig. 1c, left panel)", "ref_id": "FIGREF0"}]}, {"section": "RESULTS", "text": "The relative intracytoplasmic position of omkTRIMCyp CBs was determined according to their closest distance to the nuclear membrane and the cytoplasmic membrane (Pawlica et al., 2014) . Treatment with nocodazole caused omkTRIMCyp CBs to localize closer to the nucleus, relative to the untreated control (Fig. 1d, left panel) . This effect was highly significant (P50.001) and mirrored our previous observations with TRIM5a (Pawlica et al., 2014) . In contrast, DHC depletion had no significant effect on omkTRIMCyp relative localization (Fig. 1c, right panel) . This stands in contrast to what was observed with TRIM5a CBs, which were found to be closer to the cell's edge upon DHC depletion (Pawlica et al., 2014) . Altogether, results in Fig. 1 show that the dynamics of omkTRIMCyp are sensitive to perturbation of MTs and cytoplasmic dynein, but the specific effects are different from what is observed with TRIM5a, hinting at differences in their interactions with the cytoskeleton.", "cite_spans": [{"start": 161, "end": 183, "text": "(Pawlica et al., 2014)", "ref_id": "BIBREF63"}, {"start": 423, "end": 445, "text": "(Pawlica et al., 2014)", "ref_id": "BIBREF63"}, {"start": 692, "end": 714, "text": "(Pawlica et al., 2014)", "ref_id": "BIBREF63"}], "ref_spans": [{"start": 303, "end": 324, "text": "(Fig. 1d, left panel)", "ref_id": "FIGREF0"}, {"start": 537, "end": 559, "text": "(Fig. 1c, right panel)", "ref_id": "FIGREF0"}, {"start": 740, "end": 746, "text": "Fig. 1", "ref_id": "FIGREF0"}]}, {"section": "Nocodazole and paclitaxel partially rescue HIV-1 from restriction by omkTRIMCyp in HeLa cells", "text": "The fact that nocodazole treatment altered the dynamics of omkTRIMCyp CBs prompted us to analyse whether disrupting MTs would affect restriction. In addition to nocodazole, we also tested the effect of paclitaxel -a drug that prevents the disassembly of MTs (Jordan et al., 1992; Schiff et al., 1979) . HeLa cells stably expressing omkTRIMCyp or transduced with the parental construct were treated with two different concentrations of nocodazole (Fig. 2a) or paclitaxel ( Fig. 2b ) and then infected with increasing amounts of an HIV-1 vector, HIV-1 CMV-GFP . We previously showed that nocodazole and paclitaxel at these concentrations had the expected effects on the MT network in HeLa cells and were not strongly cytotoxic (Pawlica et al., 2014) . In the absence of drug, HIV-1 CMV-GFP was restricted 300-to 400-fold by omkTRIMCyp (Fig. 2a, b) , which is comparable with previous observations (B\u00e9rub\u00e9 et al., 2007) . Nocodazole increased infectivity of HIV-1 CMV-GFP in HeLa cells expressing omkTRIMCyp by~50-fold, whilst only slightly increasing infectivity in the permissive cells transduced with the empty vector (Fig. 2a) . Thus, nocodazole counteracted omkTRIMCyp-mediated restriction, and this effect was seen at all virus doses tested and at both drug concentrations. Likewise, paclitaxel increased HIV-1 CMV-GFP infectivity by~30-fold in HeLa cells expressing omkTRIMCyp, whilst slightly decreasing infectivity in the empty vector-transduced control cells (Fig.  2b ). In the reciprocal experiment, we infected the same cell lines with HIV-1 CMV-GFP in the presence of increasing nocodazole concentrations and using fixed virus doses. Nocodazole increased infectivity in HeLa-omkTRIMCyp cells by up to~80-fold, compared with the untreated control, and this effect was observed at a wide range of nocodazole concentrations ( Fig. 2c ; see non-normalized data in Fig. S1a , b, available in the online Supplementary Material). As before, nocodazole slightly increased HIV-1 CMV-GFP infectivity in the control cells, by up to about twofold at 1 mM (Fig. 2c ). We performed a similar experiment with increasing concentrations of paclitaxel and fixed virus doses. Paclitaxel treatment increased HIV-1 CMV-GFP infectivity in omkTRIMCyp-expressing cells by up to 15-fold compared with the untreated control ( Fig.  2d ; see non-normalized data in Fig. S1d ). The magnitude of this effect was identical at all the drug concentrations tested. In contrast, paclitaxel decreased HIV-1 CMV-GFP infectivity in the empty vector-transduced control cells by up to 2.5-fold ( Fig. 2d ; see non-normalized data in Fig. S1c ). If the effect of nocodazole and paclitaxel was calculated relative to the effect seen in treated control vector-transduced cells, rather than relative to the untreated control, then both drugs were found to stimulate infectivity by roughly the same magnitude,~50-fold. This observation mirrored previously published findings that nocodazole and paclitaxel both rescue N-MLV and HIV-1 from restriction by endogenous human TRIM5a and exogenous rhesus TRIM5a, respectively, in HeLa cells, and the effects of the two drugs were also of similar magnitude (Pawlica et al., 2014) .", "cite_spans": [{"start": 258, "end": 279, "text": "(Jordan et al., 1992;", "ref_id": "BIBREF44"}, {"start": 280, "end": 300, "text": "Schiff et al., 1979)", "ref_id": "BIBREF72"}, {"start": 725, "end": 747, "text": "(Pawlica et al., 2014)", "ref_id": "BIBREF63"}, {"start": 3167, "end": 3189, "text": "(Pawlica et al., 2014)", "ref_id": "BIBREF63"}], "ref_spans": [{"start": 446, "end": 455, "text": "(Fig. 2a)", "ref_id": "FIGREF1"}, {"start": 472, "end": 479, "text": "Fig. 2b", "ref_id": "FIGREF1"}, {"start": 833, "end": 845, "text": "(Fig. 2a, b)", "ref_id": "FIGREF1"}, {"start": 1118, "end": 1127, "text": "(Fig. 2a)", "ref_id": "FIGREF1"}, {"start": 1466, "end": 1475, "text": "(Fig.  2b", "ref_id": "FIGREF1"}, {"start": 1834, "end": 1841, "text": "Fig. 2c", "ref_id": "FIGREF1"}, {"start": 1871, "end": 1879, "text": "Fig. S1a", "ref_id": "FIGREF0"}, {"start": 2054, "end": 2062, "text": "(Fig. 2c", "ref_id": "FIGREF1"}, {"start": 2311, "end": 2319, "text": "Fig.  2d", "ref_id": "FIGREF1"}, {"start": 2349, "end": 2357, "text": "Fig. S1d", "ref_id": "FIGREF0"}, {"start": 2568, "end": 2575, "text": "Fig. 2d", "ref_id": "FIGREF1"}, {"start": 2605, "end": 2613, "text": "Fig. S1c", "ref_id": "FIGREF0"}]}, {"section": "Depletion of DHC partially rescues HIV-1 from omkTRIMCyp-mediated restriction in HeLa cells", "text": "Previously, we found that DHC depletion partially suppressed the restriction of HIV-1 by rhesus TRIM5a expressed in HeLa cells (Pawlica et al., 2014) . However, DHC depletion had a milder effect on the size and position of omkTRIMCyp CBs, compared with rhesus TRIM5a CBs (Fig. 1) . To investigate whether the presence of DHC would be important to restriction mediated by TRIMCyp, we used an siRNA to suppress its expression in HeLa cells that were transduced with omkTRIMCyp or the empty vector. DHC knockdown was efficient (.90 %), as shown in Fig. 3(a) . Then, cells were challenged with HIV-1 CMV-GFP using virus doses leading to~0.49 % infected cells (empty vector-transduced) and 0.17 % infected cells (omkTRIMCyptransduced). When cells were transfected with the DHCtargeting siRNA, infectivity in omkTRIMCyp-expressing cells increased by 34.8\u00b11.3-fold compared with cells transfected with a control siRNA against luciferase ( Fig. 3b ; see nonnormalized data in Fig. S2a ). In contrast, the DHC-targeting siRNA had no effect in control cells transduced with the empty vector. Thus, DHC depletion counteracted omkTRIMCypmediated restriction, and the magnitude seen was comparable with what was observed with nocodazole and paclitaxel (Fig.  2) . To determine whether the pharmacological disruption of MTs (using nocodazole or paclitaxel) and the siRNAmediated disruption of cytoplasmic dynein counteracted omkTRIMCyp through the same mechanism or by acting independently, HeLa cells expressing omkTRIMCyp were infected with HIV-1 CMV-GFP in the presence of an siRNA targeting DHC or luciferase and in presence or not of nocodazole or paclitaxel ( Fig. 3c ; see non-normalized data in Fig. S2b ). As before, paclitaxel (alone or in combination with DHC knockdown) slightly decreased HIV-1 CMV-GFP infectivity (~1.5-fold), whilst nocodazole and DHC depletion had no significant effect (Fig. 3c) . Compared with the untreated control, treatment with nocodazole and paclitaxel increased infectivity in omkTRIMCyp-expressing cells by 27.0\u00b12.4-and 59.2\u00b13.7-fold, respectively. DHC depletion alone increased infectivity by 16.9\u00b10.7-fold in omkTRIMCypexpressing cells. Combining DHC depletion with nocodazole and paclitaxel increased infectivity by 32.3\u00b16.9-and 53.9\u00b14.98-fold, respectively (Fig. 3c) . Thus, the effects were almost identical to those obtained with the drugs alone, Representative images are shown with outlined cell edges. (c) Sizes of CBs. All CBs were outlined in cells from a minimum of five randomly chosen fields and their area was calculated using image analysis software (AxioVision). P values were calculated using Student's t-test analysis. (d) The relative localization of all TRIMCyp CBs from a minimum of five randomly chosen cells was calculated using the formula x/(x+y), where x is the shortest distance to the nucleus and y is the shortest distance to the cell's edge. Red bars show the mean\u00b1SEM and green bars show the medians.", "cite_spans": [{"start": 127, "end": 149, "text": "(Pawlica et al., 2014)", "ref_id": "BIBREF63"}], "ref_spans": [{"start": 271, "end": 279, "text": "(Fig. 1)", "ref_id": "FIGREF0"}, {"start": 545, "end": 554, "text": "Fig. 3(a)", "ref_id": "FIGREF2"}, {"start": 932, "end": 939, "text": "Fig. 3b", "ref_id": "FIGREF2"}, {"start": 968, "end": 976, "text": "Fig. S2a", "ref_id": "FIGREF1"}, {"start": 1239, "end": 1248, "text": "(Fig.  2)", "ref_id": "FIGREF1"}, {"start": 1652, "end": 1659, "text": "Fig. 3c", "ref_id": "FIGREF2"}, {"start": 1689, "end": 1697, "text": "Fig. S2b", "ref_id": "FIGREF1"}, {"start": 1888, "end": 1897, "text": "(Fig. 3c)", "ref_id": "FIGREF2"}, {"start": 2288, "end": 2297, "text": "(Fig. 3c)", "ref_id": "FIGREF2"}]}, {"section": "Depletion of DHC partially rescues HIV-1 from omkTRIMCyp-mediated restriction in HeLa cells", "text": "strongly suggesting that DHC depletion and MT perturbation rescued HIV-1 from omkTRIMCyp by interfering with the same pathway. Of note, in this experiment, only 0.14 % of omkTRIMCyp-expressing cells were infected in the absence of drug, which implies that we would have been able to observe 100-fold increases (or more) in infectivity if they had occurred. Thus, the absence of an additive effect in Fig. 3(c) was not due to saturated infection.", "cite_spans": [], "ref_spans": [{"start": 400, "end": 409, "text": "Fig. 3(c)", "ref_id": "FIGREF2"}]}, {"section": "Overexpression of p50/dynamitin partially counteracts omkTRIMCyp-mediated restriction", "text": "As an alternative approach to analyse the importance of dynein-mediated transport in omkTRIMCyp-mediated restriction, we overexpressed p50/dynamitin in control and omkTRIMCyp-expressing HeLa cells (Fig. 4a ). p50 is a subunit of the dynactin complex that is responsible for binding cargos to the dynein complex. Its overexpression results in the disassembly of dynactin complexes, thereby disrupting cargo binding to dynein (Burkhardt et al., 1997; Melkonian et al., 2007) . Overexpression of p50 increased HIV-1 CMV-GFP infectivity in TRIMCyp-expressing cells by 2.3\u00b10.35-fold, whilst replication in the control permissive cells was not affected ( Fig. 4b ; see non-normalized data in Fig. S2c) . Altogether, the data in Figs 3 and 4 strongly suggest that functional dynein complexes are important, but not absolutely necessary, to omkTRIMCyp-mediated restriction. ) and thus using this cell line also ensured that endogenous TRIM5a did not play a role in the effects seen in HeLa cells. CRFK cells were first transfected with a construct expressing GFP-a-tubulin and then treated with nocodazole or paclitaxel before being processed for immunofluorescence microscopy. In the absence of drug, individual MTs were clearly visible (Fig. 5a, left panel) . Nocodazole prevents polymerization of MTs (Luduena & Roach, 1991) , and consequently MTs appeared shortened and/or disassociated; most of the signal was diffuse and distributed throughout the cytoplasm (Fig. 5a) . Paclitaxel, however, binds to MT polymers to prevent their disassembly (Jordan & Wilson, 2004) , resulting in the formation of abnormal MT bundles (Hornick et al., 2008 ) -a phenotype that was observed as expected in CRFK cells (Fig. 5a ). Next, we analysed the effect of these pharmacological treatments on HIV-1 infectivity under restriction by omkTRIMCyp. In the absence of treatment, HIV-1 CMV-GFP infectivity in CRFK cells expressing omkTRIMCyp was reduced by~100-fold compared with the control cells (Fig. 5b, c) , which is smaller than what was seen in HeLa cells transduced with the same omkTRIMCyp-expressing construct (Fig. 2a, b) . Treatment with nocodazole ( Fig. 5b) and paclitaxel ( Fig. 5c ) increased HIV-1 CMV-GFP infectivity by around sixfold whilst having no effect in control permissive cells. Thus, perturbing MTs partially inhibits omkTRIMCyp function in CRFK cells, similar to what was observed in HeLa cells, although the effect is smaller in CRFK cells. Moreover, the magnitudes of the effects of the two drugs in CRFK cells were similar, as was the case in HeLa cells.", "cite_spans": [{"start": 449, "end": 472, "text": "Melkonian et al., 2007)", "ref_id": "BIBREF58"}, {"start": 1296, "end": 1319, "text": "(Luduena & Roach, 1991)", "ref_id": "BIBREF52"}, {"start": 1539, "end": 1562, "text": "(Jordan & Wilson, 2004)", "ref_id": "BIBREF43"}], "ref_spans": [{"start": 197, "end": 205, "text": "(Fig. 4a", "ref_id": "FIGREF3"}, {"start": 649, "end": 656, "text": "Fig. 4b", "ref_id": "FIGREF3"}, {"start": 686, "end": 695, "text": "Fig. S2c)", "ref_id": "FIGREF1"}, {"start": 1230, "end": 1251, "text": "(Fig. 5a, left panel)", "ref_id": "FIGREF4"}, {"start": 1456, "end": 1465, "text": "(Fig. 5a)", "ref_id": "FIGREF4"}, {"start": 1696, "end": 1704, "text": "(Fig. 5a", "ref_id": "FIGREF4"}, {"start": 1974, "end": 1986, "text": "(Fig. 5b, c)", "ref_id": "FIGREF4"}, {"start": 2096, "end": 2108, "text": "(Fig. 2a, b)", "ref_id": "FIGREF1"}, {"start": 2139, "end": 2147, "text": "Fig. 5b)", "ref_id": "FIGREF4"}, {"start": 2165, "end": 2172, "text": "Fig. 5c", "ref_id": "FIGREF4"}]}, {"section": "Disrupting MT dynamics or dynein function does not counteract restriction of HIV-1 in OMK cells", "text": "Finally, we tested whether MTs and cytoplasmic dynein were important to omkTRIMCyp function when expressed endogenously in owl monkey cells. For this, we used OMK cells, which are kidney epithelial cells known to be very poorly permissive to HIV-1 (Sayah et al., 2004; Towers et al., 2003) . GFP-a-tubulin transfection allowed us to analyse the effect of nocodazole and paclitaxel on the MT network in this cell line (Fig. 6a) . Similar to what was seen in CRFK cells, treatment with 2 mM nocodazole resulted in GFP-a-tubulin being more diffuse in the cytoplasm of cells (Fig. 6a) , consistent with inhibition of MT polymerization by this drug. Conversely, treatment with 1 mM paclitaxel caused the formation of abnormal MT bundles that were found close to the cell's edge (Fig. 6a) . OMK cells were then infected with HIV-1 NL43-GFP , a vesicular stomatitis virus (VSV) G-pseudotyped HIV-1 vector devoid of an HIV-1 envelope and expressing GFP in place of Nef (He et al., 1997) . As a non-restricted control, we used SIV mac-GFP , a similarly constructed vector derived from the omkTRIMCyp-insensitive simian immunodeficiency virus (SIV) strain mac239 (Berthoux et al., 2005b) . OMK cells were infected with multiple doses of HIV-1 NL43-GFP and SIV mac-GFP , in absence of drug or in the presence of nocodazole (Fig. 6b) or paclitaxel (Fig. 6c) . After normalization of the virus amounts used according to their titres in the non-restrictive CRFK cells, we found that, as expected, HIV-1 NL43-GFP infectivity was~500-fold smaller than that of SIV mac-GFP in these cells (Fig. 6b, c) . Addition of nocodazole at 0.1 or 1 mM slightly increased HIV-1 NL43-GFP infectivity, but this drug also had a small positive effect on SIV mac-GFP infectivity (Fig. 6b) . Likewise, treatment with paclitaxel slightly increased infectivity of SIV mac-GFP and also that of HIV-1 NL43-GFP , at least at some virus doses (Fig. 6c) . Thus, HIV-1 NL43-GFP was not rescued from TRIMCyp-mediated restriction in OMK cells by nocodazole or paclitaxel treatment. The discrepancy between this result and what was observed in HeLa and CRFK cells could possibly be due to differences in restriction sensitivity between the vectors used, HIV-1 CMV-GFP and HIV-1 NL43-GFP . To exclude that possibility, we infected OMK cells with several doses of HIV-1 CMV-GFP in the absence or presence of nocodazole or paclitaxel. As shown in Fig. 6(d) , neither drug could rescue this vector from restriction by TRIMCyp in OMK cells. As additional evidence that TRIMCyp was expressed and functional in these cells, we tested whether inhibition of its interaction with HIV-1 CA would rescue HIV-1 infectivity (Sayah et al., 2004) . Treatment with 5 mM cyclosporin A during infection and introducing the G89V mutation in HIV-1 CA both increased HIV-1 infectivity by~200-fold in OMK cells (Fig. 6e) , thus completely disrupting restriction.", "cite_spans": [{"start": 269, "end": 289, "text": "Towers et al., 2003)", "ref_id": "BIBREF81"}], "ref_spans": [{"start": 417, "end": 426, "text": "(Fig. 6a)", "ref_id": "FIGREF5"}, {"start": 571, "end": 580, "text": "(Fig. 6a)", "ref_id": "FIGREF5"}, {"start": 773, "end": 782, "text": "(Fig. 6a)", "ref_id": "FIGREF5"}, {"start": 1312, "end": 1321, "text": "(Fig. 6b)", "ref_id": "FIGREF5"}, {"start": 1336, "end": 1345, "text": "(Fig. 6c)", "ref_id": "FIGREF5"}, {"start": 1571, "end": 1583, "text": "(Fig. 6b, c)", "ref_id": "FIGREF5"}, {"start": 1745, "end": 1754, "text": "(Fig. 6b)", "ref_id": "FIGREF5"}, {"start": 1902, "end": 1911, "text": "(Fig. 6c)", "ref_id": "FIGREF5"}, {"start": 2398, "end": 2407, "text": "Fig. 6(d)", "ref_id": "FIGREF5"}, {"start": 2842, "end": 2851, "text": "(Fig. 6e)", "ref_id": "FIGREF5"}]}, {"section": "Disrupting MT dynamics or dynein function does not counteract restriction of HIV-1 in OMK cells", "text": "It is conceivable, albeit unlikely (as dynein complexes translocate on MTs), that cytoplasmic dynein could have a role in TRIMCyp function in OMK cells even if the MT network does not. To test this possibility, we depleted DHC in OMK cells using the same siRNA that was used in human cells. We found that DHC knockdown by this siRNA was as efficient in OMK cells as in human cells (.90 %; Fig. 6f ). DHC depletion had no significant effect on HIV-1 NL43-GFP , even decreasing infectivity at one of the virus doses compared with the cells transfected with the control (luciferase-targeting) siRNA (Fig. 6g) . SIV mac-GFP infectivity was similarly not significantly affected by DHC depletion (Fig. 6g) . Thus, HIV-1 infectivity in OMK cells was not rescued by interfering with the integrity of the MT network or by targeting DHC, suggesting the existence of cell context specificity for the involvement of MTs and cytoplasmic dynein in the restriction process.", "cite_spans": [], "ref_spans": [{"start": 389, "end": 396, "text": "Fig. 6f", "ref_id": "FIGREF5"}, {"start": 596, "end": 605, "text": "(Fig. 6g)", "ref_id": "FIGREF5"}, {"start": 690, "end": 699, "text": "(Fig. 6g)", "ref_id": "FIGREF5"}]}, {"section": "DISCUSSION", "text": "Previously, we showed that full restriction by TRIM5a required the presence of a functional MT network, as well as functional dynein complexes (Pawlica et al., 2014) . This was true whether TRIM5a was expressed endogenously or overexpressed by retroviral transduction. Moreover, the phenotype was observed in human cells and in rhesus macaque cells, and whether the restricted virus was a lentivirus (HIV-1) or an oncoretrovirus (N-MLV). Here, we show that the antiretroviral function of TRIMCyp -a TRIM5 protein bearing a CypA domain instead of a PRYSPRY domain -can be similarly sensitive to inhibition of MTs or dynein complexes. All viruses used in this study were VSV G-pseudotyped and we cannot totally exclude that such pseudotyping modulates the involvement of MTs or dynein in omkTRIMCyp-mediated restriction. However, this seems unlikely considering that the mode of virus entry was previously shown to be irrelevant for the involvement of MTs in TRIM5a-mediated restriction of HIV-1 (Pawlica et al., 2014) . Interestingly, the MT/dynein dependency of omkTRIMCyp varied between the cell lines used, being high in HeLa cells, relatively less so in CRFK cells and absent in OMK cells. Endogenous TRIMCyp in OMK cells is expressed at much lower levels compared with overexpression in HeLa or CRFK cells, but this is unlikely to explain the differences seen here, considering that (i) the magnitude of omkTRIMCyp-mediated HIV-1 restriction is similar in OMK cells and in TRIM5a-transduced HeLa cells (100-fold or more), and (ii) MTs and dynein were shown to be important for restriction mediated by both endogenous and overexpressed TRIM5a (Pawlica et al., 2014) . However, we cannot totally exclude this possibility. Of note, none of the experimental approaches used here had a significant effect on omkTRIMCyp expression levels in HeLa cells (not shown), ruling out such a putative unspecific effect as the cause for the loss of restriction. As cytoplasmic dynein complexes translocate on MTs (H\u00f6\u00f6k & Vallee, 2006 ), it appears likely that paclitaxel and nocodazole inhibit TRIM5a and TRIMCyp indirectly, by preventing dynein-mediated transport. In support of this conclusion is the observation that combining DHC depletion with paclitaxel or nocodazole treatment has no additional effect on restriction in cells, and this has been shown for rhesus TRIM5a (Pawlica et al., 2014) and now for omkTRIMCyp as well. The fact that neither TRIM5a nor TRIMCyp is completely dependent on the presence of an intact MT network or functional dynein, regardless of the cellular context, leads us to conclude that dynein complexes have a function in TRIM5a/TRIMCyp-mediated restriction that is not absolutely required or, possibly, this function can be accomplished by another transporter complex that does not translocate on MTs. This hypothesis helps make sense of the fact that neither DHC depletion nor pharmacological disruption of MTs could rescue HIV-1 infection of OMK cells. We speculate that the Immunofluorescence microscopy analysis of MTs. CRFK cells were transfected with GFP-a-tubulin and 2 days later were left untreated or subjected to 2 h treatments using either 2 mM nocodazole (Noc) or 1 mM paclitaxel (Pxl) and then fixed. GFP fluorescence was observed by immunofluorescence microscopy, along with DNA that was stained using Hoechst 33342 (blue). OMK cells were transfected with GFP-a-tubulin and 2 days later were left untreated or subjected to 2 h treatments using endogenous omkTRIMCyp expressed in these cells does not require MTs or dynein to make initial contact with the incoming virus CA core and elucidating the molecular basis for this behaviour will require additional investigations. Alternatively, the discrepancy of results between the cell lines used in this study could stem from different effects of inhibiting MTs and dynein on virus uncoating in these cell lines. Targeting MTs and dynein may delay uncoating, as has been shown recently by us (Pawlica & Berthoux, 2014; Pawlica et al., 2014) and by others (Lukic et al., 2014) , and perhaps this has a greater impact on restriction in some cell lines than in others. Interestingly, Lukic et al. (2014) also included data showing that nocodazole treatment did not rescue HIV-1 from restriction by rhesus TRIM5a or omkTRIMCyp expressed in HeLa cells, apparently conflicting with our previous report (Pawlica et al., 2014) and the present report. However, HeLa cells have been shown to be a highly heterogeneous cell line (Carson & Pirruccello, 2013) , including clones with various permissiveness toward HIV-1 infection (De Iaco & Luban, 2014) , and it is also known that the magnitude of restriction by TRIM5a and TRIMCyp proteins can vary widely between cell lines (B\u00e9rub\u00e9 et al., 2007; Gong et al., 2011) . Altogether, it appears likely that a cellular context effect explains the different results obtained by Lukic et al. (2014) . In conclusion, the MT network and dynein complexes can potentiate the antiretroviral activity of not only TRIM5a, but also TRIMCyp, but is not strictly required.", "cite_spans": [{"start": 143, "end": 165, "text": "(Pawlica et al., 2014)", "ref_id": "BIBREF63"}, {"start": 994, "end": 1016, "text": "(Pawlica et al., 2014)", "ref_id": "BIBREF63"}, {"start": 1646, "end": 1668, "text": "(Pawlica et al., 2014)", "ref_id": "BIBREF63"}, {"start": 2364, "end": 2386, "text": "(Pawlica et al., 2014)", "ref_id": "BIBREF63"}, {"start": 3977, "end": 4003, "text": "(Pawlica & Berthoux, 2014;", "ref_id": "BIBREF63"}, {"start": 4004, "end": 4025, "text": "Pawlica et al., 2014)", "ref_id": "BIBREF63"}, {"start": 4040, "end": 4060, "text": "(Lukic et al., 2014)", "ref_id": "BIBREF54"}, {"start": 4166, "end": 4185, "text": "Lukic et al. (2014)", "ref_id": "BIBREF54"}, {"start": 4381, "end": 4403, "text": "(Pawlica et al., 2014)", "ref_id": "BIBREF63"}, {"start": 4503, "end": 4531, "text": "(Carson & Pirruccello, 2013)", "ref_id": "BIBREF17"}, {"start": 4602, "end": 4625, "text": "(De Iaco & Luban, 2014)", "ref_id": "BIBREF20"}, {"start": 4771, "end": 4789, "text": "Gong et al., 2011)", "ref_id": "BIBREF28"}, {"start": 4896, "end": 4915, "text": "Lukic et al. (2014)", "ref_id": "BIBREF54"}], "ref_spans": []}, {"section": "METHODS", "text": "Cells, pharmaceuticals and antibodies. Human embryonic kidney 293T (HEK 293T) cells, human epithelial carcinoma HeLa cells, feline renal CRFK cells and OMK cells were maintained in Dulbecco's modified Eagle's medium (DMEM) with high glucose, supplemented with 10 % FBS and antibiotics at 37 uC, 5 % CO 2 . All cell culture reagents were from HyClone (Thermo Scientific). Nocodazole, paclitaxel and cyclosporin A were from Sigma. HeLa and CRFK cells retrovirally transduced to stably express omkTRIMCyp were as described previously (B\u00e9rub\u00e9 et al., 2007; Nepveu-Traversy et al., 2009) . Rabbit polyclonal antibodies against DHC and p50/dynamitin were from Santa Cruz and Millipore, respectively. The FLAG epitope was detected using the M2 mouse mAb (Sigma). The HRP-conjugated mouse anti-actin antibody was from Sigma. HRP-conjugated goat anti-rabbit and goat anti-mouse antibodies used as secondary antibodies in Western blots were from Santa Cruz.", "cite_spans": [{"start": 553, "end": 582, "text": "Nepveu-Traversy et al., 2009)", "ref_id": "BIBREF60"}], "ref_spans": []}, {"section": "METHODS", "text": "Plasmid DNAs and retrovirus production. p50/dynamitin-HA was a gift from Tina Schroer (Schrader et al., 2000) . To produce viral vectors, 10 cm culture dishes of subconfluent HEK 293T cells were co-transfected using polyethylenimine (molecular mass 25 000; Polyscience) with the appropriate plasmids, as follows: for the viral vector HIV-1 CMV-GFP , pTRIP TRIP-CMV-GFP (10 mg), pDR8.9 (WT or G89V; 10 mg) and pMD-G (5 mg); for HIV-1 NL43-GFP , pNL-GFP (10 mg) and pMD-G (5 mg); for SIV mac-GFP , pSIVmac-GFP (10 mg) and pMD-G (5 mg) (Berthoux et al., 2003; He et al., 1997; Zufferey et al., 1997) . Media were changed 16 h post-transfection and viruscontaining supernatants were collected after an additional 1.5 days of culture. Viral stocks were clarified by centrifugation for 5 min at 400 g. siRNA and plasmid transfections. For the siRNA treatments, 10 6 cells were seeded in a 10 cm dish in Opti-MEM (Gibco) and transfected the next day with 40 nM siRNA using DharmaFECT 1 (Dharmacon). The siRNA targeting the sequence 59-GATCAA-ACATGACGGAATT-39 of the DHC has been described previously (Lehmann et al., 2009; Pawlica et al., 2014) and was purchased from Qiagen (Venlo). A control siRNA (59-CGTACGCGGAATACTTCGA-TT-39) targeting the luciferase mRNA (Pawlica et al., 2014) was purchased from Dharmacon. At 48 h post-transfection, cells were seeded in 24-well plates they were; infected the next day with HIV-1 vectors as described above. For p50 overexpression, 10 6 cells seeded in a 10 cm dish were polyethyleneimine-transfected with 5 mg p50/ dynamitin-HA or an irrelevant plasmid (pMIP). Cells were seeded in 24-well plates 24 h later and challenged with viral vectors the next day.", "cite_spans": [{"start": 86, "end": 109, "text": "(Schrader et al., 2000)", "ref_id": "BIBREF73"}, {"start": 1116, "end": 1137, "text": "Pawlica et al., 2014)", "ref_id": "BIBREF63"}, {"start": 1254, "end": 1276, "text": "(Pawlica et al., 2014)", "ref_id": "BIBREF63"}], "ref_spans": []}, {"section": "METHODS", "text": "Immunofluorescence microscopy. For siRNA treatments, HeLa cells in 3.5 cm wells were transfected 48 h prior to seeding as described above. For the cells expressing GFP-tubulin, 2 mg plasmid was transfected per well using polyethyleneimine 24 h prior to seeding on coverslips. Then, 2610 5 cells were seeded on glass coverslips placed in 3.5 cm wells. After 24 h, the cells were treated or not with nocodazole for 2 h, and then fixed and processed for either 2 mM nocodazole or 1 mM paclitaxel and then fixed. GFP fluorescence was observed by immunofluorescence microscopy, along with DNA that was stained using Hoechst 33342 (blue) immunofluorescence staining. Fixation was done for 10 min in 4 % formaldehyde/DMEM in 37 uC, followed by three washes with icecold PBS. Cells were then permeabilized by treatment with 0.1 % Triton X-100/0.1 mM sodium citrate for 1-2 min on ice. Cells were then washed again three times with PBS and treated with 10 % normal goat serum (Sigma) containing 0.3 M glycine (Sigma) for 30 min at room temperature. This was followed by a 4 h incubation with a murine antibody against the FLAG epitope diluted 1 : 400 in PBS containing 10 % normal goat serum. Cells were washed five times and fluorescently stained with the Alexa 594-conjugated goat antimouse antibody (Molecular Probes) at a 1 : 200 dilution. Cells were washed five times in PBS before mounting in Vectashield (Vector Laboratories). Hoechst 33342 (0.8 mg ml", "cite_spans": [], "ref_spans": []}, {"section": "21", "text": "; Molecular Probes) was added along with the penultimate PBS wash to reveal DNA. Z-stacks were acquired on an AxioObserver microscope (Zeiss) equipped with an Apotome module and median Z-stacks were retained for analysis. For the analysis of TRIM5a CB sizes, FLAG foci in a given cell were manually outlined in the AxioVision software for calculation of the surface. A minimum of 80 and up to 180 CBs from 10 randomly chosen cells were included in the analysis. For the analysis of TRIM5a CB localization, the cell's edge was outlined, and for each FLAG foci in a given cell we measured the closest distance to the nuclear membrane and the closest distance to the plasma membrane using AxioVision. A minimum of 170 and up to 320 CBs from a minimum of five randomly chosen cells were included in the analysis.", "cite_spans": [], "ref_spans": []}, {"section": "21", "text": "Statistical analysis. 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DHC depletion and MT perturbation alter the size and/or distribution of omkTRIMCyp CBs. (a, b) Immunofluorescence microscopy. HeLa cells transduced with FLAG-tagged omkTRIMCyp and control cells transduced with the empty vector were seeded on glass coverslips and 24 h later treated with 2 mM nocodazole (Noc) or not (Ctl) for 6 h (a), or transfected with 40 nM siRNAs targeting DHC (siDHC) or luciferase (siLuc) and 48 h later seeded on glass coverslips and incubated for an additional 24 h (b). Cells were fixed and immunostained for FLAG (red). DNA was stained with Hoechst 33342 (blue). Representative images are shown with outlined cell edges. (c) Sizes of CBs. All CBs were outlined in cells from a minimum of five randomly chosen fields and their area was calculated using image analysis software (AxioVision). P values were calculated using Student's t-test analysis. (d) The relative localization of all TRIMCyp CBs from a minimum of five randomly chosen cells was calculated using the formula x/(x+y), where x is the shortest distance to the nucleus and y is the shortest distance to the cell's edge. Red bars show the mean\u00b1SEM and green bars show the medians.", "type": "figure"}, "FIGREF1": {"text": "Fig. 2. Pharmacological perturbation of MTs partially counteracts HIV-1 restriction by omkTRIMCyp in HeLa cells. (a, b) Effect of nocodazole (Noc) and paclitaxel (Pxl) on restriction. HeLa cells transduced with FLAG-tagged omkTRIMCyp or the empty vector were infected with multiple doses of HIV-1 CMV-GFP in the presence or absence of the indicated concentrations of either nocodazole (a) or paclitaxel (b). Infections were performed for 16 h. Infected (GFP-expressing) cells were detected by flow cytometry at 2 days post-infection. (c, d) Dose-dependent effect of nocodazole or paclitaxel on restriction. Human HeLa cells transduced with FLAG-tagged omkTRIMCyp or the empty vector were infected for 16 h with a single dose of HIV-1 CMV-GFP in the presence of increasing concentrations of either nocodazole (c) or paclitaxel (d). The percentages of infected cells were determined by flow cytometry 2 days post-infection and the results are presented as the fold changes in infectivity relative to the relevant untreated controls. Higher amounts of input virus were used in omkTRIMCyp-expressing cells than in the control cells, so that all values fall within the dynamic range for this assay. The ratio of infected cells in the absence of drug was 0.06 (TRIMCyp; c), 0.16 (TRIMCyp; d), 2.15 (empty vector; c) or 7.93 % (empty vector; d).", "type": "figure"}, "FIGREF2": {"text": "Fig. 3. DHC depletion partially counteracts HIV-1 restriction by omkTRIMCyp in HeLa cells. (a) Western blot analysis of DHC expression in HeLa cells 48 h after transfection of the siRNAs against DHC (siDHC) or against luciferase (siLuc) as a control. Actin was analysed as a loading control. (b) HeLa cells transduced with omkTRIMCyp or the empty vector were transfected with the indicated siRNAs and infected 72 h later in triplicates with single doses of HIV-1 CMV-GFP for 16 h. Infected cells were detected by flow cytometry 2 days post-infection and results are presented as fold changes relative to the relevant untreated controls (relative change in infectivity). Higher amounts of input virus were used in omkTRIMCyp-expressing cells than in the control cells, so that all values fall within the dynamic range for this assay. The ratios of infected cells in the absence of drug were 0.17 (TRIMCyp) and 0.49 % (empty vector). ***P\u00a10.0001 (Student's t-test). (c) Effect of combining DHC depletion and MT perturbation on TRIMCyp-mediated HIV-1 restriction. HeLa cells transduced with omkTRIMCyp or the empty vector were transfected with 40 nM siRNA against DHC or Luc, then treated or not with either 0.2 mM nocodazole (Noc) or 0.1 mM paclitaxel (Pxl) and infected with HIV-1 CMV-GFP . Infection yields were analysed as above. The ratios of infected cells in the absence of drug were 0.14 (TRIMCyp) and 5.77 % (empty vector). **P\u00a10.005 and ***P\u00a10.0001 compared with the untreated omkTRIMCyp-transduced cells, as calculated using Student's t-test. Error bars represent SD.", "type": "figure"}, "FIGREF3": {"text": "Fig. 4. Overexpression of p50/dynamitin decreases omkTRIMCypmediated restriction of HIV-1 in HeLa cells. (a, b) HeLa cells transduced with omkTRIMCyp or the empty vector were transfected with p50/dynamitin-HA or an irrelevant control plasmid. (a) Detection of p50 in the transfected cells by Western blotting. (b) Cells were infected in triplicates with HIV-1 CMV-GFP 48 h after transfection. Infected cells were counted by flow cytometry 2 days post-infection and results are presented as fold changes in infectivity relative to the relevant mock-transfected control. Higher amounts of input virus were used in omkTRIMCyp-expressing cells than in the control cells, so that all values fall within the dynamic range for this assay. The ratios of infected cells in the mock-transfected cells were 0.25 % (for TRIMCyp) and 0.42 % (for the empty vector). **P\u00a10.005 in Student's t-test. Error bars represent SD.", "type": "figure"}, "FIGREF4": {"text": "Fig. 5. Pharmacological perturbation of MTs partially counteracts HIV-1 restriction by omkTRIMCyp in CRFK cells. (a) Immunofluorescence microscopy analysis of MTs. CRFK cells were transfected with GFP-a-tubulin and 2 days later were left untreated or subjected to 2 h treatments using either 2 mM nocodazole (Noc) or 1 mM paclitaxel (Pxl) and then fixed. GFP fluorescence was observed by immunofluorescence microscopy, along with DNA that was stained using Hoechst 33342 (blue). A representative image from each condition is presented. (b, c) Effect of nocodazole and paclitaxel on restriction. CRFK cells transduced with omkTRIMCyp or with the empty vector were infected with multiples doses of HIV-1 CMV-GFP in the presence or absence of 2 mM nocodazole (b) or 1 mM paclitaxel (c). Infections were performed for 16 h and infected cells were detected by flow cytometry 2 days later.", "type": "figure"}, "FIGREF5": {"text": "Fig. 5. Pharmacological perturbation of MTs partially counteracts HIV-1 restriction by omkTRIMCyp in CRFK cells. (a) Immunofluorescence microscopy analysis of MTs. CRFK cells were transfected with GFP-a-tubulin and 2 days later were left untreated or subjected to 2 h treatments using either 2 mM nocodazole (Noc) or 1 mM paclitaxel (Pxl) and then fixed. GFP fluorescence was observed by immunofluorescence microscopy, along with DNA that was stained using Hoechst 33342 (blue). A representative image from each condition is presented. (b, c) Effect of nocodazole and paclitaxel on restriction. CRFK cells transduced with omkTRIMCyp or with the empty vector were infected with multiples doses of HIV-1 CMV-GFP in the presence or absence of 2 mM nocodazole (b) or 1 mM paclitaxel (c). Infections were performed for 16 h and infected cells were detected by flow cytometry 2 days later.", "type": "figure"}, "FIGREF6": {"text": "Viral challenges. Cells were seeded in 24-well plates at 10 5 cells per well (CRFK and HeLa cells) or 5610 4 cells per well (OMK cells) and challenged the next day with the appropriate GFP-expressing viral vectors. When applicable, cells were pre-treated for 15 min with nocodazole, paclitaxel or cyclosporin A and supernatants were replaced with fresh medium 16 h post-infection. Cells were trypsinized 48 h post-infection and fixed in 2 % formaldehyde (Fisher Scientific). The percentages of GFP-positive cells were then determined byon a FC500 MPL cytometer (Beckman Coulter) using CXP Software (Beckman Coulter).", "type": "figure"}, "FIGREF7": {"text": "A representative image from each condition is presented. (b-d) OMK cells were infected with multiple doses of HIV-1 NL43-GFP (b, c), SIV mac-GFP (b, c) or HIV-1 CMV-GFP (d) in the presence or absence of nocodazole (b, d) or paclitaxel (c, d) at the indicated concentrations. Infections were performed for 16 h and infected cells were detected by flow cytometry 2 days later. (e) Abrogation of restriction by cyclosporin A (CsA) treatment or CA mutation. OMK cells were infected with increasing amounts of WT HIV-1 CMV-GFP or the G89V CA mutant and in presence or absence of cyclosporin A (5 mM). The x-axis shows the amounts of virus used for both G89V and WT virus as determined by their titres in CRFK cells in the absence of drug. The percentage of GFP-positive cells was determined by flow cytometry 2 days post-infection. (f) Western blot analysis of DHC expression in OMK cells 48 h after transfection of the siRNAs targeting DHC (siDHC) or, as a control, luciferase (siLuc). Actin was analysed as a loading control. (g) OMK cells were transfected with the indicated siRNAs and infected 72 h later with multiple doses of either HIV-1 NL43-GFP or SIV mac-GFP for 16 h. Infected cells were detected by flow cytometry 2 days post-infection.", "type": "figure"}}}
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{"paper_id": "2875953", "_pdf_hash": "c9732435c8aaf042d7d4b538bfa78cb48ea82f14", "abstract": [{"section": "Abstract", "text": "MediaParl is a Swiss accented bilingual database containing recordings in both French and German as they are spoken in Switzerland. The data were recorded at the Valais Parliament. Valais is a bilingual Swiss canton with many local accents and dialects. Therefore, the database contains data with high variability and is suitable to study multilingual, accented and non-native speech recognition as well as language identification and language switch detection.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "We also define monolingual and mixed language automatic speech recognition and language identifictaion tasks and evaluate baseline systems.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "The database is publicly available for download.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION", "text": "In this paper, we present a database that addresses multilingual, accented and non-native speech, which are still challenging tasks for current ASR systems. At least two bilingual databases already exist [1, 2] . The MediaParl speech corpus was recorded in Valais, a bilingual canton of Switzerland. Valais is surrounded by mountains and is better known internationally for its ski resorts like Verbier and Zermatt with the Matterhorn. Valais is an ideal place to record bilingual data, because there are two different official languages (French and German). Furthermore, even within Valais, there are many local accents and dialects (especially in the German speaking part). This language mix leads to obvious difficulties, with many people working and even living in a non-native language, and leads to high variability in the speech recordings. On the other hand, it leads to valuable data that allow study of multilingual, accented and non-native speech as well as language identification and language switch detection. MediaParl was recorded at the cantonal parliament of Valais. About two thirds of the population speak French, and one third speaks German. However, the German that is spoken in Valais is a group of dialects (also known as Walliser Deutsch) without written form. The dialects differ a lot from the standard (high) German (Hochdeutsch, spoken in Germany) and are sometimes even difficult to understand for other Swiss Germans. Close to the language border (Italy and French speaking Valais) people also use foreign words (loan words) in their dialect. In the parliament (and other formal situations), people speak in accented standard German. In the remainder of the paper, we refer simply to German and French but take this to mean Swiss German and Swiss French.", "cite_spans": [{"start": 204, "end": 207, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 208, "end": 210, "text": "2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "The political debates at the parliament are recorded and broadcasted. The recordings mostly contain prepared speeches in both languages. Some of the speakers even switch between the two languages during the speech. Therefore, the database may also be used to a certain extent to study codeswitched ASR. However, in contrast to for example [1] , the code switches always occur on sentence boundaries. While some similar databases only contain one hour of speech per language [2] , MediaParl contains 20 hours of German and 20 hours of French data.", "cite_spans": [{"start": 339, "end": 342, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 474, "end": 477, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "In the remainder of the paper, we will give more details about the recording (Section 2) and transcription (Section 3) process. We will also present the dictionary creation process in Section 4 and define tasks and training, development and test sets in Section 5. Finally we present and evaluate baseline systems on most of the tasks in Section 6.", "cite_spans": [], "ref_spans": []}, {"section": "RECORDINGS", "text": "The ", "cite_spans": [], "ref_spans": []}, {"section": "TRANSCRIPTIONS", "text": "Each recorded political debate (session) lasts about 3 hours and human-generated transcriptions are available. However, manual work was required to obtain annotated speech data of reasonable quality:", "cite_spans": [], "ref_spans": []}, {"section": "TRANSCRIPTIONS", "text": "\u2022 Speaker diarization was performed manually. Each speaker cluster is referred to as an intervention; an intervention consists of multiple sentences consecutively spoken by the same speaker.", "cite_spans": [], "ref_spans": []}, {"section": "TRANSCRIPTIONS", "text": "\u2022 Each intervention is then associated with the corresponding transcription and manually split into individual sentences.", "cite_spans": [], "ref_spans": []}, {"section": "TRANSCRIPTIONS", "text": "\u2022 The transcription of each sentence is then manually verified by two annotators and noisy utterances are discarded.", "cite_spans": [], "ref_spans": []}, {"section": "TRANSCRIPTIONS", "text": "Finally, all the transcriptions were tokenized and normalized using in-house scripts. The transcription process described above resulted in a corpus of 7,042 annotated sentences (about 20 hours of speech) for the French language and 8,526 sentences (also about 20 hours of speech) for the German language.", "cite_spans": [], "ref_spans": []}, {"section": "DICTIONARIES", "text": "The phonemes in the dictionaries are represented using the Speech Assessment Methods Phonetic Alphabet (SAMPA) 2 . SAMPA is based on the International Phonetic Alphabet (IPA), but features only ASCII characters. It supports multiple languages including German and French.", "cite_spans": [{"start": 111, "end": 112, "text": "2", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "DICTIONARIES", "text": "Manual creation of a dictionary can be quite time consuming because it requires a language expert to expand each word into its pronunciation. Therefore we bootstrap our dictionaries with publicly available sources that are designed for a general domain of speech, such as conversations. However, the speech corpus that we use includes large numbers of words, that are specific to the domain (politics) and region (Switzerland). Hence, the dictionaries need to be completed. In the reminder of this section, we first generally describe how we complete the dictionaries and then give more details about German and French in Sections 4.2 and 4.3 respectively.", "cite_spans": [], "ref_spans": []}, {"section": "Phonetisaurus", "text": "We used Phonetisaurus [3] , a grapheme-to-phoneme (g2p) tool that uses existing dictionaries to derive a finite state transducer based mapping of sequences of letters (graphemes) to their acoustic representation (phonemes). The transducer was then applied to unseen words.", "cite_spans": [{"start": 22, "end": 25, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Phonetisaurus", "text": "For languages with highly transparent orthographies such as Spanish or German [4] , g2p approaches typically work quite well [5] . However, for languages with less transparent orthographies, such as English or French [4] , it is relatively difficult to derive simple mappings from the grapheme representation of a syllable to its phoneme representation. Therefore, g2p approaches tend to work less well [5] .", "cite_spans": [{"start": 78, "end": 81, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 125, "end": 128, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 217, "end": 220, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 403, "end": 406, "text": "[5]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Phonetisaurus", "text": "Furthermore, due to the prevalence of English in many fields, domain-specific words, such as \"highspeed\", \"interview\" or \"controlling\" are often borrowed from English. Since MediaParl was recorded in a bilingual region, this effect becomes even more pronounced than in other more homogenous speaker populations. As a result, the dictionaries contain relatively large numbers of foreign words. However, the g2p mappings of one language do not necessarily generalize to a foreign language. French word suffixes for example, are often not pronounced if they form an extension to the word stem, such as plurals and conjugations. On the other hand, German word suffixes are usually pronounced, except for some cases where terminal devoicing (voiced consonants become unvoiced before vowels or breaks) applies.", "cite_spans": [], "ref_spans": []}, {"section": "Phonetisaurus", "text": "Owing to the above problems with g2p, all entries generated by Phonetisaurus were manually verified by native speakers according to the SAMPA rules for the respective language. Table 2 shows the number of unique words in each dictionary.", "cite_spans": [], "ref_spans": [{"start": 177, "end": 184, "text": "Table 2", "ref_id": "TABREF2"}]}, {"section": "German Dictionary", "text": "To bootstrap the German dictionary, we used Phonolex 3 . Phonolex was developed by a cooperation between DFKI Saarbr\u00fccken, the Computational Linguistics Lab, the Universit\u00e4t Leipzig (UL) and the Bavarian Archive for Speech Signals (BAS) in Munich.", "cite_spans": [], "ref_spans": []}, {"section": "German Dictionary", "text": "82% of the German MediaParl words were found in Phonolex. Phonetisaurus was then trained on Phonolex to generate the missing pronunciations. All g2p-based dictionary entries were manually verified in accordance to the German SAMPA rules [6] .", "cite_spans": [{"start": 237, "end": 240, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "German Dictionary", "text": "Since Phonolex is a standard German dictionary and we only use one pronunciation for each word, the actual Swiss German pronunciation of some words may significantly differ. Analyzing, for instance, various samples of the German word \"achtzig\" reveals that speakers in MediaParl pronounce it in three different ways:", "cite_spans": [], "ref_spans": []}, {"section": "German Dictionary", "text": "1. /Q a x t s I C/ 2. /Q a x t s I k/ 3. /Q a x t s I k C/ where (1) is the standard German version used in Phonolex, (2) can be found in various German dialects and (3) seems to be a Swiss German peculiarity.", "cite_spans": [], "ref_spans": []}, {"section": "French Dictionary", "text": "The French dictionary was bootstrapped with BDLEX 4 . BDLEX consists of a lexical database developed at Institut de Recherche en Informatique (IRIT) in Toulouse. The data cover lexical, phonological, and morphological information.", "cite_spans": [{"start": 50, "end": 51, "text": "4", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "French Dictionary", "text": "83% of the French MediaParl words were found in BDLEX. Similar to German, we trained Phonetisaurus on BDLEX to generate the missing pronunciations. Again, all g2p-based dictionary entries were manually verified in accordance to the French SAMPA rules.", "cite_spans": [], "ref_spans": []}, {"section": "DEFINITIONS", "text": "In this section, we first define tasks that can be performed on the database and then present the partition of the database into training, development and test data.", "cite_spans": [], "ref_spans": []}, {"section": "Tasks", "text": "The database is well suited to study the following tasks:", "cite_spans": [], "ref_spans": []}, {"section": "Tasks", "text": "Automatic speech recognition (ASR) The ASR task consists of performing monolingual independent ASR for French and German. As usually done, the performance can be measured with word accuracies.", "cite_spans": [], "ref_spans": []}, {"section": "Tasks", "text": "The database is particularly well suited to investigate non-native ASR and we will see in Section 6 that ASR on non-native utterances is more challenging.", "cite_spans": [], "ref_spans": []}, {"section": "Tasks", "text": "Language identification (LID) The LID task consists of determining the spoken language for each sentence. In that case, the performance can be measured simply as percentage of sentences for which the spoken language was correctly recognized because the decision is either correct or wrong.", "cite_spans": [], "ref_spans": []}, {"section": "Tasks", "text": "As already described in Section 3, an intervention contains multiple sentences of the same speaker. The bilingual speakers change language within one intervention, hence the database can also be used to study the detection of language switches. Note that the language switches always occur at sentence boundaries.", "cite_spans": [], "ref_spans": []}, {"section": "Tasks", "text": "Mixed language ASR Mixed language ASR is defined as ASR without knowing the language of a sentence a priori. As for the ASR task, performance can be measured in word accuracies. The mixed language ASR task is considered to be much more challenging than the standard ASR task.", "cite_spans": [], "ref_spans": []}, {"section": "Tasks", "text": "Since interventions contain language switches, the database may also be used to investigate code-switched ASR. However, note that the language switches always happen at sentence borders what is simpler than code-switched ASR as defined by for example [1] .", "cite_spans": [{"start": 251, "end": 254, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Tasks", "text": "Speaker diarization The whole database is labeled with speaker information. Therefore it may also be used to perform speaker diarization. Furthermore, many speakers can be found in multiple interventions, hence speaker diarization might also be applied across interventions.", "cite_spans": [], "ref_spans": []}, {"section": "Data partitioning", "text": "We partitioned the database into training, development and test sets. Since we focus on bilingual (accented, non-native) speech, the test set (MediaParl-TST) contains all the speakers which speak in both languages (see Table 1 ). Hence, MediaParl-TST contains all the non-native utterances. 90% of the remaining speakers (only speaking in one language) form the training set (MediaParl-TRN) and the other 10% the development set (MediaParl-DEV). Training and development speakers were randomly determined. MediaParl-TRN contains 11,425 sentences (5,471 in French and 5,955 in German) spoken by 180 different speakers and MediaParl-DEV contains 1,525 sentences (646 in French and 879 in German) from 17 different speakers. The speakers from MediaParl-TST are shown in Table 1 . As already described, each speaker uses both languages. Table 1 also displays how many French and German sentences were recorded for each test speaker. We assume that each speaker is naturally speaking more often in his mother tongue. Hence, the speakers 059, 079, 109 and 191 appear to be native German speakers and the speakers 094, 096 and 102 native French speakers. These findings were confirmed by native speakers of French and German. The speakers 109 and 191 are native German speakers but they are very fluent in the second language. French  German  059  31  195  079  22  698  094  313  72  096  89  8  102  72  7  109  233  402  191  165  310  Total  925  1692   Table 1 . MediaParl-TST: speakers using both languages form the test set. For each speaker the number of French and German sentences is given.", "cite_spans": [], "ref_spans": [{"start": 1320, "end": 1458, "text": "French  German  059  31  195  079  22  698  094  313  72  096  89  8  102  72  7  109  233  402  191  165  310  Total  925  1692   Table 1", "ref_id": "TABREF2"}]}, {"section": "Speaker Sentences in Sentences in", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "BASELINE SYSTEMS", "text": "In this section, we present baseline systems for some of the aforementioned tasks. First, we describe the acoustic feature extraction process and then present ASR, LID and mixed ASR results.", "cite_spans": [], "ref_spans": []}, {"section": "Feature extraction", "text": "For all the experiments presented in this paper, we used 39 Mel-Frequency Perceptual Linear Prediction (MF-PLP) features (C0-C12+\u2206+\u2206\u2206), extracted with the HTS variant 5 of the HTK toolkit.", "cite_spans": [], "ref_spans": []}, {"section": "Automatic Speech Recognition", "text": "For the ASR task, we built two independent ASR systems, one for French and one for German. Context dependent triphone Gaussian mixture models were trained using HTS. Each triphone was modeled with three states and each state was modeled with 16 Gaussians. To tie rare states, we applied a conventional decision tree. The minimum description length criterion was used to determine the number of tied states [7] .", "cite_spans": [{"start": 406, "end": 409, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Automatic Speech Recognition", "text": "Bigram language models were independently trained for French and German. For each language, two sources were considered for bigram probabilities estimation: the transcriptions of the training set and texts from the corpus Europarl, a multilingual corpus of European Parliament proceedings [8] . Europarl is made up of about 50 million words for each language and is used to overcome data sparsity of the MediaParl texts. However, vocabularies were limited to the sole words from MediaParl, including words from the development and test sets in order to avoid out-of-vocabulary word problems in the experiments. Statistics from both sources were smoothed using Witten-Bell smoothing and were then linearly interpolated. Interpolation weights were tuned by minimizing the perplexity of the transcriptions of the development set and no pruning was applied. Sizes and perplexities of these monolingual language models are summarized in Table 2 . Decoding was performed with HTS. Language model scaling factor and insertion penalty were tuned on the development sets.", "cite_spans": [{"start": 289, "end": 292, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": [{"start": 932, "end": 939, "text": "Table 2", "ref_id": "TABREF2"}]}, {"section": "Automatic Speech Recognition", "text": "We hypothesized that the standard speech recognition systems would perform worse on non-native speech, owing to the accent associated with even fluent speakers. Table 3 shows the performance of the HMM/GMM systems on French and German respectively for each speaker. It can clearly be seen that the German native speakers perform worse on the French data and vice versa, hence our hypothesis is confirmed. The effect seems to be more pronounced on the French data. This might have to do with the German dictionary, which seems to be suboptimal since it is based on standard German and not on the dialect.", "cite_spans": [], "ref_spans": [{"start": 161, "end": 168, "text": "Table 3", "ref_id": "TABREF3"}]}, {"section": "Language identification", "text": "To perform LID, we applied the recently proposed hierarchical multilayer perceptron (MLP) based language identification approach [9] . The first layer of the hierarchical MLP classifier is a shared phoneme set MLP classifier which was trained on French and German data. The resulting (bilingual) posterior sequence is fed into a second MLP taking a larger temporal context into account. The second MLP can learn implicitly different types of patterns such as confusion between phonemes and phonotactics for LID.", "cite_spans": [{"start": 129, "end": 132, "text": "[9]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Language identification", "text": "To train the shared phoneme set MLP classifier, we built a shared phoneme set by merging French and Ger- Table 4 . LID performance for the different speakers. The performance on all the test data is given in the rightmost column.", "cite_spans": [], "ref_spans": []}, {"section": "Language identification", "text": "The results are also split into French and German data. The system performs better on the native speech for all speakers except 094.", "cite_spans": [], "ref_spans": []}, {"section": "Language identification", "text": "man phonemes if they were represented by the same SAMPA symbol. We used nine frames temporal context (one frame every 10 ms) as input for the MLP. Following a common strategy, the number of hidden units was determined by fixing the number of parameters to 10% of the total number of training samples. As already mentioned, the second MLP was then trained on a larger temporal context. In this study, we used 29 frames. The outputs of the second MLP are language posterior probabilities given the acoustics at the input. Given a test utterance, the frame-based log posteriors for each language are summed up and a decision about the language is made by choosing the language that gets the maximum log posterior probability over the whole utterance. We hypothesized that the LID performance on non-native speech would be lower, for much the same reasons as for ASR. The results of the language identification system can be found in Table 4 . The results are split into French and German data. The LID performance is always better on data of the speaker's mother tongue except for speaker 094, who is a native French speaker. Hence our hypothesis is confirmed. The lower overall performance on French data may be explained by the fact that 49% of the sentences are non-native speech, whereas only 5% of the German sentences are nonnative speech.", "cite_spans": [], "ref_spans": []}, {"section": "Mixed language ASR", "text": "To perform mixed language ASR, we used two different approaches:", "cite_spans": [], "ref_spans": []}, {"section": "Mixed language ASR", "text": "Shared system We built one multilingual decoder trained on the data of both languages. To build the shared system, we first created a shared phoneme set that contains all the German and French phonemes. As we did for the hierarchical LID approach, we merged phonemes that share the same SAMPA symbol. Then we trained GMMs as described for the monolingual systems in Section 6.2. French  279  289  German 554 661 Table 6 . ASR performance of the different speakers. The performance of the shared system, the language switch system and a language switch with oracle LID is given.", "cite_spans": [], "ref_spans": [{"start": 379, "end": 407, "text": "French  279  289  German 554", "ref_id": "TABREF2"}]}, {"section": "DEV TST", "text": "Our multilingual language modeling is similar to an approach presented in [10] . More specifically, all words of training texts used in Section 6.2 and entries of the French and German vocabularies were first labeled with tags corresponding to their respective language 6 . Then, the multilingual vocabulary is defined as the union of tagged monolingual vocabularies. Finally, monolingual bigram probabilities were trained on the tagged texts and linearly interpolated such that each language shared the same probability mass.", "cite_spans": [{"start": 74, "end": 78, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 270, "end": 271, "text": "6", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "DEV TST", "text": "Perplexities of the multilingual language model on the French and German parts of the development and test sets are presented in Table 5 . This preliminary approach is not optimal since the sizes of the vocabularies are not exactly the same. Therefore, in our experiments, the probability of a German word is on average lower than that of a French word. Incorporating this mismatch within linear interpolation should provide better performance.", "cite_spans": [], "ref_spans": [{"start": 129, "end": 136, "text": "Table 5", "ref_id": "TABREF5"}]}, {"section": "DEV TST", "text": "Language switch For this system we first performed LID as described in Section 6.3 and then used the respective monolingual decoder from Section 6.2. For the sake of comparison, we also evaluated a system with oracle LID, i.e., a system where we know the language in advance and pick the correct monolingual recognizer.", "cite_spans": [], "ref_spans": []}, {"section": "DEV TST", "text": "Obviously, the oracle LID system will perform better than the language switch system because the LID errors cannot be corrected after the wrong decoder is chosen. We hypothesized that the language switch system would outperform the shared system because we have already seen in Section 6.3 that the LID performance is close to 100%. Table 6 confirms our hypothesis and shows the mixed language ASR performance for each speaker.", "cite_spans": [], "ref_spans": []}, {"section": "PUBLIC DISTRIBUTION", "text": "We have presented a bilingual mixed language accented database that contains French and German data recorded at the Valais Parliament. The test set contains all the speakers that use both languages during the political debates. We also presented baseline systems for ASR, LID and mixed language ASR.", "cite_spans": [], "ref_spans": []}, {"section": "PUBLIC DISTRIBUTION", "text": "We are happy to announce that this database is publicly available through http://www.idiap.ch/dataset/ mediaparl. The database contains the raw audio recordings, the transcriptions (word level) and the file lists for MediaParl-TRN, MediaParl-DEV and MediaParl-TST. The dictionaries are derived from BDLex and Phonolex, and hence cannot be provided directly. However, they can be generated automatically using scripts provided if those base dictionaries are available and the grapheme-to-phoneme tool is installed. The dictionaries are distributed through ELRA as ELRA-S0004 and ELRA-S0035 respectively; the required software tool, phonetisaurus, is available online 7 .", "cite_spans": [], "ref_spans": []}, {"section": "ACKNOWLEDGEMENT", "text": "We are grateful to the Parliament Service of the State of Valais for providing access to the parliament debate A/V recordings.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "SEAME: a Mandarin-English code-switching speech corpus in south-east asia", "authors": [{"first": "Dau-Cheng", "middle": [], "last": "Lyu", "suffix": ""}], "year": 2010, "venue": "Proc. of Interspeech", "link": "5631708"}, "BIBREF1": {"title": "Bilingual speech corpus in two phonetically similar languages", "authors": [{"first": "V", "middle": [], "last": "Alabau", "suffix": ""}, {"first": "C", "middle": [], "last": "Martinez", "suffix": ""}], "year": 2006, "venue": "International Conference on Language Resources and Evaluation", "link": "10961971"}, "BIBREF2": {"title": "Improving WFST-based G2P conversion with alignment constraints and RNNLM N-best rescoring", "authors": [{"first": "J", "middle": [], "last": "Novak", "suffix": ""}], "year": 2012, "venue": "Proc. of Interspeech", "link": "3161629"}, "BIBREF3": {"title": "The relationship between phonological awareness and orthographic representation in different orthographies", "authors": [{"first": "Usha", "middle": [], "last": "Goswani", "suffix": ""}], "year": 1999, "venue": "", "link": null}, "BIBREF4": {"title": "Graphemeto-phoneme model generation for indo-european languages", "authors": [{"first": "T", "middle": [], "last": "Schlippe", "suffix": ""}, {"first": "T", "middle": [], "last": "Ochs", "suffix": ""}, {"first": "", "middle": [], "last": "Schultz", "suffix": ""}], "year": 2012, "venue": "Proc. of ICASSP", "link": "15942415"}, "BIBREF5": {"title": "Integrating language identification to improve multilingual speech recognition", "authors": [{"first": "Caesar", "middle": [], "last": "Holger", "suffix": ""}], "year": 2012, "venue": "", "link": "62657522"}, "BIBREF6": {"title": "Acoustic modeling based on the MDL principle for speech recognition", "authors": [{"first": "Koichi", "middle": [], "last": "Shinoda", "suffix": ""}, {"first": "Takao", "middle": [], "last": "Watanabe", "suffix": ""}], "year": 1997, "venue": "Proc. of Eurospeech", "link": null}, "BIBREF7": {"title": "Europarl: A parallel corpus for statistical machine translation", "authors": [{"first": "Philipp", "middle": [], "last": "Koehn", "suffix": ""}], "year": 2005, "venue": "Proc. of the 10th Machine Translation Summit", "link": "38407095"}, "BIBREF8": {"title": "Hierarchical multilayer perceptron based language identification", "authors": [{"first": "D", "middle": [], "last": "Imseng", "suffix": ""}, {"first": "M", "middle": [], "last": "Magimai", "suffix": ""}, {"first": "H", "middle": [], "last": "Doss", "suffix": ""}, {"first": "", "middle": [], "last": "Bourlard", "suffix": ""}], "year": 2010, "venue": "Proc. of Interspeech", "link": "14861841"}, "BIBREF9": {"title": "Towards universal speech recognition", "authors": [{"first": "Z", "middle": [], "last": "Wang", "suffix": ""}, {"first": "U", "middle": [], "last": "Topkara", "suffix": ""}, {"first": "T", "middle": [], "last": "Schultz", "suffix": ""}, {"first": "A", "middle": [], "last": "Waibel", "suffix": ""}], "year": 2002, "venue": "Proceedings of the 4th IEEE International Conference on Multimodal Interfaces", "link": "872472"}}, "ref_entries": {"FIGREF0": {"text": "This research was supported by the Swiss NSF through the project In- teractive Cognitive Systems (ICS) under contract number 200021 132619/1 and the National Centre of Competence in Research (NCCR) in Interactive Multimodal Information Management (IM2) http://www.im2.ch", "type": "figure"}, "TABREF0": {"text": "MediaParl speech corpus was recorded at the cantonal parliament of Valais, Switzerland. We used the recordings of Swiss Valaisan parliament debates of the years 2006 and 2009. The parliament debates always take place in the same closed room. Each speaker intervention can last from about 10 seconds up to 15 minutes. Speakers are sitting or stand- ing when talking and their voice is recorded through a distant microphone. The recordings from 2009 that were processed at Idiap Research Institute are also available as video streams online 1 . The audio recordings of the year 2006 were formatted as \"mp3\", more specifically MPEG ADTS, layer III, v1, 128 kbps, 44.1 kHz, Monaural with16 bits per sample. The video recordings of the year 2009 were formatted as \"avi\" with un- compressed PCM (stereo, 48000 Hz, 16 bits per sample) au- dio data. All the audio data (2006 and 2009) was converted to WAVE audio, Microsoft PCM, 16 bit, mono 16000 Hz prior to any processing.", "type": "table"}, "TABREF1": {"text": "5 http://hts.sp.nitech.ac.jp/", "type": "table"}, "TABREF2": {"text": "Statistics of the monolingual language models.", "type": "table"}, "TABREF3": {"text": "", "type": "table"}, "TABREF5": {"text": "Perplexities of the multilingual language model on the French and German parts of MediaParl-DEV and MediaParl-TST.", "type": "table"}}}
{"paper_id": "2876053", "_pdf_hash": "e1fb8ab53996f06e9a35de6b553333bd6279bcbd", "abstract": [{"section": "Abstract", "text": "Abstract-Pedestrian detection based on the combination of Convolutional Neural Network (i.e., CNN) and traditional handcrafted features (i.e., HOG+LUV) has achieved great success. Generally, HOG+LUV are used to generate the candidate proposals and then CNN classifies these proposals. Despite its success, there is still room for improvement. For example, CNN classifies these proposals by the full-connected layer features while proposal scores and the features in the inner-layers of CNN are ignored. In this paper, we propose a unifying framework called Multi-layer Channel Features (MCF) to overcome the drawback. It firstly integrates HOG+LUV with each layer of CNN into a multi-layer image channels. Based on the multi-layer image channels, a multi-stage cascade AdaBoost is then learned. The weak classifiers in each stage of the multi-stage cascade is learned from the image channels of corresponding layer. With more abundant features, MCF achieves the state-of-the-art on Caltech pedestrian dataset (i.e., 10.40% miss rate). Using new and accurate annotations, MCF achieves 7.98% miss rate. As many non-pedestrian detection windows can be quickly rejected by the first few stages, it accelerates detection speed by 1.43 times. By eliminating the highly overlapped detection windows with lower scores after the first stage, it's 4.07 times faster with negligible performance loss.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "I. INTRODUCTION", "text": "P EDESTRIAN detection based on Convolutional Neural Network (i.e., CNN) has achieved great success recently [5] , [30] , [6] , [4] , [8] . The main process of CNN based methods can be divided into two steps: proposal extraction and CNN classification. Firstly, the candidate proposals are extracted by the traditional pedestrian detection algorithm (e.g., ACF [11] and LDCF [22] ). Then, these proposals are classified into pedestrian or non-pedestrian by the CNN [6] , [1] .", "cite_spans": [{"start": 108, "end": 111, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 114, "end": 118, "text": "[30]", "ref_id": "BIBREF29"}, {"start": 121, "end": 124, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 127, "end": 130, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 133, "end": 136, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 360, "end": 364, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 374, "end": 378, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 464, "end": 467, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 470, "end": 473, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "Despite its great success, it still exists some room to improve it. 1) Most methods only use the last layer features in CNN with softmax or SVM to classify the proposals. In fact, different layers in CNN represents the different image characteristic. The first few layers can better describe the image local variance, whereas the last few layers abstract the image global structure. It means that each layer in CNN contains different discriminative features, which can be used for learning the classifier. traditional methods based on the handcrafted features (i.e., HOG+LUV [10] ) to generate the candidate proposals while ignoring the proposal scores. 3) Due to the large amount of convolutional operations, the methods based very deep CNN (e.g., VGG16 [25] ) run very slowly on the common CPU (e.g., about 8s).", "cite_spans": [{"start": 575, "end": 579, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 755, "end": 759, "text": "[25]", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "Recently, researchers have done some work to solve the above problems. Li et al. [35] proposed to train the cascaded multiple CNN models of different resolutions. As the low resolution CNN can early reject many background regions, it avoids scanning the full image with high resolution CNN and then reduces the computation cost. However, the training process of multiple CNN models is relatively complex. Cai et al. [1] proposed the complexity-aware cascade to seamlessly integrate handcrafted features and the last layer features in CNN into a unifying detector. However, it still does not make full use of the multi-layer features in CNN. Bell et al. [19] concatenated the multiple layers of CNN into the fixedsize ROI pooling. With more abundant feature abstraction, it outperforms fast-RCNN [18] . Though its success, it needs complex operations of L2-normalized, concatenated, scaled, and dimension-reduced. Moreover, it ignores the scores of the proposals.", "cite_spans": [{"start": 81, "end": 85, "text": "[35]", "ref_id": "BIBREF34"}, {"start": 416, "end": 419, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 653, "end": 657, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 795, "end": 799, "text": "[18]", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "In this paper, we propose a unifying framework, which is called Multi-layer Channel Features (MCF). Firstly, it integrates handcrafted image channels (i.e., HOG+LUV) and each layer of CNN into the multi-layer image channels. HOG+LUV image channels are set as the first layer, which contains 10 image channels. The layers in CNN correspond to the remaining layers, respectively. Secondly, zero-order, one-order, and high-order features are extracted to generate a large number of candidate feature pools in each layer. Finally, a multi-stage cascade AdaBoost is used to select the discriminative features and efficiently classify object and background. The weak classifiers in each stage of multi-stage cascade are learned based on the candidate features from corresponding layer. To further accelerate detection speed, the highly overlapped detection windows with lower scores are eliminated after the first stage. Overall, the contributions of this paper and the merits of the proposed methods (MCF) can be summarized as follows:", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "1 [37] of the test set, MCF achieves 7.98% miss rate, which is superior to other methods. The rest of the paper is organized as follows. Firstly, we give a review about pedestrian detection. Then, our methods are introduced in Sec. III. Sec. IV shows the experimental results. Finally, we conclude this paper in Sec. V.", "cite_spans": [{"start": 2, "end": 6, "text": "[37]", "ref_id": "BIBREF36"}], "ref_spans": []}, {"section": "II. RELATED WORK", "text": "According to whether or not CNN is used, pedestrian detection can be divided into two main manners: the handcrafted channels based methods and CNN based methods. Handcrafted channels based methods are relatively simple and efficient, whereas CNN based methods are much more effective but inefficient. We firstly give a review about the handcrafted channels based methods and then introduce some methods based on CNN.", "cite_spans": [], "ref_spans": []}, {"section": "II. RELATED WORK", "text": "Haar features based cascade AdaBoost detector is one of the most famous object detection methods [14] , [33] . It can quickly reject a large number of non-object detection windows by the early stages of the cascade. Dalal and Triggs [12] proposed to use the Histogram of Oriented Gradients (HOG) to describe the image local variance. It can work very well with a linear SVM. To handle pose variations of objects, Felzenszwalb et al. [13] proposed the Deformable Part Model (DPM) based on HOG features, which is a mixture of six deformable part models and one root model.", "cite_spans": [{"start": 97, "end": 101, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 104, "end": 108, "text": "[33]", "ref_id": "BIBREF32"}, {"start": 233, "end": 237, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 433, "end": 437, "text": "[13]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "II. RELATED WORK", "text": "By integrating cascade AdaBoost [14] , [20] and HOG features [12] , Doll\u00e1r et al. [10] proposed Integral Channel Features (ICF). Firstly, it extracts the local sum features from HOG channels and LUV color channels (i.e., HOG+LUV). Then, cascade AdaBoost [20] , [36] is used to learn the classifier. To further speedup the detection, Doll\u00e1r et al. [11] then proposed Aggregated Channel Features (ACF), which downsamples the image channels by a factor of 4.", "cite_spans": [{"start": 32, "end": 36, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 39, "end": 43, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 61, "end": 65, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 82, "end": 86, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 254, "end": 258, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 261, "end": 265, "text": "[36]", "ref_id": "BIBREF35"}, {"start": 347, "end": 351, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "II. RELATED WORK", "text": "Following ICF [10] , SquaresChnFtrs [9] , InformedHaar [21] , LDCF [22] , Filtered Channel Features (FCF) [7] , and NNNF [31] have also been proposed. They all employ the same image channels (i.e., HOG+LUV) as ICF. In SquaresChnFtrs [9] , the pixel sums of local square regions in each channel are used for learning the classifier. InformedHaar [21] incorporates the statistical pedestrian model into the design of simple haar-like features. Inspired by [23] , Nam et al. [22] proposed to calculate the decorrelated channels by convolving the PCA-like [24] filters with HOG+LUV image channels. Recently, Zhang et al. [7] proposed to put the above different types of channel features into a unifying framework (i.e., FCF). FCF generates the candidate feature pool by convolving a filter bank (RadomFilters, Checkerboards, etc) with HOG+LUV image channels. It's found that using the simple Checkboards filters could achieve very good performance. Based on the appearance constancy and shape symmetry, Cao et al. [31] proposed NNNF features.", "cite_spans": [{"start": 14, "end": 18, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 36, "end": 39, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 55, "end": 59, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 67, "end": 71, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 106, "end": 109, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 121, "end": 125, "text": "[31]", "ref_id": "BIBREF30"}, {"start": 233, "end": 236, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 345, "end": 349, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 454, "end": 458, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 472, "end": 476, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 552, "end": 556, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 617, "end": 620, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 1010, "end": 1014, "text": "[31]", "ref_id": "BIBREF30"}], "ref_spans": []}, {"section": "II. RELATED WORK", "text": "Recently, deep Convolutional Neural Network (CNN) based methods have also achieved great success in object detection [26] , [15] , [19] , [29] , [18] , [27] , [28] . Generally speaking, it firstly generates the candidate object proposals [17] , [16] and then uses the trained CNN model [26] , [15] to classify these proposals. Hosang et al. [6] generalized CNN model for pedestrian detection after using the handcrafted features based methods to extract the candidate pedestrian proposals. To eliminate the number of hard negative proposals in the background, Tian et al. [3] proposed to jointly optimize pedestrian detection with semantic tasks. Recently, Tian et al. [2] proposed to learn deep strong part models to handle the problem of pedestrian occlusion. Li et al. [4] proposed the scale-aware fast-RCNN by incorporating a large scale sub-network and a small scale sub-network into a unifying architecture.", "cite_spans": [{"start": 117, "end": 121, "text": "[26]", "ref_id": "BIBREF25"}, {"start": 124, "end": 128, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 131, "end": 135, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 138, "end": 142, "text": "[29]", "ref_id": "BIBREF28"}, {"start": 145, "end": 149, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 152, "end": 156, "text": "[27]", "ref_id": "BIBREF26"}, {"start": 159, "end": 163, "text": "[28]", "ref_id": "BIBREF27"}, {"start": 238, "end": 242, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 245, "end": 249, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 286, "end": 290, "text": "[26]", "ref_id": "BIBREF25"}, {"start": 293, "end": 297, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 341, "end": 344, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 572, "end": 575, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 669, "end": 672, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 772, "end": 775, "text": "[4]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "II. RELATED WORK", "text": "Despite the success of CNN based pedestrian detection, it still exists some room to improve it. Firstly, the score information of the candidate proposals can be used to boost the detection performance. Secondly, each layer in CNN contains some discriminative features, which can be used for learning classifier and rejecting non-pedestrian detection windows early. Cai et al. [1] proposed to seamlessly integrate CNN and handcrafted features. Though it uses the proposal score information, it still ignores features of the inner layer of CNN. Sermanet et al. [5] proposed to concatenate the first layer feature and the second layer together. Bell et al. [19] proposed to use skip pooling to integrate multiple layers. It's called skip-layer connections. Despite its success, there is still some problems: 1) It ignores the proposals scores;", "cite_spans": [{"start": 376, "end": 379, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 559, "end": 562, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 654, "end": 658, "text": "[19]", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "II. RELATED WORK", "text": "2) The proposal should pass through the whole CNN before classification; 3) The skip-layer operations in [19] is relatively complex.", "cite_spans": [{"start": 105, "end": 109, "text": "[19]", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "III. OUR METHODS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "A. Multi-layer Channel Features (MCF)", "text": "The layers in CNN represent the different and diverse image characteristic. The image channels in the first few layers can better describe the image local variance, while the image channels in the last few layers can abstract the image global structure. Meanwhile, the handcrafted image channels (e.g., HOG+LUV) can be also able to describe the image variations very well. HOG channels can describe the image local edge directions and variances. LUV channels capture the image color information. Compared to the layers in CNN, the handcrafted image channels are very simple and efficient. In this paper, we integrate HOG+LUV and the layers of CNN to construct Multi-layer Channel Features (MCF). First of all, we give an overview about our proposed Multilayer Channel Features (i.e., MCF). Fig. 1 show the basic architecture of MCF. It can be divided into three parts: 1) Firstly, multi-layer image channels from L1 to LN are generated. The traditional handcrafted image channels (i.e., HOG+LUV) are used for the first layer (i.e., L1). The convolutional layers from C1 to C(N-1) in CNN construct the remaining layers from L2 to LN. In each layer, there are multiple image channels.", "cite_spans": [], "ref_spans": [{"start": 790, "end": 796, "text": "Fig. 1", "ref_id": "FIGREF1"}]}, {"section": "A. Multi-layer Channel Features (MCF)", "text": "2) The second step is feature extraction. Zero-order, oneorder, and high-order features can be calculated in the image channels of each layer. 3) Finally, the multi-stage cascade AdaBoost is learned from the candidate features of each layer one after another. The weak classifiers in each stage of multi-stage cascade are learned from the candidate features of corresponding layer. For example, the weak classifiers in Stage 2 (i.e., S2) are learned from candidate features F2 of Layer 2 (i.e., L2). Fig. 2 shows the test process of MCF. Give the test image, the image channels in L1 (i.e., HOG+LUV) are firstly computed. Detection windows are generated by scanning the test image. These detection windows are classified by S1 using the weak classifiers learned from L1. Some detection windows will be rejected by S1. For the detection windows accepted by S1, the image channels in L2 are computed. Then the accepted detection windows are classified by S2 using the weak classifiers learned from L2. The above process is repeated from L1 to LN. Finally, the detection windows accepted by all the stages (i.e., S1 to SN) will be merged by NMS. The merged detection windows are the final pedestrian windows.", "cite_spans": [], "ref_spans": [{"start": 500, "end": 506, "text": "Fig. 2", "ref_id": "FIGREF0"}]}, {"section": "A. Multi-layer Channel Features (MCF)", "text": "Multi-layer Image Channels Row 1 in Fig. 1 shows the multi-layer image Channels. It consists of N layers. In each layer, there are multiple image channels. Table I shows the specific parameters of multi-layer image channels based on HOG+LUV and VGG16. It contains six layers from L1 to L6. L1 is the handcrafted image channels (i.e., HOG+LUV). L2-L6 are five convolutional layers (i.e., C1-C5) in VGG16. Row 3 shows the image size in each layer. The image size in L1 is 128 \u00d7 64. The sizes of L2-L6 are 64 \u00d7 32, 32 \u00d7 16, 16 \u00d7 8, 8 \u00d7 4, and 4 \u00d7 2, respectively. Row 4 shows the number of the channels in each layer. L1 contains 10 image channels. L2-L6 each have 64, 128, 256, 512, and 512 image channels, respectively. In Table I , all the convolutional layers in CNN (i.e., C1 to C5) are used for constructing the multilayer image channels. In fact, only part convolutional layers in CNN can also construct the multi-layer image channels. For example, a five-layer image channels can be generated by HOG+LUV and C2-C5 of VGG16. C1 of VGG16 is not used. The corresponding MCF are shown in Fig. 3 . Feature Extraction Features can be divided into three classes: zero-order feature, one-order feature, and high-order feature. In zero-order feature extraction, a single pixel itself is used as a feature and no neighboring pixels are used. Oneorder feature is defined as the pixel sums or averages in the local or non-local regions in each channel. High-order feature defined by the difference of the sums or averages of two or more different regions. For L1 (i.e., HOG+LUV), there are many successful methods for feature extraction, including ICF [10] , ACF [11] , SquaresChnFtrs [9] , Informed- Haar [21] , LDCF [22] , FCF [7] , and NNNF [31] . ICF, ACF, and SquaresChnFtrs can be seen as one-order features. InformedHaar, LDCF, FCF, and NNNF are high-order features.", "cite_spans": [{"start": 1645, "end": 1649, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 1656, "end": 1660, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 1678, "end": 1681, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 1699, "end": 1703, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 1711, "end": 1715, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 1722, "end": 1725, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 1737, "end": 1741, "text": "[31]", "ref_id": "BIBREF30"}], "ref_spans": [{"start": 36, "end": 42, "text": "Fig. 1", "ref_id": "FIGREF1"}, {"start": 156, "end": 163, "text": "Table I", "ref_id": "TABREF1"}, {"start": 722, "end": 729, "text": "Table I", "ref_id": "TABREF1"}, {"start": 1089, "end": 1095, "text": "Fig. 3", "ref_id": "FIGREF4"}]}, {"section": "A. Multi-layer Channel Features (MCF)", "text": "Compared to the other features, ACF has the fastest detection speed. NNNF has the best trade-off between detection speed and detection performance. Due to the simplicity and effectiveness, ACF and NNNF are used for feature exaction in L1. The number of image channels from CNN is relatively large. For example, the fourth convolutional layer (i.e., C4) in VGG16 has 512 image channels (see Table I ). To reduce the computation cost and avoid a very large number of candidate features, only zero-order feature is used. It means that each pixel value in image channels of each layer is used for the candidate feature. The specific feature extraction in multi-layer image channels can be seen in Fig. 4 . Multi-stage Cascade AdaBoost Cascade AdaBoost is a popular method for object detection. Based on multi-layer image channels, we propose the multi-stage cascade AdaBoost for pedestrian detection. ", "cite_spans": [], "ref_spans": [{"start": 390, "end": 397, "text": "Table I", "ref_id": "TABREF1"}, {"start": 693, "end": 699, "text": "Fig. 4", "ref_id": "FIGREF5"}]}, {"section": "A. Multi-layer Channel Features (MCF)", "text": "where x represents the samples (windows), h j i (x) represents the j-th weak classifier in Stage i. k 1 , k 2 , ..., k N are the number of weak classifiers in each stage, respectively. How to set the value of k 1 , k 2 , ..., k N is an open problem. In this paper, one of simple structure is used as the follows: where N All represents the number of the total weak classifiers. Based on soft-cascade [20] , the reject thresholds are set after each weak classifier.", "cite_spans": [{"start": 400, "end": 404, "text": "[20]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "A. Multi-layer Channel Features (MCF)", "text": "The advantages about the multi-stage cascade AdaBoost structure can be concluded as the following: 1) Firstly, it avoids learning classifier from a very large feature pooling (e.g., more than one million); 2) Secondly, it makes full use of the information from multi-layer image channels. Thus, it can enrich the feature abstraction. 3) Finally, many non-pedestrian detection windows can be quickly rejected by the features in the first few layers. Thus, it avoids the computation cost of the remaining layers in CNN and accelerates the detection speed.", "cite_spans": [], "ref_spans": []}, {"section": "B. Elimination of Highly Overlapped Windows", "text": "Pedestrian detection is a multiple instance problem. Generally, the adjacent area around the pedestrian exists many positive detection windows. Many of these positive detection windows around pedestrians highly overlap. Though multi-stage cascade AdaBoost structure can reject many non-pedestrian detection windows, it cannot reject the positive detection windows around pedestrians. When the cascade classifier based on very deep CNN (e.g., VGG16), the computation cost of these positive detection windows are large.", "cite_spans": [], "ref_spans": []}, {"section": "B. Elimination of Highly Overlapped Windows", "text": "In fact, there is no need to put all the highly overlapped windows accepted by first stage into the remaining stages. Detection windows accepted by the first stage each have a classification score. The highly overlapped windows with lower scores can be eliminated after the first stage. To eliminate these highly overlapped windows with lower scores, NonMaximum Suppression (i.e., NMS) is used after the first stage. The overlap ratio O(w 1 , w 2 ) of detection windows can be defined in the following:", "cite_spans": [], "ref_spans": []}, {"section": "B. Elimination of Highly Overlapped Windows", "text": "where w 1 and w 2 are two detection windows. If O(w 1 , w 2 ) > \u03b8, it means that w 1 and w 2 highly overlap. Then the detection window with lower score will be eliminated. Instead of the standard threshold \u03b8 = 0.5, a larger threshold is used here. Experimental results show that \u03b8 = 0.8 can accelerate the detection speed with little performance loss. Fig. 6 shows the specific test process of MCF by eliminating highly overlapped detection windows.", "cite_spans": [], "ref_spans": [{"start": 352, "end": 358, "text": "Fig. 6", "ref_id": "FIGREF7"}]}, {"section": "IV. EXPERIMENTS", "text": "The challenging Caltech pedestrian detection dataset [32] , [34] is employed for the evaluation. It consists of 11 videos. The first 6 videos are used for training and the rest videos are used for testing. The raw training images are formed To enlarge the training samples, Caltech10x is used. It samples one image per 3 frames in the training videos. As a result, there are 42,782 images in which there are 16,376 positive samples. Please note that the testing data is same as [32] , [34] whenever the Caltech or Caltech10x is used. It contains 4024 images in which there are 1014 pedestrians.", "cite_spans": [{"start": 53, "end": 57, "text": "[32]", "ref_id": "BIBREF31"}, {"start": 60, "end": 64, "text": "[34]", "ref_id": "BIBREF33"}, {"start": 478, "end": 482, "text": "[32]", "ref_id": "BIBREF31"}, {"start": 485, "end": 489, "text": "[34]", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "IV. EXPERIMENTS", "text": "The first layer in MCF is HOG+LUV image channels [10] , which contains one normalized gradient magnitude channel, six histograms of oriented gradient channels, and three color channels. Two popular CNN models (i.e., AlexNet [26] and VGG16 [25] ) are used for constructing the remaining layers in MCF. Instead of using original input size 227 \u00d7 227 or 224 \u00d7 224, we use the size 128 \u00d7 64 for pedestrian detection. For AlexNet, stride 4 in the first convolutional layer is replaced by stride 2. The input size 6\u00d76 in the first full connected layer is replaced by the size 8 \u00d7 4. For VGG16, the input size 7 \u00d7 7 of the first full connected layer is replaced by the size 4 \u00d7 2. The other initial parameters follow the pre-trained models on ImageNet. The final parameters in AlexNet and VGG16 are fine-tuned on the Caltech10x. \u221a means that the corresponding layer is used for MCF. HOG+LUV image channels are always used for the first layer. The layers (i.e., C1, C2, ... or C5) are used for the remaining layers. MCF-N means that there are N layers in MCF. For example, MCF-3 in Row 3 are generated by HOG+LUV, C4 and C5 of AlexNet. The first layer is HOG+LUV image channels. The second layer is the fourth convolutional layer (i.e., C4) of AlexNet. The last layer is the fifth layer (i.e., C5) of AlexNet. Based on multi-layer image channels, the corresponding multi-stage cascade is learned. There are the following observations from Table II : 1) Compared to MCF-2, MCF-N (N>2) usually achieves the better performance. For example, the miss rate of MCF-6 based on VGG16 in the last row is lower than that of MCF-2 by 4.21%; 2) Generally, with increase of the layer number, the miss rate of MCF becomes lower and the detection performance becomes better. The above observations demonstrate that the middle layers in CNN can enrich the feature abstraction. It means that each layer in CNN contains some discriminative features, which can be used for classification. Table III shows the average number and the ratio of detection windows rejected by each stage in MCF-6. MCF-6 is based on HOG+LUV and all the five convolutional layers in CNN. Thus, the multi-stage cascade AdaBoost in MCF has six stages from S1 to S6. '*' means that the average number of detection windows accepted by stage 1, instead of that rejected by stage 1, is shown. As the weak classifiers in S1 are both learned from HOG+LUV, the number of detection windows accepted by S1 are same (i.e., 159). Among the 159 accepted detection windows, about 71% and 76.1% detection windows are rejected by the cascade based on AlexNet and that based on VGG16, respectively. Overall, the multi-stage cascade based on VGG16 can reject more detection windows. Specifically, the first two stage stages (i.e., S2 and S3) based on AlexNet reject more detection windows than that based on VGG16. The middle two stages (i.e., S4 and S5) based on VGG16 can reject more detection windows than that based on AlexNet.", "cite_spans": [{"start": 49, "end": 53, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 224, "end": 228, "text": "[26]", "ref_id": "BIBREF25"}, {"start": 239, "end": 243, "text": "[25]", "ref_id": "BIBREF24"}], "ref_spans": [{"start": 1431, "end": 1439, "text": "Table II", "ref_id": "TABREF1"}, {"start": 1962, "end": 1971, "text": "Table III", "ref_id": "TABREF1"}]}, {"section": "IV. EXPERIMENTS", "text": "As multi-stage cascade can reject many detection windows by the first few stages, MCF can accelerate the detection speed. Table IV compares the detection time and detection performance between MCF-2 and MCF-6. MCF-2 uses HOG+LUV and C5 in CNN to construct two-layer image channels. Then two-stage cascade is learned. MCF-6 uses HOG+LUV and all the five convolutional layers from C1 to C5 in CNN to Though the speed of MCF-6 is faster than that of MCF-2, it's still very slow. To further accelerate the detection speed, the highly overlapped detection windows with lower scores accepted by the first stage (i.e., S1) are eliminated by NMS. As stated in section III.B, the threshold \u03b8 is an important factor to balance detection speed and detection performance. Table  V shows that miss rates and detection time vary with \u03b8. MCF-2 and MCF-6 based on HOG+LUV and AlexNet in Table IV are used for the baseline (i.e., \u03b8 =INF). When \u03b8 = 0.5, the detection speed is very fast, but the detection performance drops rapidly. For MCF-6, the detection speed of MCF-6 with \u03b8 = 0.5 is 6.76 times faster than original MCF, while the miss rate of MCF with \u03b8 = 0.5 is higher than original MCF by 3.36%. Thus, it's not a good choice. When \u03b8 = 0.9, the detection performance is almost no loss, while the detection speed is not significantly improved. Thus, the trade-off choice is \u03b8 = 0.8. With little performance loss (e.g., 0.77%) in MCF-6, it's 2.67 times faster than original MCF. In the following section, MCF with \u03b8 = 0.8 are called MCF-f. Table VI summarizes MCF-2, MCF-6 and MCF-6-f. MCF-6-f is the fast version of MCF-6, where the highly overlapped detection windows are eliminated after the first stage. There are the following observations: 1) MCF-6 and MCF-6-f both have the lower miss rates. Specifically, MCF-6 and MCF-6-f based on AlexNet have lower miss rates than MCF-2 by 2.79% and 2.02%, respectively. MCF-6 and MCF-6-f based on VGG16 have lower miss rates than MCF-2 by 4.21% and ", "cite_spans": [], "ref_spans": [{"start": 122, "end": 130, "text": "Table IV", "ref_id": "TABREF1"}, {"start": 760, "end": 768, "text": "Table  V", "ref_id": "TABREF5"}, {"start": 871, "end": 879, "text": "Table IV", "ref_id": "TABREF1"}, {"start": 1527, "end": 1535, "text": "Table VI", "ref_id": "TABREF1"}]}, {"section": "B. Comparison with the state-of-the-Art", "text": "In this section, MCF is based on HOG+LUV and all the five convolutional layers (i.e., C1-C5) in VGG16. Thus, MCF contains six-layer image channels. The features extracted in the first layer (i.e., HOG+LUV) are NNNF [31] , which is one of the state-of-the-art features. The features extracted in the remaining five layers (i.e., C1-C5) are zero-order feature (single pixel). Caltech10x is used for training the final classifier. To speedup the training process, negative samples are accumulated by five rounds of original NNNF, where the number of the trees in each round is 32, 128, 512, 2048, and 4096, respectively. The resulting classifier contains 4096 level-4 decision trees. S1 contains 2048 decision trees. S2-S6 each have 409 decision trees. In [37] , Zhang et al. provided a new, high quality ground truth for the training and test sets. The new annotations of Caltech10x is also used for training MCF. Original Caltech test set and new Caltech test set are both used for the evaluations. Fig. 7 compares MCF with some state-of-the-art methods on the original annotations of the test set. ACF [11] , LDCF [22] , Checkboards [7] , NNNF [31] , DeepParts [2] , and CompACTDeep [1] are used. ACF [10] are trained on INRIA dataset [12] . The other methods are trained based on Caltech10x dataset. MCF achieves the state-of-the-art performance, which outperforms CompACT-Deep [1] , DeepParts [2] , NNNF [31] , and Checkboards [7] by 1.35%, 1.49%, 6.38%, and 8.07%, respectively.", "cite_spans": [{"start": 215, "end": 219, "text": "[31]", "ref_id": "BIBREF30"}, {"start": 753, "end": 757, "text": "[37]", "ref_id": "BIBREF36"}, {"start": 1102, "end": 1106, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 1114, "end": 1118, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 1133, "end": 1136, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 1144, "end": 1148, "text": "[31]", "ref_id": "BIBREF30"}, {"start": 1161, "end": 1164, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 1183, "end": 1186, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 1201, "end": 1205, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 1235, "end": 1239, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 1379, "end": 1382, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 1395, "end": 1398, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 1406, "end": 1410, "text": "[31]", "ref_id": "BIBREF30"}, {"start": 1429, "end": 1432, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "B. Comparison with the state-of-the-Art", "text": "Miss rates and Frames Per Second (FPS) of some methods based on CNN are visualized in Fig. 8 . Detection time of the methods are all tested on the common CPU (i.e., Intel Core i7-3700). The best choice is that the miss rate is as small as possible while FPS is as large as possible. Though ACF [11] has very fast detection speed (9.49 fps), miss rate of ACF are very large. Fast RCNN reported in [4] has the better .", "cite_spans": [{"start": 294, "end": 298, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 396, "end": 399, "text": "[4]", "ref_id": "BIBREF3"}], "ref_spans": [{"start": 86, "end": 92, "text": "Fig. 8", "ref_id": "FIGREF11"}]}, {"section": "30", "text": ".", "cite_spans": [], "ref_spans": []}, {"section": "40", "text": ".50", "cite_spans": [], "ref_spans": []}, {"section": "40", "text": ".64", "cite_spans": [], "ref_spans": []}, {"section": "40", "text": ". performance (11.82%), but the speed is very slow. MCF-f is the fast version of MCF with little performance loss (0.65%). Compared to Fast RCNN [4] , MCF is 4.5 times faster than it, while MCF has also lower miss rate than it by 0.77%. Therefore, MCF has a better trade-off between detection time and detection performance. Based on the new and accurate annotations of the Caltech test set, Fig. 9 compares MCF with some state-of-the-art meth-ods: CompACT-Deep [1] , DeepParts [2] , Checkboards [7] , and NNNF [31] . Miss rates log-averaged over the FPPI range of [ [2] , and NNNF [31] . Compared to M R \u22122 of MCF, M R \u2212 4 of MCF has the better performance. Specifically, M R \u22124 of MCF is 3.39%, 9.70%, and 10.05% lower than that of CompACTDeep [1] , DeepParts [2] , and NNNF [31] . It means that MCF stably outperforms the other state-of-the-art methods.", "cite_spans": [{"start": 145, "end": 148, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 462, "end": 465, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 478, "end": 481, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 496, "end": 499, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 511, "end": 515, "text": "[31]", "ref_id": "BIBREF30"}, {"start": 567, "end": 570, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 582, "end": 586, "text": "[31]", "ref_id": "BIBREF30"}, {"start": 746, "end": 749, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 762, "end": 765, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 777, "end": 781, "text": "[31]", "ref_id": "BIBREF30"}], "ref_spans": [{"start": 392, "end": 398, "text": "Fig. 9", "ref_id": "FIGREF13"}]}, {"section": "40", "text": "V. CONCLUSION In this paper, we have proposed a unifying framework, which is called Multi-layer Channels Features (MCF). Firstly, the handcrafted image channels and the layers in CNN construct the multi-layer image channels. Then a multi-stage cascade are learned from the features extracted in the layers, respectively. The weak classifiers in each stage are learned from the corresponding layer. On the one hand, due to the much more abundant candidate features, MCF achieves the state-of-the-art performance on Caltech pedestrian dataset (i.e., 10.40% miss rate). Using the new and accurate annotations of the Caltech pedestrian dataset, miss rate of MCF is 7.98%, which is superior to other methods. On the other hand, due to the cascade structure, MCF rejects many detection windows by the first few stages and then accelerates the detection speed. To further speedup the detection, the highly overlapped detection windows are eliminated after the first stage. 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China. e-mail: xuelong li@opt.ac.cn.", "type": "figure"}, "FIGREF1": {"text": "Fig. 1. The basic architecture of MCF. It can be divided into three steps: multi-layer channel generation, feature extraction, and multi-stage cascade AdaBoost classifier.", "type": "figure"}, "FIGREF3": {"text": "Fig. 2. Test process of basic MCF.", "type": "figure"}, "FIGREF4": {"text": "Fig. 3. MCF are generated by HOG+LUV and C2-C5 of VGG16. C1 of VGG16 are not used for constructing MCF.", "type": "figure"}, "FIGREF5": {"text": "Fig. 4. Feature Extraction in Multi-layer image channels. (a) feature extraction in L1 (HOG+LUV), where one-order (ACF) and high-order features (NNNF) are used. (b) feature extraction in L2-LN (the layers of CNN), where zeroorder features are extracted. Zero-order feature means that a single pixel value in each channel is used as a feature.", "type": "figure"}, "FIGREF6": {"text": "Fig. 5 gives the specific explanations about multi-stage cascade. The features in Si are learned from the candidate features Fi of Li, where i=1, 2, ..., N. Firstly, k 1 weak classifiers in S1 are learned from the candidate features F1 extracted from L1. Based on the hard negative samples and positive samples, k 2 weak classifiers in S2 are then learned from F2. The remaining stages are trained in the same manner. Finally, multi-stage (i.e., N-stage) cascade AdaBoost classifier can be obtained. This strong classifier H(x) can be expressed as the following equation:", "type": "figure"}, "FIGREF7": {"text": "Fig. 6. Test process of the fast version of MCF where the technique of NMS is used to eliminating highly overlapped detection windows with lower scores.", "type": "figure"}, "FIGREF8": {"text": "Feature extraction in L1 (i.e., HOG+LUV) is ACF [11] (Section IV.A) or NNNF [31] (Section IV.B). Feature ex- traction in the remaining layers (i.e., the layers of CNN) is zero-order feature (single pixel). The final classifier consists of 4096 level-2 or level-4 decision trees. The decision tree number of each stage are k 1 = 2048, k 2 = k 3 = ... = k N = 2048/(N \u2212 1), respectively. N is the number of the layers in MCF.", "type": "figure"}, "FIGREF9": {"text": "A. Self-Comparison of MCF In this section, some intermediate experimental results on original Caltech training set are reported to show how to setup the effective and efficient MCF. Some specific experimental setup is as follows. HOG+LUV are used for the first layer. The convolutional layers in CNN (i.e., AlexNet or VGG16) correspond to the remaining layers. The feature extraction in HOG+LUV is ACF. Feature extraction in the layers of CNN is just zero-order feature (single pixel). To speed up the training, negative samples are generated by five round training of original ACF [11], where the number of trees in each round are 32, 128, 512, 1024, and 2048, respectively. Finally, multi-stage cascade which consists of 4096 level-2 decision trees is learned based on these negative samples and positive samples. The first stage contains the first 2048 decision trees. The remaining stages equally split the remaining 2048 decision trees. For example, HOG+LUV and C2 to C5 of CNN construct a five-layer image channels. Then, the corresponding five-stage cascade can be learned. The first stage S1 has 2048 weak classifiers. The remaining stages (i.e., S2-S5) each have 512 weak classifiers. Miss Rates are log-averaged over the range of FPPI = [10 \u22122 ,10 0 ], where FPPI represents False Positive Per Image. Table II shows Miss Rates (MR) of MCF based on HOG+LUV and the different layers in CNN. The results based on AlexNet and VGG16 are both shown here.", "type": "figure"}, "FIGREF11": {"text": "Fig. 8. Miss rates and FPS on Caltech pedestrian dataset are shown. Detection time of the methods are all tested on the common CPU (i.e., Intel Core i7-3700).", "type": "figure"}, "FIGREF13": {"text": "Fig. 9. ROC of Caltech test set using the new and accurate annotations [37]. Miss rates log-averaged over the FPPI range of [10 \u22122 ,10 0 ] and the FPPI range of [10 \u22124 ,10 0 ] are shown. They are represented by M R \u22122 and M R \u22124 , respectively. M R \u22122 (M R \u22124 ) are shown in the legend.", "type": "figure"}, "TABREF0": {"text": ") The unifying framework MCF is proposed. MCF seam- lessly integrates HOG+LUV image channels and each layer of CNN into a unifying multi-layer image chan- nels. Due to the diverse characteristic of different layers, these layers can provide more rich feature abstractions. 2) Multi-stage cascade AdaBoost is learned from multi- layer image channels. It can achieve better performance with more abundant feature abstractions and quickly reject many detection windows by the first few stages. 3) The highly overlapped detection windows with lower scores are eliminated after the first stage. Thus, it can reduce the large computation cost of CNN operations.", "type": "table"}, "TABREF1": {"text": "MULTI-LAYER IMAGE CHANNELS. THE FIRST LAYER IS HOG+LUV, THE REMAINING LAYERS ARE THE CONVOLUTIONAL LAYERS (I.E., C1 TO C5) IN VGG16.", "type": "table"}, "TABREF2": {"text": "Fig. 5. Multi-stage cascade AdaBoost. Each stage learns the classifiers from the candidate features of corresponding layer.", "type": "table"}, "TABREF3": {"text": "RATES (MR) OF MCF BASED ON HOG+LUV AND THE DIFFERENT LAYERS IN CNN. \u221a MEANS THAT THE CORRESPONDING LAYER IS USED. HOG+LUV IS ALWAYS USED FOR THE FIRST LAYER. THE LAYERS IN ALEXNET OR VGG16 ARE USED FOR THE REMAINING LAYERS.", "type": "table"}, "TABREF4": {"text": "NUMBER AND REJECTED RATIO BY THE STAGES IN MCF-6 ARE SHOWN. '*' MEANS THAT THE AVERAGE NUMBER OF DETECTION WINDOWS ACCEPTED BY STAGE 1 ARE SHOWN.", "type": "table"}, "TABREF5": {"text": "RATES AND DETECTION TIME VARY WITH \u03b8. MCF USED HERE IS BASED ON HOG+LUV AND ALEXNET.", "type": "table"}, "TABREF6": {"text": "RATE (MR) AND DETECTION TIME OF MCF-2, MCF-6, AND MCF-6-F. MCF-2 IS BASED ON HOG+LUV AND C5 IN CNN. MCF-6 IS BASED ON HOG+LUV AND C1-C5 IN CNN. MCF-6-F IS THE FAST VERSION OF MCF-6.For example, detection time of MCF-2 based VGG16 is 7.69s and that of MCF-6-f based on VGG16 is 1.89s. It means that detection speed of MCF-6-f is 4.07 times faster than that of MCF-2. 3) With little performance loss, MCF-6-f have faster detection speed than MCF-6. The loss of MCF-6-f based on AlexNet is 0.77%, and the loss of MCF-6-f based on VGG16 is 0.58%.", "type": "table"}, "TABREF7": {"text": "Fig. 7. ROC of Caltech test set (reasonable).", "type": "table"}, "TABREF9": {"text": "10 \u22122 ,10 0 ] and the FPPI range of [10 \u22124 ,10 0 ] are shown. They are represented by M R \u22122 and M R \u22124 . M R \u22122 (M R \u22124 ) are shown in the legend. MCF is trained based on the Caltech10x with the new annotations. M R \u22122 and M R \u22124 of MCF achieve 7.98% and 15.45%, respectively. They are superior to all the other methods. Specifically, M R \u22122 of MCF is 1.17%, 4.92%, and 6.41% lower than that of CompACT-Deep [1], DeepParts", "type": "table"}}}
{"paper_id": "2876321", "_pdf_hash": "f9a59a7128a0e43b2599be9746764b82f15dc55c", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "TFRC-based Rate Control Scheme for Real-time JPEG 2000 Video Transmission", "authors": [{"first": "S", "middle": [], "last": "Futemma", "suffix": ""}], "year": 2005, "venue": "Proc. IEEE CCNC'05", "link": "15056265"}, "BIBREF1": {"title": "EquationBased Congestion control for Unicast Applications", "authors": [{"first": "S", "middle": [], "last": "Floyd", "suffix": ""}, {"first": "M", "middle": [], "last": "Handley", "suffix": ""}, {"first": "J", "middle": [], "last": "Padhye", "suffix": ""}, {"first": "J", "middle": [], "last": "Widmer", "suffix": ""}], "year": 2000, "venue": "Proc. ACM SGCOMM", "link": null}, "BIBREF2": {"title": "Improving Reliable Transport and Handoff Performance in Cellular Wireless Networks", "authors": [{"first": "H", "middle": [], "last": "Balakrishnan", "suffix": ""}, {"first": "S", "middle": [], "last": "Seshan", "suffix": ""}, {"first": "R", "middle": ["H"], "last": "Katz", "suffix": ""}], "year": 1995, "venue": "ACM Wireless Networks", "link": "2204005"}, "BIBREF3": {"title": "Explicit Loss Notification and wireless web performance", "authors": [{"first": "H", "middle": [], "last": "Balakrishnan", "suffix": ""}, {"first": "R", "middle": ["H"], "last": "Katz", "suffix": ""}], "year": 1998, "venue": "Proc. IEEE Globecom", "link": "1275613"}, "BIBREF4": {"title": "End-to-end differentiation of congestion and wireless losses", "authors": [{"first": "S", "middle": [], "last": "Cen", "suffix": ""}, {"first": "P", "middle": ["C"], "last": "Cosman", "suffix": ""}, {"first": "G", "middle": ["M"], "last": "Voelker", "suffix": ""}], "year": 2002, "venue": "Proc. Multimedia Computing and Networking (MMCN)", "link": "10789862"}, "BIBREF5": {"title": "TCP-Friendly Congestion control over wireless networks", "authors": [{"first": "V", "middle": ["E"], "last": "Mujica", "suffix": ""}, {"first": "V", "middle": [], "last": "", "suffix": ""}, {"first": "D", "middle": [], "last": "Sisalem", "suffix": ""}], "year": 2004, "venue": "Proc. of European Wireless", "link": "201896739"}, "BIBREF6": {"title": "Rate control for streaming video over wireless", "authors": [{"first": "M", "middle": [], "last": "Chen", "suffix": ""}, {"first": "A", "middle": [], "last": "Zakhor", "suffix": ""}], "year": 2004, "venue": "Proc. Infocom", "link": "2883143"}, "BIBREF7": {"title": "Adaptive Cross-Layer Protection Strategies for Robust Scalable Video Transmission Over 802.11 WLANs", "authors": [{"first": "M", "middle": [], "last": "Schaar", "suffix": ""}, {"first": "S", "middle": [], "last": "Krishnamachari", "suffix": ""}, {"first": "S", "middle": [], "last": "Choi", "suffix": ""}, {"first": "X", "middle": [], "last": "Xu", "suffix": ""}], "year": 2003, "venue": "IEEE J. Select. Areas Commun", "link": "14603312"}, "BIBREF8": {"title": "Cross-Layer Design for Wireless Networks", "authors": [{"first": "S", "middle": [], "last": "Shakkottai", "suffix": ""}, {"first": "T", "middle": ["S"], "last": "Rappaport", "suffix": ""}, {"first": "P", "middle": ["C"], "last": "Karlsson", "suffix": ""}], "year": 2003, "venue": "IEEE Commun. Mag", "link": "195349238"}, "BIBREF9": {"title": "JPEG2000 Based Real-time Scalable Video Communication System over the Internet", "authors": [{"first": "E", "middle": [], "last": "Itakura", "suffix": ""}, {"first": "S", "middle": [], "last": "Futemma", "suffix": ""}, {"first": "G", "middle": [], "last": "Wang", "suffix": ""}, {"first": "K", "middle": [], "last": "Yamane", "suffix": ""}], "year": 2005, "venue": "Proc. IEEE CCNC'05", "link": "16081717"}}, "ref_entries": {}}
{"paper_id": "2876633", "_pdf_hash": "3221ab3ee75779eb48d502c637e8f561f3924390", "abstract": [], "body_text": [], "bib_entries": {"BIBREF4": {"title": "Atomic Layer Deposition Conference", "authors": [{"first": "B", "middle": [], "last": "Foran", "suffix": ""}], "year": 2004, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "2876651", "_pdf_hash": "e5df25d1e49840c0a7fcdd3378ea1b13a308129e", "abstract": [{"section": "Abstract", "text": "Invariant natural killer T cells (i NKT cells) have a prominent role during infection and other inflammatory processes, and these cells can be activated through their T cell antigen receptors by microbial lipid antigens. However, increasing evidence shows that they are also activated in situations in which foreign lipid antigens would not be present, which suggests a role for lipid self antigen. We found that an abundant endogenous lipid, b-d-glucopyranosylceramide (b-GlcCer), was a potent i NKT cell self antigen in mouse and human and that its activity depended on the composition of the N-acyl chain. Furthermore, b-GlcCer accumulated during infection and in response to Toll-like receptor agonists, contributing to i NKT cell activation. Thus, we propose that recognition of b-GlcCer by the invariant T cell antigen receptor translates innate danger signals into i NKT cell activation.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "nature immunology VOLUME 12 NUMBER 12 DECEMBER 2011", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "Invariant natural killer T (iNKT) cells constitute a subset of \u03b1\u03b2 T cells that recognize lipid antigens presented by the nonpolymorphic CD1d molecule. In contrast to peptide-specific diverse \u03b1\u03b2 T cell antigen receptor (TCR) major histocompatibility complex (MHC)-restricted T cells, these cells have an invariant TCR \u03b1-chain that uses TCR \u03b1-chain variable region 14 (V \u03b1 14) and \u03b1-chain joining region 18 (J \u03b1 18) paired with a limited V \u03b2 chain repertoire in mouse or V \u03b1 24 and J \u03b1 18 paired with V \u03b2 11 in human. How iNKT cells, with an invariant TCR, restricted by a nonpolymorphic antigen-presenting molecule are activated in a wide variety of infectious and non-infectious pathological processes is not well understood 1, 2 .", "cite_spans": [{"start": 725, "end": 727, "text": "1,", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "", "text": "Much effort has focused on the identification of lipids that are cognate antigens for the iNKT cell TCR. The discovery of the pharmacologic antigen \u03b1-galactosylceramide (\u03b1-GalCer) 3 , as well as the discovery of glycolipid antigens from the bacteria Borrelia burgdorferi 4 and Sphingomonas 5, 6 , each with a primary \u03b1-linked monohexose, suggested the possibility that the major structures recognized by iNKT cells might be \u03b1-linked glycolipids. However, recognition of such lipids does not explain the role of iNKT cells during the majority of infections or during inflammation, as primary \u03b1-glycosidic linkages have not been shown to occur in most microbes or in mammalian glycolipids. Further, iNKT cells have a major role in situations where foreign lipid antigens would not be present at all, including autoinflammatory conditions, viral infection or stimulation by Toll-like receptors (TLRs) [7] [8] [9] [10] . These observations support a central role for lipid self antigen in the activation of iNKT cells.", "cite_spans": [{"start": 290, "end": 292, "text": "5,", "ref_id": "BIBREF4"}, {"start": 898, "end": 901, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 902, "end": 905, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 906, "end": 909, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 910, "end": 914, "text": "[10]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "", "text": "The rapid activation of iNKT cells by antigen-presenting cells (APCs) exposed to lipopolysaccharide (LPS) or other TLR agonists is notable [7] [8] [9] [10] and provides a robust and salient model for understanding the response of iNKT cells to innate signals. It is clear that two signals are likely required for the physiological activation of iNKT cells, with the primary signal being provided through the TCR by a CD1dlipid complex and a second signal being provided by APC-derived cytokines, predominantly interleukin 12 (IL-12) 7, 11 . Accumulation of a stimulatory lipid self antigen has been proposed to provide the TCR-mediated signal to iNKT cells after TLR-agonist stimulation 9,10 , but the specific lipid antigen responsible has not been identified.", "cite_spans": [{"start": 139, "end": 142, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 143, "end": 146, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 147, "end": 150, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 151, "end": 155, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 533, "end": 535, "text": "7,", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "", "text": "Phospholipids, including lyso-phosphatidylcholine (lyso-PC), have been proposed to be self antigens for iNKT cells, but their stimulatory activity is weak and has only been shown in a subset of iNKT cells 12, 13 . Isoglobotrihexosylceramide (iGB3) contains a terminal \u03b1-linked carbohydrate and can activate mouse iNKT cells through CD1d. Based largely on the observation that Hexb \u2212/\u2212 (the Hexb gene product converts iGB4 to iGB3) mice have defective iNKT cell development, this lipid was proposed as a relevant self antigen 14 . However, a subsequent study reported that iGB3-synthase-deficient mice have a normal iNKT cell phenotype 15 , and it has been suggested that the iNKT cell defect in Hexb \u2212/\u2212 mice might be caused by altered lysosomal function rather than lower iGB3 concentrations 16 . Further, iGB3 is present in almost undetectable concentrations in mouse lymphoid tissues 17, 18 , and it has also been reported that humans do not express the relevant synthase and are thus unable to synthesize iGB3 (ref. 19) .", "cite_spans": [{"start": 205, "end": 208, "text": "12,", "ref_id": "BIBREF11"}, {"start": 887, "end": 890, "text": "17,", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "", "text": "In this study, we screened a panel of naturally occurring glycosphingolipids (GSLs) for antigenic activity on iNKT cells. We found that \u03b2-d-glucopyranosylceramide (\u03b2-GlcCer), which has been reported as being nonantigenic 20 , potently activated iNKT cells in both mouse and human through a cognate TCR interaction. In addition, \u03b2-GlcCer, the precursor of most GSLs outside of the central nervous system, accumulated in APCs after stimulation with LPS and accumulated in vivo after bacterial infection. Blocking \u03b2-GlcCer synthesis in bone-marrow-derived dendritic cells (BMDCs) resulted in less autoreactivity and iNKT cell activation in response to LPS or whole bacteria, whereas blocking the subsequent step in GSL synthesis, the conversion of \u03b2-GlcCer to \u03b2-lactosylceramide (\u03b2-LacCer), had either no effect or an opposite effect. Our data identify \u03b2-GlcCer as a potent, physiologically relevant self antigen for iNKT cells that is upregulated in response to microbial danger signals.", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Antigenic activity among a panel of GSLs", "text": "To identify self lipids that stimulate iNKT cells, we planned to first isolate the lipids present in CD1d on APCs and then screen those lipids for activity. We have determined the dominant GSLs eluted from CD1d on APCs 21 (summary, Supplementary Table 1 ). \u03b2-GlcCer would not have been detected by our previous analysis, as carbohydrate head groups were derivatized after GSL digestion with ceramide glycanase, an enzyme that does not cleave monohexose from a ceramide backbone. For this reason, as we transitioned to the activity determination phase of our iNKT cell antigen-discovery efforts, we included \u03b2-GlcCer. We used two assay systems to screen for lipid activity: a single-TCR-specificity iNKT cell hybridoma cultured together with CD1d-trasfected macrophages from the mouse macrophage line RAW and a primary iNKT cell line cultured with primary CD11c + BMDCs. We tested GSLs ( Supplementary Table 1 ) as well as phospholipids, including phosphatidylethanolamine, phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, lyso-PC, lyso-phosphatidylethanolamine, lysophophatidylserine and lyso-phosphatidylinositol. Among the panel of lipids tested, none of the higher-order GSLs or phospholipids was stimulatory. In contrast, the simplest GSL, \u03b2-GlcCer, reproducibly activated iNKT cells (Fig. 1a,b and data not shown). In a primary mouse iNKT cell line, we further showed that \u03b2-GlcCer elicited the production of both interferon-\u03b3 (IFN-\u03b3) and IL-4 ( Fig. 1c,d) , which is a characteristic of TCR-mediated, but not cytokine-mediated, iNKT cell activation 8 . As has been reported for other signals mediated by the iNKT cell TCR, the ability of \u03b2-GlcCer to induce iNKT cell IFN-\u03b3 production could be enhanced by the addition of IL-12 ( Fig. 1e) , an indirect stimulus for iNKT cells that we proposed as a crucial second signal during infection 7, 11 . We confirmed the chemical composition of bovine milk \u03b2-GlcCer by proton nuclear magnetic resonance spectroscopy, two-dimensional correlation spectroscopy and total correlation spectroscopy nuclear magnetic resonance, and we detected no \u03b1-anomeric carbohydrate in these analyses (data not shown). From these results, we concluded that an early biosynthetic GSL, \u03b2-GlcCer, activates iNKT cells in a CD1d-dependent manner.", "cite_spans": [{"start": 1879, "end": 1881, "text": "7,", "ref_id": "BIBREF6"}], "ref_spans": [{"start": 232, "end": 253, "text": "Supplementary Table 1", "ref_id": "FIGREF0"}, {"start": 1324, "end": 1334, "text": "(Fig. 1a,b", "ref_id": "FIGREF0"}, {"start": 1487, "end": 1497, "text": "Fig. 1c,d)", "ref_id": "FIGREF0"}, {"start": 1771, "end": 1779, "text": "Fig. 1e)", "ref_id": "FIGREF0"}]}, {"section": "b-GlcCer in primary lymphoid tissues", "text": "To determine whether \u03b2-GlcCer could be detected in tissues that might be sites of iNKT cell activation, we analyzed polar lipids extracted from mouse thymus, spleen, liver and BMDCs by thin layer chromatography (TLC). We observed a monohexosyl ceramide in the thymus, spleen and BMDC extracts ( Fig. 2a) . A detectable but lower amount of monohexosyl ceramide was present in the liver polar lipid extracts. By borate-impregnated TLC analysis, we determined that the monohexosyl ceramide band in the thymus, spleen and BMDC extracts was almost exclusively composed of \u03b2-GlcCer and not \u03b2-GalCer (Supplementary Fig. 1) . To estimate the \u03b2-GlcCer content in these tissues, we used a TLC-based densitometric analysis of the tissue lipid extracts and compared it to a \u03b2-GlcCer standard titration.", "cite_spans": [], "ref_spans": [{"start": 295, "end": 303, "text": "Fig. 2a)", "ref_id": "FIGREF1"}, {"start": 593, "end": 615, "text": "(Supplementary Fig. 1)", "ref_id": "FIGREF0"}]}, {"section": "b-GlcCer in primary lymphoid tissues", "text": "The \u03b2-GlcCer content of mouse thymus, spleen and CD11c + BMDCs was estimated at 4.6 \u00b1 1.1 \u00b5g, 3.6 \u00b1 0.8 \u00b5g and 3.9 \u00b1 0.1 \u00b5g per mg of polar lipids (mean \u00b1 s.d.). In order to determine whether the \u03b2-GlcCer detected in mammalian lymphoid tissues had stimulatory activity in iNKT cells, we used preparative-scale high-performance liquid chromatography coupled with mass spectrometry to purify \u03b2-GlcCer from mouse spleen and thymus crude polar lipid extracts ( Supplementary Fig. 2) . We found the purified \u03b2-GlcCer-containing fractions to stimulate an iNKT cell hybridoma in co-culture with CD1dtransfected RAW cells (Fig. 2b) . In the assay shown in Figure 2b , we estimated the \u03b2-GlcCer concentrations at 18.0 \u00b1 4.0 \u00b5g/ml and 23.0 \u00b1 5.5 \u00b5g/ml for the thymus and spleen \u03b2-GlcCer fractions, respectively (mean \u00b1 s.d.). For the spleen polar lipid extracts, we found that \u03b2-LacCer and phospholipid-containing fractions purified by the same method that we used to purify the \u03b2-GlcCer fractions were unable to stimulate the iNKT cell hybridoma ( Fig. 2b) . Thus, \u03b2-GlcCer is present in mammalian lymphoid tissues, and, when purified from these tissues, activates iNKT cells in a CD1d-dependent manner.", "cite_spans": [], "ref_spans": [{"start": 457, "end": 478, "text": "Supplementary Fig. 2)", "ref_id": "FIGREF1"}, {"start": 614, "end": 623, "text": "(Fig. 2b)", "ref_id": "FIGREF1"}, {"start": 648, "end": 657, "text": "Figure 2b", "ref_id": "FIGREF1"}, {"start": 1039, "end": 1047, "text": "Fig. 2b)", "ref_id": "FIGREF1"}]}, {"section": "b-GlcCer in primary lymphoid tissues", "text": "Because \u03b2-GlcCer has been reported as being nonantigenic for iNKT cells 20 , we questioned whether the activity of bovine-milk and mammalian \u03b2-GlcCer that we observed depends on specific lipid structures attached to the carbohydrate head groups that are present in these purified materials. To address this possibility, we determined the fatty acid compositions of \u03b2-GlcCer in bovine milk, mouse spleen and mouse thymus by electrospray ionization mass A r t i c l e s spectrometry (ESI-MS) in the positive-ion mode (Fig. 2c,d and Supplementary Fig. 3 ). We confirmed structural assignments by collision-induced dissociation tandem mass spectrometry as described 22 . In all three samples analyzed, the major ceramide backbone consisted exclusively of sphingenine (d 18:1 ). In mouse thymus, the major N-acyl chains detected were C 24:1 , C 22:0 and C 16:0 . In mouse spleen, the major N-acyl chains detected were C 24:1 , C 24:0 , C 22:0 , C 20:0 and C 16:0 . In bovine milk, the major N-acyl chains detected were C 24:0 , C 23:0 , C 22:0 , C 20:0 and C 16:0 . We present here the structures of two abundant \u03b2-GlcCer forms in thymus and spleen ( Fig. 2e) . For all samples, we also detected other \u03b2-GlcCer molecular species in smaller quantities, confirming the diversity of N-acyl chains in mammalian GSLs. These results show that the \u03b2-GlcCer present in mammalian tissues contains multiple N-acyl chain structures, with C 24:1 being the most abundant of these chains in lymphoid tissues.", "cite_spans": [], "ref_spans": [{"start": 515, "end": 525, "text": "(Fig. 2c,d", "ref_id": "FIGREF1"}, {"start": 530, "end": 550, "text": "Supplementary Fig. 3", "ref_id": "FIGREF2"}, {"start": 1146, "end": 1154, "text": "Fig. 2e)", "ref_id": "FIGREF1"}]}, {"section": "b-GlcCer in primary lymphoid tissues", "text": "b-GlcCer C 24:1 is a potent mouse iNKT cell antigen To functionally test the role of N-acyl chain composition on the activity of \u03b2-GlcCer, we studied a panel of synthetic \u03b2-GlcCer compounds that all contained sphingenine as the ceramide backbone, with the N-acyl chains varying from 8 to 24 carbons and being either fully saturated or containing one unsaturation ( Supplementary Fig. 4 ). We detected \u03b2-GlcCer C 24:1 , C 18:1 , C 18:0 and C 16:0 in primary mouse tissue by ESI-MS, but we did not detect the 12-and 8-carbon N-acyl chain forms of this lipid ( Fig. 2c,d) , and these forms have not, to our knowledge, been reported to occur in mammals. \u03b2-GlcCer C 24:1 , C 12:0 and C 18:1 activated an iNKT hybridoma in vitro, whereas \u03b2-GlcCer C 18:0 and C 16:0 showed no activity ( Fig. 3a) . Lyso-\u03b2-GlcCer (d 18:1 ) and free ceramide backbones corresponding to each synthetic \u03b2-GlcCer were not active (data not shown). We then compared the potency of \u03b2-GlcCer C 24:1 to the microbial antigen GSL-1 from Sphingomonas 5, 6 and two previously proposed self antigens, iGB3 (ref. 14) and lyso-PC 12 . The iGB3 we used was d 18:1 -C 26:0 , and, although it is not matched to \u03b2-GlcCer C 24:1 in N-acyl chain structure, the C 26:0 acyl chain would be expected to impart maximal activity based on data from \u03b1-GalCer analogs 23, 24 . As determined by assay with a primary iNKT cell line in co-culture with CD11c + BMDCs, the antigenicity of \u03b2-GlcCer C 24:1 was less than that of GSL-1 but was greater than that of iGB3, and, as reported before 25 , we did not detect any activity for lyso-PC in mouse ( Fig. 3b) . Although we did not detect \u03b2-GalCer at potential sites of peripheral iNKT cell activation ( Supplementary Fig. 1) , and a \u03b2-GalCer-deficient mouse was reported not to have a demonstrable iNKT cell defect 20 , given the structural similarity of \u03b2-GalCer to \u03b2-GlcCer, we hypothesized that \u03b2-GalCer might also activate iNKT cells.", "cite_spans": [{"start": 1015, "end": 1017, "text": "5,", "ref_id": "BIBREF4"}, {"start": 1314, "end": 1317, "text": "23,", "ref_id": "BIBREF22"}], "ref_spans": [{"start": 365, "end": 385, "text": "Supplementary Fig. 4", "ref_id": "FIGREF4"}, {"start": 558, "end": 568, "text": "Fig. 2c,d)", "ref_id": "FIGREF1"}, {"start": 780, "end": 788, "text": "Fig. 3a)", "ref_id": "FIGREF2"}, {"start": 1592, "end": 1600, "text": "Fig. 3b)", "ref_id": "FIGREF2"}, {"start": 1695, "end": 1716, "text": "Supplementary Fig. 1)", "ref_id": "FIGREF0"}]}, {"section": "b-GlcCer in primary lymphoid tissues", "text": "Purified bovine brain \u03b2-GalCer, \u03b2-GalCer d 18:1 -C 24:1 , and, as shown before 26, 27 , the non-physiological lipid \u03b2-GalCer d 18:1 -C 12:0 activated mouse iNKT cells in a CD1d-dependent manner, albeit less potently than each corresponding \u03b2-GlcCer ( Supplementary Fig. 5 ).", "cite_spans": [{"start": 79, "end": 82, "text": "26,", "ref_id": "BIBREF25"}], "ref_spans": [{"start": 251, "end": 271, "text": "Supplementary Fig. 5", "ref_id": "FIGREF5"}]}, {"section": "b-GlcCer in primary lymphoid tissues", "text": "To examine self antigen activity in vivo, we injected mice intravenously with a subset of the \u03b2-GlcCer synthetic panel and iGB3. Two hours after injection with \u03b2-GlcCer C 24:1 , two-thirds of liver iNKT cells were IFN-\u03b3 positive and greater than 40% were IL-4 positive, which is a substantially higher percentage than that seen in mice injected with iGB3 ( Fig. 3c,d) . In liver mononuclear T cells from CD1d-deficient mice that lack NKT cells, there was no detectable response to \u03b2-GlcCer C 24:1 injection. We also observed potent activation of CD11c + dendritic cells and B cells in vivo 24 h after \u03b2-GlcCer C 24:1 injection, most likely as a result of transactivation ( Supplementary Fig. 6 ). We concluded from these studies that the activity of \u03b2-GlcCer is dependent on the N-acyl chain structure and that the abundant d 18:1 -C 24:1 form of \u03b2-GlcCer is a potent antigen for iNKT cells in vivo.", "cite_spans": [], "ref_spans": [{"start": 357, "end": 367, "text": "Fig. 3c,d)", "ref_id": "FIGREF2"}]}, {"section": "b-GlcCer in primary lymphoid tissues", "text": "In addition to iNKT cells with an invariant TCR \u03b1-chain, there are CD1d-restricted T cells in the diverse \u03b1\u03b2 TCR compartment called 'diverse NKT cells' . Because there is no method available at present with which to identify primary diverse NKT cells, we screened a panel of ten individual diverse NKT cell hybridomas for activity by coculture with primary mouse BMDCs and the synthetic \u03b2-GlcCer panel described above. Two of these ten diverse NKT cell hybridomas, VII68 and XV19 (ref. 28) , showed reactivity to a subset of \u03b2-GlcCer compounds ( Supplementary Fig. 7 and data not shown). We concluded from these data that \u03b2-GlcCer also activates diverse NKT cells, but that this reactivity may depend on different N-acyl chain structures than do iNKT cells.", "cite_spans": [], "ref_spans": []}, {"section": "b-GlcCer in primary lymphoid tissues", "text": "b-GlcCer C 24:1 mediates a cognate TCR interaction To confirm that \u03b2-GlcCer directly mediates iNKT cell stimulation through CD1d, we tested a synthetic \u03b2-GlcCer panel and bovine milk \u03b2-GlcCer in an APC-free system with purified, plate-bound CD1d. In this system, bovine milk \u03b2-GlcCer, \u03b2-GlcCer C 24:1 and \u03b2-GlcCer C 12:0 activated a primary iNKT cell line ( Fig. 4a) , showing direct, CD1d-dependent activation of iNKT cells by \u03b2-GlcCer. Next, we asked if CD1d tetramers loaded with \u03b2-GlcCer C 24:1 could bind iNKT cells directly. Indeed, tetramers loaded with \u03b2-GlcCer C 24:1 stained a portion of the iNKT cells from both C57BL/6 and BALB/c mice, as identified by sequential double staining with a CD1d tetramer loaded with PBS-57 (an \u03b1-GalCer analog; Fig. 4b ).", "cite_spans": [], "ref_spans": [{"start": 358, "end": 366, "text": "Fig. 4a)", "ref_id": "FIGREF4"}, {"start": 753, "end": 760, "text": "Fig. 4b", "ref_id": "FIGREF4"}]}, {"section": "b-GlcCer in primary lymphoid tissues", "text": "The staining seemed to be limited to the portion of the iNKT cells that stained most brightly with the PBS-57-loaded tetramer, suggesting that \u03b2-GlcCer C 24:1 -loaded tetramer staining was brightest for the iNKT cell population with the highest affinity TCRs. The TCR V \u03b2chain repertoire of mouse iNKT cells is limited, and those cells with the V \u03b2 -chains V \u03b2 2, V \u03b2 7, V \u03b2 8.1, V \u03b2 8.2 and V \u03b2 8.3 have been found to have a higher affinity for \u03b1-GalCer-loaded CD1d tetramers compared with less frequently used V \u03b2 -chains (V \u03b2 6, V \u03b2 9, V \u03b2 10 and V \u03b2 14) 29 . Consistent with the affinity hierarchy described for \u03b1-GalCer-loaded tetramers, \u03b2-GlcCer C 24:1 -loaded tetramers identified the most frequently used iNKT cell TCR V \u03b2 -chains ( Fig. 4c,d) .", "cite_spans": [], "ref_spans": [{"start": 741, "end": 751, "text": "Fig. 4c,d)", "ref_id": "FIGREF4"}]}, {"section": "b-GlcCer in primary lymphoid tissues", "text": "Although \u03b2-GlcCer tetramer staining was limited to a fraction of mouse iNKT cells (Fig. 4b) , the majority of the iNKT cells produced cytokines after stimulation with \u03b2-GlcCer in vivo (Fig. 3) . Further, iNKT cells substantially downregulate their surface TCR expression after activation with a strong antigen but not after indirect activation 30 . Twenty-four hours after intravenous injection of \u03b2-GlcCer C 24:1 , iNKT cells were almost undetectable, suggesting TCR-dependent activation of almost all mouse iNKT cells ( Supplementary  Fig. 8) . The difference, then, between iNKT cell activation and tetramer binding is likely because of a higher affinity requirement for tetramer binding relative to activation. We concluded from these tetramer studies that \u03b2-GlcCer C 24:1 mediates a cognate interaction between the iNKT cell TCR and CD1d in mouse. b-GlcCer is a self antigen for human iNKT cells Given the high degree of evolutionary conservation seen for both CD1d and iNKT cells 1 , we would expect a physiologically relevant self antigen to activate both mouse and human iNKT cells. We asked whether \u03b2-GlcCer was a self antigen in humans by testing the synthetic \u03b2-GlcCer panel described above for activity on human iNKT cells. Similar to mouse iNKT cells, \u03b2-GlcCer C 24:1 , C 12:0 and, to a lesser degree, C 18:1 , activated three independent human iNKT cell clones 31 when presented by human peripheral blood mononuclear cell (PBMC)-derived APCs, and this activation was efficiently inhibited by a monoclonal antibody against CD1d (Fig. 5a,b ). In this system, iGB3 did not activate iNKT cells. In a primary human iNKT cell line, we compared the antigenic potency of Sphingomonas GSL-1, \u03b2-GlcCer C 24:1 , iGB3 and lyso-PC. In humans, \u03b2-GlcCer C 24:1 was less potent than GSL-1 but was far more potent than iGB3 or lyso-PC. In fact, in contrast to mouse iNKT cells, we did not detect activity for iGB3 in primary human iNKT cells. Lyso-PC did not stimulate iNKT cells to produce detectable IFN-\u03b3 or IL-4, but, as has been reported 12 , we did detect a small amount of granulocyte macrophage colony-stimulating factor ( Fig. 5c and data not shown).", "cite_spans": [], "ref_spans": [{"start": 82, "end": 91, "text": "(Fig. 4b)", "ref_id": "FIGREF4"}, {"start": 184, "end": 192, "text": "(Fig. 3)", "ref_id": "FIGREF2"}, {"start": 1541, "end": 1551, "text": "(Fig. 5a,b", "ref_id": "FIGREF5"}, {"start": 2128, "end": 2135, "text": "Fig. 5c", "ref_id": "FIGREF5"}]}, {"section": "b-GlcCer in primary lymphoid tissues", "text": "Having shown the activity of \u03b2-GlcCer on human iNKT cell clones and a primary human iNKT cell line, we next cultured freshly isolated PBMCs overnight with \u03b2-GlcCer without the addition of exogenous APCs and measured iNKT cell intracellular cytokine production. A r t i c l e s \u03b2-GlcCer C 24:1 was able to stimulate cytokine production by this assay, and this effect was completely blocked by monoclonal antibody to CD1d (Supplementary Fig. 9a,b) . We also used freshly isolated human PBMCs to assay iNKT cell proliferation in response to various \u03b2-GlcCer N-acyl chain variants. \u03b2-GlcCer C 24:1 , C 12:0 , and C 18:1 in co-culture led to a marked expansion of iNKT cells over an 8-day period (Supplementary Fig. 9c) .", "cite_spans": [], "ref_spans": []}, {"section": "b-GlcCer in primary lymphoid tissues", "text": "To confirm the cognate interaction between \u03b2-GlcCer-loaded CD1d and the iNKT cell TCR in humans, we made tetramers with \u03b2-GlcCerloaded human CD1d. Staining with PBS-57-loaded tetramers allowed for unambiguous identification of iNKT cells, and we confirmed the iNKT cells to be V \u03b1 24 + V \u03b2 11 + (Fig. 5d) . Double staining of freshly isolated PBMCs with \u03b2-GlcCer-loaded CD1d tetramers and PBS-57loaded tetramers showed that a substantial portion of human iNKT cells bind tetramers loaded with \u03b2-GlcCer C 24:1 , C 12:0 and C 18:1 (Fig. 5e) .", "cite_spans": [], "ref_spans": [{"start": 295, "end": 304, "text": "(Fig. 5d)", "ref_id": "FIGREF5"}, {"start": 529, "end": 538, "text": "(Fig. 5e)", "ref_id": "FIGREF5"}]}, {"section": "b-GlcCer in primary lymphoid tissues", "text": "In complementary experiments, we examined if iNKT cell TCR tetramers 32 could recognize CD1d loaded with \u03b2-GlcCer. We again found an interaction dependent on the N-acyl chain, with \u03b2-GlcCer C 24:1 and C 12:0 mediating TCR tetramer binding ( Supplementary  Fig. 10a ). \u03b2-GlcCer-loaded CD1d tetramer staining was positive but was of variable intensity between subjects ( Supplementary  Fig. 10b) ; for clarity, a subject with a high percentage of \u03b2-GlcCer CD1d tetramer-positive iNKT cells is shown in Figure 5 .", "cite_spans": [], "ref_spans": [{"start": 241, "end": 264, "text": "Supplementary  Fig. 10a", "ref_id": "FIGREF0"}, {"start": 369, "end": 393, "text": "Supplementary  Fig. 10b)", "ref_id": "FIGREF0"}, {"start": 500, "end": 508, "text": "Figure 5", "ref_id": "FIGREF5"}]}, {"section": "b-GlcCer in primary lymphoid tissues", "text": "As seen in the mouse, \u03b2-GlcCer tetramers recognized only a portion of the human iNKT cell population identified by \u03b1-GalCer-loaded tetramers. The percentage of cells recognized by \u03b2-GlcCer tetramers did not decrease after double staining with \u03b1-GalCer tetramers under the staining conditions used, suggesting that tetramer competition was not a factor (data not shown). We hypothesized that, as in the mouse, \u03b2-GlcCer tetramers might identify human iNKT cells with high-affinity TCRs. To address this possibility, we used OCH, an \u03b1-GalCer analog that, when loaded in human CD1d tetramers, has been reported to bind a population of human iNKT cells with high-affinity TCRs 32 . Double staining with CD1d tetramers loaded with OCH and \u03b2-GlcCer C 24:1 identified the same population (Supplementary Fig. 10c ), which suggested that \u03b2-GlcCer tetramers identified iNKT cells with high-affinity TCRs. We saw robust iNKT cell activation by \u03b2-GlcCer in all human subjects and in all iNKT cell clones tested irrespective of the intensity of \u03b2-GlcCer CD1d tetramer staining, which suggested, as in our mouse studies, that tetramer binding may have a more demanding threshold than does iNKT cell activation.", "cite_spans": [], "ref_spans": [{"start": 780, "end": 803, "text": "(Supplementary Fig. 10c", "ref_id": "FIGREF0"}]}, {"section": "b-GlcCer in primary lymphoid tissues", "text": "b-GlcCer contributes to iNKT cell self reactivity GSL self lipid antigens have been proposed to contribute to iNKT cell activation in the absence of foreign lipid antigens 33 . Because \u03b2-GlcCer is relatively abundant in lymphoid tissues, and because we found that it potently activates iNKT cells from both mice and humans, we postulated that it might contribute to iNKT cell self reactivity. We assessed the contribution of \u03b2-GlcCer to iNKT cell autoreactivity by perturbing the pathways involved in the synthesis of this lipid. We present the pathways involved in the synthesis and degradation of \u03b2-GlcCer for reference ( Supplementary Fig. 11a) . In a primary mouse iNKT cell line, we found that, as has been shown before 10, 20 , inhibition of GSL synthesis by either N-butyldeoxygalactonojirimycin (NB-DGJ) or D-Threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP) resulted in less iNKT cell autoreactivity (Fig. 6a) .", "cite_spans": [{"start": 725, "end": 728, "text": "10,", "ref_id": "BIBREF9"}], "ref_spans": [{"start": 624, "end": 647, "text": "Supplementary Fig. 11a)", "ref_id": "FIGREF0"}]}, {"section": "b-GlcCer in primary lymphoid tissues", "text": "To assess antigen processing and presentation in BMDCs after treatment with GSL synthesis inhibitors, we used Gal-\u03b1-GalCer, an \u03b1-GalCer analog that requires lysosomal uptake and processing for antigenicity 34 (Fig. 6b) . NB-DGJ and D-PDMP did not diminish the activation of iNKT cells by Gal-\u03b1-GalCer. Because both NB-DGJ and D-PDMP inhibit \u03b2-GlcCer synthesis, and, consequently, the synthesis of all higher order ceramides that are based on \u03b2-GlcCer, we used small interfering RNA (siRNA) silencing of either glucosylceramide synthase (encoded by Ugcg) or the downstream enzyme that converts \u03b2-GlcCer to \u03b2-LacCer, lactosylceramide synthase (encoded by B4galt6), in BMDCs to isolate the \u03b2-GlcCer-dependent signal (Fig. 6c) . siRNA silencing of Ugcg in BMDCs resulted in less iNKT cell autoreactivity, whereas B4galt6 silencing increased autoreactivity (Fig. 6d) . Silencing through the use of siRNA did not alter the ability of BMDCs to present Gal-\u03b1-GalCer ( Fig. 6e) and did not alter CD1d surface concentrations as determined by flow cytometry (Fig. 6f) . Thus, modulation of \u03b2-GlcCer concentrations determines iNKT cell self reactivity to BMDCs.", "cite_spans": [], "ref_spans": []}, {"section": "b-GlcCer mediates iNKT cell activation during infection", "text": "The iNKT response to LPS-exposed BMDCs requires both a signal through CD1d and APC-derived IL- 12 (refs. 7,9,10) . We hypothesized that \u03b2-GlcCer might be a prominent component of an LPS-induced, CD1d-mediated signal and investigated the pathways involved in the synthesis and degradation of \u03b2-GlcCer after TLR agonist exposure. Using a published gene-expression data set 35 , we examined the regulation of Ugcg and B4galt6 in mouse BMDCs in response to five TLR agonists. Four of five of the stimuli led to the upregulation of Ugcg, with a peak expression occurring at 2-6 h after exposure to the TLR agonists. All stimuli resulted in a decrease in the expression of B4galt6 mRNA over the first 8 h of exposure to the TLR agonists (Supplementary Fig. 11b) . We saw only minimal changes in the expression of Gba and Glb1, which encode the molecules responsible for the degradation of \u03b2-GlcCer and \u03b2-LacCer, respectively (data not shown). The LPS concentration used for generation of the dataset above was 100 ng/ml, which is substantially higher than we found to be required to stimulate iNKT cells in co-culture with BMDCs. With 1 ng/ml of LPS, we determined the expression of the genes involved in \u03b2-GlcCer metabolism by quantitative PCR and (Fig. 7a) . TLC analysis of polar lipid extracts from CD11c + BMDCs after treatment with LPS showed an increase in \u03b2-GlcCer (Fig. 7b) as quantified by densitometry ( Fig. 7c; additional  controls, Supplementary Fig. 12a,b) . Naturally occurring \u03b2-GlcCer migrated as a doublet by TLC in the solvent system used, and the potent antigen \u03b2-GlcCer C 24:1 migrated in the accumulating upper band (Supplementary Fig. 12c ).", "cite_spans": [], "ref_spans": [{"start": 731, "end": 755, "text": "(Supplementary Fig. 11b)", "ref_id": "FIGREF0"}, {"start": 1409, "end": 1465, "text": "Fig. 7c; additional  controls, Supplementary Fig. 12a,b)", "ref_id": "FIGREF0"}, {"start": 1633, "end": 1656, "text": "(Supplementary Fig. 12c", "ref_id": "FIGREF0"}]}, {"section": "b-GlcCer mediates iNKT cell activation during infection", "text": "Having shown that \u03b2-GlcCer accumulated in BMDCs after TLR agonist stimulation, we next asked whether this lipid contributes to iNKT cell activation. We confirmed that, as has been shown for TLR agonists 9,10 , inhibition of GSL synthesis resulted in a lower response of iNKT cells to LPS-exposed BMDCs (Fig. 7d) . To isolate the \u03b2-GlcCer contribution to this GSL-dependent activation, we used siRNA silencing. We found that Ugcg silencing limited the iNKT cell response to LPS-treated BMDCs, whereas B4galt6 silencing enhanced this response (Fig. 7e) . By TLC analysis, we observed lower \u03b2-GlcCer concentrations after treatment with NB-DGJ or D-PDMP and after silencing of Ugcg, whereas we saw higher \u03b2-GlcCer concentrations after silencing of B4galt6 (Supplementary Fig. 13 ). We did not detect changes in LPS-mediated IL-12 production or BMDC maturation as assessed by flow cytometry after NB-DGJ, D-PDMP or siRNA targeting of Ugcg or B4galt6 compared with controls. D-PDMP did, however, lead to a slight decrease in CD1d surface concentrations on CD11c + BMDCs, potentially contributing to the decreased iNKT cell activation seen after treatment of BMDCs with this inhibitor ( Supplementary Fig. 14) . Alteration in some lipid synthesis pathways has been shown to alter endosomal or lysosomal function and subsequently diminish iNKT cell activation 16 . For that reason, we used confocal fluorescence microscopy to assess the endosomal and lysosomal systems in CD11c + BMDCs after treatment with \u03b2-GlcCer synthesis inhibitor or siRNA. We saw no morphological abnormalities in the endosomal or lysosomal systems (Supplementary Fig. 15 ).", "cite_spans": [], "ref_spans": [{"start": 752, "end": 774, "text": "(Supplementary Fig. 13", "ref_id": "FIGREF0"}, {"start": 1180, "end": 1202, "text": "Supplementary Fig. 14)", "ref_id": "FIGREF0"}, {"start": 1614, "end": 1636, "text": "(Supplementary Fig. 15", "ref_id": "FIGREF0"}]}, {"section": "b-GlcCer mediates iNKT cell activation during infection", "text": "We concluded from these studies that the presentation of \u03b2-GlcCer by CD1d is a substantial component of the TCR-mediated activation signal provided to iNKT cells by BMDCs after TLR agonist exposure. Because bacteria might contain iNKT cell lipid antigens in addition to TLR agonists, we investigated the relative functional contribution of \u03b2-GlcCer as a self lipid antigen in the activation of iNKT cells by whole bacteria. Ugcg silencing resulted in less activation of iNKT cells in response to BMDCs cultured together with Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus pneumoniae or Listeria monocytogenes (Fig. 8a) . As we noted after LPS exposure in BMDCs, B4galt6 silencing did not diminish iNKT cell activation. These results suggested that \u03b2-GlcCer contributes to iNKT cell activation during bacterial infection.", "cite_spans": [], "ref_spans": []}, {"section": "b-GlcCer mediates iNKT cell activation during infection", "text": "To extend the physiological importance of \u03b2-GlcCer accumulation in BMDCs after LPS exposure, we examined \u03b2-GlcCer concentrations in vivo during infection. As a model of Gram-negative bacterial sepsis, we transferred E. coli intravenously and assessed \u03b2-GlcCer in the spleen. At 24 h after E. coli injection, \u03b2-GlcCer increased as a portion of the total polar lipids and remained elevated at 48 h after injection (Fig. 8b) . As a model of Gram-positive bacterial infection, we investigated S. pneumoniae pulmonary infection, a model in which iNKT cells have been shown to have a prominent role 11, 36 . Because S. pneumoniae produces \u03b1-glucosyldiacylglycerol (GlcDAG), a lipid that co-migrates with \u03b2-GlcCer by TLC in some solvent systems, we modified our solvent system to separate these two lipids and included GlcDAG as a lipid standard. As we saw in the spleen after E. coli infection, we observed an increase in \u03b2-GlcCer concentrations in the total lung polar lipid extracts of mice infected with S. pneumoniae (Fig. 8c) . This increase was prominent by day 3 after infection, corresponding to iNKT cell activation in this model 11 . We concluded from these studies that \u03b2-GlcCer accumulates in involved organs after bacterial infection.", "cite_spans": [{"start": 593, "end": 596, "text": "11,", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "Although iNKT cells are considered to be innate lymphocytes, they use the machinery of the adaptive immune system to express TCRs of limited diversity. The nature of the specificity of these invariant TCRs, and how this specificity might regulate activation of an innate lymphocyte population, are fundamental in understanding the increasingly appreciated role of innate lymphocytes in immunity. Because iNKT cells are activated in contexts where foreign lipid antigens may not always be present to provide cognate TCR-mediated signals, self lipid antigens have been proposed to participate in this activation. Identification of the involved self lipid antigens has remained a central issue in the field 33 . We now find that \u03b2-GlcCer, the simplest GSL, acts as a physiologically relevant self lipid antigen for iNKT cells.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "Here we have shown activity for both naturally occurring and synthetic \u03b2-GlcCer in vitro with mouse iNKT cell hybridomas, mouse and human primary iNKT cell lines and freshly isolated human iNKT cells. By injecting \u03b2-GlcCer intravenously, we showed activity in vivo on unperturbed mouse iNKT cells. \u03b2-GlcCer also activates in an APC-free system, as shown with plate-bound, lipid-loaded CD1d. As an additional important proof of principle, \u03b2-GlcCer-loaded CD1d tetramers specifically stain a subset of iNKT cells from both mouse and human directly ex vivo, providing strong evidence that the iNKT cell TCR can directly bind CD1d complexes loaded with \u03b2-GlcCer C 24:1 . Based on these observations, we conclude that \u03b2-GlcCer activates both mouse and human iNKT cells through a direct cognate interaction between the iNKT cell TCR and \u03b2-GlcCer-loaded CD1d.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "In mammals, GSLs have diverse structures, varying in both the fatty acyl chain and the carbohydrate head group. Examination of each of these structural features for \u03b2-GlcCer provides important insight into the crucial determinants of iNKT cell self antigenicity. We found evidence that the activity of \u03b2-GlcCer varies with N-acyl chain structure. Such differences also have been observed for \u03b1-GalCer variants and have been attributed to the kinetics, stability and subcellular location of antigen loading 23, 24, 37 . Notably, \u03b2-GlcCer C 24:1 , the most potent \u03b2-GlcCer variant tested for iNKT cells, is the specific form found in the highest abundance in mammalian lymphoid tissues.", "cite_spans": [{"start": 506, "end": 509, "text": "23,", "ref_id": "BIBREF22"}, {"start": 510, "end": 513, "text": "24,", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "Various approaches have been used to clarify the contribution of the lipid head group in iNKT cell activation. Two informative studies looked at the role of the iNKT TCR complementary-determining region 3 \u03b2-loop (CDR3\u03b2) in iNKT cell autoreactivity. Research from one study has shown that naturally occurring, high-affinity human iNKT cell TCR interactions with CD1d are dependent on TCR CDR3\u03b2 and that \u03b2-GlcCer-loaded tetramers, similar to OCH-loaded tetramers, could discriminate between high-and low-affinity iNKT cell TCRs 32 . Research from a second study examined a particularly autoreactive V \u03b1 14-V \u03b2 6 iNKT TCR generated by random mutagenesis of mouse CDR3\u03b2 and showed that multiple cellular lipids can influence the binding of this TCR to CD1d, either positively or negatively 29 . Although several higher-order GSLs resulted in less binding relative to unloaded tetramer, \u03b2-GlcCer and \u03b2-GalCer did not have this effect 29 . These studies, although not specifically implicating monohexosyl ceramides as iNKT self antigens, are consistent with the idea that \u03b2-GlcCer might support iNKT cell TCR binding to CD1d for autoreactive iNKT cells.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "Comparison of co-crystal structures of CD1d-\u03b2-GSL-TCR with the reported CD1d-\u03b1-GalCer-TCR structure 38 has shown that the primary \u03b2-linked sugar is 'molded' by the TCR into a configuration similar to that seen with \u03b1-GalCer, providing a structural explanation for the antigenic activity of \u03b2-linked lipids 39, 40 . In addition to iGB3, other antigenic primary \u03b2-linked GSLs have been described, including \u03b2-mannosylceramide and \u03b2-GalCer C 12:0 (refs. 26, 27, 41) . Together with our data, such reports suggest that CD1d-bound, \u03b2-linked monohexosyl ceramides can fulfill the structural requirements of a self antigen for iNKT cell TCR. The 'energetic penalty' incurred with altering the conformation of a monohexosyl ceramide bound to CD1d to adopt a topology similar to that of \u03b1-GalCer is probably lower than that required for more complex GSLs, and our data suggest that the acyl chain composition of the lipid may also have a role in this process.", "cite_spans": [{"start": 306, "end": 309, "text": "39,", "ref_id": "BIBREF38"}, {"start": 451, "end": 454, "text": "26,", "ref_id": "BIBREF25"}, {"start": 455, "end": 458, "text": "27,", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "In addition to fulfilling structural requirements for antigenicity, a physiologically relevant self antigen must be present at sites of iNKT cell activation. As with iGB3, \u03b2-GalCer and \u03b2-mannosylceramide would not be found in any substantial amounts at most sites of peripheral iNKT cell activation. We show that \u03b2-GlcCer C 24:1 , however, is detectable in lymphoid tissues, accumulates during infection and, therefore, is likely to have a physiological role. This is of particular importance, as elution studies have shown that CD1d presents lipids representative of the total cellular lipid profile or compartment surveyed 21, 42, 43 .", "cite_spans": [{"start": 625, "end": 628, "text": "21,", "ref_id": "BIBREF20"}, {"start": 629, "end": 632, "text": "42,", "ref_id": "BIBREF41"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "Several lines of evidence have suggested the possibility that GSLs contribute to iNKT cell self reactivity, although GSLs may not be the only lipid class contributing to iNKT cell autoreactivity 25 . Notably, an iNKT-cell-dependent immunomodulatory or inhibitory role A r t i c l e s has been reported for \u03b2-GlcCer in vivo 44 . Through the use of GSL synthesis inhibitors, published studies have indirectly indicated that GSLs are important iNKT cell antigens in BMDCs after TLR agonist stimulation 9, 10, 20 . Our identification of a specific antigenic \u03b2-GSL, \u03b2-GlcCer, allowed us to target the pathways involved in the synthesis of that lipid. Silencing of Ugcg, the gene that encoded \u03b2-GlcCer synthase, resulted in less self-reactivity and lower response of iNKT cells to BMDCs in the presence of LPS or whole bacteria. Targeting B4galt6, which encodes the main enzyme involved in the conversion of \u03b2-GlcCer to \u03b2-LacCer, increased self reactivity as well as the response of iNKT cells to LPS and some bacteria, likely as a result of the observed accumulation of \u03b2-GlcCer. Our siRNA silencing results, controlled for antigen presentation, IL-12 production, APC activation status and endosomal morphology, strongly suggest that \u03b2-GlcCer has an important role in the CD1d-dependent signal in APCs during many infections. Additionally, \u03b2-GlcCer has been reported to accumulate in spleen, serum and liver of LPS-exposed rodents 45 , suggesting that endosomal uptake of systemically circulating \u03b2-GlcCer by APCs could provide another source of antigen. Thus, the induction of GSL biosynthesis, both in antigen-presenting cells and systemically, provides a mechanism for danger sensing by iNKT cells, which is mediated by \u03b2-GlcCer.", "cite_spans": [{"start": 499, "end": 501, "text": "9,", "ref_id": "BIBREF8"}, {"start": 502, "end": 505, "text": "10,", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "Two signals have an important role in iNKT cell activation during microbial infection: the first is a lipid antigen presented by CD1d to the iNKT cell TCR, and the second is an inflammatory cytokine, such as IL-12. We propose that \u03b2-GlcCer, a self antigen that accumulates after APC activation, provides a major TCR signal for iNKT cells. The ability of an iNKT cell to be activated by the integration of APCdependent innate signals explains how these cells, with an invariant TCR, can be activated in multiple pathologic contexts in the absence of foreign lipid antigens. 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(c-e) ELISA of the production of IFN-\u03b3 (c,e) and IL-4 (d) by a primary mouse iNKT cell line cultured together with CD11c + BMDCs in the presence of \u03b1-GalCer (10 ng/ml) or bovine milk \u03b2-GlcCer (fivefold dose titration with a top concentration of 20 \u00b5g/ml), in the absence (c,d) or presence (e) of IL-12 (20 pg/ml). Data are representative of at least three independent experiments (mean and range of duplicate wells).", "type": "figure"}, "FIGREF1": {"text": "\u03b2-GlcCer is present in primary lymphoid tissues and activates iNKT cells. (a) TLC analysis of polar lipids extracted from mouse thymus, spleen, whole liver and BMDCs along with GSL standards and bovine milk \u03b2-GlcCer dose titration. Arrow indicates mobility of \u03b2-GlcCer. (b) ELISA of IL-2 production by the iNKT hybridoma DN32 cultured together with RAW cells or CD1d-transfected RAW cells as APCs, with lipid fractions from mouse thymus and spleen, or bovine milk \u03b2-GlcCer (fivefold dose titration to a top concentration of 20 \u00b5g/ml). Data are representative of two separate experiments (mean and range of duplicate wells). (c,d) ESI-MS analysis of \u03b2-GalCer purified from thymus (c) and spleen (d), assessed in the electrospray-positive mode and presented relative to the most abundant species, set as 100 (m/z, mass/charge). Major \u03b2-GlcCer ions are presented with a lithium adduct; fatty acid composition (determined by collision-induced dissociation tandem mass spectrometry) is in parentheses. Data are representative of two experiments. (e) Structures of two abundant \u03b2-GlcCer forms detected by ESI-MS.", "type": "figure"}, "FIGREF2": {"text": "Reactivity of iNKT cells to a \u03b2-GlcCer panel with differing N-acyl chains. (a) ELISA of IL-2 production by the iNKT cell hybridoma DN32 cultured together with RAW cells or CD1d-transfected RAW cells, plus \u03b2-GlcCer with various N-acyl chains (horizontal axis; fivefold-dose titration of with a top concentration of 10 \u00b5g/ml) or \u03b1-GalCer (10 ng/ml). (b) ELISA of IFN-\u03b3 production by a primary mouse iNKT cell line cultured together with wild-type CD11c + BMDCs, plus \u03b2-GlcCer C 24:1 , reported iNKT cell lipid self antigens or a microbial GSL antigen. (c,d) Cytokine capture assay of IFN-\u03b3 (c) and IL-4 (d) in liver mononuclear cells from mice given intravenous injection of 25 \u00b5g lipid (above plots) or 1 \u00b5g \u03b1-GalCer, presented as the TCR\u03b2 + PBS-57-loaded tetramer-positive gate, except bottom right plot (total TCR\u03b2 + gate is shown for a CD1d-deficient mouse injected with \u03b2-GlcCer C 24:1 ). Numbers in outlined areas indicate percent iNKT cells producing IFN-\u03b3 or IL-4. Structures of the synthetic lipids used here are inSupplementary Figure 4, and as all structures contained a d 18:1 shingenine base, they are abbreviated throughout with only the N-acyl chain composition listed (for example, '\u03b2-GlcCer 24:1' indicates \u03b2-d-glucopyranosylceramide d 18:1 -C 24:1 ). FSC, forward scatter. Data are representative of three separate experiments (a,b; mean and range of duplicate wells) or at least three independent experiments (c,d).", "type": "figure"}, "FIGREF4": {"text": "\u03b2-GlcCer presented by CD1d activates iNKT cells through cognate TCR interaction. (a) ELISA of IFN-\u03b3 produced by a primary mouse iNKT cell line stimulated with plate-bound biotin-conjugated CD1d or BSA loaded with equal molar concentrations of various lipids (horizontal axis). (b) Flow cytometry of freshly isolated splenocytes from C57BL/6 and BALB/c mice, stained with PBS-57-CD1d tetramer (tet) and unloaded tetramer or \u03b2-GlcCer C 24:1 tetramer. Numbers adjacent to outlined areas indicate percent iNKT cells (PBS-57 tetramer-positive, TCR\u03b2 + CD19 \u2212 cells) that stained positive with \u03b2-GlcCer C 24:1 -loaded tetramer. (c) Flow cytometry of C57BL/6 splenocytes stained with \u03b2-GlcCer C 24:1 CD1d tetramer and antibody to various TCR V \u03b2 chains (Anti-V \u03b2 ; above plot). Results for iNKT cells are presented; numbers in quadrants indicate percent cells in each. (d) Frequency of iNKT cells from the \u03b2-GlcCer C 24:1 tetramer-positive population bearing each TCR V \u03b2 in c (horizontal axis). Data are representative of three experiments (a,c; mean and range of duplicate wells in a) or two experiments (b) or are from three separate experiments (d; mean and s.e.m.).", "type": "figure"}, "FIGREF5": {"text": "-GlcCer is a cognate antigen for human iNKT cells. (a,b) IFN-\u03b3 production by human iNKT cell clones (J3N.5, BM2A.3 and J24L.17) cultured together with human PBMC-derived monocytes in the presence of various lipids (10 \u00b5g/ml; horizontal axis; a) or \u03b1-GalCer (10 ng/ml; a) and with monoclonal antibody to CD1d (anti-CD1d) or isotype-matched control antibody (b). (c) ELISA of IFN-\u03b3 production by a primary human iNKT cell line cultured together with PBMC-derived monocytes, plus \u03b2-GlcCer C 24:1 , reported iNKT cell lipid self antigens or a microbial GSL antigen. (d) Identification of iNKT cells with anti-CD3\u03b5 and PBS-57 tetramers (top) and staining of CD3\u03b5 + PBS-57 tetramer-positive gated cells with anti-V \u03b1 24 and anti-V \u03b2 11 to confirm invariant TCR chain use (bottom). Numbers adjacent to outlined areas indicate percent positive cells in each. (e) Flow cytometry of PBMCs costained with PBS-57-loaded CD1d tetramer and CD1d tetramers loaded with \u03b2-GlcCer N-acyl chain variants (above plots), presented as the CD3\u03b5 + gate. CD1d tetramers loaded with \u03b2-GlcCer C 24:1 , C 18:1 and C 12:0 stain human iNKT cells. Data are representative of three experiments (a-c; mean and range of duplicate wells), two experiments (d) or least three separate experiments (e).", "type": "figure"}, "FIGREF6": {"text": "\u03b2-GlcCer contributes to iNKT cell self-reactivity. (a) ELISA of IFN-\u03b3 production by an iNKT cell line cultured together with CD11c + BMDCs at a ratio of 5:1, with vehicle alone or with NB-DGJ or D-PDMP (inhibitors of \u03b2-GlcCer synthesis). (b) IFN-\u03b3 production by iNKT cells cultured together with CD11c + BMDCs and Gal-\u03b1-GalCer, in the presence of vehicle alone or NB-DGJ or D-PDMP. (c) Quantitative PCR analysis of Ugcg and B4galt6 in CD11c + BMDCs cultured for 48 h with control siRNA (Ctrl) or Ugcg-or B4galt6-specific siRNA, presented relative to Gapdh expression (encoding glyceraldehyde phosphate dehydrogenase). (d) ELISA of the production of IFN-\u03b3 and IL-4 by a primary iNKT cell line cultured together with the BMDCs in c (ratio, horizontal axes), assessing autoreactivity. (e) IFN-\u03b3 production by an iNKT cell line cultured together with CD11c + BMDCs treated with siRNA as in c, assessing the presentation of Gal-\u03b1-GalCer. (f) Flow cytometry analysis of CD1d surface expression on CD11c + BMDCs treated with siRNA as in c. Data are representative of three separate experiments (mean and range in duplicate wells in a,b,d,e; mean and s.e.m. of triplicates in c). NUMBER 12 DECEMBER 2011 nature immunology A r t i c l e s again observed rapid upregulation of Ugcg and concomitant downregulation of B4galt6", "type": "figure"}, "FIGREF7": {"text": "role for \u03b2-GlcCer in the iNKT cell response to LPS-exposed BMDCs. (a) Quantitative PCR analysis of the expression of genes involved in \u03b2-GlcCer metabolism in CD11c + BMDCs exposed for 0-24 h (horizontal axes) to LPS (1 ng/ml), presented relative to Gapdh expression.(b) TLC of polar lipid extracts from LPS-treated CD11c + BMDCs; arrow indicates the relative mobility of \u03b2-GlcCer. (c) Densitometry of the upper and lower \u03b2-GlcCer TLC bands in b. (d) ELISA of IFN-\u03b3 production by an iNKT cell line cultured together with CD11c + BMDCs in the presence of LPS plus vehicle alone or NB-DGJ or D-PDMP. (e) ELISA of IFN-\u03b3 production by a primary iNKT cell line cultured together with siRNA-treated CD11c + BMDCs (as in Fig. 6c), in the presence of LPS. Data are representative of three independent experiments (error bars, s.e.m. of triplicates (a), s.d. (c) or mean and range of duplicate wells (d,e)). \u03b2-GlcCer contributes to microbial activation of iNKT cells. (a) ELISA of IFN-\u03b3 production by a primary iNKT cell line cultured together with siRNA-treated CD11c + BMDCs (as in Fig. 6c) in the presence of heat-killed bacteria (horizontal axes), assessing activation. (b) TLC of polar lipid extracts from spleens collected on days 0-2 after intravenous infection of mice with E. coli. (c) TLC analysis of whole-lung lipid extracts on days 0,1 and 3 after intranasal infection with S. pneumoniae, with a solvent system that allowed separation of bacterial GlcDAG from \u03b2-GlcCer. Arrows indicate mobility of \u03b2-GlcCer. Below (b,c), densitometry of \u03b2-GlcCer bands; each symbol represents an individual mouse, and small horizontal lines indicate the mean. Data are representative of three separate experiments (a; mean and range of duplicate wells) or two experiments (b,c).", "type": "figure"}}}
{"paper_id": "2876770", "_pdf_hash": "03cbf87fcf4c46adaf76e2dec9500dee4571dc3d", "abstract": [{"section": "Abstract", "text": "Background: pneumococcal conjugate vaccines (pCV) reduce nasopharyngeal carriage of vaccine type (Vt) pneumococci, an important driver of vaccine programs' overall benefits. the dosing schedule that best reduces carriage is unclear. Methods: We performed a systematic review of english language publications from 1994 to 2010 (supplemented post hoc with studies from 2011) reporting pCV effects on Vt carriage to assess variability in effect by dosing schedule. Results: We identified 32 relevant studies (36 citations) from 12,980 citations reviewed. twenty-one (66%) evaluated pCV7; none used pCV10 or pCV13. Five studies evaluated 2 primary doses and 13 three primary doses. After the first year of life, 14 evaluated 3-dose primary series with pCV booster (3+1), seven 3 doses plus 23-valent polysaccharide booster \"3+1ppV23,\" five \"3+0,\" four \"2+1,\" three \"2+1ppV23\" and two \"2+0.\" Four studies directly compared schedules. From these, 3 primary doses reduced Vt carriage more than 2 doses at 1-7 months following the series (1 study significant; 2 borderline). In a study, the 2+1 schedule reduced Vt carriage more than 2+0 at 18, but not at 24 months of age. One study of a 23-valent pneumococcal polysaccharide vaccine booster showed no effect. All 16 clinical trials with unvaccinated controls and 11 observational studies with before-after designs showed reduction in Vt carriage. Conclusions: the available literature demonstrates Vt-carriage reduction for 2+0, 2+1, 3+0 and 3+1 pCV schedules, but not for 23-valent pneumococcal polysaccharide vaccine booster. Comparisons between schedules show that 3 primary doses and a 2+1 schedule may reduce carriage more than 2 primary doses and a 2+0 schedule, respectively.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Key Words: pneumococcal conjugate vaccine, immunization schedule, nasopharyngeal carriage, nasopharyngeal colonization, systematic review (Pediatr Infect Dis J 2014;33:S152-S160) S treptococcus pneumoniae (pneumococcus) colonizes the human nasopharynx, particularly in young children, and is part of the normal nasopharyngeal (np) bacterial flora.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "1 Although pneumococcal colonization is usually asymptomatic, in some cases, it progresses to a disease state, with spread from the nasopharynx resulting in sinusitis, otitis media, pneumonia and invasive diseases, such as bacteremia and meningitis.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "2 Vaccines targeting pneumococcus have been shown to differ in their protective efficacy against np carriage. the 23-valent pneumococcal polysaccharide vaccine (ppV23), licensed in 1983, protects against invasive pneumococcal disease (IpD, infection of a normally sterile body site) in adults, 3 but not against np carriage.", "cite_spans": [{"start": 294, "end": 295, "text": "3", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Abstract", "text": "4 pneumococcal conjugate vaccine (pCV), first licensed for infant use in 2000, protects against invasive and non-IpD 5 and against acquisition and density of vaccine serotype (Vt) np carriage.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "6,7 pCV use among children leads to simultaneous decreases in Vt IpD and carriage in non-vaccinated age groups (eg, adults), demonstrating that infant and toddler np carriage is an important driver of pneumococcal transmission in the household and community.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "8 Based on the precondition of np carriage for development of disease and its role in transmission, the effect of pCV on Vt carriage is important and may be used along with other data to infer pCV impact on disease.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "pCV7 and pCV10 were initially licensed for 3 primary doses plus a booster (3+1 schedule), and pCV7, pCV10 and pCV13 were later granted licenses in europe and elsewhere for schedules using 2 primary doses plus a booster (2+1).", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "9-11 However, we lack a clear understanding of the full impact of reduced-dose schedules relative to 3+1. One previous report reviewed clinical trials, cohort and case-control studies that made direct comparisons of various pCV schedules within each study; however, only 2 studies from the large body of evidence on pCV and np-carriage effects met the report's inclusion criteria for np-carriage evaluations.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "We examined the larger set of literature regarding pCV dosing schedules to address the following key policy questions regarding direct effects of vaccine on Vt carriage: (1) What is the evidence that a 3-dose primary series is superior or inferior to a 2-dose primary series? (2) If only 3 doses are used, is there any evidence to prefer a 2+1 or a 3+0 schedule? (3) What is the evidence that a schedule including a booster dose is superior to one without a booster dose? and (4) Is there evidence to support the choice of pCV or ppV23 as a booster dose?", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "METHODS", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "this analysis is part of a larger project describing the impact of pCV dosing schedules on IpD, immunogenicity, np carriage, ). In brief, a systematic literature review was performed to collect all available english language data published from January 1994 to September 2010 (supplemented post hoc with studies from 2011) on the effect of various pCV vaccination schedules among immunized children on immunogenicity, np colonization, IpD, pneumonia and on indirect effects among unvaccinated populations. Articles published in 14 databases, from ad hoc unpublished sources and abstracts from meetings of the International Symposium on pneumococci and pneumococcal Disease (1998Disease ( -2010 and the Interscience Conference on Antimicrobial Agents and Chemotherapeutics (1994-2010), were searched. We included all randomized controlled clinical trials, nonrandomized trials, surveillance database analyses and observational studies of any pCV schedule on 1 or more outcomes of interest. Studies were included for abstraction if ppV23 was used as a booster dose, but not if used as a primary dose. titles and abstracts were reviewed twice and those with relevant content on 1 of the 5 outcomes (immunogenicity, carriage, invasive disease, pneumonia and indirect effects) underwent full review using a standardized data collection instrument. We did not search non-english language literature because of the low likelihood they would have on relevant data for this project. Details on the search methods are provided elsewhere (methods Appendix 17 ).", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Citations recovered through the literature search went through several stages of independent review to determine their eligibility, as described elsewhere (methods Appendix 17 ). Citations meeting inclusion criteria were categorized on an outcome specific basis into \"study families,\" where each family included abstracts or publications generated from a single protocol, population, surveillance system or other data collection system relevant to that outcome. Investigators identified primary data from the individual studies making up each study family for inclusion in the analysis. the primary data were selected as the most current and complete data available for that study family. In some cases, these data were drawn from more than 1 publication within a family. We also defined \"study arms\" as a group of children distinguished by immunization schedule or pCV product.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "We abstracted core information on the following: number of children in a \"study arm\"; pCV manufacturer, valency and conjugate protein; co-administered vaccines; country; age at each dose and date of study and publication. Additional data abstracted for the direct effect of pCV on Vt np carriage included age at each np specimen collection.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "We included data published from randomized controlled trials, nonrandomized trials, surveillance databases and observational studies of pCV schedules on Vt carriage. We included all pCV products (denoted as pCV with a number indicating the valency, eg, pCV7). We excluded studies with all vaccination series beginning after 12 months of life, studies that only reported data before or after pCV introduction but not for both periods and studies that did not report direct pCV effects on Vt carriage.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "We included pCV schedules with 2 primary doses only (2+0), 2 primary doses plus a pCV booster (2+1) or a ppV23 booster (2+1ppV23), 3 primary doses only (3+0) and 3 primary doses plus a pCV booster (3+1) or a ppV23 booster (3+1ppV23).", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Because the included studies used various designs and methods, we were unable to perform a meta-analysis. thus, we summarized the data across studies in descriptive analyses to provide an overview of the amount and variability of data by schedule. each study was divided into arms, defined as a unique combination of vaccine schedule, age at np specimen collection and vaccine product used. Studies could have multiple arms. Vt was defined as each study defined it, based on the product used. no studies included pCV products with serotype 19A; none classified 19A as Vt. two pCV7 studies included serotype 6A as a Vt. 18, 19 We defined percent Vt carriage as the percentage of children sampled who carried a Vt strain, except in 7 citations that only reported percent of pneumococcal isolates that were Vt, in which case this percent was used. 7, [20] [21] [22] [23] [24] [25] For clinical trials, we abstracted the difference in Vt-carriage prevalence with confidence intervals (CI) between vaccinated children and controls. If not reported, we calculated the difference in carriage between vaccinated children and controls. We separated clinical trials into those that directly compared np effects of various schedules and trials that evaluated effects only between a given schedule and unvaccinated controls. We separated these latter trials into those that examined carriage early (during the first year of life or prior to any booster dose given in the study) and late (after the first year of life or after any booster dose given in the study).", "cite_spans": [{"start": 619, "end": 622, "text": "18,", "ref_id": "BIBREF17"}, {"start": 623, "end": 625, "text": "19", "ref_id": "BIBREF18"}, {"start": 845, "end": 847, "text": "7,", "ref_id": "BIBREF6"}, {"start": 848, "end": 852, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 853, "end": 857, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 863, "end": 867, "text": "[23]", "ref_id": "BIBREF21"}, {"start": 868, "end": 872, "text": "[24]", "ref_id": "BIBREF22"}, {"start": 873, "end": 877, "text": "[25]", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Abstract", "text": "For pre-and postvaccine introduction observational studies among age groups targeted for vaccination, we calculated percent change in Vt carriage by defining the baseline prevalence as the mean of all data points reported prior to introduction. In cases where only the postintroduction Vt-carriage prevalence over a period was provided, we calculated percent change from the baseline prevalence to the reported prevalence and assigned it to the median year of the date range provided. When possible, the year of vaccine introduction was excluded from these calculations. We used microsoft Access 2003 and 2007 (microsoft Corporation, Redmond, WA) for data abstraction and SAS 9.2 and 9.3 (SAS Institute Inc., Cary, nC) for analyses. Statistical significance was defined as P < 0.05.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "RESULTS", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Of 12,980 citations reviewed, 145 had carriage data; of these, 36 met inclusion criteria for Vt carriage among children targeted to receive the vaccine (Fig. 1) . 4, 7, these 36 citations represented 32 study families with 4 supplemental citations. Among the 32 studies, 25 (78%) were published in 2003 or later; 17 (53%) were from europe or north America (table 1) .", "cite_spans": [{"start": 163, "end": 165, "text": "4,", "ref_id": "BIBREF3"}, {"start": 166, "end": 168, "text": "7,", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Abstract", "text": "52 Seven (22%) evaluated children at high risk for pneumococcal disease, such as children with HIV or sickle cell disease, indigenous children or children with acute pneumonia or otitis media. twenty-one (66%) studies evaluated pCV7; no studies evaluated pCV10 or pCV13.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Among the 32 studies, 4 directly compared Vt-carriage reduction among dosing regimens. the first study, conducted in Fiji, compared 0, 1, 2 and 3 pCV7 doses (given at 14 weeks, 6 and 14 weeks or 6, 10 and 14 weeks, respectively) with and without a ppV23 booster at 12 months.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "4 the investigators found a significant difference in Vt-carriage prevalence between the 2-and 3-dose groups at 9 months; the 3-dose group had significantly less Vt carriage [odds ratio 0.30 (CI: 0.09-0.9)]. At 6, 12 and 17 months of age, Vt carriage among the 2-and 3-dose groups was not significantly different. the receipt of a ppV23 booster showed no effect on Vt carriage, as no difference in Vt carriage at 17 months was 4 the second study, conducted in the Gambia, compared 1, 2 and 3 pCV7 doses (given at 2 months, 2 and 3 months and 2, 3 and 4 months); all children received a ppV23 booster at 10 months. 44 At 11 months, 3 pCV doses showed a borderline significant reduction in Vt carriage compared with 2 pCV doses (10.0% vs. 16.7%, P = 0.056). However, at 5 and 15 months, the Vt carriage prevalence was not significantly different among children who received 2 and 3 doses.", "cite_spans": [{"start": 614, "end": 616, "text": "44", "ref_id": "BIBREF43"}], "ref_spans": []}, {"section": "Abstract", "text": "44 the third study, conducted in Israel with pCV7, compared a 3+1 schedule (2, 4, 6 and 12 months) with 2+1 (4, 6 and 12 months) and 0+2 (12 and 18 months) schedules.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "19 Between 7 and 12 months of age (prebooster), the mean Vt prevalence was nonsignificantly lower in the 3+1 group when compared with the 2+1 group (22.6% vs. 28.4%, P = 0.089). the 0+2 group between 7 and 12 months, that is, before children were vaccinated, had a mean Vt prevalence of 35.2%, which was significantly higher than the 3+1 group (P < 0.001). Between 13 and 18 months (ie, after the booster dose) and between 19 and 30 months, the 3+1 and 2+1 groups had equivalent Vt prevalence, but both groups had significantly lower Vt prevalence than the 0+2 group.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "A fourth study, conducted in the netherlands, compared children who received pCV7 at 2 and 4 months (2+0); 2, 4 and 11 months (2+1) and unvaccinated controls. 48 At 12, 18 and 24 months of age, children in the 2+0 and 2+1 groups had significantly less Vt carriage than unvaccinated controls. Although children in the 2+1 group had a significantly lower prevalence of Vt carriage at 18 months (16%) than the 2+0 group (24%, P = 0.01), no difference was found at 24 months.", "cite_spans": [{"start": 159, "end": 161, "text": "48", "ref_id": "BIBREF48"}], "ref_spans": []}, {"section": "Abstract", "text": "Early Assessment of VT Carriage During First Year of Life: Clinical Trials ten clinical trials evaluated 2-and 3-dose primary regimens during the first year of life compared with control subjects who received either placebo or no vaccine. two trials examined both regimens 4, 19 ; 1 trial examined only a 2-dose regimen 48 and 7 studies examined only a 3-dose regimen (Fig. 2) . 7, 27, 29, 38, 43, 46 ,50 these 10 trials included 23 study arms. All 5 arms evaluating a 2-dose primary series found reductions in Vt-carriage prevalence among pCV recipients compared with controls, although only 1 arm reached statistical significance. Of 18 arms, 17 with 3-dose primary regimens observed reductions in Vt carriage; 11 arms were statistically significant. One 3-dose primary series arm (merck, pCV7) observed a nonsignificant increase of Vt-carriage prevalence at 7 months of age. 50 two trials examined the Vt-carriage effect of 3 primary doses but provided results that could not be compared with other studies. One, a clinical trial in Iceland, examined 81 children who received pCV8 conjugated to diphtheria or tetanus toxoid given in 3 primary doses (3, 4 and 6 months) and 40 unvaccinated controls.", "cite_spans": [{"start": 273, "end": 275, "text": "4,", "ref_id": "BIBREF3"}, {"start": 276, "end": 278, "text": "19", "ref_id": "BIBREF18"}, {"start": 320, "end": 322, "text": "48", "ref_id": "BIBREF48"}, {"start": 379, "end": 381, "text": "7,", "ref_id": "BIBREF6"}, {"start": 382, "end": 385, "text": "27,", "ref_id": "BIBREF25"}, {"start": 386, "end": 389, "text": "29,", "ref_id": "BIBREF27"}, {"start": 390, "end": 393, "text": "38,", "ref_id": "BIBREF37"}, {"start": 394, "end": 397, "text": "43,", "ref_id": "BIBREF42"}, {"start": 398, "end": 400, "text": "46", "ref_id": "BIBREF46"}], "ref_spans": []}, {"section": "Abstract", "text": "Swabs were collected at 3, 4, 6, 7, 10, 14 and 18 months. For swabs at ages \u22646 months, Vt carriage was not significantly different between controls (21%) and vaccinees (18%, P = 0.5). Vaccinees were then given either a pCV8 booster or a ppV23 booster at 13 months, but results from swabs at ages >6 months were not reported separately for those who received pCV8 and ppV23 boosters and thus are not presented here.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "34 the other study, a trial conducted in Kenya, compared 3 primary doses of pCV7 starting at either birth FIGURE 1. Literature search results for carriage citations identified from search strategy, as strategy as detailed in the Methods Appendix.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Study families include 1 or more citation generated from a single protocol or data collection system, and the primary citation identifies the citation within each study family that contains the most detailed information regarding vaccinetype carriage. Supplemental citations contain additional data not contained in the citation for the primary study.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "The Pediatric Infectious Disease Journal \u2022 Volume 33, Number 1, Supplement 2, January 2014 Dosing and Pneumococcal Carriage", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "www.pidj.com | S155 or 6 weeks of age with subsequent doses at 10 and 14 weeks and found no significant differences in Vt carriage at 18 and 36 weeks among the regimens. (Fig. 3) . two trials examined 2+0 schedules 4, 48 ; one 2+1 48 ; two 2+1ppV23 4, 42 ; four 3+0 4, 27, 37, 41 ; five 3+1 7, 30, 39, 45, 46, 50 and four 3+1ppV23. 4, 29, 35, 42 Among the 29 arms reported in these 13 studies, 28 showed reduction in Vt compared with control subjects; 15 arms were statistically significant (Fig. 3) . One arm conducted among South African children with HIV who received a 3+0 pCV9 schedule had a nonsignificant increase in Vt carriage when compared with controls.", "cite_spans": [{"start": 215, "end": 217, "text": "4,", "ref_id": "BIBREF3"}, {"start": 218, "end": 220, "text": "48", "ref_id": "BIBREF48"}, {"start": 249, "end": 251, "text": "4,", "ref_id": "BIBREF3"}, {"start": 252, "end": 254, "text": "42", "ref_id": "BIBREF41"}, {"start": 266, "end": 268, "text": "4,", "ref_id": "BIBREF3"}, {"start": 269, "end": 272, "text": "27,", "ref_id": "BIBREF25"}, {"start": 273, "end": 276, "text": "37,", "ref_id": "BIBREF36"}, {"start": 277, "end": 279, "text": "41", "ref_id": "BIBREF40"}, {"start": 291, "end": 293, "text": "7,", "ref_id": "BIBREF6"}, {"start": 294, "end": 297, "text": "30,", "ref_id": "BIBREF28"}, {"start": 298, "end": 301, "text": "39,", "ref_id": "BIBREF38"}, {"start": 302, "end": 305, "text": "45,", "ref_id": "BIBREF44"}, {"start": 306, "end": 309, "text": "46,", "ref_id": "BIBREF46"}, {"start": 310, "end": 312, "text": "50", "ref_id": "BIBREF50"}, {"start": 332, "end": 334, "text": "4,", "ref_id": "BIBREF3"}, {"start": 335, "end": 338, "text": "29,", "ref_id": "BIBREF27"}, {"start": 339, "end": 342, "text": "35,", "ref_id": "BIBREF34"}, {"start": 343, "end": 345, "text": "42", "ref_id": "BIBREF41"}], "ref_spans": []}, {"section": "Abstract", "text": "37", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Results by schedule from 11 observational, pre/postvaccine introduction studies (13 citations) are shown in Figure 4 . 18, [20] [21] [22] [23] [24] [25] [26] 28, 31, 36, 47, 49 All observational studies used pCV7. none examined a 3+0 schedule. two observational studies examined 2+1 schedules. One conducted in england with national introduction with a catch-up campaign showed a statistically significant reduction.", "cite_spans": [{"start": 119, "end": 122, "text": "18,", "ref_id": "BIBREF17"}, {"start": 123, "end": 127, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 128, "end": 132, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 138, "end": 142, "text": "[23]", "ref_id": "BIBREF21"}, {"start": 143, "end": 147, "text": "[24]", "ref_id": "BIBREF22"}, {"start": 148, "end": 152, "text": "[25]", "ref_id": "BIBREF23"}, {"start": 153, "end": 157, "text": "[26]", "ref_id": "BIBREF24"}, {"start": 158, "end": 161, "text": "28,", "ref_id": "BIBREF26"}, {"start": 162, "end": 165, "text": "31,", "ref_id": "BIBREF29"}, {"start": 166, "end": 169, "text": "36,", "ref_id": "BIBREF35"}, {"start": 170, "end": 173, "text": "47,", "ref_id": "BIBREF47"}, {"start": 174, "end": 176, "text": "49", "ref_id": "BIBREF49"}], "ref_spans": []}, {"section": "Abstract", "text": "18 A study in Switzerland with private-market introduction among children <2 years of age with acute otitis media or pneumonia also showed reduction; statistical significance was not reported. 21 Additional observational studies met inclusion criteria but were not comparable to other studies because of their unique designs. A cohort study from Korea evaluated the effect of a 3+1 schedule (given at 2, 4, 6 and 16.5 months), following pCV7 private-market introduction. 33 this study compared vaccinated children in daycare from a highly vaccinated region to unvaccinated children in daycare from a region with low vaccination rates. 33 An openlabel, prospective study in mexico evaluated Vt-carriage acquisition in children receiving either 3 pCV7 doses (given between 6 weeks and 6 months) or 2 doses (given between 7 and 11 months); no unvaccinated controls were included in the study.", "cite_spans": [{"start": 193, "end": 195, "text": "21", "ref_id": "BIBREF20"}, {"start": 471, "end": 473, "text": "33", "ref_id": "BIBREF32"}], "ref_spans": []}, {"section": "Abstract", "text": "32 Vt acquisition decreased over time in both the 2-and 3-dose primary regimens, but the groups were not directly compared. An observational follow-up study to a clinical trial in the philippines compared children with pneumonia between 6 weeks and 23 months old, who had received pCV11 or placebo at a median age of 7, 12 and 16 weeks. 40 Vt was reduced in the pCV11 group versus placebo; quantitative results were not provided. 40 Finally, a pre/postintroduction study from France also included a sub-analysis examining the effect of the booster dose. 28 Among children >1 year of age during all years of the study, Vt carriage was 44.4% in unvaccinated children, 23.9% in children vaccinated without a booster dose and 11.8% in children vaccinated with the booster dose.", "cite_spans": [{"start": 337, "end": 339, "text": "40", "ref_id": "BIBREF39"}, {"start": 430, "end": 432, "text": "40", "ref_id": "BIBREF39"}], "ref_spans": []}, {"section": "Abstract", "text": "28", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "We found that all schedules reviewed-2+0, 2+1, 2+1ppV23, 3+0, 3+1 and 3+1ppV23-reduced carriage of Vts of pneumococcus compared with no pCV. However, the strength of evidence supporting each schedule varies and effects differ among the schedules. First, in studies with direct comparisons of 2 versus 3 primary doses, 3 doses result in a greater reduction in Vt carriage compared with 2 doses at 1-7 months following the primary series. 4, 19, 44 However, measurable differences in *One cohort study 33 and 1 open-label, prospective, observational trial. 32 \u2020 Acute otitis media or pneumonia at time of NP swab collection. \u2021 \u2021Percentages add up to >100%, as studies may have multiple dosing schedules and may have assessed carriage both during and after the first year of life.", "cite_spans": [{"start": 437, "end": 439, "text": "4,", "ref_id": "BIBREF3"}, {"start": 440, "end": 443, "text": "19,", "ref_id": "BIBREF18"}, {"start": 444, "end": 446, "text": "44", "ref_id": "BIBREF43"}, {"start": 500, "end": 502, "text": "33", "ref_id": "BIBREF32"}], "ref_spans": []}, {"section": "Abstract", "text": "\u00a7Total study arms with carriage specimens during the first year of life (n = 18). \u00b6Total study arms with carriage specimens after the first year of life (n = 35). \u2016Products are listed as PCV, valency and manufacturer name. **Includes PCV4-Sanofi, PCV5-Wyeth, PCV7-Merck, PCV8-Sanofi and PCV11-Glaxo SmithKline.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "The Pediatric Infectious Disease Journal \u2022 Volume 33, Number 1, Supplement 2, January 2014 S156 | www.pidj.com", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Vt-carriage reduction between 2 and 3 primary doses are not seen on further follow up following primary vaccination in schedules with pCV boosters, 19 ppV23 boosters 4,44 or no boost. 4 Differences between the schedules are difficult to discern when comparing the impact of 2-and 3-dose primary series between studies rather than within studies.", "cite_spans": [{"start": 184, "end": 185, "text": "4", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Abstract", "text": "Very little evidence is available on Vt-carriage prevalence after the first year of life in children who received a 2-dose schedule without a booster dose. Both clinical trials that evaluated 2+0 schedules after the first year of life demonstrated reductions in Vt carriage. 4, 48 However, in 1 of these studies, the 2+1 schedule reduced Vt carriage more than the 2+0 schedule at 1 of 3 time points, suggesting that the 2+1 schedule may be better than the 2+0. 48 Furthermore, there is no evidence regarding effect of 2+0 schedules on Vt carriage from observational studies or for longterm effects of this schedule since no country is using this schedule. Concerns regarding the immunogenicity of 2+0 schedules and the lack of evidence regarding the impact of 2+0 schedules on IpD, pneumonia and indirect effects have precluded its use in national immunization programs to date. more evidence is needed regarding the optimal timing of the doses in a 3-dose schedule, but available evidence supports the use of both 2+1 and 3+0 schedules. While no published studies directly compare the impact of 2+1 and 3+0 schedules on Vt carriage, both schedules reduce Vt carriage compared with no pCV use. A study of 2+1, 3+0 and 3+1 schedules using pCV7 from Israel was done and has been published in part. 19, 54 Results suggest that the 2+1 schedule results in similar Vt-carriage prevalence to 3+1 when Vt-carriage prevalence is sampled after the booster doses; however, 2+1 appears to be inferior to 3+1 prior to the booster dose. Additionally, this study directly compared 3+0 and 3+1 schedules and showed no difference in Vt-carriage prevalence. these data suggest that 2+1 and 3+0 schedules may have similar effects on Vt carriage after the first year of life, but these schedules were not directly compared in this study. It is important to note that data supporting 2+1 schedules come from a clinical trial and 2 observational studies in europe (the netherlands, 48 england 18 and Switzerland), 21 whereas data supporting a 3+0 schedule come from clinical trials in middle income and developing countries (philippines, 40,41 Fiji, 4 the Gambia 27 and South Africa).", "cite_spans": [{"start": 275, "end": 277, "text": "4,", "ref_id": "BIBREF3"}, {"start": 278, "end": 280, "text": "48", "ref_id": "BIBREF48"}, {"start": 461, "end": 463, "text": "48", "ref_id": "BIBREF48"}, {"start": 1296, "end": 1299, "text": "19,", "ref_id": "BIBREF18"}, {"start": 1300, "end": 1302, "text": "54", "ref_id": "BIBREF55"}], "ref_spans": []}, {"section": "Abstract", "text": "37 While both 3+0 and 2+1 schedules appear to be effective, differences between 2+1 and 3+0 schedules may exist that are relevant to settings with particular pneumococcal transmission patterns, burden of disease or colonization. For example, vaccine programs serving populations with disease early in life, heavy transmission and young age of transmitters may prefer 3+0 schedules; however, the data in our review do not provide a conclusive determination of which schedule is optimal for each of these settings.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Some evidence suggests that schedules with pCV boosters may provide additional reductions in Vt carriage.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "28,48 the available evidence does not support the use of schedules with ppV23 boosters for improving np-carriage reductions. While no studies directly compared pCV and ppV23 boosters, a Fijian study compared schedules with and without ppV23 boosters and showed no benefit of 2+1ppV23 and 3+1ppV23 schedules compared with 2+0 and 3+0 schedules, respectively, despite boosts in antibodies seen with ppV23 boosters. 4 FIGURE 2. Difference in VT carriage prevalence between vaccinated and unvaccinated or placebo groups for clinical trials by primary dosing series (2 or 3 doses) for carriage assessed in the first year of life. 4, 7, 19, 27, 29, 38, 43, 46, 48, 50 Two and 3 primary doses were given between 6 weeks and 6 months for all regimens. Studies denoted on y-axis with primary dosing series (2 or 3 doses), first author's last name (with reference number in brackets) and mean or median age in months (m) of children at time of NP specimen collection. Products are listed as PCV-valency and manufacturer name. Confidence intervals are displayed by error bars. Data points are labeled with sample size, an asterisk (*) if statistically significant when compared with controls and/or NR if statistical significance was not reported. All others were not statistically significant. GSK, GlaxoSmithKline. Determining the relative benefit for np-carriage reductions of 1 schedule over another is difficult. limited data are available from studies with direct comparisons between schedules. Few are conducted in regions where child mortality is high, and some studies were in the setting of catch-up campaigns, which would blur the measured effect of the primary schedule. these limitations should be considered when assessing the potential benefits of particular schedules. For example, while 2+1 schedules reduced Vt carriage in 2 observational studies, it is important to note that 1 study was conducted among vaccinated children in the setting of a privatemarket introduction, 21 where vaccinated children may have lower inherent risk of colonization, and 1 study was conducted among all children <5 years old in the setting of a national immunization program with a catch-up campaign.", "cite_spans": [{"start": 625, "end": 627, "text": "4,", "ref_id": "BIBREF3"}, {"start": 628, "end": 630, "text": "7,", "ref_id": "BIBREF6"}, {"start": 631, "end": 634, "text": "19,", "ref_id": "BIBREF18"}, {"start": 635, "end": 638, "text": "27,", "ref_id": "BIBREF25"}, {"start": 639, "end": 642, "text": "29,", "ref_id": "BIBREF27"}, {"start": 643, "end": 646, "text": "38,", "ref_id": "BIBREF37"}, {"start": 647, "end": 650, "text": "43,", "ref_id": "BIBREF42"}, {"start": 651, "end": 654, "text": "46,", "ref_id": "BIBREF46"}, {"start": 655, "end": 658, "text": "48,", "ref_id": "BIBREF48"}, {"start": 659, "end": 661, "text": "50", "ref_id": "BIBREF50"}, {"start": 1980, "end": 1982, "text": "21", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Abstract", "text": "18 Furthermore, only 7 np studies evaluated pCV schedule impact in children at high risk for colonization and disease; the only study to specifically evaluate children with HIV failed to show efficacy of a 3+0 schedule on Vt carriage. 37 none of the studies included evaluated pCV10 or pCV13, which are currently being used in national immunization programs. However, a study in France, conducted in the year following the switch from pCV7 to pCV13, showed a significant reduction in the additional 6 serotypes included in pCV13 among children partially and fully vaccinated with pCV13 when compared with those vaccinated with pCV7. 55 this study was not included in this analysis due to a lack of pre-pCV introduction data for pCV13 serotypes. 55 this analysis focused on Vt carriage and did not address the effect of dosing schedules on all pneumococcal carriage or non-Vt carriage, as the impact on Vt carriage is the most important factor for policy makers when deciding which dosing schedules to recommend. most studies show that pCV does not affect the overall prevalence of all-serotype pneumococcal carriage, 4, 7, [18] [19] [20] [21] [22] [23] 27, 31, 36, 39, 41, 43 although some show a reduction at some or all time points. 19, 25, 28, 48 Additionally, most studies show that non-Vts increase in prevalence following pCV, 4, 7, 18, 19, 23, 27, 28, 31, 36, 38, 39, 42, 48 although a few studies show no change at some or all time points. 4, 7, 19 many, but not all, non-Vts have lower invasive potential than most Vt strains, meaning that they are less likely to cause IpD if carried, 18 and invasive potential does not appear to change with time 47, 56 or vaccine introduction. 47 thus, the potential for many replacing serotypes to cause IpD is not as high as for serotypes included by currently available pCV products.", "cite_spans": [{"start": 235, "end": 237, "text": "37", "ref_id": "BIBREF36"}, {"start": 1117, "end": 1119, "text": "4,", "ref_id": "BIBREF3"}, {"start": 1120, "end": 1122, "text": "7,", "ref_id": "BIBREF6"}, {"start": 1123, "end": 1127, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 1128, "end": 1132, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 1133, "end": 1137, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 1138, "end": 1142, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 1148, "end": 1152, "text": "[23]", "ref_id": "BIBREF21"}, {"start": 1153, "end": 1156, "text": "27,", "ref_id": "BIBREF25"}, {"start": 1157, "end": 1160, "text": "31,", "ref_id": "BIBREF29"}, {"start": 1161, "end": 1164, "text": "36,", "ref_id": "BIBREF35"}, {"start": 1165, "end": 1168, "text": "39,", "ref_id": "BIBREF38"}, {"start": 1169, "end": 1172, "text": "41,", "ref_id": "BIBREF40"}, {"start": 1173, "end": 1175, "text": "43", "ref_id": "BIBREF42"}, {"start": 1235, "end": 1238, "text": "19,", "ref_id": "BIBREF18"}, {"start": 1239, "end": 1242, "text": "25,", "ref_id": "BIBREF23"}, {"start": 1243, "end": 1246, "text": "28,", "ref_id": "BIBREF26"}, {"start": 1247, "end": 1249, "text": "48", "ref_id": "BIBREF48"}, {"start": 1333, "end": 1335, "text": "4,", "ref_id": "BIBREF3"}, {"start": 1336, "end": 1338, "text": "7,", "ref_id": "BIBREF6"}, {"start": 1339, "end": 1342, "text": "18,", "ref_id": "BIBREF17"}, {"start": 1343, "end": 1346, "text": "19,", "ref_id": "BIBREF18"}, {"start": 1347, "end": 1350, "text": "23,", "ref_id": "BIBREF21"}, {"start": 1351, "end": 1354, "text": "27,", "ref_id": "BIBREF25"}, {"start": 1355, "end": 1358, "text": "28,", "ref_id": "BIBREF26"}, {"start": 1359, "end": 1362, "text": "31,", "ref_id": "BIBREF29"}, {"start": 1363, "end": 1366, "text": "36,", "ref_id": "BIBREF35"}, {"start": 1367, "end": 1370, "text": "38,", "ref_id": "BIBREF37"}, {"start": 1371, "end": 1374, "text": "39,", "ref_id": "BIBREF38"}, {"start": 1375, "end": 1378, "text": "42,", "ref_id": "BIBREF41"}, {"start": 1379, "end": 1381, "text": "48", "ref_id": "BIBREF48"}, {"start": 1448, "end": 1450, "text": "4,", "ref_id": "BIBREF3"}, {"start": 1451, "end": 1453, "text": "7,", "ref_id": "BIBREF6"}, {"start": 1454, "end": 1456, "text": "19", "ref_id": "BIBREF18"}, {"start": 1595, "end": 1597, "text": "18", "ref_id": "BIBREF17"}, {"start": 1657, "end": 1660, "text": "47,", "ref_id": "BIBREF47"}, {"start": 1661, "end": 1663, "text": "56", "ref_id": "BIBREF57"}], "ref_spans": []}, {"section": "Abstract", "text": "this analysis has several strengths and limitations. the strengths of this analysis are its comprehensive nature with the diversity of countries and study designs included. Very few np studies directly compare schedules, and this analysis allows for all FIGURE 3. Difference in VT-carriage prevalence between vaccinated and unvaccinated or placebo groups for clinical trials by dosing series for carriage assessed after the first year of life. 4, 7, 27, 29, 30, 35, 37, 39, 41, 42, 45, 46, 48, 50 All primary doses were given between 6 weeks and 6 months of age (6 weeks to 4 months for 2 doses, 6 weeks to 6 months for 3 doses), and booster doses given at 11-18 months of age. Studies denoted on y-axis with schedule, first author's last name (with reference number in brackets) and mean or median age in months (m) of children at time of NP specimen collection. Products are listed as PCV-valency and manufacturer name. Confidence intervals are displayed by error bars. Data points are labeled with sample size, an asterisk (*) if statistically significant when compared with controls, and NR if statistical significance compared with controls was not reported. All others were not statistically significant. GSK, GlaxoSmithKline.", "cite_spans": [{"start": 444, "end": 446, "text": "4,", "ref_id": "BIBREF3"}, {"start": 447, "end": 449, "text": "7,", "ref_id": "BIBREF6"}, {"start": 450, "end": 453, "text": "27,", "ref_id": "BIBREF25"}, {"start": 454, "end": 457, "text": "29,", "ref_id": "BIBREF27"}, {"start": 458, "end": 461, "text": "30,", "ref_id": "BIBREF28"}, {"start": 462, "end": 465, "text": "35,", "ref_id": "BIBREF34"}, {"start": 466, "end": 469, "text": "37,", "ref_id": "BIBREF36"}, {"start": 470, "end": 473, "text": "39,", "ref_id": "BIBREF38"}, {"start": 474, "end": 477, "text": "41,", "ref_id": "BIBREF40"}, {"start": 478, "end": 481, "text": "42,", "ref_id": "BIBREF41"}, {"start": 482, "end": 485, "text": "45,", "ref_id": "BIBREF44"}, {"start": 486, "end": 489, "text": "46,", "ref_id": "BIBREF46"}, {"start": 490, "end": 493, "text": "48,", "ref_id": "BIBREF48"}, {"start": 494, "end": 496, "text": "50", "ref_id": "BIBREF50"}], "ref_spans": []}, {"section": "Abstract", "text": "The Pediatric Infectious Disease Journal \u2022 Volume 33, Number 1, Supplement 2, January 2014 S158 | www.pidj.com", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "of the supporting evidence for each of these regimens to be considered. However, the analysis is limited because fully differentiating the relative magnitude of the impact on Vt carriage of each schedule is not possible. Geographic region, socioeconomic level and other factors affect carriage of pneumococci and thus confound our ability to compare magnitudes of impact across studies. Additionally, we were unable to account for vaccine coverage in the target populations or the presence of catch-up campaigns due to limited information in the study reports.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "In conclusion, 2+0, 2+1, 3+0 and 3+1 schedules all reduce pneumococcal Vt carriage. Importantly, the evidence indicates that 3 primary doses may reduce Vt carriage more than 2 primary doses; that both 2+1 and 3+0 schedules are effective; pCV booster doses may be helpful, especially in the setting of 2 primary doses and the use of ppV23 boosters after a pCV schedule does not further reduce Vt carriage. Our analysis supports recent recommendations by the pan American Health Organization and the World Health Organization for the use of 3 doses of pCV and the acceptability to be administered either as 3+0 or 2+1 schedule. 57, 58 However, np carriage is only part of the picture, and the effect of each schedule on IpD, pneumonia, immunogenicity and indirect effects in the context of local epidemiology and programmatic considerations should be considered by public health when recommending and countries when choosing a schedule. 4. Percent of vaccine-type carriage among children in pre-post trend studies over time by schedule. Year of PCV introduction is denoted as year 0. Studies, which include the primary citation and any supplemental citations, are identified by country, age group in years of children at time of NP specimen collection, and by first author's last name (with reference number in brackets).", "cite_spans": [{"start": 626, "end": 629, "text": "57,", "ref_id": "BIBREF58"}, {"start": 630, "end": 632, "text": "58", "ref_id": "BIBREF59"}], "ref_spans": []}, {"section": "Abstract", "text": "ACKNOWLEDGMENTS", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "S", "text": "treptococcus pneumoniae (pneumococcus) colonizes the human nasopharynx, particularly in young children, and is part of the normal nasopharyngeal (np) bacterial flora. 1 Although pneumococcal colonization is usually asymptomatic, in some cases, it progresses to a disease state, with spread from the nasopharynx resulting in sinusitis, otitis media, pneumonia and invasive diseases, such as bacteremia and meningitis. 2 Vaccines targeting pneumococcus have been shown to differ in their protective efficacy against np carriage. the 23-valent pneumococcal polysaccharide vaccine (ppV23), licensed in 1983, protects against invasive pneumococcal disease (IpD, infection of a normally sterile body site) in adults, 3 but not against np carriage.", "cite_spans": [{"start": 167, "end": 168, "text": "1", "ref_id": "BIBREF0"}, {"start": 417, "end": 418, "text": "2", "ref_id": "BIBREF1"}, {"start": 711, "end": 712, "text": "3", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "S", "text": "4 pneumococcal conjugate vaccine (pCV), first licensed for infant use in 2000, protects against invasive and non-IpD 5 and against acquisition and density of vaccine serotype (Vt) np carriage. 6, 7 pCV use among children leads to simultaneous decreases in Vt IpD and carriage in non-vaccinated age groups (eg, adults), demonstrating that infant and toddler np carriage is an important driver of pneumococcal transmission in the household and community. 8 Based on the precondition of np carriage for development of disease and its role in transmission, the effect of pCV on Vt carriage is important and may be used along with other data to infer pCV impact on disease.", "cite_spans": [{"start": 117, "end": 118, "text": "5", "ref_id": "BIBREF4"}, {"start": 193, "end": 195, "text": "6,", "ref_id": "BIBREF5"}, {"start": 196, "end": 197, "text": "7", "ref_id": "BIBREF6"}, {"start": 453, "end": 454, "text": "8", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "S", "text": "pCV7 and pCV10 were initially licensed for 3 primary doses plus a booster (3+1 schedule), and pCV7, pCV10 and pCV13 were later granted licenses in europe and elsewhere for schedules using 2 primary doses plus a booster (2+1). [9] [10] [11] However, we lack a clear understanding of the full impact of reduced-dose schedules relative to 3+1. One previous report reviewed clinical trials, cohort and case-control studies that made direct comparisons of various pCV schedules within each study; however, only 2 studies from the large body of evidence on pCV and np-carriage effects met the report's inclusion criteria for np-carriage evaluations. 12 We examined the larger set of literature regarding pCV dosing schedules to address the following key policy questions regarding direct effects of vaccine on Vt carriage: (1) What is the evidence that a 3-dose primary series is superior or inferior to a 2-dose primary series? (2) If only 3 doses are used, is there any evidence to prefer a 2+1 or a 3+0 schedule? (3) What is the evidence that a schedule including a booster dose is superior to one without a booster dose? and (4) Is there evidence to support the choice of pCV or ppV23 as a booster dose?", "cite_spans": [{"start": 230, "end": 234, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 644, "end": 646, "text": "12", "ref_id": "BIBREF11"}, {"start": 817, "end": 820, "text": "(1)", "ref_id": "BIBREF0"}, {"start": 923, "end": 926, "text": "(2)", "ref_id": "BIBREF1"}, {"start": 1010, "end": 1013, "text": "(3)", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "METHODS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Literature Search", "text": "this analysis is part of a larger project describing the impact of pCV dosing schedules on IpD, immunogenicity, np carriage, ). In brief, a systematic literature review was performed to collect all available english language data published from January 1994 to September 2010 (supplemented post hoc with studies from 2011) on the effect of various pCV vaccination schedules among immunized children on immunogenicity, np colonization, IpD, pneumonia and on indirect effects among unvaccinated populations. Articles published in 14 databases, from ad hoc unpublished sources and abstracts from meetings of the International Symposium on pneumococci and pneumococcal Disease (1998-2010) and the Interscience Conference on Antimicrobial Agents and Chemotherapeutics (1994-2010), were searched. We included all randomized controlled clinical trials, nonrandomized trials, surveillance database analyses and observational studies of any pCV schedule on 1 or more outcomes of interest. Studies were included for abstraction if ppV23 was used as a booster dose, but not if used as a primary dose. titles and abstracts were reviewed twice and those with relevant content on 1 of the 5 outcomes (immunogenicity, carriage, invasive disease, pneumonia and indirect effects) underwent full review using a standardized data collection instrument. We did not search non-english language literature because of the low likelihood they would have on relevant data for this project. Details on the search methods are provided elsewhere (methods Appendix 17 ).", "cite_spans": [{"start": 1536, "end": 1538, "text": "17", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Data Abstraction", "text": "Citations recovered through the literature search went through several stages of independent review to determine their eligibility, as described elsewhere (methods Appendix   17 ). Citations meeting inclusion criteria were categorized on an outcome specific basis into \"study families,\" where each family included abstracts or publications generated from a single protocol, population, surveillance system or other data collection system relevant to that outcome. Investigators identified primary data from the individual studies making up each study family for inclusion in the analysis. the primary data were selected as the most current and complete data available for that study family. In some cases, these data were drawn from more than 1 publication within a family. We also defined \"study arms\" as a group of children distinguished by immunization schedule or pCV product.", "cite_spans": [], "ref_spans": [{"start": 155, "end": 177, "text": "(methods Appendix   17", "ref_id": "TABREF2"}]}, {"section": "Data Abstraction", "text": "We abstracted core information on the following: number of children in a \"study arm\"; pCV manufacturer, valency and conjugate protein; co-administered vaccines; country; age at each dose and date of study and publication. Additional data abstracted for the direct effect of pCV on Vt np carriage included age at each np specimen collection.", "cite_spans": [], "ref_spans": []}, {"section": "Inclusion and Exclusion Criteria", "text": "We included data published from randomized controlled trials, nonrandomized trials, surveillance databases and observational studies of pCV schedules on Vt carriage. We included all pCV products (denoted as pCV with a number indicating the valency, eg, pCV7). We excluded studies with all vaccination series beginning after 12 months of life, studies that only reported data before or after pCV introduction but not for both periods and studies that did not report direct pCV effects on Vt carriage.", "cite_spans": [], "ref_spans": []}, {"section": "Pneumococcal Vaccine Dosing Schedules", "text": "We included pCV schedules with 2 primary doses only (2+0), 2 primary doses plus a pCV booster (2+1) or a ppV23 booster (2+1ppV23), 3 primary doses only (3+0) and 3 primary doses plus a pCV booster (3+1) or a ppV23 booster (3+1ppV23).", "cite_spans": [], "ref_spans": []}, {"section": "Data Analysis", "text": "Because the included studies used various designs and methods, we were unable to perform a meta-analysis. thus, we summarized the data across studies in descriptive analyses to provide an overview of the amount and variability of data by schedule. each study was divided into arms, defined as a unique combination of vaccine schedule, age at np specimen collection and vaccine product used. Studies could have multiple arms. Vt was defined as each study defined it, based on the product used. no studies included pCV products with serotype 19A; none classified 19A as Vt. two pCV7 studies included serotype 6A as a Vt. 18, 19 We defined percent Vt carriage as the percentage of children sampled who carried a Vt strain, except in 7 citations that only reported percent of pneumococcal isolates that were Vt, in which case this percent was used. 7, [20] [21] [22] [23] [24] [25] For clinical trials, we abstracted the difference in Vt-carriage prevalence with confidence intervals (CI) between vaccinated children and controls. If not reported, we calculated the difference in carriage between vaccinated children and controls. We separated clinical trials into those that directly compared np effects of various schedules and trials that evaluated effects only between a given schedule and unvaccinated controls. We separated these latter trials into those that examined carriage early (during the first year of life or prior to any booster dose given in the study) and late (after the first year of life or after any booster dose given in the study).", "cite_spans": [{"start": 619, "end": 622, "text": "18,", "ref_id": "BIBREF17"}, {"start": 623, "end": 625, "text": "19", "ref_id": "BIBREF18"}, {"start": 845, "end": 847, "text": "7,", "ref_id": "BIBREF6"}, {"start": 848, "end": 852, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 853, "end": 857, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 863, "end": 867, "text": "[23]", "ref_id": "BIBREF21"}, {"start": 868, "end": 872, "text": "[24]", "ref_id": "BIBREF22"}, {"start": 873, "end": 877, "text": "[25]", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Data Analysis", "text": "For pre-and postvaccine introduction observational studies among age groups targeted for vaccination, we calculated percent change in Vt carriage by defining the baseline prevalence as the mean of all data points reported prior to introduction. In cases where only the postintroduction Vt-carriage prevalence over a period was provided, we calculated percent change from the baseline prevalence to the reported prevalence and assigned it to the median year of the date range provided. When possible, the year of vaccine introduction was excluded from these calculations. We used microsoft Access 2003 and 2007 (microsoft Corporation, Redmond, WA) for data abstraction and SAS 9.2 and 9.3 (SAS Institute Inc., Cary, nC) for analyses. Statistical significance was defined as P < 0.05.", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Description of Included Studies", "text": "Of 12,980 citations reviewed, 145 had carriage data; of these, 36 met inclusion criteria for Vt carriage among children targeted to receive the vaccine (Fig. 1) . 4, 7, these 36 citations represented 32 study families with 4 supplemental citations. Among the 32 studies, 25 (78%) were published in 2003 or later; 17 (53%) were from europe or north America (table 1) . 52 Seven (22%) evaluated children at high risk for pneumococcal disease, such as children with HIV or sickle cell disease, indigenous children or children with acute pneumonia or otitis media. twenty-one (66%) studies evaluated pCV7; no studies evaluated pCV10 or pCV13.", "cite_spans": [{"start": 163, "end": 165, "text": "4,", "ref_id": "BIBREF3"}, {"start": 166, "end": 168, "text": "7,", "ref_id": "BIBREF6"}, {"start": 368, "end": 370, "text": "52", "ref_id": "BIBREF52"}], "ref_spans": [{"start": 356, "end": 365, "text": "(table 1)", "ref_id": "TABREF2"}]}, {"section": "Direct Comparisons of Dosing Schedules Within Studies: Clinical Trials", "text": "Among the 32 studies, 4 directly compared Vt-carriage reduction among dosing regimens. the first study, conducted in Fiji, compared 0, 1, 2 and 3 pCV7 doses (given at 14 weeks, 6 and 14 weeks or 6, 10 and 14 weeks, respectively) with and without a ppV23 booster at 12 months. 4 the investigators found a significant difference in Vt-carriage prevalence between the 2-and 3-dose groups at 9 months; the 3-dose group had significantly less Vt carriage [odds ratio 0.30 (CI: 0.09-0.9)]. At 6, 12 and 17 months of age, Vt carriage among the 2-and 3-dose groups was not significantly different. the receipt of a ppV23 booster showed no effect on Vt carriage, as no difference in Vt carriage at 17 months was S154 | www.pidj.com", "cite_spans": [{"start": 276, "end": 277, "text": "4", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "\u00a9 2013 Lippincott Williams & Wilkins", "text": "seen between those who did and did not receive the ppV23 booster in each pCV dosing group. 4 the second study, conducted in the Gambia, compared 1, 2 and 3 pCV7 doses (given at 2 months, 2 and 3 months and 2, 3 and 4 months); all children received a ppV23 booster at 10 months. 44 At 11 months, 3 pCV doses showed a borderline significant reduction in Vt carriage compared with 2 pCV doses (10.0% vs. 16.7%, P = 0.056). However, at 5 and 15 months, the Vt carriage prevalence was not significantly different among children who received 2 and 3 doses. 44 the third study, conducted in Israel with pCV7, compared a 3+1 schedule (2, 4, 6 and 12 months) with 2+1 (4, 6 and 12 months) and 0+2 (12 and 18 months) schedules. 19 Between 7 and 12 months of age (prebooster), the mean Vt prevalence was nonsignificantly lower in the 3+1 group when compared with the 2+1 group (22.6% vs. 28.4%, P = 0.089). the 0+2 group between 7 and 12 months, that is, before children were vaccinated, had a mean Vt prevalence of 35.2%, which was significantly higher than the 3+1 group (P < 0.001). Between 13 and 18 months (ie, after the booster dose) and between 19 and 30 months, the 3+1 and 2+1 groups had equivalent Vt prevalence, but both groups had significantly lower Vt prevalence than the 0+2 group. 19 A fourth study, conducted in the netherlands, compared children who received pCV7 at 2 and 4 months (2+0); 2, 4 and 11 months (2+1) and unvaccinated controls. 48 At 12, 18 and 24 months of age, children in the 2+0 and 2+1 groups had significantly less Vt carriage than unvaccinated controls. Although children in the 2+1 group had a significantly lower prevalence of Vt carriage at 18 months (16%) than the 2+0 group (24%, P = 0.01), no difference was found at 24 months. 48 ", "cite_spans": [{"start": 91, "end": 92, "text": "4", "ref_id": "BIBREF3"}, {"start": 278, "end": 280, "text": "44", "ref_id": "BIBREF43"}, {"start": 551, "end": 553, "text": "44", "ref_id": "BIBREF43"}, {"start": 718, "end": 720, "text": "19", "ref_id": "BIBREF18"}, {"start": 1286, "end": 1288, "text": "19", "ref_id": "BIBREF18"}, {"start": 1448, "end": 1450, "text": "48", "ref_id": "BIBREF48"}, {"start": 1761, "end": 1763, "text": "48", "ref_id": "BIBREF48"}], "ref_spans": []}, {"section": "Early Assessment of VT Carriage During First Year of Life: Clinical Trials", "text": "ten clinical trials evaluated 2-and 3-dose primary regimens during the first year of life compared with control subjects who received either placebo or no vaccine. two trials examined both regimens 4, 19 ; 1 trial examined only a 2-dose regimen 48 and 7 studies examined only a 3-dose regimen (Fig. 2) . 7, 27, 29, 38, 43, 46 ,50 these 10 trials included 23 study arms. All 5 arms evaluating a 2-dose primary series found reductions in Vt-carriage prevalence among pCV recipients compared with controls, although only 1 arm reached statistical significance. Of 18 arms, 17 with 3-dose primary regimens observed reductions in Vt carriage; 11 arms were statistically significant. One 3-dose primary series arm (merck, pCV7) observed a nonsignificant increase of Vt-carriage prevalence at 7 months of age. 50 two trials examined the Vt-carriage effect of 3 primary doses but provided results that could not be compared with other studies. One, a clinical trial in Iceland, examined 81 children who received pCV8 conjugated to diphtheria or tetanus toxoid given in 3 primary doses (3, 4 and 6 months) and 40 unvaccinated controls. 34 Swabs were collected at 3, 4, 6, 7, 10, 14 and 18 months. For swabs at ages \u22646 months, Vt carriage was not significantly different between controls (21%) and vaccinees (18%, P = 0.5). Vaccinees were then given either a pCV8 booster or a ppV23 booster at 13 months, but results from swabs at ages >6 months were not reported separately for those who received pCV8 and ppV23 boosters and thus are not presented here. 34 the other study, a trial conducted in Kenya, compared 3 primary doses of pCV7 starting at either birth FIGURE 1. Literature search results for carriage citations identified from search strategy, as strategy as detailed in the Methods Appendix. 17 Study families include 1 or more citation generated from a single protocol or data collection system, and the primary citation identifies the citation within each study family that contains the most detailed information regarding vaccinetype carriage. Supplemental citations contain additional data not contained in the citation for the primary study. (Fig. 3) . two trials examined 2+0 schedules 4, 48 ; one 2+1 48 ; two 2+1ppV23 4, 42 ; four 3+0 4, 27, 37, 41 ; five 3+1 7, 30, 39, 45, 46, 50 and four 3+1ppV23. 4, 29, 35, 42 Among the 29 arms reported in these 13 studies, 28 showed reduction in Vt compared with control subjects; 15 arms were statistically significant (Fig. 3) . One arm conducted among South African children with HIV who received a 3+0 pCV9 schedule had a nonsignificant increase in Vt carriage when compared with controls.", "cite_spans": [{"start": 198, "end": 200, "text": "4,", "ref_id": "BIBREF3"}, {"start": 201, "end": 203, "text": "19", "ref_id": "BIBREF18"}, {"start": 245, "end": 247, "text": "48", "ref_id": "BIBREF48"}, {"start": 304, "end": 306, "text": "7,", "ref_id": "BIBREF6"}, {"start": 307, "end": 310, "text": "27,", "ref_id": "BIBREF25"}, {"start": 311, "end": 314, "text": "29,", "ref_id": "BIBREF27"}, {"start": 315, "end": 318, "text": "38,", "ref_id": "BIBREF37"}, {"start": 319, "end": 322, "text": "43,", "ref_id": "BIBREF42"}, {"start": 323, "end": 325, "text": "46", "ref_id": "BIBREF46"}, {"start": 803, "end": 805, "text": "50", "ref_id": "BIBREF50"}, {"start": 1127, "end": 1129, "text": "34", "ref_id": "BIBREF33"}, {"start": 1545, "end": 1547, "text": "34", "ref_id": "BIBREF33"}, {"start": 1792, "end": 1794, "text": "17", "ref_id": "BIBREF16"}, {"start": 2192, "end": 2194, "text": "4,", "ref_id": "BIBREF3"}, {"start": 2195, "end": 2197, "text": "48", "ref_id": "BIBREF48"}, {"start": 2208, "end": 2210, "text": "48", "ref_id": "BIBREF48"}, {"start": 2226, "end": 2228, "text": "4,", "ref_id": "BIBREF3"}, {"start": 2229, "end": 2231, "text": "42", "ref_id": "BIBREF41"}, {"start": 2243, "end": 2245, "text": "4,", "ref_id": "BIBREF3"}, {"start": 2246, "end": 2249, "text": "27,", "ref_id": "BIBREF25"}, {"start": 2250, "end": 2253, "text": "37,", "ref_id": "BIBREF36"}, {"start": 2254, "end": 2256, "text": "41", "ref_id": "BIBREF40"}, {"start": 2268, "end": 2270, "text": "7,", "ref_id": "BIBREF6"}, {"start": 2271, "end": 2274, "text": "30,", "ref_id": "BIBREF28"}, {"start": 2275, "end": 2278, "text": "39,", "ref_id": "BIBREF38"}, {"start": 2279, "end": 2282, "text": "45,", "ref_id": "BIBREF44"}, {"start": 2283, "end": 2286, "text": "46,", "ref_id": "BIBREF46"}, {"start": 2287, "end": 2289, "text": "50", "ref_id": "BIBREF50"}, {"start": 2309, "end": 2311, "text": "4,", "ref_id": "BIBREF3"}, {"start": 2312, "end": 2315, "text": "29,", "ref_id": "BIBREF27"}, {"start": 2316, "end": 2319, "text": "35,", "ref_id": "BIBREF34"}, {"start": 2320, "end": 2322, "text": "42", "ref_id": "BIBREF41"}], "ref_spans": []}, {"section": "The Pediatric Infectious Disease", "text": "Journal \u2022 Volume 33, Number 1, Supplement 2, January 2014 Dosing and Pneumococcal", "cite_spans": [], "ref_spans": []}, {"section": "37", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Impact of Vaccine Introduction on VT Carriage: Observational Studies", "text": "Results by schedule from 11 observational, pre/postvaccine introduction studies (13 citations) are shown in Figure 4 . 18, [20] [21] [22] [23] [24] [25] [26] 28, 31, 36, 47, 49 All observational studies used pCV7. none examined a 3+0 schedule. two observational studies examined 2+1 schedules. One conducted in england with national introduction with a catch-up campaign showed a statistically significant reduction. 18 A study in Switzerland with private-market introduction among children <2 years of age with acute otitis media or pneumonia also showed reduction; statistical significance was not reported. 21 36 while a British study among children with sickle cell disease found a nonsignificant reduction in Vt carriage following a 3+1ppV23 schedule. 26 Additional observational studies met inclusion criteria but were not comparable to other studies because of their unique designs. A cohort study from Korea evaluated the effect of a 3+1 schedule (given at 2, 4, 6 and 16.5 months), following pCV7 private-market introduction. 33 this study compared vaccinated children in daycare from a highly vaccinated region to unvaccinated children in daycare from a region with low vaccination rates. 33 An openlabel, prospective study in mexico evaluated Vt-carriage acquisition in children receiving either 3 pCV7 doses (given between 6 weeks and 6 months) or 2 doses (given between 7 and 11 months); no unvaccinated controls were included in the study. 32 Vt acquisition decreased over time in both the 2-and 3-dose primary regimens, but the groups were not directly compared. An observational follow-up study to a clinical trial in the philippines compared children with pneumonia between 6 weeks and 23 months old, who had received pCV11 or placebo at a median age of 7, 12 and 16 weeks. 40 Vt was reduced in the pCV11 group versus placebo; quantitative results were not provided. 40 Finally, a pre/postintroduction study from France also included a sub-analysis examining the effect of the booster dose. 53 In this study, children 6-24 months with acute otitis media in French day care centers were enrolled in annual cross-sectional surveys from 2001 to 2006. 28 Among children >1 year of age during all years of the study, Vt carriage was 44.4% in unvaccinated children, 23.9% in children vaccinated without a booster dose and 11.8% in children vaccinated with the booster dose. 28 ", "cite_spans": [{"start": 119, "end": 122, "text": "18,", "ref_id": "BIBREF17"}, {"start": 123, "end": 127, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 128, "end": 132, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 138, "end": 142, "text": "[23]", "ref_id": "BIBREF21"}, {"start": 143, "end": 147, "text": "[24]", "ref_id": "BIBREF22"}, {"start": 148, "end": 152, "text": "[25]", "ref_id": "BIBREF23"}, {"start": 153, "end": 157, "text": "[26]", "ref_id": "BIBREF24"}, {"start": 158, "end": 161, "text": "28,", "ref_id": "BIBREF26"}, {"start": 162, "end": 165, "text": "31,", "ref_id": "BIBREF29"}, {"start": 166, "end": 169, "text": "36,", "ref_id": "BIBREF35"}, {"start": 170, "end": 173, "text": "47,", "ref_id": "BIBREF47"}, {"start": 174, "end": 176, "text": "49", "ref_id": "BIBREF49"}, {"start": 417, "end": 419, "text": "18", "ref_id": "BIBREF17"}, {"start": 610, "end": 612, "text": "21", "ref_id": "BIBREF20"}, {"start": 613, "end": 615, "text": "36", "ref_id": "BIBREF35"}, {"start": 757, "end": 759, "text": "26", "ref_id": "BIBREF24"}, {"start": 1035, "end": 1037, "text": "33", "ref_id": "BIBREF32"}, {"start": 1199, "end": 1201, "text": "33", "ref_id": "BIBREF32"}, {"start": 1454, "end": 1456, "text": "32", "ref_id": "BIBREF30"}, {"start": 1791, "end": 1793, "text": "40", "ref_id": "BIBREF39"}, {"start": 1884, "end": 1886, "text": "40", "ref_id": "BIBREF39"}, {"start": 2008, "end": 2010, "text": "53", "ref_id": "BIBREF54"}, {"start": 2165, "end": 2167, "text": "28", "ref_id": "BIBREF26"}, {"start": 2385, "end": 2387, "text": "28", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "We found that all schedules reviewed-2+0, 2+1, 2+1ppV23, 3+0, 3+1 and 3+1ppV23-reduced carriage of Vts of pneumococcus compared with no pCV. However, the strength of evidence supporting each schedule varies and effects differ among the schedules. First, in studies with direct comparisons of 2 versus 3 primary doses, 3 doses result in a greater reduction in Vt carriage compared with 2 doses at 1-7 months following the primary series. 4, 19, 44 However, measurable differences in *One cohort study 33 and 1 open-label, prospective, observational trial. 32 \u2020 Acute otitis media or pneumonia at time of NP swab collection. \u2021 \u2021Percentages add up to >100%, as studies may have multiple dosing schedules and may have assessed carriage both during and after the first year of life.", "cite_spans": [{"start": 437, "end": 439, "text": "4,", "ref_id": "BIBREF3"}, {"start": 440, "end": 443, "text": "19,", "ref_id": "BIBREF18"}, {"start": 444, "end": 446, "text": "44", "ref_id": "BIBREF43"}, {"start": 500, "end": 502, "text": "33", "ref_id": "BIBREF32"}, {"start": 555, "end": 557, "text": "32", "ref_id": "BIBREF30"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "\u00a7Total study arms with carriage specimens during the first year of life (n = 18). \u00b6Total study arms with carriage specimens after the first year of life (n = 35). \u2016Products are listed as PCV, valency and manufacturer name. **Includes PCV4-Sanofi, PCV5-Wyeth, PCV7-Merck, PCV8-Sanofi and PCV11-Glaxo SmithKline. S156 | www.pidj.com", "cite_spans": [], "ref_spans": []}, {"section": "\u00a9 2013 Lippincott Williams & Wilkins", "text": "Vt-carriage reduction between 2 and 3 primary doses are not seen on further follow up following primary vaccination in schedules with pCV boosters, 19 ppV23 boosters 4, 44 or no boost. 4 Differences between the schedules are difficult to discern when comparing the impact of 2-and 3-dose primary series between studies rather than within studies.", "cite_spans": [{"start": 166, "end": 168, "text": "4,", "ref_id": "BIBREF3"}, {"start": 169, "end": 171, "text": "44", "ref_id": "BIBREF43"}, {"start": 185, "end": 186, "text": "4", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "\u00a9 2013 Lippincott Williams & Wilkins", "text": "Very little evidence is available on Vt-carriage prevalence after the first year of life in children who received a 2-dose schedule without a booster dose. Both clinical trials that evaluated 2+0 schedules after the first year of life demonstrated reductions in Vt carriage. 4, 48 However, in 1 of these studies, the 2+1 schedule reduced Vt carriage more than the 2+0 schedule at 1 of 3 time points, suggesting that the 2+1 schedule may be better than the 2+0. 48 Furthermore, there is no evidence regarding effect of 2+0 schedules on Vt carriage from observational studies or for longterm effects of this schedule since no country is using this schedule. Concerns regarding the immunogenicity of 2+0 schedules and the lack of evidence regarding the impact of 2+0 schedules on IpD, pneumonia and indirect effects have precluded its use in national immunization programs to date. more evidence is needed regarding the optimal timing of the doses in a 3-dose schedule, but available evidence supports the use of both 2+1 and 3+0 schedules. While no published studies directly compare the impact of 2+1 and 3+0 schedules on Vt carriage, both schedules reduce Vt carriage compared with no pCV use. A study of 2+1, 3+0 and 3+1 schedules using pCV7 from Israel was done and has been published in part. 19, 54 Results suggest that the 2+1 schedule results in similar Vt-carriage prevalence to 3+1 when Vt-carriage prevalence is sampled after the booster doses; however, 2+1 appears to be inferior to 3+1 prior to the booster dose. Additionally, this study directly compared 3+0 and 3+1 schedules and showed no difference in Vt-carriage prevalence. these data suggest that 2+1 and 3+0 schedules may have similar effects on Vt carriage after the first year of life, but these schedules were not directly compared in this study. It is important to note that data supporting 2+1 schedules come from a clinical trial and 2 observational studies in europe (the netherlands, 48 england 18 and Switzerland), 21 whereas data supporting a 3+0 schedule come from clinical trials in middle income and developing countries (philippines, 40, 41 Fiji, 4 the Gambia 27 and South Africa). 37 While both 3+0 and 2+1 schedules appear to be effective, differences between 2+1 and 3+0 schedules may exist that are relevant to settings with particular pneumococcal transmission patterns, burden of disease or colonization. For example, vaccine programs serving populations with disease early in life, heavy transmission and young age of transmitters may prefer 3+0 schedules; however, the data in our review do not provide a conclusive determination of which schedule is optimal for each of these settings.", "cite_spans": [{"start": 275, "end": 277, "text": "4,", "ref_id": "BIBREF3"}, {"start": 278, "end": 280, "text": "48", "ref_id": "BIBREF48"}, {"start": 461, "end": 463, "text": "48", "ref_id": "BIBREF48"}, {"start": 1296, "end": 1299, "text": "19,", "ref_id": "BIBREF18"}, {"start": 1300, "end": 1302, "text": "54", "ref_id": "BIBREF55"}, {"start": 1961, "end": 1963, "text": "48", "ref_id": "BIBREF48"}, {"start": 1972, "end": 1974, "text": "18", "ref_id": "BIBREF17"}, {"start": 1993, "end": 1995, "text": "21", "ref_id": "BIBREF20"}, {"start": 2117, "end": 2120, "text": "40,", "ref_id": "BIBREF39"}, {"start": 2121, "end": 2123, "text": "41", "ref_id": "BIBREF40"}, {"start": 2130, "end": 2131, "text": "4", "ref_id": "BIBREF3"}, {"start": 2143, "end": 2145, "text": "27", "ref_id": "BIBREF25"}, {"start": 2165, "end": 2167, "text": "37", "ref_id": "BIBREF36"}], "ref_spans": []}, {"section": "\u00a9 2013 Lippincott Williams & Wilkins", "text": "Some evidence suggests that schedules with pCV boosters may provide additional reductions in Vt carriage.", "cite_spans": [], "ref_spans": []}, {"section": "\u00a9 2013 Lippincott Williams & Wilkins", "text": "28,48 the available evidence does not support the use of schedules with ppV23 boosters for improving np-carriage reductions. While no studies directly compared pCV and ppV23 boosters, a Fijian study compared schedules with and without ppV23 boosters and showed no benefit of 2+1ppV23 and 3+1ppV23 schedules compared with 2+0 and 3+0 schedules, respectively, despite boosts in antibodies seen with ppV23 boosters. 4 FIGURE 2. Difference in VT carriage prevalence between vaccinated and unvaccinated or placebo groups for clinical trials by primary dosing series (2 or 3 doses) for carriage assessed in the first year of life. 4, 7, 19, 27, 29, 38, 43, 46, 48, 50 Two and 3 primary doses were given between 6 weeks and 6 months for all regimens. Studies denoted on y-axis with primary dosing series (2 or 3 doses), first author's last name (with reference number in brackets) and mean or median age in months (m) of children at time of NP specimen collection. Products are listed as PCV-valency and manufacturer name. Confidence intervals are displayed by error bars. Data points are labeled with sample size, an asterisk (*) if statistically significant when compared with controls and/or NR if statistical significance was not reported. All others were not statistically significant. GSK, GlaxoSmithKline.", "cite_spans": [{"start": 625, "end": 627, "text": "4,", "ref_id": "BIBREF3"}, {"start": 628, "end": 630, "text": "7,", "ref_id": "BIBREF6"}, {"start": 631, "end": 634, "text": "19,", "ref_id": "BIBREF18"}, {"start": 635, "end": 638, "text": "27,", "ref_id": "BIBREF25"}, {"start": 639, "end": 642, "text": "29,", "ref_id": "BIBREF27"}, {"start": 643, "end": 646, "text": "38,", "ref_id": "BIBREF37"}, {"start": 647, "end": 650, "text": "43,", "ref_id": "BIBREF42"}, {"start": 651, "end": 654, "text": "46,", "ref_id": "BIBREF46"}, {"start": 655, "end": 658, "text": "48,", "ref_id": "BIBREF48"}, {"start": 659, "end": 661, "text": "50", "ref_id": "BIBREF50"}], "ref_spans": []}, {"section": "\u00a9 2013 Lippincott Williams & Wilkins", "text": "Determining the relative benefit for np-carriage reductions of 1 schedule over another is difficult. limited data are available from studies with direct comparisons between schedules. Few are conducted in regions where child mortality is high, and some studies were in the setting of catch-up campaigns, which would blur the measured effect of the primary schedule. these limitations should be considered when assessing the potential benefits of particular schedules. For example, while 2+1 schedules reduced Vt carriage in 2 observational studies, it is important to note that 1 study was conducted among vaccinated children in the setting of a privatemarket introduction, 21 where vaccinated children may have lower inherent risk of colonization, and 1 study was conducted among all children <5 years old in the setting of a national immunization program with a catch-up campaign. 18 Furthermore, only 7 np studies evaluated pCV schedule impact in children at high risk for colonization and disease; the only study to specifically evaluate children with HIV failed to show efficacy of a 3+0 schedule on Vt carriage. 37 none of the studies included evaluated pCV10 or pCV13, which are currently being used in national immunization programs. However, a study in France, conducted in the year following the switch from pCV7 to pCV13, showed a significant reduction in the additional 6 serotypes included in pCV13 among children partially and fully vaccinated with pCV13 when compared with those vaccinated with pCV7. 55 this study was not included in this analysis due to a lack of pre-pCV introduction data for pCV13 serotypes. 55 this analysis focused on Vt carriage and did not address the effect of dosing schedules on all pneumococcal carriage or non-Vt carriage, as the impact on Vt carriage is the most important factor for policy makers when deciding which dosing schedules to recommend. most studies show that pCV does not affect the overall prevalence of all-serotype pneumococcal carriage, 4, 7, [18] [19] [20] [21] [22] [23] 27, 31, 36, 39, 41, 43 although some show a reduction at some or all time points. 19, 25, 28, 48 Additionally, most studies show that non-Vts increase in prevalence following pCV, 4, 7, 18, 19, 23, 27, 28, 31, 36, 38, 39, 42, 48 although a few studies show no change at some or all time points. 4, 7, 19 many, but not all, non-Vts have lower invasive potential than most Vt strains, meaning that they are less likely to cause IpD if carried, 18 and invasive potential does not appear to change with time 47, 56 or vaccine introduction. 47 thus, the potential for many replacing serotypes to cause IpD is not as high as for serotypes included by currently available pCV products.", "cite_spans": [{"start": 674, "end": 676, "text": "21", "ref_id": "BIBREF20"}, {"start": 883, "end": 885, "text": "18", "ref_id": "BIBREF17"}, {"start": 1118, "end": 1120, "text": "37", "ref_id": "BIBREF36"}, {"start": 1516, "end": 1518, "text": "55", "ref_id": "BIBREF56"}, {"start": 1628, "end": 1630, "text": "55", "ref_id": "BIBREF56"}, {"start": 2000, "end": 2002, "text": "4,", "ref_id": "BIBREF3"}, {"start": 2003, "end": 2005, "text": "7,", "ref_id": "BIBREF6"}, {"start": 2006, "end": 2010, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 2011, "end": 2015, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 2016, "end": 2020, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 2021, "end": 2025, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 2031, "end": 2035, "text": "[23]", "ref_id": "BIBREF21"}, {"start": 2036, "end": 2039, "text": "27,", "ref_id": "BIBREF25"}, {"start": 2040, "end": 2043, "text": "31,", "ref_id": "BIBREF29"}, {"start": 2044, "end": 2047, "text": "36,", "ref_id": "BIBREF35"}, {"start": 2048, "end": 2051, "text": "39,", "ref_id": "BIBREF38"}, {"start": 2052, "end": 2055, "text": "41,", "ref_id": "BIBREF40"}, {"start": 2056, "end": 2058, "text": "43", "ref_id": "BIBREF42"}, {"start": 2118, "end": 2121, "text": "19,", "ref_id": "BIBREF18"}, {"start": 2122, "end": 2125, "text": "25,", "ref_id": "BIBREF23"}, {"start": 2126, "end": 2129, "text": "28,", "ref_id": "BIBREF26"}, {"start": 2130, "end": 2132, "text": "48", "ref_id": "BIBREF48"}, {"start": 2216, "end": 2218, "text": "4,", "ref_id": "BIBREF3"}, {"start": 2219, "end": 2221, "text": "7,", "ref_id": "BIBREF6"}, {"start": 2222, "end": 2225, "text": "18,", "ref_id": "BIBREF17"}, {"start": 2226, "end": 2229, "text": "19,", "ref_id": "BIBREF18"}, {"start": 2230, "end": 2233, "text": "23,", "ref_id": "BIBREF21"}, {"start": 2234, "end": 2237, "text": "27,", "ref_id": "BIBREF25"}, {"start": 2238, "end": 2241, "text": "28,", "ref_id": "BIBREF26"}, {"start": 2242, "end": 2245, "text": "31,", "ref_id": "BIBREF29"}, {"start": 2246, "end": 2249, "text": "36,", "ref_id": "BIBREF35"}, {"start": 2250, "end": 2253, "text": "38,", "ref_id": "BIBREF37"}, {"start": 2254, "end": 2257, "text": "39,", "ref_id": "BIBREF38"}, {"start": 2258, "end": 2261, "text": "42,", "ref_id": "BIBREF41"}, {"start": 2262, "end": 2264, "text": "48", "ref_id": "BIBREF48"}, {"start": 2331, "end": 2333, "text": "4,", "ref_id": "BIBREF3"}, {"start": 2334, "end": 2336, "text": "7,", "ref_id": "BIBREF6"}, {"start": 2337, "end": 2339, "text": "19", "ref_id": "BIBREF18"}, {"start": 2478, "end": 2480, "text": "18", "ref_id": "BIBREF17"}, {"start": 2540, "end": 2543, "text": "47,", "ref_id": "BIBREF47"}, {"start": 2544, "end": 2546, "text": "56", "ref_id": "BIBREF57"}, {"start": 2572, "end": 2574, "text": "47", "ref_id": "BIBREF47"}], "ref_spans": []}, {"section": "\u00a9 2013 Lippincott Williams & Wilkins", "text": "this analysis has several strengths and limitations. the strengths of this analysis are its comprehensive nature with the diversity of countries and study designs included. Very few np studies directly compare schedules, and this analysis allows for all FIGURE 3. Difference in VT-carriage prevalence between vaccinated and unvaccinated or placebo groups for clinical trials by dosing series for carriage assessed after the first year of life. 4, 7, 27, 29, 30, 35, 37, 39, 41, 42, 45, 46, 48, 50 All primary doses were given between 6 weeks and 6 months of age (6 weeks to 4 months for 2 doses, 6 weeks to 6 months for 3 doses), and booster doses given at 11-18 months of age. Studies denoted on y-axis with schedule, first author's last name (with reference number in brackets) and mean or median age in months (m) of children at time of NP specimen collection. Products are listed as PCV-valency and manufacturer name. Confidence intervals are displayed by error bars. Data points are labeled with sample size, an asterisk (*) if statistically significant when compared with controls, and NR if statistical significance compared with controls was not reported. All others were not statistically significant. GSK, GlaxoSmithKline. S158 | www.pidj.com", "cite_spans": [{"start": 444, "end": 446, "text": "4,", "ref_id": "BIBREF3"}, {"start": 447, "end": 449, "text": "7,", "ref_id": "BIBREF6"}, {"start": 450, "end": 453, "text": "27,", "ref_id": "BIBREF25"}, {"start": 454, "end": 457, "text": "29,", "ref_id": "BIBREF27"}, {"start": 458, "end": 461, "text": "30,", "ref_id": "BIBREF28"}, {"start": 462, "end": 465, "text": "35,", "ref_id": "BIBREF34"}, {"start": 466, "end": 469, "text": "37,", "ref_id": "BIBREF36"}, {"start": 470, "end": 473, "text": "39,", "ref_id": "BIBREF38"}, {"start": 474, "end": 477, "text": "41,", "ref_id": "BIBREF40"}, {"start": 478, "end": 481, "text": "42,", "ref_id": "BIBREF41"}, {"start": 482, "end": 485, "text": "45,", "ref_id": "BIBREF44"}, {"start": 486, "end": 489, "text": "46,", "ref_id": "BIBREF46"}, {"start": 490, "end": 493, "text": "48,", "ref_id": "BIBREF48"}, {"start": 494, "end": 496, "text": "50", "ref_id": "BIBREF50"}], "ref_spans": []}, {"section": "\u00a9 2013 Lippincott Williams & Wilkins", "text": "of the supporting evidence for each of these regimens to be considered. However, the analysis is limited because fully differentiating the relative magnitude of the impact on Vt carriage of each schedule is not possible. Geographic region, socioeconomic level and other factors affect carriage of pneumococci and thus confound our ability to compare magnitudes of impact across studies. Additionally, we were unable to account for vaccine coverage in the target populations or the presence of catch-up campaigns due to limited information in the study reports.", "cite_spans": [], "ref_spans": []}, {"section": "\u00a9 2013 Lippincott Williams & Wilkins", "text": "In conclusion, 2+0, 2+1, 3+0 and 3+1 schedules all reduce pneumococcal Vt carriage. Importantly, the evidence indicates that 3 primary doses may reduce Vt carriage more than 2 primary doses; that both 2+1 and 3+0 schedules are effective; pCV booster doses may be helpful, especially in the setting of 2 primary doses and the use of ppV23 boosters after a pCV schedule does not further reduce Vt carriage. Our analysis supports recent recommendations by the pan American Health Organization and the World Health Organization for the use of 3 doses of pCV and the acceptability to be administered either as 3+0 or 2+1 schedule. 57, 58 However, np carriage is only part of the picture, and the effect of each schedule on IpD, pneumonia, immunogenicity and indirect effects in the context of local epidemiology and programmatic considerations should be considered by public health when recommending and countries when choosing a schedule.", "cite_spans": [{"start": 626, "end": 629, "text": "57,", "ref_id": "BIBREF58"}, {"start": 630, "end": 632, "text": "58", "ref_id": "BIBREF59"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Report from a WHO Working Group: standard method for detecting upper respiratory carriage of Streptococcus pneumoniae", "authors": [{"first": "H", "middle": [], "last": "O&apos;brien Kl", "suffix": ""}], "year": 2003, "venue": "Pediatr Infect Dis J", "link": "12619711"}, "BIBREF1": {"title": "Streptococcus pneumoniae colonisation: the key to pneumococcal disease", "authors": [{"first": "D", "middle": [], "last": "Bogaert", "suffix": ""}, {"first": "De", "middle": [], "last": "Groot", "suffix": ""}, {"first": "R", "middle": [], "last": "", "suffix": ""}, {"first": "Hermans", "middle": [], "last": "Pw", "suffix": ""}], "year": 2004, "venue": "Lancet Infect Dis", "link": "23587885"}, "BIBREF2": {"title": "updated recommendations for prevention of invasive pneumococcal disease among adults using the 23-valent pneumococcal polysaccharide vaccine (ppSV23)", "authors": [], "year": 2010, "venue": "Morb Mort Wkly Rep", "link": "44986556"}, "BIBREF3": {"title": "pneumococcal nasopharyngeal carriage following reduced doses of a 7-valent pneumococcal conjugate vaccine and a 23-valent pneumococcal polysaccharide vaccine booster", "authors": [{"first": "Russell", "middle": [], "last": "Fm", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Carapetis", "suffix": ""}, {"first": "C", "middle": [], "last": "Satzke", "suffix": ""}], "year": 2010, "venue": "Clin Vaccine Immunol", "link": "24349300"}, "BIBREF4": {"title": "Centers for Disease Control and prevention (CDC). prevention of pneumococcal disease among infants and children-use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine-recommendations of the Advisory Committee on Immunization practices (ACIp)", "authors": [{"first": "", "middle": [], "last": "Nuorti Jp", "suffix": ""}, {"first": "C", "middle": ["G"], "last": "Whitney", "suffix": ""}], "year": 2010, "venue": "MMWR Recomm Rep", "link": null}, "BIBREF5": {"title": "nasopharyngeal colonization: a target for pneumococcal vaccination", "authors": [{"first": "H", "middle": [], "last": "K\u00e4yhty", "suffix": ""}, {"first": "K", "middle": [], "last": "Auranen", "suffix": ""}, {"first": "H", "middle": [], "last": "Nohynek", "suffix": ""}], "year": 2006, "venue": "Expert Rev Vaccines", "link": "23310997"}, "BIBREF6": {"title": "Zell eR, et al. effect of pneumococcal conjugate vaccine on nasopharyngeal colonization among immunized and unimmunized children in a community-randomized trial", "authors": [{"first": "", "middle": [], "last": "O&apos;brien Kl", "suffix": ""}, {"first": "Ev", "middle": [], "last": "Millar", "suffix": ""}], "year": 2007, "venue": "J Infect Dis", "link": null}, "BIBREF7": {"title": "Impact of heptavalent pneumococcal conjugate vaccine on invasive disease, antimicrobial resistance and colonization in Alaska natives: progress towards elimination of a health disparity", "authors": [{"first": "", "middle": [], "last": "Hennessy Tw", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Singleton", "suffix": ""}, {"first": "", "middle": [], "last": "Bulkow Lr", "suffix": ""}], "year": 2005, "venue": "Vaccine", "link": "10375236"}, "BIBREF9": {"title": "european medicines Agency. 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Health Organization. meeting of the Strategic Advisory Group of experts on Immunization", "authors": [], "year": 2011, "venue": "Wkly Epidemiol Rec", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Assessment of VT Carriage After the First Year of Life: Clinical Trials thirteen clinical trials (14 citations) assessed Vt car- riage with samples taken after the first year of life", "type": "figure"}, "FIGREF1": {"text": "33 At mean ages of 35.2 months for vaccinated and 42.3 months for unvaccinated children, Vt carriage was found in 4 (2%) of 200 vac- cinated and 33 (16.5%) of 200 unvaccinated children.", "type": "figure"}, "FIGREF2": {"text": "in France in 2001 and reimbursed for chil- dren with high-risk medical or living conditions in 2003 using a schedule of 2, 3 and 4 months with a booster in the second year of life.", "type": "figure"}, "TABREF0": {"text": "Carriage \u00a9 2013 Lippincott Williams & Wilkins www.pidj.com | S155 or 6 weeks of age with subsequent doses at 10 and 14 weeks and found no significant differences in Vt carriage at 18 and 36 weeks among the regimens.", "type": "table"}, "TABREF2": {"text": "Characteristics", "type": "table"}}}
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{"paper_id": "2877217", "_pdf_hash": "6d2420a5d985f49fa81a6cc659d64a41d3342759", "abstract": [{"section": "Abstract", "text": "Fault Tree Analysis (FTA) is widely applied to assess the failure probability of industrial systems. Many computer packages are available which are based on conventional Kinetic Tree Theory methods. When dealing with large (possibly non-coherent) fault trees, the limitations of the technique in terms of accuracy of the solutions and the efficiency of the processing time becomes apparent. Over recent years the Binary Decision Diagram (BDD) method has been developed that solves fault trees and overcomes the disadvantages of the conventional FTA approach. First of all, a fault tree for a particular system failure mode is constructed and then converted to a BDD for analysis. This paper analyses alternative methods for the fault tree to BDD conversion process.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "For most fault tree to BDD conversion approaches the basic events of the fault tree are placed in an ordering. This can dramatically affect the size of the final BDD and the success of qualitative and quantitative analyses of the system. A set of rules are then applied to each gate in the fault tree to generate the BDD. An alternative approach can also be used, where BDD constructs for each of the gate types are first built and then merged to represent a parent gate. A powerful and efficient property, sub-node sharing, is also incorporated in the enhanced method proposed in this paper. Finally a combined approach is developed taking the best features of the alternative methods. The efficiency of the techniques is analysed and discussed.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Keywords: Fault Tree Analysis, Binary Decision Diagrams", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "The Binary Decision Diagram (BDD) method [1] has been introduced as a method for efficient and accurate fault tree analysis. This method has been shown to have advantages over the conventional Kinetic Tree Theory [2] . The main strength of the BDD method is the fact that top event probabilities can be calculated without the need to apply approximations or the need to obtain minimal cut sets as intermediate results.", "cite_spans": [{"start": 41, "end": 44, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 213, "end": 216, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Abstract", "text": "In the BDD method the fault tree is converted to a binary decision diagram, which represents the Boolean logic expression of the particular system failure mode. The method requires to set the variable ordering, and if it is not chosen suitably, the size of the final BDD can grow exponentially. The ordering rules are then applied to construct the BDD (ite method [1]). Alternative conversion methods are presented in this paper. These include component connection methods [3] where BDDs for each of the gate types are formed and then joined together according to the type of the parent gate in the fault tree. The basic component connection method is then enhanced by introducing a form of sub-node sharing and then by the development of the hybrid technique utilising the advantageous parts of the component connection method and the ite method.", "cite_spans": [{"start": 473, "end": 476, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Abstract", "text": "The efficiency of the alternative approaches is evaluated and compared with the conventional ite method. Three measures are applied while investigating the suitability of the different techniques. These measures are the final size of the resulting BDD, the number of calculations undertaken and the processing time.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "The Binary Decision Diagram (BDD) method [1] has been introduced as a method for efficient and accurate fault tree analysis. This method has been shown to have advantages over the conventional Kinetic Tree Theory [2] . The main strength of the BDD method is the fact that top event probabilities can be calculated without the need to apply approximations or the need to obtain minimal cut sets as intermediate results.", "cite_spans": [{"start": 41, "end": 44, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 213, "end": 216, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Introduction", "text": "In the BDD method the fault tree is converted to a binary decision diagram, which represents the Boolean logic expression of the particular system failure mode. The method requires to set the variable ordering, and if it is not chosen suitably, the size of the final BDD can grow exponentially. The ordering rules are then applied to construct the BDD (ite method [1] ). Alternative conversion methods are presented in this paper. These include component connection methods [3] where BDDs for each of the gate types are formed and then joined together according to the type of the parent gate in the fault tree. The basic component connection method is then enhanced by introducing a form of sub-node sharing and then by the development of the hybrid technique utilising the advantageous parts of the component connection method and the ite method.", "cite_spans": [{"start": 364, "end": 367, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 474, "end": 477, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Introduction", "text": "The efficiency of the alternative approaches is evaluated and compared with the conventional ite method. Three measures are applied while investigating the suitability of the different techniques. These measures are the final size of the resulting BDD, the number of calculations undertaken and the processing time.", "cite_spans": [], "ref_spans": []}, {"section": "Binary decision diagram method", "text": "A BDD, shown in Figure 1 , is a directed acyclic graph, where all paths through the BDD start at the root vertex and terminate in one of two states -a 1-state (system failure), or a 0-state (system success). The BDD consists of terminal and non-terminal vertices, connected by branches. Every terminal vertex represents the final state of the system and every non-terminal vertex -a basic event of the fault tree. By convention all left branches in the BDD are the 1-branches (component failure occurs), all right branches are the 0-braches (component functions successfully).", "cite_spans": [], "ref_spans": []}, {"section": "Binary decision diagram method", "text": "The application of the BDD method for system reliability is based on the fact that the BDD encodes the logic function of the system failure in its disjoint form. In the example of a fault tree and its equivalent BDD shown in Figure 2 the logic function is:", "cite_spans": [], "ref_spans": []}, {"section": "Binary decision diagram method", "text": "where \"+\" represents Boolean operator OR, \"\u00b7\" represents Boolean operator AND.", "cite_spans": [], "ref_spans": []}, {"section": "Binary decision diagram method", "text": "There are two possible paths in the BDD shown in Figure 2 that terminate in a system 1 state (failure):", "cite_spans": [], "ref_spans": []}, {"section": "Binary decision diagram method", "text": ".", "cite_spans": [], "ref_spans": []}, {"section": "Binary decision diagram method", "text": "[2] Each path is a combination of component states whose existence will result in system failure. Two cut sets can be obtained from these two paths if only the failure events are considered:", "cite_spans": [], "ref_spans": []}, {"section": "Binary decision diagram method", "text": "{a,b} and {a,c,d}.", "cite_spans": [], "ref_spans": []}, {"section": "Binary decision diagram method", "text": "[3] Cut sets consist only of the vertices that lie on the 1 branches from component nodes in the paths. The cut sets obtained in this example are minimal (they contain necessary and sufficient elements), because the BDD is minimal. Usually it would be necessary to develop a different form of BDD which encodes only the minimal cut sets [1] .", "cite_spans": [{"start": 337, "end": 340, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Binary decision diagram method", "text": "In the BDD method the probability of system failure, SYS Q , can be expressed as the sum of the probabilities of the disjoint paths to a terminal 1 in the BDD. This is possible because paths through the BDD are mutually exclusive. The probability of system failure in the example is:", "cite_spans": [], "ref_spans": []}, {"section": "Binary decision diagram method", "text": ", then for a gate in the fault tree for which these are inputs:", "cite_spans": [], "ref_spans": []}, {"section": "Binary decision diagram method", "text": "here <op> is the Boolean operator of the gates in the fault tree.", "cite_spans": [], "ref_spans": []}, {"section": "Binary decision diagram method", "text": "The ite technique is explained using the example in Figure 3 . The ordering a < b < c < d < e is obtained by traversing the fault tree in a simple top-down left-right way. Applying the connection rules gives the expressions for gates G1, G2 and Top:", "cite_spans": [], "ref_spans": []}, {"section": "Binary decision diagram method", "text": "The resulting BDD is also shown in Figure 3 . The ite technique produces an ordered BDD, where the variable ordering is retained throughout the BDD. This is observed because every step of the conversion process is performed taking into account the variable ordering.", "cite_spans": [], "ref_spans": []}, {"section": "Binary decision diagram method", "text": "The ite method automatically uses sub-node sharing where each ite structure is stored in the memory only once and is reused if calculated further in the process.", "cite_spans": [], "ref_spans": []}, {"section": "Component connection methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Basic approach (approach 2)", "text": "The basic algorithm of the component connection method is explained in [3] . First of all, gates of a fault tree which have only basic events as inputs are considered. Every gate is expressed as a BDD structure for \"OR\" or \"AND\" gate types. Then the fault tree structure is ascended considering gates whose inputs have already been expressed as BDDs. A BDD for an \"OR\" gate or an \"AND\" gate utilising simple rules of connection is created. Initially BDDs are constructed without considering the repetition of basic events in the fault tree. Then a simplification process for the resulting BDD is performed.", "cite_spans": [{"start": 71, "end": 74, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Basic approach (approach 2)", "text": "The connection and simplification rules with some alternative strategies are presented in this section. The ordering of basic events is not required for this method, because the connection process can be performed without following a fixed ordering scheme. Only a selection scheme has to be set which will describe the way in which gate inputs are selected for the connection process.", "cite_spans": [], "ref_spans": []}, {"section": "Basic approach (approach 2)", "text": "The connection rules are presented below: 1. For a fault tree gate with only basic events as inputs. If a gate is an \"OR\" gate, the BDD nodes representing its inputs are connected to each other through the 0-branches of the nodes. If a gate is an \"AND\" gate, the BDD nodes are connected through the 1-branches of the nodes (see Figure 4 (i) and (ii)). 2. For a fault tree gate where the inputs are already represented as BDDs. Then the BDDs are merged to form a BDD of the gate output event. For the two BDDs which represent two inputs to a parent gate, one of them is set to be the main BDD, to which the other will be attached using a rule of selection. Then, if two BDDs are inputs to an \"OR\" gate, the secondary BDD is connected to every terminal 0-node of the main BDD or if two BDDs are inputs to an \"AND\" gate, the secondary BDD is connected to every terminal 1-node of the main BDD (see Figure 4 (iii) and (iv)). Using this algorithm the resulting BDD can contain more than one node representing the same basic event on a path. In order to remove repeated events in the BDD each path featuring a repeated variable is simplified using one of the two rules: 1. The first occurrence of an event in the path defines the state of the repeated variable. The node, that represents the second occurrence of the event, needs to be replaced by the events below it on either its 1 or 0 branch. The branch depends on the variable state specified by its first occurrence in the path. For example, if the path passes through the 0-branch of a repeated node, the second appearance of that event should be removed replacing it by the BDD structure below the 0-branch of this second node. 2. If the BDD structures below the 1 and 0 branches of any node are identical, this node is irrelevant and needs to be replaced by the structure below either one of the branches. In other words, if the state of the system does not depend on the occurrence of the basic event, the insignificant node must be removed.", "cite_spans": [], "ref_spans": []}, {"section": "Basic approach (approach 2)", "text": "This method has been applied to the fault tree illustrated in Figure 3 resulting in the BDD shown in Figure 5 . In this example the fault tree is traversed in the bottom-up manner when constructing a BDD for every gate. The variables are considered in a left-right variable ordering. The left-most BDD input for any gate is set to be the main BDD to which the others are joined.", "cite_spans": [], "ref_spans": []}, {"section": "Basic approach (approach 2)", "text": "The conversion process starts constructing two BDDs for gates G1 and G2, shown in Figure 5 (i) and Figure 5 (ii) respectively. Gates G1 and G2 are \"AND\" gates, therefore, the resulting BDDs are \"AND\" chains.", "cite_spans": [], "ref_spans": []}, {"section": "Basic approach (approach 2)", "text": "Then the top event of the fault tree is considered. The left-most BDD, which represents basic event a, is selected to be the main BDD. Then the two BDDs from Figure 5 (i) and 5(ii) are connected one by one to the 0 branch of the main BDD, because the top gate is an \"OR\" gate. The first connection results in the BDD in Figure 5 (iii). The BDD after the second connection is presented in Figure 5 (iv).", "cite_spans": [], "ref_spans": []}, {"section": "Basic approach (approach 2)", "text": "Since there are some repeated events in the final BDD ( Figure 5 (iv)) the simplification rules are applied. Only one event, b, is repeated, therefore, its repetitions need to be removed from three current paths. In the first path F1-F2-F5-F6 node F5 is replaced by the terminal 0-node. This simplification rule is applied because this path traverses the 0-branch of node F2, the first occurrence of the repeated event. In the second path F1-F2-F3-F7-F8 the repeated event b is removed, replacing node F7 by node F8. In the same way node F9 is replaced by node F10 in the third path F1-F2-F3-F4-F9-F10. The final BDD is shown in Figure 5 (v).", "cite_spans": [], "ref_spans": []}, {"section": "Basic approach (approach 2)", "text": "While developing this example no global variable ordering system was used and the basic events were connected according to the order that they appear in the list of gate inputs. However, it is possible to apply a defined ordering scheme for basic events. A number of structural and weighted ordering schemes [5] can be used. The chosen ordering scheme can influence the efficiency of the conversion process.", "cite_spans": [{"start": 308, "end": 311, "text": "[5]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Basic approach (approach 2)", "text": "Using a variable ordering sets the order in which basic events are considered for gates which only feature basic event inputs which are then placed in an \"OR\" chain or an \"AND\" chain dependent upon the gate type. When gates are encountered where their inputs have been previously generated it has to be determined how the BDDs will be connected.", "cite_spans": [], "ref_spans": []}, {"section": "Basic approach (approach 2)", "text": "During the connection process BDDs were previously selected according to the order that gate inputs are listed, i.e. the BDD, presenting the left-most gate, is set to be the main BDD. Other selection schemes can be used which can result in a smaller BDD and/or in a shorter processing time.", "cite_spans": [], "ref_spans": []}, {"section": "Basic approach (approach 2)", "text": "Where a global variable ordering scheme is used BDDs can be ordered according to the position of their root vertex in the ordering scheme of basic events. Alternatively selecting according to the smallest number of available branches where connections will be made can offer an advantage in efficiency. Then the efficiency of different strategies can be analysed over a library of different fault tree structures.", "cite_spans": [], "ref_spans": []}, {"section": "Basic approach (approach 2)", "text": "The component connection method does not require the introduction of a variable ordering in the conversion process. Therefore, even if the variable ordering is assigned at the start, it is not retained when merging two BDDs. The resulting BDD is not an ordered BDD as it is if obtained using the conventional ite approach but it still retains the disjoint path property and can be used for the quantitative analysis.", "cite_spans": [], "ref_spans": []}, {"section": "Basic approach (approach 2)", "text": "The most significant disadvantage of the basic component connection method is that it does not use sub-node sharing and this can lead to inefficient memory usage. For example, in Figure 5 (v) there are two identical nodes F8 and F10, which are shared in the BDD obtained using the ite technique ( Figure 3 ). Therefore, a form of sub-node sharing is introduced as an extension to the component connection method.", "cite_spans": [], "ref_spans": []}, {"section": "Sub-node sharing (approach 3)", "text": "The sub-node sharing is used in the conventional ite technique and provides a significant contribution towards the efficiency of the approach. This property can also be implemented to an extent in the component connection method while two BDDs are connected. Consider for example, merging two inputs for an \"OR\" gate, as it is shown in Figure 6 .", "cite_spans": [], "ref_spans": []}, {"section": "Sub-node sharing (approach 3)", "text": "In this example the two BDDs are independent (have no nodes in common), the left BDD is set to be the main BDD. It has two available connection points, i.e. two terminal 0-vertices. They can be connected to the same second BDD. This merging is always suitable since no repeated events appear in the BDDs.", "cite_spans": [], "ref_spans": []}, {"section": "Sub-node sharing (approach 3)", "text": "The conversion method of a fault tree to a BDD starts considering those gates which have only basic events as inputs and applying the first connection rule, presented in the previous section. Subnode sharing is applied while performing the second rule and connecting previously formed BDDs for gate inputs. In this case, when the BDDs contain repeated events the state of each repeated event needs to be considered. During the connection process the secondary BDD can be connected to all appropriate terminal nodes if the path from the root vertex to those terminal nodes has each repeated event in the same state. In other words, the sub-node sharing can be applied if while descending the BDD from the root vertex the same branches (1-branches or 0-branches) of repeated events were traversed. Otherwise, a new copy of the secondary BDD needs to be used.", "cite_spans": [], "ref_spans": []}, {"section": "Sub-node sharing (approach 3)", "text": "The sub-node sharing rule is:", "cite_spans": [], "ref_spans": []}, {"section": "If two paths to terminal vertices (terminal 1-nodes for BDDs being inputs to an AND gate and terminal 0-nodes for BDDs being inputs to an OR gate) fall below the same branches of the repeated events, the same second BDD can be connected to both of the two terminal nodes.", "text": "Consider the example from Figure 5 , during the last connection of the two BDDs in Figure 5 (ii) and in Figure 5 (iii), the BDD in 5(iii) is set to be the main BDD and that of Figure 5 (ii) the secondary BDD. Since these two BDDs have event b in common and represent two gate inputs to an OR gate the paths from the root vertex to the three terminal 0-nodes of the main BDD are investigated. There is only one repeated event b in the fault tree. The first path passes the 0-branch of node b, the second and the third paths pass the 1-branch of node b. The second and the third terminal nodes can be replaced by the same copy of the secondary BDD because the second and the third paths fix the same state for the basic event on the repeated node. The final BDD is shown in Figure 7 (i) and 7(ii), after the connection and after the simplification processes respectively.", "cite_spans": [], "ref_spans": []}, {"section": "If two paths to terminal vertices (terminal 1-nodes for BDDs being inputs to an AND gate and terminal 0-nodes for BDDs being inputs to an OR gate) fall below the same branches of the repeated events, the same second BDD can be connected to both of the two terminal nodes.", "text": "The resulting BDD in Figure 7 (ii) matches the one obtained using the ite technique, Figure 3 .", "cite_spans": [], "ref_spans": []}, {"section": "If two paths to terminal vertices (terminal 1-nodes for BDDs being inputs to an AND gate and terminal 0-nodes for BDDs being inputs to an OR gate) fall below the same branches of the repeated events, the same second BDD can be connected to both of the two terminal nodes.", "text": "It is important to note that when applying the sub-node sharing in the component connection method all repeated events in the system must to be considered, not only those between the two BDDs under the current connection.", "cite_spans": [], "ref_spans": []}, {"section": "Hybrid approach (approach 4)", "text": "This method is introduced to utilise the efficient parts of the two algorithms presented -the ite technique and the component connection method. It is clear, that: i) using the gate constructs for basic events and branches without repeated events BDDs can be immediately formulated without any of processing required by the ite method. ii) the sub-node sharing feature of the ite method provides a more efficient representation of the logic function than its equivalent introduced in the component connection method. Therefore, a new method has been created based on the effective features of each approach to obtain the best efficiency for BDD conversion.", "cite_spans": [], "ref_spans": []}, {"section": "Hybrid approach (approach 4)", "text": "As was described before, the variable ordering is not required for the component connection method. However, since the hybrid approach also utilises the ite method a variable ordering needs to be introduced. The method then produces ordered BDDs.", "cite_spans": [], "ref_spans": []}, {"section": "Hybrid approach (approach 4)", "text": "While converting a fault tree to a BDD using the hybrid method, a variable ordering needs to be established. Then the building of BDDs for gates containing event inputs only starts, where events are put in a chain according to the type of the gate (the component connection approach). This construction process can be applied regardless of the number of events into a gate without breaking them down into pairs. In comparison, the rules in the ite technique deal only with two ite structures at once, therefore each gate needs to be preprocessed. The variable ordering needs to be retained while putting basic events in a chain. The comparison of the component connection method and its application in the hybrid method is shown in Figure 8 .", "cite_spans": [], "ref_spans": []}, {"section": "Hybrid approach (approach 4)", "text": "Further while building a BDD for a gate, when gate inputs are already represented as BDDs and they do not contain any repeated events, the straightforward connection can be also applied. In this case the variable ordering needs to be applied, i.e. tho BDDs can be merged if all the events of the main BDD stand before the events of the secondary BDD in the variable ordering. This rule is shown in Figure 9 .", "cite_spans": [], "ref_spans": []}, {"section": "Hybrid approach (approach 4)", "text": "Finally, while building a BDD for a gate, when inputs are converted to BDDs and they contain repeated events, the ite technique rules are applied.", "cite_spans": [], "ref_spans": []}, {"section": "Hybrid approach (approach 4)", "text": "For example, if we are applying the hybrid method for the conversion of a fault tree in Figure 3 , BDDs for gates G1 and G2 are created using the component connection method, i.e. placing its basic events in \"OR\" chains as it was shown in Figure 5 (i) and (ii). Then the two BDDs are merged applying the ite rules, given in equations 5 and 6.", "cite_spans": [], "ref_spans": []}, {"section": "Comparison of the methods", "text": "The efficiency of each of the methods in the conversion of a fault tree to a BDD depends on the structure of the fault tree. An indication of any advantages of different conversion techniques would need to be determined experimentally and measured over a large range of problems. The four approaches presented in this paper were analysed using a set of 11 fault trees from a benchmark set [6] . Their complexity is indicated in Table 1 .", "cite_spans": [], "ref_spans": []}, {"section": "Comparison of the methods", "text": "This table describes the complexity of the fault tree in terms of the number of gates, the number of basic events, the number of repeated events and the number of minimal cut sets. In order to obtain a consistent comparison of the four techniques the variable ordering was applied not only for the conventional method but also for the component connection method, i.e. even when it is not needed. The depth-first ordering scheme was applied [5] . In this ordering the left-most gate is always explored completely before considering the remaining gate inputs. The basic events with the greatest number of occurrences are ordered first.", "cite_spans": [{"start": 441, "end": 444, "text": "[5]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Comparison of the methods", "text": "The comparison of the four methods was performed by considering the following measurements: \uf0b7 the number of nodes in the final BDD, \uf0b7 the maximum number of lines in the storage array (representing the number of intermediate calculations performed), and \uf0b7 the processing time. The results of the three measurements obtained by applying the four methods to the example fault trees are shown in Table 2, Table 3 and Table 4 . For the analysis a computer with the 2.16 GHz processor was used.", "cite_spans": [], "ref_spans": []}, {"section": "Comparison of the methods", "text": "Remark. Fault trees were simplified [7] prior to BDD conversion process. The simplification process contains the reduction [8] and modularisation [9] techniques. It allows a more efficient analysis of fault trees. The time taken to perform the simplification process has been included in the processing time in Table 4 .", "cite_spans": [{"start": 36, "end": 39, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 123, "end": 126, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 146, "end": 149, "text": "[9]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Comparison of the methods", "text": "The conventional BDD conversion technique (the ite method) resulted in smaller BDDs and smaller number of lines in the storage array for all the example fault trees than the basic component connection method. The processing time was also shorter than in the basic component connection method. More results for the basic approach of the component connection method are presented in [10] .", "cite_spans": [{"start": 381, "end": 385, "text": "[10]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Comparison of the methods", "text": "When sub-node sharing was introduced in the component connection approach the resulting BDDs were smaller than using the basic component connection method but still larger than from the ite technique. Calculation time slightly decreased for the majority of example fault trees. Only for those fault trees with a large number of intermediate calculations (examples 3 and 4) the calculation time increased, due to an extra time taken while identifying parts in the BDD suitable for the sub-node sharing. Therefore, the total time increased when the sub-node sharing was used. More results on the sub-node sharing method were shown in [11] .", "cite_spans": [{"start": 632, "end": 636, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Comparison of the methods", "text": "The hybrid method resulted in BDDs that contain the same number of nodes as the ite approach. Calculation time also remained very similar for all example fault trees. However, the hybrid technique gave slightly better results in terms of the number of lines in the storage array, except example 4. The slightly improved efficiency was due to the fact that the hybrid method used the best rules of the two techniques. Firstly, it was improved because the hybrid method provided the capability to obtain the BDDs for gates with event inputs only in a straightforward way, i.e. putting inputs of a gate in a chain one by one. Secondly, more complex parts of the fault tree were converted to the BDD using the component connection method if repeated events did not appear.", "cite_spans": [], "ref_spans": []}, {"section": "Comparison of the methods", "text": "Summarising it is clear that the ite technique performs better than the basic component connection method. However, the hybrid method, as a combination of the two methods, can provide the efficiency which is as good as the one of the ite method. Despite the fact that the hybrid method is more complex than the ite technique, according to the efficiency analysis the hybrid method is a good alternative technique for constructing BDDs.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "Four methods of constructing BDDs from fault trees were presented in this paper. The first approach is the conventional ite technique. The second approach is the basic component connection method. The third approach investigated enhances the basic component connection method by developing a sub-node sharing property. The last method, the hybrid method, utilises the more efficient features of the two basic methods. Some example fault trees were used in order to evaluate the efficiency of the four methods. Three efficiency measures were considered -number of nodes in the final BDD, number of nodes in the storage array and calculation time. It was shown that the ite method performs well, whereas the basic component connection method does not provide a good efficiency even if the sub-node sharing is used. When the efficiency of the two techniques was combined and the hybrid method was applied, the efficiency of the conversion method was slightly improved. Therefore, the hybrid can be used as an alternative approach to the ite technique for conversion of fault trees to BDDs.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "New Algorithms for Fault Tree Analysis", "authors": [{"first": "A", "middle": [], "last": "Rauzy", "suffix": ""}], "year": 1993, "venue": "Reliability Engineering and System Safety", "link": null}, "BIBREF1": {"title": "A Time Dependent Methodology for Fault Tree Evaluation", "authors": [{"first": "W", "middle": ["E"], "last": "Vesely", "suffix": ""}], "year": 1970, "venue": "Nuclear Design and Engineering", "link": "111154575"}, "BIBREF2": {"title": "A simple component-connection method for building binary decision diagrams encoding a fault tree", "authors": [{"first": "Y", "middle": ["S"], "last": "Way", "suffix": ""}, {"first": "D", "middle": ["Y"], "last": "Hsia", "suffix": ""}], "year": 2000, "venue": "Reliability Engineering and System Safety", "link": "27822096"}, "BIBREF3": {"title": "Improved Accuracy in Quantitative Fault Tree Analysis", "authors": [{"first": "R", "middle": ["M"], "last": "Sinnamon", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Andrews", "suffix": ""}], "year": 1997, "venue": "Quality and Reliability Engineering International", "link": "121689911"}, "BIBREF4": {"title": "Efficient Fault Tree Analysis Using Binary Decision Diagrams", "authors": [{"first": "K", "middle": ["A"], "last": "Reay", "suffix": ""}], "year": 2002, "venue": "", "link": "60169828"}, "BIBREF6": {"title": "Qualitative Analysis of Complex, Modularised Fault Trees Using Binary Decision Diagrams", "authors": [{"first": "J", "middle": ["D"], "last": "Andrews", "suffix": ""}, {"first": "R", "middle": [], "last": "Remenyte", "suffix": ""}], "year": 2006, "venue": "Proceedings of the IMechE, Part O", "link": null}, "BIBREF7": {"title": "FAUNET: A program Package for Evaluation of Fault Trees and Networks", "authors": [{"first": "O", "middle": [], "last": "Platz", "suffix": ""}, {"first": "J", "middle": ["V"], "last": "Olsen", "suffix": ""}], "year": 1976, "venue": "", "link": "58743629"}, "BIBREF8": {"title": "A Linear-Time Algorithm to Find Modules of Fault Trees", "authors": [{"first": "Y", "middle": [], "last": "Dutuit", "suffix": ""}, {"first": "A", "middle": [], "last": "Rauzy", "suffix": ""}], "year": 1993, "venue": "IEEE Trans. Reliability", "link": "45712315"}, "BIBREF9": {"title": "Fault Tree Conversion to Binary Decision Diagrams", "authors": [{"first": "J", "middle": ["D"], "last": "Andrews", "suffix": ""}, {"first": "R", "middle": [], "last": "Remenyte", "suffix": ""}], "year": 2005, "venue": "Proceedings of the 23rd ISSC", "link": "56032273"}, "BIBREF10": {"title": "A Simple Component Connection Approach for Fault Tree Conversion to Binary Decision Diagram", "authors": [{"first": "J", "middle": ["D"], "last": "Andrews", "suffix": ""}, {"first": "R", "middle": [], "last": "Remenyte", "suffix": ""}], "year": 2006, "venue": "Proceedings of the 1 st AReS", "link": "16393256"}}, "ref_entries": {}}
{"paper_id": "2877361", "_pdf_hash": "c3d83fc202c98cacb2ff513e213dcd7551743907", "abstract": [{"section": "Abstract", "text": "The isolation of crystalline ribonuclease by Kunitz (1) provided a specific enzymatic reagent which has been widely used in the study of ribonucleic acid. Our interest in obtaining a purified preparation of the corresponding enzyme acting on nucleic acid of the desoxyribose type arose in connection with studies on the chemical nature of the substance inducing transformation of pneumococcal types. Highly purified preparations of the transforming substance isolated from Pneumococcus Type III have been sho~n to consist largely, if not exclusively, of desoxyribonucleic acid, and evidence has been obtained which indicates that the nucleic acid is itself responsible for biological activity (2). Since it seemed desirable to provide confirmatory evidence regarding the nature of the transforming substance by the use of specific enzymatic techniques, a study of the enzyme which attacks native desoxyribonucleic acid was undertaken, especially with a view to obtaining the enzyme in purified form.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "The enzyme which breaks down highly polymerized desoxyribonudeic acid has been known for many years under various names. In 1903, Araki (3) reported that crude preparations of trypsin and erepsin brought about liquefaction of gels of athymonudeate prepared according to the method of Neumann (4) Although Araki interpreted the effect as being proteolytic in nature, his experiments represent the first observations on the enzymatic breakdown of this type of nucleic acid. Two years later Sachs (5) demonstrated that liquefaction of the nucleate gel by pancreatic extracts is caused by an enzyme distinct from trypsin, and further presented evidence indicating that trypsin rapidly inactivates the nudease. De la Blanchardi~re (6) confirmed the findings of Sachs, and made several unsuccessful attempts to separate the nudease from the inactivating tryptic enzymes. This writer also devised a more quantitative method of measuring the nudease activity by following the faU in viscosity of a dilute solution of thymonudeate during digestion with the enzyme.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "All of the early workers were somewhat handicapped by the poorly defined character of the substrate used in the enzyme studies. Neumann's method of obtaining a-thymonudeate from the thymus gland depended on the use of heat and alkali,", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "The enzyme which breaks down highly polymerized desoxyribonudeic acid has been known for many years under various names. In 1903, Araki (3) reported that crude preparations of trypsin and erepsin brought about liquefaction of gels of athymonudeate prepared according to the method of Neumann (4) Although Araki interpreted the effect as being proteolytic in nature, his experiments represent the first observations on the enzymatic breakdown of this type of nucleic acid. Two years later Sachs (5) demonstrated that liquefaction of the nucleate gel by pancreatic extracts is caused by an enzyme distinct from trypsin, and further presented evidence indicating that trypsin rapidly inactivates the nudease. De la Blanchardi~re (6) confirmed the findings of Sachs, and made several unsuccessful attempts to separate the nudease from the inactivating tryptic enzymes. This writer also devised a more quantitative method of measuring the nudease activity by following the faU in viscosity of a dilute solution of thymonudeate during digestion with the enzyme.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "All of the early workers were somewhat handicapped by the poorly defined character of the substrate used in the enzyme studies. Neumann's method of obtaining a-thymonudeate from the thymus gland depended on the use of heat and alkali, which inevitably resulted in a partial breakdown of the material, so that the final preparation consisted of a mixture of hydrolytic products. Experimental demonstration of this partial destruction has been provided by the ultracentrifuge studies of Schmidt, Pickels, and Levene (7) who showed that nucleic acid of the Neumann type sediments with a very diffuse boundary, and that the estimated particle weight varies from 50,000 to above 1,000,000.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "The first studies in which a more suitable substrate was used were those of Greenstein and Jenrette (8) who employed sodium thymonucleate prepared by the method of Hammarsten (9) . This method avoids the use of drastic reagents, and all procedures are carried out at 0\u00b0C. and at neutrality, The preparations so obtained are considerably more homogeneous and highly polymerized than those obtained by Neumann's method. Greenstein and Jenrette were primarily interested in the comparison of the nuclease activity of normal and cancerous tissues, and they investigated a wide variety of organs for the presence of the enzyme, which they now refer to as desoxyribonucleodepolymerase (10) . The activity of the enzyme was determined by measuring the progressive fall in viscosity of the nucleate solution when mixed with tissue extracts. It was shown that the enzyme is present in a large number of organs, as well as in the milk and sera of certain mammalian species.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "In the several studies mentioned, as well as in others, such as those of Feulgen (11) , in which the enzyme was used in investigating the end products of digestion of nucleic acid, relatively crude tissue extracts were employed as the source of the enzyme. In the present paper a method is described for the purification of this enzyme, which for purposes of convenience will hereinafter be referred to as desoxyribonuclease. In addition, certain observations are reported on the chemical properties and kinetics of action of the purified enzyme. The effect of the purified enzyme on the biological activity of the pneumocOccal transforming substance will be the subject of a separate communication (12) .", "cite_spans": [], "ref_spans": []}, {"section": "EXPERIMENTAL", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Measurement of Desoxyribonuclease Activity Source of Enzyme.--The results of previous investigators indicate that pancreas", "text": "is by far the richest source of desoxyribonudease available. Commercial pancreatin was used early in the present study, and was found to provide highly active enzyme preparations. However, attempted fractionation of pancreatin was not particularly successful, and the use of this type of material was discontinued in favor of fres~a beef pancreas.", "cite_spans": [], "ref_spans": []}, {"section": "Measurement of Desoxyribonuclease Activity Source of Enzyme.--The results of previous investigators indicate that pancreas", "text": "Substrate.--Sodium desoxyribonucleate was prepared from calf thymus by the method described by Mirsky (13) . In this procedure, minced tissue is thoroughly washed with 0.14 M NaC1 and then extracted with 1 M NaC1 to obtain the nucleohistone. Purification of the nucleohistone is achieved by repeated precipitation at a concentration of 0.14 M NaC1, and resolution in 1 ~r NaC1. The histone is then removed by shaking the solution with chloroform and amyl alcohol, the process being repeated until no further chloroform-protein gel is formed. Deproteiniz&tion is considerably facilitated by first dissociating the nucleic acid and histone by the addi-tion of alkali to the 1 \u2022 NaC1 solution (14) . The criterion for dissociation is the lack of formation of a fibrous precipitate whefi a sample of the solution is diluted with six volumes of water. The deproteinized sodium desoxyribonudeate is precipitated by alcohol, washed with absolute alcohol and ether, and dried in ~acuo.", "cite_spans": [{"start": 102, "end": 106, "text": "(13)", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Measurement of Desoxyribonuclease Activity Source of Enzyme.--The results of previous investigators indicate that pancreas", "text": "A characteristic sample of sodium desoxyribonucleate prepared by this method has a phosphorus content of 8.12 per cent and nitrogen content of 13.5 per cent (nitrogen-phosphorus ratio 1.66). The material dissolves readily in water to give clear, highly viscous solutions which may be stored in the refrigerator for long periods of time without loss of viscosity. Even at higher temperatures, e.g. 37\u00b0C., there is no apparent loss of viscosity over a period of several days. The fact that the nucleate solutions show little evidence of spontaneous depolymerization enhances the reliability of a method of measuring enzymatic breakdown based on decrease in viscosity.", "cite_spans": [], "ref_spans": []}, {"section": "Measurement of Desoxyribonuclease Activity Source of Enzyme.--The results of previous investigators indicate that pancreas", "text": "Method of Measuring Enzyme Activity.--Measurement of the progressive fall in viscosity of nucleate solutions during treatment with the enzyme has yielded constant and reproducible results and has proved a reliable method for determining enzymatic activity. The test is carried out as follows: In all the experiments recorded in this paper Ostwald viscosimeters with a uniform capillary size, giving a flow time for water of from 80 to 100 seconds have been used. 4.8 cc. of a 0.05 to 0.1 per cent solution of sodium desoxyribonudeate in veronal buffer pH 7.5 are introduced into the viscosimeter, which is then placed in a water bath at 30\u00b0C. The concentration of substrate is selected so as to give an initial viscosity of not over 3 to 4 times that of water, in order that the rate of flow--and thus the time required for each reading--will not be too greatly prolonged. To 4.8 cc. of substrate, 0.2 cc. of the enzyme dilution is added at zero time, thoroughly mixed with the substrate, and readings of viscosity are made at intervals over a period of about 30 minutes. The enzyme solution under test is diluted so as to give a rate of fall in viscosity that is constant for at least 10 minutes.", "cite_spans": [], "ref_spans": []}, {"section": "Measurement of Desoxyribonuclease Activity Source of Enzyme.--The results of previous investigators indicate that pancreas", "text": "The use of a constant external pressure in measuring the viscosity of desoxyribonude.ate solutions has been emphasized by Greenstein (8) because of the structural viscosity displayed by these solutions. Under the conditions of the present experiments, in which dilute solutions of desoxyribonucleate are used, the application of an external pressure of 16 cm. H,O was found to have little effect on the slope of the viscosity curves or on the reproducibility of the results, and consequently in the interest of simplicity external pressure was not employed in the routine procedure.", "cite_spans": [], "ref_spans": []}, {"section": "Measurement of Desoxyribonuclease Activity Source of Enzyme.--The results of previous investigators indicate that pancreas", "text": "Magnesium Acti~ation.--In the course of preparative procedures it was observed that the activity of desoxyribonuclease is greatly reduced following dialysis, and that original activity can be completely restored by the addition of magnesium ion to the dialyzed material. Thus, the enzyme is apparently among those requiring a metallic activator. Manganese can replace magnesium and is equally effective at an equivalent molar concentration. Zinc also activates slightly but is less effective than magnesium or manganese. Calcium and iron have no activating effect.", "cite_spans": [], "ref_spans": []}, {"section": "Measurement of Desoxyribonuclease Activity Source of Enzyme.--The results of previous investigators indicate that pancreas", "text": "The optimum concentration of magnesium ion is in the order of 0.003 M, andas a routine procedure the enzyme dilutions are made in 0.075 ~r MgSO4 so Fig. 1 shows the discrepancy in proportionality between the concentration of enzyme and the rate of fall in viscosity in the absence of a protective agent. Fig. 2 illustrates an experiment carried out under the same conditions, except that gelatin was added to the system in a final concentration of 0.01 per cent. In this case a direct relationship is shown between the concentration of enzyme and the rate of fall in viscosity. reaction, and it was not possible to relate the activity of one enzyme preparation to another on the basis of rate of fall in viscosity. A typical experiment is illustrated in Fig. 1 . Twofold decreases in enzyme concentration were made. In decreasing the final concentration from 0.006 mg. per cc. to 0.003 rag. per cc. there resulted a fivefold decrease in the slope of the viscosity curve, and with a further twofold decrease in enzyme concentration activity was no longer detectable. I t was thought that this discrepancy in results was probably explicable on the basis of denaturation of the enzyme protein in dilute solu-tion, and that the addition of a protective colloid to the system might prevent inactivation of the enzyme. Since gelatin has been used successfully as a protective to prevent or retard loss of activity in the case of other enzymes, such as tyrosinase (15) and ascorbic acid oxidase (16), its effect was tested in the desoxyribonuclease system. An experiment in which gelatin was used as protective agent is recorded in Fig. 2 . The enzyme preparation and concentrations were the same as those of the preceding experiment ( Fig. 1 .) The enzyme diluent contained, in addition to the MgSO4, gelatin in a concentration of 0.25 per cent. The final concentration of gelatin in the viscosimeter was therefore 0.01 per cent, and this amount of gelatin exerted no measurable effect on the viscosity of the substrate. The effect of gelatin in protecting the enzyme was striking. In contrast to measurements carried out without gelatin ( Fig.  1 ), twofold reductions in enzyme concentration resulted in a corresponding t~;ofold decrease in the slope of the viscosity curve (Fig. 2) .", "cite_spans": [], "ref_spans": []}, {"section": "Measurement of Desoxyribonuclease Activity Source of Enzyme.--The results of previous investigators indicate that pancreas", "text": "Thus in a system containing gelatin the inactivation of the enzyme is sufficiently reduced so that a direct relationship is shown between the concentration of the enzyme and the rate of fall in viscosity, and it is possible to characterize the activity of a given enzyme preparation from the slope of a single curve. per cc. is illustrated in Fig. 3 . The initial relative viscosity varied from below 3 to almost 5. The slopes of the curves at the various concentrations are identical, showing that the rate of fall in viscosity is independent of the substrate concentration within these narrow limits. Thus, under the conditions of the test, the concentration of the enzyme is the limiting factor in determining the rate of fall in viscosity. In summary, the activity of the enzyme is tested against a 0.05 to 0.1 per cent solution of sodium desoxyribOnucleate in M/40 veronal buffer pH 7.5 at 30\u00b0C. in the presence of 0.003 ~t magnesium and 0.01 per cent gelatin. For the purpose of comparing the activity of various preparations, one unit of the enzyme has been defined as that amount which causes a fall of 1.0 in relative viscosity in 20 minutes under the conditions described.", "cite_spans": [], "ref_spans": [{"start": 343, "end": 349, "text": "Fig. 3", "ref_id": "FIGREF0"}]}, {"section": "Isolation and Purification of the Enzyme", "text": "The major difficulty encountered in purification of desoxyribonuclease was the marked susceptibility of the enzyme to destruction by the action of proteolytic enzymes in the source material. Thus, pancreatic extracts with extraordinarily high desoxyribonuclease activity were readily obtained by extraction of fresh pancreas with water, but the activity was rapidly lost as the proteolytic enzymes became activated. When fractionation procedures were attempted, solutions of the partially purified material proved to be unstable because of the contaminating tryptic enzymes. Therefore, although pancreas is the richest source of desoxyribonuclease, it has the disadvantage of having at the same time high concentrations of proteolytic enzymes, which in turn digest the active nuclease.", "cite_spans": [], "ref_spans": []}, {"section": "Isolation and Purification of the Enzyme", "text": "This difficulty has been largely overcome by the use of the acid extract method described by Kunitz and Northrop (17) for the preparation of crystalline chymotrypsin and trypsin from beef pancreas. Fractionation of the acid extract results in more effective separation of the nuclease from the proteolytic enzymes, and a simple procedure for obtaining desoxyribonuclease in a purified form has been devised.", "cite_spans": [], "ref_spans": []}, {"section": "Isolation and Purification of the Enzyme", "text": "Following the procedure of Ktmitz and Northrop, fresh beef pancreas is obtained at the slaughter house and immediately immersed in cold 0.25 N H2SO4 to retard autol.ytic processes during transportation. The pancreas is passed through a meat grinder, and the ground tissue suspended in two volumes of cold 0.25 N H2SO4. Extraction Is allowed to proceed in the refrigerator overnight, and the suspension is then filtered through cheesecloth. The residue is reextracted with one volume of 0.25 N H~SO4, and immediately filtered through cheesecloth. The combined filtrates are brought to 0.2 saturation with ammonium sulfate by the addition of 114 gin. of solid 7-10~000 * Protein estimated colorimetricaUy with phenol reagent using method of Herriott (18). ~,The value for total activity of the acid extract is consistently lower than that of the filtrate at 0.2 saturation with ammonium sulfate. This may possibly be explained on the basis of an inhibitor present in the initial extract which is lost on fractionation.", "cite_spans": [], "ref_spans": []}, {"section": "Isolation and Purification of the Enzyme", "text": "salt per liter of filtrate. Ten gin. of filter eel and 10 gin. of standard super eel are added for each liter of filtrate, and filtration is carried out with suction on a large Biichner funnel. The precipitate is discarded. The dear, straw-colored 0.2 saturated filtrate is brought to 0.4 saturation by the addition of 121 gm. of solid ammonium sulfate per liter, and the resulting precipitate is allowed to settle for 1 or 2 days in the refrigerator. The slightly turbid supematant is siphoned off as far as possible, and the precipitate recovered on hard filter paper (Schleicher and Schull No. 275). The precipitate at 0.4 saturation contains practically all of the desoxyribonudease. Chymotrypsinogen, trypsinogen, and ribonudease are present in the filtrate, which can be subjected to further fractionation procedures, as described by Kunitz and Northrop (17) and by Kunitz (1) to obtain these enzymes in crystalline form.", "cite_spans": [], "ref_spans": []}, {"section": "Isolation and Purification of the Enzyme", "text": "The precipitate at 0.4 saturation is redissolved in a small volume of water (50 ec. to each 10 gin. of moist precipitate) and brought to 0.17 saturation by the addition of 20 cc. of saturated ammonium sulfate solution to each 100 cc. of enzyme solution. A small amount of precipitate forms, which is removed by filtration after stirring in 2 gin. of standard super cel for each 100 cc. of solution. The filtrate is brought to 0.3 saturation with ammonium sulfate, and the precipitate formed is recovered on hard paper. This precipitate is dissolved in water and refractionated between 0.17 and 0.3 saturation with ammonium sulfate. Precipitation of the enzyme at the relatively low concentrations of ammonium sulfate used is dependent upon the pH and concentration of the solution. The pH of the solutions from which the enzyme is precipitated at 0.3 saturation is 4.0-4.5, and if the pH is increased to 7 or above, considerably larger amounts of salt are required to bring down the desoxyribonudease.", "cite_spans": [], "ref_spans": []}, {"section": "Isolation and Purification of the Enzyme", "text": "The final 0.3 saturated precipitate is dissolved in a small volume of water (10 to 20 cc.) and dialyzed in the cold against 0.002 N I-I2SO4. The dialyzed solution is then dried in vacuo from the frozen state. A summary of the method of preparation, giving average values for the amount and activity of the various fractions is presented in Table I .", "cite_spans": [], "ref_spans": [{"start": 340, "end": 347, "text": "Table I", "ref_id": "TABREF1"}]}, {"section": "Isolation and Purification of the Enzyme", "text": "The yield of dried enzyme from 10 pounds of pancreas is 1 to 2 gin. Numerous attempts have been made to crystallize this purified product, but none has so far been successful.", "cite_spans": [], "ref_spans": []}, {"section": "Properties of the Purified Enzyme", "text": "General Properties.--The activity of the dried enzyme is well preserved on storage. The dried material dissolves readily in water to yield clear, colorless solutions with a pH between 4 and 5. The enzyme has its maximun stability in this pH range, so that aqueous solutions are relatively stable. At higher pH values, and especially above pH 7, loss of activity is much more rapid, but this instability may be chiefly the result of the action of small amounts of proteolytic enzymes still present in the purified preparations.", "cite_spans": [], "ref_spans": []}, {"section": "Properties of the Purified Enzyme", "text": "Highly dilute solutions of the enzyme are unstable even in the presence of gelatin, and in order to obtain reproducible results it is necessary to measure activity immediately after preparation of the dilution. Increasing the amount of gelatin has not served to augment significantly the stability of the dilute enzyme solutions, but as mentioned above, the activity of the enzyme is remarkably well preserved in complex mixtures such as neopeptone. Because of its complex nature and variable constitution, peptone cannot be considered ideal for this purpose, but it has proved very useful in those cases where stable dilutions are required.", "cite_spans": [], "ref_spans": []}, {"section": "Properties of the Purified Enzyme", "text": "The results of preliminary studies in the electrophoresis apparatus indicate that the isoelectric point of the enzyme is from pH 5.0 to 5.2. One major electrophoretic component is present with a small amount of at least one other component. 1 Specific Activity on Sodium Desoxyribonucleate.--Purified preparations display high activity as measured by the fall in viscosity of desoxyribonueleic acid. As indicated in Table I, in water in a volumetric flask. From this dilution a further 100-fold dilution (final 1:10,000) was made in the gelatin-MgSO4 diluent. 0.2 cc. of this dilution (containing 0.1 microgram of enzyme) was mixed with the substrate as described under measurement of activity. The curves obtained with three separate preparations of the enzyme are recorded in Fig. 4 , and serve to demonstrate the uniformity in activity of different lots prepared by the method described.", "cite_spans": [], "ref_spans": [{"start": 416, "end": 424, "text": "Table I,", "ref_id": "TABREF1"}, {"start": 778, "end": 784, "text": "Fig. 4", "ref_id": "FIGREF3"}]}, {"section": "Action of tie Purified Enzyme on Substrates Other Tkan Desoxyribonudeic", "text": "Acid.--The purified preparations were tested for enzymatic activity on a variety of substrates other than desoxyribonucleic acid in an attempt to obtain information as to the completeness of the separation from other constituents of the pancreatic extracts. Proteolytic activity was measured using gelatin and casein as substrates. The effect on the viscosity of 2.5 per cent gelatin at pH 7.5 was employed as a method of detecting minute amounts of proteolytic enzyme. One to two rag. of purified desoxyribonuclease caused no fall in the viscosity of 5.0 cc. of the gelatin solution, even after attempts to activate the enzyme solution, on the assumption that inactive precursors of the proteolytic enzymes (trypsinogen or chymotrypsinogen) might be present. When 5 rag. of the enzyme were used, a slight effect was noted, corresponding to the effect given by 0.0005 mg. of crystalline trypsin when tested in the same system.", "cite_spans": [], "ref_spans": []}, {"section": "Action of tie Purified Enzyme on Substrates Other Tkan Desoxyribonudeic", "text": "At concentrations of 0.2 to 1.0 mg. per cc. the enzyme also caused definite proteolysis of a 2 per cent solution of casein (pH 7.8) as measured by the increase in tyrosine not precipitable by trichloracetic acid. In general, casein seemed to be much more readily attacked than gelatin. These findings indicate that a small amount of some proteolytic enzyme is present in the purified preparations.", "cite_spans": [], "ref_spans": []}, {"section": "Action of tie Purified Enzyme on Substrates Other Tkan Desoxyribonudeic", "text": "The effect of the enzyme on ribonucleic acid was determined by using the method of Kunitz (1) for measuring ribonuclease activity. A 0.5 per cent solution of yeast nucleic acid was treated for 2 hours (at 37\u00b0C. and pH 5.0) with 5 mg. of the enzyme, with no resultant increase in acid-soluble phosphorus. The results indicate that desoxyribonuclease has no action on ribonucleic acid, and this is in conformity with the observations of others on the specificity of ribonuclease, which in turn has no action on desoxyribonucleic acid.", "cite_spans": [], "ref_spans": []}, {"section": "Action of tie Purified Enzyme on Substrates Other Tkan Desoxyribonudeic", "text": "The purified enzyme was also tested for lipase activity using tributyrin as substrate, and for alkaline phosphatase using sodium-fl-glycerophosphate. In neither instance was any evidence of splitting detected. It is concluded that the purified preparations do not contain significant amounts of lipase, phosphatase, or ribonuclease.", "cite_spans": [], "ref_spans": []}, {"section": "Action of tie Purified Enzyme on Substrates Other Tkan Desoxyribonudeic", "text": "Optimum pH.--The optimum pH for the action of the enzyme covers a broad range from 6.8 to 8.2. The viscosimetric method is not suitable for measurement of activity below pH 6, because in the acid range non-enzymatic depolymerization of the substrate occurs.", "cite_spans": [], "ref_spans": []}, {"section": "Action of tie Purified Enzyme on Substrates Other Tkan Desoxyribonudeic", "text": "Heat Liability,--In contrast to ribonuclease, which is remarkably heatstable, desoxyribonuclease is readily inactivated by heat. Experiments Carried out with 0.5 per cent solutions of desoxyribonuclease in N/100 HCI, in acetate buffer pH 5.0, and in veronal buffer pH 7.8 gave comparable results. In each case, heating at 55\u00b0C. for 15 minutes resulted in a loss of 90 per cent or more of the original activity, and after 1 hour no residual activity was detectable.", "cite_spans": [], "ref_spans": []}, {"section": "Action of tie Purified Enzyme on Substrates Other Tkan Desoxyribonudeic", "text": "Inhibition of Desoxyribonudease.--In the course of studies on the pneumococcal transforming substance, it was observed that crude preparations of desoxyribonuclease from diverse sources were inhibited by sodium fluoride (2) . It is now apparent that fluoride inhibition is probably related to the fact that the enzyme is magnesium-activated, since other magnesium-activated enzymes have been shown to be inhibited by fluoride. A relatively high concentration of fluoride (0.02 to 0.1 ~t) is required for effective inhibition of desoxyribonuclease under the conditions of the test, and further study of the inhibition is not readily adaptable to the viscosimetric method because the precipitate of magnesium fluoride which is formed interferes with accurate measurement of viscosity. It has not been determined whether phosphate plays an important r61e in fluoride inhibition as it does in the case of the magnesium-activated enolase studied by Warburg and Christian (19) .", "cite_spans": [], "ref_spans": []}, {"section": "Action of tie Purified Enzyme on Substrates Other Tkan Desoxyribonudeic", "text": "Citrate forms a soluble complex with magnesium similar to that which it forms with calcium. Because of this fact sodium citrate was tested for its effect on enzyme activity and was found to be a potent inhibitor. In 0.01 ~t concentration sodium citrate exerts a profound inhibitory effect on the mag- nesium-activated enzyme even when relatively high concentrations of the enzyme are used. It is of interest, however, that citrate has no such inhibitory effect when manganese is used as the metallic activator. The results of an experiment showing the relationship between the nature of the metallic activator and citrate inhibition are given in Fig. 5 . The same enzyme concentration was used in each determination. It is evident that manganese and magnesium ion at 0.003 \u2022 concentration activated the enzyme equally. In the presence of 0.01 ~ sodium citrate, the magnesium-activated enzyme was completely inhibited, while there was no appreciable effect on the manganese-activated enzyme.", "cite_spans": [], "ref_spans": []}, {"section": "Action of tie Purified Enzyme on Substrates Other Tkan Desoxyribonudeic", "text": "Citrate has a similar marked inhibitory action on desoxyribonuclease in crude tissue extracts, and it thus seems likely that magnesium is the naturally occurring activator of the enzyme. In view of this fact, sodium citrate may prove useful as an inhibitor of desoxyribonuclease in biological material. It has been found, for example, that the enzymatic breakdown of desoxyribonucleic acid which takes place during the autolysis of pneumococci can be completely prevented by citrate without otherwise affecting the course of lysis (20) Immunological Dat~.--Attemps were made to prepare antisera to desoxyribonuclease by injecting rabbits intra,;renously with solutions of the enzyme protein. However, after repeated injections by the intravenous route, the sera of the treated animals showed neither precipitins nor inhibitory action on the enzyme. On the contrary, potent precipitating antisera were obtained by the intraperitoneal injection of alum-precipitated enzyme.", "cite_spans": [], "ref_spans": []}, {"section": "Action of tie Purified Enzyme on Substrates Other Tkan Desoxyribonudeic", "text": "A 1 per cent solution of enzyme (preparation 16) was mixed with an equal volume of 10 per cent potassium alum. The pH of the solution was brought to slightly above 7 with N NaOH with the formation of a voluminous precipitate. The suspended precipitate was injected intraperitoneally without washing or centrifugation. Each of two rabbits received a single injection of 10 rag. of enzyme protein by this route. The sera obtained from these animals 1 week later possessed a high titer of specific precipitins. A second intraperitoneal injection of 50 rag. of alum-precipitated enzyme 2 weeks later resulted in a considerable increase in antibody titer.", "cite_spans": [], "ref_spans": []}, {"section": "Action of tie Purified Enzyme on Substrates Other Tkan Desoxyribonudeic", "text": "In Table II are recorded qualitative precipitin tests with the homologous antigen as well as with crystalline preparations of ribontlclease, chymotrypsin, and trypsin which were prepared from a similar acid extract of beef pancreas. ~ The sera were diluted with 1.5 volumes of saline and mixed with an equal volume of the antigen dilutions in saline. Readings were made after incubation at 37\u00b0C. for 2 hours and refrigeration overnight.", "cite_spans": [], "ref_spans": [{"start": 3, "end": 11, "text": "Table II", "ref_id": "TABREF1"}]}, {"section": "Action of tie Purified Enzyme on Substrates Other Tkan Desoxyribonudeic", "text": "The data in Table II show that desoxyribonuclease reacts with its antiserum in dilutions beyond 1:1,000,000, indicating a high degree of serological activity for a protein antigen. On the other hand, the crystalline preparations of ribonuclease, chymotrypsin, and trypsin show negligible cross-reactions with the desoxyribonuclease antiserum. Thus, although the desoxyribonuclease is produced by the same organ that elaborates ribonuclease and tryptic enzymes, there is no evidence from the results of precipitin tests that would suggest a serological relationship on the basis of organ or species specificity. These results are in accord with the findings of TenBroeck (21), who showed that trypsin and chymotrypsin from the same species could be d/stinguished by means of the anaphylactic test. Thus, the incomplete evidence suggests that each of several enzymes making up a part of the external secretion of the same organ have a distinct serological specificity as well as enzyme specificity.", "cite_spans": [], "ref_spans": [{"start": 12, "end": 20, "text": "Table II", "ref_id": "TABREF1"}]}, {"section": "Action of tie Purified Enzyme on Substrates Other Tkan Desoxyribonudeic", "text": "Evidence for the presence of a species-specific antibody in the desoxyribonuclease antisera is afforded by the fact that precipitates are obtained when beef serum is used as antigen. However, the amount of precipitate obtained is relatively small. All the cross-reacting precipitins can be removed by adsorption with beef serum, with only a slight decrease in the titer of antibody specificaUy reactive with the purified enzyme. It is likely that the beef serum reactive antibody is formed as the result of the presence of extraneous protein in the desoxyribonuclease preparation used as immunizing antigen. In this connection it is of interest that antisera prepared against crystalline ribonuclease by Smolens and Sevag (22) showed no evidence of cross-reaction with beef serum. The possibility of cross-reactivity with trypsin and ehymotrypsin was not tested by these authors. Effect of Specific Antibody on Ensyme Actidty.--The specific antisera were tested for their effect on the ezymatic activity of desoxyribonuclease. The viscosimetric tests for nuclease activity were carried out as previously described, except that in this instance the final dilution of the enzyme was made in the presence of the antiserum under test, rather than in the gelatin diluent. under the conditions described, desoxyribonuclease falls in that group of enzymes which are inhibited by their specific antibodies.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "The present paper describes the purification and properties of an enzyme isolated from beef pancreas which attacks native desoxyribonucleic acid. This desoxyribonuclease has been obtained in a highly active and relatively purified form, but has not been crystallized. The enzyme is activated by either magnesium or manganese, and its activity is dependent upon the presence of one or the other of these ions in the system. Previous workers have characterized the action of the enzyme as a depolymerization, since no release of inorganic phosphorus or other readily dialyzable substance occurs, and the end products of the reaction are apparently relatively large in size. Notwithstanding the fact that the enzyme causes only a limited breakdown of the nucleic acid molecule, its primary action is essential for further degradation of this substance by other enzymes. For example, Schmidt, Pickels, and Levene (7) showed that the high polymer desoxyribonucleic acid prepared by the Hammarstea method was not dephosphorylated by a purified intestinal nucleophosphata~, whereas the latter enzyme could split off phosphorus from the more degraded form of nucleic acid as prepared by Neumann or Levene. After pretreatment of the Hammarsten nucleic acid with pancreatin, until it no longer gave a fibrous precipitate with alcohol, the material was readily dephosphorylated. Thus, enzymatic depolymerization was required before the dephosphorylating enzyme could act.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "More recently Wilson (23) has found that strains of hemolytic streptococcus which require certain purines for growth in vitro are unable to utilize highly polymerized desoxyribonucleic acid as a source of these purines. However, the same preparation of nucleic acid after hydrolysis by purified desoxyribo~u-clease supplies the essential growth factor. The streptococcus apparently lacks an enzyme analogous to desoxyribonuclease, but is capable of metabolizing the units which represent the end products of action d this enzyme.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "In the light of these and other similar observations, it seems apparent that desoxyribonuclease is a true \"nuclease\" in that it splits the intact nucleic acid molecule and must act before further enzymatic degradation can occur. For this reason, and in the interest of brevity, the name desoxyribonuclease has been used in this paper in preference to the term desoxyribonucleodepolymerase suggested by Greenstein.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "For the purpose d standardizing the conditions, allthe experiments described in the present paper were carried out with the highly polymerized form of desoxyribonucleic acid obtained from a single source, calf thymus. However, the enzyme appears to attack indiscriminately desoxy~ibonucleic acid from a variety of animal and bacterial cells. Similar preparations of desoxyrihonucleic acid from beef spleen, shad sperm, and pneumococci are broken down at the same rate and under the same conditions which obtained in 'the case of can thymus nucleic acid.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "At present there has been no effective procedure developed for removing the traces of proteolytic enzyme which are present as contaminant in the desoxyribonuclease preparations. Fortunately, the activity of the nuclease is sufficiently great so that it may be diluted far beyond the range of detectable proteolytic activity. Thus, while the proteolytic activity of the best preparations can be demonstrated only when I n~g. per cc. of the enzyme is used, the desoxyribonuclease is active at concentrations below 0.01 microgram per cc. The disproportion between the two types d enzymatic activity is more than adequate to allow practical use of the nuclease under conditions in which proteolytic activity is totally absent. For example, 0.01 rag. per cc. final concentration of the enzyme causes almost instantaneous loss of viscosity of a desoxyribonucleate solution, but at this concentration none of the ordinary protein substrates is ~ttacked.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "Detailed investigations of the enzyme in the electrophoresis apparatus or ultracentrifuge have not been carried out, and it is hoped that greater purification of the enzyme can be accomplished by means of crystallization before study of the physical properties or molecular size is attempted. The degree of purification of desoxyribonuclease achieved in the present work, together with the information obtained concerning the properties of the enzyme, is ~ufficient to provide the specific enzymatic reagent that was sought for use in the study of the transforming substance of Pneumococcus.", "cite_spans": [], "ref_spans": []}, {"section": "SUM'.~ARY", "text": "Addendum.--After the present work was finished and the manuscript completed, a paper came to our attention which describes the purification of the same enzyme under the name thymo-polynucleotidase (Fischer, F. G., B6ttger, I., and Lehmann-Echternacht, H., Z. physiol. Ckem., 1941, 9.71, 245) . Although the paper has not been available locally, due to the international situation, a photostatic reproduction has been obtained. The German workers prepared the enzyme from both dried and fresh pancreas. One of the methods described involves ammonium sulfate fractionation of an acid extract of beef pancreas, and in general the procedure is similar to the method presented above, except in the final steps of purification. It is impossible to compare the activity of their preparations with those made in this Laboratory, however, because entirely different methods of measuring activity are employed. The fact that magnesium ion is essential for the action of the enzyme is pointed out, and it is stated that arsenate and arsanilic acid inhibit completely at 10 4 ~ concentration. These workers demonstrated that their preparations had no activity on a variety of substrates other than nucleic acid, including gelatin, ribonucleic acid, nucleotides, nucleosides, and several organic phosphates.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "The enzyme is highly active, a measurable effect being obtained at concentrations of less than 0.01 microgram per cc. In highly dilute solution the enzyme is rapidly inactivated, and the use of a protective agent such as gelatin or peptone is necessary", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF1": {"title": "The purified material contains traces of a proteolytic enzyme, but displays no ribonuclease, lipase, or phosphatase activity. 4. The enzyme requires activation by magnesium or manganese ion, and citrate serves as a potent inhibitor of the magnesium-activated enzyme. 3. Its enzymatic activity is inhibited by the specific antibody present in the serum of rabbits immunized with enzyme protein", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF14": {"title": "Proc. Nat. Acad. Sv", "authors": [{"first": "A", "middle": ["E"], "last": "Mirsky", "suffix": ""}, {"first": "A", "middle": ["W"], "last": "Poulster", "suffix": ""}], "year": 1942, "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Effect of varying the concentration of the substrate, sodium desoxyribonu- c]eate.", "type": "figure"}, "FIGREF1": {"text": "I~RO~ BEEF PANCREAS In some later experiments 1 per cent neopeptone has been used in place of gelatin. Identical results are obtained in terms of activity, and indeed very dilute solutions of the enzyme retain activity for longer periods of time in neopeptone than in gelatin. (See below.) Effect of Varying the Substrate Concentration.--The effect of varying the substrate concentration was studied only within a relatively narrow range in which the viscosity of the solution allowed rapid measurement of enzyme activ- ity. An experiment in which the same enzyme preparation was tested against sodium desoxyribonucleate in concentrations of 0.63, 0.75, 0.88, and 1.0 rag.", "type": "figure"}, "FIGREF3": {"text": "the dried material contains approximately 10,000 units per rag. of protein. Thus, 0.1 microgram of the enzyme represents one unit. A definite effect can be demonstrated with enzyme concentrations of less than 0.01 microgram per cc. The measurement of activity of the dried enzyme is illustrated in Fig. 4. An aqueous solution containing 5 rag. of enzyme per cc. was diluted 100Activity of purified preparations of desoxyribonudease.", "type": "figure"}, "FIGREF4": {"text": "FIG. S. Effect of citrate on magnesium-activated and manganese-activated desoxyribonuclease.", "type": "figure"}, "FIGREF5": {"text": "The samples of crystalline enzymes were obtained through the courtesy of Dr. John H. Northrop and Dr. M. Kunitz of The Rockefeller Institute for Medical Re- search, Princeton, New Jersey.", "type": "figure"}, "FIGREF6": {"text": "marked precipitation with dear supernatant. --= no precipitation. 0 = indicates that reactions were not carried out at higher dilutions of antigen with serum of the same rabbit, obtained before immunization was begun.", "type": "figure"}, "FIGREF7": {"text": "FIG. 6. Effect of specific antibody on the enzymatic activity of desoxyribonuclease.", "type": "figure"}, "TABREF1": {"text": "Preparation of Desoxyribonudease", "type": "table"}, "TABREF2": {"text": "Tests ~q~h Antldesoxyribonudea~e Rabbit Serum", "type": "table"}}}
{"paper_id": "2877377", "_pdf_hash": "1bb313d67fc02d362b33acad992f9ee5d68be261", "abstract": [{"section": "Abstract", "text": "Rapid diagnostic tests (RDTs) are less reliant on expert microscopy and have the potential to reduce errors in malaria diagnosis but have not been extensively evaluated in nonimmune persons or in countries where infection is not endemic. We evaluated the ICT P.f/P.v (ICT-Amrad, Sydney, Australia) and OptiMal (Flow Inc., Portland, Oreg.) assays prospectively for the diagnosis of malaria in 158 specimens from 144 febrile returned travellers in Australia by using expert microscopy and PCR as reference standards. Malaria was diagnosed in 93 specimens from 87 patients by expert microscopy, with 3 additional specimens from recently treated patients testing positive for Plasmodium falciparum by PCR. For the diagnosis of asexual-stage P. falciparum malaria, the sensitivity and specificity of the ICT P.f/P.v assay were 97 and 90%, respectively, and those of the OptiMal assay were 85 and 96%, respectively. The ICT P.f/P.v assay missed one infection with a density of 45 parasites/l, whereas the OptiMal assay missed infections up to 2,500/l; below 1,000/l, its sensitivity was only 43%. For the diagnosis of P. vivax malaria, the sensitivity and specificity of the ICT P.f/P.v assay were 44 and 100%, respectively, and those of the OptiMal assay were 80 and 97%, respectively. Both assays missed infections with parasite densities over 5,000/l: up to 10,000/l with the former and 5,300/l with the latter. Despite the high sensitivity of the ICT P.f/P.v assay for P. falciparum malaria, caution is warranted before RDTs are widely adopted for the diagnosis of malaria in nonimmune patients or in countries where malaria is not endemic.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "Although regions with endemic infection incur most of the burden of malaria-associated morbidity and mortality, the infection also presents a considerable problem in other countries. Cases of imported malaria have increased in Western countries over the past several decades (6, 20) and are related to increased international travel and immigration. Given that 80% or more of travelers who contract malaria do not develop symptoms until returning home (2, 13) , the diagnosis of malaria generally depends on laboratories in areas where infection is not endemic. However, in such settings, expertise in malaria diagnosis is often limited and, consequently, diagnostic inaccuracies are a well-recognized problem (2, 13, 16) . Mortality from imported malaria, primarily due to Plasmodium falciparum, is 0.6 to 3.8%, (5, 20 ; H. O. Lobel, C. C. Campbell, and J. M. Roberts, Letter, Lancet i: 873, 1985) and is strongly associated with delays in diagnosis and institution of appropriate treatment (5, 19, 31) . Strategies to improve the accuracy and timeliness of malaria diagnosis, particularly where expertise in microscopy is limited, are thus priorities.", "cite_spans": [{"start": 275, "end": 278, "text": "(6,", "ref_id": "BIBREF5"}, {"start": 279, "end": 282, "text": "20)", "ref_id": "BIBREF19"}, {"start": 452, "end": 455, "text": "(2,", "ref_id": "BIBREF1"}, {"start": 456, "end": 459, "text": "13)", "ref_id": "BIBREF12"}, {"start": 710, "end": 713, "text": "(2,", "ref_id": "BIBREF1"}, {"start": 714, "end": 717, "text": "13,", "ref_id": "BIBREF12"}, {"start": 718, "end": 721, "text": "16)", "ref_id": "BIBREF15"}, {"start": 813, "end": 816, "text": "(5,", "ref_id": "BIBREF4"}, {"start": 817, "end": 819, "text": "20", "ref_id": "BIBREF19"}, {"start": 992, "end": 995, "text": "(5,", "ref_id": "BIBREF4"}, {"start": 996, "end": 999, "text": "19,", "ref_id": "BIBREF18"}, {"start": 1000, "end": 1003, "text": "31)", "ref_id": "BIBREF30"}], "ref_spans": []}, {"section": "", "text": "Microscopy remains the diagnostic technique of choice for malaria. It is relatively inexpensive, sensitive to a threshold of 5 to 50 parasites/l (depending on technical factors such as the expertise of the microscopist) (17, 33) , and able to characterize the infecting species and their relative densities. However, it requires considerable technical expertise for optimal blood film preparation, examination, and interpretation. Immunocapture rapid diagnostic tests (RDTs) based on the detection of malarial antigens have been developed to improve the timeliness, sensitivity, and objectivity of malaria diagnosis, through less reliance on expert microscopy. The ParaSight-F (Becton Dickinson, Franklin Lakes, N.J). and ICT P.f (Amrad-ICT, Sydney, Australia) assays detect the histidine-rich protein 2 (HRP2) antigen of the asexual stages and young gametocytes of P. falciparum and have a detection threshold of around 40 to 60 parasites/l and an overall sensitivity of 84 to 100% for P. falciparum infections (17, 24, 27, 29, 34) . Two other recently developed RDTs can detect P. vivax in addition to P. falciparum. The ICT P.f/P.v assay (Amrad-ICT) detects the same P. falciparum-specific HRP2 antigen as the ICT P.f assay and a panmalarial antigen expressed by P. falciparum, P. vivax, and possibly also P. ovale and P. malariae (D. P. Mason, C. Wongsrichanalai, K. Lin, R. S. Miller, and F. Kawamoto, Letter, J. Clin. Microbiol. 39:2035, 2001). The OptiMal assay (Flow Inc., Portland, Oreg.) detects Plasmodium-specific lactate dehydrogenase (pLDH) antigens that are expressed by both sexual and asexual parasitic stages, one P. falciparum specific and one Plasmodium genus specific (23) . From limited evaluations, both assays appear sensitive for the detection of P. falciparum infections but variable for non-falciparum infections (1, 3, 7-9, 12, 18, 21, 24, 27, 29) .", "cite_spans": [{"start": 220, "end": 224, "text": "(17,", "ref_id": "BIBREF16"}, {"start": 225, "end": 228, "text": "33)", "ref_id": "BIBREF32"}, {"start": 1012, "end": 1016, "text": "(17,", "ref_id": "BIBREF16"}, {"start": 1017, "end": 1020, "text": "24,", "ref_id": "BIBREF23"}, {"start": 1021, "end": 1024, "text": "27,", "ref_id": "BIBREF26"}, {"start": 1025, "end": 1028, "text": "29,", "ref_id": "BIBREF28"}, {"start": 1029, "end": 1032, "text": "34)", "ref_id": "BIBREF33"}, {"start": 1689, "end": 1693, "text": "(23)", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "", "text": "These RDTs, however, have a number of important limitations, including suboptimal sensitivity at low parasite densities, an inability to accurately identify parasites to the species level or to quantify infection density, and a higher unit cost relative to microscopy. False-positive results occur with HRP2-based assays because of antigen persistence for up to 28 days despite clearance of asexual-stage parasites with chemotherapy (15) , and they occur with both HRP2-and pLDH-based assays in the presence of rheumatoid factor (10; A. Bartoloni, G. Sabatinelli, and M. Benucci, Letter, N. Engl. J. Med. 338:1075, 1998; M. P. Grobusch, U. Alpermann, S. Schwenke, T. Jelinek, and D. C. Warhurst, Letter, Lancet 353:297, 1999). Despite these limitations, RDTs are a potentially useful adjunct to microscopy, particularly where expertise is limited, and have been adopted in laboratories in many countries where infection is not endemic. In Australia, 43% of laboratories participating in the Royal Australasian College of Pathologists quality assurance program for malaria diagnosis routinely use RDTs to supplement microscopy (S. Neville, personal communication). The performance characteristics of such assays, however, have not been extensively established for febrile returned travelers.", "cite_spans": [{"start": 433, "end": 437, "text": "(15)", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "", "text": "The objective of this study was to determine prospectively the performance characteristics of two recently developed RDTs (ICT P.f/P.v and OptiMal) in the diagnosis of malaria in febrile patients presenting in New South Wales, Australia. Reference standards used for comparison were expert microscopy and PCR.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "( Study design and specimens. Consecutive specimens submitted to the Parasitology Department from August 2000 to June 2001 were included in the study; these comprised specimens referred directly from medical practitioners and those referred secondarily from other laboratories in New South Wales for confirmation. Inclusion in the study required the availability of thick blood films and the primary whole-blood specimen (collected in EDTA) stored at 2 to 8\u00b0C. Microscopy (J.W.), PCR (E.G.P.), and the RDTs (M.A.) were performed in parallel on all specimens by separate experienced operators blinded to the results of the other assays. All identifying details were removed from specimens after allocation of a study number, and the results were correlated after completion of all assays.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Microscopy. Thick and thin films were prepared from primarily referred whole-blood specimens and stained with Field's stain by standard procedures within 1 h of receipt (32) . Blood films submitted from other laboratories were examined as submitted (if stained) or were stained with Field's stain. A microscopist with more than 30 years of experience examined each thick film for at least 20 min under a 40\u03eb oil immersion lens (total magnification, \u03eb500) such that at least 200 to 300 fields were examined. The parasite density was calculated with reference to the white cell count measured from simultaneously drawn blood and was expressed as the number of parasites per microliter (26) .", "cite_spans": [{"start": 169, "end": 173, "text": "(32)", "ref_id": "BIBREF31"}, {"start": 683, "end": 687, "text": "(26)", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "", "text": "PCR assay. DNA was extracted from 200 l of whole blood using the QIAamp DNA mini kit (Qiagen, Clifton Hill, Victoria, Australia) as specified by the manufacturer. Extracted DNA was amplified in a seminested multiplex PCR assay using primers targeting the small ribosomal subunit gene, allowing the simultaneous detection and identification to the species level of malaria species as previously described (25) . Bands were visualized on a 2% agarose gel after electrophoresis at 200 V for 40 min. Contamination control measures included the use of dedicated equipment in separate laboratory areas for each assay step as well as other standard measures (14) . A negative control was included for each specimen, and a positive control (incorporating a mixture of all four malaria species) was included for each assay run.", "cite_spans": [{"start": 404, "end": 408, "text": "(25)", "ref_id": "BIBREF24"}, {"start": 651, "end": 655, "text": "(14)", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "", "text": "Rapid diagnostic tests. Each whole-blood specimen was tested immediately on receipt by using the ICT P.f/P.v and OptiMal assays as specified by the manufacturers. The RDTs were stored at 4\u00b0C until use. Both assays were considered valid if the control line was visible. For the ICT P.f/P.v assay, a visible HRP2 line was interpreted as indicating infection with P. falciparum and a visible panmalarial antigen line was interpreted as indicating infection with P. vivax. Where both the HRP2 and the panmalarial antigen lines were visible, P. falciparum infection was diagnosed, although this is also consistent with a mixed infection with P. falciparum and another malaria species. For the OptiMal test, where both the P. falciparum-specific and the panmalarial pLDH lines were visible, infection with P. falciparum was diagnosed, although this is also consistent with a mixed infection as above. A visible panmalarial pLDH line was interpreted as infection with P. vivax.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Reference standards. Following validation against microscopy, PCR was used as the reference standard for the diagnosis of all malaria, P. falciparum (all stages) malaria, P. vivax malaria, and non-falciparum malaria. Since PCR cannot differentiate between sexual and asexual P. falciparum parasites, microscopy was used as the reference standard for the diagnosis of asexual-stage P. falciparum infection.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Statistical analysis. Specimens were classified as true positive, true negative, false positive, or false negative for each test under evaluation compared with the reference standard. Sensitivity, specificity, positive and negative predictive values, and likelihood ratios (LRs) for positive and negative test results were calculated (4). Comparison of independent means was performed using a two-sample t test, and comparison of independent proportions was performed using a 2 test. All significance tests were two tailed. Data were analyzed using EpiInfo version 6 and Minitab for Windows release 12 (Minitab Inc., State College, Pa.).", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "General characteristics and microscopy of study specimens. During the study period, 158 specimens from 144 patients were tested by microscopy, PCR, and the two RDTs. Of the study patients, 96 were males, and the median age was 31 years (range, 1 to 75 years).", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "Microscopy was positive for 93 specimens from 88 episodes of malaria in 87 patients (Table 1) . Of the infections, 28 were acquired in the Pacific region (mostly Papua New Guinea), 27 were acquired in Africa, 21 were acquired in Southeast Asia (mostly East Timor), 11 were acquired in southern Asia (mostly from the Indian subcontinent), and 1 was acquired in South America.", "cite_spans": [], "ref_spans": [{"start": 84, "end": 93, "text": "(Table 1)", "ref_id": "TABREF1"}]}, {"section": "RESULTS", "text": "P. falciparum parasites were detected in 37 specimens (from 35 patients). Asexual-stage (with or without sexual-stage) parasites were present in 33 specimens (from 31 patients) at densities of 5 to 992,000/l (median, 4,830/l; interquartile range, 500 to 27,000/l); one specimen also contained P. vivax parasites. Four specimens (from four patients) contained only sexual-stage parasites; one also contained P. ovale parasites. P. vivax parasites were detected in 52 specimens (from 49 patients) at densities of 14 to 28,500 parasites/l (median, 2,970/ l; interquartile range, 690 to 7,080/l). P. ovale was detected in four specimens (from four patients; densities, 630 to 16,930/ l), and P. malariae was detected in two specimens (from two patients; densities, 340 and 770/l).", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "Comparison of PCR with microscopy. Microscopy and PCR were concordant for 155 (98%) of 158 specimens for the detection of malaria parasites ( Table 1 ). The three discrepant specimens were PCR positive for P. falciparum but microscopy negative. Although no parasites were detected after repeated microscopic examination, these specimens probably represented true-positive results by PCR since they were obtained after initiation of treatment for microscopy-confirmed P. falciparum infection. Microscopy and PCR results were concordant for the identification to the species level of malaria parasites in 92 (99%) of 93 specimens in which parasites were detected by both techniques. The single discrepancy was identified as P. ovale by PCR but P. vivax by microscopy; subsequent blinded review of the blood film by microscopy favored a diagnosis of P. ovale.", "cite_spans": [], "ref_spans": [{"start": 142, "end": 149, "text": "Table 1", "ref_id": "TABREF1"}]}, {"section": "RESULTS", "text": "Comparison of RDTs with PCR and microscopy. The performance of the RDTs compared with the reference standards of PCR and microscopy is presented in Tables 2 and 3 . The median duration of whole-blood storage at 2 to 8\u00b0C until performance of the RDTs was 2 days (range, 0 to 12 days).", "cite_spans": [], "ref_spans": [{"start": 148, "end": 162, "text": "Tables 2 and 3", "ref_id": "TABREF2"}]}, {"section": "RESULTS", "text": "For the diagnosis of P. falciparum infections (all stages), the ICT P.f/P.v assay was significantly more sensitive than the OptiMal assay (97.5 and 75%, respectively; 2 1 \u03ed 8.54, P \u03ed 0.003). It was also more sensitive for asexual-stage P. falciparum infections (97 and 84.8%, respectively), but the difference was not statistically significant ( 2 1 \u03ed 2.92, P \u03ed 0.09). The only false-negative result with the ICT P.f/P.v assay was a specimen with a parasite density of 45/l (Table 4) . False-negative results, however, occurred with the OptiMal assay up to parasite densities of 2,500/l; below this level, only 62% of infections were detected, and for infections at less than 1,000/l, only 43% were detected ( Table 4 ). The ICT P.f/P.v and OptiMal assays were positive for all seven and one of seven specimens, respectively, with only sexual stages of P. falciparum or that were PCR positive but microscopy negative.", "cite_spans": [], "ref_spans": [{"start": 474, "end": 483, "text": "(Table 4)", "ref_id": "TABREF4"}, {"start": 710, "end": 717, "text": "Table 4", "ref_id": "TABREF4"}]}, {"section": "RESULTS", "text": "The ICT P.f/P.v assay performed poorly for the diagnosis of P. vivax infection (sensitivity, 44%); false-negative results occurred at parasite densities up to 10,000/l, and below this level only 33% of infections were detected (Table 4) . Although the OptiMal assay was significantly more sensitive than the ICT P.f/P.v assay (sensitivity, 80%; 2 1 \u03ed 13.8, P \u03fd 0.001), false-negative results still occurred at parasite densities up to 5,300/l. The ICT P.f/P.v assay failed to detect any of the P. ovale and P. malariae infections, whereas the OptiMal assay detected three of four P. ovale infections but neither of the P. malariae infections. The ICT P.f/P.v assay produced false-positive P. falciparum results in two PCR-negative specimens, whereas the OptiMal assay produced P. falciparum false-positive results in one PCRnegative specimen and two specimens containing only P. vivax parasites. No specimen gave a false-positive result in both assays. Clinical follow-up did not suggest recent or subsequent P. falciparum malaria in patients with false-positive results.", "cite_spans": [], "ref_spans": [{"start": 227, "end": 236, "text": "(Table 4)", "ref_id": "TABREF4"}]}, {"section": "RESULTS", "text": "Based on recorded intervals between specimen collection and testing, there was no evidence that false-negative or falsepositive results were related to a delay in performing RDTs.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "The diagnosis of malaria may be challenging for laboratories in countries where infection is not endemic, such that inaccuracies are relatively common (2, 13, 16) . Immunocapture RDTs that detect circulating malaria antigens have the potential to improve the accuracy and timeliness of malaria diagnosis, particularly in areas where expertise in microscopy is limited. Given that delays in the diagnosis and institution of treatment for malaria are important and potentially avoidable contributors to malaria-associated mortality (5, 19, 31) , such improvements are important priorities. Although the ICT P.f and ParaSight assays are generally highly sensitive and specific for P. falciparum infection (17, 22, 28, 30, 34) , they are unable to detect non-falciparum species. The recently developed ICT P.f/P.v and OptiMal assays can detect both P. falciparum and non-falciparum species but have not been extensively evaluated, particularly in nonimmune persons. We evaluated the performance characteristics of these two assays for malaria diagnosis in febrile travelers returning to a country where infection is not endemic. The study was designed to evaluate consecutive specimens prospectively, using the reference standards of expert microscopy and PCR as reference standards, with independent operators performing each assay while blinded to the other results.", "cite_spans": [{"start": 151, "end": 154, "text": "(2,", "ref_id": "BIBREF1"}, {"start": 155, "end": 158, "text": "13,", "ref_id": "BIBREF12"}, {"start": 159, "end": 162, "text": "16)", "ref_id": "BIBREF15"}, {"start": 530, "end": 533, "text": "(5,", "ref_id": "BIBREF4"}, {"start": 534, "end": 537, "text": "19,", "ref_id": "BIBREF18"}, {"start": 538, "end": 541, "text": "31)", "ref_id": "BIBREF30"}, {"start": 702, "end": 706, "text": "(17,", "ref_id": "BIBREF16"}, {"start": 707, "end": 710, "text": "22,", "ref_id": "BIBREF21"}, {"start": 711, "end": 714, "text": "28,", "ref_id": "BIBREF27"}, {"start": 715, "end": 718, "text": "30,", "ref_id": "BIBREF29"}, {"start": 719, "end": 722, "text": "34)", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "The ICT P.f/P.v assay was highly sensitive (97%) for the diagnosis of clinically significant P. falciparum infections (i.e., those with asexual-stage parasites), consistent with previously published evaluations of the assay in its current and previous formats (17, 24, 27, 29) . It demonstrated a low detection threshold, although only two specimens with parasite densities of \u03fd100/l were assessed. However, the assay performed particularly poorly in diagnosing P. vivax malaria (sensitivity, 44%), with false-negative results encountered for infections with densities up to 10,000 parasites/l. These results are considerably inferior to those in other reports from countries with endemic infection (27, 29) , possibly reflecting the lower parasite densities encountered in infected nonimmune patients.", "cite_spans": [{"start": 260, "end": 264, "text": "(17,", "ref_id": "BIBREF16"}, {"start": 265, "end": 268, "text": "24,", "ref_id": "BIBREF23"}, {"start": 269, "end": 272, "text": "27,", "ref_id": "BIBREF26"}, {"start": 273, "end": 276, "text": "29)", "ref_id": "BIBREF28"}, {"start": 699, "end": 703, "text": "(27,", "ref_id": "BIBREF26"}, {"start": 704, "end": 707, "text": "29)", "ref_id": "BIBREF28"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "On the other hand, the OptiMal assay demonstrated only moderate sensitivity for both P. falciparum and non-falciparum malaria, generally consistent with previous reports (7, 8, 12, 18, 21) . False-negative results occurred with P. falciparum malaria at densities up to 2,500 parasites/l and with P. vivax malaria at densities up to 5,300/l.", "cite_spans": [{"start": 170, "end": 173, "text": "(7,", "ref_id": "BIBREF6"}, {"start": 174, "end": 176, "text": "8,", "ref_id": "BIBREF7"}, {"start": 177, "end": 180, "text": "12,", "ref_id": "BIBREF11"}, {"start": 181, "end": 184, "text": "18,", "ref_id": "BIBREF17"}, {"start": 185, "end": 188, "text": "21)", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "The specificities of both assays were generally high, despite the occurrence of occasional false-positive P. falciparum detections. In addition, the specificity of the ICT P.f/P.v assay for asexual-stage P. falciparum infections suffered from the detection of all seven clinically insignificant infections (i.e., those that contained only sexual-stage P. falciparum parasites or that were PCR positive and microscopy negative).", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "LRs can be used to quantitate the impact of either a positive or a negative test result on the pretest disease probability; from knowledge of the LR and an estimate of the pretest probability, the posttest probability can be derived directly or with a nomogram (11) . Thus, LRs are of greater practical value for clinicians as performance parameters of diagnostic tests than are sensitivity, specificity, and predictive values. In general, large and generally conclusive changes in disease probability are produced by tests with LRs greater than 10 or less than 0.1 (11) . From this study, both assays have LRs for a positive test result greater than 10 for all malarial diagnoses (Table 3) ; a positive test result thus makes the likelihood of malaria very high across a wide range of pretest probabilities. In contrast, Tables 1 and 3. VOL. 40, 2002 ICT P.f/P.v AND OptiMal ASSAYS FOR MALARIA 4169 with one exception, the LRs for a negative test result with both assays are greater than 0.2; a negative test result therefore does not substantially alter the pretest disease probability. However, with an LR of 0.03, a negative ICT P.f/P.v assay result would virtually exclude the diagnosis of asexual-stage P. falciparum malaria. This study used expert microscopy and PCR as reference standards. The concordance of these standards was high; the only discrepancies involved three post-treatment specimens in which P. falciparum was detected by PCR but not by microscopy and one misidentification of P. ovale as P. vivax by microscopy. Although PCR is an impractical primary diagnostic technique because of the turnaround time, expense, and technical expertise required, its accuracy makes it an important reference standard for evaluating new diagnostic assays. RDTs have the potential to improve the accuracy and timeliness of malaria diagnosis, particularly for laboratories in countries without endemic infection, where expertise with microscopy may be limited. Consequently, such assays are becoming increasingly utilized in such settings. Given that malaria in nonimmune returned travelers is generally associated with lowlevel parasitemias of between 50 and 5,000/l (17), the relatively poor performance characteristics of RDTs at these densities demands caution regarding their use in nonimmune infected persons. The incremental utility of RDTs over nonreference microscopy in countries without endemic infection has also not been evaluated; such an evidence-based approach is required before their application can be widely recommended. On the basis of the published evaluations of these assays, the most rational potential application of RDTs in countries without endemic infection would be where expert microscopy is unavailable for the detection or exclusion of P. falciparum parasites in suspicious negative blood films or in the presence of a non-falciparum species. However, the latter situation is uncommon in Australia, since mixed infections with P. falciparum constituted only 21 (1.4%) of 1,473 malaria notifications in Australia during 1992 to 1993 (2) . Therefore, we think that the results of this study emphasize that microscopy should remain the diagnostic technique of choice for malaria diagnosis in nonimmune patients and that they also emphasize the importance of close links with a reference microscopy service where expertise is limited such as in countries where infection is not endemic. The accuracy and utility of RDTs require further investigation before their widespread adoption in such settings can be recommended.", "cite_spans": [{"start": 261, "end": 265, "text": "(11)", "ref_id": "BIBREF10"}, {"start": 566, "end": 570, "text": "(11)", "ref_id": "BIBREF10"}, {"start": 3070, "end": 3073, "text": "(2)", "ref_id": "BIBREF1"}], "ref_spans": [{"start": 681, "end": 690, "text": "(Table 3)", "ref_id": "TABREF3"}, {"start": 822, "end": 837, "text": "Tables 1 and 3.", "ref_id": "TABREF1"}]}], "bib_entries": {"BIBREF0": {"title": "Diagnostic performance characteristics of rapid dipstick test for Plasmodium vivax malaria", "authors": [{"first": "G", "middle": [], "last": "Aslan", "suffix": ""}, {"first": "M", "middle": [], "last": "Ulukanligil", "suffix": ""}, {"first": "A", "middle": [], "last": "Seyrek", "suffix": ""}, {"first": "O", "middle": [], "last": "Erel", "suffix": ""}], "year": 2001, "venue": "Mem. Inst. 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The Parasitology Department pro- vides both a primary diagnostic service for locally referred specimens and a reference service for malaria diagnosis for the state of New South Wales.", "type": "table"}, "TABREF1": {"text": "Comparison of the results of microscopy and PCRPM, P. malariae; PO, P. ovale; PV, P. vivax; PF/PV, mixed P. falciparum and P. vivax; PF/PO, mixed P. falciparum and P. ovale; NEG, negative.", "type": "table"}, "TABREF2": {"text": "Comparison of the results of the ICT P.f/P.v and OptiMal assays with PCRSee Materials and Methods for interpretation of the ICT P.f/P.v and OptiMal assays. Abbreviations are as in Table 1.", "type": "table"}, "TABREF3": {"text": "Performance characteristics of ICT P.f/P.v and OptiMal compared with PCR and microscopyMicroscopy was used as the reference standard for calculating the performance characteristics for asexual-stage P. falciparum infection; PCR was used for all other diagnoses (see Materials and Methods).", "type": "table"}, "TABREF4": {"text": "Sensitivities of the ICT P.f/P.v and OptiMal assays for the diagnosis of asexual-stage P. falciparum and P. vivax infections, stratified by parasite density", "type": "table"}}}
{"paper_id": "2877431", "_pdf_hash": "074c5dde29ded413c79e36a076a2cba486312892", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Experiments for an approach to language identification with conversational telephone speech", "authors": [{"first": "Y", "middle": [], "last": "Yan", "suffix": ""}, {"first": "E", "middle": [], "last": "Barnard", "suffix": ""}], "year": 1996, "venue": "Proceedings of the IEEE International Conference on Acoustics, Speech and Signal Processing", "link": "1165443"}, "BIBREF1": {"title": "Language identification using phoneme recognition and phonotactic language modelling", "authors": [{"first": "M", "middle": ["A"], "last": "Zissman", "suffix": ""}], "year": 1995, "venue": "Proceedings of the IEEE International Conference on Acoustics, Speech and Signal Processing", "link": "41124752"}, "BIBREF2": {"title": "Automatic language identification using large vocabulary continuous speech recognition", "authors": [{"first": "S", "middle": [], "last": "Mendoza", "suffix": ""}, {"first": "L", "middle": [], "last": "Gillick", "suffix": ""}, {"first": "Y", "middle": [], "last": "Ito", "suffix": ""}, {"first": "S", "middle": [], "last": "Lowe", "suffix": ""}, {"first": "M", "middle": [], "last": "Newman", "suffix": ""}], "year": 1996, "venue": "Proceedings of the IEEE International Conference on Acoustics, Speech and Signal Processing", "link": "1419068"}, "BIBREF3": {"title": "Discrete-Time Processing of Speech Signals", "authors": [{"first": "J", "middle": ["R"], "last": "Deller", "suffix": ""}, {"first": "J", "middle": ["G"], "last": "Proakis", "suffix": ""}, {"first": "J", "middle": ["H L"], "last": "Hansen", "suffix": ""}], "year": 1993, "venue": "", "link": "60886106"}, "BIBREF4": {"title": "Efficient high-order hidden Markov modelling", "authors": [{"first": "J", "middle": ["A"], "last": "Du Preez", "suffix": ""}], "year": 1998, "venue": "", "link": "5996876"}, "BIBREF5": {"title": "Automatic language recognition using high-order HMMs", "authors": [{"first": "J", "middle": ["A"], "last": "Du Preez", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Weber", "suffix": ""}], "year": 1998, "venue": "Proceedings of the International Conference on Spoken Language Processing", "link": "8001946"}, "BIBREF6": {"title": "Efficient mixedorder hidden Markov model inference", "authors": [{"first": "L", "middle": ["C"], "last": "Schwardt", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Du Preez", "suffix": ""}], "year": 2000, "venue": "Proceedings of the International Conference on Spoken Language Processing", "link": null}, "BIBREF7": {"title": "Efficient high-order hidden Markov modelling", "authors": [{"first": "J", "middle": ["A"], "last": "Du Preez", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Weber", "suffix": ""}], "year": 1998, "venue": "Proceedings of the International Conference on Spoken Language Processing", "link": "5996876"}, "BIBREF8": {"title": "Predicting, diagnosing and improving automatic language identification performance", "authors": [{"first": "M", "middle": ["A"], "last": "Zissman", "suffix": ""}], "year": 1997, "venue": "Proceedings of European Conference on Speech Communication and Technology", "link": "17056695"}, "BIBREF9": {"title": "Unsupervised language acquisition", "authors": [{"first": "C", "middle": ["G"], "last": "De Marcken", "suffix": ""}], "year": 1996, "venue": "", "link": null}, "BIBREF10": {"title": "Multigrams for language identification", "authors": [{"first": "S", "middle": [], "last": "Harbeck", "suffix": ""}, {"first": "U", "middle": [], "last": "Ohler", "suffix": ""}], "year": 1999, "venue": "Proceedings of European Conference on Speech Communication and Technology", "link": "245294"}, "BIBREF11": {"title": "Stochastic Complexity in Statistical Inquiry", "authors": [{"first": "J", "middle": [], "last": "Rissanen", "suffix": ""}], "year": 1989, "venue": "", "link": "9365056"}, "BIBREF12": {"title": "Automatic language identification using Gaussian mixture and hidden Markov models", "authors": [{"first": "M", "middle": ["A"], "last": "Zissman", "suffix": ""}], "year": 1993, "venue": "Proceedings of the IEEE International Conference on Acoustics, Speech and Signal Processing", "link": "7662527"}}, "ref_entries": {}}
{"paper_id": "2877446", "_pdf_hash": "e49110017d70a0c70aac79b93e0a2fb9ef46622a", "abstract": [{"section": "Abstract", "text": "We have assessed the effects of intraplantar local anaesthetics (bupivacaine and lignocaine) on carrageenan-induced oedema, mechanical allodynia and spinal c-fos protein expression. Mechanical allodynia was evaluated using the vocalization threshold to paw pressure (VTPP) every 30 min until 60, 180 or 240 min after administration of carrageenan. Peripheral oedema, mechanical allodynia and spinal c-fos protein expression were maximal 180 min after carrageenan. Lignocaine did not influence either oedema or VTPP, but reduced spinal c-fos expression at 60 min after carrageenan without later effects. Bupivacaine induced an increase in VTPP at 30 and 60 min, limitation of oedema at 60 min and a reduction in spinal c-fos expression at 60 and 180 min, but these effects were not present 240 min after carrageenan. Intraplantar infiltration with lignocaine and bupivacaine before carrageenan transiently limited signs of inflammatory pain but did not prevent them. (Br.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "Bupivacaine and lignocaine, long-and short-acting local anaesthetics respectively, are used in both acute and chronic pain therapy (see references in Bonica and Butler 1 ). There is evidence that pain processing may be reduced by pre-administration of various agents (e.g. opioids, local anaesthetics, non-steroidal anti-inflammatory drugs (NSAID)) leading to the concept of pre-emptive analgesia. 2 However, this concept is still debated 3 and few clinical studies have confirmed the clinical significance of pre-emptive analgesia. [4] [5] [6] Administration of local anaesthetics before tissue injury may prevent peripheral and central sensitization of the nervous system induced by nociceptive input (see references in Coderre and colleagues 4 ). The pre-emptive analgesic effect of local anaesthetics has been observed in different animal models of pain (see references in Coderre and colleagues 4 ). In this study, we have investigated the possible pre-emptive effects of local anaesthetics (lignocaine and bupivacaine) in the carrageenan model of inflammatory pain in rats. 7 As shown previously, intraplantar injection of carrageenan induces ipsilateral inflammation (see references in Kocher and colleagues 8 ) associated with mechanical allodynia 9 and c-fos-protein-like immunoreactivity (c-fos LI) in the ipsilateral dorsal horn of the spinal cord. [10] [11] [12] The method based on the immunoreactivity of c-fos-protein is used widely as a form of neuronal-activity mapping (see references in Morgan and Curran 13 ). For a recent review of the mechanisms of expression of c-fos protein within the nervous system see Hughes and Dragunow. 14 Many studies following the original report 15 have provided evidence that various noxious stimulations evoked expression of c-fos protein in spinal neurones (see references in Zimmermann and Herdegen 16 ), thus providing an indirect marker of neurones involved in spinal nociceptive transmission. In our previous studies, we used immunohistochemical revelation of spinal c-fos expression in the carrageenan model of inflammatory pain to assess the effects of analgesic/anti-inflammatory drugs, including systemic 17 and intraplantar 18 morphine and various systemic NSAID (see Buritova and colleagues 19 and references therein). In this study, we have combined behavioural and immunohistochemical approaches to investigate the effects of pre-administered intraplantar local anaesthetics in carrageenan-induced inflammatory pain in rats.", "cite_spans": [{"start": 533, "end": 536, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 537, "end": 540, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 541, "end": 544, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 1360, "end": 1364, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 1365, "end": 1369, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 1370, "end": 1374, "text": "[12]", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "Materials and methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "EXPERIMENTAL ANIMALS", "text": "Experiments were performed on 52 adult male albino Sprague-Dawley rats (Charles River, France; 48 carrageenan-stimulated and four non-stimulated rats), weighing 225-250 g. Rats were acclimatized to the laboratory for 8 days before the experiment. Rats were tested using the vocalization threshold to paw pressure (VTPP) and were trained in the experimental conditions during the last 2 days before the experiment. The ethics guidelines of the IASP were followed for investigations of experimental pain in conscious animals. 20 ", "cite_spans": [], "ref_spans": []}, {"section": "DRUG ADMINISTRATION", "text": "Peripheral inflammation was induced by intraplantar injection of carrageenan (-carrageenan, Sigma; 6 mg per 150 l of saline (0.9% NaCl)) in the right hind paw of the non-anaesthetized rat. In this study, control rats receiving intraplantar injection of saline were not included as we have shown previously negligible spinal c-fos expression after intraplantar saline (:5 c-fos LI neurones per section L4-L5) which was not significantly different from that observed in non-stimulated rats. 12 The preliminary unpublished study demonstrated that intraplantar administration of local anaesthetics (0.5% Marcaine, 2% xylocaine) without carrageenan injection did not induce spinal c-fos expression significantly different from that observed in intraplantar saline injected rat (:5 c-fos LI neurones per section L4-L5).", "cite_spans": [], "ref_spans": []}, {"section": "DRUG ADMINISTRATION", "text": "Intraplantar bupivacaine (0.5% Marcaine, Astra, France) and lignocaine (2% Xylocaine, Astra, France) were injected into the right hind paw of nonanaesthetized rats (200 l for both drugs) 5 min before intraplantar injection of carrageenan. The timing, concentration and volume of local anaesthetic were chosen according to a previous study to obtain complete anaesthesia of the paw before injection of carrageenan. 21 Control carrageenan rats received 200 l of saline under the same experimental conditions. Intraplantar injections of carrageenan or local anaesthetic were made subcutaneously with a 25-gauge needle.", "cite_spans": [], "ref_spans": []}, {"section": "MEASUREMENT OF CARRAGEENAN-INDUCED PERIPHERAL OEDEMA", "text": "Two indicators of peripheral oedema, ankle and paw diameters, were measured with a calliper square, immediately before perfusion at 60, 180 or 240 min after injection of carrageenan. Ankle and paw diameters of carrageenan-stimulated and nonstimulated rats were measured. Oedema was determined as percentage increases in ankle and paw diameters of carrageenan-treated rats compared with non-stimulated rats.", "cite_spans": [], "ref_spans": []}, {"section": "TEST OF VOCALIZATION THRESHOLD TO PAW PRESSURE", "text": "The vocalization threshold to paw pressure (VTPP) was measured using a Basile Analgesimeter (Apelex, tip diameter of the probe : 1 mm) according to a method adapted from the Randall-Selitto description. 22 All VTPP measurements were performed blind by the same investigator. For each rat, the thresholds for vocalization (mean of two values), expressed in grams (g), were determined by applying increasing pressure to the right hind paw until an audible squeak was elicited. A control value was determined before injection of carrageenan. We then determined, at each time after carrageenan, two stable consecutive thresholds, which were averaged. This criterion of the VTPP was chosen according to a previous study, 22 as it represents a more integrated nociceptive behaviour than paw withdrawal. The choice of a cut-off value was necessary to limit injury to the paw and excessive stimulation of the nociceptors. The cut-off value was 600 g and was considered sufficient to represent an anaesthetic state.", "cite_spans": [], "ref_spans": []}, {"section": "IMMUNOHISTOCHEMISTRY FOR EVALUATION OF SPINAL C-FOS PROTEIN EXPRESSION", "text": "As demonstrated previously, carrageenan-evoked spinal c-fos expression was detected at 60 min 17 and was maximal at 180 min 12 after intraplantar injection of carrageenan. Therefore, in this study of the time course of the local anaesthetic effects, rats were perfused at various times after injection of carrageenan: 60, 180 and 240 min, immediately after the last test of VTPP. As described previously (see references in Buritova and colleagues 19 ), rats were deeply anaesthetized (pentobarbitone (Sanofi) 55 mg kg 91 i.p.) and perfused intracardially with phosphate-buffered saline (PBS) 0.1 mol litre 91 followed by 4% paraformaldehyde in phosphate buffer (PB) 0.1 mol litre", "cite_spans": [], "ref_spans": []}, {"section": "91", "text": ". The spinal cord was removed, post-fixed for 4 h and cryoprotected in 30% sucrose overnight. Frozen serial frontal sections (40 m) of the lumbar L4-L5 segments were cut. Immunohistochemistry of the free floating sections was performed with polyclonal antiserum, generated in rabbits, directed against the c-fos protein (Oncogene Science Inc., Ab-2 solution 0.1 mg ml 91 diluted 1:4000), using the conventional avidin-biotin-peroxidase complex method with visualization by 1-naphthol ammonium carbonate solution (for more details see methods in Buritova and colleagues 19 ).", "cite_spans": [], "ref_spans": []}, {"section": "COUNTING OF SPINAL C-FOS L1 NEURONES", "text": "As described previously (see Buritova and colleagues 19 and references therein), distribution of c-fos LI neurones was studied in four defined regions: superficial laminae (laminae I-II), nucleus proprius (laminae III-IV) and neck (laminae V-VI) of the dorsal horn and, in addition, ventral horn (laminae VII-X; ventral) of the spinal cord. For each rat, two counts were made: (1) the total number of c-fos LI neurones in the grey matter for 10 sections through L4-L5 segments, and (2) in these 10 sections, the number of c-fos LI neurones in the four defined regions. Plotting and counting the c-fos LI neurones were performed blind to the experimental condition. Statistical analysis was performed using analysis of variance (ANOVA) and the Fisher's protected least squares difference test (Fisher's PLSD test) for multiple comparisons. The effects of local anaesthetics on peripheral oedema, VTPP and number of spinal c-fos LI neurones were determined compared with controls (control group).", "cite_spans": [], "ref_spans": []}, {"section": "EXPERIMENTAL DESIGN", "text": "To evaluate the time course of the effects of local anaesthetics on carrageenan-induced inflammatory nociceptive processing, the experiment was per-formed in three different series. In each series, rats were perfused immediately after the last test of VTPP.", "cite_spans": [], "ref_spans": []}, {"section": "EXPERIMENTAL DESIGN", "text": "In the first series (n : 18), rats in the control, lignocaine and bupivacaine groups were tested for VTPP every 30 min for 60 min after administration of carrageenan at which time rats were perfused. In the second series (n : 18), rats in the control, lignocaine and bupivacaine groups were tested for VTPP every 30 min for 180 min after administration of carrageenan at which time rats were perfused. In the third series (n : 12), control and bupivacaine groups were tested for VTPP every 30 min for 240 min after administration of carrageenan at which time rats were perfused. In this series, the lignocaine group was not included as intraplantar pre-administration of lignocaine was not efficacious as early as 180 min after carrageenan administration.", "cite_spans": [], "ref_spans": []}, {"section": "EXPERIMENTAL DESIGN", "text": "In these experimental series, three distinct groups of rats were defined: in the control group (n : 6 for each time), rats received saline 200 l, 5 min before administration of carrageenan and were tested for VTPP after carrageenan; in the bupivacaine group (n : 6 for each time) rats received bupivacaine 200 l, 5 min before carrageenan and were tested for VTPP after carrageenan; in the lignocaine group (n : 6 for each time) rats received lignocaine 200 l, 5 min before carrageenan and were tested for VTPP after carrageenan.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "DEVELOPMENT OF CARRAGEENAN-EVOKED OEDEMA", "text": "In the control group, 60, 180 and 240 min after intraplantar administration of carrageenan, both paw (0.8 (SEM 0.1), 1.1 (0.1) and 1.1 (0.1) cm, respectively) and ankle (0.8 (0.1), 1.2 (0.1) and 1.1 (0.1) cm, respectively) diameters were increased significantly compared with carrageenan nonstimulated rats (mean values for paw and ankle diameters: 0.5 (0.1) and 0.7 (0.1) cm, respectively). Inflammatory oedema was not present in the contralateral hind paw at each time.", "cite_spans": [], "ref_spans": []}, {"section": "DEVELOPMENT OF CARRAGEENAN-EVOKED OEDEMA", "text": "At 60 min after carrageenan, in the bupivacaine group, carrageenan-evoked ankle oedema (0.75 (0.02) cm) was reduced slightly compared with the control group (P : 0.01) but paw oedema was not influenced. Bupivacaine had no effect on paw or ankle oedema at 180 and 240 min after carrageenan.", "cite_spans": [], "ref_spans": []}, {"section": "DEVELOPMENT OF CARRAGEENAN-EVOKED OEDEMA", "text": "In the lignocaine group, paw and ankle oedema were not influenced at each time after carrageenan.", "cite_spans": [], "ref_spans": []}, {"section": "CARRAGEENAN-EVOKED DECREASE OF VTPP", "text": "The results were similar for the three series and were therefore pooled (see fig. 1 ).", "cite_spans": [], "ref_spans": [{"start": 77, "end": 83, "text": "fig. 1", "ref_id": "FIGREF0"}]}, {"section": "CARRAGEENAN-EVOKED DECREASE OF VTPP", "text": "Intraplantar carrageenan decreased VTPP at each time, with a final decrease to 35% of control values at 240 min after carrageenan ( fig. 1) . Overall, VTPP decreased from 288 (7) g at time 0 min, to 100 (3) g at 240 min after carrageenan ( fig. 1 ).", "cite_spans": [], "ref_spans": [{"start": 132, "end": 139, "text": "fig. 1)", "ref_id": "FIGREF0"}, {"start": 240, "end": 246, "text": "fig. 1", "ref_id": "FIGREF0"}]}, {"section": "CARRAGEENAN-EVOKED DECREASE OF VTPP", "text": "In the lignocaine group, VTPP never reached the cut-off value at each time after carrageenan. At 60 and 180 min after carrageenan, VTPP decreased to 76% and 37% of control values, respectively, reflecting the development of mechanical allodynia. Overall, VTPP decreased from 287 (6) g at time 0 min to 108 (9) g at 180 min after carrageenan ( fig. 1 ).", "cite_spans": [], "ref_spans": [{"start": 343, "end": 349, "text": "fig. 1", "ref_id": "FIGREF0"}]}, {"section": "CARRAGEENAN-EVOKED DECREASE OF VTPP", "text": "In the bupivacaine group, VTPP reached the cutoff value in 95% of rats at 60 min after carrageenan. At later times, 180 and 240 min, VTPP decreased to 37% and 35% of control values, respectively. Overall, VTPP decreased from 287 (6) g at time ", "cite_spans": [], "ref_spans": []}, {"section": "TIME COURSE OF CARRAGEENAN-EVOKED SPINAL C-FOS EXPRESSION", "text": "In the control group, the total number of c-fos LI neurones was greatly increased in the ipsilateral spinal cord at 60, 180 and 240 min after carrageenan ( fig. 2, fig. 4A ; table 1). At all times after carrageenan, spinal c-fos LI neurones of the control group were located predominantly in laminae I-II and V-VI of the dorsal horn of the lumbar spinal cord ( fig. 2, fig. 4B ,C, table 1). At 60, 180 and 240 min after carrageenan, the number of c-fos LI neurones in the nucleus proprius (laminae III-IV: 6 (1), 10 (2) and 8 (1) c-fos LI neurones per L4-L5 section, respectively) was moderate compared with the total number of c-fos LI neurones per L4-L5 section (101 (8), 200 (15) and 141 (6), respectively) (table  1) . At each time, c-fos LI neurones were almost absent in the contralateral spinal cord (:5 c-fos LI neurones per L4-L5 section). At 60 min after intraplantar carrageenan, carrageenan-evoked spinal c-fos expression in the bupivacaine and lignocaine groups was significantly different from that observed in the control group, for both the total number of c-fos LI neurones in segments L4-L5 (F (3, 20) : 16.17; P : 0.001) and their laminar distribution (F (3, 80) : 34.20; P : 0.001). Intraplantar pre-administration of both bupivacaine and lignocaine reduced the total number of c-fos LI neurones induced at 60 min after carrageenan (60 (3) % and 37 (6) % reduction of control group values, respectively; P : 0.001 for both drugs) ( fig. 4A, table 1) . Furthermore, in both the bupivacaine and lignocaine groups, the significant reduction in the number of superficial (laminae I-II: 63 (6) % and 44 (6) % reduction of control group values, respectively; P : 0.001 for both drugs) ( fig. 3 ) and deep (laminae V-VI: 59 (3) % and 39 (5) % reduction of control group values, respectively; P : 0.001 for both drugs) c-fos LI neurones was observed at 60 min after carrageenan ( fig. 4B,C, table 1) . Therefore, intraplantar pre-administration of both bupivacaine and lignocaine had a similar effect on the number of superficial and deep c-fos LI neurones induced at 60 min after carrageenan (table 1).", "cite_spans": [], "ref_spans": [{"start": 156, "end": 171, "text": "fig. 2, fig. 4A", "ref_id": "FIGREF2"}, {"start": 361, "end": 376, "text": "fig. 2, fig. 4B", "ref_id": "FIGREF2"}, {"start": 1452, "end": 1469, "text": "fig. 4A, table 1)", "ref_id": "FIGREF0"}, {"start": 1701, "end": 1707, "text": "fig. 3", "ref_id": "FIGREF3"}, {"start": 1892, "end": 1911, "text": "fig. 4B,C, table 1)", "ref_id": "FIGREF0"}]}, {"section": "TIME COURSE OF CARRAGEENAN-EVOKED SPINAL C-FOS EXPRESSION", "text": "In the bupivacaine group, a significant reduction in the total number of c-fos LI neurones induced at 180 min after intraplantar carrageenan was observed (29 (4)% reduction of control group values; P : 0.01) (fig. 4A, table 1 ). This effect resulted from a significant reduction in the number of deep c-fos LI neurones (31 (5) % reduction of control group values; P : 0.001) without effect on the superficial laminae ( fig. 4B,C, table 1 ). In contrast, in the lignocaine group, the number of spinal c-fos LI neurones induced at 180 min after carrageenan was not affected (table 1) .", "cite_spans": [], "ref_spans": [{"start": 208, "end": 225, "text": "(fig. 4A, table 1", "ref_id": "FIGREF0"}, {"start": 419, "end": 437, "text": "fig. 4B,C, table 1", "ref_id": "FIGREF0"}]}, {"section": "TIME COURSE OF CARRAGEENAN-EVOKED SPINAL C-FOS EXPRESSION", "text": "Intraplantar pre-administration of bupivacaine did not influence spinal c-fos expression induced at 240 min after carrageenan (table 1). As intraplantar lignocaine did not influence spinal c-fos expression at 180 min after carrageenan, the study Figure 4 Effects of intraplantar 0.5% bupivacaine (G) and 2% lignocaine (I) on the number of c-fos LI neurones in the L4-L5 segments of the rat spinal cord at 1, 3 and 4 h after intraplantar carrageenan. Results are expressed as absolute mean (SEM) of (A) total number of carrageenan evoked c-fos LI neurones per section of segments L4-L5 and number of superficial (B) and deep (C) c-fos LI neurones per section for each region in the L4-L5 segments, 3 h after intraplantar carrageenan. Significance compared with control group (\u232c) was performed using ANOVA and Fisher's PLSD test (**P : 0.01, ***P : 0.001). The study of the effect of lignocaine at 4 h was not performed. of its effect at 240 min after carrageenan was not performed.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Intraplantar administration of a long-acting local anaesthetic, bupivacaine, postponed mechanical allodynia and spinal c-fos protein expression associated with the inflammatory state induced by intraplantar injection of carrageenan in rats, while a short-acting local anaesthetic, lignocaine, reduced only transiently carrageenaninduced spinal c-fos protein expression. Overall, the effects of intraplantar bupivacaine and lignocaine in the carrageenan model of inflammatory pain were related to the duration of action of the anaesthetics.", "cite_spans": [], "ref_spans": []}, {"section": "TIME COURSE OF VOCALIZATION THRESHOLD AND OEDEMA", "text": "In accordance with previous studies (Kayser and Guilbaud 9 , see references in Buritova and colleagues 19 ) intraplantar injection of carrageenan induced ipsilateral oedema, without influencing the contralateral hind paw, at all times. The lack of effect of pre-administered intraplantar 2% lignocaine 200 l on either oedema or VTPP after carrageenan was in concordance with previous studies showing the short duration of the antinociceptive effect of similar doses of lignocaine in behavioural experiments using the carrageenan model of inflammatory pain (18 min after 2% lignocaine 50 l . In a carrageenan model of inflammatory pain, analgesia was defined previously as VTPP within the range of usual variability of the control value in normal situations (i.e. 85-115% of control value 9 ). In this study, the duration of analgesic action of 0.5% bupivacaine 200 l was estimated to be 55 (16) min after carrageenan. Similarly, preadministered intraplantar bupivacaine reduced ankle oedema evoked at 60 min after carrageenan but this effect did not persist. The combined effect of bupivacaine on extension of oedema and reduction of VTPP may be related, at least in part, to the transient abolition of the axon reflex involved in the development and extension of inflammation 24 . The mechanism of action of bupivacaine involves binding of bupivacaine to voltage-dependent Na ; channels which reduces neuronal transmission, axon reflex and consequently development of inflammation (see Butterworth and Strichartz 25 and references therein). In addition, local anaesthetics have been shown to block peripheral release of inflammatory substances such as substance P. 26 Thus the mechanisms mentioned above may be involved in the transient peripheral anti-inflammatory effect of intraplantar bupivacaine. The limited extent of peripheral oedema in the bupivacaine group, at 60 min after carrageenan, corresponded to the peripheral analgesic effect of bupivacaine during the period of its action. Overall, the peripheral effects of local anaesthetics probably reduced the nociceptive inputs and consequently influenced carrageenaninduced spinal c-fos expression.", "cite_spans": [], "ref_spans": []}, {"section": "TIME COURSE OF SPINAL C-FOS EXPRESSION", "text": "In the control group, spinal c-fos expression at 60, 180 and 240 min after intraplantar carrageenan was in agreement with our previous study showing the time course of spinal c-fos expression in the same model of inflammatory pain (see references in Buritova and colleagues 19 ). This carrageenan evoked spinal c-fos expression was localized predominantly in the superficial (I-II) and deep (V-VI) laminae of the dorsal horn of the spinal cord in accordance with the spinal areas containing neurones activated by noxious stimuli driven by C-and A\u2426-fibres 27 which evoked the spinal c-fos expression. 28 Pre-administration of lignocaine attenuated spinal c-fos expression in both superficial and deep laminae at 60 min after carrageenan. This effect did not persist and the maximal number of c-fos neurones similar to the control group was reached at 180 min after carrageenan. This effect is in keeping with an electrophysiological study showing that administration of 2% lignocaine 50 l s.c. into the site of peripheral injection of formalin completely blocked the first phase of the response to formalin of the deep dorsal horn neurones (about the first 10 min) without affecting second phase activity. 29 Thus 2% lignocaine 50-200 l seems to be sufficient to prevent transmission of nociceptive inputs during the initial phase of nociceptive primary afferent activation with consequent attenuation of the time pattern of spinal c-fos expression. In this study, the reduced number of c-fos LI neurones at 60 min may reflect both a short duration of block of noxious input produced by lignocaine at the initial phase of inflammation and c-fos protein synthesis delay related to delay of c-fos messenger RNA (mRNA) expression about 30 min after carrageenan. 30 In the bupivacaine group, the reduction in spinal c-fos expression in both superficial and deep laminae was observed 60 min after carrageenan. At 180 min after carrageenan when the reduction in VTPP, reflecting mechanical allodynia, was equivalent to control group values, c-fos expression in the superficial laminae was similar to the control group. However, at this time the total number of c-fos LI neurones and c-fos expression in deep laminae were lower than in the control group. This laminar pattern is not surprising as c-fos protein is initially expressed in superficial neurones, and subsequently in the neurones in the deep laminae of the spinal dorsal horn at a later phase of noxious stimulus transmission, as has been shown after intraplantar injection of formalin 31 and carrageenan. 12 17 Thus, in this study, the laminar pattern of carrageenaninduced spinal c-fos expression, influenced by intraplantar administration of both bupivacaine and lignocaine, may result from peripheral block of nociceptive input by local anaesthetics and consequently delayed c-fos expression at the spinal cord level.", "cite_spans": [], "ref_spans": []}, {"section": "TIME COURSE OF SPINAL C-FOS EXPRESSION", "text": "Interestingly, the effect of pre-administered intraplantar bupivacaine on the laminar pattern of carrageenan-induced spinal c-fos expression at 60 min after carrageenan was similar to that observed with pre-administered intraplantar morphine 18 and various systemic NSAID (see references in Buritova and colleagues 19 ) observed previously in the same experimental paradigm at 180 min after carrageenan. In these previous studies, the period of 180 min after intraplantar carrageenan had been covered by activity of the analgesic/anti-inflammatory drugs which resulted in reduction of c-fos expression in both superficial and deep laminae of the spinal dorsal horn. Overall, during the period of drug activity, both bupivacaine (60 min after carrageenan) and analgesic/anti-inflammatory drugs (180 min after carrageenan (see references in Buritova and colleagues 19 ) had a similar effect on reducing spinal c-fos expression in both superficial and deep laminae. In contrast, after the period of drug activity (e.g. at 180 min after carrageenan), administration of bupivacaine induced a dissociative laminar pattern of spinal c-fos expression without effect on c-fos expression in superficial laminae. This dissociative effect of bupivacaine was similar to that described previously with the NMDA receptor antagonist, ( ; )-HA966, in the same experimental paradigm. 32 Interestingly, bupivacaine and ( ; )-HA 966 33 have a similar duration of antinociceptive effect (about 60 min).", "cite_spans": [], "ref_spans": []}, {"section": "TIME COURSE OF SPINAL C-FOS EXPRESSION", "text": "In this study, the absence of persistent effects of intraplantar local anaesthetic on both behavioural nociceptive test and spinal c-fos expression in the superficial laminae does not support the hypothesis of efficacy of pre-emptive analgesia. However, the reduction in both total and deep laminae c-fos expression by bupivacaine may have an influence on the development of chronic pain states but additional studies are required to test this hypothesis.", "cite_spans": [], "ref_spans": []}, {"section": "LOCAL ANAESTHETICS AND PREVENTION OF PAIN", "text": "In this study we used parallel behavioural and immunohistochemical approaches to assess the possible pre-emptive effect of local anaesthetics. The reduction in spinal c-fos expression in both the superficial and deep laminae at 60 min suggests that local anaesthetic pre-infiltration interrupted nociceptive inputs during the initial phase of carrageenan inflammation. However, a longer block may be necessary to reveal a pre-emptive analgesic effect of local anaesthetics. Thus an increase in the dose of local anaesthetic used for infiltration or a nerve block technique may be proposed. Unfortunately, re-injection in this study would have been toxic (1 mg of bupivacaine was already injected; i.e. more than 4 mg kg", "cite_spans": [], "ref_spans": []}, {"section": "91", "text": "). Furthermore, we have previously used 0.5% bupivacaine with adrenaline or higher doses (5 mg of bupivacaine instead of 1 mg in 200 l) of bupivacaine included in microspheres 34 which produced, respectively, a 100% 21 and 175% (unpublished data) increase in analgesia related to infiltration but without a pre-emptive effect detected by behavioural tests in the same carrageenan model. In contrast, the intervention required for nerve block may induce additional nociceptive stimulation which influences carrageenan-induced spinal c-fos expression and consequently impairs the homogeneity of control values. In addition, the behavioural test used in this study (vocalization threshold to paw pressure) may be difficult to evaluate when there is total paralysis of the limb.", "cite_spans": [], "ref_spans": []}, {"section": "91", "text": "The development of inflammatory nociception induced by intraplantar carrageenan in the rat is comparable to the time course of postoperative pain (24-96 h) and it might explain the similar results of this study and clinical studies on pre-emptive analgesia with local anaesthetic infiltration of the site of superficial surgery (see references in Dahl and Kehlet 5 ). Our results extend clinical studies showing that pre-emptive anaesthesia with infiltration by local anaesthetics has no long-term benefits for postoperative analgesia (see references in Dahl and Kehlet 5 ). In summary, the effects of intraplantar pre-administration of bupivacaine and lignocaine on carrageenan-induced mechanical allodynia did not persist beyond the direct local anaesthetic effect. 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From 0 to 60 min: n : 18; from 60 to 180 min: n : 12; from 180 to 240 min: n : 6. Results are expressed as absolute mean (SEM) of the threshold value, each 30 min after intraplantar carrageenan. Significance compared with control group (\u232c) was performed using ANOVA and Fisher's PLSD test (***P : 0.001). The study of the effect of lignocaine at 4 h was not performed.", "type": "figure"}, "FIGREF1": {"text": "Effects of intraplantar 0.5% bupivacaine and 2% lignocaine on the number of c-fos LI neurones in the superficial (I-II) and deep (V-VI) laminae of the dorsal horn and in the ventral horn (Ventral) of the L4-L5 segments of the rat spinal cord at 1, 3 and 4 h after intraplantar carrageenan. Results are expressed as the absolute mean (SEM) of the number of c-fos LI neurones per section for each region. Significance of the effects of both anaesthetics, compared with the control group, was performed using ANOVA and Fisher's PLSD test (**P:0.01, ***P:0.001). The effect of lignocaine at 4 h was not performed No. c-fos/LI neurones/section of L4-15) 59 (4) 87 (6) 43 (5) 141 (6) 51 (2) 54 (4) 27 (1) Bupivacaine 40 (3)*** 16 (3)*** 16 (1)*** 5 (1)*** 143 (8)** 49 (2) 60 (5)*** 28 (3)** 130 (12) 45 (4) 51 (4) 27 (to 100 (3) g at 240 min after carrageenan (fig. 1). The mean duration of analgesic effect of bupivacaine was 55 (16) min.", "type": "figure"}, "FIGREF2": {"text": "Figure 2 Camera lucida drawings of individual sections (40 m) of the L4-L5 segments of the rat spinal cord showing effects of intraplantar 0.5% bupivacaine and 2% lignocaine on the number of spinal c-fos LI neurones, at 1, 3 and 4 h after intraplantar administration of carrageenan. The boundaries of the superficial laminae and the reticular part of the neck of the dorsal horn are outlined; each dot represents one c-fos labelled nucleus (one c-fos LI neurone).", "type": "figure"}, "FIGREF3": {"text": "Figure 3 Microphotographs of superficial laminae of spinal dorsal horn showing reducing effects of intraplantar 0.5% bupivacaine and 2% lignocaine on the number of c-fos LI neurones, 1 h after intraplantar carrageenan in rats. Each microphotograph is an individual example, including labelled nuclei of c-fos LI neurones in superficial laminae (laminae I-II) per section (40 m) of L4-L5 segments of the spinal cord; scale bar : 100 m. A : Control; B : 0.5% bupivacaine; C : 2% lignocaine.", "type": "figure"}}}
{"paper_id": "2877491", "_pdf_hash": "3aaa2125f17333f1e8d416e6e79b371119268325", "abstract": [{"section": "Abstract", "text": "Health literacy has been associated with adherence to antiretroviral therapy (ART) in HIV-infected adults, but this association has not been demonstrated in HIV-infected adolescents. Using an expanded health literacy model, we examined the relationship between health literacy, functional literacy, beliefs about ART, media use, and adherence to ART. A convenience sample of HIVinfected adolescents (n = 50) was recruited for this cross sectional study. The primary outcome of adherence was measured with 3-day self-reports. Health literacy as measured by the Test of Functional Health Literacy in Adults (TOFHLA) was not predictive of adherence (p = .15). Participants with higher positive outcome expectancy scores regarding ART were more likely to report 100% adherence, and participants with below grade level reading were less likely to report 100% adherence (p < .05). Our findings highlight the importance of assessing both health beliefs and reading skills as part of adherence support for HIV-infected youth.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "\u00a9 2012 Association of Nurses in AIDS Care. Published by Elsevier Inc. All rights reserved. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "The authors report no real or perceived vested interests that relate to this article (including relationships with pharmaceutical companies, biomedical device manufactures, grantors, or other entities whose products or services are related to subjects covered in this manuscript) that could be constructed as a conflict of interest. Among HIV-infected adults, lower health literacy has been associated with higher serum viral loads, decreased CD4+ T lymphocyte cell counts, and poor adherence to antiretroviral therapy (ART; Kalichman, Cherry, & Cain, 2005; Kalichman & Rompa, 2000) . Suboptimal adherence is associated with the development of resistance to ART and subsequent reduction of treatment options (Williams et al., 2006) ; it is one of the main causes of ART failure (Paterson et al., 2000; Sethi, Celentano, Gange, Moore, & Gallant, 2003) . Treatment of HIV infection with ART has resulted in significant reductions in HIV-related morbidity and mortality (El-Sadr et al., 2006; Helleberg et al., 2012), further highlighting the importance of optimal adherence.", "cite_spans": [{"start": 525, "end": 557, "text": "Kalichman, Cherry, & Cain, 2005;", "ref_id": "BIBREF17"}, {"start": 558, "end": 582, "text": "Kalichman & Rompa, 2000)", "ref_id": "BIBREF18"}, {"start": 708, "end": 731, "text": "(Williams et al., 2006)", "ref_id": "BIBREF40"}, {"start": 778, "end": 801, "text": "(Paterson et al., 2000;", "ref_id": "BIBREF32"}, {"start": 802, "end": 850, "text": "Sethi, Celentano, Gange, Moore, & Gallant, 2003)", "ref_id": "BIBREF36"}, {"start": 967, "end": 989, "text": "(El-Sadr et al., 2006;", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Abstract", "text": "In the adolescent population there is limited research on the relationship between health literacy and health outcomes; most research to date on adolescents has focused on functional literacy or ability to read and write rather than health literacy (Manganello, 2008) . Health literacy has been described as the skill to gain access to, understand, and use information in ways that promote and maintain health (Nutbeam, 1998) and therefore must be viewed in the broader context of individual factors, language, and culture (Institute of Medicine, 2009).", "cite_spans": [{"start": 249, "end": 267, "text": "(Manganello, 2008)", "ref_id": "BIBREF21"}, {"start": 410, "end": 425, "text": "(Nutbeam, 1998)", "ref_id": "BIBREF29"}], "ref_spans": []}, {"section": "Abstract", "text": "For example, the current generation of youth has unprecedented access to the larger world due to advances in media and technology (Brown & Bobkowski, 2011) and commonly uses the Internet to gain health-related information (Gray, Klein, Noyce, Sesselberg, & Cantrill, 2005) . Yet adolescents will only obtain maximum benefit if they are able to search for, evaluate, and use online Internet information effectively. Individual beliefs surrounding health care are also an important component of health-related decision-making, and perceived threat of illness has been shown to be predictive of better ART adherence in behaviorally HIV-infected youth (Garvie et al., 2011) . A single study in HIV-infected teens reported no significant association between health literacy and adherence to ART (Murphy et al., 2010). These findings, however, were inconsistent with results of a study with HIVinfected adults, where a robust relationship between health literacy and adherence was demonstrated (Kalichman et al., 2008) . The primary objective of this exploratory study was to examine the relationship between health literacy, functional literacy, beliefs about antiretroviral (ARV) medications, media use, and adherence to ART in HIV-infected adolescents (ages 13-24 years). ", "cite_spans": [{"start": 130, "end": 155, "text": "(Brown & Bobkowski, 2011)", "ref_id": "BIBREF2"}, {"start": 222, "end": 272, "text": "(Gray, Klein, Noyce, Sesselberg, & Cantrill, 2005)", "ref_id": "BIBREF12"}, {"start": 648, "end": 669, "text": "(Garvie et al., 2011)", "ref_id": "BIBREF9"}, {"start": 988, "end": 1012, "text": "(Kalichman et al., 2008)", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Abstract", "text": "This was a multi-site cross-sectional descriptive survey design study. Potential predictors of adherence to ART were analyzed in a sample of 50 HIV-infected adolescents.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "A convenience sample of youth with HIV infection was recruited from four HIV specialty clinical settings; both perinatally (mother-to-child) and behaviorally infected youth were eligible. Criteria for study participation were: HIV seropositive status, ages 13-24 years, fully disclosed of HIV diagnosis, English speaking, current treatment with a prescribed ART regimen for 6 months or longer, and absence of major neurocognitive deficits allowing for completion of survey instruments.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "After approval by the appropriate institutional review boards (IRB), recruitment of eligible participants from four HIV specialty clinics occurred from September 2010 through April 2011. Clinical sites were affiliates of a large, urban, academic health care center. Informed consent and/or assent were obtained from all study participants in accordance with the regulations specific to the protection of study volunteers of the IRB at each institution. If the study candidate was between the ages of 13 and 17 years, the research study was described in detail by the principal investigator or physician collaborator to both the eligible participant and his or her parent/legal guardian; signed written and verbal assent was then obtained. Eligible participants ages 18 years and older were able to provide signed written and verbal consent in the absence of a parent/legal guardian. During the consent process, participants were given an opportunity to ask questions and at study completion were compensated with a $20.00 gift card.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Screening for study eligibility was performed with the Mini Mental Health State Exam (MMSE) and Rosenbaum hand held vision card. The MMSE (Folstein, Folstein, & McHugh, 1975 ) was used to assess neurocognitive deficits. A cut-off score of 24 was selected because in the one known study to date with HIV-infected youth, a score of less than 24 was used to identify HIV dementia (Lyon, McCarter, & D'Angelo, 2009) . Visual screening was performed as recommended as a preliminary procedure for the TOFHLA.", "cite_spans": [{"start": 138, "end": 173, "text": "(Folstein, Folstein, & McHugh, 1975", "ref_id": "BIBREF8"}, {"start": 377, "end": 411, "text": "(Lyon, McCarter, & D'Angelo, 2009)", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Abstract", "text": "The TOFHLA is a validated health literacy-screening tool that measures both numeracy and literacy. Classification of health literacy scores is categorized into three levels, inadequate (0-59), marginal (60-74), and adequate (75-100; Parker, Baker, Williams, & Nurss, 1995) . Adequate reliability of the shortened version TOFHLA (S-TOFHLA) has been reported in the adolescent HIV-infected population (Cronbach's alpha > 0.7); the numeracy component of the S-TOFHLA has been described as less reliable in HIV-infected youth (alpha = 0.56; Murphy et al., 2010) . Therefore, the full version TOFHLA was selected for use in this study. Rapid Estimate of Adult Literacy in Medicine-teen (REALM-teen)-REALM-teen is a brief and reliable word recognition measure designed to predict general reading ability in health care settings among teens in sixth through twelfth grades (Davis et al., 2006) , consisting of 66 health related words arranged in increasing order of difficulty. Adolescents are asked to speak the word aloud, in the order listed. The total score is based on the number of words pronounced correctly and is related to grade level. The internal consistency is excellent (Cronbach's alpha = 0.94) with strong test-retest reliability (r = 0.98); the REALM-teen has high criterion based validity, when correlated with the Wide Range Achievement Test, third Edition (WRAT-3; r = 0.83) and takes less than 3 minutes to administer (Davis et al., 2006) .", "cite_spans": [{"start": 241, "end": 272, "text": "Baker, Williams, & Nurss, 1995)", "ref_id": "BIBREF30"}, {"start": 537, "end": 557, "text": "Murphy et al., 2010)", "ref_id": "BIBREF23"}, {"start": 866, "end": 886, "text": "(Davis et al., 2006)", "ref_id": "BIBREF6"}, {"start": 1432, "end": 1452, "text": "(Davis et al., 2006)", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Abstract", "text": "The BAMS is a 59-item questionnaire using a 7-point Likert scale to assess perceived threat of illness, positive outcome expectancy, negative outcome expectancy, and intent to adhere regarding oral medication adherence (Riekert & Drotar, 2002) . Psychometric properties include demonstrated reliability (alpha = 0.79-0.87; test-retest reliability, r = 0.71-0.77) and validity with a sample of chronically ill teens (n = 133), including youth with HIV-infection (Riekert & Drotar, 2002) .", "cite_spans": [{"start": 219, "end": 243, "text": "(Riekert & Drotar, 2002)", "ref_id": "BIBREF34"}, {"start": 461, "end": 485, "text": "(Riekert & Drotar, 2002)", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "Abstract", "text": "Media Use Questionnaire-This measure was developed by the investigator to assess media ownership and also daily time spent with media devices outside of school or work related to, and not related to, use of the Internet. The Media Use Questionnaire included 12 survey items. Items measuring time spent using common media devices were categorical and developed based on categories and results of the Kaiser Family Foundation (2010) report. The number of categories ranged from no time to various levels of minutes and hours. There were also two survey items designed to evaluate the preferred media source for obtaining health related information. The tool was pilot tested for face validity and usability by 12 teens from a local high school, who reported that the instrument was easily comprehended, reflective of modern media devices and daily time usage, and required 10 minutes or less to complete.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "3-Day Self-Reported Adherence Estimates-Because self-reported adherence has been significantly associated with HIV-1 RNA levels in HIV-infected individuals ages 18 years and older (Nieuwkerk & Oort, 2005; Simoni et al., 2006) and in HIV-infected children and adolescents (Garvie, Wilkins, & Young, 2010; Van Dyke et al., 2002) , adherence estimates were measured by 3-day participant self-report. Assessment of adherence to ART with self-report of missed doses has been widely used in HIV clinical and research practice, since the development of the adherence questionnaire used in the Adult AIDS Clinical Trial Group (AACTG) studies (Chesney et al., 2000) , and a priori reliability estimates have been described as good; Cronbach's alpha of questions relating to missed doses (yesterday, 2, 3, and 4 days ago) was 0.81 (Reynolds et al., 2007) .", "cite_spans": [{"start": 180, "end": 204, "text": "(Nieuwkerk & Oort, 2005;", "ref_id": "BIBREF28"}, {"start": 205, "end": 225, "text": "Simoni et al., 2006)", "ref_id": "BIBREF37"}, {"start": 271, "end": 303, "text": "(Garvie, Wilkins, & Young, 2010;", "ref_id": "BIBREF10"}, {"start": 304, "end": 326, "text": "Van Dyke et al., 2002)", "ref_id": "BIBREF39"}, {"start": 634, "end": 656, "text": "(Chesney et al., 2000)", "ref_id": "BIBREF5"}, {"start": 821, "end": 844, "text": "(Reynolds et al., 2007)", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "Abstract", "text": "To minimize the potential for social desirability bias (Garvie et al., 2010; Simoni et al., 2006) , questions were worded in a non-punitive manner, assuming a missed dose. For ", "cite_spans": [{"start": 55, "end": 76, "text": "(Garvie et al., 2010;", "ref_id": "BIBREF10"}, {"start": 77, "end": 97, "text": "Simoni et al., 2006)", "ref_id": "BIBREF37"}], "ref_spans": []}, {"section": "Abstract", "text": "This method has been previously tested and validated in HIVinfected youth, and 3-day recall of missed ARV dosing has been shown to predict HIVquantitative viral load among HIV-infected adolescents (Garvie et al., 2010 ).", "cite_spans": [{"start": 197, "end": 217, "text": "(Garvie et al., 2010", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Abstract", "text": "An average missed doses calculation (Garvie et al., 2010) was computed: reported number of doses missed per medication multiplied by the dosing schedule (once daily, twice daily, etc.) during the previous 3 days divided by total number of prescribed doses over the previous 3 days. This percentage was subtracted from 100% to obtain the 3-day adherence estimate. Medications that were not a component of the ART regimen were not included in the calculation and participants reporting don't know to the number of missed ARV medications were scored as having missed the dosage for the time period assessed (morning and/or evening of the specific day).", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "The MMSE and vision screen were first administered and then self-reported adherence estimates were obtained. Data from the screening instruments (TOFHLA, REALM-teen, BAMS, and Media Use Questionnaire) were collected in face-to-face interviews during a regularly scheduled clinic visit. The order of the study instruments was randomly selected. Because of potential for low literacy in this population (Brackis-Cott, Kang, Dolezal, Abrams, & Mellins, 2009), the investigator read each survey item from the BAMS and Media Use instruments to the participant. This was done to minimize the potential for any embarrassment related to reading difficulties (Wolf et al., 2007) . The average time to complete the screening measures, primary study instruments, and adherence estimate was 43 minutes.", "cite_spans": [{"start": 650, "end": 669, "text": "(Wolf et al., 2007)", "ref_id": "BIBREF41"}], "ref_spans": []}, {"section": "Abstract", "text": "Data extraction from the medical records included demographic, psychosocial and HIV clinical history, and laboratory biomarkers, and were typically based on the date of study enrollment. Quantitative serum HIV viral load and CD4+ T lymphocyte counts were examined for 6 months prior to study interview.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Dichotomous variables were created for continuous variables including TOFHLA scores (inadequate health literacy = 0-74, adequate health literacy = 75-100), 3-day adherence estimates (< 100% adherent, 100% adherent; Simoni et al., 2006) , and quantitative HIV viral loads (< 400 copies/ml, > 400 copies/ml). Reading grade level equivalent for participant raw scores on the REALM-teen were compared to the chronological age of each participant and a dichotomous age-level reading variable was created (< grade level reading, \u2265 grade level reading). Binary variables based on self-reported frequencies were computed for time spent using media devices/sources. A composite variable was constructed to describe the combined time spent using television, audio devices, and playing video games (TAV). Scores for total TAV time were divided into three categories (< 1 hour per day, 1-3 hours per day, and > 3 hours per day). A total beliefs composite score was computed by combining Bivariate analyses were computed to examine the correlation between each of these potential confounders and level of adherence (< 100% adherence, 100% adherence). Because of potential clinical and psychosocial differences between youth with perinatally and behaviorally acquired HIV infection, bivariate analyses were performed to test for differences by mode of HIV transmission in potential confounders, as well as health literacy, reading age levels, and scores on the BAMS. Statistically significant variables were included into the multivariable analyses.", "cite_spans": [{"start": 215, "end": 235, "text": "Simoni et al., 2006)", "ref_id": "BIBREF37"}], "ref_spans": []}, {"section": "Abstract", "text": "IBM SPSS Statistics, version 19 (Chicago, IL), was used to perform all statistical analyses. Descriptive statistics, and bivariate and multivariable analyses using logistic regression were computed with the level of significance set to 0.05. Log transformation of quantitative serum HIV viral load was performed, and if zero values existed, the number 1 was added. Nonparametric statistical tests were used for non-normally distributed data.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "The final sample population included 50 participants, ages 13-24 years, (M = 19.7 years; SD = 3.13; median = 20.4 years [range = 13.75 -24.83]) either perinatally (n = 40) or behaviorally (n = 10) infected. Demographic and HIV characteristics of the cohort are summarized in Tables 1 and 2 . HIV biomarkers (CD4+T lymphocytes counts, serum HIV viral load) were available from the participant's medical record on the same day selfreported adherence estimates were obtained in 56.0% (28/50) of the sample population. Of the remaining participants, the date of HIV biomarkers preceded adherence estimates by 1 day to 5 weeks in 16.0% (8/50) and 6 to 9 weeks in 24.0% (12/50) of the remaining sample. Two of the 50 participants (4.0%) had either one or both of the documented HIV biomarkers preceding self-reported adherence estimates by 13 to 16 weeks.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "There was a statistically significant difference in reported substance use by mode of HIV transmission, with 94.3% of perinatally HIV-infected youth reporting no use in comparison to the 5.7% of youth with behavioral transmission (p = .0001). No other statistically significant differences were observed when comparing youth by mode of HIV transmission. However, a trend toward statistical significance (p = .052) was observed when comparing mean positive outcome expectancy scores with higher mean rank scores in youth with behavioral infection (mean rank = 33.5) in comparison to scores in youth with perinatal infection (mean rank = 23.5). ", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Thirty-six of the 50 subjects (72.0%) had below-grade-level reading, despite nearly half having completed high school and 30.0% being enrolled in college courses at the time of study enrollment. Although the mean age was 19.7 years, 42.0% of participants had raw scores on the REALM-teen consistent with a sixth to seventh reading grade level equivalent.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Common media devices (computer, Internet access, DVD/VCR player, television, cable/ satellite television) were reported in the homes of more than 90.0% of the sample, and cellular phone ownership was reported by 46 of 50 participants. More than half of participants reported not spending any time reading offline (56.0%) or online (60.0%).", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Television viewing was more than 1 hour in 30 of 50 (60.0%) participants, and this included 8 respondents reporting television-viewing times of more than 5 hours daily. Time spent on social Websites was more than 1 hour in nearly half the sample (48.0%), including 17 youths who reported spending more than 3 hours on these websites. Text messaging of more than 25 texts during the previous day was frequently reported in more than half the respondents (54.0%), and listening to music offline was reported by 25 of the participating youth (50.0%). The minimum amount of total time spent using television and audio devices and playing video games was 1-3 hours/day in 58.0% of youth.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Total beliefs and subscale scores are depicted in Table 3 . Higher scores were suggestive of higher levels of reported agreement.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Three-day self-reported adherence was highly negatively skewed with a median 3-day adherence estimate of 100.0% (M = 86.0, SD = 26.92; range = 0-100). There were no statistically significant correlations between self-reported adherence estimates (dichotomized as 100% or < 100%) and gender, education, mode of HIV transmission, AIDS diagnosis, substance use, psychological/psychiatric illness (all p values > .05) or between age and self-reported adherence (Spearman's rho = \u22120.087, p = .55).", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "There was a strong, negative correlation between self-reported adherence and quantitative serum HIV viral load (Spearman's rho = \u22120.615, p < .001), and a statistically significant positive, moderate correlation existed between adherence and both CD4+T-lymphocyte count (Spearman's rho = 0.378, p = .007) and CD4+ T-lymphocyte percentage (Spearman's rho = 0.371, p = .008). There were no statically significant associations between health literacy and adherence or functional literacy and adherence (all p values > .05), but total beliefs, positive outcome expectancy, and intent to adhere were positively and significantly associated with adherence (Table 4) . Among the 40 HIV-infected youth with adequate health literacy, 21 (95.5%) reported spending 5 minutes or more reading offline rather than no time at all, in comparison to one of the 10 participants (4.5%) with inadequate health literacy who spent at least 5 minutes reading (p = .02). No other statistically significant findings were found with time spent using other media devices and health literacy levels.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Using self-reported 3-day adherence estimates (100% adherent, < 100% adherent) in a fitted logistic regression model, health literacy was not predictive of adherence (p = .15). Participants with higher positive outcome expectancy scores were significantly more likely to have self-reported adherence estimates of 100% (adjusted OR = 1.07, 95 % CI = 1.018-1.117), and the odds of 100% adherence were significantly lower among participants with below-grade-level reading compared to those with grade level or above grade level reading and 100% adherence (63.9% and 85.7% respectively; adjusted OR = 0.07, 95% CI = 0.005-0.831; Table 5 ).", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Keywords", "text": "adherence; antiretroviral adherence; beliefs; functional literacy; health literacy; HIV-infected adolescents; media use", "cite_spans": [], "ref_spans": []}, {"section": "Keywords", "text": "In the United States, approximately 90 million individuals have inadequate levels of health literacy (National Research Council, 2011) , and the need for improved health literacy is included as an objective in Healthy People 2020 (U.S. Department of Health and Human Services, 2012) . Individuals with inadequate levels of health literacy have been shown to have more hospitalizations, emergency room visits, lack of preventative health care services, and increased risk of death (Berkman, Sheridan, Donahue, Halpern, & Crotty, 2011) .", "cite_spans": [{"start": 480, "end": 533, "text": "(Berkman, Sheridan, Donahue, Halpern, & Crotty, 2011)", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Keywords", "text": "Among HIV-infected adults, lower health literacy has been associated with higher serum viral loads, decreased CD4+ T lymphocyte cell counts, and poor adherence to antiretroviral therapy (ART; Kalichman, Cherry, & Cain, 2005; Kalichman & Rompa, 2000) . Suboptimal adherence is associated with the development of resistance to ART and subsequent reduction of treatment options (Williams et al., 2006) ; it is one of the main causes of ART failure (Paterson et al., 2000; Sethi, Celentano, Gange, Moore, & Gallant, 2003) . Treatment of HIV infection with ART has resulted in significant reductions in HIV-related morbidity and mortality (El-Sadr et al., 2006; Helleberg et al., 2012) , further highlighting the importance of optimal adherence.", "cite_spans": [{"start": 192, "end": 224, "text": "Kalichman, Cherry, & Cain, 2005;", "ref_id": "BIBREF17"}, {"start": 225, "end": 249, "text": "Kalichman & Rompa, 2000)", "ref_id": "BIBREF18"}, {"start": 375, "end": 398, "text": "(Williams et al., 2006)", "ref_id": "BIBREF40"}, {"start": 445, "end": 468, "text": "(Paterson et al., 2000;", "ref_id": "BIBREF32"}, {"start": 469, "end": 517, "text": "Sethi, Celentano, Gange, Moore, & Gallant, 2003)", "ref_id": "BIBREF36"}, {"start": 634, "end": 656, "text": "(El-Sadr et al., 2006;", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Keywords", "text": "In the adolescent population there is limited research on the relationship between health literacy and health outcomes; most research to date on adolescents has focused on functional literacy or ability to read and write rather than health literacy (Manganello, 2008) . Health literacy has been described as the skill to gain access to, understand, and use information in ways that promote and maintain health (Nutbeam, 1998) and therefore must be viewed in the broader context of individual factors, language, and culture (Institute of Medicine, 2009) . For example, the current generation of youth has unprecedented access to the larger world due to advances in media and technology (Brown & Bobkowski, 2011) and commonly uses the Internet to gain health-related information (Gray, Klein, Noyce, Sesselberg, & Cantrill, 2005) . Yet adolescents will only obtain maximum benefit if they are able to search for, evaluate, and use online Internet information effectively. Individual beliefs surrounding health care are also an important component of health-related decision-making, and perceived threat of illness has been shown to be predictive of better ART adherence in behaviorally HIV-infected youth (Garvie et al., 2011) . A single study in HIV-infected teens reported no significant association between health literacy and adherence to ART (Murphy et al., 2010) . These findings, however, were inconsistent with results of a study with HIVinfected adults, where a robust relationship between health literacy and adherence was demonstrated (Kalichman et al., 2008) . The primary objective of this exploratory study was to examine the relationship between health literacy, functional literacy, beliefs about antiretroviral (ARV) medications, media use, and adherence to ART in HIV-infected adolescents (ages 13-24 years).", "cite_spans": [{"start": 249, "end": 267, "text": "(Manganello, 2008)", "ref_id": "BIBREF21"}, {"start": 410, "end": 425, "text": "(Nutbeam, 1998)", "ref_id": "BIBREF29"}, {"start": 685, "end": 710, "text": "(Brown & Bobkowski, 2011)", "ref_id": "BIBREF2"}, {"start": 777, "end": 827, "text": "(Gray, Klein, Noyce, Sesselberg, & Cantrill, 2005)", "ref_id": "BIBREF12"}, {"start": 1203, "end": 1224, "text": "(Garvie et al., 2011)", "ref_id": "BIBREF9"}, {"start": 1345, "end": 1366, "text": "(Murphy et al., 2010)", "ref_id": "BIBREF23"}, {"start": 1544, "end": 1568, "text": "(Kalichman et al., 2008)", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Methods", "text": "This was a multi-site cross-sectional descriptive survey design study. Potential predictors of adherence to ART were analyzed in a sample of 50 HIV-infected adolescents.", "cite_spans": [], "ref_spans": []}, {"section": "Sample", "text": "A convenience sample of youth with HIV infection was recruited from four HIV specialty clinical settings; both perinatally (mother-to-child) and behaviorally infected youth were eligible. Criteria for study participation were: HIV seropositive status, ages 13-24 years, fully disclosed of HIV diagnosis, English speaking, current treatment with a prescribed ART regimen for 6 months or longer, and absence of major neurocognitive deficits allowing for completion of survey instruments.", "cite_spans": [], "ref_spans": []}, {"section": "Settings/Recruitment", "text": "After approval by the appropriate institutional review boards (IRB), recruitment of eligible participants from four HIV specialty clinics occurred from September 2010 through April 2011. Clinical sites were affiliates of a large, urban, academic health care center. Informed consent and/or assent were obtained from all study participants in accordance with the regulations specific to the protection of study volunteers of the IRB at each institution. If the study candidate was between the ages of 13 and 17 years, the research study was described in detail by the principal investigator or physician collaborator to both the eligible participant and his or her parent/legal guardian; signed written and verbal assent was then obtained. Eligible participants ages 18 years and older were able to provide signed written and verbal consent in the absence of a parent/legal guardian. During the consent process, participants were given an opportunity to ask questions and at study completion were compensated with a $20.00 gift card.", "cite_spans": [], "ref_spans": []}, {"section": "Instruments", "text": "Screening for study eligibility was performed with the Mini Mental Health State Exam (MMSE) and Rosenbaum hand held vision card. The MMSE (Folstein, Folstein, & McHugh, 1975) was used to assess neurocognitive deficits. A cut-off score of 24 was selected because in the one known study to date with HIV-infected youth, a score of less than 24 was used to identify HIV dementia (Lyon, McCarter, & D'Angelo, 2009) . Visual screening was performed as recommended as a preliminary procedure for the TOFHLA.", "cite_spans": [{"start": 138, "end": 174, "text": "(Folstein, Folstein, & McHugh, 1975)", "ref_id": "BIBREF8"}, {"start": 376, "end": 410, "text": "(Lyon, McCarter, & D'Angelo, 2009)", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Test of Functional Health Literacy in Adults (TOFHLA)-", "text": "The TOFHLA is a validated health literacy-screening tool that measures both numeracy and literacy. Classification of health literacy scores is categorized into three levels, inadequate (0-59), marginal (60-74), and adequate (75-100; Parker, Baker, Williams, & Nurss, 1995) . Adequate reliability of the shortened version TOFHLA (S-TOFHLA) has been reported in the adolescent HIV-infected population (Cronbach's alpha > 0.7); the numeracy component of the S-TOFHLA has been described as less reliable in HIV-infected youth (alpha = 0.56; Murphy et al., 2010) . Therefore, the full version TOFHLA was selected for use in this study.", "cite_spans": [{"start": 233, "end": 272, "text": "Parker, Baker, Williams, & Nurss, 1995)", "ref_id": "BIBREF30"}, {"start": 537, "end": 557, "text": "Murphy et al., 2010)", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Rapid Estimate of Adult Literacy in Medicine-teen (REALM-teen)-REALM-teen", "text": "is a brief and reliable word recognition measure designed to predict general reading ability in health care settings among teens in sixth through twelfth grades (Davis et al., 2006) , consisting of 66 health related words arranged in increasing order of difficulty. Adolescents are asked to speak the word aloud, in the order listed. The total score is based on the number of words pronounced correctly and is related to grade level. The internal consistency is excellent (Cronbach's alpha = 0.94) with strong test-retest reliability (r = 0.98); the REALM-teen has high criterion based validity, when correlated with the Wide Range Achievement Test, third Edition (WRAT-3; r = 0.83) and takes less than 3 minutes to administer (Davis et al., 2006) .", "cite_spans": [{"start": 161, "end": 181, "text": "(Davis et al., 2006)", "ref_id": "BIBREF6"}, {"start": 727, "end": 747, "text": "(Davis et al., 2006)", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Beliefs about Medication Scale (BAMS)-", "text": "The BAMS is a 59-item questionnaire using a 7-point Likert scale to assess perceived threat of illness, positive outcome expectancy, negative outcome expectancy, and intent to adhere regarding oral medication adherence (Riekert & Drotar, 2002) . Psychometric properties include demonstrated reliability (alpha = 0.79-0.87; test-retest reliability, r = 0.71-0.77) and validity with a sample of chronically ill teens (n = 133), including youth with HIV-infection (Riekert & Drotar, 2002) .", "cite_spans": [{"start": 219, "end": 243, "text": "(Riekert & Drotar, 2002)", "ref_id": "BIBREF34"}, {"start": 461, "end": 485, "text": "(Riekert & Drotar, 2002)", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "Beliefs about Medication Scale (BAMS)-", "text": "Media Use Questionnaire-This measure was developed by the investigator to assess media ownership and also daily time spent with media devices outside of school or work related to, and not related to, use of the Internet. The Media Use Questionnaire included 12 survey items. Items measuring time spent using common media devices were categorical and developed based on categories and results of the Kaiser Family Foundation (2010) report. The number of categories ranged from no time to various levels of minutes and hours. There were also two survey items designed to evaluate the preferred media source for obtaining health related information. The tool was pilot tested for face validity and usability by 12 teens from a local high school, who reported that the instrument was easily comprehended, reflective of modern media devices and daily time usage, and required 10 minutes or less to complete.", "cite_spans": [], "ref_spans": []}, {"section": "Measurement of Adherence", "text": "3-Day Self-Reported Adherence Estimates-Because self-reported adherence has been significantly associated with HIV-1 RNA levels in HIV-infected individuals ages 18 years and older (Nieuwkerk & Oort, 2005; Simoni et al., 2006) and in HIV-infected children and adolescents (Garvie, Wilkins, & Young, 2010; Van Dyke et al., 2002) , adherence estimates were measured by 3-day participant self-report. Assessment of adherence to ART with self-report of missed doses has been widely used in HIV clinical and research practice, since the development of the adherence questionnaire used in the Adult AIDS Clinical Trial Group (AACTG) studies (Chesney et al., 2000) , and a priori reliability estimates have been described as good; Cronbach's alpha of questions relating to missed doses (yesterday, 2, 3, and 4 days ago) was 0.81 (Reynolds et al., 2007) .", "cite_spans": [{"start": 180, "end": 204, "text": "(Nieuwkerk & Oort, 2005;", "ref_id": "BIBREF28"}, {"start": 205, "end": 225, "text": "Simoni et al., 2006)", "ref_id": "BIBREF37"}, {"start": 271, "end": 303, "text": "(Garvie, Wilkins, & Young, 2010;", "ref_id": "BIBREF10"}, {"start": 304, "end": 326, "text": "Van Dyke et al., 2002)", "ref_id": "BIBREF39"}, {"start": 634, "end": 656, "text": "(Chesney et al., 2000)", "ref_id": "BIBREF5"}, {"start": 821, "end": 844, "text": "(Reynolds et al., 2007)", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "Measurement of Adherence", "text": "To minimize the potential for social desirability bias (Garvie et al., 2010; Simoni et al., 2006) , questions were worded in a non-punitive manner, assuming a missed dose. For", "cite_spans": [{"start": 55, "end": 76, "text": "(Garvie et al., 2010;", "ref_id": "BIBREF10"}, {"start": 77, "end": 97, "text": "Simoni et al., 2006)", "ref_id": "BIBREF37"}], "ref_spans": []}, {"section": "example, the investigator would state, \"Before beginning the questionnaires, could you tell me how many doses of your HIV medicines you missed yesterday? How many doses did you miss on (investigator names day 2 days ago)? How many doses did you miss on (investigator names day 3 days ago)?\"", "text": "This method has been previously tested and validated in HIVinfected youth, and 3-day recall of missed ARV dosing has been shown to predict HIVquantitative viral load among HIV-infected adolescents (Garvie et al., 2010 ).", "cite_spans": [{"start": 197, "end": 217, "text": "(Garvie et al., 2010", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "example, the investigator would state, \"Before beginning the questionnaires, could you tell me how many doses of your HIV medicines you missed yesterday? How many doses did you miss on (investigator names day 2 days ago)? How many doses did you miss on (investigator names day 3 days ago)?\"", "text": "An average missed doses calculation (Garvie et al., 2010) was computed: reported number of doses missed per medication multiplied by the dosing schedule (once daily, twice daily, etc.) during the previous 3 days divided by total number of prescribed doses over the previous 3 days. This percentage was subtracted from 100% to obtain the 3-day adherence estimate. Medications that were not a component of the ART regimen were not included in the calculation and participants reporting don't know to the number of missed ARV medications were scored as having missed the dosage for the time period assessed (morning and/or evening of the specific day).", "cite_spans": [{"start": 36, "end": 57, "text": "(Garvie et al., 2010)", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Data Collection", "text": "The MMSE and vision screen were first administered and then self-reported adherence estimates were obtained. Data from the screening instruments (TOFHLA, REALM-teen, BAMS, and Media Use Questionnaire) were collected in face-to-face interviews during a regularly scheduled clinic visit. The order of the study instruments was randomly selected. Because of potential for low literacy in this population (Brackis-Cott, Kang, Dolezal, Abrams, & Mellins, 2009), the investigator read each survey item from the BAMS and Media Use instruments to the participant. This was done to minimize the potential for any embarrassment related to reading difficulties (Wolf et al., 2007) . The average time to complete the screening measures, primary study instruments, and adherence estimate was 43 minutes.", "cite_spans": [{"start": 650, "end": 669, "text": "(Wolf et al., 2007)", "ref_id": "BIBREF41"}], "ref_spans": []}, {"section": "Data Collection", "text": "Data extraction from the medical records included demographic, psychosocial and HIV clinical history, and laboratory biomarkers, and were typically based on the date of study enrollment. Quantitative serum HIV viral load and CD4+ T lymphocyte counts were examined for 6 months prior to study interview.", "cite_spans": [], "ref_spans": []}, {"section": "Data Analysis", "text": "Dichotomous variables were created for continuous variables including TOFHLA scores (inadequate health literacy = 0-74, adequate health literacy = 75-100), 3-day adherence estimates (< 100% adherent, 100% adherent; Simoni et al., 2006) , and quantitative HIV viral loads (< 400 copies/ml, > 400 copies/ml). Reading grade level equivalent for participant raw scores on the REALM-teen were compared to the chronological age of each participant and a dichotomous age-level reading variable was created (< grade level reading, \u2265 grade level reading). Binary variables based on self-reported frequencies were computed for time spent using media devices/sources. A composite variable was constructed to describe the combined time spent using television, audio devices, and playing video games (TAV). Scores for total TAV time were divided into three categories (< 1 hour per day, 1-3 hours per day, and > 3 hours per day). A total beliefs composite score was computed by combining each of the subscales in the BAMS (positive outcome expectancy, negative outcome expectancy, intent to adhere, perceived threat). Survey items were reverse coded as per the scoring instructions of the BAMS, so that a higher score indicated more positive beliefs.", "cite_spans": [{"start": 215, "end": 235, "text": "Simoni et al., 2006)", "ref_id": "BIBREF37"}], "ref_spans": []}, {"section": "Data Analysis", "text": "Potential confounding variables in this study included age, gender, education, mode of HIV transmission, clinical stage of HIV disease, current psychological/psychiatric history, and substance use (Comulada, Swendeman, Rotheram-Borus, Mattes, & Weiss, 2003; Murphy et al., 2005; Rudy, Murphy, Harris, Muenz, & Ellen, 2009 ). Bivariate analyses were computed to examine the correlation between each of these potential confounders and level of adherence (< 100% adherence, 100% adherence). Because of potential clinical and psychosocial differences between youth with perinatally and behaviorally acquired HIV infection, bivariate analyses were performed to test for differences by mode of HIV transmission in potential confounders, as well as health literacy, reading age levels, and scores on the BAMS. Statistically significant variables were included into the multivariable analyses.", "cite_spans": [{"start": 197, "end": 257, "text": "(Comulada, Swendeman, Rotheram-Borus, Mattes, & Weiss, 2003;", "ref_id": "BIBREF3"}, {"start": 258, "end": 278, "text": "Murphy et al., 2005;", "ref_id": "BIBREF24"}, {"start": 279, "end": 321, "text": "Rudy, Murphy, Harris, Muenz, & Ellen, 2009", "ref_id": "BIBREF35"}], "ref_spans": []}, {"section": "Data Analysis", "text": "IBM SPSS Statistics, version 19 (Chicago, IL), was used to perform all statistical analyses. Descriptive statistics, and bivariate and multivariable analyses using logistic regression were computed with the level of significance set to 0.05. Log transformation of quantitative serum HIV viral load was performed, and if zero values existed, the number 1 was added. Nonparametric statistical tests were used for non-normally distributed data.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "The final sample population included 50 participants, ages 13-24 years, (M = 19.7 years; SD = 3.13; median = 20.4 years [range = 13.75 -24.83]) either perinatally (n = 40) or behaviorally (n = 10) infected. Demographic and HIV characteristics of the cohort are summarized in Tables 1 and 2 . HIV biomarkers (CD4+T lymphocytes counts, serum HIV viral load) were available from the participant's medical record on the same day selfreported adherence estimates were obtained in 56.0% (28/50) of the sample population. Of the remaining participants, the date of HIV biomarkers preceded adherence estimates by 1 day to 5 weeks in 16.0% (8/50) and 6 to 9 weeks in 24.0% (12/50) of the remaining sample. Two of the 50 participants (4.0%) had either one or both of the documented HIV biomarkers preceding self-reported adherence estimates by 13 to 16 weeks.", "cite_spans": [], "ref_spans": []}, {"section": "Mode of HIV Transmission", "text": "There was a statistically significant difference in reported substance use by mode of HIV transmission, with 94.3% of perinatally HIV-infected youth reporting no use in comparison to the 5.7% of youth with behavioral transmission (p = .0001). No other statistically significant differences were observed when comparing youth by mode of HIV transmission. However, a trend toward statistical significance (p = .052) was observed when comparing mean positive outcome expectancy scores with higher mean rank scores in youth with behavioral infection (mean rank = 33.5) in comparison to scores in youth with perinatal infection (mean rank = 23.5).", "cite_spans": [], "ref_spans": []}, {"section": "Health Literacy Characteristics", "text": "Most participants (80.0%) had adequate health literacy levels as measured by the TOFHLA (median total TOFHLA score = 83.5; range = 35-99). Median numeracy and reading comprehension raw scores among youth were 14.5 (range = 5-17 out of a possible range of 0-17) and 44.0 (range = 14-50 out of a possible range of 0-50).", "cite_spans": [], "ref_spans": []}, {"section": "Literacy Skills", "text": "Thirty-six of the 50 subjects (72.0%) had below-grade-level reading, despite nearly half having completed high school and 30.0% being enrolled in college courses at the time of study enrollment. Although the mean age was 19.7 years, 42.0% of participants had raw scores on the REALM-teen consistent with a sixth to seventh reading grade level equivalent.", "cite_spans": [], "ref_spans": []}, {"section": "Media Use", "text": "Common media devices (computer, Internet access, DVD/VCR player, television, cable/ satellite television) were reported in the homes of more than 90.0% of the sample, and cellular phone ownership was reported by 46 of 50 participants. More than half of participants reported not spending any time reading offline (56.0%) or online (60.0%). Television viewing was more than 1 hour in 30 of 50 (60.0%) participants, and this included 8 respondents reporting television-viewing times of more than 5 hours daily. Time spent on social Websites was more than 1 hour in nearly half the sample (48.0%), including 17 youths who reported spending more than 3 hours on these websites. Text messaging of more than 25 texts during the previous day was frequently reported in more than half the respondents (54.0%), and listening to music offline was reported by 25 of the participating youth (50.0%). The minimum amount of total time spent using television and audio devices and playing video games was 1-3 hours/day in 58.0% of youth.", "cite_spans": [], "ref_spans": []}, {"section": "Beliefs about Medications", "text": "Total beliefs and subscale scores are depicted in Table 3 . Higher scores were suggestive of higher levels of reported agreement.", "cite_spans": [], "ref_spans": [{"start": 50, "end": 57, "text": "Table 3", "ref_id": "TABREF0"}]}, {"section": "Self-Reported Adherence", "text": "Three-day self-reported adherence was highly negatively skewed with a median 3-day adherence estimate of 100.0% (M = 86.0, SD = 26.92; range = 0-100). There were no statistically significant correlations between self-reported adherence estimates (dichotomized as 100% or < 100%) and gender, education, mode of HIV transmission, AIDS diagnosis, substance use, psychological/psychiatric illness (all p values > .05) or between age and self-reported adherence (Spearman's rho = \u22120.087, p = .55).", "cite_spans": [], "ref_spans": []}, {"section": "Self-Reported Adherence", "text": "There was a strong, negative correlation between self-reported adherence and quantitative serum HIV viral load (Spearman's rho = \u22120.615, p < .001), and a statistically significant positive, moderate correlation existed between adherence and both CD4+T-lymphocyte count (Spearman's rho = 0.378, p = .007) and CD4+ T-lymphocyte percentage (Spearman's rho = 0.371, p = .008).", "cite_spans": [], "ref_spans": []}, {"section": "Self-Reported Adherence", "text": "There were no statically significant associations between health literacy and adherence or functional literacy and adherence (all p values > .05), but total beliefs, positive outcome expectancy, and intent to adhere were positively and significantly associated with adherence (Table 4) . Among the 40 HIV-infected youth with adequate health literacy, 21 (95.5%) reported spending 5 minutes or more reading offline rather than no time at all, in comparison to one of the 10 participants (4.5%) with inadequate health literacy who spent at least 5 minutes reading (p = .02). No other statistically significant findings were found with time spent using other media devices and health literacy levels.", "cite_spans": [], "ref_spans": [{"start": 276, "end": 285, "text": "(Table 4)", "ref_id": "TABREF1"}]}, {"section": "Multivariable Analyses", "text": "Using self-reported 3-day adherence estimates (100% adherent, < 100% adherent) in a fitted logistic regression model, health literacy was not predictive of adherence (p = .15). Participants with higher positive outcome expectancy scores were significantly more likely to have self-reported adherence estimates of 100% (adjusted OR = 1.07, 95 % CI = 1.018-1.117), and the odds of 100% adherence were significantly lower among participants with below-grade-level reading compared to those with grade level or above grade level reading and 100% adherence (63.9% and 85.7% respectively; adjusted OR = 0.07, 95% CI = 0.005-0.831; Table 5 ).", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "The findings of this study make several important contributions to the body of knowledge regarding HIV-infected adolescents. At the time of this research, we describe the results of the first known study to examine the relationships between health and functional literacy levels, beliefs about ART, media use, and adherence to ART in HIV-infected youth. We also report the first known data quantifying media use in the HIV-infected adolescent population. Clearly, media may offer tremendous potential for novel and improved methods to deliver health education in high-risk youth such as the adolescent participants in this study. Although health literacy was not predictive of adherence in this study, beliefs of positive outcome expectancy and functional literacy skills were predictive of self-reported adherence.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "The proportion of youth who reported 3-day adherence of 100% in this study was higher than previous reports in HIV-infected youth (Chandwani et al., in press; Murphy et al., 2010 , Murphy et al., 2005 Murphy, Wilson, Durako, Muenz, & Belzer, 2001; Naar-King et al., 2006; Williams et al., 2006) . While it is crucial to consider the inherent risk of bias in the interpretation of these self-reported adherence estimates, the strong correlation between selfreported adherence and quantitative HIV viral load strengthen these results because viral load has been significantly associated with self-reported adherence in other studies with HIV-infected youth (Garvie et al., 2010; Murphy et al., 2005; Williams et al., 2006) and adults (Reynolds et al., 2007; Simoni et al., 2006) . Additionally, our method of data collection of self-reported adherence estimated in this study was designed to reduce social desirability bias and over inflation of the results.", "cite_spans": [{"start": 159, "end": 178, "text": "Murphy et al., 2010", "ref_id": "BIBREF23"}, {"start": 179, "end": 200, "text": ", Murphy et al., 2005", "ref_id": "BIBREF24"}, {"start": 201, "end": 247, "text": "Murphy, Wilson, Durako, Muenz, & Belzer, 2001;", "ref_id": "BIBREF25"}, {"start": 248, "end": 271, "text": "Naar-King et al., 2006;", "ref_id": "BIBREF26"}, {"start": 272, "end": 294, "text": "Williams et al., 2006)", "ref_id": "BIBREF40"}, {"start": 655, "end": 676, "text": "(Garvie et al., 2010;", "ref_id": "BIBREF10"}, {"start": 677, "end": 697, "text": "Murphy et al., 2005;", "ref_id": "BIBREF24"}, {"start": 698, "end": 720, "text": "Williams et al., 2006)", "ref_id": "BIBREF40"}, {"start": 732, "end": 755, "text": "(Reynolds et al., 2007;", "ref_id": "BIBREF33"}, {"start": 756, "end": 776, "text": "Simoni et al., 2006)", "ref_id": "BIBREF37"}], "ref_spans": []}, {"section": "Discussion", "text": "Consistent with the findings from one other study of health literacy and adherence in HIVinfected youth (Murphy et al., 2010) , we found no significant correlation between health literacy and adherence to HIV treatment in our study. However, there were some important differences between our study and that of Murphy and colleagues (2010) , including a larger sample size (N = 186) of primarily behaviorally HIV-infected youth with 50.0% having education of less than high school graduation, and their inclusion of participants with high risk behaviors such as unprotected sex during the previous 3 months, substance use issues, or poor adherence. These differences may explain the lower percentage of youth (33.7%) in Murphy and colleagues' (2010) study with 3-day self-reported adherence of 90.0% and greater. Despite these distinctions, in both studies 80.0% and more of participants had adequate levels of health literacy and were receiving care at multidisciplinary, primary HIV care centers. Such state-of-the-art medical care may have positively influenced health literacy levels.", "cite_spans": [{"start": 104, "end": 125, "text": "(Murphy et al., 2010)", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Discussion", "text": "In this study, the high number of participants (72.0%) with below-grade-level reading was of particular concern, and may be explained by multiple factors. Potential biologic considerations include subtle cognitive deficits due to the impact of ongoing HIV viral replication in the central nervous system, the role of chronic inflammation, and the effect of HIV on the developing brain in perinatally HIV-infected youth (Hazra, 2010) . Although there has been a significant decrease in the incidence of HIV-related encephalopathy since the development of effective ART (Patel et al., 2009) , HIV-associated neurocognitive disorders persist despite treatment with ART (Mothobi & Brew, 2012) . Additionally, possible psychosocial factors contributing to low literacy include lower socioeconomic backgrounds of study participants and primary residence in disadvantaged neighborhoods. Similar to the findings in our study, reading grade level has been associated with ART adherence. In one study with HIV-infected adults, low literacy as measured by the REALM was a significant predictor of medication non-adherence during the preceding 4 days (AOR 3.3, 95% CI = 1.3-8.7) but this relationship was mediated by self-efficacy (Wolf et al., 2007) .", "cite_spans": [{"start": 419, "end": 432, "text": "(Hazra, 2010)", "ref_id": "BIBREF13"}, {"start": 568, "end": 588, "text": "(Patel et al., 2009)", "ref_id": "BIBREF31"}, {"start": 666, "end": 688, "text": "(Mothobi & Brew, 2012)", "ref_id": "BIBREF22"}, {"start": 1219, "end": 1238, "text": "(Wolf et al., 2007)", "ref_id": "BIBREF41"}], "ref_spans": []}, {"section": "Discussion", "text": "One surprising finding not previously described among HIV-infected youth was the disconnect between the functional and health literacy scores in this study (i.e., relatively higher health literacy scores). A likely explanation is related to the long-term exposure of the participants to the health care system, health care professionals, and frequent medical encounters throughout their life spans. This finding highlights the larger context in which health literacy exists and supports movement away from definitions with an exclusive focus on functional literacy.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "In our study, beliefs of positive outcome expectancy regarding ART were significantly associated with adherence, indicating that health beliefs may be assessed and targeted for intervention. Individual beliefs (total beliefs and perceived threat of illness) were significant predictors of medication adherence in one study of behaviorally HIV-infected youth (Garvie et al., 2011) . Health beliefs of the modern adolescent are influenced by a wide variety of factors including the education system, cultural norms, and media.", "cite_spans": [{"start": 358, "end": 379, "text": "(Garvie et al., 2011)", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Discussion", "text": "The HIV-infected youth in our study were well equipped with media; more than 90.0% owned a computer with Internet access and 74.0% reported going online during the preceding day. This information is valuable because 70.0% reported that their first choice for seeking health related information would be via the Internet. Considering the combined effects of low reported time spent reading and the high percentage of below-grade-level reading in this sample population, augmentation of traditional education extending beyond written pamphlets may be needed. Efforts to promote adolescent health literacy should include online access to reliable sources of health information (Ghaddar, Valerio, Garcia, & Hansen, 2012) .", "cite_spans": [{"start": 674, "end": 716, "text": "(Ghaddar, Valerio, Garcia, & Hansen, 2012)", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "Discussion", "text": "The methodological limitations of this study include use of self-reported adherence, a small sample size, and a wide age span given that age-related developmental differences may have influenced beliefs about HIV illness and ART. Additionally, the read-along style of the BAMS and Media Use Questionnaire may have influenced participant responses. Although the Media Use Questionnaire underwent initial pilot testing in this study, additional testing will be needed to establish reliability for future research.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "In summary, our research tested an expanded health literacy framework in an HIV-infected cohort specifically for the outcome of adherence to ART. Both beliefs and reading levels were predictive of ART adherence, highlighting the importance of comprehensive models in the care of HIV-infected youth.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "Health literacy as measured with the TOFHLA was not predictive of self-reported adherence, and this may have been explained by the smaller than anticipated sample size as well as the high levels of both adherence and health literacy among the participants. Although it is plausible that the favorable HIV health outcomes (i.e., high self-reported adherence, good HIV biomarkers) observed among participating youth may have been explained by the high percentage with adequate health literacy levels; the study was not sufficiently powered to provide confirmatory data. Considering the paucity of evidence examining the relationship between health literacy and treatment adherence in HIV-infected adolescents and young adults and the significant association shown in HIV-infected adults, additional research is warranted.", "cite_spans": [], "ref_spans": []}, {"section": "Clinical Considerations", "text": "\u2022 Health beliefs about ART need to be assessed as part of ongoing adherence support and especially before the initiation of an ARV regimen.", "cite_spans": [], "ref_spans": []}, {"section": "Clinical Considerations", "text": "\u2022 Three-day self-reported adherence estimates, when used in combination with HIV-biomarkers, offer a feasible and practical method to measure ART adherence in HIV-infected youth.", "cite_spans": [], "ref_spans": []}, {"section": "Clinical Considerations", "text": "\u2022 Considering that low functional literacy is a risk factor for suboptimal adherence among HIV-infected youth, augmentation of traditional education extending beyond written pamphlets is needed.", "cite_spans": [], "ref_spans": []}, {"section": "Clinical Considerations", "text": "\u2022 Media use and ownership is high in HIV-infected youth, and nurses need to periodically assess media sources used to obtain HIV-and ART-related health information. Table 1 Demographic Characteristics of Study Population (N =50)", "cite_spans": [], "ref_spans": []}, {"section": "Variable Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "M (SD)", "text": "Age in years 19.7 (3.13) Table 5 Predictors of Adherence as Measured by 3-day Self-Report (N = 50) ", "cite_spans": [], "ref_spans": []}, {"section": "n (%)", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Gender", "text": "", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Low health literacy and health outcomes: An updated systematic review", "authors": [{"first": "N", "middle": ["D"], "last": "Berkman", "suffix": ""}, {"first": "S", "middle": ["L"], "last": "Sheridan", "suffix": ""}, {"first": "K", "middle": ["E"], "last": "Donahue", "suffix": ""}, {"first": "D", "middle": ["J"], "last": "Halpern", "suffix": ""}, {"first": "K", "middle": [], "last": "Crotty", "suffix": ""}], "year": 2011, "venue": "Annals of Internal Medicine", 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Patient Education and Counseling", "authors": [{"first": "M", "middle": ["S"], "last": "Wolf", "suffix": ""}, {"first": "T", "middle": ["C"], "last": "Davis", "suffix": ""}, {"first": "C", "middle": ["Y"], "last": "Osborn", "suffix": ""}, {"first": "S", "middle": [], "last": "Skripkauskas", "suffix": ""}, {"first": "C", "middle": ["L"], "last": "Bennett", "suffix": ""}, {"first": "G", "middle": [], "last": "Makoul", "suffix": ""}], "year": 2007, "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "NOTE: M = mean; SD = standard deviation", "type": "figure"}, "FIGREF1": {"text": "\u03b2 = beta coefficient; CI = confidence interval; a reference category Health literacy was measured with TOFHLA, possible range of scores = 0-100 Positive outcome expectancy was a subscale in the BAMS, possible range of scores = 20-140.", "type": "figure"}, "TABREF0": {"text": "Participant Scores on the Beliefs about Medications Scale (BAMS; N =50)NOTE: M = mean; SD = standard deviation; Upper/lower limits of scores on Beliefs about Medications Scale (BAMS) shown above in parentheses", "type": "table"}, "TABREF1": {"text": "Correlation of Adherence with Beliefs, Health Literacy, and Literacy (N =50)NOTE: TOFHLA = Test of Functional Health Literacy in Adults; REALM = Rapid Estimate of Adult Literacy in Medicine; Self-reported 3-day antiretroviral adherence estimates used in analyses * Correlation tested using Spearman's Rank Correlation Coefficient", "type": "table"}}}
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{"paper_id": "2877573", "_pdf_hash": "cad0a728afd79395fa3d76360421961695d1dd5e", "abstract": [{"section": "Abstract", "text": "Cytotoxic T-lymphocytes (CTL) kill their targets by cytolytic granule secretion at the immunological synapse. The Sec/Munc protein, Munc18-2, and its binding partner Syntaxin 11 (STX11) are both required for granule secretion, with mutations in either leading to the primary immunodeficiency, Familial Haemophagocytic Lymphohistiocytosis (FHL4 and 5). Understanding how Munc18-2 and STX11 function in CTL has been hampered by not knowing the endogenous localization of these proteins. Using a novel FHL5 Munc18-2 mutation that results in loss of protein, cytotoxicity and degranulation together with CTL from an FHL4 patient lacking STX11, enabled us to localize endogenous STX11 and Munc18-2 in CTL. Munc18-2 localized predominantly to cytolytic granules with low levels associated with the plasma membrane where STX11 localized. Importantly, while Munc18-2 localization is unaffected by the absence of STX11 in FHL4 CTL, STX11 is lost from the plasma membrane in FHL5 CTL lacking Munc18-2. These findings support a role for Munc18-2 in chaperoning STX11 to the plasma membrane where the final fusion events involved in secretion occur.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "CD8-positive cytotoxic T-lymphocytes (CTL) are key players of the mammalian immune system, providing protection from viral infection and cancerous cells. CTL kill through precise delivery of perforin and granzymes across a highly organized CTL:target interface that is known as the immune synapse. CTL protect themselves from the potent pro-apoptotic factors by storing these proteins in specialized secretory lysosomes, termed cytolytic granules. During CTL attack, these granules are delivered to the synapse where they fuse with the plasma membrane and release their deadly contents onto the target (reviewed in 1).", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "The biogenesis of cytolytic granules and their final fusion with the plasma membrane requires a specialized fusion machinery. Two components of this are the SNAP (Soluble NSF Attachment Protein) Receptor (SNARE)-protein Syntaxin 11 (STX11) (2) and the Syntaxin binding protein Munc18-2 (3,4) and genetic mutations that cause loss of function of either of these proteins gives rise to Familial Haemophagocytic Lymphohistiocytosis (FHL), a devastating autosomal hereditary immune deficiency condition that is marked by the failure of CTL to kill infected cells efficiently (reviewed by 5, 6) .", "cite_spans": [{"start": 240, "end": 243, "text": "(2)", "ref_id": "BIBREF1"}, {"start": 584, "end": 586, "text": "5,", "ref_id": "BIBREF4"}, {"start": 587, "end": 589, "text": "6)", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "", "text": "In neuronal and epithelial cells, Munc18 proteins were found to be required for stable plasma membrane localization of Syntaxin 1A (STX1A) (7, 8) . Interestingly, in FHL5 patient CTL (in which Munc18-2 is lost) STX11 levels are usually strongly reduced and the inability of STX11 and Munc18-2 deficient cells to kill target cells efficiently was shown to be due to a degranulation defect (3, 4, 9) . This led to the suggestion that a chaperoning interaction similar to the Munc18/STX1A pair is given between Munc18-2 and STX11 and that the two proteins drive the last step of granule secretion at the CTL plasma membrane (3, 4, (9) (10) (11) (12) . Notably, the finding that FHL5 patients with mutations R65Q/W retain the ability to interact with STX11 supports an additional direct role in secretion for Munc18-2 (13) . Whether Munc18-2 and STX11 function at the plasma membrane, or at a late granule maturation step (14) remains unclear, in part due to the lack of information on the precise localization of these proteins.", "cite_spans": [{"start": 139, "end": 142, "text": "(7,", "ref_id": "BIBREF6"}, {"start": 143, "end": 145, "text": "8)", "ref_id": "BIBREF7"}, {"start": 388, "end": 391, "text": "(3,", "ref_id": "BIBREF2"}, {"start": 392, "end": 394, "text": "4,", "ref_id": "BIBREF3"}, {"start": 395, "end": 397, "text": "9)", "ref_id": "BIBREF8"}, {"start": 621, "end": 624, "text": "(3,", "ref_id": "BIBREF2"}, {"start": 625, "end": 627, "text": "4,", "ref_id": "BIBREF3"}, {"start": 628, "end": 631, "text": "(9)", "ref_id": "BIBREF8"}, {"start": 632, "end": 636, "text": "(10)", "ref_id": "BIBREF9"}, {"start": 637, "end": 641, "text": "(11)", "ref_id": "BIBREF10"}, {"start": 642, "end": 646, "text": "(12)", "ref_id": "BIBREF11"}, {"start": 814, "end": 818, "text": "(13)", "ref_id": "BIBREF12"}, {"start": 918, "end": 922, "text": "(14)", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "", "text": "STX11 and Munc18-2 are widely expressed (15) (16) (17) and studies in other secretory cells flagged up several roles for Munc18-2 on compartments other than the plasma membrane. In mast cells, Munc18-2 on the limiting membrane of secretory granules appeared to provide a link to microtubules and thus promote the transport of granules to the cell periphery (18) . A study in the pancreatic beta-cell line MIN6 reported a role for Munc18-2 in modulating calcium responsiveness during the secretion of granules. Sucrose gradient analysis detected Munc18-2 predominantly in low-density fractions that correspond to 'small membranous organelles and soluble proteins' (19) . Furthermore, it has been suggested that in CTL the granules themselves undergo one (or several) maturation steps before they become 'secretion competent bullets' that carry all the machinery required for fusion at the plasma membrane (14) . These reports highlight multiple potential roles for Munc18-2 but exactly when and where STX11 and Munc18-2 function in CTL is not fully understood.", "cite_spans": [{"start": 40, "end": 44, "text": "(15)", "ref_id": "BIBREF14"}, {"start": 45, "end": 49, "text": "(16)", "ref_id": "BIBREF15"}, {"start": 50, "end": 54, "text": "(17)", "ref_id": "BIBREF16"}, {"start": 357, "end": 361, "text": "(18)", "ref_id": "BIBREF17"}, {"start": 663, "end": 667, "text": "(19)", "ref_id": "BIBREF18"}, {"start": 904, "end": 908, "text": "(14)", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "", "text": "Precise localization of proteins within the cellular environment can give important clues about their function. However, several issues have been reported previously when it comes to the localization of tagged SNARE-protein and Munc18-2 constructs: One of the key functional domains of any SNARE-protein is either a transmembrane domain or a lipidic membrane anchor enabling these proteins to associate directly with membranes (review: 20,21). Thus, when a SNARE is even slightly over-expressed, the possibility of mis-localization of the tagged construct to non-physiological compartments is a major concern.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Although it has been reported that over-expressed STX11 localizes to the recycling endosome in human CTL it is not known whether this corresponds to localization of the endogenous protein (12, 22) . Munc18-2 on the other hand has no domains that suggest an ability to associate with membranes independently of helper proteins. Indeed over-expressed Munc18-2 constructs remain diffuse cytoplasmic (23) unless a membrane-associated binding partner such as STX11 is expressed in parallel (24) .", "cite_spans": [{"start": 188, "end": 192, "text": "(12,", "ref_id": "BIBREF11"}, {"start": 193, "end": 196, "text": "22)", "ref_id": "BIBREF21"}, {"start": 485, "end": 489, "text": "(24)", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "", "text": "We therefore assessed the distribution of endogenous Munc18-2 and STX11 in CTL. Four new polyclonal antibodies were raised against near full-length human Munc18-2 and STX11 protein. By comparing immunofluorescence microscopy (IF) in healthy donor (HD) CTL versus FHL4 and FHL5 patient cells, lacking Munc18-2 or STX11, we were able to determine specific staining and now show the localization of endogenous Munc18-2 and STX11 in human CTL. In order to do this we also report a novel patient mutation in Munc18-2 that abolishes protein expression, and used CTL from a previously reported patient mutation lacking STX11. This approach allowed us to define the endogenous localization of both proteins. Our data reveal that endogenous Munc18-2 localizes predominantly to the cytolytic granules, with low levels on the plasma membrane, and is required for STX11 delivery to the plasma membrane.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "FHL4 and FHL5 CTL validate STX11 and Munc18-2 antibody specificity FHL4 CTL with a homozygous loss of the entire STX11 coding exon (AL135917:g.25561-44749_del, 25) and FHL5 CTL with a homozygous deletion-insertion mutation (c.1468_1470delCGGinsTGGACAGCCCTGGAC AGGG p.R490WfsX95, UPN666), leading to a frameshift from amino acid 490 onwards and predicting a premature stop-codon were used to confirm the antibody specificities ( Figure 1A ).", "cite_spans": [], "ref_spans": [{"start": 428, "end": 437, "text": "Figure 1A", "ref_id": "FIGREF1"}]}, {"section": "Results", "text": "Western blotting with the Munc18-2 and STX11 antibodies 5182 and 5412 showed a complete loss of Munc18-2 and STX11 protein from the FHL4 and 5 CTL, respectively. As described previously for other FHL5 patients (3,4) STX11 levels are reduced in the absence of Munc18-2 ( Figure 1B ). The frameshift mutation in UPN666 has not been described before. We therefore investigated the effects of this novel mutation on CTL killing and degranulation and found both to be reduced even after 2 weeks of culture in the presence of IL-2 ( Figure 1C,D) . This stands in contrast to several previously published FHL5 patient CTL that did not show abnormal cytotoxicity in culture (26) .", "cite_spans": [{"start": 666, "end": 670, "text": "(26)", "ref_id": "BIBREF25"}], "ref_spans": [{"start": 270, "end": 279, "text": "Figure 1B", "ref_id": "FIGREF1"}, {"start": 527, "end": 539, "text": "Figure 1C,D)", "ref_id": "FIGREF1"}]}, {"section": "Results", "text": "Endogenous Munc18-2 localizes to cytolytic granules and the plasma membrane in human CTL We tested both anti-Munc18-2 antibodies (5182 and 5184) by IF on HD as well as FHL5 CTL ( Figure 2 ). In HD derived CTL, both antibodies localized predominantly to intracellular granules and a central puncta, with low levels detected on the plasma membrane. We subsequently focused on antibody 5182 because it provided a stronger signal. By staining HD and FHL5 patient cells in parallel we confirmed that the granular and the plasma membrane staining are specific to Munc18-2 ( Figure 2A ,B). Colocalization with LAMP1 (n = 158 HD cells) and the cytolytic granule marker perforin (n = 119 HD cells) identified the predominant granular staining as the cytolytic granules. Munc18-2 colocalized with LAMP1 on the limiting membrane of the granule ( Figure 2C ) surrounding perforin ( Figure 2D ). This staining was lost from FHL5 CTL (Figure 2A-D) while the central puncta, identified as the centrosome by gamma-tubulin colocalization, remained (data not shown). A weak cytoplasmic staining could also be detected in HD cells, consistent with a small pool of Munc18-2 dispersed throughout the cytoplasm. With six independent experiments revealing strong granular staining in HD CTL, our experiments suggest that endogenous Munc18-2 is localized to cytolytic granules in CTL. Although some plasma membrane staining was observed it was weaker and variable between experiments ( As Munc18-2 localized to cytolytic granules in CTL, we asked whether this was maintained when granules polarized toward target cells. Two-thirds of CTL-target conjugates showed granules clustered at the immunological synapse, and in each case Munc18-2 remained associated with the granules ( Figure 2E , n = 63). Any plasma membrane staining, remained equally distributed in all conjugates without accumulation at the synapse ( Figure 2E ).", "cite_spans": [], "ref_spans": [{"start": 179, "end": 187, "text": "Figure 2", "ref_id": "FIGREF3"}, {"start": 568, "end": 577, "text": "Figure 2A", "ref_id": "FIGREF2"}, {"start": 835, "end": 844, "text": "Figure 2C", "ref_id": "FIGREF3"}, {"start": 870, "end": 879, "text": "Figure 2D", "ref_id": "FIGREF3"}, {"start": 920, "end": 933, "text": "(Figure 2A-D)", "ref_id": "FIGREF2"}, {"start": 1754, "end": 1763, "text": "Figure 2E", "ref_id": "FIGREF3"}, {"start": 1890, "end": 1899, "text": "Figure 2E", "ref_id": "FIGREF3"}]}, {"section": "Results", "text": "Endogenous STX11 associates with the plasma membrane accumulating at the leading edge of human CTL We next sought to determine whether STX11 localized to the same cellular compartments as Munc18-2. Again, both our custom-made STX11 antibodies (5412 and 5413) showed the same staining pattern in CTL and one antibody (5412) yielded considerably stronger signal.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "In five independent experiments we compared STX11 staining with 5412 in HD cells (n = 328) and FHL4 control cells (n = 312). We observed staining of the plasma membrane exclusively in HD cells while punctate cytoplasmic and centrosome staining was found in both HD and FHL4 cells, suggesting that these signals were non-specific ( Figure 3A ). It should be noted that as cells were fixed with methanol any free cytoplasmic pool of STX11 would be lost after fixation. Hundred percent of HD CTL showed plasma membrane localization of STX11, with 30% showing accumulation at the leading edge ( Figure 3B ). In CTL-target conjugates, STX11 accumulated either across or clustered at the immune synapse in \u226416% of conjugates ( Figure 3C ). In contrast to Munc18-2 we did not observe colocalization of STX11 with LAMP1 ( Figure 3D ).", "cite_spans": [], "ref_spans": [{"start": 331, "end": 340, "text": "Figure 3A", "ref_id": "FIGREF5"}, {"start": 591, "end": 600, "text": "Figure 3B", "ref_id": "FIGREF5"}, {"start": 721, "end": 730, "text": "Figure 3C", "ref_id": "FIGREF5"}, {"start": 814, "end": 823, "text": "Figure 3D", "ref_id": "FIGREF5"}]}, {"section": "Results", "text": "Munc18-2 localization is independent of STX11 but in the absence of Munc18-2, STX11 is lost from the plasma membrane It has been suggested that Munc18-2 might act as a chaperone to transport STX11 to the plasma membrane as observed for the Munc18/STX1A pair (7, 8) . Therefore, we asked whether the localization of endogenous STX11 at the plasma membrane depends upon the presence of Munc18-2 and vice versa. We performed parallel Munc18-2 and STX11 staining in HD, FHL4 and FHL5 cells in three independent experiments and co-stained with LAMP1 or CD8 in order to assess potential effects on colocalization with these markers.", "cite_spans": [{"start": 258, "end": 261, "text": "(7,", "ref_id": "BIBREF6"}, {"start": 262, "end": 264, "text": "8)", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Results", "text": "As observed previously, we found strong Munc18-2 staining on granules and weaker staining on the plasma membrane in HD cells (n = 265) but no Munc18-2 staining on FHL5 cells (n = 263). Centrosomal staining was non-specific as it was present in both HD and patient cells. Munc18-2 staining in FHL4 cells (n = 252) resembled staining in HD cells, indicating that Munc18-2 localization was not affected by the absence of STX11. In contrast, FHL5 CTL (lacking Munc18-2) completely lost the plasma membrane STX11 localization seen in HD CTL (Figure 4) , confirmed by colocalization with the T cell plasma membrane protein, CD8 ( Figure 5 ). These results support a role for Munc18-2 in STX11 stability and are consistent with leading edge. B) Quantitation of Munc18-2 antibody staining from 6 independent experiments: HD (white, n = 397) and FHL5 (gray, n = 374). Gran: granular staining, PM: plasma membrane staining, hatched bar = HD CTL with an accumulation of Munc18-2 at the leading edge. Shown is the mean with standard deviation, *** indicates a significant difference with p < 0.0001, two-tailed students t-test (unpaired), 95% confidence limits. C) Co-staining for Munc18-2 (green) and LAMP1 (red) in three independent experiments comparing HD and FHL5 CTL (n = 158 each). Yellow lines (i) and (ii) were drawn via the IMAGEJ line tool (linewidth: 3 pixel) to obtain Munc18-2 and LAMP1 intensity profiles. Imaris display adjustments optimized for granular signal. D) Co-staining of a CTL-P815 conjugate for Munc18-2 (green) and perforin (red, exclusively expressed in CTL). The white arrowhead indicates a perforin core surrounded by Munc18-2 (n = 119 HD, 2 independent experiments). E) Co-staining of a CTL-P815 conjugate for Munc18-2 (green) and CD8 (red) showing polarization of granule-associated Munc18-2 toward the synapse (n = 63). All images show single confocal planes. Scale bars: 5 \u03bcm.", "cite_spans": [], "ref_spans": [{"start": 536, "end": 546, "text": "(Figure 4)", "ref_id": "FIGREF6"}, {"start": 624, "end": 632, "text": "Figure 5", "ref_id": "FIGREF7"}]}, {"section": "1334", "text": "Traffic 2015; 16: 1330-1341 a role for Munc18-2 in chaperoning STX11 to the plasma membrane.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Munc18-2 and STX11 play essential roles in secretion from CTL and NK cells. Mutations in the genes encoding these two proteins give rise to FHL, a profound immunodeficiency that can be cured only by bone marrow transplantation. Functional studies have shown that these proteins play a role in secretion (2-4), but do not reveal at which stage in the secretory pathway they are required. In order to identify the sites of action of Munc18-2 and STX11 we asked where the endogenous proteins were localized in CTL.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "There are two well-acknowledged problems with establishing the cellular localization of SNARE and associated Munc18 proteins: over-expression often results in mis-localization because SNARE component proteins can recombine promiscuously and levels of binding partners become limiting (7, 20, 27) . Furthermore, the multitude of homologous proteins (15 syntaxins; 3 Munc18-proteins) means that it can be difficult to determine the specificity of antibody binding for any single protein. In order to overcome these difficulties, we investigated the localization of endogenous STX11 and Munc18-2 in human CTL through the use of novel antibodies raised against (near) full-length human Munc18-2 and STX11 protein. Importantly, the use of patient CTL lacking STX11 (FHL4) and Munc18-2 (FHL5) allowed us to establish the specificity of staining. Our results demonstrate that endogenous Munc18-2 is localized predominantly on secretory lysosomes of CTL although lower levels are observed on the plasma membrane, where STX11 is found, raising the possibility that Munc18-2 might transit the plasma membrane and deliver STX11 to this site.", "cite_spans": [{"start": 284, "end": 287, "text": "(7,", "ref_id": "BIBREF6"}, {"start": 288, "end": 291, "text": "20,", "ref_id": "BIBREF19"}, {"start": 292, "end": 295, "text": "27)", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "Discussion", "text": "Previous studies in CTL and NK cells have examined the localization of over-expressed, tagged constructs of these proteins (11, 12, 22, 24, 28) or using antibodies raised against peptide or mouse epitopes in human CTL (13, 29) . These studies suggested many possible localizations in CTL, with Munc18-2 diffusely cytoplasmic (24), on dense puncta (13) or associated with cytolytic granules (24) and STX11 on distinct cytoplasmic puncta (11, 12, 22, 28, 29) colocalizing with CD3 and granzyme B (12) but not perforin (28, 29) and/or associated with the plasma membrane (12, 24) .", "cite_spans": [{"start": 123, "end": 127, "text": "(11,", "ref_id": "BIBREF10"}, {"start": 128, "end": 131, "text": "12,", "ref_id": "BIBREF11"}, {"start": 132, "end": 135, "text": "22,", "ref_id": "BIBREF21"}, {"start": 136, "end": 139, "text": "24,", "ref_id": "BIBREF23"}, {"start": 140, "end": 143, "text": "28)", "ref_id": "BIBREF27"}, {"start": 218, "end": 222, "text": "(13,", "ref_id": "BIBREF12"}, {"start": 223, "end": 226, "text": "29)", "ref_id": "BIBREF28"}, {"start": 347, "end": 351, "text": "(13)", "ref_id": "BIBREF12"}, {"start": 390, "end": 394, "text": "(24)", "ref_id": "BIBREF23"}, {"start": 436, "end": 440, "text": "(11,", "ref_id": "BIBREF10"}, {"start": 441, "end": 444, "text": "12,", "ref_id": "BIBREF11"}, {"start": 445, "end": 448, "text": "22,", "ref_id": "BIBREF21"}, {"start": 449, "end": 452, "text": "28,", "ref_id": "BIBREF27"}, {"start": 453, "end": 456, "text": "29)", "ref_id": "BIBREF28"}, {"start": 516, "end": 520, "text": "(28,", "ref_id": "BIBREF27"}, {"start": 521, "end": 524, "text": "29)", "ref_id": "BIBREF28"}, {"start": 568, "end": 572, "text": "(12,", "ref_id": "BIBREF11"}, {"start": 573, "end": 576, "text": "24)", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Discussion", "text": "Our localization of endogenous STX11 staining confirms the plasma membrane component of the localization observed when TFP-STX11 and GFP-STX11 was expressed in human CTL and YTS NK cells, respectively (12, 24) . However, we do not observe the additional localization of STX11 on vesicular structures observed when STX11 is over-expressed (12, 22, 24, 28) or with previous antibody localizations (13, 29) . Although vesicular staining was observed in several studies, there was little consensus over the identity of this compartment. Recent reports based on over-expressed TFP-STX11 colocalization with mCherry-Rab11a propose a model by which STX11 is only delivered to the plasma membrane immediately prior to granule fusion via VAMP8-mediated fusion of the recycling endosome (12, 22) . In the present study, we show that there is a steady-state localization of endogenous STX11 on the plasma membrane, which requires Munc18-2 for its delivery to this site.", "cite_spans": [{"start": 201, "end": 205, "text": "(12,", "ref_id": "BIBREF11"}, {"start": 206, "end": 209, "text": "24)", "ref_id": "BIBREF23"}, {"start": 338, "end": 342, "text": "(12,", "ref_id": "BIBREF11"}, {"start": 343, "end": 346, "text": "22,", "ref_id": "BIBREF21"}, {"start": 347, "end": 350, "text": "24,", "ref_id": "BIBREF23"}, {"start": 351, "end": 354, "text": "28)", "ref_id": "BIBREF27"}, {"start": 395, "end": 399, "text": "(13,", "ref_id": "BIBREF12"}, {"start": 400, "end": 403, "text": "29)", "ref_id": "BIBREF28"}, {"start": 777, "end": 781, "text": "(12,", "ref_id": "BIBREF11"}, {"start": 782, "end": 785, "text": "22)", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Discussion", "text": "Interestingly in a previous study the diffuse cytoplasmic GFP-Munc18-2 localization changed to a vesicular colocalization with mcherry-Munc18-2 when both Munc18-2 and STX11 were over-expressed, demonstrating the inter-dependence of these two proteins and the importance of determining the endogenous localization of these proteins with physiological expression levels (24) .", "cite_spans": [{"start": 368, "end": 372, "text": "(24)", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Discussion", "text": "The localization of Munc18-2 on cytolytic granules in CTL that we observe matches the endogenous Munc18-2 staining observed on the secretory granules of mast cells (18, 30) and in neutrophils (31) . Intriguingly these granules are all secretory lysosomes, suggesting that Munc18-2 localizes to this compartment in immune cells.", "cite_spans": [{"start": 164, "end": 168, "text": "(18,", "ref_id": "BIBREF17"}, {"start": 169, "end": 172, "text": "30)", "ref_id": "BIBREF29"}, {"start": 192, "end": 196, "text": "(31)", "ref_id": "BIBREF30"}], "ref_spans": []}, {"section": "Discussion", "text": "We found the distribution of Munc18-2 to be the same in HD cells and STX11-deficient FHL4-cells. This suggests that Munc18-2 does not depend on STX11 for its association with granule membranes and the plasma membrane and could be explained by Munc18-2 associating with an alternative SNARE-protein in the absence of STX11. Hackmann et al. (25) demonstrated that the N-terminal peptide of the STX11 homologue Syntaxin3 (STX3) binds Munc18-2 in vitro (albeit with 20 times lower affinity compared to the STX11 peptide) and that STX3 expression is upregulated through IL-2 culture of human NK cells, a culture condition that has previously been reported to partially restore granule release and killing through FHL4 and five NK cells and CTL (2-4,32). Hackmann et al. furthermore showed STX3 re-localized from intracellular vesicles to the plasma membrane in STX11 deficient CTL. These findings suggest STX3 as one likely candidate for interaction with Munc18-2 at the granule and plasma membrane in the absence of STX11. Conversely, STX11 is lost from the plasma membrane in FHL5 patient cells lacking Munc18-2. STX11 thus appears to require Munc18-2 either to reach the plasma membrane or to remain stably associated with it, although we cannot rule out the possibility that Munc18-2 might stabilize STX11 at an earlier stage during its biosynthesis. Either way, Munc18-2 appears to be required to build up a steady-state pool of STX11 on the plasma membrane of CTL.", "cite_spans": [{"start": 339, "end": 343, "text": "(25)", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Discussion", "text": "Two observations invite further speculation on additional roles for both proteins: STX11 readily accumulates at the leading edge of migrating CTL but we only rarely observed an accumulation at the immune synapse. Fusion of the small number of cytolytic granules that is needed to eliminate a target may not necessarily require a high density of SNARE proteins. At the leading edge of a migrating cell, however, a high number of vesicles that deliver migratory or target sensing factors to the plasma membrane may need to be turned over (33) and it is tempting to speculate that STX11 may be involved in these processes. Similarly, based on the fact that only Munc18-2 (but not STX11) localized to CTL granules it is possible that Munc18-2 may play additional roles on this compartment as previously suggested for granular Munc18-2 in mast cells (18) .", "cite_spans": [{"start": 536, "end": 540, "text": "(33)", "ref_id": "BIBREF32"}, {"start": 845, "end": 849, "text": "(18)", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "Materials and Methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Cells", "text": "Patient UPN666 presented at the age of 1 month with full-blown HLH (fever, splenomegaly, bi-cytopenia, low plasma levels of fibrinogen, high levels of triglycerides and ferritin). Functional study showed defective GRA results; sequencing of the Syntaxin binding protein 2 (Munc18-2) (STXBP2) gene revealed a homozygous deletion-insertion mutation (c.1468_1470delCGGinsTGGACAGCCCTGGACAGGG p.R490 WfsX95), leading to a frameshift at amino acid 490 and predicting a premature stop-codon 95 amino acids later; thus, FHL5 was diagnosed.", "cite_spans": [], "ref_spans": []}, {"section": "Cells", "text": "Ethical approval was obtained in accordance with the standards of the Declaration of Helsinki. A bulk CD8 line (CTL) FHL4 patient (847-1850) was described previously (25) . Bulk CD8+ cells from the FHL5 patient (UPN666) were isolated by negative selection from peripheral blood mononuclear cells (PBMCs) using the Dynabeads Untouched Human CD8 T-cell purification kit from Invitrogen. HD CTL were from donor 434-722.", "cite_spans": [{"start": 166, "end": 170, "text": "(25)", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Cell culture", "text": "CTL were cultured at 37 \u2218 C in a humidified atmosphere with 8-10% CO 2 in RPMI 1640, 2 mM L-glutamine, 1 mM sodium pyruvate, 0.9 M sodium bicarbonate, 50 \u03bcM beta-mercaptoethanol (Invitrogen-GIBCO), 5%", "cite_spans": [], "ref_spans": []}, {"section": "Cell culture", "text": "human AB-Serum (SeraLab) and recombinant human IL-2 (\u223c100 U/mL). CTL were stimulated every 3-4 weeks using irradiated PBMCs isolated from buffy coats in the presence of PHA. ", "cite_spans": [], "ref_spans": []}, {"section": "Antibodies and reagents", "text": "Polyclonal rabbit antibodies were raised against full-length human Munc18-2 (5182 and 5184) and STX11\u0394Cys-GST (5412 and 5413) as previously described (25 Incubation with primary antibody in blocking buffer was 1 h at room temperature. Membranes were washed 3\u00d7 for 10 min in PBS-Tween solution and incubated with HRP-coupled secondary antibody in blocking buffer for 30-45 min at room temperature. Membranes were washed as before followed by an additional wash in PBS for 10 min. Blots were developed using ECL Western Blotting solutions (Amersham).", "cite_spans": [], "ref_spans": []}, {"section": "Immunofluorescence microscopy and confocal imaging", "text": "CTL were washed into pre-warmed serum-free RPMI medium and allowed to settle onto hydrophobic multiwell slides (50 000 cells/well in 50 \u03bcL medium) for 20-25 min at 37 \u2218 C. For conjugates P815 target cells were mixed at 1:1 ratio with human CTL , with 1 \u03bcg/mL PHA in RPMI at 4 \u00d7 10 6 cells/mL concentration, incubated in suspension for 5 min, diluted to 1 \u00d7 10 6 cells/mL, plated onto glass multiwell slides (Hendley), and incubated for a further 20-25 min at 37 \u2218 C to adhere to the glass. Cells were fixed with ice-cold methanol for 5 min on ice (except Figure 2C were Samples were imaged at room temperature with an Andor Revolution Spinning disk system with CSU-X1 spinning disk (Yokogawa), 512 \u00d7 512, 16 \u03bcm 2 -pixel camera (iXon, Andor) IX81 microscope (Olympus) using the 60\u00d7 or 100\u00d7 objective (numerical aperture 1.45) and 2.5\u00d7 camera adapter and with lasers exciting at 405, 488 and 561 nm. Images were acquired using IQ2 (Andor) and processed using IMARIS software (Bitplane).", "cite_spans": [], "ref_spans": [{"start": 555, "end": 569, "text": "Figure 2C were", "ref_id": "FIGREF3"}]}, {"section": "Cytotoxicity assay", "text": "Cytotoxicity was determined with the CytoTox 96 Non-Radioactive Cytotoxicity Assay (Promega) following manufacturers instructions. In brief: CTL were washed 2\u00d7 in killing assay medium (RPMI 1640 medium minus phenol red, 2% fetal calf serum, FCS) and added in serial dilution to a round-bottomed 96-well plate to achieve titrated effector:target (E:T) ratios. P815 target cells were washed 2\u00d7 and resuspended in killing assay media at 1 \u00d7 10 5 cells/mL. Mouse anti-human CD3\u03b5 antibody [UCHT-1] (BD Biosciences, 555330) was added to the target cells at a concentration of 1 \u03bcg/mL (leading to a final concentration of 0.5 \u03bcg/mL upon addition of target cells to CTL suspension). Plates were incubated at 37 \u2218 C. The absorbance of the supernatants at 490 nm determined the release of lactate dehydrogenase and percentage cytotoxicity after 2.5 h.", "cite_spans": [], "ref_spans": []}, {"section": "Granule release assay", "text": "CTL of about 2-5 \u00d7 10 5 were plated in 100 \u03bcL human CTL medium + 1.6 \u03bcL anti-hLAMP1-PE antibody per well on a flat bottom 96-well plate (unstained and CD8+ single stained samples were plated in CTL medium only),100 \u03bcL human CTL medium containing 1 \u03bcg/mL Ionomycin plus 4 \u03bcM PMA or DMSO only were added to each well and the plate was incubated at 37 \u2218 C. At each time point cells were transferred to a pre-cooled round-bottom 96-well plate and spun down at 493 \u00d7 g for 6 min at 5 \u2218 C. The medium was discarded, the cells were resuspended in 200 \u03bcL FACS buffer (PBS, 1% HI FCS, Biosera) per well and stored on ice in the dark until all time points were collected.", "cite_spans": [], "ref_spans": []}, {"section": "Granule release assay", "text": "Cells were pelleted, resuspended in FACS buffer plus anti-CD8-APC antibody (50 \u03bcL per well) and incubated for 30 min on ice in the dark. Cells were washed 1\u00d7 and resuspended in 160 \u03bcL FACS buffer per well.", "cite_spans": [], "ref_spans": []}, {"section": "Granule release assay", "text": "Cells were analyzed using a FACSCalibur instrument (Becton Dickson) ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Cell polarisation and the immunological synapse", "authors": [{"first": "K", "middle": ["L"], "last": "Angus", "suffix": ""}, {"first": "G", "middle": ["M"], "last": "Griffiths", "suffix": ""}], "year": 2013, "venue": "Curr Opin Cell Biol", "link": "13945288"}, "BIBREF1": {"title": "Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11", "authors": [{"first": "U", "middle": [], "last": "Zur Stadt", "suffix": ""}, {"first": "S", "middle": [], "last": "Schmidt", "suffix": ""}, {"first": "B", "middle": [], "last": "Kasper", "suffix": ""}, {"first": "K", "middle": [], "last": "Beutel", "suffix": ""}, 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11 and Munc18-2 antibody specificity. A) Schematic representation of the STX11 and Munc18-2 amino acid sequences indicating the effects of the homozygous mutations present in the FHL4 (847-1850) and FHL5 (UPN666) patient cells used in this study compared to healthy donor (HD). B) Western Blots on human CTL lysates against Munc18-2 and STX11 using the two polyclonal rabbit antibodies 5182 and 5412. C) Percentage of P815 target cells lysis (% killing) for HD (solid black line, squares) or FHL5 patient UPN666 CTL (dotted black line, triangles) at Effector:Target ratios shown. CTL,10 days post restimulation. D) Granule release assay showing surface LAMP1 after 30 minutes PMA-Ionomycin stimulation of CTL from HD (solid black) and FHL5 patient UPN666 (dotted black line). Solid gray line: unstimulated HD CTL. CTL, 10 days post restimulation.", "type": "figure"}, "FIGREF2": {"text": "D). When Munc18-2 was observed on the", "type": "figure"}, "FIGREF3": {"text": "Figure 2: Legend on Next page.", "type": "figure"}, "FIGREF4": {"text": "Figure 2: Endogenous Munc18-2 localizes predominantly to cytolytic granules in human CTL. A) Immunofluorescence microscopy showing localization of Munc18-2 (antibody 5182) in healthy donor (HD) and FHL5 CTL (UPN666). White arrowheads: leading edge. B) Quantitation of Munc18-2 antibody staining from 6 independent experiments: HD (white, n = 397) and FHL5 (gray, n = 374). Gran: granular staining, PM: plasma membrane staining, hatched bar = HD CTL with an accumulation of Munc18-2 at the leading edge. Shown is the mean with standard deviation, *** indicates a significant difference with p < 0.0001, two-tailed students t-test (unpaired), 95% confidence limits. C) Co-staining for Munc18-2 (green) and LAMP1 (red) in three independent experiments comparing HD and FHL5 CTL (n = 158 each). Yellow lines (i) and (ii) were drawn via the IMAGEJ line tool (linewidth: 3 pixel) to obtain Munc18-2 and LAMP1 intensity profiles. Imaris display adjustments optimized for granular signal. D) Co-staining of a CTL-P815 conjugate for Munc18-2 (green) and perforin (red, exclusively expressed in CTL). The white arrowhead indicates a perforin core surrounded by Munc18-2 (n = 119 HD, 2 independent experiments). E) Co-staining of a CTL-P815 conjugate for Munc18-2 (green) and CD8 (red) showing polarization of granule-associated Munc18-2 toward the synapse (n = 63). All images show single confocal planes. Scale bars: 5 \u03bcm.", "type": "figure"}, "FIGREF5": {"text": "Figure 3: Endogenous STX11 is on the plasma membrane of human CTL. A) Localization of STX11 in healthy donor (HD) and FHL4 patient 847-1850 CTL using antibody 5412. White arrowheads: leading edge. B) Percentage of cells with plasma membrane staining for HD (white, n = 328) and FHL4 (black, n = 312) CTL using antibody 5412. PM: plasma membrane staining, hatched bar = HD CTL with an accumulation of STX11 at the leading edge. Results shown as mean from five independent experiments with standard deviation, *** indicate a significant difference with p < =0.0001, two-tailed students t-test (unpaired), 95% confidence limits. C) STX11 staining using antibody 5412 in HD CTL-target conjugates illustrating STX11 accumulation at the synapse (5 experiments, n = 128). D) Co-staining for anti-STX11 5412 (green) and LAMP1 (red) in HD cells (2 experiments, n = 135). Yellow lines (i) and (ii) were drawn via the IMAGEJ line tool (linewidth: 3 pixel) to obtain STX11 and LAMP1 intensity profiles. All images show single confocal planes. Scale bars: 5 \u03bcm.", "type": "figure"}, "FIGREF6": {"text": "Figure 4: Munc18-2 localization is independent of STX11 but in the absence of Munc18-2, STX11 is lost from the plasma membrane. Localization of endogenous Munc18-2 and STX11 in CTL from healthy donor (HD) (n = 265), FHL4 (847-1850, n = 252) and FHL5 (UPN666, n = 263) using antibodies 5182 and 5412 respectively. All images show single confocal planes and represent three independent experiments. Scale bars: 5 \u03bcm.", "type": "figure"}, "FIGREF7": {"text": "Figure 5: STX11 colocalizes with CD8 at the plasma membrane. Co-staining for anti-STX11 5412 (green) and plasma membrane marker CD8 (red) in healthy donor (HD) (n = 149, 4 experiments), FHL4 (847-1850, n = 144, 4 experiments) and FHL5 (UPN666, n = 56, 1 experiment) CTL. Yellow lines (i) and (ii) were drawn via the IMAGEJ line tool (linewidth: 15 pixel) to obtain STX11 and CD8 intensity profiles. All images show single confocal planes. Scale bars: 5 \u03bcm.", "type": "figure"}, "FIGREF8": {"text": "). Other antibodies were sourced: mouse anti-human LAMP1 [H4A3] (Iowa University Hybridoma cell bank), mouse anti-human CD8 [UCHT4] (Sigma-Aldrich, C7423), mouse anti-human perforin [\u03b4G9] (BD Pharmingen, 556434), mouse anti-beta actin [AC-15] (Sigma-Aldrich, A5441), mouse anti-human LAMP1-PE [H4A3] (eBioscience, 12-1079), mouse anti-human CD8-APC [MEM-31] (Abcam, ab26004), mouse anti-human CD4-PE [MEM-241] (Abcam, ab18282). Secondary antibodies goat anti-rabbit-AF488 (A11034, highly cross-adsorbed) and goat anti-mouse-AF568 (A11031, highly cross-adsorbed) and Hoechst nuclear stain 33342 were from Invit- rogen. HRP-conjugated secondary antibodies used for immunoblotting were goat anti-rabbit IgG (Jackson, 111-035-144) and goat anti-mouse IgG (Jackson, 113-035-146). Ionomycin and PMA were obtained from Sigma-Aldrich. Immunoblotting CTL were washed 2-3\u00d7 in ice-cold sterile PBS. Cells (4 \u00d7 10 7 /mL) were lysed in lysis buffer (50 mM Tris-HCl, 100 mM NaCl, 5 mM Mg Cl 2 , 1% Triton X-100, pH 7.6) supplemented with Protease Inhibitor Cocktail (Roche), loaded in SDS Sample Buffer [2\u00d7 sample buffer was: 187.5 mM Tris-HCl (pH 6.8); 6% v/v SDS; 30% v/v glycerol; 0.03% w/v bromophe- nol blue (BioRad)] on 4-12% NuPage Bis-Tris Gels under reducing con- ditions [5% beta-mercaptoethanol (Sigma)] in MES buffer (Invitrogen) and transferred for 90 min at 300 mA to Hybond-C Extra nitrocellu- lose membrane (Amersham Biosciences) using transfer buffer (25 mM Tris, 192 mM glycine, 25% methanol). Membranes were blocked in PBS, 5% Milk (Marvel semi-skimmed) and 0.05% Tween-20 (Sigma-Aldrich).", "type": "figure"}, "FIGREF9": {"text": "and FLOWJO software where gates were set as follows: Live cells (based on forward versus side scatter), CD8+ T-cells (based on APC staining), CD8+/LAMP1+ T-cells based on PE-staining. The use of PE and APC fluorophores meant that no compensation was necessary during data acquisition. % of Max is 'the number of cells in each bin divided by the number of cells in the bin that contains the largest number of cells'. Bins are defined as 'numerical ranges for the parameter on the X axis' (FlowJo manual, http://www.flowjo.com/v6/html/faq.html#2.4.4).", "type": "figure"}, "TABREF1": {"text": "cells were fixed in PFA for 20 min at room temperature), washed extensively in PBS prior to blocking in IF blocking buffer [1% BSA (Sigma-Aldrich) in PBS] for 60 min at room temperature. All antibodies were diluted into IF blocking buffer. Samples were incubated with primary antibodies for 1 h at room temperature in a humidified environment, washed extensively and incubated with secondary antibody for 30-40 min in the dark. Samples were washed with blocking buffer and nuclei were stained with Hoechst diluted (1:25 000) in PBS for 7-10 min at room temperature. Samples were washed prior to mounting with non-setting mounting medium (Vec- tashield, Vectalabs) and sealed with clear nail varnish.", "type": "table"}}}
{"paper_id": "2877653", "_pdf_hash": "5cf0bfb3050798a56db404a346a7e7df54e9f07f", "abstract": [], "body_text": [{"section": "Introduction", "text": "What are traditionally called Noun Phrases seem to come in two varieties--those that begin with a determiner (or a quantifier-like expression), and those that don't. So, at first g lance, while phrases like those desks and most new cars show both a determiner-type eleme nt and a nominal, phrases like Fred, her, linguistics papers, and wheat, do not. The questio n of whether to analyze these latter types of noun phrases as being similar in structure to the former--and if so, how--has often boiled down the the question of the exact identity of the missing determiner element. It has been suggested, for instance, that proper names have a c overt definite article associated with them, so that Fred should be analyzed syntactially and s emantically along the lines of the Fred, with the proviso that the definite article is deleted or otherwise fails to surface phonetically in these and similar instances (see especially Sloat 19 69). Or, with pronouns, it has been proposed (Postal 1969a ) that they are a species of defin ite determiners themselves, and so she for instance should be analyzed as something like sh e one (parallel to that one), with the proviso that the nominal element be phonetically unreali zed.", "cite_spans": [{"start": 979, "end": 992, "text": "(Postal 1969a", "ref_id": "BIBREF140"}], "ref_spans": []}, {"section": "Introduction", "text": "The set of issues with the other determinerless noun phrases like linguistics papers or wheat is a bit different, and it's what we're going to be discussing here. These have been discussed most often in connection with genericity (some of the basic background works b eing Dahl 1975 , Smith 1975 , and Lawler 1973 . The terminology of \"bare plural\" and \"mas s term'\"to describe these has become most familiar in current generative linguistics, though a current term encompassing both is lacking; however, as the two have a great deal in comm on despite their well-known differences, the lack of an appropriate cover term is apparent. S o somewhat irrationally, I'll use the term \"Bare Plurals' (BP's) but in so doing I also inten d to include mass terms (unless otherwise noted).", "cite_spans": [{"start": 273, "end": 282, "text": "Dahl 1975", "ref_id": "BIBREF43"}, {"start": 283, "end": 295, "text": ", Smith 1975", "ref_id": "BIBREF147"}, {"start": 296, "end": 313, "text": ", and Lawler 1973", "ref_id": "BIBREF103"}], "ref_spans": []}, {"section": "Introduction", "text": "The basic fact about BP's is, first, that they appear have more than one interpretation . In a given sentence they might be interpreted existentially, as in (1a), or as something like a universal, (1b). Curious people like to travel a lot. (All, or nearly all, curious people; curious people in general)", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "They also typically have just one of these interpretations available in any given sentence (on a constant interpretation of the sentence less the BP). So, for instance, (1a) has no universal or general reading, nor does (1b) have an existential reading. This observation is by no me ans hard and fast, however. In a sentence like (2), from Longobardi (1994) , both readings a ppear accessible:", "cite_spans": [{"start": 340, "end": 357, "text": "Longobardi (1994)", "ref_id": "BIBREF110"}], "ref_spans": []}, {"section": "Introduction", "text": "(2) I only excluded old ladies (=Longobardi's (41a)).", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Such a sentence can be understood as excluding only some older women (and admitting oth ers), or as excluding all who are older.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Facts such as these have spurred a great deal of work, and controversy. It is possible to separate out two closely-related issues concerning the syntax and semantics of BP's:", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "(A) What do BP noun phrases mean? Do they have a single, unified meaning which appears to be different in different contexts, or are there two or more meanings?", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "(B) How do the syntactic and semantic (and pragmatic) contexts determine which interpretation(s) of the BP is/are appropriate?", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "While these two questions are intertwined, we are going to focus on the former question.", "cite_spans": [], "ref_spans": []}, {"section": "An early unified analysis", "text": "Traditional grammars of English assume that BP's have covert determiners associat ed with them. One of these is the plural form of the indefinite singular a(n) and accounts fo r the existential interpretation; the other is a universal sort of determiner or quantifier, having something like the force of all or any. This analysis presents two quite different problems.", "cite_spans": [], "ref_spans": []}, {"section": "An early unified analysis", "text": "First, it would appear to predict systematic ambiguity of BP's, when one finds more genera lly lack of it. Second, it is no trivial matter to specify the exact identity of the \"universal\" n ull determiner, as it is clearly not universal, nor quite like any of the other non-null determin ers/quantifiers. These problems were discussed in Carlson (1977 Carlson ( , 1980 , the work inspired by that of Milsark (1974) . The reason, I argued there, that bare plurals are not generally am biguous in a given sentence, is that they are not ambiguous in and of themselves. Rather, it i s the syntactic/semantic context in which they appear that makes them appear to have differe nt interpretations, not any difference in the determiner or any other element in the noun phra se. Thus, the interpretation of the noun phrase 'curious people' in (1a), in terms of the cont ribution that that noun phrase makes to the meaning of the whole, is identical to the interpret ation it receives in (1b).", "cite_spans": [{"start": 338, "end": 351, "text": "Carlson (1977", "ref_id": "BIBREF16"}, {"start": 352, "end": 368, "text": "Carlson ( , 1980", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "An early unified analysis", "text": "That interpretation, it was argued, was the name of a kind of thing, thus aligning the i nterpretation of bare plurals with that of proper names and definites as unquantified/referent ial noun phrases. If one were to assign the covert determiner a meaning (though there it was accomplished syncategorematically), it would be a function from predicate meanings to gene ralized quantifier meanings of the logical sort of names and definite singular terms. This ide ntification was supported by some data showing some similarities between BP's and prope r names, such as the ability of the phrase \"So-Called\" to appear with each (Postal 1969b ) o r to appear in contexts favoring definites over indefinites (Postal 1969a) ; but it appeared to l eave other data not easily accounted for which aligned BP's with indefinites or noun phrases with weak determiners, such as the easy appearance of BP's in English existential constructi ons.", "cite_spans": [{"start": 626, "end": 639, "text": "(Postal 1969b", "ref_id": "BIBREF141"}, {"start": 704, "end": 718, "text": "(Postal 1969a)", "ref_id": "BIBREF140"}], "ref_spans": []}, {"section": "An early unified analysis", "text": "The mechanism for providing the apparently differing interpretations was based on a n analysis of the stage-level/individual-level distinction, in which stage-level predicates (as f ound in (1a)) introduced as a part of their meanings existential quantifiers, giving rise to the existential readings found in such examples as (1a); individual-level predicates, as in (1b), d", "cite_spans": [], "ref_spans": []}, {"section": "An early unified analysis", "text": "id not introduce any similar existential quantifiers, so that an existential reading does not ap pear. That is, existential readings of BP's were attributed to an existential quantifier in the i nterpretation of the sentence that is not a part of the meaning of the BP itself.", "cite_spans": [], "ref_spans": []}, {"section": "An early unified analysis", "text": "The \"kinds\" treatment of bare plurals is motivated chiefly by several factors, only a c ouple of which I'll mention here. One is the existence of predicates which appear only appli cable to kinds, such as: which allows John to polish some apples and Mary to eat some other apples (that he never p olished); on the other reading the apples are, of course, identical. In Carlson (1980) this dif ference was attributed to whether the pronoun was interpreted coreferentially or as an E-type pronoun.", "cite_spans": [{"start": 369, "end": 383, "text": "Carlson (1980)", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "An early unified analysis", "text": "Further, NP's of the form \"that kind of x\" also, it is claimed, exhibit \"generic\" and \"e xistential\" readings as well:", "cite_spans": [], "ref_spans": []}, {"section": "An early unified analysis", "text": "That kind of animal eats wood. (\"generic\")", "cite_spans": [], "ref_spans": []}, {"section": "An early unified analysis", "text": "b.", "cite_spans": [], "ref_spans": []}, {"section": "An early unified analysis", "text": "I saw that type of animal at the pet store yesterday (\"existential\")", "cite_spans": [], "ref_spans": []}, {"section": "An early unified analysis", "text": "Additional arguments can be found in Carlson (1977 Carlson ( , 1980 and elsewhere. This was, I beli eve, the first attempt to deal with the phenomena systematically within a formal semantics fra mework (though see especially Lawler 1973) , and it didn't take long for researchers to work on improvements.", "cite_spans": [{"start": 37, "end": 50, "text": "Carlson (1977", "ref_id": "BIBREF16"}, {"start": 51, "end": 67, "text": "Carlson ( , 1980", "ref_id": "BIBREF17"}, {"start": 225, "end": 237, "text": "Lawler 1973)", "ref_id": "BIBREF103"}], "ref_spans": []}, {"section": "Critiques and criticisms", "text": "The unified \"kinds\" view was certainly not beyond criticism. DeMey (1980 DeMey ( , 1982 was among the first to question the necessity of \"stages\" for an analysis. More detailed pre sentations of alternative views are found in ter Meulen (1979) , on mass terms, and more spe cifically in Wilkinson (1991) , on bare plurals, who offers perhaps the most comprehensive c ritique to date. Kratzer (1980) presents a very interesting criticism of the \"kinds\" analysis t hat has had some reply (Carlson 1996; \u00c9. Kiss1998) . Lasersohn (1997) likewise critiques some of the semantic claims associated with a \"kinds\" analysis from examining the detaile d semantics of donkey sentences. Schubert & Pelletier (1987) have a detailed critical discus sion of the framework. Condoravdi (1994) and \u00c9. Kiss (1998) argue that a notion of specifi city (though characterized differently in each case) distinguishes apparently universal from i ndefinite appearances of bare plurals; Condoravdi (1994) , like Wilkinson, presents criticis ms fairly comprehensively. Even on a unitary \"kinds\" analysis, there remain several alterna tive points of view (e.g., see Ojeda,1993) , and while a unified analysis would seem a priori d esirable it is by no means taken for granted.", "cite_spans": [{"start": 516, "end": 532, "text": "Lasersohn (1997)", "ref_id": "BIBREF102"}, {"start": 675, "end": 702, "text": "Schubert & Pelletier (1987)", "ref_id": "BIBREF145"}, {"start": 758, "end": 775, "text": "Condoravdi (1994)", "ref_id": "BIBREF38"}, {"start": 783, "end": 794, "text": "Kiss (1998)", "ref_id": "BIBREF58"}, {"start": 960, "end": 977, "text": "Condoravdi (1994)", "ref_id": "BIBREF38"}], "ref_spans": []}, {"section": "Critiques and criticisms", "text": "As the semantic theory of indefinites developed during the 1980's (Lewis 1975; Ka mp 1981; Heim 1982) , another analysis of BP's appeared that made quite different assumpt ions about their character. The most detailed proposals are to be found in Krifka and Gerst ner-Link (1986) , Wilkinson (1991) , Kratzer (1995 Kratzer ( , initially written in 1989 One very fertile version is Diesing (1992) and related work. In this theory, there is a simple algorithm for determining how the free variable introduced by the noun phrase gets bound: if (at LF) an NP is found within the VP of the sentence, it gets bound by an existent ial quantifier (\"existential closure\") and mapped to a nuclear scope; and if it appears in the IP of the sentence, it gets bound by something else and appears in a restrictor. That \"somet hing else,\" in the case of quantified noun phrases that have undergone QR, would be the qua ntifier expression (e.g., the universal all in the noun phrase all men), but there are other poss ible binders as well. For instance, adverbs of quantification, as found in (7) below, can bind the free variable in the (interpretation of the) subject noun phrase linguists, appearing at LF in the IP of the sentence.", "cite_spans": [{"start": 66, "end": 78, "text": "(Lewis 1975;", "ref_id": "BIBREF105"}], "ref_spans": []}, {"section": "Critiques and criticisms", "text": "Linguists are often good musicians.", "cite_spans": [], "ref_spans": []}, {"section": "Critiques and criticisms", "text": "For a sentence like (8), in which there is no overt element to provide binding, a generic opera tor GEN is usually assumed of the sort outlined in Krifka et al (1995) (see also Krifka 198 7), and, earlier, Farkas and Sugioka (1983) ) to serve as a binder for the variable introduced b y the BP subject noun phrase: Krifka et al (1995) , the point of view espoused by Krifka & Gerstner-Link, Kratzer, Wi lkinson, Diesing, and others was presented and treated as the \"center-of-opinion\" and prev ailing view (even if there may have been some very minor split of opinion among the numer ous co-authors).", "cite_spans": [{"start": 147, "end": 166, "text": "Krifka et al (1995)", "ref_id": "BIBREF91"}, {"start": 206, "end": 231, "text": "Farkas and Sugioka (1983)", "ref_id": "BIBREF61"}, {"start": 315, "end": 334, "text": "Krifka et al (1995)", "ref_id": "BIBREF91"}], "ref_spans": []}, {"section": "Critiques and criticisms", "text": "However, looking at things in this way also has some distinct advantages. For insta nce, in the Carlson (1977) analysis, the fact that indefinite singulars in English and other lan guages may also have generic readings along with their usual existential readings, as in (9), t akes a bit of extra work. But within the DRT framework coupled with some of the principle s mentioned above (along with a few others), this appears to fall out naturally and, in fact, w ould be a bit hard to prevent given assumptions. ", "cite_spans": [{"start": 96, "end": 110, "text": "Carlson (1977)", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Some additional facts about English BP's", "text": "For example, the similarities noted earlier about the relationship between bare plurals and proper names-the other side of the coin-haven't been dealt with. And long-noted sc oping facts about existential readings of bare plurals have also tended to get set aside. It has been observed, and generally agreed, that bare plurals exhibit only narrowest-scope reading s, in contrast to overt indefinites, which exhibit variable scope. For instance, a sentence like (10 a) does not mean there are specific shoes that are being sought; nor does (10 b) have a meaning equivalent to \"There are some cows that are not in the garden\", thereby allowing s ome (other) cows to be there:", "cite_spans": [], "ref_spans": []}, {"section": "Some additional facts about English BP's", "text": "(10) a. Mary is looking for shoes.", "cite_spans": [], "ref_spans": []}, {"section": "Some additional facts about English BP's", "text": "b.", "cite_spans": [], "ref_spans": []}, {"section": "Some additional facts about English BP's", "text": "Cows are not in the garden.", "cite_spans": [], "ref_spans": []}, {"section": "Some additional facts about English BP's", "text": "These and other unexpected properties of BP's on their existential readings are missed on a ny analysis such as this which equates BP empty determiners with the indefinite plural. On e particular issue that has received only minor attention in the literature (see for instance Lo ngobardi 1994) is whether BP's are real contrasting plurals in the sense of excluding singul ar objects from their denotations. It appears to make some sense, at least, to claim that a que stion like \"Are there holes in the wall?\" is truly answerable with \"Yes\" under the circumst ance where just one hole is in the wall and no more. If this is so, it argues that BP's are not indefinite plurals that stand in contrast to the indefinite singular, but rather forms whose inte rpretation encompasses both.", "cite_spans": [], "ref_spans": []}, {"section": "Some additional facts about English BP's", "text": "There are several other aspects of the interpretation of BP's that remain more near th e periphery of research, but which have arisen in the course of this research, and which have motivated more detailed examination of BP's. For instance, Condoravdi (1994) has success fully focused attention on examples where bare plurals appear interpreted existentially, yet a ppears as subjects of individual-level predicates.", "cite_spans": [{"start": 240, "end": 257, "text": "Condoravdi (1994)", "ref_id": "BIBREF38"}], "ref_spans": []}, {"section": "Some additional facts about English BP's", "text": "(11) (There was a ghost haunting campus) Students were aware of this danger.", "cite_spans": [], "ref_spans": []}, {"section": "Some additional facts about English BP's", "text": "As Condoravdi points out, this is not a simple existential statement, as (11) above does not mean the same as (12): (12) (There was a ghost haunting campus). There were students who were aware of this danger.", "cite_spans": [], "ref_spans": []}, {"section": "Some additional facts about English BP's", "text": "But this is interpreted much more like a sentence with a definite article:", "cite_spans": [], "ref_spans": []}, {"section": "Some additional facts about English BP's", "text": "...The students were aware of this danger.", "cite_spans": [], "ref_spans": []}, {"section": "Some additional facts about English BP's", "text": "Such \"functional\" readings, as Condoravdi calls them, can be teased apart from truly generi c readings; she ultimately argues that there is an extensional generic reading--the functional reading--that stands alongside the generic and existential readings.", "cite_spans": [], "ref_spans": []}, {"section": "Some additional facts about English BP's", "text": "\u00c9.. Kiss (1998) also points out some facts about bare plurals when focused, in that th ey can take on purely existential readings, unlike their unfocused counterparts. So, for insta nce, in (14): (14) GIRLS know mathematics the best in my school.", "cite_spans": [{"start": 4, "end": 15, "text": "Kiss (1998)", "ref_id": "BIBREF58"}], "ref_spans": []}, {"section": "Some additional facts about English BP's", "text": "it can mean that those students who know it best, are among the girls in the school; it may a lso be read generically as about \"all\" girls, as well. \u00c9.Kiss argues that this possibility of inte rpretation results from the fact that something must be interpreted specifcially in order to be topicalized (or, contrastively focused).", "cite_spans": [], "ref_spans": []}, {"section": "Some additional facts about English BP's", "text": "A further fact about bare plurals, noted in Longobardi (1994 Longobardi ( , 2000 though also reco gnized (but not accounted for) in Carlson (1980) , is that when a relative clause or other post verbal modifier (in English) is appended, an existential interpretation may arise where none was possible before. So, for instance, with:", "cite_spans": [{"start": 44, "end": 60, "text": "Longobardi (1994", "ref_id": "BIBREF110"}, {"start": 61, "end": 80, "text": "Longobardi ( , 2000", "ref_id": "BIBREF111"}, {"start": 132, "end": 146, "text": "Carlson (1980)", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "Some additional facts about English BP's", "text": "(15) Neighbors are tall.", "cite_spans": [], "ref_spans": []}, {"section": "Some additional facts about English BP's", "text": "only the (slightly implausible) generic reading seems possible, but in (16) In the second sentence, but not in the first, the object of John's search can be a specific set o f books; both sentences have a clear narrow-scope reading. Again, these facts are different from what we observe with indefinite singulars in corresponding cases. These facts are disc ussed in more depth by Chierchia (1998b) . One further lingering fact, noted by Barbara Pa rtee (1985) , is that when bare plurals (though not mass terms, in this instance) function as \" dependent plurals\", they show scoping effects as well.", "cite_spans": [{"start": 381, "end": 398, "text": "Chierchia (1998b)", "ref_id": "BIBREF30"}], "ref_spans": []}, {"section": "Some additional facts about English BP's", "text": "Exactly what the facts are, and how all these relate to each other, remains not very wi dely examined at the moment, but there is getting to be a rich enough set of data and sufficie nt theoretical development to support growing work in this somewhat obscure area.", "cite_spans": [], "ref_spans": []}, {"section": "BP's in Romance (and Germanic)", "text": "Somewhat ironically, some of the most interesting work on BP's comes from consid eration of languages which don't have lots of them. The most highly developed body of liter ature is on Romance, especially Spanish and Italian, which have fewer BP's than English, an d French (which has virtually none). To foreshadow some, the problem raised by the \"kind s\" analysis as well as by the more commonly assumed indefinites analysis is that one woul d expect any language with BP's to exhibit them fairly freely, as in Germanic, and for BP's to have both generic and existential readings. However, consideration of other languages sh ows this is not always the case. What has resulted thus far from this line of research has bee n a return to a more sophisticated \"kinds\" analysis, which nonetheless makes critical use of the insights of the theory of indefiniteness. One such analysis is found in de Swart (1993), who bases her analysis on facts from English and French, and others I discuss below. (He re, as above, I can really only point to but cannot do full justice to the scope of the individual works, which contain a great deal more than the few facts presented here.)", "cite_spans": [], "ref_spans": []}, {"section": "BP's in Romance (and Germanic)", "text": "It has been known for some time that in Spanish, the distribution and interpretation of BP's is limited. Contreras (1986) notes such facts as these: (21) On the semantic side, Laca (1990) presents a number of keen observations about ho w one expresses generic objects in such a language, which has restricted occurrences of BP'", "cite_spans": [{"start": 176, "end": 187, "text": "Laca (1990)", "ref_id": "BIBREF97"}], "ref_spans": []}, {"section": "BP's in Romance (and Germanic)", "text": "s. Spanish generally uses the definite article to express what we are calling the generic readi ng (though Laca argues the informational notion of \"inclusive\" presents a better understandi ng), and the bare plural form is generally reserved for existential (= \"non-inclusive\") reading s. Consider, for instance, the ambiguity inherent in the English:", "cite_spans": [], "ref_spans": []}, {"section": "BP's in Romance (and Germanic)", "text": "(22) The Gwamba-Mamba worship bears.", "cite_spans": [], "ref_spans": []}, {"section": "BP's in Romance (and Germanic)", "text": "The preferred reading for this is that the species represents the object of worship; however, there is also a reading where there are some specific bears they keep caged up, which they w orship to the exclusion of other bears. This is the reading most favored for:", "cite_spans": [], "ref_spans": []}, {"section": "BP's in Romance (and Germanic)", "text": "(23) The Gwamba-Mamba worship idols.", "cite_spans": [], "ref_spans": []}, {"section": "BP's in Romance (and Germanic)", "text": "That is, the object of worship is some specific group of idols, not idols in general (though th is is still a possible reading). The following Spanish sentences express these preferred read ings: In this case, the use of the definite form is correlated with focus on the verb.", "cite_spans": [], "ref_spans": []}, {"section": "BP's in Romance (and Germanic)", "text": "Some very interesting proposals can be found in Vergnaud and Zubizarreta (1992) regarding the possibility of generic interpretations in a comparison of French and English (f ocusing on expressions of inalienable possession). They lay out the idea that in the DP, spe cific reference arises from the Determiner itself, whereas the NP is the source of type-level r eference (or denotation) (Svenonius 1996 , recasts this as a distinction based on whether refe rence to context is available). Vergnaud and Zubizarreta express this as their \"Correspond ence Law\" (p. 612):", "cite_spans": [{"start": 388, "end": 403, "text": "(Svenonius 1996", "ref_id": "BIBREF151"}], "ref_spans": []}, {"section": "BP's in Romance (and Germanic)", "text": "(28) When a DP or an NP denotes, the DP denotes a token and the NP denotes a type Phrases exhibiting determiners that nonetheless denote types require a notion of 'expletive determiner', that is, a determiner that appears without semantic effect, except to allow the de notation of the NP to serve as the whole DP's denotation. The claim is that French allows e xpletive determiners (the definite article, in most cases), whereas English does not, and that t his accounts for many differences between French and English discussed in the article. proposal here is that in Germanic, determinerless common nouns can move into the empty D position at the level of LF, which gives rise to a referential, generic reading for BP's; failu re to move into the D position will result in a \"default\" instance of existential interpretation.", "cite_spans": [], "ref_spans": []}, {"section": "BP's in Romance (and Germanic)", "text": "In this case, the presumption would need to be that the existential interpretation is available o nly for those positions which in Germanic would count as governed positions, generic readi ngs being the only available in ungoverned positions. Thus, to speculate for a moment, the I P position that Diesing has suggested for generic subjects would probably count as an ungo verned position, allowing only the generic reading; the VP-internal position Diesing assume s for stage-level subjects would be governed, and thus would allow for existential readings, a nd generic readings as well, unless otherwise restricted.", "cite_spans": [], "ref_spans": []}, {"section": "BP's in Romance (and Germanic)", "text": "The notion of an expletive determiner is also developed in Brugger (1993) , who focu ses on German as well as Italian, comparing them both with English. Brugger argues that th e definite article in German, but not in English (at least for the constructions considered), ca n be expletive. One basic fact pointed out is that while English plural definites cannot be int erpreted generically (or if so, only marginally), in German this is an entirely natural way of e xpressing genericity. Thus, (30) has a generic reading, while its English counterpart does n ot, referring instead only to some contextually determined set of elephants, which is also a p ossibility for the German. Brugger concludes that German (and Dutch) BP's cannot be kind-denoting; the definite plu rals, however, have an expletive determiner in them, which fills the D position which would h ave to otherwise be bound by another operator. The possibility of the English definite funct ioning this way is precluded because the English definite article carries no grammatical featu res (such as case, number, gender), and hence must function semantically.", "cite_spans": [{"start": 59, "end": 73, "text": "Brugger (1993)", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "BP's in Romance (and Germanic)", "text": "The most comprehensive attempt to deal with both the syntax and the formal semanti cs of BP's in Romance and Germanic is found in Gennaro Chierchia's work (1998a Chierchia's work ( , 1998b . Chierchia takes as his starting point a \"kinds\" approach that he also developed in his disse rtation (Chierchia1988, written in 1984)), which involves a formal semantics making use of t ype-shifting, chiefly as a way of characterizing the meanings of nominalizations more gener ally. Type-shifting is also a means of resolving type mismatches between function and argu ment (Partee,1987 In unpublished work, Delfitto (1998) has explored many of these same issues, again with emphasis on Romance and Germanic, and also arguing for a unitary analysis of BP's.", "cite_spans": [], "ref_spans": []}, {"section": "BP's in Romance (and Germanic)", "text": "One of Delfitto's main theses is that the existential readings of BP's arises from an existe ntial quantifier associated with the event-argument position of verbs, and that genericity arise s not from the presence of a GEN-type quantifier, but from the aspectual character of the se ntence itself. Possibly taking a cue from Diesing and Longobardi, Delfitto proposes that ge neric sentences involve an aspectual structure which requires one of its arguments (typically the subject) to be marked as an external argument (in Diesing's terms, in the IP). The effect is to create a predicational structure which demands that type-shifting take place on the exter nal argument whereby it gets interpreted intensionally--as a property set. Delfitto also deals with the apparent scopelessness of existential readings of BP's and the cases where they tak e on scopal properties, also discussed in Chierchia. One particular issue Delfitto wishes to deal with is the fact that the presence of a modifier, such as a relative clause, can make for ac ceptable BP's in cases where a bare noun seems unacceptable. The emphasis on localization is highly reminiscent of many analyses of \"stage-level\" predi cates (Kratzer1995; McNally 1995, to mention but two), but Dobrovie-Sorin and Laca put t his common theme into a new and richer setting which addresses the types of issues also di scussed extensively by Fernald (1994) .", "cite_spans": [], "ref_spans": []}, {"section": "A Little on Bare Singulars", "text": "Less work has focused on singular count common nouns lacking determiners, as in the Romance and Germanic languages these do not appear systematically in argument positi ons (though may in vocative and predicative constructions). However, this does not mean th ey are totally lacking. English has them sporadically (\"I saw it on television\" or, as Richard", "cite_spans": [], "ref_spans": []}, {"section": "A Little on Bare Singulars", "text": "Oehrle pointed out to me, \"The special relation between doctor and patient deserves special legal protection.\"). In Scandinavian languages, they appear quite a bit more systematically.", "cite_spans": [], "ref_spans": []}, {"section": "A Little on Bare Singulars", "text": "Borthen (1998) discusses these in Norwegian. Here we find, for instance: Work on bare singulars in other languages that likewise have articles and/or pluralit y has yielded a very similar pattern of syntactic and semantic observations. The work on Al banian (Kallulli 1996 (Kallulli ,1999 shows a pattern there strikingly similar to the facts presented ab ove. Bare singulars in Brazilian Portuguese have been investigated in detail by Schmidt and Munn (1999) and Schmidt (1999, 2000) , where a similar set of facts seems to fa ll out, though there bare singulars also may function as subjects. Dayal (1999) examines ba re singulars in Hindi, which are restricted to objects position, and again the same array of se mantic observations hold. A quite different set of observations about bare singulars, though, appears to hold for English (e.g., \"He went to prison; She is at school\") as discussed in det ail by Stvan (1998) .", "cite_spans": [{"start": 258, "end": 272, "text": "(Kallulli 1996", "ref_id": "BIBREF82"}, {"start": 436, "end": 459, "text": "Schmidt and Munn (1999)", "ref_id": "BIBREF144"}, {"start": 911, "end": 923, "text": "Stvan (1998)", "ref_id": "BIBREF150"}], "ref_spans": []}, {"section": "A Little on Bare Singulars", "text": "It is widely recognized that bare singulars occur in any of the large number of langu ages which lack overt definite and indefinite articles, but their study in the context of the issu es raised within the framework of BP's has lagged somewhat in comparison. Chierchia's wo rk makes an attempt to deal with such languages as the Slavic languages, Japanese, and Chin ese. A partial effort in this direction for Slavic languages can be found in Filip (1993) and e lsewhere, but the most detailed effort to date that I am aware of is to be found in Cheng and Sybesma (1999) , who undertake a detailed comparison between Mandarin and Cantonese w ithin the context of these issues (see also Gelman & Tardif 1997 and Basilico 1998 for som e observations regarding Chinese bare nouns as well).", "cite_spans": [{"start": 443, "end": 455, "text": "Filip (1993)", "ref_id": "BIBREF66"}, {"start": 546, "end": 570, "text": "Cheng and Sybesma (1999)", "ref_id": "BIBREF26"}, {"start": 686, "end": 694, "text": "Gelman &", "ref_id": "BIBREF70"}, {"start": 695, "end": 710, "text": "Tardif 1997 and", "ref_id": "BIBREF70"}], "ref_spans": []}, {"section": "A Little on Bare Singulars", "text": "Mandarin Chinese, like many others, is a language without plural morphology or arti cles, so many noun phrases have the appearance of bare singulars. These may be interpreted That is, bare nouns have more structure than just the noun (or NP) itself. To achieve a defin ite interpretation, the N moves into the empty Cl position in Mandarin (similar to the Longo bardi analysis of proper names). As a consequence, the empty position is filled and it need not be governed, which allows it to appear in preverbal position. The indefinite interpretatio n arises when the N does not move into Cl, and as a result the empty position must be gover ned, as in the Spanish/Italian analyses with empty D position that must also be governed. In", "cite_spans": [], "ref_spans": []}, {"section": "A Little on Bare Singulars", "text": "Cantonese, on the other hand, the fact that an overt Cl is used to express definiteness preclu des the possibility of also using the covert strategy of movement into Cl to express definiten ess (this also follows a suggestion of Chierchia), and as a result the empty Cl is interpreted i ndefinitely if governed, or if the N moves into Cl it may also be interpreted generically. Pre sence of an overt Cl blocks a generic interpretation. This work certainly sets the stage for fu ture work in languages lacking articles, making use of the body of literature duscussed abov e.", "cite_spans": [], "ref_spans": []}, {"section": "A Little on Bare Singulars", "text": "Before closing, it is worthwhile mentioning some other recent work. Brockett (1991 ) contains a detailed examination of Japanese; we also find Dayal (1992) on the situation in Hindi and Portersfield & Srivastav (1988) on the contrast between Hindi and Indonesian.", "cite_spans": [{"start": 143, "end": 155, "text": "Dayal (1992)", "ref_id": "BIBREF44"}], "ref_spans": []}, {"section": "A Little on Bare Singulars", "text": "Chung (2000), in a reply to Chierchia, also examines Indonesian in detail. Petronio (1995) discusses ASL (which has no plurality or articles; see also the other papers in the same volu me). Greenberg (1994) comprehensively presents facts about Hebrew, and \u00c9. Kiss (1998 ), Hungarian. Bittner (1994 and Van Geenhoven (1998) discuss West Greenlandic incorpor ated nominals within this tradition, where one finds the most detailed semantic observations about these structures (along with the work on Hindi bare singulars--which are arguably inc orprated forms--mentioned above). It appears that incorporated nominals (chiefly, objects o f verbs) follow the general pattern of semantic interpretation characteristic of BP's and bare singulars as well--chiefly, in having nearly always weak indefinite existential and number-ne utral interpetations. The same range of interpretations also appears to hold for \"pseudo-inc orprated\" forms (Massam 2001) . This suggests that incorporated nominals and BP's share a lot in common that deserves closer examination, as argued most pointedly by van Geenhov en (1995) . In some languages, such as West Greenlandic, incorporated nominals can be mo dified or quantified from outside the word; this gives rise to a discontinuous syntactic form--a \"split\" construction--which likewise raises interesting questions about the semantics of de terminerless nouns even in languages which do not have incorporation (Diesing 1992; Beer man 1997; also Geurts 1996) .", "cite_spans": [{"start": 75, "end": 90, "text": "Petronio (1995)", "ref_id": "BIBREF137"}, {"start": 259, "end": 269, "text": "Kiss (1998", "ref_id": "BIBREF58"}], "ref_spans": []}, {"section": "A Little on Bare Singulars", "text": "Perhaps the most comprehensive survey of the range of nominal forms used to expr ess genericity is to be found in Gerstner-Link (1998), who compares forty disparate langua ges and summarizes the results in a series of proposed universals. The patterns she finds ar e largely in keeping with the detailed work on a more limited set of languages (she uses Ger man as her base case), but there are some surprises, for example, that not all languages with indefinites can use indefinites generically; but definites can be consistently used that way.", "cite_spans": [], "ref_spans": []}, {"section": "A codicil on stages", "text": "I would be remiss not to bring up one closely related issue before concluding. The Carlson (1977 Carlson ( , 1980 analysis makes use of a construct of \"stages\", temporally-restricted portions of individuals, as a means of characterizing existential readings of bare plurals. M ost researchers, including the majority of those discussed above, have found such constructs dispensible, using existential quantification over individuals instead for the indefinite readin g. This results in equivalent truth-conditions (in most cases) but also in an ontologically mo re parsimonious framework (though many make use of an event-semantics that introduces v ery similar types of entities into the model). However, a good number of researchers have f ound that stages themselves are useful constructs in their own right, as in Stump's (1981) 1997a, 1997b) , in some provocative work, has also employed and defended stages in the a nalysis of St'at'imcets (Lillooet Salish) noun phrases in order to account for their temporal restrictedness. Lin (1999) has proposed that stages be countenanced in order to account for the semantics of shenme 'what' in donkey-type conditional sentences in Chinese (also exa mined in great detail by Huang and Cheng (1996) though they focus on the semantics of 'w ho', which turns out to have some different properties). The stage/individual contrast has al so been invoked in unpublished work to form an account of the semantic distinction betwee n the Japanese anaphoric expressions sore vs. kare. Carlson (1991) discusses the use of st ages for the analysis of certain demonstratives in English--see B\u00fcring (1998) for an interesti ng and closely-related discussion.", "cite_spans": [{"start": 83, "end": 96, "text": "Carlson (1977", "ref_id": "BIBREF16"}, {"start": 97, "end": 113, "text": "Carlson ( , 1980", "ref_id": "BIBREF17"}, {"start": 818, "end": 832, "text": "Stump's (1981)", "ref_id": "BIBREF148"}, {"start": 1222, "end": 1244, "text": "Huang and Cheng (1996)", "ref_id": "BIBREF25"}, {"start": 1625, "end": 1638, "text": "B\u00fcring (1998)", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Outcomes and Conclusions", "text": "Researchers now have on hand a large and sophisticated set of both data and analys es to draw from in considering the appropriate syntax and semantics of BP's. This presents us with an excellent base from which to work on this and related problems from a variety of perspectives, in a variety of the world's languages. On some matters, there is quite solid ge neral agreement. One is that BP's on both existential and generic readings should try to be analyzed as having something basic in common. Another is that very close attention needs t o be paid to issues of specificity and scoping for the indefinite readings. We have also seen a general trend towards taking elements of both the theory of indefinites and the kinds anal ysis, and trying to preserve something like a unitary analysis of BP's across languages: few if any of the reseachers noted, in particular, defend an analysis in which there are multiple n ull D's. The success of assuming an empty D position that must be properly governed in so me languages is also widely appealing, as is the idea that there is a connection between move ment into D and definiteness/genericity.", "cite_spans": [], "ref_spans": []}, {"section": "Outcomes and Conclusions", "text": "An area that can use closer scrutiny, aside from extending research to a broader num ber of languages, is a more careful understanding of the relation between definite singular, d", "cite_spans": [], "ref_spans": []}, {"section": "Outcomes and Conclusions", "text": "efinite plural, BP, singular indefinite generics, incorporated nominals, and the relation of the se expressions to overtly expressive \"kind\" NP's in general, in languages which allow the m. This has not been entirely ignored by any means, but not enough has been done to creat e a consensus opinion. One also does not find convincing analyses (to my mind) of exampl es such as (2) (41) --DRT existential closure (Diesing 1992 , Krifka 1987 --Type-shifting (Chierchia 1998b) --Quantification over stages (Carlson 1980) --Binding of a situation variable (de Swart 1993; Delfitto 1997) --Default interpertation of an empty D (Longobardi 1994) --Binding due to sentence information structure (Glasbey, 1993) --Location-argument binding (Dobrovie-Sorin 1996) --Categorical/thetic structure (Basilico1998, Ladusaw 1994; Kuroda1972) --Specificity (Condoravdi 1994) --Mapping from properties to propositions (Carlson 2000) --Referential anchoring (L\u00f6bner 2000) and so forth. The variety here is perhaps best understood as a reflection of the differing the oretical asumptions and/or machinery that are available, but it certainly reflects the wide-ope n state of the area as it stands. The question is, how much difference do these various assu mptions make?", "cite_spans": [{"start": 456, "end": 473, "text": "(Chierchia 1998b)", "ref_id": "BIBREF30"}, {"start": 503, "end": 517, "text": "(Carlson 1980)", "ref_id": "BIBREF17"}, {"start": 552, "end": 567, "text": "(de Swart 1993;", "ref_id": "BIBREF153"}, {"start": 568, "end": 582, "text": "Delfitto 1997)", "ref_id": "BIBREF49"}, {"start": 622, "end": 639, "text": "(Longobardi 1994)", "ref_id": "BIBREF110"}, {"start": 688, "end": 703, "text": "(Glasbey, 1993)", "ref_id": "BIBREF73"}, {"start": 732, "end": 753, "text": "(Dobrovie-Sorin 1996)", "ref_id": "BIBREF55"}, {"start": 840, "end": 857, "text": "(Condoravdi 1994)", "ref_id": "BIBREF38"}], "ref_spans": []}, {"section": "Outcomes and Conclusions", "text": "In some cases, they appear to make little difference. For instance, if one attributes V P-level existential quantification to existential closure, as Diesing suggests, or to an existenti al quantifier connected with the event structure, as Delfitto suggests, the effect on BP's is ab out the same. Type-shifting (Chierchia) quite clearly locates the source of the existential qu antifier at the boundary between the NP and the predicate it is combining with, but then Carl son's existential quantification over stages can be looked upon in much the same way, thoug h the ontologies differ. Longobardi's \"default\" existential quantifier is very much in the sam e vein. At the current state of research, there is no strong consensus about what source of e xistential quantification is correct or incorrect (nor does there seem to be one about the preci se source of generic readings as well), so it is possible to focus on the correlated structures within the DP itself, and still make very productive contributions. 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(existential) b. A curious person likes to travel. (all curious people, curious people in general) So this approach certainly has its advantages, though other alternatives are clearly possible ( e.g., Cohen 2000). However, the DRT approach exemplified in Diesing and elsewhere does not, to this point, take account of certain features of bare plurals that other analyses have foc used attention on.", "type": "figure"}, "FIGREF2": {"text": "We spoke with some friends' BP's may not occur as subjects of non-ergative verbs, whether post-or pre-verbal, and in ge neral cannot be interpreted generically, only existentially; further, when contrastively stresse d, BP's may appear. The type of account offered by Contreras centers on the notion of pro per government as applied to an NP with an empty determiner position; Torrego (1989) give s an account very similar in spirit. That is, BP's are claimed to have a determiner position rep resented in the syntax that, like other empty categories, requires proper government, and the N within the NP (or DP) itself cannot govern that position. The account of the data above, a nd much more, centers around defining government and the syntactic structures of Spanish i n such a way as to account for patterns such as those found in (21). Governing items inclu de verbs and prepositions, but subjects (as in (21 c,d)) have no governor, and the empty dete rminer position remains unlicensed, resulting in ungrammaticality. Note that it is necessary, on this account, to have an actual empty D position in the DP; the data from English on an y of the accounts reviewed above do not motivate such an analysis as the appearance of BP's in English is basically unrestricted.", "type": "figure"}, "FIGREF3": {"text": "Los G-M adoran a los osos Def G-M worship (to) Def bears 'The G-M worship bears (in general)' (25) Los G-M adoras idolos Def G-M worship idols 'The GM worship (some) idols' But this distinction between definites and bare plurals is not limited to intensionalizing verbs such as \"worship\". So, for example, both are possible after an extensional verb like \"chase \", with differential effects: (26) Mi perro persigue a los gatos My dog chases (to) Def cats 'My dog chases cats' = 'What my dog does with cats is chase them' (27) Mi perro persigue gatos My dog chases cats 'My dog chases cats' = 'My dog has a habit of cat-chasing'", "type": "figure"}, "FIGREF4": {"text": ", while focusing on proper names in Italian, presents an analysis with implications for the use of bare plurals which draws inspiration from Delfitto and Schr oten's (1992), and can be seen as a reinterpretation of some of the Vergnaud and Zubizarreta facts. Longobardi takes some of the crucial assumptions also presented in Contreras, and f ocuses on data from Italian. Like Spanish, Italian has some bare plurals in about the same r estricted positions which are (almost) always interpreted existentially (and, according to Chi erchia, have a slightly literary flavor to them); the generic reading is conveyed with a definit e article or a singular indefinite article in some cases, as in French and Spanish. Longobardi 's main thesis is that in the case of proper names (and pronouns) there is movement within t he DP from the N position into the empty D position, resulting in a structure which does no t have an empty D that must be governed externally. This means that proper names, like (ne arly) any noun phrase with an overt determiner, will appear in any position a DP may alsolargely from facts about Italian word-order. In the case of empty D's in Ital ian, one gets about the right results by assuming that common nouns, lacking reference of th eir own, do not move into the D position like proper names can, leaving only those positions where the D is governed, giving rise to a narrow-scope existential reading. But then, what o f English (Germanic) BP's? In these languages there is little word-order evidence of the typ e to be found in Italian regarding movement of names and pronouns into D, and BP's may a ppear in any DP position at all; further, BP's can have generic interpretations. Longobardi's", "type": "figure"}, "FIGREF5": {"text": "For instance: (33) a. *Cane creano guai seri Dogs create troubles serious b. Cane di grosse dimensioni creano guai seri Dogs of large size create troubles serious 'Dogs of great size create serious trouble' In order to account for such differences, an empty D position is assumed within a minimalis t framework; the issue is what types of features are transmitted to the D position. It is prop osed that when there is a postnominal modifier, the system works in such a way that the D p osition remains devoid of nominal features, thus allowing for the D to be \"identified\" and int erpreted. Delfitto in this respect presents an alternative to the somewhat simpler analysis off ered by Longobardi. Delfitto offers a perspective on BP's that aims for a unitary analysis, and, further, do es not rely upon the standardly assumed GEN operator, nor on any existential quantifiers ov er and above the one to bind event-arguments in VP's. This work, along with Chierchia's, is much in the same vein as work by Dobrovie-Sorin (1996) and Dobrovie-Sorin and Laca (19 97), who aim for a unitary analysis of BP's in English as well as Romance which again treat s them as distinct from indefinites, and, additionally, incorporates an analysis of Condoravdi 's functional readings of BP's. One of the main contributions (among others) of this work is to emphasize that the stage/individual-level contrast is cross-cut by another relevant contra st, that of spatio-temporal localization, and it is this dimension which determines the possibil ity. Evidence surrounds stative (adjectival) stage-level predicates which appear only capable of taking generic subjects. So, for instance, emotional-type predicates appear to be stage-lev el, but do not readily accept localizers: (34) a. ??During Chomsky's lecture, top-models were hungry/tired/drunk b. ??Look! Top-models are drunk/hungry in the street. c. ??Children are nasty/sick/happy in school (no existential reading; a frequentitive/conditional) d. ??Where is John happy/nasty/angry? (only frequentitive/conditional rdg)", "type": "figure"}, "FIGREF6": {"text": "kj\u00f8rer bortover veien Car drives along road-the Borthen considers the semantics of these bare singulars where they may occur, detailing ho w, on almost anyone's analysis, they must be regarded as non-specific (i.e. the observations are similar to those made in En\u00e7 1991 for determinerless bare singulars in Turkish); further , they exhibit the same sort of scopelessness as (most instances of) BP's. Borthen does not find a specific syntactic mechanism to account for the distribution and interpretation of bare singulars in Norwegian, in the end settling on a semantic account which limits their appeara nce to argument positions exhibiting only certain semantic roles which are enumerated and motivated in the account.", "type": "figure"}, "FIGREF7": {"text": "as definite, indefinite (existential), or as generic, but not all these interpretations may appear in all argument positions. So, for instance, in preverbal position, these noun phrases cannot (typically) be interpreted as indefinites, only as definites or generically; but postverbally an i ndefinite (and non-specific) reading emerges. (37) a. Gou jintian tebie tinghua dog today very obedient 'The dog was very obedient today' OR 'Dogs (in general) were very obedient today' But NOT: \"A dog was very obedient today\" b. Hufei mai shu qu le Hufei buy book go PRT 'Hufei went to buy a book/some books' In Cantonese, however, bare nouns cannot be interpreted as definites. Definiteness is expre ssed by the use of a classifier (CL); as in Mandarin, bare nouns cannot be interpreted as de finites preverbally (though they may be interpreted generically). (38) a. *Gau soeng gwo maalou Dog want cross road (Not possible for 'The dog wants to cross the road') b. Zek gau zung-ji sek juk CL dog like eat meat 'The dog (NOT dogs in general) likes to eat meat' c. Gau zung-ji sek juk Dog like eat meat 'Dogs like to eat meat' Mandarin, Cheng and Sybesma argue, also has CL+Noun phrases as well; however, there, t he interpretation is always indefinite, and never definite as in Cantonese. The thrust of the w ork is to argue that classifiers in both Chinese languages function very much like D position s, in that any bare noun is a part of a classifier phrase, the basic structure being: (39) [ ClP Cl [ NP N]]", "type": "figure"}, "FIGREF8": {"text": "above, where both a generic and an indefinite reading may appear, and I have t o regard this as an open area of research. There has also not been quite enough work done i n light of Condoravdi's observations about functional readings of BP's. However, the area where one finds the most bewildering variety of proposals is acco unting for the source of the existential quantification in the case of existentially-interpreted BP's. A sampling of some include:", "type": "figure"}, "TABREF3": {"text": "Neighbors that live just down the block are tall. an existential reading may appear (along with generic readings of varying degrees of plausib ility). Similar facts obtain with singular indefinites in English:If we change the type of relative clause in the examples above, the existential reading seems tThis stands in contrast to what occurs with the indefinite singular, where the existential readiThe types of postnominal modifiers that allow for existential readings are, intuitively, those t hat locate the corresponding individuals in time and/or space. Under most circumstances, a BP will, as noted above, exhibit most clearly only a narrow scope reading. However, with an appropriate postnominal modifier, not only is an existential reading possible, but the NP als o can exhibit scopal properties just like an indefinite singular. Compare, for instance:", "type": "table"}, "TABREF5": {"text": "). Chierchia takes the point of view, pace Longobardi, that NP's can, subj ect to parametrization, function as arguments just like DP's can: that is, on his analysis there is no empty determiner slot in the case of BP's or determinerless mass terms, on this paramOne main point of Chierchia's analysis is to account for the scopelessness of the ex istential reading of BP's, and to answer some questions raised by the prevailing view that geThere was every kind of animal in the garden\" vs. ??\"There was every guest in the garden\"). McNally (1998) proposes, along with Chierchia, that the definit eness restriction should be supplanted by a semantics for existentials that requires the denot ation of the NP to be something that can have individual instantiation--like kinds.", "type": "table"}, "TABREF6": {"text": "a nalysis of constructions such as \"an occasional sailor walked by\". The literature making u se of stages is more scattered than the literature reviewed above, but the issue occasionally s urfaces when temporal restrictions are examined more closely. One recent comprehensive d iscussion is to be found in Musan (1995), who builds on the work of En\u00e7 (1981). Yoon (1 998) considers the semantics of English indefinite NP's with a proper name modified by an adjective. (40) ...a handcuffed Jones protested as two Columbus police officers pushed him into the Franklin County jail. Yoon notes, first of all, that the adjectives appearing in this construction are stage-level and n ot individual-level adjectives (\"a startled Kato Kaelin\" vs. ??\"an intelligent Kato Kealin\"); further, that despite their indefiniteness, they appear to make reference to individuals alread y introduced into the discourse. However, if the NP refers to a stage of an individual, then t hat stage itself consititues a novel entity into the discourse, hence the indefinite. Dermidach e (", "type": "table"}, "TABREF7": {"text": "As research continues an d the theoretical issues become increasingly sharpened, however, I expect people are going t o have to increasing reason to choose among them.Abney, Steven 1987. The English noun phrase in its sentential aspect. Massachusetts Institute of Technology Ph.D. disse rtation. van der Auwera, Johan. 1980 The semantics of determiners. London: Croom Helm.", "type": "table"}}}
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{"paper_id": "2878121", "_pdf_hash": "cec95fc52aa7dccfbf6f9b2a18df1098689df322", "abstract": [{"section": "Abstract", "text": "a b s t r a c t Let (P, \u2264) be a partially ordered set (poset, briefly) with a least element 0 and S \u2286 P. An element x \u2208 P is a lower bound of S if s \u2265 x for all s \u2208 S. A simple graph G(P) is associated to each poset P with 0. The vertices of the graph are labeled by the elements of P, and two vertices x, y are connected by an edge in case 0 is the only lower bound of {x, y} in P. We show that if the chromatic number \u03c7 (G(P)) and the clique number \u03c9(G(P)) are finite, then \u03c7 (G(P)) = \u03c9(G(P)) = n + 1 in which n is the number of minimal prime ideals of P.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "In [1] , Beck associated to any commutative ring R a simple graph G(R) whose vertices are labeled by the elements of R, and with two vertices adjacent (connected by an edge) if x \u00b7 y = 0. The problem Beck studied was the chromatic number \u03c7(G(R)) and the clique number \u03c9(G(R)) of G(R). Beck conjectured that \u03c7 (G(R)) = \u03c9(G(R)) for an arbitrary ring R, but Beck's question was settled in the negative in [2] .", "cite_spans": [{"start": 3, "end": 6, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 402, "end": 405, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Introduction", "text": "Recently in [3] , DeMeyer et al. defined the zero-divisor graph of a commutative semigroup S with zero (0x = 0 for all x \u2208 S). The zero-divisor graph of a commutative semigroup with zero is a graph whose vertices are the nonzero zero divisors of the semigroup, with two distinct vertices joined by an edge whenever their product is zero. They have shown that the number of minimal ideals of S gives a lower bound to the clique number of S. The zero-divisor graph of various algebraic structures has been studied by several authors [4] [5] [6] [7] [8] .", "cite_spans": [{"start": 12, "end": 15, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 531, "end": 534, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 535, "end": 538, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 539, "end": 542, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 543, "end": 546, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 547, "end": 550, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Introduction", "text": "In this paper, to any poset (P, \u2264) with a least element 0 we first define the zero-divisor graph, denoted by G(P), of P. We show that if the chromatic number \u03c7 (G(P)) and the clique number \u03c9(G(P)) are both finite, then \u03c7 (G(P)) = \u03c9(G(P)) = n+1 in which n is the number of minimal prime ideals of P.", "cite_spans": [], "ref_spans": []}, {"section": "Definition and notation of graphs and partially ordered sets", "text": "Next we introduce some definitions and notations on graphs and partially ordered sets. We use the standard terminology of graphs in [9] and partially ordered sets in [10] .", "cite_spans": [{"start": 132, "end": 135, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 166, "end": 170, "text": "[10]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Definition and notation of graphs and partially ordered sets", "text": "Recall that the complete graph K n of order n is a simple graph with n vertices in which every vertex is adjacent to every other vertex. A clique in a graph is a set of pairwise adjacent vertices. Since any subgraph induced by a clique is a complete subgraph, the two terms and their notations are usually used interchangeably. number \u03c9(G) of a graph G is the order of a largest clique in G. Graph coloring is a special case of graph labeling. It is an assignment of labels traditionally called ''colors'' to elements of a graph subject to certain constraints. Vertex coloring is a way of coloring the vertices of a graph such that no two adjacent vertices share the same color. The smallest number of colors needed to color a graph G is called its chromatic number \u03c7 (G). Since vertices of a clique require distinct colors, we have the following result. ", "cite_spans": [], "ref_spans": []}, {"section": "Definition and notation of graphs and partially ordered sets", "text": "Thus (1) holds. If A \u2286 B, then any element of B is a lower bound of B and so is a lower bound of A and hence belongs to A . Thus, obviously", "cite_spans": [], "ref_spans": []}, {"section": "Definition and notation of graphs and partially ordered sets", "text": "(2) holds.", "cite_spans": [], "ref_spans": []}, {"section": "Definition and notation of graphs and partially ordered sets", "text": "For a poset (P, \u2264) and a proper ideal I of P, I is called n-prime (n \u2265 2) if for any x 1 , . . . , x n \u2208 P, {x 1 , . . . , x n } \u2286 I implies x i \u2208 I for some i \u2208 {1, . . . , n}.", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 3. For every poset (P, \u2264), if I is a proper ideal of P, then for all n \u2265 2, I is prime if and only if I is n-prime.", "text": "Proof. We first show that any prime ideal I of P is n-prime for all n \u2265 2. We proceed by induction on n. Clearly, I is 2-prime if and only if I is prime. So for n = 2 the result holds.", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 3. For every poset (P, \u2264), if I is a proper ideal of P, then for all n \u2265 2, I is prime if and only if I is n-prime.", "text": "Assume the statement holds for n \u2212 1. Let {x 1 , . . . , x n\u22121 , x n } \u2286 I for some prime ideal I of P. Take y \u2208 {x 1 , . . . , x n\u22121 } arbitrarily. Then {y, x n } \u2286 {x 1 , . . . , x n\u22121 , x n } \u2286 I. If x n \u2208 I, then by the primeness of I, y \u2208 I. Since y is an arbitrarily element of {x 1 , . . . , x n\u22121 } and x n \u2208 I, we have {x 1 , . . . , x n\u22121 } \u2286 I. By induction hypothesis we conclude that x i \u2208 I for some i \u2208 {1, . . . , n \u2212 1}. The converse holds trivially. This complete the proof.", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 3. For every poset (P, \u2264), if I is a proper ideal of P, then for all n \u2265 2, I is prime if and only if I is n-prime.", "text": "To any poset (P, \u2264) with a least element 0 we define the zero-divisor graph, denoted by G(P), of P as follows: its vertices are just the elements of P, and x, y \u2208 G(P) are connected by an edge if and only if {x, y} = {0}. The chromatic number \u03c7 (P) of P is the chromatic number of G(P).", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 3. For every poset (P, \u2264), if I is a proper ideal of P, then for all n \u2265 2, I is prime if and only if I is n-prime.", "text": "Recall the symbol used to denote non-comparability. Let (P, \u2264) be a poset in which the element set of P = {0, x 1 , . . . , x n }, 0 \u2264 x i for i \u2208 {1, . . . , n} and x i x j for i = j. For n = 4, the Hasse diagram of P and the associated zero-divisor graph G(P) of P see Fig. 1(a) and (b), respectively.", "cite_spans": [], "ref_spans": [{"start": 271, "end": 280, "text": "Fig. 1(a)", "ref_id": "FIGREF0"}]}, {"section": "Lemma 3. For every poset (P, \u2264), if I is a proper ideal of P, then for all n \u2265 2, I is prime if and only if I is n-prime.", "text": "Let (P, \u2264) be a poset. P is called a chain if, \u2200x, y \u2208 P, either x \u2264 y or y \u2264 x (that is, if any two elements of P are comparable). The poset P is an antichain if x \u2264 y in P only if x = y. Let (P, \u2264) be a chain in which the element set of P = {0, x 1 , . . . , x n }, 0 \u2264 x i for i \u2208 {1, . . . , n} and x i \u2264 x i+1 . For n = 4, the Hasse diagram of P and the associated zero-divisor graph G(P) of P see Fig. 2(a) and (b), respectively. Let (P, \u2264) be a poset with the element set P = {0, x 1 , . . . , x n , y 1 , . . . , y m }, in which 0 \u2264 x i , 0 \u2264 y j , x i y j and x i \u2264 x i+1 , y j \u2264 y j+1 for 1 \u2264 i \u2264 n, 1 \u2264 j \u2264 m. For n = 4 and m = 3, the Hasse diagram of P and the associated zero-divisor graph G(P)", "cite_spans": [], "ref_spans": [{"start": 403, "end": 412, "text": "Fig. 2(a)", "ref_id": "FIGREF4"}]}, {"section": "Lemma 3. For every poset (P, \u2264), if I is a proper ideal of P, then for all n \u2265 2, I is prime if and only if I is n-prime.", "text": "of P see Fig. 3 (1) If Z x is maximal among {Z a | a \u2208 P, Z a = P}, then Z x is a prime ideal of P. (2) Assume to the contrary that {x, y} = {0}, thus x \u2208 Z y and y \u2208 Z x . \u2200a \u2208 Z x , {a, x} = {0} \u2286 Z y , so {a, x} \u2286 Z y . By the primeness of Z y , a \u2208 Z y due to x \u2208 Z y . We have Z x \u2286 Z y . Similarly Z y \u2286 Z x , thus Z x = Z y , a contradiction. Lemma 5. Let (P, \u2264) be a poset with 0. If \u03c9(P) is finite, then any proper zero-divisor ideal Z x is contained in a maximal one and the set of all distinct maximal zero-divisor ideals of P is finite.", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 3. For every poset (P, \u2264), if I is a proper ideal of P, then for all n \u2265 2, I is prime if and only if I is n-prime.", "text": "Proof. Assume to the contrary that Z x 1 \u2282 Z x 2 \u2282 \u00b7 \u00b7 \u00b7 is a strictly ascending chain of zero-divisor ideals of P. For j \u2265 2, let", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 3. For every poset (P, \u2264), if I is a proper ideal of P, then for all n \u2265 2, I is prime if and only if I is n-prime.", "text": "Clearly y j = y k for all j = k. In fact, if y j = y k for k \u2265 j + 1, we would have", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 3. For every poset (P, \u2264), if I is a proper ideal of P, then for all n \u2265 2, I is prime if and only if I is n-prime.", "text": "This shows that {y i | i = 1, 2, . . .} is an infinite clique of P which contradicts the finiteness of \u03c9(P).", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 3. For every poset (P, \u2264), if I is a proper ideal of P, then for all n \u2265 2, I is prime if and only if I is n-prime.", "text": "Let Z = {Z x k | Z x k is maximal} be the set of all maximal zero-divisor ideals of P. By Lemma 4(1) Z x k is prime ideal. Obviously x k = 0 and Z x k = Z x j whenever k = j. By Lemma 4(2) {x k , x j } = {0} for all k = j. This shows \u03c9(P) \u2265 |Z|. Since \u03c9(P) is finite so Z is. Lemma 6. Let (P, \u2264) be a poset with 0. If \u03c9(P) is finite, then any minimal prime ideal I of P is of the form Z x for some x \u2208 P, moreover {0} is the intersection of a finite set of minimal prime ideals of P.", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 3. For every poset (P, \u2264), if I is a proper ideal of P, then for all n \u2265 2, I is prime if and only if I is n-prime.", "text": "Proof. Let I be a minimal prime ideal of P. Since Z x = {y \u2208 P | {x, y} = {0}}, we have {x, y} \u2286 I. As I is prime, x \u2208 I or y \u2208 I. Thus for x \u2208 I we have Z x \u2286 I. By Lemma 5 there exist maximal zero-divisor ideals among Z = {Z x | x \u2208 I}. In fact there is a greatest one. Let Z y 1 , Z y 2 be two maximal elements of Z . Since I is prime and y 1 , y 2 \u2208 I we have {y 1 , y 2 } \u2286 I. Thus there is 0 = y \u2208 {y 1 , y 2 } with y \u2208 I. Clearly, Z y 1 \u2286 Z y , Z y 2 \u2286 Z y , and as both Z y 1 and Z y 2 are maximal in Z , we have Z y = Z y 1 = Z y 2 . This shows that Z has a greatest element Z y .", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 3. For every poset (P, \u2264), if I is a proper ideal of P, then for all n \u2265 2, I is prime if and only if I is n-prime.", "text": "For some maximal zero-divisor ideal Z w , Z w \u2287 Z y (as Z y is greatest only in Z ). Since Z w is maximal, by Lemma 4(1), we have Z w is prime. In the following we show that Z w \u2286 I. Assume to the contrary that there is a \u2208 Z w with a \u2208 I. Then {a, w} = {0}, hence w \u2208 Z a \u2208 Z . By the maximality of Z y , we have w \u2208 Z a \u2286 Z y \u2286 Z w , a contradiction. Thus Z w \u2286 I and Z w is prime. Since I is a minimal prime ideal of P, thus I = Z w .", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 3. For every poset (P, \u2264), if I is a proper ideal of P, then for all n \u2265 2, I is prime if and only if I is n-prime.", "text": "In the following we prove that {0} is the intersection of a finite set of minimal prime ideals of P. We first show {0} = 1\u2264i\u2264n Z x i , then Z x i are minimal prime ideals of P.", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 3. For every poset (P, \u2264), if I is a proper ideal of P, then for all n \u2265 2, I is prime if and only if I is n-prime.", "text": "By Lemma 5 there is a finite set Z = {Z x i | 1 \u2264 i \u2264 n} the set of all maximal zero-divisor ideals of P. By Lemma 4 all these ideals are prime and {x j ,", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 3. For every poset (P, \u2264), if I is a proper ideal of P, then for all n \u2265 2, I is prime if and only if I is n-prime.", "text": "Let I be an arbitrary prime ideal of P. To show Z x i are minimal prime ideals it suffices to show that Z x i \u2286 I for any i \u2208 {1, . . . , n}. Since Z x i are assumed to be maximal zero-divisor ideals, none of Z x i contains Z x j for i = j. Assume only for some j, Z x j is not minimal. Then there exists a prime ideal J with J \u2286 Z x j , J = Z x j and certain Z x k with Z x k \u2286 J. Thus Z x k \u2286 J \u2286 Z x j , J = Z x j which contradicts the maximality of Z x k . So assume to the contrary that Z x i were not minimal for all i, i.e. for all i there is y i \u2208 Z x i \\ I. Thus {y 1 , . . . , y n } \u2286 1\u2264i\u2264n Z x i = {0}, i.e. {y 1 , . . . , y n } = {0}. Then {y 1 , . . . , y n } \u2286 I. Since I is prime, by Lemma 3 y i \u2208 I for some i which contradicts y i \u2208 Z x i \\ I.", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 3. For every poset (P, \u2264), if I is a proper ideal of P, then for all n \u2265 2, I is prime if and only if I is n-prime.", "text": "Recall the width of P is defined to be the size of the largest antichain in P and is denoted by w(P). Dilworth's Theorem (see [11] ) states that the width w(P) of a finite poset equals the least n \u2208 N such that P can be represented as a union of n chains. Motivated by this result we have the following similar result. Theorem 7. Let (P, \u2264) be a poset with 0. If \u03c9(P) is finite, then the number n of all minimal prime ideals of P is finite and \u03c7(P) = \u03c9(P) = n + 1.", "cite_spans": [{"start": 126, "end": 130, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Lemma 3. For every poset (P, \u2264), if I is a proper ideal of P, then for all n \u2265 2, I is prime if and only if I is n-prime.", "text": "Proof. By Lemma 6, we have {0} = I 1 \u2229 \u00b7 \u00b7 \u00b7 \u2229 I n with I i being minimal prime ideals of P, and any minimal prime ideal I i of P is of the form Z x for some x \u2208 P.", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 3. For every poset (P, \u2264), if I is a proper ideal of P, then for all n \u2265 2, I is prime if and only if I is n-prime.", "text": "We obtain \u03c9(P) \u2265 n + 1. For \u2200x = 0, since {0} = 1\u2264i\u2264n Z x i , x cannot be in all Z x i . Therefore, the set of {i | x \u2208 Z x i } is nonempty and there exists the minimum of their cardinalities. Then we can define a coloring f of P as follows: f (0) = 0 and f (x) = min{i | x \u2208 Z x i } for x = 0.", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 3. For every poset (P, \u2264), if I is a proper ideal of P, then for all n \u2265 2, I is prime if and only if I is n-prime.", "text": "If a, b are adjacent vertices, then {a, b} = {0}. We show f (a) = f (b). If f (a) = k + 1, then a \u2208 Z x i for some 1 \u2264 i \u2264 k, and a \u2208 Z x k+1 . Thus we can deduce that b \u2208 Z x k+1 since {a, b} = {0} \u2286 Z x k+1 and a \u2208 Z x k+1 . This shows that f (b) = k + 1 and thus f (a) = f (b). Hence f is a coloring of P. This yields \u03c7 (P) \u2264 n + 1. By Lemma 1 we have n + 1 \u2265 \u03c7 (P) \u2265 \u03c9(P) \u2265 n + 1. Thus we obtain \u03c7 (P) = \u03c9(P) = n + 1. This complete the proof.", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 3. For every poset (P, \u2264), if I is a proper ideal of P, then for all n \u2265 2, I is prime if and only if I is n-prime.", "text": "Example. In Fig. 1 we can see the number n of all minimal prime ideals of P is 4. The associated zero-divisor graph G(P) of P is the complete graph K 5 . Clearly \u03c7 (G(P)) = \u03c9(G(P)) = n + 1 = 5. In Fig. 2 the associated zero-divisor graph is a 5-vertex star (the biclique K 1,4 ) where \u03c7 (G(P)) = \u03c9(G(P)) = 2. 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The clique $ The work was supported by the National Nature Science Foundation (No. 60974082) and the Foundation of State Key Lab. of Integrated Services Networks of China. (a) Hasse diagram of P; (b) The associated zero-divisor graph G(P) of P.", "type": "figure"}, "FIGREF1": {"text": "For every graph G, \u03c7 (G) \u2265 \u03c9(G). Given a partially ordered set (P, \u2264) (poset, briefly) with a least element 0 and S \u2286 P. An element x \u2208 P is a lower bound of S if s \u2265 x for all s \u2208 S. An upper bound is defined dually. The set of all lower bounds of S is denoted by S and the set of all upper bounds by S u , where S := {x \u2208 P | (\u2200s \u2208 S) s \u2265 x} and S u := {x \u2208 P | (\u2200s \u2208 S) s \u2264 x}. Let A u = (A ) u . We present some properties of poset in the following. They are necessary to show our main result in the next section. For a poset (P, \u2264), if A and B are subsets of P, then", "type": "figure"}, "FIGREF2": {"text": "(a) and (b), respectively. (a) Hasse diagram of chain P; (b) The associated zero-divisor graph G(P) of P. a b (a) Hasse diagram of P; (b) The associated zero-divisor graph G(P) of P.3. Ideals, chromatic number and clique numberGiven a poset (P, \u2264) with a least element 0 and x \u2208 P, denote by Z x := {y \u2208 P | {x, y} = {0}} the so-called zero divisors of x.", "type": "figure"}, "FIGREF3": {"text": "Let (P, \u2264) be a poset with 0.", "type": "figure"}, "FIGREF4": {"text": "If Z x and Z y are distinct prime ideals of P, then {x, y} = {0}. Proof. (1) Obviously, Z x is an ideal of P. To prove the primeness, assume that {a, b} \u2286 Z x and a \u2208 Z x . It suffices to show b \u2208 Z x . Since {a, b} \u2286 Z x , we have {a, b, x} = {0}. Let 0 = y \u2208 {a, x} be an arbitrary element. Then {b, y} \u2286 {a, b, x} = {0}, thus b \u2208 Z y . As 0 = y \u2208 {a, x} , y \u2264 x thus Z x \u2286 Z y = P. By the maximality of Z x , we have Z x = Z y , hence b \u2208 Z x .", "type": "figure"}}}
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{"paper_id": "2878307", "_pdf_hash": "3748d18b36b6bf880f12312263054207f5264514", "abstract": [], "body_text": [{"section": "A B S T R A C T", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Background", "text": "People with cystic fibrosis and pancreatic insufficiency are at risk of fat soluble vitamin deficiency as these vitamins (A, D, E and K) are co-absorbed with fat. Thus, some cystic fibrosis centres routinely administer these vitamins as supplements but the centres vary in their approach of addressing the possible development of deficiencies in these vitamins. Vitamin A deficiency causes predominantly eye and skin problems while supplementation of vitamin A to excessive levels may cause harm to the respiratory and skeletal systems in children. Thus a systematic review on vitamin A supplementation in people with cystic fibrosis would help guide clinical practice.", "cite_spans": [], "ref_spans": []}, {"section": "Objectives", "text": "To determine if vitamin A supplementation in children and adults with CF:", "cite_spans": [], "ref_spans": []}, {"section": "Objectives", "text": "1. reduces the frequency of vitamin A deficiency disorders; 2. improves general and respiratory health; 3. increases the frequency of vitamin A toxicity.", "cite_spans": [], "ref_spans": []}, {"section": "Search methods", "text": "We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises of references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.", "cite_spans": [], "ref_spans": []}, {"section": "Search methods", "text": "Date of the most recent search of the Group's Cystic Fibrosis Trials Register: 26 November 2009.", "cite_spans": [], "ref_spans": []}, {"section": "Selection criteria", "text": "All randomised or quasi-randomised controlled trials comparing all preparations of oral vitamin A used as a supplement compared to either no supplementation (or placebo) at any dose and for any duration, in children or adults with cystic fibrosis (defined by sweat tests or genetic testing) with and without pancreatic insufficiency.", "cite_spans": [], "ref_spans": []}, {"section": "Data collection and analysis", "text": "No relevant studies for inclusion were identified in the search.", "cite_spans": [], "ref_spans": []}, {"section": "Main results", "text": "No studies were included in this review.", "cite_spans": [], "ref_spans": []}, {"section": "Authors' conclusions", "text": "As there were no randomised or quasi-randomised controlled trials identified, we cannot draw any conclusions on the benefits (or otherwise) of regular administration of vitamin A in people with cystic fibrosis. Until further data are available, country or region specific guidelines on the use of vitamin A in people with cystic fibrosis should be followed.", "cite_spans": [], "ref_spans": []}, {"section": "P L A I N L A N G U A G E S U M M A R Y", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "The use of regular vitamin A preparations for children and adults with cystic fibrosis", "text": "Cystic fibrosis can cause certain vitamins, such as vitamin A, to be inadequately absorbed leading to problems caused by vitamin deficiency. Lack of vitamin A (vitamin A deficiency) can cause specific problems such as eye and skin problems. It can also be associated with poorer general and respiratory health. Thus people with cystic fibrosis are usually given regular vitamin A preparations from a very young age. However, excess vitamin A can also cause respiratory and bone problems. The review found no studies to show whether giving vitamin A regularly for people with cystic fibrosis is beneficial or not. The authors are unable to draw any conclusions regarding the routine administration of vitamin A supplements and recommend that until further evidence is available, local guidelines are followed regarding this practice.", "cite_spans": [], "ref_spans": []}, {"section": "B A C K G R O U N D", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Description of the condition", "text": "Cystic fibrosis (CF) is a genetic disorder that affects multiple organs. Pancreatic insufficiency affects up to 90% of people with CF, whereby fat malabsorption occurs and pancreatic enzyme replacement is required to prevent steatorrhoea and malnutrition (Dodge 2006) . Fat soluble vitamins (A, D, E and K) are co-absorbed with fat and thus deficiency of these vitamins may occur (Dodge 2006) . Some CF centres routinely administer these vitamins as supplements from the neonatal period, whilst others administer them only later in life or when deficiencies are detected clinically or on routine monitoring. While deficiencies may occur from the disease process of CF and insufficient supplementation, vitamin toxicity may also occur from excess supplementation. Both deficiency and excess of these vitamins may lead to specific medical problems (Dodge 2006; Sethuraman 2006) . Vitamin A is an essential nutrient for epithelial cell maintenance and repair in the respiratory, urinary and intestinal tract, immune response, and bone growth (DAA 2006) . Dietary vitamin A (retinol or retinol esters) is found in liver, beef, eggs, fish, the fat of dairy products and vitamin A fortified margarine. Beta-and alphacarotene can act as precursors for the synthesis of vitamin A. The dietary carotenoid (beta-carotene) is found in red, orange, yellow and leafy green vegetables (e.g. carrots, sweet potato, silverbeet) and red and orange fruit (e.g. mangos, oranges). Vitamin A deficiency can be defined as serum retinol (SROL) concentration less than 0.70 \u00b5mol/L (less than 20 \u00b5g/dl) (West 2003) . However, SROL levels may be influenced by albumin and retinol binding protein (RBP) as well as acute illnesses with infection and inflammation (Napoli 1996; Stephensen 1994) . SROL levels should be measured during clinical stability (DAA 2006) . The major consequence of vitamin A deficiency is ocular (eye) with abnormal dark adaptation (night blindness), conjunctival and corneal xerosis (thickening) which can lead to blindness (DAA 2006; West 2003) . Another consequence of vitamin A deficiency is the skin condition phrynoderma (a form of follicular hyperkeratosis associated with some micronutrient deficiencies). Vitamin A deficiency has also been linked to impaired mechanisms of host resistance to infection, poor growth and increased mortality in a study of mothers and children (West 2003) .", "cite_spans": [], "ref_spans": []}, {"section": "Description of the intervention", "text": "Vitamin A is available as a sole supplement as well as in combination form with other vitamins.", "cite_spans": [], "ref_spans": []}, {"section": "How the intervention might work", "text": "Normalisation of vitamin A levels may avoid the afore-mentioned problems. However supplementation of these vitamins to excessive levels may cause harm to the respiratory system, the skeletal system (osteoporosis and fractures) and liver abnormality ( ", "cite_spans": [], "ref_spans": []}, {"section": "Why it is important to do this review", "text": "The approach of addressing the possibility of the development deficiency of these fat soluble vitamins is variable among CF centres. Thus a systematic review on the efficacy of vitamins A, D, E and K supplementation in children and adults with CF in preventing effects of the deficiency of these vitamins would help guide clinical practice. Supplementation of vitamins D, E and K will be addressed in other Cochrane Systematic Reviews (Ferguson 2008; Shamseer 2008) . This review will evaluate vitamin A supplementation in children and adults with CF.", "cite_spans": [], "ref_spans": []}, {"section": "O B J E C T I V E S", "text": "To determine if vitamin A supplementation in children and adults with CF:", "cite_spans": [], "ref_spans": []}, {"section": "O B J E C T I V E S", "text": "1. reduces the frequency of vitamin A deficiency disorders; 2. improves general and respiratory health; 3. increases the frequency of vitamin A toxicity.", "cite_spans": [], "ref_spans": []}, {"section": "M E T H O D S Criteria for considering studies for this review", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Types of studies", "text": "Randomised (RCTs) and quasi-randomised trials (controlled clinical trials).", "cite_spans": [], "ref_spans": []}, {"section": "Types of participants", "text": "Children or adults with CF (defined by sweat tests or genetic testing) with and without pancreatic insufficiency.", "cite_spans": [], "ref_spans": []}, {"section": "Types of interventions", "text": "All preparations of oral vitamin A used as a supplement compared to either no supplementation or placebo at any dose for at least three months.", "cite_spans": [], "ref_spans": []}, {"section": "Types of outcome measures", "text": "We planned to obtain data on at least one of the following outcome measures: ", "cite_spans": [], "ref_spans": []}, {"section": "Searching other resources", "text": "Searches of bibliographies and texts of selected studies were also conducted to identify additional studies.", "cite_spans": [], "ref_spans": []}, {"section": "Data collection and analysis", "text": "The authors did not apply the process described below since no studies were identified. In future updates of this review, the authors will apply the following methods if studies are identified:", "cite_spans": [], "ref_spans": []}, {"section": "Selection of studies", "text": "From the title, abstract, or descriptors, two authors will independently review results of the literature searches to identify studies potentially relevant to the review according to our inclusion criteria for further assessment. From these studies, the same two authors will independently examine the papers in further detail in order to select studies for inclusion using the criteria stated before. The authors will resolve disagreement by consensus.", "cite_spans": [], "ref_spans": []}, {"section": "Data extraction and management", "text": "The authors will review studies that satisfy the inclusion criteria for the review and independently extract data on the outcomes described as follows: study setting; year of study; source of funding; participant recruitment details (including number of eligible participants); inclusion and exclusion criteria; randomisation and allocation concealment method; numbers of participants randomised; blinding (masking) of participants, care providers and outcome assessors; dose and type of intervention; duration of therapy; co-interventions; numbers of participants not followed up; reasons for withdrawals from study protocol (clinical, side effects, refusal and other); side effects of therapy; and whether intentionto-treat analyses were possible.", "cite_spans": [], "ref_spans": []}, {"section": "Assessment of risk of bias in included studies", "text": "In order to assess the risk of bias, two review authors will independently assess the quality of the studies included in the review according to the criteria described by J\u00fcni (J\u00fcni 2001):", "cite_spans": [], "ref_spans": []}, {"section": "Allocation concealment", "text": "Allocation concealment in each study will be assessed as follows: 1. Adequate, if the allocation of participants involved a central independent unit, on-site locked computer, identically appearing numbered drug bottles or containers prepared by an independent pharmacist or investigator, or sealed opaque envelopes; 2. Unclear, if the method used to conceal the allocation was not described; 3. Inadequate, if the allocation sequence was known to the investigators who assigned participants or if the study was quasirandomised.", "cite_spans": [], "ref_spans": []}, {"section": "Generation of the allocation sequence", "text": "Each study will be graded for allocation concealment as follows:", "cite_spans": [], "ref_spans": []}, {"section": "Generation of the allocation sequence", "text": "1. Adequate, if methods of randomisation include using a random number table, computer-generated lists or similar methods;", "cite_spans": [], "ref_spans": []}, {"section": "Generation of the allocation sequence", "text": "2. Unclear, if the study is described as randomised, but no description of the methods used to allocate participants to treatment group was described; 3. Inadequate, if methods of randomisation include alternation; the use of case record numbers, dates of birth or day of the week, and any procedure that is entirely transparent before allocation.", "cite_spans": [], "ref_spans": []}, {"section": "Blinding (or masking)", "text": "Each study will be graded for blinding as follows:", "cite_spans": [], "ref_spans": []}, {"section": "Blinding (or masking)", "text": "1. blinding of clinician (person delivering treatment) to treatment allocation; 2. blinding of participant to treatment allocation; 3. +blinding of outcome assessor to treatment allocation.", "cite_spans": [], "ref_spans": []}, {"section": "Follow up", "text": "Each study will be graded as to whether numbers of and reasons for dropouts and withdrawals in all intervention groups were described; or if it was specified that there were no dropouts or withdrawals. We will also report on whether the investigators had performed a sample-size calculation and if they used an intention-to-treat (ITT) analysis.", "cite_spans": [], "ref_spans": []}, {"section": "Measures of treatment effect", "text": "The results from studies that meet the inclusion criteria and reports any of the outcomes of interest will be included in the subsequent meta-analyses if any data are applicable. For the dichotomous outcome variables of each individual study, we will calculate the odds ratio (OR) using a modified ITT analysis, i.e. if the original investigators did not use ITT analysis, we will consider dropouts to be failures. We will also calculate the summary weighted odds ratios and 95% confidence intervals (CIs) (fixed-effect model) using the Cochrane Collaboration's statistical package (RevMan 2008) . Numbers needed to treat (NNT) and their 95% CIs will be calculated from the pooled OR and its 95% CI for a specific baseline risk, which is the sum of all the events in the control groups (in all studies) divided by the total participant numbers in control groups in all studies using an online calculator (Cates 2003) .", "cite_spans": [], "ref_spans": []}, {"section": "Measures of treatment effect", "text": "For continuous outcomes, we will record the mean relative change from baseline for each group or mean post-treatment or postintervention values and standard deviation. If standard errors are reported, we will calculate the standard deviations. We will then calculate a pooled estimate of treatment effect by the weighted mean difference and 95% confidence interval (fixed-effect model) again using RevMan (RevMan 2008).", "cite_spans": [], "ref_spans": []}, {"section": "Unit of analysis issues", "text": "For cross-over studies, we will calculate the mean treatment differences where possible and enter these using the fixed-effect generic inverse variance (GIV) analysis in RevMan, to provide summary weighted differences and 95% CIs (RevMan 2008). In cross-over studies, if we believe there is a carryover effect which will outlast any washout period included in the study, we will include only data from the first arm in the meta-analysis (Elbourne 2002). If studies report outcomes using different measurement scales, we will estimate the standardised mean difference and 95% CIs.", "cite_spans": [], "ref_spans": []}, {"section": "Dealing with missing data", "text": "The authors will request further information from the primary investigators where required.", "cite_spans": [], "ref_spans": []}, {"section": "Assessment of heterogeneity", "text": "We will describe any heterogeneity between the study results and test this to see if it reached statistical significance using the chisquared test. We will consider heterogeneity to be significant when the P value is less than 0.10 (Higgins 2006). We also plan to use the I 2 statistic where heterogeneity is categorised such that a value of under 25% is considered low, around 50% is considered moderate and over 75% is considered a high degree of heterogeneity (Higgins 2003) .", "cite_spans": [], "ref_spans": []}, {"section": "Data synthesis", "text": "We will include the 95% CI, estimated using a fixed-effect model. However the random-effects model will be utilised whenever there are concerns about statistical heterogeneity.", "cite_spans": [], "ref_spans": []}, {"section": "Subgroup analysis and investigation of heterogeneity", "text": "We plan to perform the following a priori subgroup analyses to investigate any heterogeneity which has been identified. 1. children (aged 18 years or less) and adults (over 18 years); 2. formulations of the vitamin (single or multivitamin); 3. presence of significant liver synthetic dysfunction (low baseline albumin);", "cite_spans": [], "ref_spans": []}, {"section": "Subgroup analysis and investigation of heterogeneity", "text": "4. presence of previous bowel resections; 5. presence of pancreatic insufficiency; 6. method of CF diagnosis (i.e. screening versus symptomatic diagnosis).", "cite_spans": [], "ref_spans": []}, {"section": "Sensitivity analysis", "text": "Sensitivity analyses are also planned to assess the impact of the potentially important factors on the overall outcomes:", "cite_spans": [], "ref_spans": []}, {"section": "Sensitivity analysis", "text": "1. analysis using a random-effects model; 2. analysis by \"treatment received\" (as opposed to ITT analysis).", "cite_spans": [], "ref_spans": []}, {"section": "R E S U L T S Description of studies", "text": "See: Characteristics of excluded studies.", "cite_spans": [], "ref_spans": []}, {"section": "Results of the search", "text": "We identified a single study in our searches (Wood 2003) .", "cite_spans": [], "ref_spans": []}, {"section": "Excluded studies", "text": "The only study identified was excluded because it was not placebo controlled (see Characteristics of excluded studies).", "cite_spans": [], "ref_spans": []}, {"section": "Risk of bias in included studies", "text": "We did not find any eligible studies that fulfilled the inclusion criteria.", "cite_spans": [], "ref_spans": []}, {"section": "Effects of interventions", "text": "We did not find any eligible studies that fulfilled the inclusion criteria.", "cite_spans": [], "ref_spans": []}, {"section": "D I S C U S S I O N", "text": "Daily vitamin A supplementation is almost universally recommended for people with CF who are pancreatic insufficient. However, it is unfortunate that there are no controlled studies that have examined this. The appropriate dose and frequency of vitamin A supplementation is also unknown. Furthermore while vitamin A deficiency causes eye and skin disorders, excess vitamin A can also cause problems (Griffiths 2000; Penniston 2006 ). Indeed, increasingly data on micronutrients have shown that micronutrient supplementation is only beneficial in states of deficiency and harmful when no deficiency exists (Chang 2006; Shenkin 2006) . For vitamin A, Griffiths has termed this the 'vitamin A paradox' as vitamin A supplementation is likely to be \"protective against pneumonia in malnourished children (who are likely to be vitamin A-deficient) and is paradoxically detrimental for adequately nourished children\" (Griffiths 2000) . It is well accepted that people with cystic fibrosis and pancreatic insufficiency are at risk of vitamin A deficiency. However, it is also biologically plausible that currently, with improved pancreatic replacement therapies and attention to macro nutrition and caloric supplements, the majority of people with CF are vitamin A sufficient and may not require daily vitamin A supplementation. Daily supplementation in these situations at best causes no harm, but it adds a further burden to the daily medical regimen of people with CF and it is possible that it may be biologically harmful.", "cite_spans": [], "ref_spans": []}, {"section": "A U T H O R S ' C O N C L U S I O N S", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Implications for practice", "text": "As there were no randomised or quasi-randomised controlled trials identified, we cannot draw any conclusions on the benefits (or otherwise) of regular administration of vitamin A in people with cystic fibrosis. Until further data are available, country or region specific guidelines (e.g. UK CF Trust Nutrition Guidelines (CF Trust 2002)) on the use and monitoring of vitamin A in people with cystic fibrosis should be followed.", "cite_spans": [], "ref_spans": []}, {"section": "Implications for research", "text": "The need for a well-designed, parallel, adequately-powered, multicentre, randomised controlled trial to assess if vitamin A supplementation in children and adults with cystic fibrosis is beneficial or otherwise, is obvious. The study should examine if vitamin A supplementation positively or negatively influences the frequency of symptoms of vitamin A deficiency or general and respiratory outcomes. The possible negative effects should be examined in light of recent data showing possible harm when micronutrients are used in people who are not micronutrient-deficient. Safety monitoring during such a study would be important as the current practice is to use supplementation of vitamin A in people with CF. Vitamin A levels should be measured before and during the studies when clinically stable and related to serum albumin and retinol binding protein. Studies involving both children and adults are required and results should be related to nutritional status and pancreatic status. Data relating to appropriate dose and frequency of supplementation are also needed.", "cite_spans": [], "ref_spans": []}, {"section": "A C K N O W L E D G E M E N T S", "text": "We thank Nikki Jahnke and Dr Gerard Ryan from the Cochrane Cystic Fibrosis & Genetic Disorders Group for their advice, supportive role and comments to the protocol and review and to Natalie Yates for help with the searches.", "cite_spans": [], "ref_spans": []}, {"section": "D A T A A N D A N A L Y S E S", "text": "This review has no analyses.", "cite_spans": [], "ref_spans": []}, {"section": "W H A T ' S N E W", "text": "Last assessed as up-to-date: 25 November 2009. ", "cite_spans": [], "ref_spans": []}, {"section": "Date", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "H I S T O R Y", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "C O N T R I B U T I O N S O F A U T H O R S", "text": "Protocol: CO and AC wrote the protocol. ES reviewed the protocol.", "cite_spans": [], "ref_spans": []}, {"section": "C O N T R I B U T I O N S O F A U T H O R S", "text": "Review: When any studies are identified, CO and AC will select relevant studies, perform data extraction and analysis and write the review. ES will contribute to writing of the review.", "cite_spans": [], "ref_spans": []}], "bib_entries": {}, "ref_entries": {"FIGREF0": {"text": "Penniston 2006) in children with and without CF (Graham-Maar 2006; Sethuraman 2006).", "type": "figure"}, "FIGREF1": {"text": "December 2009 New search has been performed A search of the Group's Cystic Fibrosis Trials Register identified a single reference which was excluded (Wood 2003).", "type": "figure"}, "TABREF0": {"text": "Growth and nutritional status (e.g. weight, height, body mass index, z score for weight, etc.) 3. Mortality Secondary outcomes 1. Respiratory outcomes i) bronchiectasis severity control (e.g. Likert scale, visual analogue scale or radiological score (Marchant 2001)) ii) lung function indices (spirometry e.g. FEV 1 and FVC) iii) proportions of participants who had respiratory exacerbations or hospitalisations or both iv) total number of hospitalised days or days off work or school 2. Quality of life 3. Adverse events (e.g. vomiting, loss of appetite, osteoporosis, fractures or any other adverse event noted) 4. Possible toxicity events (e.g. liver dysfunction) 5. Measured levels of vitamin A We planned to evaluate outcomes based on 1. short term (12 months or less), and 2. medium to long term (longer than one year)We attempted to identify relevant studies from the Group's Cystic Fibrosis Trials Register using the term 'vitamin A'. The Cystic Fibrosis Trials Register is compiled from electronic searches of the Cochrane Central Register of Controlled Trials (Clinical Trials) (updated each new issue of The Cochrane Library), quarterly searches of MEDLINE, a search of EMBASE to 1995 and the prospective handsearching of two journals -Pediatric Pul- monology and the Journal of Cystic Fibrosis. Unpublished work is identified by searching through the abstract books of three major cystic fibrosis conferences: the International Cystic Fibrosis Con- ference; the European Cystic Fibrosis Conference and the North American Cystic Fibrosis Conference. For full details of all search- ing activities for the register, please see the relevant sections of the Cystic Fibrosis and Genetic Disorders Group Module.", "type": "table"}, "TABREF1": {"text": "Protocol first published: Issue 4, 2007 Review first published: Issue 1, 2008New search has been performed A search of the Group's Cystic Fibrosis Trials Register did not identify any trials which might be eligible for inclusion in this review", "type": "table"}}}
{"paper_id": "2878351", "_pdf_hash": "b236646dd6796b13e9ce4240f64b0bfd1be8840e", "abstract": [{"section": "Abstract", "text": "Abstract. Viale introduced covering matrices in his proof that SCH follows from PFA. In the course of the proof and subsequent work with Sharon, he isolated two reflection principles, CP and S, which, under certain circumstances, are satisfied by all covering matrices of a certain shape. Using square sequences, we construct covering matrices for which CP and S fail. This leads naturally to an investigation of square principles intermediate between \u03ba and (\u03ba + ) for a regular cardinal \u03ba. We provide a detailed picture of the implications between these square principles.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "There is a fundamental and well-studied tension in set theory between large cardinals and reflection phenomena on the one hand and combinatorial principles (various square principles, in particular) witnessing incompactness (see, for example, [2] ) on the other. Reflection and large cardinals place limits on the type of combinatorial structures which can exist, and vice versa.", "cite_spans": [{"start": 243, "end": 246, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Introduction", "text": "Covering matrices were introduced by Viale in his proof that the Singular Cardinals Hypothesis follows from the Proper Forcing Axiom [10] . Here and in later work with Sharon [8] , Viale also isolated two natural properties, CP(D) and S(D), which can hold for a given covering matrix D. The statement that CP(D) (or S(D)) holds for every covering matrix D of a certain type can be seen as a reflection statement and is thus at odds with the aforementioned incompactness phenomena.", "cite_spans": [{"start": 133, "end": 137, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 175, "end": 178, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Introduction", "text": "We start this paper by constructing various covering matrices for which CP(D) and S(D) fail and investigating the relationship between the failure of CP(D) and S(D) and the existence of square sequences. This leads naturally to the definition of certain square principles which, for a regular, uncountable cardinal \u03ba, are intermediate between \u03ba and (\u03ba + ). We conclude by obtaining a detailed picture of the implications between these square principles.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Our notation is for the most part standard. Unless otherwise specified, the reference for all notation and definitions is [5] . If A is a set and \u03b8 is a cardinal, then [A] \u03b8 is the collection of subsets of A of size \u03b8. If A is a set of ordinals and \u03b1 < sup(A) is an ordinal of uncountable cofinality, we say A reflects at \u03b1 if A \u2229 \u03b1 is stationary in \u03b1. If A is a set of ordinals, then A \u2032 denotes the set of limit ordinals of A, i.e. the set of \u03b1 such that A \u2229 \u03b1 is unbounded in \u03b1, and otp(A) denotes the order type of A. If \u03c6 : A \u2192 B is a (partial) function and X \u2286 A, then \u03c6[X] is the image of X under \u03c6, and \u03c6 \u21be X is the restriction of \u03c6 to dom(\u03c6) \u2229 X. If \u03bb is a cardinal and \u00b5 < \u03bb is a regular cardinal, then S \u03bb \u00b5 = {\u03b1 < \u03bb | cf(\u03b1) = \u00b5}. S \u03bb <\u00b5 is defined in the obvious way. If s is a sequence, then |s| denotes the length of s, and, if t is also a sequence, s \u2322 t denotes the concatenation of the two.", "cite_spans": [{"start": 122, "end": 125, "text": "[5]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Introduction", "text": "Date: May 21, 2013.", "cite_spans": [], "ref_spans": []}, {"section": "Covering Matrices", "text": "Definition Let \u03b8 < \u03bb be regular cardinals. D = {D(i, \u03b2) | i < \u03b8, \u03b2 < \u03bb} is a \u03b8-covering matrix for \u03bb if:", "cite_spans": [], "ref_spans": []}, {"section": "Covering Matrices", "text": "(1) For all \u03b2 < \u03bb, \u03b2 = i<\u03b8 D(i, \u03b2).", "cite_spans": [], "ref_spans": []}, {"section": "Covering Matrices", "text": "(2) For all \u03b2 < \u03bb and all i < j < \u03b8, D(i, \u03b2) \u2286 D(j, \u03b2).", "cite_spans": [], "ref_spans": []}, {"section": "Covering Matrices", "text": "(3) For all \u03b2 < \u03b3 < \u03bb and all i < \u03b8, there is j < \u03b8 such that D(i, \u03b2) \u2286 D(j, \u03b3). \u03b2 D is the least \u03b2 such that for all \u03b3 < \u03bb and all i < \u03b8, otp(D(i, \u03b3)) < \u03b2. D is normal if \u03b2 D < \u03bb.", "cite_spans": [], "ref_spans": []}, {"section": "Covering Matrices", "text": "D is transitive if, for all \u03b1 < \u03b2 < \u03bb and all i < \u03b8, if \u03b1 \u2208 D(i, \u03b2), then D(i, \u03b1) \u2286 D(i, \u03b2).", "cite_spans": [], "ref_spans": []}, {"section": "Covering Matrices", "text": "D is uniform if for all \u03b2 < \u03bb there is i < \u03b8 such that D(j, \u03b2) contains a club in \u03b2 for all j \u2265 i. (Note that this is equivalent to the statement that there is i < \u03b8 such that D(i, \u03b2) contains a club in \u03b2.)", "cite_spans": [], "ref_spans": []}, {"section": "Covering Matrices", "text": "D is closed if for all \u03b2 < \u03bb, all i < \u03b8, and all X \u2208 [D(i, \u03b2)] \u2264\u03b8 , sup X \u2208 D(i, \u03b2).", "cite_spans": [], "ref_spans": []}, {"section": "Covering Matrices", "text": "The first part of this paper will be concerned with constructing covering matrices for which the following two reflection properties fail.", "cite_spans": [], "ref_spans": []}, {"section": "Covering Matrices", "text": "Definition Let \u03b8 < \u03bb be regular cardinals, and let D be a \u03b8-covering matrix for \u03bb.", "cite_spans": [], "ref_spans": []}, {"section": "Covering Matrices", "text": "(1) CP(D) holds if there is an unbounded T \u2286 \u03bb such that for every X \u2208 [T ] \u03b8 , there are i < \u03b8 and \u03b2 < \u03bb such that X \u2286 D(i, \u03b2) (in this case, we say that D covers [T ] \u03b8 ). (2) S(D) holds if there is a stationary S \u2286 \u03bb such that for every family {S j | j < \u03b8} of stationary subsets of S, there are i < \u03b8 and \u03b2 < \u03bb such that, for every j < \u03b8, S j \u2229 D(i, \u03b2) = \u2205.", "cite_spans": [], "ref_spans": []}, {"section": "Covering Matrices", "text": "Definition Let \u03b8 < \u03bb be regular cardinals. R(\u03bb, \u03b8) is the statement that there is a stationary S \u2286 \u03bb such that for every family {S j | j < \u03b8} of stationary subsets of S, there is \u03b1 < \u03bb of uncountable cofinality such that, for all j < \u03b8, S j reflects at \u03b1. If D is a nice enough covering matrix, then CP(D) and S(D) are equivalent and R(\u03bb, \u03b8) implies both. The following is proved in [8] :", "cite_spans": [{"start": 383, "end": 386, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Covering Matrices", "text": "Lemma 2.1. Let \u03b8 < \u03bb be regular cardinals, and let D be a \u03b8-covering matrix for \u03bb.", "cite_spans": [], "ref_spans": []}, {"section": "Covering Matrices", "text": "(", "cite_spans": [], "ref_spans": []}, {"section": "1) If D is transitive, then S(D) implies CP(D). (2) If D is closed, then CP(D) implies S(D). (3) If D is uniform, then R(\u03bb, \u03b8) implies S(D).", "text": "The following lemma is a key component of Viale's proof that SCH follows from PFA. Let \u03ba be an uncountable regular cardinal. We first consider the question of what types of \u03ba covering matrices for \u03ba + can exist. In particular, we will be interested in the existence of a covering matrix that is transitive, normal, and uniform. It turns out that one can always ask for any two of these three properties.", "cite_spans": [], "ref_spans": []}, {"section": "Proposition 2.3.", "text": "There is a uniform, transitive \u03ba-covering matrix for \u03ba + .", "cite_spans": [], "ref_spans": []}, {"section": "Proposition 2.3.", "text": "Proof. Simply let D(i, \u03b2) = \u03b2 for every i < \u03ba and \u03b2 < \u03ba + . \u22a3 Proposition 2.4. There is a transitive, normal \u03ba-covering matrix for \u03ba + .", "cite_spans": [], "ref_spans": []}, {"section": "Proposition 2.3.", "text": "Proof. For each \u03b1 < \u03ba + , let \u03c6 \u03b1 : \u03ba \u2192 \u03b1 be a surjection. For i < \u03ba and \u03b2 < \u03ba + , recursively define", "cite_spans": [], "ref_spans": []}, {"section": "D(i, \u03b1).", "text": "Let D = {D(i, \u03b2) | i < \u03ba, \u03b2 < \u03ba + }. It is clear that D is a covering matrix and, inductively, |D(i, \u03b2)| < \u03ba for every i and \u03b2. Thus, \u03b2 D \u2264 \u03ba, so D is normal. For each i < \u03ba, we show by induction on \u03b2 < \u03ba", "cite_spans": [], "ref_spans": []}, {"section": "D(i, \u03b1).", "text": "The following lemma on ordinal arithmetic will be quite useful in our construction of covering matrices. Lemma 2.5. Let \u03b8 be a regular cardinal, \u00b5 < \u03b8, and m < \u03c9. Suppose that for each i < \u00b5, X i is a set of ordinals such that otp(", "cite_spans": [], "ref_spans": []}, {"section": "D(i, \u03b1).", "text": "Proof. By induction on m. The conclusion is immediate for m = 0 and m = 1. Let m \u2265 2 and suppose for sake of contradiction that otp(X) \u2265 \u03b8 m . Fix A \u2286 X of order type exactly \u03b8 m . Enumerate A in increasing order as", "cite_spans": [], "ref_spans": []}, {"section": "D(i, \u03b1).", "text": "There is a uniform, normal \u03ba-covering matrix for \u03ba + .", "cite_spans": [], "ref_spans": []}, {"section": "D(i, \u03b1).", "text": "Proof. For each \u03b1 < \u03ba + , let C \u03b1 be a club in \u03b1 such that otp(C \u03b1 ) \u2264 \u03ba, and let \u03c6 \u03b1 : \u03ba \u2192 \u03b1 be a surjection. We define D = {D(i, \u03b2) | i < \u03ba, \u03b2 < \u03ba + } by recursion on \u03b2 and, for fixed \u03b2, by recursion on i. For each \u03b2 < \u03ba + , let D(0, \u03b2) = C \u03b2 . If i < \u03ba is a limit ordinal, let", "cite_spans": [], "ref_spans": []}, {"section": "D(i, \u03b1).", "text": "It is easily verified that D is a \u03ba-covering matrix for \u03ba + and, by construction, D(0, \u03b2) contains a club in \u03b2 for each \u03b2 < \u03ba + . It remains to show that D is normal. We in fact prove by induction on \u03b2 < \u03ba + and, for fixed \u03b2, by induction on i < \u03ba, that otp(D(i, \u03b2)) < \u03ba 2 for all i and \u03b2. Fix i < \u03ba and \u03b2 < \u03ba + . By the inductive hypothesis, D(i, \u03b2) is a union of fewer than \u03ba-many sets, all of which have order type less than \u03ba 2 . Then, by the previous lemma, otp(D(i, \u03b2)) < \u03ba 2 . Thus,", "cite_spans": [], "ref_spans": []}, {"section": "D(i, \u03b1).", "text": "However, we can not always get all three properties, since CP(D) and S(D) necessarily fail for a transitive, normal, uniform \u03ba-covering matrix for \u03ba + . Proof. MM implies that R(\u2135 n , \u2135 1 ) holds for every 1 < n < \u03c9 as witnessed by S \u2135n", "cite_spans": [], "ref_spans": []}, {"section": "\u21350", "text": ". \u22a3", "cite_spans": [], "ref_spans": []}, {"section": "\u21350", "text": "The existence of a transitive, normal, uniform covering matrix does follow, however, from sufficiently strong square principles. Proof. Let C \u03b1 | \u03b1 \u2208 lim(\u03ba + ) be a \u03ba,<\u03ba -sequence. We construct a transitive, normal, uniform \u03ba-covering matrix for \u03ba + , D = {D(i, \u03b2) : i < \u03ba, \u03b2 < \u03ba + }, by recursion on \u03b2 as follows:", "cite_spans": [], "ref_spans": []}, {"section": "\u21350", "text": "\u2022 D(i, \u03b2 + 1) = D(i, \u03b2) \u222a {\u03b2} \u2022 If \u03b2 is a limit ordinal and cf(\u03b2) < \u03ba, fix E, a club in \u03b2 of order type less than \u03ba, and let", "cite_spans": [], "ref_spans": []}, {"section": "\u21350", "text": "\u2022 If cf(\u03b2) = \u03ba, fix C \u2208 C \u03b2 , and let", "cite_spans": [], "ref_spans": []}, {"section": "\u21350", "text": "It is routine to check that D is a uniform \u03ba-covering matrix for \u03ba + , and an easy induction shows that it is transitive. We claim that D is normal. We prove that otp(D(i, \u03b2)) < \u03ba 2 for every i < \u03ba and \u03b2 < \u03ba + by induction on \u03b2. If \u03b2 is a successor ordinal or a limit ordinal of cofinality less than \u03ba, then D(i, \u03b2) is the union of fewer than \u03ba-many sets, each, by the induction hypothesis, of order type less than \u03ba 2 . Thus, otp(D(i, \u03b2)) < \u03ba 2 . Suppose cf(\u03b2) = \u03ba. Let C \u2208 C \u03b2 be the club used in the construction of D(i, \u03b2). Enumerate C \u2032 in increasing order as {\u03b1 \u03b3 | \u03b3 < \u03ba}. For each \u03b3 < \u03ba, C \u2229 \u03b1 \u03b3 \u2208 C \u03b1\u03b3 , so for \u03b3 \u2265 i, D(i, \u03b1 \u03b3 ) = \u2205. Thus, D(i, \u03b2) is itself a union of fewer than \u03ba-many sets, each of order type less than \u03ba 2 , so otp(D(i, \u03b2)) < \u03ba 2 . \u22a3", "cite_spans": [], "ref_spans": []}, {"section": "\u21350", "text": "We now show that \u03ba,<\u03ba is the optimal hypothesis in the previous proposition by producing, via a standard argument due originally to Baumgartner [1] , a model in which * \u03ba and R(\u03ba + , \u03ba) both hold. We need the following lemma, due to Shelah.", "cite_spans": [{"start": 144, "end": 147, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "\u21350", "text": "Lemma 2.11. Let \u00b5 \u2264 \u03ba be regular cardinals, let S \u2286 S \u03ba + <\u00b5 be stationary, and let P be a \u00b5-closed forcing poset. If", "cite_spans": [], "ref_spans": []}, {"section": "\u21350", "text": "Proposition 2.12. Let \u03ba < \u03bb, with \u03ba regular and \u03bb measurable. Let P = Coll(\u03ba, < \u03bb), and let", "cite_spans": [], "ref_spans": []}, {"section": "\u21350", "text": "Proof. First note that, since P is \u03ba-closed, it doesn't add any new bounded subsets of \u03ba, so, since \u03bb is measurable in V ,", "cite_spans": [], "ref_spans": []}, {"section": "\u21350", "text": ". We now show that R(\u03bb, \u03ba) holds in V [G] as witnessed by S \u03bb <\u03ba . Let j : V \u2192 M be an elementary embedding with M transitive and crit(j) = \u03bb, and let H be Coll(\u03ba, < j(\u03bb))-generic over V such that G \u2282 H. We can then lift the embedding to j :", "cite_spans": [], "ref_spans": []}, {"section": "\u21350", "text": ", the sets {j(S \u03b1 ) | \u03b1 < \u03ba} reflect simultaneously to a point of uncountable cofinality below j(\u03bb), namely \u03bb, so, by elementarity, in V [G], the sets {S \u03b1 | \u03b1 < \u03ba} reflect simultaneously to a point of uncountable cofinality below \u03bb.", "cite_spans": [], "ref_spans": []}, {"section": "\u21350", "text": "Thus, * \u03ba does not imply the existence of a transitive, normal, uniform \u03ba-covering matrix for \u03ba + . We now prove that the converse of Proposition 2.10 does not hold in general by showing that, if \u03ba is regular and not strongly inaccessible, one can force to add a transitive, normal, uniform \u03ba-covering matrix D for \u03ba + without adding a \u03ba,<\u03ba -sequence. The argument is similar to that introduced by Jensen to distinguish between various weak square principles (see [6] ). Let Q be the forcing poset consisting of conditions of the form q = {D q (i, \u03b2) | i < \u03ba, \u03b2 \u2264 \u03b2 q } such that:", "cite_spans": [{"start": 464, "end": 467, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "\u21350", "text": "contains a club in \u03b2 for sufficiently large i < \u03ba.", "cite_spans": [], "ref_spans": []}, {"section": "\u21350", "text": "For p, q \u2208 Q, p \u2264 q if and only if p end-extends q, i.e.", "cite_spans": [], "ref_spans": []}, {"section": "\u21350", "text": "Proof. Suppose \u00b5 < \u03ba and q \u03b1 | \u03b1 < \u00b5 is a descending sequence of conditions from Q. We will define q \u2208 Q such that for all \u03b1 < \u00b5, q \u2264 q \u03b1 . Let \u03b2 q = sup({\u03b2 q\u03b1 | \u03b1 < \u00b5}). We may assume without loss of generality that the \u03b2 q\u03b1 were strictly increasing, so, for all \u03b1 < \u00b5, \u03b2 q\u03b1 < \u03b2 q . For all \u03b2 < \u03b2 q and i < \u03ba, let", "cite_spans": [], "ref_spans": []}, {"section": "\u21350", "text": "To this end, fix a club C \u2286 \u03b2 q whose order type is cf(\u03b2 q ). Note that |C| < \u03ba.", "cite_spans": [], "ref_spans": []}, {"section": "\u21350", "text": "is the union of fewer than \u03ba-many sets of order type less than \u03ba 2 , the order type of D q (i, \u03b2 q ) is also less than \u03ba 2 . It easily follows that q \u2208 Q and, for all \u03b1 < \u00b5, q \u2264 q \u03b1 . \u22a3", "cite_spans": [], "ref_spans": []}, {"section": "\u21350", "text": "We now need the notion of strategic closure. Definition Let P be a partial order and let \u03b2 be an ordinal.", "cite_spans": [], "ref_spans": []}, {"section": "\u21350", "text": "(1) The two-player game G \u03b2 (P) is defined as follows: Players I and II alternately play entries in p \u03b1 | \u03b1 < \u03b2 , a decreasing sequence of conditions in P with p 0 = 1 P . Player I plays at odd stages, and Player II plays at even stages (including all limit stages). If there is an even stage \u03b1 < \u03b2 at which Player II can not play, then Player I wins. Otherwise, Player II wins. (2) P is said to be \u03b2-strategically closed if Player II has a winning strategy for the game G \u03b2 (P).", "cite_spans": [], "ref_spans": []}, {"section": "\u21350", "text": "The following is immediate. Proof. We need to exhibit a winning strategy for Player II in the game G \u03ba+1 (Q). Suppose \u03b3 \u2264 \u03ba is an even or limit ordinal and that q \u03b1 | \u03b1 < \u03b3 has been played. We specify Player II's next move, q \u03b3 . Let C \u03b3 = {\u03b2 q\u03b1 | \u03b1 < \u03b3 is an even or limit ordinal} (C \u03b3 is thus the set of the top points of the conditions played by Player II thus far). We assume the following induction hypotheses are satisfied:", "cite_spans": [], "ref_spans": []}, {"section": "\u21350", "text": "(1) C \u03b3 is closed beneath its supremum. There are three cases. Case 1: \u03b3 is a successor ordinal:", "cite_spans": [], "ref_spans": []}, {"section": "\u21350", "text": "Case 2: \u03b3 < \u03ba is a limit ordinal:", "cite_spans": [], "ref_spans": []}, {"section": "\u21350", "text": "is the union of fewer than \u03ba-many sets of order type less than \u03ba 2 and thus has order type less than \u03ba 2 .", "cite_spans": [], "ref_spans": []}, {"section": "\u21350", "text": "is the union of fewer than \u03ba-many sets of order type less than \u03ba 2 and thus has order type less than \u03ba 2 . It is easy to check that in each case the inductive hypotheses are preserved and that this provides a winning strategy for Player II in G \u03ba+1 (Q). Thus, Q is (\u03ba + 1)-strategically closed. Proof. Since Q is (\u03ba + 1)-strategically closed, forcing with Q does not add any new \u03ba-sequences of ordinals, so all cardinals \u2264 \u03ba + are preserved. Since 2 \u03ba = \u03ba + , |Q| = \u03ba + , so Q has the \u03ba ++ -chain condition and hence preserves all cardinals \u2265 \u03ba ++ . Finally, a proof similar to that of the previous proposition yields the fact that for all \u03b1 < \u03ba + , the set E \u03b1 = {q | \u03b2 q \u2265 \u03b1} is dense in Q. Thus, if G is Q-generic over V , then G is a transitive, normal, uniform \u03ba-covering matrix for \u03ba + . \u22a3 Given a \u03ba-covering matrix D for \u03ba + , we define a forcing notion T D whose purpose is to add a club in \u03ba + of order type \u03ba which interacts nicely with D. It plays a similar role in our argument as the forcing to thread a square sequence plays in [2] and [6] . Elements of T D are sets t such that:", "cite_spans": [{"start": 1042, "end": 1045, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 1050, "end": 1053, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "\u21350", "text": "(1) t is a closed, bounded subset of", "cite_spans": [], "ref_spans": []}, {"section": "\u21350", "text": "In general, T D may be very poorly behaved. For example, the set it adds may not be cofinal in \u03ba + and, even if it is, its order type might be less than \u03ba. However, if D has been added by Q immediately prior to forcing with T D , then it has some nice properties.", "cite_spans": [], "ref_spans": []}, {"section": "\u21350", "text": "Proof. This follows from the fact that, in V , for every \u03b1 < \u03ba + and every j < \u03ba, the set E j,\u03b1 = {q | \u03b1 \u2264 \u03b2 q and for every i < j, D(i, \u03b2 q ) = \u2205} is easily seen to be dense in Q. \u22a3 Proposition 2.18. If D is the covering matrix added by Q, then Q * \u1e6a D has a \u03ba-closed dense subset.", "cite_spans": [], "ref_spans": []}, {"section": "\u21350", "text": "Proof. Let S = {(q,\u1e6b) | q decides the value of\u1e6b and q \"\u03c4 \u03b3t = \u03b2 q \"}. We first show that S is dense in Q * \u1e6a D . To this end, let (q 0 ,\u1e6b 0 ) \u2208 Q * \u1e6a D . Find q 1 \u2264 q 0 such that q 1 decides the value of\u1e6b to be some \u03c4 \u03b1 | \u03b1 \u2264 \u03b3 t < \u03ba (this is possible, since Q is (\u03ba + 1)-strategically closed and hence doesn't add any new \u03ba-sequences of ordinals). Without loss of generality, \u03b2 q1 > \u03c4 \u03b3t . Now form q 2 \u2264 q 1 by setting \u03b2 q2 = \u03b2 q1 + 1 and", "cite_spans": [], "ref_spans": []}, {"section": "\u21350", "text": "Finally, let\u1e6b 1 be such that q 2", "cite_spans": [], "ref_spans": []}, {"section": "\u21350", "text": "Next, we show that S is \u03ba-closed. Let (q \u03b1 ,\u1e6b \u03b1 ) | \u03b1 < \u03bd be a decreasing sequence of conditions from S with \u03bd < \u03ba a limit ordinal. We will find a lower bound (q,\u1e6b) \u2208 S. Let \u03b2 q = sup({\u03b2 q\u03b1 | \u03b1 < \u03bd}) and let X = {\u03b2 | for some \u03b1 < \u03bd, q \u03b1 \"\u03b2 \u2208\u1e6b \u03b1 \"}. Note that by our definition of S, X is club in \u03b2 q . Let \u03b3 = otp(X). Define q as a lower bound to the q \u03b1 's by letting", "cite_spans": [], "ref_spans": []}, {"section": "\u21350", "text": "Let\u1e6b be a name forced by q to be equal to X \u222a {\u03b2 q }. Then (q,\u1e6b) \u2208 S and, for all \u03b1 < \u03bd, (q,\u1e6b) \u2264 (q \u03b1 ,\u1e6b \u03b1 ). \u22a3 Thus, if D has been added by Q, then T D does in fact add a club in \u03ba + and, since Q * \u1e6a D has a \u03ba-closed dense subset and therefore doesn't add any new sets of ordinals of order type less than \u03ba, the club added by T D has order type \u03ba.", "cite_spans": [], "ref_spans": []}, {"section": "\u21350", "text": "We will need the following fact, due to Magidor (see [7] ):", "cite_spans": [{"start": 53, "end": 56, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "\u21350", "text": "Fact 2.19. Let \u03ba be a regular cardinal, and let \u03ba < \u03bb < \u00b5. Suppose that, in V Coll(\u03ba,<\u03bb) , P is a \u03ba-closed partial order and |P| < \u00b5. Let i be the natural complete embedding of Coll(\u03ba, < \u03bb) into Coll(\u03ba, < \u00b5) (namely, the identity embedding). Then i can be extended to a complete embedding j of Coll(\u03ba, < \u03bb) * P into Coll(\u03ba, < \u00b5) so that the quotient forcing Coll(\u03ba, < \u00b5)/j[Coll(\u03ba, < \u03bb) * P] is \u03ba-closed. ", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 2.20. Let \u03ba be a regular cardinal that is not strongly inaccessible, and", "text": "Fix an elementary embedding j : V \u2192 M with critical point \u03bb. Then j(P) = Coll(\u03ba, < j(\u03bb)), and j \u21be P is the identity map. V [G] |= |Q * T| = \u03bb, and |Q * T| has a \u03ba-closed dense subset, so we can extend j \u21be P to a complete embedding of Coll(\u03ba, < \u03bb) * Q * T into Coll(\u03ba, < j(\u03bb)) so that the quotient forcing is \u03ba-closed. Then, letting I be T-generic", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 2.20. Let \u03ba be a regular cardinal that is not strongly inaccessible, and", "text": "we can further extend j to an elementary embedding j :", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 2.20. Let \u03ba be a regular cardinal that is not strongly inaccessible, and", "text": "We would now like to extend j further still to an embedding with domain V [G * H]. To do this, consider the partial order j(Q). In M [G * H * I * J], j(Q) is the partial order to add a transitive, normal, uniform \u03ba-covering matrix for j(\u03bb). Let E = I. E is a club in \u03bb of order type \u03ba, and if \u03b2 \u2208 E is such that otp(E \u2229 \u03b2) = \u03b3, then for every i < \u03b3, D(i, \u03b2) = \u2205. We use E to define a \"master condition\" q * \u2208 j(Q) as follows. Let \u03b2", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 2.20. Let \u03ba be a regular cardinal that is not strongly inaccessible, and", "text": "Suppose for sake of contradiction that", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 2.20. Let \u03ba be a regular cardinal that is not strongly inaccessible, and", "text": "Suppose the subclaim fails for some (q,\u1e6b,\u1e59,\u1e57). Define a Q-name\u1e1f \u2032 such that for all q \u2032 \u2264 q and \u03b1 < \u03ba", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 2.20. Let \u03ba be a regular cardinal that is not strongly inaccessible, and", "text": "\"\u1e1f =\u1e1f \u2032 \", contradicting our choice of\u1e1f . This proves the subclaim. Since \u03ba is not strongly inaccessible, letting \u03b3 be the least cardinal such that 2 \u03b3 \u2265 \u03ba, we have \u03b3 < \u03ba. Recall that S is the previously defined \u03ba-closed dense subset of Q * T. We will construct q i | i \u2264 \u03b3 , (\u1e6b s ,\u1e59 s ,\u1e57 s ) | s \u2208 \u2264\u03b3 2 and \u03b1 i | i \u2264 \u03b3 such that:", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 2.20. Let \u03ba be a regular cardinal that is not strongly inaccessible, and", "text": "Suppose for a moment that we have successfully completed this construction. Find q * \u2264 q \u03b3 such that q * decides the set C \u03b1\u03b3 (this can be done, since Q is (\u03ba + 1)-strategically closed). Then, for each s \u2208 \u03b3 2, (q * ,\u1e6b s ,\u1e59 s ,\u1e57 s ) \u2208 Q * T * R * j(Q) and (q * ,\u1e6b s ,\u1e59 s ,\u1e57 s ) \"\u03b1 \u03b3 is a limit point of\u1e1f \". Moreover, if s, u \u2208 \u03b3 2 and s = u, then (q * ,\u1e6b s ,\u1e59 s ,\u1e57 s ) and (q * ,\u1e6b u ,\u1e59 u ,\u1e57 u ) force contradictory information about\u1e1f \u2229 \u03b1 \u03b3 , which is forced to be an element of C \u03b1\u03b3 . But 2 \u03b3 \u2265 \u03ba, contradicting the fact that C is a \u03ba,<\u03ba -sequence.", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 2.20. Let \u03ba be a regular cardinal that is not strongly inaccessible, and", "text": "We now turn to the construction. Fix (q 0 ,\u1e6b ,\u1e59 ,\u1e57 ) such that (q 0 ,\u1e6b ,\u1e59 ,\u1e57 ) \"\u1e1f is a thread through C\", and let \u03b1 0 = 0. We first consider the successor case. Fix i < \u03b3 and suppose that q i , (\u1e6b s ,\u1e59 s ,\u1e57 s ) | s \u2208 i 2 , and \u03b1 i have been defined Enumerate i 2 as s j | j < 2 i , noting that 2 i < \u03ba. Now, using the \u03ba-closure of Q, S, R, and j(Q), the density of S in Q * T, the subclaim, and the fact that (q 0 ,\u1e6b ,\u1e59 ,\u1e57 ) \"\u1e1f is unbounded in \u03ba + \", it is straightforward to construct q", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 2.20. Let \u03ba be a regular cardinal that is not strongly inaccessible, and", "text": "Now let \u03be = sup({\u03b4 | for some j < 2 i and \u2113 \u2208 {0, 1}, q", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 2.20. Let \u03ba be a regular cardinal that is not strongly inaccessible, and", "text": ". Let E i+1 be a club in \u03b1 i+1 of order type cf(\u03b1 i+1 ) < \u03ba. Define q i+1 to be a lower bound of q i j | j < 2 i by letting \u03b2 qi+1 = \u03b1 i+1 and, for all k < \u03ba,", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 2.20. Let \u03ba be a regular cardinal that is not strongly inaccessible, and", "text": "Finally, for all j < 2 i and \u2113 \u2208 {0, 1}, let (", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 2.20. Let \u03ba be a regular cardinal that is not strongly inaccessible, and", "text": "Next, suppose that i \u2264 \u03b3 is a limit ordinal and that q j | j < i , (\u1e6b s ,\u1e59 s ,\u1e57 s ) | s \u2208 <i 2 and \u03b1 j | j < i have been defined. Let \u03be = sup({\u03b4 | for some s \u2208 <i 2, q |s| \"otp(\u1e6b s ) =\u03b4\"}). Since 2 <i < \u03ba, we know that \u03be < \u03ba. Let \u03b1 i = sup({\u03b2 qj | j < i}) and let E i be a club in \u03b1 i of order type cf(\u03b1 i ) < \u03ba. Define q i to be a lower bound for q j | j < i by letting \u03b2 qi = \u03b1 i and", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 2.20. Let \u03ba be a regular cardinal that is not strongly inaccessible, and", "text": "Finally, for all s \u2208 i 2, let\u1e6b s be such that q i \"\u1e6b s = j<i\u1e6b s\u21bej \u222a {\u03b1 i }\" and let (\u1e59 s ,\u1e57 s ) be forced by (q i ,\u1e6b s ) to be a lower bound for (\u1e59 s\u21bej ,\u1e57 s\u21bej ) | j < i . This is possible, since R * j(Q) is \u03ba-closed. It is easily verified that this construction satisfies conditions 1-5 above.", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 2.20. Let \u03ba be a regular cardinal that is not strongly inaccessible, and", "text": "But now we have shown that F , which threads C, is in", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 2.20. Let \u03ba be a regular cardinal that is not strongly inaccessible, and", "text": "Note that, if \u03ba is supercompact and \u03bb > \u03ba is measurable, we can also obtain a model in which there is a transitive, normal, uniform \u03ba-covering matrix for \u03ba + but \u03ba,<\u03ba fails by first making the supercompactness of \u03ba indestructible under \u03ba-directed closed forcing and then forcing with Q. We conjecture that we can obtain such a model for all regular, uncountable \u03ba but do not have a proof when \u03ba is inaccessible but not supercompact.", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 2.20. Let \u03ba be a regular cardinal that is not strongly inaccessible, and", "text": "We now investigate counterexamples to CP(D) and S(D) for more general shapes of covering matrices. Recall the following definitions: Definition Let \u03ba be an infinite cardinal.", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 2.20. Let \u03ba be a regular cardinal that is not strongly inaccessible, and", "text": "(", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 2.20. Let \u03ba be a regular cardinal that is not strongly inaccessible, and", "text": "is a (\u03ba)-sequence if it is a coherent sequence that has no thread. We say that (\u03ba) holds if there is a (\u03ba)-sequence. Let \u03b8 < \u03bb be regular, infinite cardinals and suppose that (\u03bb) holds. Fix a (\u03bb)-sequence \u2212 \u2192 C . Arrange so that C \u03b1 is defined for all \u03b1 < \u03bb by letting C \u03b1+1 = {\u03b1}. The definitions of the following functions are due to Todorcevic [9] : First, define", "cite_spans": [{"start": 347, "end": 350, "text": "[9]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Theorem 2.20. Let \u03ba be a regular cardinal that is not strongly inaccessible, and", "text": "Proofs of the following lemmas can be found in [9] .", "cite_spans": [{"start": 47, "end": 50, "text": "[9]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Theorem 2.20. Let \u03ba be a regular cardinal that is not strongly inaccessible, and", "text": "Lemma 2.23. Let \u03b1 < \u03b2 < \u03b3 < \u03bb.", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 2.20. Let \u03ba be a regular cardinal that is not strongly inaccessible, and", "text": "Lemma 2.24. Let i < \u03b8 and \u03b2 < \u03bb. {\u03b1 < \u03b2 | \u03c1 \u03b8 (\u03b1, \u03b2) \u2264 i} is closed.", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 2.20. Let \u03ba be a regular cardinal that is not strongly inaccessible, and", "text": "(2) Let \u00b5 < \u03ba be infinite regular cardinals.", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 2.20. Let \u03ba be a regular cardinal that is not strongly inaccessible, and", "text": "\u03b1 is bounded below \u03b1} is stationary. \u00b5 (\u03ba) is the statement that a \u00b5 (\u03ba)-sequence exists.", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 2.20. Let \u03ba be a regular cardinal that is not strongly inaccessible, and", "text": "Lemma 2.25. Let \u03b2 < \u03bb be such that cf(\u03b2) = \u03b8 and C", "cite_spans": [], "ref_spans": []}, {"section": "[\u03b8]", "text": "\u03b2 is bounded below \u03b2. Then, for every i < \u03b8, D(i, \u03b2) is bounded below \u03b2.", "cite_spans": [], "ref_spans": []}, {"section": "[\u03b8]", "text": "\u03b2 ). Since \u03be < \u03b2 and cf(\u03b2) = \u03b8, otp(C \u03b2 \\ (\u03be + 1)) = \u03b8. Enumerate C \u03b2 \\ (\u03be + 1) in increasing order as \u03b2 i | i < \u03b8 . Now, if i < \u03b8 and", "cite_spans": [], "ref_spans": []}, {"section": "[\u03b8]", "text": "Proof. Suppose for sake of contradiction that CP(D) holds and is witnessed by an unbounded", "cite_spans": [], "ref_spans": []}, {"section": "[\u03b8]", "text": "\u03b8 be an unbounded subset of \u03b1. Find i < \u03b8 and \u03b2 < \u03bb", "cite_spans": [], "ref_spans": []}, {"section": "[\u03b8]", "text": ". This is a contradiction, as the previous lemma implies that D(i, \u03b1) is bounded below \u03b1. Thus, CP(D) fails. Since D is transitive, this means that S(D) fails as well. \u22a3", "cite_spans": [], "ref_spans": []}, {"section": "[\u03b8]", "text": "The question now naturally arises whether \u03b8 (\u03bb) is a strictly stronger assumption than (\u03bb). This and related questions are addressed in the remainder of this paper.", "cite_spans": [], "ref_spans": []}, {"section": "Squares", "text": "Definition Let A \u2286 \u03ba and let", "cite_spans": [], "ref_spans": []}, {"section": "Squares", "text": "It is well known that if \u03ba holds and S \u2286 \u03ba + is stationary, then there is a stationary T \u2286 S and a \u03ba -sequence that avoids T . We would like to know to what extent similar phenomena occur in connection with (\u03ba). The following proposition, whose proof we include for completeness, provides some information in this direction by showing that, if \u03ba is regular and S \u2286 \u03ba is stationary, then every (\u03ba)-sequence must, in a certain sense, avoid a pair of stationary subsets of S.", "cite_spans": [], "ref_spans": []}, {"section": "Squares", "text": "Proposition 3.1. Let \u03ba > \u03c9 1 be a regular cardinal, and let \u2212 \u2192 C = C \u03b1 | \u03b1 \u2208 lim(\u03ba) be a coherent sequence. Then the following are equivalent:", "cite_spans": [], "ref_spans": []}, {"section": "Squares", "text": "\u03b1 \u2229 S 1 = \u2205 and suppose for sake of contradiction that there is a club D in \u03ba that threads \u2212 \u2192 C . Since S 0 and S 1 are stationary, there are \u03b1 < \u03b2 < \u03b3 in D \u2032 such that \u03b1 \u2208 S 0 and \u03b2 \u2208 S 1 . Since D \u2229 \u03b3 = C \u03b3 , we have", "cite_spans": [], "ref_spans": []}, {"section": "Squares", "text": "Next, suppose that \u2212 \u2192 C is a (\u03ba)-sequence and that T \u2286 \u03ba is stationary. There are two cases:", "cite_spans": [], "ref_spans": []}, {"section": "Squares", "text": "and let T * = S 0 \u222a S 1 be any partition of T * into disjoint stationary sets. Then S 0 and S 1 are as desired. \u03b1 is bounded below \u03b1}.", "cite_spans": [], "ref_spans": []}, {"section": "+1). It is easy to verify that", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "\u2212 \u2192 C is a (\u03ba)-sequence and, if", "text": "The remainder of the paper investigates the implications and non-implications that exist among the traditional square properties and those of the form \u00b5 (\u03ba) and (\u03ba, S). A diagram illustrating the complete picture when \u03ba = \u03c9 2 can be found at the end of the paper. Proof. First, suppose that", "cite_spans": [], "ref_spans": []}, {"section": "\u2212 \u2192 C is a (\u03ba)-sequence and, if", "text": "\u03b1 is bounded below \u03b1}. It is easily seen that the construction from the proof of Proposition 3.3 yields a (\u03ba, S)-sequence, where S = T \u2229 S Proof. Assume \u03bd (\u03ba) holds, and fix a (\u03ba)-sequence \u2212 \u2192 C such that T 0 = {\u03b1 < \u03ba | otp(C \u03b1 ) = \u03bd} is stationary. We claim that T 1 = {\u03b1 \u2208 S \u03ba \u00b5 | otp(C \u03b1 ) < \u03bd} is also stationary. To see this, let E be club in \u03ba.", "cite_spans": [], "ref_spans": []}, {"section": "\u2212 \u2192 C is a (\u03ba)-sequence and, if", "text": "We can now apply Fodor's Lemma to T 1 \\ \u03bd to find a \u03b3 < \u03bd and a stationary S \u2286 T 1 such that \u03b1 \u2208 S implies otp(C \u03b1 ) = \u03b3. Let \u03b3 \u03be | \u03be < \u00b5 enumerate a club in \u03b3 with each \u03b3 \u03be a limit ordinal (this will not be possible if \u00b5 = \u03c9 and \u03b3 is not a limit of limit ordinals, but in that case \u2212 \u2192 C is already a \u00b5 (\u03ba)-sequence).", "cite_spans": [], "ref_spans": []}, {"section": "\u2212 \u2192 C is a (\u03ba)-sequence and, if", "text": "We now define a", "cite_spans": [], "ref_spans": []}, {"section": "\u2212 \u2192 C is a (\u03ba)-sequence and, if", "text": ". Note again that this is well-defined.", "cite_spans": [], "ref_spans": []}, {"section": "\u2212 \u2192 C is a (\u03ba)-sequence and, if", "text": "If there is \u03b1 \u2032 \u2208 S such that \u03b1 \u2032 \u2208 C \u2032 \u03b1 (note that such an \u03b1 \u2032 must be unique), then", "cite_spans": [], "ref_spans": []}, {"section": "\u2212 \u2192 C is a (\u03ba)-sequence and, if", "text": "In all other cases, let D \u03b1 = C \u03b1 . It is now easy to verify that \u2212 \u2192 D is a (\u03ba)-sequence and, since \u03b1 \u2208 S implies that otp(D \u03b1 ) = \u00b5, that it is in fact a \u00b5 (\u03ba)-sequence. \u22a3", "cite_spans": [], "ref_spans": []}, {"section": "\u2212 \u2192 C is a (\u03ba)-sequence and, if", "text": "The following corollary is now immediate. We now show that the above implications are generally not reversible. We begin by recalling the definition of the forcing poset that adds a (\u03ba) sequence by specifying its initial segments.", "cite_spans": [], "ref_spans": []}, {"section": "\u2212 \u2192 C is a (\u03ba)-sequence and, if", "text": "Definition Let \u03ba be a regular cardinal. Q(\u03ba) is the partial order whose elements are of the form q = C q \u03b1 | \u03b1 \u2264 \u03b2 q , where Proof. We specify a winning strategy for Player II in G \u03ba (Q(\u03ba)). First, let q 0 = \u2205. Let 0 < \u03b1 < \u03ba be even and suppose that q \u03b4 | \u03b4 < \u03b1 has already been played. We specify Player II's next move, q \u03b1 . Let E \u03b1 = {\u03b2 q \u03b4 | \u03b4 < \u03b1 is even} and suppose that we have satisfied the following inductive hypotheses:", "cite_spans": [], "ref_spans": []}, {"section": "\u2212 \u2192 C is a (\u03ba)-sequence and, if", "text": "(1) E \u03b1 is closed below its supremum.", "cite_spans": [], "ref_spans": []}, {"section": "\u2212 \u2192 C is a (\u03ba)-sequence and, if", "text": "(2) For all even ordinals \u03b4 < \u03be < \u03b1, \u03b2 q \u03b4 < \u03b2 q \u03be and \u03b2", "cite_spans": [], "ref_spans": []}, {"section": "\u2212 \u2192 C is a (\u03ba)-sequence and, if", "text": "First, suppose that \u03b1 is a successor ordinal. Since it is even, it is in fact a double successor. Let \u03b1 = \u03b1 \u2032 + 1 = \u03b1 \u2032\u2032 + 2. In this case, let", "cite_spans": [], "ref_spans": []}, {"section": "\u2212 \u2192 C is a (\u03ba)-sequence and, if", "text": "Next, suppose that \u03b1 is a limit ordinal. Let \u03b2 q\u03b1 = sup({\u03b2 q \u03b4 | \u03b4 < \u03b1}). For limit ordinals \u03b6 < \u03b2 q\u03b1 , find \u03b4 < \u03b1 such that \u03b6 \u2264 \u03b2 q \u03b4 and let C By our inductive hypotheses, this is a club in \u03b2 q\u03b1 and satisfies the coherence requirements.", "cite_spans": [], "ref_spans": []}, {"section": "\u2212 \u2192 C is a (\u03ba)-sequence and, if", "text": "It is clear that this procedure produces a valid condition q \u03b1 \u2208 Q(\u03ba) that is a lower bound for q \u03b4 | \u03b4 < \u03b1 and maintains the inductive hypotheses. Thus, Q(\u03ba) is \u03ba-strategically closed. \u22a3 An argument similar to the proof of the previous proposition shows that, for every \u03b1 < \u03ba, the set {q | \u03b2 q \u2265 \u03b1} is dense in Q(\u03ba). Proof. Let G be Q(\u03ba)-generic over V . Since Q(\u03ba) is \u03ba-strategically closed, it doesn't add any < \u03ba-sequences of ordinals and hence preserves all cardinals \u2264 \u03ba. Since {q | \u03b2 q \u2265 \u03b1} is dense in Q(\u03ba) for every \u03b1 < \u03ba, we can define C \u03b1 = C Proof. Let S = {\u03b1 < \u03ba | otp(C \u03b1 ) = \u00b5}. It suffices to show that, in V [G], S is stationary in \u03ba. Note that this implies that \u2212 \u2192 C doesn't have a thread, since any club in \u03ba must meet S in two points.", "cite_spans": [], "ref_spans": []}, {"section": "\u2212 \u2192 C is a (\u03ba)-sequence and, if", "text": "Work in V , let\u1e0a be a Q(\u03ba)-name forced by the empty condition to be a club in \u03ba, let\u1e60 be a Q(\u03ba)-name for S, and let q \u2208 Q(\u03ba). We will find p \u2264 q such that p \u1e0a \u2229\u1e60 = \u2205.", "cite_spans": [], "ref_spans": []}, {"section": "\u2212 \u2192 C is a (\u03ba)-sequence and, if", "text": "We construct q \u03b1 | \u03b1 \u2264 \u00b5 , a decreasing sequence of conditions from Q(\u03ba) such that for every \u03b1 \u2264 \u00b5,", "cite_spans": [], "ref_spans": []}, {"section": "\u2212 \u2192 C is a (\u03ba)-sequence and, if", "text": "To carry out this construction, we first let \u03b2 q0 = \u03b2 q +\u03c9. For limit ordinals \u03b6 \u2264 \u03b2 q , let C q0 \u03b6 = C q \u03b6 . Let C q0 \u03b2 q 0 = {\u03b2 q + n | n < \u03c9}. Next, suppose that \u03b1 = \u03b1 \u2032 + 1 and that we have already constructed", "cite_spans": [], "ref_spans": []}, {"section": "\u2212 \u2192 C is a (\u03ba)-sequence and, if", "text": "q * * \u03b1 + n | n < \u03c9}. Now suppose that \u03b1 < \u00b5 is a limit ordinal and we have constructed q \u03b4 | \u03b4 < \u03b1 . Let \u03b2 q\u03b1 = sup({\u03b2 q \u03b4 | \u03b4 < \u03b1}). For limit ordinals \u03b6 < \u03b2 q\u03b1 , find \u03b4 < \u03b1 such that \u03b2 q \u03b4 \u2265 \u03b6 and let", "cite_spans": [], "ref_spans": []}, {"section": "\u2212 \u2192 C is a (\u03ba)-sequence and, if", "text": "It is clear that this construction satisfies requirements 1-4 above. Let p = q \u00b5 . We have arranged so that cf(\u03b2 p ) = \u00b5 and otp(C p \u03b2 p ) = \u00b5. We have also arranged that, for every \u03b6 < \u03b2 p , p \"\u1e0a \u2229 (\u03b6, \u03b2 p ) = \u2205\". Thus, since\u1e0a is forced by the empty condition to be a club, p \u03b2 p \u2208\u1e0a. Thus we have found our desired p \u2264 q such that p\" \u1e0a \u2229\u1e60 = \u2205\". \u22a3", "cite_spans": [], "ref_spans": []}, {"section": "\u2212 \u2192 C is a (\u03ba)-sequence and, if", "text": "We now introduce a forcing poset designed to add a thread of order type \u03ba through a (\u03ba)-sequence.", "cite_spans": [], "ref_spans": []}, {"section": "\u2212 \u2192 C is a (\u03ba)-sequence and, if", "text": "Definition Let \u03ba be a regular cardinal and let \u2212 \u2192 C be a (\u03ba)-sequence. T( \u2212 \u2192 C ) is the partial order consisting of elements t such that:", "cite_spans": [], "ref_spans": []}, {"section": "\u2212 \u2192 C is a (\u03ba)-sequence and, if", "text": "(1) t is a closed, bounded subset of \u03ba.", "cite_spans": [], "ref_spans": []}, {"section": "\u2212 \u2192 C is a (\u03ba)-sequence and, if", "text": "We denote the maximum element of a condition t by \u03b3 t . s \u2264 t if and only if s end-extends t, i.e. \u03b3 s \u2265 \u03b3 t and s \u2229 (\u03b3 t + 1) = t.", "cite_spans": [], "ref_spans": []}, {"section": "\u2212 \u2192 C is a (\u03ba)-sequence and, if", "text": "As was the case with the previously defined T D , if \u2212 \u2192 C was added by Q(\u03ba), then T( \u2212 \u2192 C ) is quite nice.", "cite_spans": [], "ref_spans": []}, {"section": "Proposition 3.10. Let \u03ba be a regular cardinal and let", "text": "for the (\u03ba)-sequence added by Q, and\u1e6a be a Q-name for T(\u2212 \u2192 C ). Then Q * \u1e6a has a \u03ba-closed dense subset.", "cite_spans": [], "ref_spans": []}, {"section": "Proposition 3.10. Let \u03ba be a regular cardinal and let", "text": "Proof. Let S = {(q,\u1e6b) | q decides the value of\u1e6b and q \"\u03b2 q = \u03b3 t \"}. We first show that S is dense in Q * \u1e6a. To this end, let (q 0 ,\u1e6b 0 ) \u2208 Q * \u1e6a. Since Q is \u03ba-strategically closed,\u1e6b 0 is forced to be in the ground model. Find q \u2264 q 0 and t * such that q \"\u1e6b 0 =\u0165 * \". Without loss of generality, we may assume that \u03b2 q > max(t * ). Le\u1e6b t be such that q \"\u1e6b =\u1e6b 0 \u222a {\u03b2 q }\". Then (q,\u1e6b) \u2264 (q 0 ,\u1e6b 0 ) and (q,\u1e6b) \u2208 S. Next, we claim that S is \u03ba-closed. Let \u03b1 < \u03ba and let (q \u03b4 ,\u1e6b \u03b4 ) | \u03b4 < \u03b1 be a decreasing sequence of conditions from S. Without loss of generality, we may assume that, for every \u03b4 < \u03b1, \u03b2 q \u03b4 < \u03b2 q . We will construct a lower bound (q,\u1e6b). Let \u03b2 q = sup({\u03b2 q \u03b4 | \u03b4 < \u03b1}). For limit \u03b6 < \u03b2 q , let \u03b4 < \u03b1 be such that \u03b2 q \u03b4 \u2265 \u03b6 and set C q \u03b6 = C q \u03b4 \u03b6 . Let X = {\u03b6 | for some \u03b4 < \u03b1, q \u03b4 \"\u03b6 \u2208\u1e6b \u03b1 \"}. By our definition of S, X is club in \u03b2 q and for every \u03b6 \u2208 X \u2032 , X \u2229 \u03b6 = C q \u03b6 . Thus, we can let C q \u03b2 q = X. Finally, let\u1e6b be such that q \"\u1e6b =X \u222a {\u03b2 q }\". (q,\u1e6b) is then a lower bound of (q \u03b4 ,\u1e6b \u03b4 ) | \u03b4 < \u03b1 in S. \u22a3 A key point here, which will be exploited in the proof of the next theorem, is that, for an uncountable cardinal \u03ba, one can force to add and then thread a (\u03ba + )-sequence with a two-step iteration which is \u03ba + -closed, whereas if one wants to add and thread, for example, a \u03ba,<\u03ba -sequence, the best one can do is a two-step iteration which is \u03ba-closed.", "cite_spans": [], "ref_spans": []}, {"section": "Proposition 3.10. Let \u03ba be a regular cardinal and let", "text": "Theorem 3.12. Suppose \u00b5 < \u03ba are regular cardinals and \u03bb > \u03ba is a measurable", "cite_spans": [], "ref_spans": []}, {"section": "Proposition 3.10. Let \u03ba be a regular cardinal and let", "text": "\u00b5 (\u03ba + ) holds and \u03ba,<\u03ba fails.", "cite_spans": [], "ref_spans": []}, {"section": "Proposition 3.10. Let \u03ba be a regular cardinal and let", "text": "Proof. We have already shown that \u00b5 (\u03ba + ) holds in any extension by Q(\u03ba + ), so it remains to show that \u03ba,<\u03ba fails. Let Q = Q(\u03ba + ), and let \u2212 \u2192 C be the (\u03ba", "cite_spans": [], "ref_spans": []}, {"section": "Proposition 3.10. Let \u03ba be a regular cardinal and let", "text": "Fix an elementary embedding j : V \u2192 M with critical point \u03bb. j \u21be Coll(\u03ba, < \u03bb) : Coll(\u03ba, < \u03bb) \u2192 Coll(\u03ba, < j(\u03bb)) is the identity map and, in V Coll(\u03ba,<\u03bb) , Q * \u1e6a has a \u03ba + -closed dense subset which has size \u03ba + . Thus, we can extend j to a complete embedding of Coll(\u03ba, < \u03bb) * Q * \u1e6a into Coll(\u03ba, < j(\u03bb)) such that the quotient forcing, R, is \u03ba-closed. Then, letting I be T-generic over V [G * H] and letting J be R-generic over V [G * H * I], we can further extend j to an elementary embedding j :", "cite_spans": [], "ref_spans": []}, {"section": "Proposition 3.10. Let \u03ba be a regular cardinal and let", "text": "We would like to extend j still further to have domain V [G * H]. This is precisely the reason for introducing the threading poset. In V [G * H * I * J], j(Q) is the forcing poset to add a (j(\u03bb))-sequence. C \u03b1 | \u03b1 < \u03bb would be a condition in j(Q) if it had a top element. To arrange this, we define q * \u2208 j(Q) by letting \u03b2", "cite_spans": [], "ref_spans": []}, {"section": "Proposition 3.10. Let \u03ba be a regular cardinal and let", "text": "Now suppose for sake of contradiction that", "cite_spans": [], "ref_spans": []}, {"section": "Proposition 3.10. Let \u03ba be a regular cardinal and let", "text": "F \u2208 V [G * H * I * J * K]. However, K is generic for j(Q), which is j(\u03bb)-strategically closed in V [G * H * I * J] and thus does not add any \u03ba-sequences of ordinals. Thus,", "cite_spans": [], "ref_spans": []}, {"section": "Proposition 3.10. Let \u03ba be a regular cardinal and let", "text": "Then there is an R-name\u1e1e such that F =\u1e1e J and R \"\u1e1e is not in the ground model\". Suppose first that \u03ba is not strongly inaccessible. Let \u03b3 be the least cardinal such that 2 \u03b3 \u2265 \u03ba. We will construct p s | s \u2208 \u2264\u03b3 2 and \u03b1 \u03b2 | \u03b2 \u2264 \u03b3 satisfying:", "cite_spans": [], "ref_spans": []}, {"section": "Proposition 3.10. Let \u03ba be a regular cardinal and let", "text": "(6) For all limit ordinals \u03b2 \u2264 \u03b3 and all s \u2208 \u03b2 2, p s \"\u03b1 \u03b2 is a limit point of\u1e1e \" and there is", "cite_spans": [], "ref_spans": []}, {"section": "Proposition 3.10. Let \u03ba be a regular cardinal and let", "text": "Suppose for a moment that we have successfully constructed these sequences. Then, for all s \u2208 \u03b3 2, there is D s \u2208 D \u03b1\u03b3 such that p s \"\u03b1 \u03b3 is a limit point of\u1e1e and\u1e1e \u2229 \u03b1 \u03b2 = D s \". But if s, u \u2208 \u03b3 2 and s = u, then there is \u03b1 < \u03b1 \u03b3 such that p s and p u decide the statement \"\u03b1 \u2208\u1e1e \" in opposite ways, so D s = D u . But 2 \u03b3 \u2265 \u03ba, so this contradicts the fact that |D \u03b1\u03b3 | < \u03ba.", "cite_spans": [], "ref_spans": []}, {"section": "Proposition 3.10. Let \u03ba be a regular cardinal and let", "text": "Now we turn our attention to the construction of such sequences. Fix p such that p \"\u1e1e is a thread through \u2212 \u2192 D \", and let \u03b1 0 = 0. Fix \u03b2 < \u03b3 and suppose that p s | s \u2208 \u03b2 2 and \u03b1 \u03b2 have been defined. Fix s \u2208 \u03b2 2. Since R \"\u1e1e is unbounded in \u03ba + \", we can find \u03b1 > \u03b1 \u03b2 and p \u2032 s \u2264 p s such that p \u2032 s \"\u03b1 \u2208\u1e1e \". Since R \"\u1e1e is not in the ground model\", we can find \u03b1 s > \u03b1 and p 0 , p 1 \u2264 p \u2032 s such that p 0 and p 1 decide the statement \"\u03b1 s \u2208\u1e1e \" in opposite ways. Let p s \u2322 0 = p 0 and p s \u2322 1 = p 1 . Do this for all s \u2208 \u03b2 2, and let \u03b1 \u03b2+1 = sup({\u03b1 s +1 | s \u2208 \u03b2 2}). 2 \u03b2 < \u03ba, so \u03b1 \u03b2+1 < \u03ba + . If \u03b2 \u2264 \u03b3 is a limit ordinal and p s | s \u2208 <\u03b2 2 and \u03b1 \u03b4 | \u03b4 < \u03b2 have been constructed, let \u03b1 \u03b2 = sup({\u03b1 \u03b4 | \u03b4 < \u03b2}). Fix s \u2208 \u03b2 2. Since R is \u03ba-closed, there is p \u2208 R such that, for every \u03b4 < \u03b2, p \u2264 p s\u21be\u03b4 . We have arranged that for every \u03b4 < \u03b2 there is \u03b1 > \u03b1 \u03b4 such that p s\u21be(\u03b4+1) \"\u03b1 \u2208\u1e1e \". Thus, p \"\u03b1 \u03b2 is a limit point of\u1e1e \". Find p", "cite_spans": [], "ref_spans": []}, {"section": "Proposition 3.10. Let \u03ba be a regular cardinal and let", "text": ". Requirements 1-6 above are easily seen to be satisfied by this construction. Now suppose that \u03ba is strongly inaccessible. We modify the above construction slightly. By Fodor's Lemma, find \u03bd < \u03ba and a stationary S \u2286 S \u03bb <\u03ba such that if \u03b1 \u2208 S, then |D \u03b1 | \u2264 \u03bd. Construct p s | s \u2208 \u2264\u03bd 2 and \u03b1 \u03b2 | \u03b2 \u2264 \u03bd exactly as above. Fix a sufficiently large regular cardinal \u03b8 and let M \u227a H(\u03b8) contain all relevant information (including\u1e1e , \u2212 \u2192 D , R, p s | s \u2208 \u2264\u03bd 2 , and \u03b1 \u03b2 | \u03b2 \u2264 \u03bd ) such that |M | = \u03ba \u2286 M and \u03bb M = M \u2229 \u03bb \u2208 S. Fix \u03bb \u03b7 | \u03b7 < \u03b3 < \u03ba increasing and cofinal in \u03bb M . Using the \u03ba-closure of R and the fact that\u1e1e is forced to be a club, find, for each s \u2208 \u03bd 2, a decreasing sequence of conditions from R, p s,\u03b7 | \u03b7 < \u03b3 such that, for every \u03b7 < \u03b3, p s,\u03b7 \u2208 M and there is a \u03be \u03b7 such that \u03bb \u03b7 < \u03be \u03b7 < \u03bb M and p s,\u03b7 \"\u03be \u03b7 \u2208\u1e1e \". Let p * s be a lower bound for p s,\u03b7 | \u03b7 < \u03b3 . For each s \u2208 \u03bd 2, p * s \"\u03bb M \u2208\u1e1e \u2032 \" and, for s = u \u2208 \u03bd 2, p * s and p * u force contradictory information about\u1e1e \u2229 \u03bb M . Since 2 \u03bd > \u03bd, this contradicts the fact that ", "cite_spans": [], "ref_spans": []}, {"section": "Proposition 3.10. Let \u03ba be a regular cardinal and let", "text": "Proof. Let the initial model be called", "cite_spans": [], "ref_spans": []}, {"section": "Proposition 3.10. Let \u03ba be a regular cardinal and let", "text": ", and let\u2212 \u2192 C be a name for the (\u03ba + )-sequence added", "cite_spans": [], "ref_spans": []}, {"section": "Proposition 3.10. Let \u03ba be a regular cardinal and let", "text": "we define a sequence of posets S \u03b1 | \u03b1 \u2264 \u03bb + by induction on \u03b1. We will show that each S \u03b1 is \u03bb-distributive and thus does not change any cofinalities \u2264 \u03bb. For each \u03b2 < \u03bb + , we will fix a Q * S \u03b2 -name\u1e8a \u03b2 for a subset of S \u03bb \u03bd such that Q * S \u03b2 * T \"\u1e8a \u03b2 is non-stationary\" and a Q * S \u03b2 * T-name\u0116 \u03b2 for a club in \u03bb such that Q * S \u03b2 * T \"\u1e8a \u03b2 \u2229\u0116 \u03b2 = \u2205\". Elements of S \u03b1 are then functions s such that:", "cite_spans": [], "ref_spans": []}, {"section": "Proposition 3.10. Let \u03ba be a regular cardinal and let", "text": "(", "cite_spans": [], "ref_spans": []}, {"section": "Proposition 3.10. Let \u03ba be a regular cardinal and let", "text": "For every \u03b2 \u2208 dom(s), s(\u03b2) is a closed, bounded subset of \u03bb. (4) For every \u03b2 \u2208 dom(s), s \u21be \u03b2 \"s(\u03b2) \u2229\u1e8a \u03b2 = \u2205\". For s, t \u2208 S \u03b1 , t \u2264 s if and only if dom(s) \u2286 dom(t) and, for every \u03b2 \u2208 dom(s), t(\u03b2) end-extends s(\u03b2). S \u03bb + can be seen as a dense subset of an iteration with \u2264 \u03ba-support in which the \u03b1 th iterand shoots a club disjoint to the interpretation of\u1e8a \u03b1 . Thus, for each \u03b1 < \u03bb + , Q * S \u03bb + \"\u1e8a \u03b1 is non-stationary\". By a standard \u2206-system argument, it is easy to see that, in V Q , S \u03bb + has the \u03bb + -chain condition. Thus, since, in V Q , 2 \u03bb = \u03bb + , we can choose the sequence \u1e8a \u03b1 | \u03b1 < \u03bb + in such a way that, for every \u03b2 < \u03bb + and every Q * S \u03b2 -name\u1e8a for a subset of S \u03bb \u03bd , if there is \u03b1 \u2265 \u03b2 such that Q * S\u03b1 * T \"\u1e8a is non-stationary\", then there is \u03b1 * \u2265 \u03b1 such that Q * S \u03b1 * \"\u1e8a \u03b1 * =\u1e8a\". Also, again by the \u03bb + -chain condition of S \u03bb + , if\u1e8a is a Q * S \u03bb + -name for a subset of S \u03bb \u03bd and Q * S \u03bb + * T \"\u1e8a is non-stationary\", then there is \u03b1 < \u03bb + and a Q * S \u03b1 -name\u1e8e for a subset of S \u03bb \u03bd such that Q * S \u03bb + \"\u1e8a =\u1e8e \" and Q * S\u03b1 * T \"\u1e8e is non-stationary\". Putting this together, we have that for every Q * S \u03bb + -name\u1e8a for a subset of S \u03bb \u03bd , if Q * S \u03bb + * T \"\u1e8a is non-stationary\", then already Q * S \u03bb + \"\u1e8a is non-stationary\".", "cite_spans": [], "ref_spans": []}, {"section": "Proposition 3.10. Let \u03ba be a regular cardinal and let", "text": ". If i is a limit ordinal, then, by the inductive hypothesis, U \u03b1i is \u03bb-closed, so we can find (q i ,\u1e61 i ,\u1e6b i ) \u2208 U \u03b1i that is a lower bound for (q j ,\u1e61 j ,\u1e6b j ) | j < i .", "cite_spans": [], "ref_spans": []}, {"section": "Proposition 3.10. Let \u03ba be a regular cardinal and let", "text": "We now define (q,\u1e61,\u1e6b) \u2208 U \u03b1 which is a lower bound for (q i ,\u1e61 i ,\u1e6b i ) | i < \u03be . First, by previous arguments, find (q,\u1e6b) \u2208 U 0 which is a lower bound for (q i ,\u1e6b i ) | i < \u03be . Next, let X = {\u03b2 | for some i < \u03be, q i \"\u03b2 \u2208 dom(\u1e61 i )}. If \u03b2 \u2208 X, let\u1e61 * (\u03b2) be such that q \"\u1e61 * (\u03b2) = i<\u03be\u1e61 i (\u03b2). Let\u1e61 be such that q \"dom(\u1e61) = X and, if \u03b2 \u2208 X, then\u1e61(\u03b2) =\u1e61 * (\u03b2) \u222a {sup(\u1e61 * (\u03b2)}\". It is routine to check that (q,\u1e61,\u1e6b) \u2208 U \u03b1 and (q,\u1e61,\u1e6b) \u2264 (q 0 ,\u1e61 0 ,\u1e6b 0 ).", "cite_spans": [], "ref_spans": []}, {"section": "Proposition 3.10. Let \u03ba be a regular cardinal and let", "text": "The proof that U \u03b1 is \u03bb-closed is the same as in the successor case. \u22a3 It follows that, for all \u03b1 \u2264 \u03bb + , S \u03b1 is \u03bb-distributive and thus preserves all cardinals and cofinalities. It remains to show that, in V Q * S \u03bb + , (\u03bb, T ) fails for every", "cite_spans": [], "ref_spans": []}, {"section": "Proposition 3.10. Let \u03ba be a regular cardinal and let", "text": ", and let J be T-generic over V [H * I]. Since, in V , Q * S \u03bb + * T has a \u03bb-closed dense subset and has size \u03bb + , by Fact 2.19 we can extend the identity map i : P \u2192 j(P) to a complete embedding i * : P * Q * S \u03bb + * T \u2192 j(P) such that the quotient forcing R = j(P)/i", "cite_spans": [], "ref_spans": []}, {"section": "Proposition 3.10. Let \u03ba be a regular cardinal and let", "text": "Suppose now for sake of contradiction that, in V [H * I], T \u2286 S \u03bb \u03bd is stationary and", "cite_spans": [], "ref_spans": []}, {"section": "Proposition 3.10. Let \u03ba be a regular cardinal and let", "text": ". We would like to lift j further to have domain V [H * I \u03be * ]. To do this, we define a master condition (q * ,\u0161 * ,\u0165 * ) \u2208 j(Q * S \u03be * * T). q * is defined exactly as in the proof of Theorem 3.12. Let E be the club added by J, and let t * = E \u222a {\u03bb}. Then (q * ,\u0165 * ) \u2208 j(Q * T). Let s be the generic object added by I \u03be * . s is thus a function with domain \u03be * , where, for each \u03b1 < \u03be * , s(\u03b1) is a club in \u03bb. Let s * be such that dom(s * ) = j[\u03be * ] and, for each \u03b1 < \u03be * , s * (j(\u03b1)) = s(\u03b1) \u222a {\u03bb}. It is clear that, if (q * ,\u0161 * ) \u2208 j(Q * S \u03be * ), then it is a lower bound for j[H * I \u03be * ]. Thus, all that needs to be checked is that, for every \u03b1 < \u03be * , (q", "cite_spans": [], "ref_spans": []}, {"section": "Proposition 3.10. Let \u03ba be a regular cardinal and let", "text": "We show this by induction on \u03b1. It suffices to show that (q * ,\u0161 * \u21be j(\u03b1)) \"\u03bb \u2208 j(\u1e8a \u03b1 )\". Suppose for sake of contradiction that there is (q", "cite_spans": [], "ref_spans": []}, {"section": "Proposition 3.10. Let \u03ba be a regular cardinal and let", "text": ". This is a contradiction.", "cite_spans": [], "ref_spans": []}, {"section": "Proposition 3.10. Let \u03ba be a regular cardinal and let", "text": "Thus, (q * ,\u0161 * ) is a lower bound for j[H * I \u03be * ] in j(Q * S \u03be * ), so, if we let Proof. By Theorem 3.18, fix a stationary S \u2286 \u03bb consisting of inaccessible cardinals and a (\u03bb, S)-sequence, \u2212 \u2192 C . Let P = Coll(\u03ba, < \u03bb). In V P , we define an iteration Q \u03b1 | \u03b1 \u2264 \u03bb + , which will shoot clubs disjoint to non-reflecting sets of ordinals, by induction on \u03b1. For each \u03b1 < \u03bb + , we will fix a Q \u03b1 -name\u1e8a \u03b1 such that Q\u03b1 \"\u1e8a \u03b1 \u2286 S \u03bb <\u03ba and\u1e8a \u03b1 does not reflect at any ordinal of uncountable cofinality\". Elements of Q \u03b1 are functions q such that:", "cite_spans": [], "ref_spans": []}, {"section": "Proposition 3.10. Let \u03ba be a regular cardinal and let", "text": "(1) dom(q) \u2286 \u03b1.", "cite_spans": [], "ref_spans": []}, {"section": "Proposition 3.10. Let \u03ba be a regular cardinal and let", "text": "(2) |q| \u2264 \u03ba. (3) For every \u03b2 \u2208 dom(q), q(\u03b2) is a closed, bounded subset of \u03bb. (4) For every \u03b2 \u2208 dom(q), q \u21be \u03b2 \"q(\u03b2) \u2229\u1e8a \u03b2 = \u2205\". For p, q \u2208 Q \u03b1 , q \u2264 p if and only if dom(p) \u2286 dom(q) and, for every \u03b2 \u2208 dom(p), q(\u03b2) end-extends p(\u03b2). An easy \u2206-system argument shows that Q \u03bb + has the \u03bb + -c.c. Thus, with a suitable choice of the names\u1e8a \u03b1 , we can arrange that, in V P * Q \u03bb + , every stationary subset of S \u03bb <\u03ba reflects. Back in V , fix a sufficiently large, regular cardinal \u03b8 (in particular, \u03b8 > \u03bb + ). Let N be the set of N such that P \u2208 N , N (H(\u03b8), \u2208, \u22b3) (where \u22b3 is a well-ordering of H(\u03b8)), \u03bb N := N \u2229 \u03bb is an inaccessible cardinal, |N | = \u03bb N , and N <\u03bbN \u2286 N . For N \u2208 N , let \u03c0 N : N \u2192N be the transitive collapse. If x \u2208 N , let x N = \u03c0 N (x).", "cite_spans": [], "ref_spans": []}, {"section": "Proposition 3.10. Let \u03ba be a regular cardinal and let", "text": "Lemma 3.20. For every x \u2208 H(\u03b8), there is N \u2208 N such that x \u2208 N . Proof. Fix x \u2208 H(\u03b8). We find the desired N \u2208 N by building an increasing, continuous chain N \u03b1 | \u03b1 < \u03bb such that, for each \u03b1 < \u03bb,", "cite_spans": [], "ref_spans": []}, {"section": "Proposition 3.10. Let \u03ba be a regular cardinal and let", "text": "(1) x, \u03bb \u2208 N \u03b1 (2) N \u03b1 \u227a H(\u03b8). . Let E be the set of \u03b1 < \u03bb such that N \u03b1 \u2229 \u03bb = \u03b1 = |N \u03b1 |. E is a club in \u03bb, so, since \u03bb is Mahlo, there is \u03b1 * \u2208 E such that \u03b1 * is inaccessible. N \u03b1 * is then in N . \u22a3 If N \u2208 N , then, since N is closed under < \u03bb N -sequences, P N = P\u2229N = Coll(\u03ba, < \u03bb N ), so N P \u227a H(\u03b8) P . Also, since P N has the \u03bb N -c.c.,N PN \u223c = N P is closed under < \u03bb N -sequences from V PN . The following Lemma, which will show that Q \u03bb + is \u03bb-distributive, is proven in [4] . By the chain condition, every < \u03bb-sequence in V P * Q \u03bb + appears in V P * Q\u03b1 for some \u03b1 < \u03bb + , so we have that, in V P , Q \u03bb + is \u03bb-distributive and thus preserves all cardinals \u2264 \u03bb. Proof. Let E \u2208 V P * Q \u03bb + be a club in \u03bb. By the chain condition, there is \u03b1 < \u03bb + such that E \u2208 V P * Q\u03b1 . Thus, it suffices to show that S remains stationary in V P * Q\u03b1 for every \u03b1 < \u03bb + . To this end, fix \u03b1 < \u03bb + , (p,q) \u2208 P * Q \u03b1 , and\u0116, a P * Q \u03b1 -name for a club in \u03bb. By the argument from the proof of Lemma 3.20, we can find N \u2208 N such that {(p,q),\u0116, \u03b1} \u2286 N and \u03bb N \u2208 S. Let G be P-generic over V with p \u2208 G, and let G N be the restriction of G to Coll(\u03ba, < \u03bb N ). Since P has the \u03bb-c. (1) and the fact thatN [G N ] is closed under < \u03bb N -sequences, we can find a decreasing sequence q \u03be | \u03be < \u03bb N of conditions from the \u03bb N -closed dense subset of (Q \u03b1 ) N such that q 0 = q and, for all \u03be < \u03bb N , q \u03be+1 \u2208 D \u03be \u2229N [G N ]. We define q * to be a lower bound for \u03c0 \u22121 N (q \u03be ) | \u03be < \u03bb N in Q \u03b1 by letting dom(q * ) = N \u2229 \u03b1 and, for each \u03b2 \u2208 dom(q * ),", "cite_spans": [{"start": 480, "end": 483, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 1167, "end": 1170, "text": "(1)", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Proposition 3.10. Let \u03ba be a regular cardinal and let", "text": "cf(\u03bb N ) = \u03ba in V P * Q \u03b2 , so \u03bb N is forced not to be in\u1e8a \u03b2 and thus q * \u2208 Q \u03b1 . For every \u03b3 < \u03bb N , there is \u03be < \u03bb N and \u03b4 \u2208 (\u03b3, \u03bb N ) such that q \u03be (Q\u03b1)N \"\u03b4 \u2208 \u03c0(\u0116)\". Thus, \u03c0 \u22121 N (q \u03be ) Q\u03b1 \"\u03b4 \u2208\u0116\". so q * Q\u03b1 \"\u0116 is unbounded in\u03bb N \". Since\u0116 is a name for a club, q * Q\u03b1 \"\u03bb N \u2208\u0116 \u2229\u0160\", so S is stationary in V P * Q\u03b1 . \u22a3", "cite_spans": [], "ref_spans": []}, {"section": "Proposition 3.10. Let \u03ba be a regular cardinal and let", "text": "We conclude with a diagram illustrating the situation at \u03c9 2 , where we now have a complete picture. Arrows correspond to implications, and struck-out arrows to non-implications. 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Transactions of the", "authors": [{"first": "A", "middle": [], "last": "Sharon", "suffix": ""}, {"first": "M", "middle": [], "last": "Viale", "suffix": ""}], "year": 2010, "venue": "", "link": null}, "BIBREF8": {"title": "Walks on ordinals and their characteristics", "authors": [{"first": "S", "middle": [], "last": "Todorcevic", "suffix": ""}], "year": 2007, "venue": "Progress in Mathematics", "link": "117922094"}, "BIBREF9": {"title": "The proper forcing axiom and the singular cardinal hypothesis", "authors": [{"first": "M", "middle": [], "last": "Viale", "suffix": ""}], "year": 2006, "venue": "Journal of Symbolic Logic", "link": "6553086"}}, "ref_entries": {"FIGREF0": {"text": "Let \u03bb > \u2135 2 be a regular cardinal. PFA implies that CP(D) holds for every \u03c9-covering matrix D for \u03bb.", "type": "figure"}, "FIGREF1": {"text": "Suppose \u03ba is a regular cardinal and \u03ba,<\u03ba holds. Then there is a transitive, normal, uniform \u03ba-covering matrix for \u03ba + .", "type": "figure"}, "FIGREF2": {"text": "If \u03b1 < \u03b1 \u2032 < \u03b3 and \u03b1, \u03b1 \u2032 are even ordinals, then \u03b2 q\u03b1 < \u03b2 q \u03b1 \u2032 . (3) For all even ordinals \u03b1 < \u03b3 and all i < \u03b1, D q\u03b1 (i, \u03b2 q\u03b1 ) = \u2205.", "type": "figure"}, "FIGREF3": {"text": "Proposition 2.16. If 2 \u03ba = \u03ba + , then Q is a cardinal-preserving forcing poset that adds a transitive, normal, uniform \u03ba-covering matrix for \u03ba + .", "type": "figure"}, "FIGREF4": {"text": "There is \u03b1 \u2208 lim(\u03ba) such that S 0 \u03b1 and S 1 \u03b1 are both stationary. Proof. Suppose this is not the case. Let A be the set of \u03b1 \u2208 lim(\u03ba) such that S 0 \u03b1 is nonstationary. We claim that A is unbounded in \u03ba. To show this, fix \u03b1 0 < \u03ba. By Fodor's Lemma, we can fix an \u03b1 \u2265 \u03b1 0 and a stationary T * \u2286 T such that if \u03b2 \u2208 T * , then \u03b1 = min(C \u2032 \u03b2 \\ \u03b1 0 ). Then \u03b1 \u2208 A. Now let \u03b1 < \u03b1 \u2032 be elements of A, and let D \u03b1 and D \u03b1 \u2032 be clubs in \u03ba disjoint from S 0 \u03b1 and S 0 \u03b1 \u2032 , respectively. Fix \u03b2", "type": "figure"}, "FIGREF5": {"text": "routine to check that S 0 and S 1 are as desired. \u22a3 The preceding observations lead us to make the following definition. Definition Let \u03ba be a regular, uncountable cardinal, and let S \u2286 \u03ba. \u2212 \u2192 C is a (\u03ba, S)- sequence if \u2212 \u2192 C is a (\u03ba)-sequence and \u2212 \u2192 C avoids S. (\u03ba, S) is the statement that a (\u03ba, S)-sequence exists. We start our investigation of these intermediate square principles with the fol- lowing simple observation.", "type": "figure"}, "FIGREF6": {"text": "Let \u00b5 < \u03ba be infinite regular cardinals. The following are equiv- alent:There is a (\u03ba)-sequence \u2212 \u2192 C such that {\u03b1 < \u03ba | otp(C \u03b1 ) = \u00b5} is stationary. Proof. A (\u03ba)-sequence as in 2. is clearly a \u00b5 (\u03ba) sequence. For the other direction, let \u2212 \u2192 D be a \u00b5 (\u03ba)-sequence, and let T = {\u03b1 < \u03ba | D [\u00b5]", "type": "figure"}, "FIGREF7": {"text": "Let \u00b5 < \u03ba be infinite, regular cardinals. (1) If \u00b5 (\u03ba) holds, then there is a stationary S \u2286 S \u03ba \u00b5 such that (\u03ba, S) holds. (2) If there is a stationary S \u2286 S \u03ba \u03c9 such that (\u03ba, S) holds, then \u03c9 (\u03ba) holds.", "type": "figure"}, "FIGREF8": {"text": "is a (\u03ba, S)-sequence. For \u03b1 < \u03ba, define C \u03b1 as follows: If \u03b1 \u2208 S, let C \u03b1 = D \u03b1 . If \u03b1 \u2208 S, let C \u03b1 be any set of order type \u03c9 unbounded in \u03b1. Since \u2212 \u2192 D avoids S, this does not interfere with the coherence of the sequence, so \u2212 \u2192 C is a \u03c9 (\u03ba)-sequence. \u22a3 Proposition 3.5. Let \u00b5 < \u03bd < \u03ba be infinite, regular cardinals. If \u03bd (\u03ba) holds, then \u00b5 (\u03ba) holds.", "type": "figure"}, "FIGREF9": {"text": "Let \u00b5 < \u03bd < \u03ba be infinite, regular cardinals. If \u03bd (\u03ba) holds, then there is a stationary S \u2286 S \u03ba \u00b5 such that (\u03ba, S) holds. (2) Let \u00b5 \u2264 \u03ba be infinite, regular cardinals, with \u00b5 regular. If \u03ba holds, then \u00b5 (\u03ba + ) holds.", "type": "figure"}, "FIGREF10": {"text": "and only if p end-extends q, i.e. \u03b2 p \u2265 \u03b2 q and, for all \u03b1 \u2264 \u03b2 q ,Proposition 3.7. Q(\u03ba) is \u03ba-strategically closed.", "type": "figure"}, "FIGREF12": {"text": "Forcing with Q(\u03ba) preserves all cardinals \u2264 \u03ba and adds a coherent sequence C \u03b1 | \u03b1 < \u03ba . In addition, if \u03ba <\u03ba = \u03ba, then all cardinals are preserved.", "type": "figure"}, "FIGREF13": {"text": "q \u2208 G and \u03b2 q \u2265 \u03b1. It is clear that \u2212 \u2192 C = C \u03b1 | \u03b1 < \u03ba is well-defined and a coherent sequence. Finally, if \u03ba <\u03ba , then |Q(\u03ba)| = \u03ba. Thus, Q(\u03ba) has the \u03ba + -c.c. and preserves all cardinals \u2265 \u03ba + . \u22a3 Lemma 3.9. If \u00b5 < \u03ba are regular cardinals and G is Q(\u03ba)-generic over V , then the coherent sequence \u2212 \u2192 C added by G is a \u00b5 (\u03ba)-sequence.", "type": "figure"}, "FIGREF14": {"text": "since K is generic for \u03ba-closed forcing, the argument from Theorem 3.12 shows that it can not add a thread through \u2212 \u2192 D , so D \u03bb \u2208 V [H * I * J] and witnesses that T is not stationary in V [H * I * J]. But we arranged our iteration S \u03bb + so that this implies that T is already non-stationary in V [H * I]. This is a contradiction, so (\u03bb, T ) fails in V [H * I]. \u22a3 Finally, we show that the existence of a stationary S \u2282 S \u03ba + \u03ba such that (\u03ba + , S) holds does not imply the existence of a stationary T \u2282 S \u03ba + <\u03ba for which (\u03ba + , T ) holds. In [4], Harrington and Shelah show that, after collapsing a Mahlo cardinal to be \u03ba + , one can iteratively force to shoot clubs disjoint to non-reflecting subsets of S \u03ba + <\u03ba , thus obtaining a model in which every stationary subset of S \u03ba + <\u03ba reflects. We will work in L and carry out the forcing iteration used by Harrington and Shelah, arguing that our desired conclusion holds in the final model. We use the following theorem of Jensen about squares in L ([3], Chapter VII).", "type": "figure"}, "FIGREF15": {"text": "Suppose V = L. Let \u03bb be an inaccessible cardinal which is not weakly compact, and let S \u2286 \u03bb be stationary. Then there is a stationary S \u2032 \u2286 S such that (\u03bb, S \u2032 ) holds.", "type": "figure"}, "FIGREF16": {"text": "Suppose V = L, \u03ba is a regular, uncountable cardinal, and \u03bb > \u03ba is the least Mahlo cardinal greater than \u03ba. Then there is a forcing extension in which \u03bb = \u03ba + , there is a stationary S \u2286 S \u03bb \u03ba such that (\u03bb, S) holds, and all stationary subsets of S \u03bb <\u03ba reflect (and hence (\u03bb, T ) fails for every stationary T \u2286 S \u03bb <\u03ba ).", "type": "figure"}, "FIGREF17": {"text": "|N \u03b1 | < \u03bb. (4) P(N \u03b1 ) \u2286 N \u03b1+1 . (5) sup(N \u03b1 \u2229 \u03bb) \u2286 N \u03b1+1", "type": "figure"}, "FIGREF18": {"text": "For all N \u2208 N such that \u03b1 \u2208 N , in V PN , (Q \u03b1 ) N has a \u03bb N -closed dense subset. (2) In V P , Q \u03b1 is \u03bb-distributive. (3) For all N \u2208 N such that \u03b1 \u2208 N , in V PN * (Q \u03b2 )N , (X \u03b2 ) N is not stationary in \u03bb N .", "type": "figure"}, "FIGREF19": {"text": "In V P * Q \u03bb + , there is no stationary T \u2286 S \u03bb <\u03ba such that (\u03bb, T ) holds. Proof. Suppose there is such a T , and let \u2212 \u2192 D be a (\u03bb, T )-sequence. Then, for each \u03b1 < \u03bb of uncountable cofinality, D \u2032 \u03b1 witnesses that T \u2229 \u03b1 is non-stationary, so T does not reflect. However, in V P * Q \u03bb + , every stationary subset of S \u03bb <\u03ba reflects. Contradiction. \u22a3 In V P * Q \u03bb + , \u2212 \u2192 C is clearly still a coherent sequence avoiding S and S \u2286 S \u03bb \u03ba . Thus, the following lemma suffices to prove the theorem.", "type": "figure"}, "FIGREF20": {"text": "Lemma 3.23. S is stationary in V P * Q \u03bb + .", "type": "figure"}, "FIGREF21": {"text": "c., S is still stationary in V [G]. Let q be the interpretation ofq in V [G], and reinterpret\u0116 in V [G] as a Q \u03b1 - name. Also, we can extend \u03c0 N to an isomorphism of N [G] andN [G N ]. Enumerate the dense open sets of (Q \u03b1 ) N lying inN [G N ] as D \u03be | \u03be < \u03bb N . By Lemma 3.21", "type": "figure"}, "TABREF0": {"text": "Lemma 2.7. If D is a normal \u03ba-covering matrix for \u03ba + , then CP(D) fails. Proof. Let T be an unbounded subset of \u03ba + . Then any X \u2208 [T ] \u03ba whose order type is greater than \u03b2 D can not be contained in any D(i, \u03b2). \u22a3", "type": "table"}, "TABREF3": {"text": "sets not preserved by the threading forcing is, in a sense, easy to destroy. Thus, by shooting clubs disjoint to these sets, we can arrange so that the threading forcing does in fact preserve stationary subsets of S", "type": "table"}}}
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{"paper_id": "2878464", "_pdf_hash": "6424744a5149b5cadd7b1a4e85d253bcb1f4a844", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "A Study of Speech Recognition for Children and Elderly", "authors": [{"first": "J", "middle": ["G"], "last": "Wilpon", "suffix": ""}, {"first": "C", "middle": ["N"], "last": "Jacobsen", "suffix": ""}], "year": 1996, "venue": "Proc. of ICASSP", "link": null}, "BIBREF1": {"title": "Robust Recognition of Children's Speech", "authors": [{"first": "A", "middle": [], "last": "Potamianos", "suffix": ""}, {"first": "S", "middle": [], "last": "Narayanan", "suffix": ""}], "year": 2003, "venue": "IEEE Trans. on Speech and Audio Processing", "link": "29929729"}, "BIBREF2": {"title": "Investigating Recognition of Children's Speech", "authors": [{"first": "D", "middle": [], "last": "Giuliani", "suffix": ""}, {"first": "M", "middle": [], "last": "Gerosa", "suffix": ""}], "year": 2003, "venue": "Proc. of ICASSP", "link": "15359980"}, "BIBREF3": {"title": "Acoustic of children's speech: Developmental changes of temporal and spectral parameters", "authors": [{"first": "S", "middle": [], "last": "Lee", "suffix": ""}, {"first": "A", "middle": [], "last": "Potamianos", "suffix": ""}, {"first": "S", "middle": [], "last": "Narayanan", "suffix": ""}], "year": 1999, "venue": "Journal of Acoust. Soc. Amer", "link": "15161139"}, "BIBREF4": {"title": "Children's Speech Recognition with Application to Interactive Books and Tutors", "authors": [{"first": "A", "middle": [], "last": "Hagen", "suffix": ""}, {"first": "B", "middle": [], "last": "Pellom", "suffix": ""}, {"first": "R", "middle": [], "last": "Cole", "suffix": ""}], "year": 2003, "venue": "Proc. of ASRU Workshop", "link": "14754715"}, "BIBREF5": {"title": "Speaker Normalization through Constrained MLLR Based Transforms", "authors": [{"first": "D", "middle": [], "last": "Giuliani", "suffix": ""}, {"first": "M", "middle": [], "last": "Gerosa", "suffix": ""}, {"first": "F", "middle": [], "last": "Brugnara", "suffix": ""}], "year": 2004, "venue": "Proc. of INTERSPEECH/ICSLP", "link": "18718952"}, "BIBREF6": {"title": "An Analysis of the Causes of Increased Error Rates in Children's Speech Recognition", "authors": [{"first": "Q", "middle": [], "last": "Li", "suffix": ""}, {"first": "M", "middle": [], "last": "Russell", "suffix": ""}], "year": 2002, "venue": "Proc. of ICSLP", "link": "9148828"}, "BIBREF7": {"title": "From broadcast news to spontaneous dialogue transcription: Portability issues", "authors": [{"first": "N", "middle": [], "last": "Bertoldi", "suffix": ""}, {"first": "F", "middle": [], "last": "Brugnara", "suffix": ""}, {"first": "M", "middle": [], "last": "Cettolo", "suffix": ""}, {"first": "M", "middle": [], "last": "Federico", "suffix": ""}, {"first": "D", "middle": [], "last": "Giuliani", "suffix": ""}], "year": 2001, "venue": "Proc. of ICASSP", "link": "7986970"}, "BIBREF8": {"title": "Speaker Normalization Using Efficient Frequency Warping Procedure", "authors": [{"first": "L", "middle": [], "last": "Lee", "suffix": ""}, {"first": "R", "middle": ["C"], "last": "Rose", "suffix": ""}], "year": 1996, "venue": "Proc. of ICASSP", "link": "12263198"}, "BIBREF9": {"title": "Improved Methods for Vocal Tract Normalization", "authors": [{"first": "L", "middle": [], "last": "Welling", "suffix": ""}, {"first": "S", "middle": [], "last": "Kanthak", "suffix": ""}, {"first": "H", "middle": [], "last": "Ney", "suffix": ""}], "year": 1999, "venue": "Proc. of ICASSP", "link": "14522767"}, "BIBREF10": {"title": "A Compact Model for Speaker-Adaptive Training", "authors": [{"first": "T", "middle": [], "last": "Anastasakos", "suffix": ""}, {"first": "J", "middle": [], "last": "Mcdonough", "suffix": ""}, {"first": "R", "middle": [], "last": "Schwartz", "suffix": ""}, {"first": "J", "middle": [], "last": "Makhoul", "suffix": ""}], "year": 1996, "venue": "Proc. of ICSLP", "link": "15921794"}, "BIBREF11": {"title": "Maximum likelihood linear transformations for HMM-based speech recognition", "authors": [{"first": "M", "middle": ["J F"], "last": "Gales", "suffix": ""}], "year": 1998, "venue": "Computer Speech and Language", "link": "9241826"}, "BIBREF12": {"title": "Towards Speech Rate Independence in Large Vocabulary Continuous Speech Recognition", "authors": [{"first": "F", "middle": [], "last": "Martnez", "suffix": ""}, {"first": "D", "middle": [], "last": "Tapias", "suffix": ""}, {"first": "J", "middle": [], "last": "Alvarez", "suffix": ""}], "year": 1998, "venue": "Proc. of ICASSP, Seattle", "link": null}}, "ref_entries": {}}
{"paper_id": "2879071", "_pdf_hash": "f2a000735a794313534bac8b3a821f9fb31e2344", "abstract": [{"section": "Abstract", "text": "Background: Targeted therapies are emerging treatment options for gastric cancer (GC). Patient-derived tumor xenograft(PDX) models of GC closely retain the features of the original clinical cancer, offering a powerful tool for preclinical drug efficacy testing. This study aimed to establish PDX GC models, and explore therapeutics targeting Her2, MET(cMet), and FGFR2, which may assist doctor to select the proper target therapy for selected patients. Methods: GC tissues from 32 patients were collected and implanted into immuno-deficient mice. Using immunohistochemistry(IHC) and fluorescent in-situ hybridization (FISH), protein levels and/or gene amplification of Her2, cMet and FGFR2 in those tissues were assessed. Finally, anti-tumor efficacy was tested in the PDX models using targeted inhibitors. Results: A total of 9 passable PDX models were successfully established from 32 gastric cancer xenograft donors, consisting of HER2,cMet and FGFR2 alterations with percentages of 4(12.5%), 8(25.0%) and 1(3.1%) respectively. Crizotinib and AZD4547 exerted marked antitumor effects exclusively in PDX models with cMet (G30,G31) and FGFR2(G03) amplification. Interestingly, synergistic antitumor activity was observed in G03 (FGFR2-amplifed and cMet non-amplified but IHC [2+]) with simultaneous treatment with Crizotinib and ADZ4547 at day 30 post-treatment. Further in vitro biochemistry study showed a synergistic inhibition of the MAPK/ERK pathway. HER2,cMet and FGFR2 alterations were found in 17 (10.4%), 32(19.6%) and 6(3.7%) in a group of 163 GC patients, and cMet gene amplification or protein overexpression(IHC 3+) was associated with poor prognosis. Conclusions: These PDX GC models provide an ideal platform for drug screening and evaluation. GC patients with positive cMet or FGFR2 gene amplification may potentially benefit from cMet or FGFR2 targeted therapies or combined targeted therapy.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Background", "text": "Gastric cancer (GC) is one of the most commonly diagnosed cancers and one of the leading cause of cancer related deaths worldwide [1, 2] . Despite improvements in surgery and chemotherapy, the prognosis of advanced gastric cancer remains poor, with a five-year survival rate of nearly 20% [3] . Over the past decade, targeted therapies have greatly improved the outcomes of patients with certain malignancies, including breast, colorectal, and lung cancer, however, less progress has been made with regard to gastric cancer [4] [5] [6] [7] . Therefore, developing new therapeutic approaches, particularly through the use of targeted therapeutic agents, is crucial in gastric cancer research.", "cite_spans": [{"start": 134, "end": 136, "text": "2]", "ref_id": "BIBREF1"}, {"start": 289, "end": 292, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 524, "end": 527, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 528, "end": 531, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 532, "end": 535, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 536, "end": 539, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Background", "text": "One of the main obstacles that hamper progress in therapeutic approaches is the lack of appropriate preclinical models. Conventional cell-implanted xenograft models are commonly used for the development of new drugs. However, prolonged in vitro culture and possible selection cause cell-implanted xenograft models to lose the original molecular characteristics and heterogeneity of primary tumors, which results in poor prediction of the clinical tumor's drug response [8] . In contrast to cell line-derived xenografts, patient derived tumor xenografts(PDX) closely retain the histopathologic, genetic, and phenotypic features of the patients' original tumors [8] [9] [10] . Recently, PDX models have been widely established for certain tumors, including lung, colorectal, breast, pancreatic, and gastric cancers [9, [11] [12] [13] [14] . PDX models are now becoming a powerful tool for the study of tumor biology and the evaluation of anticancer drugs.", "cite_spans": [{"start": 469, "end": 472, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 660, "end": 663, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 664, "end": 667, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 668, "end": 672, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 813, "end": 816, "text": "[9,", "ref_id": "BIBREF8"}, {"start": 817, "end": 821, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 822, "end": 826, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 827, "end": 831, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 832, "end": 836, "text": "[14]", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Background", "text": "Approving trastuzumab for HER2-positive GC patients represents a milestone in targeted therapy for gastric cancer [15] . Recently, ramucirumab(anti-VEGFR2 monoclonal antibody) has been approved for advanced gastric cancer as second-line treatment; however, the improved overall survival by targeted therapy is still limited [16, 17] . Therefore, developing targeted therapeutic agents and increasing the population benefiting from them is urgent in gastric cancer research. MET(cMet) is a member of the RTK family and plays a key role in tumor survival, growth, angiogenesis, and metastasis [18] . A significant proportion of gastric cancers display cMet overexpression and/or gene amplification, and aberrant signaling of cMet pathways in gastric cancer is correlated with advanced tumor stage and poor prognosis [19] . The initial results of preclinical and clinical studies assessing cMet inhibitors such as onartuzumab and crizotinib were negative [20, 21] . FGFR2 is another member of the RTK family that regulates cellular proliferation, survival, migration and differentiation [22] .", "cite_spans": [{"start": 114, "end": 118, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 324, "end": 328, "text": "[16,", "ref_id": "BIBREF15"}, {"start": 329, "end": 332, "text": "17]", "ref_id": "BIBREF16"}, {"start": 591, "end": 595, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 814, "end": 818, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 952, "end": 956, "text": "[20,", "ref_id": "BIBREF19"}, {"start": 957, "end": 960, "text": "21]", "ref_id": "BIBREF20"}, {"start": 1084, "end": 1088, "text": "[22]", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Background", "text": "Approximately 4-7% of gastric cancers show FGFR2 amplification, which may correlate with poor prognosis of gastric cancer patients [23, 24] . A recent study revealed that AZD4547(a selective FGFR kinase inhibitor) exerts marked antitumor effects on GC xenografts carrying FGFR2 gene amplification [25] . Thus, it has become increasingly apparent that FGFR2 is a potential therapeutic candidate for gastric cancer.", "cite_spans": [{"start": 131, "end": 135, "text": "[23,", "ref_id": "BIBREF22"}, {"start": 136, "end": 139, "text": "24]", "ref_id": "BIBREF23"}, {"start": 297, "end": 301, "text": "[25]", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Background", "text": "In this study, we successfully established nine PDX models using thirty-two implanted GC samples from patients. Then, Her2, cMet, and FGFR2 gene copy number and protein expression levels were assessed in a cohort of 163 GC patients as well as in the 32 GC patients who donated the xenografts. Finally, targeted therapy's antitumor efficacy was evaluated in PDX models.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Patients and tumor samples", "text": "Thirty-two tumor specimens were obtained at initial surgery from 32 gastric patients at the Department of Surgical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University. Written informed consent was obtained from each patient, and the study was approved by the hospital ethics committee. This study also included a cohort of 163 patients with GC who received a surgical resection of primary gastric cancer from January 2010 to December 2011 at the Department of Surgical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University. The only criteria used for patient selection included the availability of tumor tissue from primary gastric cancer and that of survival data. Follow-up data were obtained by phone, letter, and from the out-patient clinical database, after written informed consent forms provided by all patients. This retrospective study was approved by the institutional review board of the First Affiliated Hospital of Zhejiang University.", "cite_spans": [], "ref_spans": []}, {"section": "Cell lines and cell culture", "text": "The gastric cancer cell lines AGS, KATOIII, SNU5 were purchased from Shanghai Institute for Biological Sciences, Chinese Academy of Science in Sep 2016. The cell lines were characterized by the provider using short tandem repeat (STR) markers. All the cell lines used in this manuscript were tested for mycoplasma contamination in Oct 2016 before setting up for the biochemistry study. Primary GC cells were derived from the tumor excised from the PDX model of G03. Briefly, primary cells were purified with differential adhesion technique and grew in RPMI-1640 medium with 20% fetal bovine serum.", "cite_spans": [], "ref_spans": []}, {"section": "Reagents", "text": "Anti-cMet(ab51067) and anti-Her2(ab134182) antibodies were from Abcam (Cambridge, UK), p-Met antibody (Tyr 1365) (sc-3408), p-ALK antibody (Tyr 1586) (sc-109905), p-Akt1/2/3 antibody (Ser 473)-R (sc-7985-R) and horseradish peroxidase-conjugated secondary antibodieswere purchased from Santa Cruz Biotechnology, Inc. (Santa Cruz, USA). Phospho-FGFR (tyr653/654,#3471), phosp hor-p44/p42 MAPK (Erk1/2, #4370), total-Erk1/2 (#4960) were purchased from Cell Signaling Technology. Trastuzumab was obtained from Roche, Inc. (Roche, USA), while crizotinib and ADZ4547 were from Selleck Chemicals, LLC (Houston, CA, USA).", "cite_spans": [], "ref_spans": []}, {"section": "Reagents", "text": "Cell treatment and Western-blotting GC cells were seeded at a density of 3 \u00d7 10 5 cells/mL in RPMI-1640 medium containing 10% FBS and cultured overnight. The cells were then incubated with 200nM/L crizotinib or 30 nmol/L AZD4547 for 1 hour or with a combo of both reagent for one hour before being lysed in RIPA cell lysis buffer containing phosphatase and protease inhibitors(sigma). Each 20 \u03bcg of protein was loaded onto SDS-PAGE gel; followed by electrophoresis and transferred to polyvinylidene difluoride (PVDF) membranes and probed with antibodies.", "cite_spans": [], "ref_spans": []}, {"section": "Xenograft models and treatment protocol", "text": "Four-to-six-week-old female BALB/c nude mice, purchased from Shanghai Slac Laboratory Animal Corporation (Shanghai, China), were housed with regular 12/ 12-hour light-dark cycle for at least three days before the study. Animal care was carried out in accordance with the Principles of Laboratory Animal Care (NIH publication#85-23, revised in 1985). All experimental protocols were approved by the Institutional Animal Care and Use Committee of Zhejiang University (approval ID: SYXK[ZHE]2005-0072). Tumor specimens were obtained at initial surgery from patients after written informed consent as mentioned above. PDX gastric carcinoma xenograft models were established as previously described [8, 12] . The tumors were subcutaneously implanted into the flanks of mice under anesthesia with isoflurane; xenograft growth was monitored at least twice weekly by Vernier caliper measuring of the tumor length (a) and width (b).At about 1500 mm 3 , tumors were extracted for serial transplantation. Numerous samples from early passages were stored in the tissue bank, cryopreserved in liquid nitrogen, and used for further experiments. Third generation xenografts (i.e. the second mouse-to-mouse passage) were used for experiments at tumor volumes of about 100-200 mm 3 . Totally, 136 mice were used in this research. Mice with third generation xenografts were randomized divided into several groups (n = 5), including i) vehicle (DMSO as vehicle); ii) AZD4547, daily 6.25 mg/kg oral administration; iii) crizotinib, daily 50 mg/kg oral administration; iv) trastuzumab, weekly 20 mg/kg intraperitoneal injection; v) daily 6.25 mg/kg AZD4547 + 50 mg/kg crizotinib per os. All treatments were administered for 4 weeks, and the dosages were selected according to previous reports [21, 25, 26] . Mouse weights and tumor volumes were assessed daily, with tumor volume derived as (length \u00d7 width 2)/2. Relative tumor growth inhibition (TGI) was determined by the following formula: TGI = 1 -T/C, where T/C represents the relative tumor growth of compound-treated mice divided by that of control mice. For tumor regression, in which the tumor volume after treatment was smaller than the initial value before dosing, the following equation was used: regression % = 100 \u00d7 (T0-Ti)/T0. T0 and Ti are tumor volumes in the same group, measured at different time points, with T0 representing the tumor volume on the day preceding the first treatment and Ti the tumor volume at the last measurement day after treatment.", "cite_spans": [{"start": 694, "end": 697, "text": "[8,", "ref_id": "BIBREF7"}, {"start": 698, "end": 701, "text": "12]", "ref_id": "BIBREF11"}, {"start": 940, "end": 941, "text": "3", "ref_id": "BIBREF2"}, {"start": 1263, "end": 1264, "text": "3", "ref_id": "BIBREF2"}, {"start": 1772, "end": 1776, "text": "[21,", "ref_id": "BIBREF20"}, {"start": 1777, "end": 1780, "text": "25,", "ref_id": "BIBREF24"}, {"start": 1781, "end": 1784, "text": "26]", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "Immunohistochemistry (IHC)", "text": "For immunohistochemical staining, four-micrometer sections were obtained, dewaxed, rehydrated, and subjected to antigen retrieval. After quenching endogenous peroxidase activity and blocking nonspecific binding sites, the sections were incubated with primary antibodies against HER2 (1:100) and cMet (1:100) at 4\u00b0C for 12 h. This was followed by a 30-min incubation with secondary antibodies. Detection was carried out using the streptavidin-biotin peroxidase complex method (LabVision, Fremont, CA, USA) and sections were analyzed under an optical microscope (Nikon, Tokyo Japan; 200\u00d7).Her2and cMet expression levels were graded according to Hercep Test guidelines as follows: score 0, no membrane staining or membrane staining in <10% of tumor cells; score 1+, faint/barely perceptible partial membrane staining in >10% of tumor cells; score 2+, weak-to-moderate staining of the entire membrane in >10%of tumor cells; score 3+, strong staining of the entire membrane in >10% of tumor cells. Scores of 0 and1 + were considered negative for overexpression, and scores of 2+ and3+ considered positive. HER2 positive cases were defined by IHC 3+ or IHC 2+ plus Her2 amplification [15] . MET overexpression cases were defined by IHC 2+/3 + .All immunohistochemical slides were reviewed by two independent pathologists.", "cite_spans": [{"start": 1178, "end": 1182, "text": "[15]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Fluorescence in situ hybridization (FISH)", "text": "FISH was performed for HER2 and MET gene assessment on 4 \u03bcm dewaxed and dehydrated FFPE sections using the HER2/CEN 17 Dual Color Probe (ZytoLight, Cat#Z-2020-20), MET/CEN 7 Dual Color Probe(ZytoLight, Cat# Z-2087-200) and FGFR2/CEN10 Dual Color Probe (ZytoLight, Cat# Z-2122-200) kits, according to the manufacturer's instructions. Probes were co-denatured for 5 min at 80\u00b0C on the slide and incubated overnight at 37\u00b0C. Then, slides were washed with post-hybridization wash buffer(0.5X SSC / 0.1% SDS) for 5 min at 37\u00b0C, airdried, and counterstained with DAPI dissolved in an anti-fade mounting solution. Using a fluorescence microscope equipped with appropriate filters, the hybridization signals of labeled HER2 /cMet/FGFR2 genes appeared green; those of CEN 17/ CEN 7/ CEN10 appeared orange. The HER2 and cMet genes were considered amplified at FISH signal ratios of HER2/CEP17 or cMet/CEN 7 of \u22652.0 [15, 24, 27] . FGFR2gene amplification was defined as FGFR2/CEP10 ratio \u22652 or tight FGFR2 gene clusters in \u226510% of the nuclei analyzed per tissue section [25] .", "cite_spans": [{"start": 905, "end": 909, "text": "[15,", "ref_id": "BIBREF14"}, {"start": 910, "end": 913, "text": "24,", "ref_id": "BIBREF23"}, {"start": 914, "end": 917, "text": "27]", "ref_id": "BIBREF26"}, {"start": 1059, "end": 1063, "text": "[25]", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Statistical analysis", "text": "Overall survival was measured from the surgery date to death. The Kaplan-Meier method was used to estimate survival distributions, the log-rank test to compare survival distributions, and the Pearson's chi-squared test or Fisher's exact test to assess differences between groups. Tumor volume differences between groups were assessed using two-tailed Student's t-test or one-way ANOVA. P < 0.05 was considered statistically significant. Statistical analyses were performed using the SPSS 16.0 software (SPSS, USA).", "cite_spans": [], "ref_spans": []}, {"section": "Results and discussion", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Patient characteristics and establishment of PDX models", "text": "Nine passable PDX models were established by implantation of GC specimens from 32 patients into immuno-deficient mice. Model passage success rates of first, second, and third generations were 43.7%(14/ 32),37.5%(12/32), and 28.1%(9/32), respectively. The detailed characteristics of the patients are shown in Table 1 . No differences were observed in success rates of model establishment and patient characteristics for different genders, age groups, tumor stages, differentiation statuses, Lauren classes and pre-surgery chemotherapy administration, as shown in Table 1 . The established PDX models showed different latency periods (from the day of implantation to palpable tumor) and tumor growth curves (Fig. 1) .", "cite_spans": [], "ref_spans": [{"start": 309, "end": 316, "text": "Table 1", "ref_id": "TABREF0"}, {"start": 563, "end": 570, "text": "Table 1", "ref_id": "TABREF0"}, {"start": 706, "end": 714, "text": "(Fig. 1)", "ref_id": "FIGREF0"}]}, {"section": "Her2, cMet and FGFR2 status in PDX models and GC patient cohort", "text": "Of the 163 GC patients(detailed characteristics in Additional file 1: Table S1 ) and 32 GC xenograft donors, HER2 was positive(IHC3+ or FISH +) in 10.4%(17/ 163)and 12.5%(4/32), respectively; cMet was overexpressed (IHC3+/2+) in 19.6%(32/163) and 25%(8/32), respectively; the cMet gene was amplified in 4.3%(7/163) and 9.4%(3/32), respectively, while FGFR2 gene amplification was found in 3.7%(6/163) and 3.1%(1/32), respectively (Table 2 ). Representative images of IHC and FISH analyses of gastric cancer tumor tissues are provided in Fig. 2 . Patients with cMet protein IHC3+ or gene amplification had poorer survival rates compared with those without IHC3+ or gene amplification (Fig. 3) . FGFR2 gene amplification tended to reflect a lower survival rate compared with FGFR2 non-amplificated GC patients, although statistical significance was not reached (Fig. 3) . While evaluating Her2, cMet and FGFR2 status in PDX models(\u22651 generation, as shown in Table 3 ), a concordance rate of Her2, cMet and FGFR2 status between primary tumors from patients and PDX models of 92.9% (13/14) was found. Only the G23 model with cMet IHC 3+/FISH(+) changed to cMet IHC 0/FISH(-), as shown in Additional file 2: Figure S1 .", "cite_spans": [], "ref_spans": [{"start": 70, "end": 78, "text": "Table S1", "ref_id": "TABREF0"}, {"start": 430, "end": 438, "text": "(Table 2", "ref_id": "TABREF1"}, {"start": 683, "end": 691, "text": "(Fig. 3)", "ref_id": "FIGREF1"}, {"start": 859, "end": 867, "text": "(Fig. 3)", "ref_id": "FIGREF1"}, {"start": 956, "end": 963, "text": "Table 3", "ref_id": "TABREF2"}, {"start": 1203, "end": 1212, "text": "Figure S1", "ref_id": "FIGREF0"}]}, {"section": "Gastric cancer PDX model responses to different molecularly targeted agents", "text": "The main purpose of PDX models is to provide a platform for the evaluation of molecularly targeted agents. A total of 9 passable PDX models were established, which harbored alterations of Her2,cMet, and FGFR2 (Table 3) . Several tyrosine kinase inhibitors which target cMet or FGFR2 pathways show marked antitumor efficacy in gastric cancer; these include crizotinib(cMet TKI)and AZD4547(FGFR2 TKI). cMet or FGFR2 gene amplification seems to be a potential predictive biomarker for drug sensitivity. In order to test the hypothesis that use of crizotinib or AZD4547 could offer therapeutic benefits to GC patients harboring cMet or FGFR2 amplification, PDX models of G30 (cMet-amplified), G31(cMet-amplified), G03 (FGFR2-amplifed and cMet non-amplified but IHC(2 +)), G01(both cMet and FGFR2 non-amplified) were assessed in vivo (Fig. 4) . Meanwhile, G05(positive for Her2) was also selected for Her2-targeted therapy.We next evaluated the antitumor activity of crizotinib, AZD4547 and trastuzumab on PDX GC models. Crizotinib(50 mg/kg/day), AZD4547 (6.25 mg/kg/day), trastuzumab (20 mg/kg/week) were administered, respectively, for 4 weeks as described above. A significant tumor growth inhibition was observed in G30 and G31(cMetamplified) after treatment with crizotinib, in contrast to G03 and G01(cMet non-amplified) (Fig. 5a, b, d and e). However, a statistically significant tumor growth inhibition was observed in G03 (FGFR2-amplified)treated with AZD4547, while only minimal to partial tumor growth inhibition was observed in G01 (FGFR2 non-amplified) ( Fig. 5a and b) . Interestingly, a statistically significant difference in tumor volume was obtained in G03 after treatment with AZD4547 plus crizotinib at day 30 posttreatment (Fig. 5b) . Moreover, a marked tumor growth inhibition was observed upon trastuzumab treatment of G05 (Her2-positivy) but not G01 (Her2-negative) (Fig. 5c) . The gastric cancer cells derived from G03 PDX and commercial gastric cancer cell line AGS, KATOIII, SNU5, were assigned for further biochemistry study. The indicated cells were treated by anti-FGFR2 or anti-MET treatment ,or by a combo treatment of both inhibitors. Total protein was extracted and subsequently sent to Western-blotting study. In the G03 PDX derived cell, which was positive for FGFR2, showed synergetic inhibition of p-ERK expression by a combo treatment of crizotinib and AZD4547, however, no obvious inhibition of AKT was observed (Fig. 6) . To determine whether the synergetic effect was cMet or FGFR2 status dependent, we did the same assay in GC cell lines with different status of the two receptors. We also observed the synergetic inhibition of p-ERK expression in the KATOIII cell which was positive of FGFR2 amplification, and in the SNU5 cell which was positive of cMet expression (Additional file 3: Figure S2 ). However, no synergetic inhibiting effect was observed in AGS cell line which was negative for both receptor expression (Additional file 4: Figure S3 ).", "cite_spans": [], "ref_spans": [{"start": 209, "end": 218, "text": "(Table 3)", "ref_id": "TABREF2"}, {"start": 829, "end": 837, "text": "(Fig. 4)", "ref_id": "FIGREF3"}, {"start": 2977, "end": 2986, "text": "Figure S3", "ref_id": "FIGREF1"}]}, {"section": "Discussion", "text": "Mouse xenografts derived from prolonged in vitro cultured cells have been the standard toolkit for cancer biologists for decades; however, the high failure rate of compounds entering clinical trials indicates a low clinical predictive power of traditional tumor model systems.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Compared with cell line derived xenografts, patient derived tumor xenografts models closely retain the histopathologic, genetic and phenotypic features of patients' original tumors, and could better predict drug efficacy in humans [8] [9] [10] . In the last few years, PDX models have been widely established in various tumor, including gastric cancer [9, [11] [12] [13] [14] . PDX models are now becoming a valuable tool for evaluating new anticancer drugs before the initiation of clinical trials. The main purpose of this study was to establish and characterize a panel of PDX GC models, mimicking the genetic alteration of gastric cancer patients and further use them as a platform for the evaluation of potential targeted medicine.", "cite_spans": [{"start": 231, "end": 234, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 235, "end": 238, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 239, "end": 243, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 352, "end": 355, "text": "[9,", "ref_id": "BIBREF8"}, {"start": 356, "end": 360, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 361, "end": 365, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 366, "end": 370, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 371, "end": 375, "text": "[14]", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Discussion", "text": "Recently, Choi et al. reported the genomic fidelities of the gastric PDX systems and identified factors correlated with engraftment success of PDX tumors. They found the tumor cell percentages in the implanted tissues were correlated with higher success rates [28] . Zhang et al. established 32 PDGCX and the genetic characters of which were confirmed to be consistent with the original tumors [29] . Here, a panel of 9 PDX models were established with a success rate of 28.1%, which is similar to previously reported data [8] . When comparing the success rates between the first, second and third generations, we found the first implantation is a critical step in the process, while the success rate after the third generation nearly reached 100%.No significant correlation was observed between the engraftment achievement ratio and patients' clinical feature. However, a recent study revealed that prior chemotherapy may reduce the engraftment achievement ratio [30] . Indeed, patients who showed complete response after pre-surgery chemotherapy were excluded from further implantation in our study. A vital question of the utility of PDX models is whether the passage of tumors in experimental mice alters their histopathological and molecular features. As shown above, only one model with cMet IHC 3+/FISH(+) changed to cMet IHC 0/ FISH(-) (Additional file 2: Figure S1) ; the concordance rate of Her2,cMet and FGFR2 alteration between patients' primary tumors and xenografts was 92.9% (Table 3) . We speculate that tumor heterogeneity may be one of the possible cause of discordance between PDX models and donors. Previous studies have revealed that established PDX models are biologically stable when passaged in mice, in terms of global gene-expression patterns, mutational status, and drug responsiveness [8, 10] . Therefore, PDX models, mimicking the histopathological and molecular features of patients, constitute a superior Fig. 2 Representative images of IHC and FISH analyses of gastric cancer tumor tissues. Her2 and cMet expression levels were interpreted as scores 0, 1+, 2+, and 3+, respectively. For the FISH assay, orange signals represent Her2,cMet and FGFR2, and the green ones are CEN 17/ CEN 7/ CEN10, respectively. AP, amplification tool for the preclinical study of new emerging targeted therapies.", "cite_spans": [{"start": 260, "end": 264, "text": "[28]", "ref_id": "BIBREF27"}, {"start": 394, "end": 398, "text": "[29]", "ref_id": "BIBREF28"}, {"start": 523, "end": 526, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 964, "end": 968, "text": "[30]", "ref_id": "BIBREF29"}, {"start": 1813, "end": 1816, "text": "[8,", "ref_id": "BIBREF7"}, {"start": 1817, "end": 1820, "text": "10]", "ref_id": "BIBREF9"}], "ref_spans": [{"start": 1364, "end": 1374, "text": "Figure S1)", "ref_id": "FIGREF0"}, {"start": 1490, "end": 1499, "text": "(Table 3)", "ref_id": "TABREF2"}]}, {"section": "Discussion", "text": "Approving trastuzumab for HER2-positive GC patients represents a milestone in gastric cancer targeted therapy [15] . Recently, cMet and FGFR2, two other members of the RTK family, have been intensely investigated in gastric cancer. A high-resolution genomic analysis of a large cohort of gastric primary tumors revealed that approximately 4% and 9% gastric patients harbor cMet and FGFR2 amplification, respectively. The prevalence rates of cMet and FGFR2 alterations in Chinese gastric cancer patients have rarely been reported. Liu et al. reported that nearly 6.1% and 5.1% gastric cancer specimens harbor cMet or FGFR2 amplification in a cohort of Chinese gastric cancer, respectively. Here, we simultaneously studied the status of Her2, cMet and FGFR2 amplification in a cohort of Chinese GC patients and a panel of PDX models. Our data showed cMet overexpression and amplification in 19.6% and 4.3% of GC patients, respectively. Survival analysis revealed that patients with cMet protein IHC3+ or gene amplification have a poorer survival rate, in agreement with a recent study [24] . In addition, FGFR2 amplification was harboured in 3.7% GC patients. FGFR2 amplification tended to indicate a lower survival rate, although a statistical significance was not obtained. A recent international multi-center study reported that FGFR2 amplification is associated with poor prognosis in gastric cancer. Her2 positive rate was 10.4%, which was consistent with previously reported data [31] .", "cite_spans": [{"start": 110, "end": 114, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 1083, "end": 1087, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 1484, "end": 1488, "text": "[31]", "ref_id": "BIBREF30"}], "ref_spans": []}, {"section": "Discussion", "text": "Based on the above findings, we confirm that a significant proportion of gastric cancer patients harbour cMet and FGFR2 alterations, and may benefit from cMet and FGFR2 targeted therapies. A phase I study showed that patients with cMet-amplified gastroesophageal cancer treated with crizotinib experience significant tumor shrinkage [32] . In addition, a preclinical study revealed that AZD4547 exerts marked antitumor effects on GC xenografts carrying FGFR2 gene amplification [25] . Therefore, cMet or FGFR2 gene amplification seems to be a potential predictive biomarker for drug sensitivity; however, there is a possible correlation between gene amplification and protein expression as well as possible inconsistencies between IHC data and gene amplifications in terms of tumor take rates, growth kinetics and/or sensitivities to the respective treatment regimens. To further evaluate the translational significance of the above findings, the antitumor efficacy of crizotinib and AZD4547 was assessed on the panel of PDX models generated. As shown above, PDX models with cMet and FGFR2 amplification were highly sensitive to crizotinib, while others showed minimal or even no response. Interestingly, we found that combined treatment of crizotinib and AZD4547 enhances the antitumor effect of AZD4547 in G03 (FGFR2-amplifed 5 Antitumor efficacy of crizotinib, AZD4547 and trastuzumab in 5 PDX models. Tumor-bearing mice were treated starting from tumor volume of 100~200 mm 3 . crizotinib, AZD4547, and trastuzumab were administered as described in the experimental section. Subcutaneous tumor volumes were measured using calipers and calculated as mean \u00b1 SEM. Statistical analysis of tumor growth inhibition was performed using Student's t-test or one-way ANOVA. P < 0.05 was considered statistically significant. (a) Antitumor activity of crizotinib, AZD4547 or Transtuzumab on G01 PDTX models (Her2-, cMet-, FGFR2-); (b) Antitumor activity of crizotinib, AZD4547 or combo treatment on G03 PDTX models (FGFR2+); (c) Antitumor activity of Transtuzumab on G05 PDTX models (Her2+); (d) Antitumor activity of crizotinib on G30 PDTX models (cMet+); (e) Antitumor activity of crizotinib on G31 PDTX models (cMet+) Fig. 6 AZD4547 and crizotinib synergistically inhibited activation of MAPK/ERK pathway in G03 xenograft derived GC cells. GC cells derived from G03 xenograft were treated with 200nM/L crizotinib or 30nM/L AZD4547, either alone or as a combo treatment(Cri + AZD) for 1 hour. Whole cell lysates were collected and analyzed by western blot. Cell lysates were immunoblotted for phospho-and total protein as indicated and cMet non-amplified but IHC(2+)). The in vitro data showed obvious inhibition of Erk activation by crizotinib in the G03 derived cells, however, crizotinib monotherapy in vivo showed no significant tumor growth inhibition compared with the control group. There might be some mechanism causing this discrepancy which need further investigation. A recent study also demonstrated that activation of several receptor tyrosine kinases (RTKs), including EGFR, HER3 and MET, contributes to AZD4547 hyposensitivity in FGFR2 amplified GC cells, and the rescue effect was abrogated by inhibiting these RTKs with their targeted tyrosine kinase inhibitors (TKIs) [33] . Another study demonstrated that FGFR is one of the combinatorial targets to overcome resistance to cMettargeted therapy in gastric cancer [34] . The underlying mechanisms for the enhanced antitumor effect by combined treatment of crizotinib and AZD4547 in G03 is still unknown. By using the G03 xenograft derived cells, in vitro assay showed that a combination treatment of crizotinib and AZD4547 led to synergetic inhibition of MAPK/ERK pathway. Further biochemistry study on the GC cell lines with different status of cMet or FGFR2 amplification showed that the synergetic effect were obtained only in cMet or FGFR2 amplified cells, we speculated that co-targeting cMet and FGFR2 may exhibit a synergetic tumor inhibition through MAPK/ERK pathway. We observed the trans-phosphorylation of MET and FGFR2, however, the trans-phosphorylation were not consistent in the four cell lines(data not shown). The synergistic effect of the combo treatment of the crizotinib and FGFR2 inhibitor at the level of ERK phosphorylation is consistent in all the four different cell lines except the AGS cells which is negative for both receptor expression. We believe that the molecular mechanism underlying the synergistic effect of concomitant inhibition of the two parallel pathways, is more like to involve the downstream effectors of MET and FGFR2, but not the transphosphorylation of the two parallel receptors. Further studies are needed to explore the crosstalk between cMet and FGFR2 signaling pathway. Co-targeting cMet and FGFR2 may be a promising strategy for gastric cancer patients with amplification of cMet or FGFR2.", "cite_spans": [{"start": 333, "end": 337, "text": "[32]", "ref_id": "BIBREF31"}, {"start": 478, "end": 482, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 1478, "end": 1479, "text": "3", "ref_id": "BIBREF2"}, {"start": 3281, "end": 3285, "text": "[33]", "ref_id": "BIBREF32"}, {"start": 3426, "end": 3430, "text": "[34]", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "Conclusions", "text": "In conclusion, a panel of 9 PDX GC models were successfully established, providing an ideal platform for the evaluation of targeted agents. In addition, Her2, cMet and FGFR2 statuses were profiled in a cohort of GC patients and the PDX models. Finally, our data indicate that a significant proportion of GC patients harbouring cMet or FGFR2 gene amplification can benefit from cMet or FGFR2 targeted therapies or combined targeted therapies.", "cite_spans": [], "ref_spans": []}, {"section": "Additional files", "text": "Additional file 1: Table S1 . Characteristics of GC cohort patients. The clinical and pathological characteristics of 163 GC cohort patients were described in the table. (DOC 34 ", "cite_spans": [], "ref_spans": [{"start": 19, "end": 27, "text": "Table S1", "ref_id": "TABREF0"}, {"start": 159, "end": 177, "text": "the table. 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The models were established subcutaneously and median tumor volumes in 5 tumor-bearing mice from each model are represented", "type": "figure"}, "FIGREF1": {"text": "Fig. 3 Kaplan-Meier survival analyses of overall survival in a cohort of gastric cancer patients. a OS according to Her2 status, Her2+ (IHC3+ or FISH +); b OS according to cMet protein expression or gene amplification; c OS according to FGFR2 gene amplification. AP, gene amplification", "type": "figure"}, "FIGREF2": {"text": "a PDX models only transplanted to the second generation; b PDX models only transplanted to the first generation; c discordance of cMet status between primary tumors and xenografts in G23", "type": "figure"}, "FIGREF3": {"text": "Fig. 4 Molecular characterization of the PDX models. Immunohistochemical staining for cMet and HER2, and FISH assay for Her2,cMet and FGFR2 are shown. Immuno-detectable proteins are indicated by brown staining; nuclei are counterstained in blue. Original magnification, \u00d7200", "type": "figure"}, "FIGREF4": {"text": "Abbreviations FGFR: Fibroblast growth factor receptor; FISH: Fluorescence in situ hybridization; GC: Gastric cancer; IHC: Immunohistochemistry; PDX: Patient derived tumor xenografts; RTK: Receptor tyrosine kinase; TKIs: Tyrosine kinase inhibitors", "type": "figure"}, "TABREF0": {"text": "Characteristics of GC patients who donated xenografts for the PDX models", "type": "table"}, "TABREF1": {"text": "HER2,cMet, and FGFR2 statuses in a cohort of GC patients and corresponding PDX donors", "type": "table"}, "TABREF2": {"text": "Her2,cMet, and FGFR2 statuses of patients and PDX models", "type": "table"}}}
{"paper_id": "2879214", "_pdf_hash": "72754cba9d8487211f3992997e130c79368bfd6f", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Spectral efficiency of CDMA with random spreading", "authors": [{"first": "S", "middle": [], "last": "Verd\u00b4u", "suffix": ""}, {"first": "S", "middle": [], "last": "Shamai", "suffix": ""}], "year": 1999, "venue": "IEEE Trans. Inform. Thoery", "link": "15935862"}, "BIBREF1": {"title": "Comparison of orthogonal and nonorthogonal approaches to future wireless cellular systems", "authors": [{"first": "P", "middle": [], "last": "Wang", "suffix": ""}, {"first": "J", "middle": [], "last": "Xiao", "suffix": ""}, {"first": "Li", "middle": [], "last": "Ping", "suffix": ""}], "year": 2006, "venue": "IEEE Veh. Technol. 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{"paper_id": "2879216", "_pdf_hash": "09c596e7f139d3e3c2f74e62f2ec3d1f9d148ec5", "abstract": [], "body_text": [{"section": "", "text": "COMBINED use of X-rays and bleomycin was initially proposed by J0rgensen (1972) . The demonstration of synergism attracted much attention from clinicians as well as basic researchers. The question arose whether the effect can be attributed to a tissue mechanism or to cellular potentiation. In the mean time, several investigations have been carried out to see whether the combination is synergistic in bacterial and mammalian cell systems (Bleehen, Gillies and Twentyman, 1974; Terasima, Takabe and Yasukawa, 1975; Bistrovic, Marici6 and Kolaric, 1976) . Although the experimental results were not consistent among the cell lines used, the synergism was found to a slight or moderate extent.", "cite_spans": [{"start": 479, "end": 515, "text": "Terasima, Takabe and Yasukawa, 1975;", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "", "text": "The potentiation presented here, with Ehrlich ascites tumour cells treated with a combination of X-rays and bleomycin, may involve an interaction of different types of damage and repair induced by both agents.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Experiments were carried out with Ehrlich ascites tumour cells grown in 4-week-old male mice 1CR/JCL, weighing 20-25 g (CLEA JAPAN IInc., Tokyo). By inoculating 106 tumour cells i.p., the early plateau phase of growth was reached on the 7th day, when all the experiments were initiated.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "To assay survival of tumour cells, they were removed from the abdominal cavity and suspended in F10 medium (Ham, 1963) with 10% calf serum. The cells were plated Accepted 13 May 1977 out in triplicate dishes of soft agar after they had been counted with electronic counter (Coulter, Model B) and diluted appropriately with F1O medium. The agar colony assay has been described in detail by Takabe et al. (1977 Starting from 1 h after administration of bleomycin, the survival increased quickly with time and finally levelled off at 5 h (open circles), whereas the X-ray survival increased rather slowly, and almost attained a plateau at about 7 h (closed circles). The survivals, measured as a ratio of 7-h value to the value of initial determination (surviving fraction ratio, after Evans et al., 1974) were 1-7 and 1.5 respectively. The number ofascites tumour cells was determined following treatment with either single agent. The result showed that cells did not resume their proliferation within the 7-h observation period. Therefore, the observed enhancement of survival represents the repair of damage which was potentially lethal and reparable only when cells were in the abdominal cavity (Belli, Dicus and Nagle, 1970; Little et at., 1973) .", "cite_spans": [{"start": 107, "end": 118, "text": "(Ham, 1963)", "ref_id": "BIBREF6"}, {"start": 389, "end": 408, "text": "Takabe et al. (1977", "ref_id": "BIBREF11"}, {"start": 783, "end": 802, "text": "Evans et al., 1974)", "ref_id": "BIBREF4"}, {"start": 1196, "end": 1226, "text": "(Belli, Dicus and Nagle, 1970;", "ref_id": "BIBREF1"}, {"start": 1227, "end": 1247, "text": "Little et at., 1973)", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "", "text": "Survivals were also determined with time after both agents were given simultaneously, and are shown in Fig. IA (open triangles). The surviving fraction ratio was about 2-5 during the first 7 h, indicating that repair took place as found after administration of either single agent. The survival level was consistently lower throughout the 7-h period than the level expected when damage produced by each agent was independently repaired (broken line).", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "A similar experiment was carried out with single doses of 30 mg/kg bleomycin and of 1000 rad X-rays, as shown in Fig. 1B . The surviving fraction ratios given by each agent were much greater than those in the preceding experiment, i.e., 441 for bleomycin and 4-2 for X-ray. In this case, the survivals after simultaneous administration of agents (open triangles) were obviously lower than the level expected from independent (or additive) effects of each agent (broken line). This finding indicates that bleomycin potentiated the effect of X-rays, either by interfering with the repair process of, or by closed circles-1000 rad X-rays alone; triangles-simultaneous administration. Broken line was given by a product of surviving fractions obtained at various times after the single treatment with bleomycin (open circles) and X-rays (closed circles). It represents survival level which would be expected from additive effect of both agents. Survival value with error bar denotes mean \u00b1 s. (Fig. 3) were carried out in a similar fashion to the preceding ones, except that bleomycin was injected at various times before X-ray exposure. A group of tumour-bearing mice was treated with a single 0-1-mg/kg dose of bleomycin at zero time. Fig. IA . If the effect of each agent were independent, the expected survival would follow the broken line, which is a product of survivals of both agents. Experimental points were obviously lower than the broken line over the first 3 h, and then became close to the level of independent or additive effect. These results revealed that (i) more than additive effect can be obtained only when the interval between two agents was less than 3 h, whatever the order of administration, and (ii) the potentiation is greater if two agents are given at closer intervals.", "cite_spans": [], "ref_spans": [{"start": 989, "end": 997, "text": "(Fig. 3)", "ref_id": "FIGREF1"}]}, {"section": "", "text": "Recently, the induction and repair of potentially lethal damage was demonstrated in tumour cells treated with bleomycin (Takabe et al., 1974; Barranco, Novak and Humphrey, 1975; Twentyman and Bleehen, 1975) . Nevertheless, the antibiotic does not induce sublethal damage and repair, as the simple exponential nature of the survival curve suggested (Terasima et al., 1972; Barranco et al., 1975) .", "cite_spans": [{"start": 120, "end": 141, "text": "(Takabe et al., 1974;", "ref_id": "BIBREF10"}, {"start": 142, "end": 177, "text": "Barranco, Novak and Humphrey, 1975;", "ref_id": "BIBREF0"}, {"start": 178, "end": 206, "text": "Twentyman and Bleehen, 1975)", "ref_id": "BIBREF17"}, {"start": 348, "end": 371, "text": "(Terasima et al., 1972;", "ref_id": "BIBREF13"}, {"start": 372, "end": 394, "text": "Barranco et al., 1975)", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "", "text": "To effect maximal sterilization of tumour cells treated with an agent inducing potentially lethal damage, the repair must be controlled, either by inhibiting enzymatic repair reactions or by fixing potentially lethal damage per 8e. The potentiation found after the simultaneous administration of both agents (Fig. 1) suggests that at least portions of the damage, either potentially lethal or sublethal, induced by the two agents interacted each other and were converted to lethal damage. The limited period of potentiation found in Fig. 2 may suggest that the potentiation involves X-ray-induced sublethal damage, the repair of which normally completes approximately 3 h after X-irradiation. Similarly, the combined effect of bleomycin administered before X-rays may be also related to repair of bleomycin-induced damage (Fig. 3) . The fact that both agents induce reparable damage of cellular DNA (Tsuboi and Terasima, 1970; Yasukawa and Umezawa, 1970; Fujiwara and Kondo, 1973; Saito and Andoh, 1973) may be a basis for part of the potentiation.", "cite_spans": [{"start": 940, "end": 954, "text": "Umezawa, 1970;", "ref_id": "BIBREF12"}, {"start": 955, "end": 980, "text": "Fujiwara and Kondo, 1973;", "ref_id": "BIBREF5"}, {"start": 981, "end": 1003, "text": "Saito and Andoh, 1973)", "ref_id": "BIBREF9"}], "ref_spans": [{"start": 822, "end": 830, "text": "(Fig. 3)", "ref_id": "FIGREF1"}]}, {"section": "", "text": "The observed interaction between damages due to X-ray and bleomycin may provide practicable means to control repair. Using transplantable mouse tumour, J0rgensen (1972) demonstrated that simultaneous administration resulted in greater reduction in tumour weight than alternating administration. 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J. Cancer", "link": "9345966"}}, "ref_entries": {"FIGREF0": {"text": "FIG. 1.-Change in survival of Ehrlich ascites tumour cells after separate or simultaneous administration of bleomycin and X-rays. A: open circles-0-1 mg/kg bleomycin alone; closed circles 400 rad X-ray alone; triangles-simultaneous administration. B: open circles-30 mg/kg bleomycin alone;", "type": "figure"}, "FIGREF1": {"text": "FIG. 3. Effect of pre-irradiation exposure to bleomycin on survival of Ehrlich ascites tumour cells. Closed symbols: survival for X-ray with BLM pretreatment. Bar denotes the range of determinations. Open symbols: survival for BLM alone (from Fig. IA). Broken line represents the expected level of additive effect, obtained as a product of surviving fraction at various times after administration of BLM and surviving fraction after 400 rad X-rays (i.e. 0 495 from Fig. IA).", "type": "figure"}, "TABREF0": {"text": "). The plating effi- ciency (PE) for untreated cells was usually 40-90%. To estimate the surviving frac- tion, a portion of ascites was removed from each animal just before the initial treatment with either agent and the PE of untreated tumour cells was assayed for individual mice. Thus, surviving fraction was expressed as the PE of tumour cells treated with agent(s) divided by the PE of untreated cells from the same animal. Bleomycin complex (Lot No. FlOOS41, Nippon Kayaku Co., Ltd, Tokyo) was dissolved in distilled water and diluted in FIO medium at the time of experiments. Approximately 0 3 ml of drug solution was injected through an s.c. route in the back of the mouse. The volume varied slightly with the body weight ofindividual tumour- bearing mice. All irradiations were given as whole-body doses to unanaesthetized mice by X-ray generator (Sinai, Shimazu Rad. Instr. Co., Ltd, Kyoto) operated at", "type": "table"}}}
{"paper_id": "2879417", "_pdf_hash": "52dcb9f3d006294174edd20c0e45694e4161725c", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
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{"paper_id": "2879800", "_pdf_hash": "684646cd75b4ad92f179bd295e4a3cbafed467d9", "abstract": [{"section": "Abstract", "text": "ABSTRACT Bayesian shrinkage analysis is arguably the state-of-the-art technique for large-scale multiple quantitative trait locus (QTL) mapping. However, when the shrinkage model does not involve indicator variables for marker inclusion, QTL detection remains heavily dependent on significance thresholds derived from phenotype permutation under the null hypothesis of no phenotype-to-genotype association. This approach is computationally intensive and more importantly, the hypothetical data generation at the heart of the permutation-based method violates the Bayesian philosophy. Here we propose a fully Bayesian decision rule for QTL detection under the recently introduced extended Bayesian LASSO for QTL mapping. Our new decision rule is free of any hypothetical data generation and relies on the well-established Bayes factors for evaluating the evidence for QTL presence at any locus. Simulation results demonstrate the remarkable performance of our decision rule. An application to real-world data is considered as well.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "W IDELY recognized to be effective for genomic prediction, Bayesian regularization or shrinkage methods are also arguably the state-of-the-art approach to genomewide multiple quantitative trait locus (QTL) mapping (e.g., Che and Xu 2010). In both the maximum-likelihood (ML) and Bayesian approaches, QTL can be informally identified as locations corresponding to bumps in the plot of the estimated genetic effects against marker genomic positions.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "In Bayesian shrinkage models involving marker inclusion indicators, Bayes factors (BFs) (Kass and Raftery 1995) provide a convenient tool for QTL detection (e.g., Yi et al. 2007). pointed out that including indicators as an additional source of shrinkage may induce a downward bias on the resulting BFs.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "When the Bayesian shrinkage model does not involve marker inclusion indicators, these can still be indirectly generated with regard to a user-specific effect-size threshold, following Hoti and Sillanp\u00e4\u00e4 (2006) . However, the subsequent BFs may heavily depend on the prespecified effect-size cutoff value. Kn\u00fcrr et al. (2011) proposed a Bayesian shrinkage model where the marker inclusion indicators are indirectly generated based on a priori fixed and biologically meaningful hyperparameters, allowing the use of BFs to evaluate the strength of evidence in the data in support of QTL presence at any locus.", "cite_spans": [{"start": 184, "end": 209, "text": "Hoti and Sillanp\u00e4\u00e4 (2006)", "ref_id": "BIBREF8"}, {"start": 305, "end": 324, "text": "Kn\u00fcrr et al. (2011)", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Abstract", "text": "A QTL significance threshold can alternatively be derived from Wald test statistic (Yang and Xu 2007). This may, however, be unrealistic in the presence of highly correlated markers, due to overly inflated standard errors of the estimated genetic effects as a consequence of multicollinearity. Moreover, under the Bayesian shrinkage approach, the posterior densities of QTL effects are typically bimodal with a spike at the prior mode (zero) and a second mode around the actual QTL effect (see, e.g., Figure 2 in Che and Xu 2010). This makes equal-tail credibility intervals (Li et al. 2011) impractical for detecting QTL since intervals will often include zero.", "cite_spans": [{"start": 575, "end": 591, "text": "(Li et al. 2011)", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Abstract", "text": "In The permutation-based method is computationally intensive. This is more so when the model fitting is carried out with a Bayesian approach through Markov chain Monte Carlo (MCMC) (Gilks et al. 1996) simulation. More importantly, from a Bayesian perspective, the posterior distribution embodies the data-updated state of knowledge about the model parameters and is therefore the sole basis for all inferences, including prediction and hypothesis testing. Bayesian conclusions arise in the form of probabilistic statements about unobserved quantities including model parameters and yet unobserved data (prediction), conditionally on the data actually observed (Gelman et al. 2003) . Thus, the hypothetical data generation under the null hypothesis at the heart of the permutation-based method is inconsistent with the Bayesian philosophy.", "cite_spans": [{"start": 181, "end": 200, "text": "(Gilks et al. 1996)", "ref_id": "BIBREF6"}, {"start": 660, "end": 680, "text": "(Gelman et al. 2003)", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Abstract", "text": "In an attempt to mitigate the heavy computational load characterizing the randomization approach in MCMC-based Bayesian shrinkage analysis of QTL, Che and Xu (2010) proposed a within-MCMC phenotype permutation approach intended to reduce the computational time burden, but still rooted in the hypothetical data generation at issue with the Bayesian thinking. The authors were the first to recognize the lack of theory behind their method.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Hypothesis testing methods for variable selection that stand firm on the Bayesian philosophy are missing within Bayesian shrinkage analysis of high-dimensional regression models. This article attempts to bridge this gap by proposing a fully Bayesian decision rule for QTL detection under the extended Bayesian LASSO (EBL) model introduced by Mutshinda and Sillanp\u00e4\u00e4 (2010) .", "cite_spans": [{"start": 342, "end": 372, "text": "Mutshinda and Sillanp\u00e4\u00e4 (2010)", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "Abstract", "text": "Before proceeding to describe our new QTL detection rule, a brief review of the EBL is worthwhile.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "The EBL (Mutshinda and Sillanp\u00e4\u00e4 2010) extends the hierarchical prior specification of the regression coefficients in the Bayesian LASSO (BL) (Park and Casella 2008; Yi and Xu 2008) with an additional level implementing the separation between the overall model sparsity and the degree of shrinkage specific to individual regression parameters (the marker effects). In simulation studies (Mutshinda and Sillanp\u00e4\u00e4 2010; Fang et al. 2012; K\u00e4rkk\u00e4inen and Sillanp\u00e4\u00e4 2012; Li and Sillanp\u00e4\u00e4 2012) , the EBL has proved to be among the best LASSO-type shrinkage methods in terms of estimation and prediction accuracy. Throughout, we consider the following multiple linear regression model for QTL mapping,", "cite_spans": [{"start": 387, "end": 417, "text": "(Mutshinda and Sillanp\u00e4\u00e4 2010;", "ref_id": "BIBREF15"}, {"start": 418, "end": 435, "text": "Fang et al. 2012;", "ref_id": "BIBREF4"}, {"start": 436, "end": 466, "text": "K\u00e4rkk\u00e4inen and Sillanp\u00e4\u00e4 2012;", "ref_id": "BIBREF10"}, {"start": 467, "end": 489, "text": "Li and Sillanp\u00e4\u00e4 2012)", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Abstract", "text": "where y i is the phenotypic trait value of the ith individual (i \u00bc 1; . . . ; n), b 0 is the common intercept, and x ij is the genotype value of individual i at locus j. Here, attention is restricted to experimental crosses derived from inbred lines, more specifically on backcross (BC) or double-haploid (DH) progeny with only one of two possible genotypes at any locus, and x ij is coded as 0 for one genotype and 1 for the other. b j is the genetic effect of marker j \u00f0j \u00bc 1; . . . ; p\u00de, and e i \u00f0i \u00bc 1; . . . ; n\u00de are mutually independent errors assumed to follow a zero-mean Gaussian distribution with common variance s ", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "The model specification is completed with prior assumptions on the parameters b 0 and s 2 0 and the hyperparameters d and h j \u00f0j \u00bc 1; . . . ; p\u00de. Our new QTL detection rule operates at the hyperparameter level and more specifically on the idiosyncratic hyperparameters h j .", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Bayesian LASSO arises as a particular case of the EBL when all h j are set to 1, implying that l j \u00bc l \u00bc d for 1 # j # p. The tenet of our new QTL detection rule is that genuine QTL effects should undergo less shrinkage than implied by the overall model sparsity level determined by d. In other words,", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "C. M. Mutshinda and M. J. Sillanp\u00e4\u00e4 h j should be consistently less than 1 for genuine QTL and vice versa. Biologically, we take the effects of non-QTL loci as reference for comparison, understanding that the effects of actual QTL should not be shrunken beyond the overall model sparsity level.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Our new QTL detection rule is based on the posterior of the locus-specific shrinkage hyperparameters, h j , without involving any hypothetical data generation. Basically, the method boils down to testing the hypothesis H j 1 : h j , 1 of QTL presence at locus j \u00f0j \u00bc 1; . . . ; p\u00de, against the alternative hypothesis H j 2 : h j $ 1 of having no QTL at locus j for each 1 # j # p.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "In the Bayesian paradigm, the specification of priors about the model parameters and the hypotheses being tested is a critical stage whereby subjective probability enters the inference. Prior odds can be used to add context to the analysis. For example, model sparsity can be enforced by assigning low prior odds for QTL presence at any locus, i.e., setting Pr\u00f0H j 1 \u00de \u00bc Pr\u00f0h j , 1\u00de to be small relative to Pr\u00f0H j 2 \u00de \u00bc 1 2 Pr\u00f0H j 1 \u00de. As we discuss below, the uniform prior h j Uni\u00f0u; w\u00de, u , 1 , w provides much flexibility in calibrating the prior assumption about Pr \u00f0h j , 1\u00de and, consequently, the prior odds for H j 1 , \u00f0j \u00bc 1; . . . ; p\u00de. More specifically, if we assume a priori that h j Uni\u00f0u; w\u00de, u , 1 , w independently for j \u00bc 1; . . . ; p, then the prior probability, Pr\u00f0H 1 \u00de \u00bc Pr \u00f0h j , 1\u00de, of QTL presence at locus j is nothing but \u00f01 2 u\u00de=\u00f0w 2 u\u00de. This prior can be duly adjusted through a judicious choice of u and w. In the sequel, we assume, without loss of generality, that u \u00bc 0 so that the prior probability of QTL presence at locus j is simply Pr \u00f0h j , 1\u00de \u00bc 1=w, the corresponding odds being 1=\u00f0w 2 1\u00de.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "The essence of a Bayesian analysis is to update prior beliefs about model parameters and hypotheses in light of the observed data. Posterior odds reflect the analyst's state of knowledge about the relative strengths of two competing and mutually exclusive hypotheses after taking the data information into account. They are therefore well suited to hypothesis testing and decision making with regard to QTL presence at different loci. However, Bayes factors provide a better alternative to posterior odds as they free the analyst from reporting prior odds (e.g., Schervish 1995, p. 221) and allow the strength of evidence provided by the data in favor of a hypothesis to be evaluated on the widely used Jeffreys (1961) empirical scale described below. Let H j 1 and H j 2 denote the hypotheses \"QTL present at locus j\" and \"no QTL at locus j,\" corresponding to h j , 1 and h j $ 1, respectively. The Bayes factor", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "quantifies the evidence provided by the data in favor of H (2) and, as a rule of thumb, we use 3 as the cutoff value of BF j 1;2 above which to declare QTL presence at locus j. The choice of this somewhat stringent cutoff value is motivated by the need to optimize the power of detecting QTL by reducing the false discovery rate.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "A critical quantity for the computation of the Bayes factor BF ", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "j is the ith MCMC sample for h j . This probability is easily evaluated in Win-BUGS/OpenBUGS through the logical function step(.) that takes the value 1 when its argument is larger than zero and the value zero otherwise. For more details on this, see supporting information, File S1.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "We next report on two simulation studies designed to investigate the performance of our new QTL detection rule under different scenarios. We subsequently utilize our decision rule to reanalyze the genetic basis of time to heading in barley (Hordeum vulgare L.), using real-world data from the North American Barley Genome Mapping project (Tinker et al. 1996).", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "To evaluate the performance of our new decision rule for QTL detection, we carried out two simulation studies, hereafter simulation study 1 and simulation study 2. Simulation study 1 involved two replicated analyses based, respectively, on the moderately dense barley marker data and on a computer-simulated dense marker data set. Simulation study 2 was based on a very dense and particularly challenging marker data set generated through computer simulation.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Simulation study 1: This simulation study is based on the following two marker data sets differing in both the marker density and the n-to-p ratio:", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "1. The real-world marker data set from the North American Barley Genome Mapping project (Tinker et al. 1996), which involves 145 DH lines and 127 biallelic markers covering seven chromosomes, the distance between consecutive markers being 10.5 cM: We refer to Tinker et al. (1996) for more details on this data set. The few missing genotypes were imputed with random draws from Bernoulli(0.5) before the analysis. A more appropriate approach to missing genotype imputation would be to utilize their genotype probabilities given the genotypes In both cases, the phenotypic trait values were simulated assuming sparse underlying biology with only four QTL at loci 4, 25, 50, and 65, with respective effects 2.5, 22.5, 4, and 24. In the data simulation process, the intercept was set to zero without loss of generality. The residual variance, s 2 0 , was set to 2 and 1 under the barley marker data and the simulated dense marker data, respectively, yielding an approximate heritability of 0.80 in both cases. Our analyses are based on data with high heritabilities and small sample sizes. Sillanp\u00e4\u00e4 and Hoti (2007) pointed out that, with regard to power analysis, similar results arise under small heritabilities and large samples.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "One hundred phenotype replicates were simulated under each marker data set. The R codes for generating the replicated phenotypic data are provided in File S1, along with the simulated dense marker data and a realization of the simulated phenotypes under the parameter setting described above. A typical vector of simulated phenotypes under the barley marker data is provided as well.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "The model specification was completed with the following (essentially noninformative) prior specification: b 0 N\u00f00; 100\u00de; and s 2 0 Inv-Gamma \u00f00:01; 0:01\u00de, d Uni\u00f00; 100\u00de, and h j Uni\u00f00; w\u00de for j \u00bc 1; . . . ; p independently. Finally, w was set to 10, yielding a prior probability Pr\u00f0h j , 1\u00de \u00bc 0:1 of QTL presence at any locus j \u00f01 # j # p\u00de.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "We used MCMC simulation, through the Bayesian freeware OpenBUGS (Thomas et al. 2006), to sample from the joint posterior of the model parameters. The BUGS code is available in File S1. All computations were carried out on an AMD Turion X2 Dual, with a 64-bit operating system and 4 GB of RAM. We initially ran three Markov chains for 100,000 iterations to assess, through visual inspection of traceplots, the time to convergence and the quality of the mixing of the chains. The Markov chains reached apparently their target distributions after 500 and 2000 iterations under the barley data and the simulated dense marker data set, respectively. The 100,000 iterations of three Markov chains took 7 hr under the barley data and 2 hr under the simulated dense marker data set.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "We then fitted the model to the 100 replicated data sets, running a single Markov chain for 7000 iterations after a burn-in period of 3000 iterations and thinning the remainder to each 10th sample. The model fitting to each replicated data set took 770 sec under the barley marker data and 420 sec under the simulated dense marker data set. Figure 1 shows the Bayes factors for QTL presence at each marker locus on a natural logarithmic scale, averaged over the 100 replicated data sets plotted against the marker genomic positions for simulations based on the barley marker data ( Figure 1A ) and the simulated dense marker data set ( Figure 1B ). In Figure 1 , A and B, the threshold, log\u00f03\u00de 1:1, above which QTL are declared is indicated by a horizontal shaded dashed line.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "From the results plotted in Figure 1 , the four \"true\" QTL are clearly singled out with BFs far larger than the cutoff value log\u00f03\u00de 1:1, in contrast to the non-QTL candidate loci. The four QTL were also the only loci with BFs exceeding the detection threshold under the barley marker data set, implying a false discovery rate of 0%. The BFs for QTL presence at non-QTL loci were consistently ,1 and did not even approach the selection threshold in the few cases where they happened to exceed 1. In analyses based on the simulated dense marker data set, some loci close to the actual QTL locations could occasionally have BFs .1 due to linkage disequilibrium, but these should not be considered as false positives.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "We also evaluated the performance of the permutationbased method for QTL detection under the EBL with the parameter setting described above, using 100 phenotype permutations. For each permuted data set, we ran 15,000 iterations of a single Markov chain and discarded the first 4000 iterations as burn-in, thinning the remainder to each 10th sample. Figure 2 shows the posterior mean genetic effects averaged over the 100 replicated data sets, plotted against the Figure 1 (A and B) Natural logarithms of the Bayes factors for QTL presence at each marker plotted against the marker number, averaged over 100 replicated data sets under the barley marker data (A) and the simulated dense marker data (B). The horizontal shaded dashed line indicates the log(BF) threshold, log\u00f03\u00de 1:1, above which QTL are declared.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "C. M. Mutshinda and M. J. Sillanp\u00e4\u00e4 marker numbers for analyses based on the barley marker data ( Figure 2A ) and for those based on the simulated dense marker data set ( Figure 2B ). The horizontal shaded dashed lines therein represent the permutation-based effect size thresholds for declaring QTL. It seems that QTL 25 could be missed under a number of data replicates. From Figures 1B and 2B , one can realize that the correlation among markers is high in the vicinity of QTL 25. On the other hand, we know that the effect of QTL 25 was simulated to be relatively small. This suggests that the permutation-based method may be ineffective at detecting small-effect size QTL in the presence of strongly correlated markers, in contrast to the method proposed here (Figure 1) .", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "One a priori for this may be that in MCMC-based Bayesian replicated data analysis, permutation thresholds are often, as is also the case here, based on a single realization so that its behavior may heavily depend on the particular data realization under consideration. Moreover, Churchill and Doerge (1994) emphasized that a large number of phenotype permutations are required to produce a more accurate estimate of the critical value. With the MCMC-based Bayesian approach, one should also ensure that the MCMCs are run long enough under each phenotype permutation and not rely on a small number of permutations. With the approach proposed here, the MCMCs are run only once, with no extra computational cost required for variable selection that is a by-product of the model-fitting effort, rather than the result of a post-model-fitting exercise as is the case for the permutation-based counterpart.", "cite_spans": [{"start": 279, "end": 306, "text": "Churchill and Doerge (1994)", "ref_id": "BIBREF2"}], "ref_spans": []}], "body_text": [{"section": "", "text": "W IDELY recognized to be effective for genomic prediction, Bayesian regularization or shrinkage methods are also arguably the state-of-the-art approach to genomewide multiple quantitative trait locus (QTL) mapping (e.g., Che and Xu 2010) . In both the maximum-likelihood (ML) and Bayesian approaches, QTL can be informally identified as locations corresponding to bumps in the plot of the estimated genetic effects against marker genomic positions.", "cite_spans": [{"start": 221, "end": 237, "text": "Che and Xu 2010)", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "", "text": "In Bayesian shrinkage models involving marker inclusion indicators, Bayes factors (BFs) (Kass and Raftery 1995) provide a convenient tool for QTL detection (e.g., Yi et al. 2007) . pointed out that including indicators as an additional source of shrinkage may induce a downward bias on the resulting BFs.", "cite_spans": [{"start": 88, "end": 111, "text": "(Kass and Raftery 1995)", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "", "text": "When the Bayesian shrinkage model does not involve marker inclusion indicators, these can still be indirectly generated with regard to a user-specific effect-size threshold, following Hoti and Sillanp\u00e4\u00e4 (2006) . However, the subsequent BFs may heavily depend on the prespecified effect-size cutoff value. Kn\u00fcrr et al. (2011) proposed a Bayesian shrinkage model where the marker inclusion indicators are indirectly generated based on a priori fixed and biologically meaningful hyperparameters, allowing the use of BFs to evaluate the strength of evidence in the data in support of QTL presence at any locus.", "cite_spans": [{"start": 184, "end": 209, "text": "Hoti and Sillanp\u00e4\u00e4 (2006)", "ref_id": "BIBREF8"}, {"start": 305, "end": 324, "text": "Kn\u00fcrr et al. (2011)", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "", "text": "A QTL significance threshold can alternatively be derived from Wald test statistic (Yang and Xu 2007) . This may, however, be unrealistic in the presence of highly correlated markers, due to overly inflated standard errors of the estimated genetic effects as a consequence of multicollinearity. Moreover, under the Bayesian shrinkage approach, the posterior densities of QTL effects are typically bimodal with a spike at the prior mode (zero) and a second mode around the actual QTL effect (see, e.g., Figure 2 in Che and Xu 2010) . This makes equal-tail credibility intervals (Li et al. 2011) impractical for detecting QTL since intervals will often include zero.", "cite_spans": [{"start": 514, "end": 530, "text": "Che and Xu 2010)", "ref_id": "BIBREF1"}, {"start": 577, "end": 593, "text": "(Li et al. 2011)", "ref_id": "BIBREF13"}], "ref_spans": [{"start": 502, "end": 510, "text": "Figure 2", "ref_id": "FIGREF2"}]}, {"section": "", "text": "In general, rigorous decision making with regard to true and false signals remains an open problem within highdimensional Bayesian shrinkage analysis (Heaton and Scott 2010) . Nevertheless, the phenotype permutation-based (or randomization) method of Churchill and Doerge (1994) is widely used for QTL discovery under both the ML-based (e.g., Churchill and Doerge 1994; Doerge and Churchill 1995) and the Bayesian (e.g., Xu 2003; Mutshinda and Sillanp\u00e4\u00e4 2010) frameworks. The permutation-based method involves the following three stages:", "cite_spans": [{"start": 150, "end": 173, "text": "(Heaton and Scott 2010)", "ref_id": "BIBREF7"}, {"start": 251, "end": 278, "text": "Churchill and Doerge (1994)", "ref_id": "BIBREF2"}, {"start": 343, "end": 369, "text": "Churchill and Doerge 1994;", "ref_id": "BIBREF2"}, {"start": 370, "end": 396, "text": "Doerge and Churchill 1995)", "ref_id": "BIBREF3"}, {"start": 430, "end": 459, "text": "Mutshinda and Sillanp\u00e4\u00e4 2010)", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "", "text": "1. Based on the genotypic data at hand, generate a large number of hypothetical phenotypic data under the null hypothesis of no phenotype-to-genotype association by pairing one individual's genotype with another's phenotype to generate data with the observed linkage disequilibrium and no phenotype-to-genotype association. 2. Fit the model to each permuted data set and monitor the value of a suitable test statistic (e.g., the largest absolute effect size). This yields an empirical distribution of the test statistic under the null hypothesis. 3. Select a specific percentile of this empirical distribution [e.g., the 100 \u00b7 \u00f01 2 a\u00de percentile for a suitable 0 , a , 1] as the effect-size significance threshold above which to declare QTL.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "The permutation-based method is computationally intensive. This is more so when the model fitting is carried out with a Bayesian approach through Markov chain Monte Carlo (MCMC) (Gilks et al. 1996) simulation. More importantly, from a Bayesian perspective, the posterior distribution embodies the data-updated state of knowledge about the model parameters and is therefore the sole basis for all inferences, including prediction and hypothesis testing. Bayesian conclusions arise in the form of probabilistic statements about unobserved quantities including model parameters and yet unobserved data (prediction), conditionally on the data actually observed (Gelman et al. 2003) . Thus, the hypothetical data generation under the null hypothesis at the heart of the permutation-based method is inconsistent with the Bayesian philosophy.", "cite_spans": [{"start": 178, "end": 197, "text": "(Gilks et al. 1996)", "ref_id": "BIBREF6"}, {"start": 657, "end": 677, "text": "(Gelman et al. 2003)", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "", "text": "In an attempt to mitigate the heavy computational load characterizing the randomization approach in MCMC-based Bayesian shrinkage analysis of QTL, Che and Xu (2010) proposed a within-MCMC phenotype permutation approach intended to reduce the computational time burden, but still rooted in the hypothetical data generation at issue with the Bayesian thinking. The authors were the first to recognize the lack of theory behind their method.", "cite_spans": [{"start": 147, "end": 164, "text": "Che and Xu (2010)", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "", "text": "Hypothesis testing methods for variable selection that stand firm on the Bayesian philosophy are missing within Bayesian shrinkage analysis of high-dimensional regression models. This article attempts to bridge this gap by proposing a fully Bayesian decision rule for QTL detection under the extended Bayesian LASSO (EBL) model introduced by Mutshinda and Sillanp\u00e4\u00e4 (2010) .", "cite_spans": [{"start": 342, "end": 372, "text": "Mutshinda and Sillanp\u00e4\u00e4 (2010)", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "Methods", "text": "Before proceeding to describe our new QTL detection rule, a brief review of the EBL is worthwhile.", "cite_spans": [], "ref_spans": []}, {"section": "The EBL in a nutshell", "text": "The EBL (Mutshinda and Sillanp\u00e4\u00e4 2010) extends the hierarchical prior specification of the regression coefficients in the Bayesian LASSO (BL) (Park and Casella 2008; Yi and Xu 2008) with an additional level implementing the separation between the overall model sparsity and the degree of shrinkage specific to individual regression parameters (the marker effects). In simulation studies (Mutshinda and Sillanp\u00e4\u00e4 2010; Fang et al. 2012; K\u00e4rkk\u00e4inen and Sillanp\u00e4\u00e4 2012; Li and Sillanp\u00e4\u00e4 2012) , the EBL has proved to be among the best LASSO-type shrinkage methods in terms of estimation and prediction accuracy. Throughout, we consider the following multiple linear regression model for QTL mapping,", "cite_spans": [{"start": 8, "end": 38, "text": "(Mutshinda and Sillanp\u00e4\u00e4 2010)", "ref_id": "BIBREF15"}, {"start": 387, "end": 417, "text": "(Mutshinda and Sillanp\u00e4\u00e4 2010;", "ref_id": "BIBREF15"}, {"start": 418, "end": 435, "text": "Fang et al. 2012;", "ref_id": "BIBREF4"}, {"start": 436, "end": 466, "text": "K\u00e4rkk\u00e4inen and Sillanp\u00e4\u00e4 2012;", "ref_id": "BIBREF10"}, {"start": 467, "end": 489, "text": "Li and Sillanp\u00e4\u00e4 2012)", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "The EBL in a nutshell", "text": "x ij b j \u00fe e i \u00f0i \u00bc 1; . . . ; n; j \u00bc 1; . . . ; p\u00de;", "cite_spans": [], "ref_spans": []}, {"section": "The EBL in a nutshell", "text": "where y i is the phenotypic trait value of the ith individual (i \u00bc 1; . . . ; n), b 0 is the common intercept, and x ij is the genotype value of individual i at locus j. Here, attention is restricted to experimental crosses derived from inbred lines, more specifically on backcross (BC) or double-haploid (DH) progeny with only one of two possible genotypes at any locus, and x ij is coded as 0 for one genotype and 1 for the other. b j is the genetic effect of marker j \u00f0j \u00bc 1; . . . ; p\u00de, and e i \u00f0i \u00bc 1; . . . ; n\u00de are mutually independent errors assumed to follow a zero-mean Gaussian distribution with common variance s . . . ; p. Each locus-specific regularization parameter l j $ 0 is further modeled as l j \u00bc dh j , where the quantities d $ 0 and h j . 0 are, respectively, intended to control the overall model sparsity level and the degree of shrinkage specific to b j , with a larger h j implying more shrinkage on b j .", "cite_spans": [], "ref_spans": []}, {"section": "The EBL in a nutshell", "text": "Marginally, each b j has a priori a zero-mean Laplacian or double-exponential (DE) distribution with variance 2=l 2 j , according the following representation of the DE distribution as a scaled mixture of normals with exponentially distributed mixing variances: DE \u00f0x j 0; l=2\u00de and Casella 2008) .", "cite_spans": [], "ref_spans": []}, {"section": "The EBL in a nutshell", "text": "The model specification is completed with prior assumptions on the parameters b 0 and s 2 0 and the hyperparameters d and h j \u00f0j \u00bc 1; . . . ; p\u00de. Our new QTL detection rule operates at the hyperparameter level and more specifically on the idiosyncratic hyperparameters h j .", "cite_spans": [], "ref_spans": []}, {"section": "The novel QTL detection rule", "text": "Bayesian LASSO arises as a particular case of the EBL when all h j are set to 1, implying that l j \u00bc l \u00bc d for 1 # j # p. The tenet of our new QTL detection rule is that genuine QTL effects should undergo less shrinkage than implied by the overall model sparsity level determined by d. In other words, h j should be consistently less than 1 for genuine QTL and vice versa. Biologically, we take the effects of non-QTL loci as reference for comparison, understanding that the effects of actual QTL should not be shrunken beyond the overall model sparsity level.", "cite_spans": [], "ref_spans": []}, {"section": "The novel QTL detection rule", "text": "Our new QTL detection rule is based on the posterior of the locus-specific shrinkage hyperparameters, h j , without involving any hypothetical data generation. Basically, the method boils down to testing the hypothesis H j 1 : h j , 1 of QTL presence at locus j \u00f0j \u00bc 1; . . . ; p\u00de, against the alternative hypothesis H j 2 : h j $ 1 of having no QTL at locus j for each 1 # j # p.", "cite_spans": [], "ref_spans": []}, {"section": "The novel QTL detection rule", "text": "In the Bayesian paradigm, the specification of priors about the model parameters and the hypotheses being tested is a critical stage whereby subjective probability enters the inference. Prior odds can be used to add context to the analysis. For example, model sparsity can be enforced by assigning low prior odds for QTL presence at any locus, i.e., setting Pr\u00f0H j 1 \u00de \u00bc Pr\u00f0h j , 1\u00de to be small relative to Pr\u00f0H j 2 \u00de \u00bc 1 2 Pr\u00f0H j 1 \u00de. As we discuss below, the uniform prior h j Uni\u00f0u; w\u00de, u , 1 , w provides much flexibility in calibrating the prior assumption about Pr \u00f0h j , 1\u00de and, consequently, the prior odds for H j 1 , \u00f0j \u00bc 1; . . . ; p\u00de. More specifically, if we assume a priori that h j Uni\u00f0u; w\u00de, u , 1 , w independently for j \u00bc 1; . . . ; p, then the prior probability, Pr\u00f0H 1 \u00de \u00bc Pr \u00f0h j , 1\u00de, of QTL presence at locus j is nothing but \u00f01 2 u\u00de=\u00f0w 2 u\u00de. This prior can be duly adjusted through a judicious choice of u and w. In the sequel, we assume, without loss of generality, that u \u00bc 0 so that the prior probability of QTL presence at locus j is simply Pr \u00f0h j , 1\u00de \u00bc 1=w, the corresponding odds being 1=\u00f0w 2 1\u00de.", "cite_spans": [], "ref_spans": []}, {"section": "The novel QTL detection rule", "text": "The essence of a Bayesian analysis is to update prior beliefs about model parameters and hypotheses in light of the observed data. Posterior odds reflect the analyst's state of knowledge about the relative strengths of two competing and mutually exclusive hypotheses after taking the data information into account. They are therefore well suited to hypothesis testing and decision making with regard to QTL presence at different loci. However, Bayes factors provide a better alternative to posterior odds as they free the analyst from reporting prior odds (e.g., Schervish 1995, p. 221) and allow the strength of evidence provided by the data in favor of a hypothesis to be evaluated on the widely used Jeffreys (1961) empirical scale described below. Let H j 1 and H j 2 denote the hypotheses \"QTL present at locus j\" and \"no QTL at locus j,\" corresponding to h j , 1 and h j $ 1, respectively. The Bayes factor", "cite_spans": [], "ref_spans": []}, {"section": "The novel QTL detection rule", "text": "quantifies the evidence provided by the data in favor of H Our new decision rule for QTL detection is based on the Bayes factor BF j 1;2 defined in (2) and, as a rule of thumb, we use 3 as the cutoff value of BF j 1;2 above which to declare QTL presence at locus j. The choice of this somewhat stringent cutoff value is motivated by the need to optimize the power of detecting QTL by reducing the false discovery rate.", "cite_spans": [], "ref_spans": []}, {"section": "The novel QTL detection rule", "text": "A critical quantity for the computation of the Bayes factor BF j 1;2 is the posterior probability Pr \u00f0h j , 1 Data\u00de. A Monte", "cite_spans": [], "ref_spans": []}, {"section": "The novel QTL detection rule", "text": "Carlo-based estimate of this probability under MCMC sampling is given by Pr \u00f0h j , 1 j Data\u00de \u00f01=N m \u00de P N m i\u00bc1 I\u00f0h \u00f0i\u00de j , 1\u00de, where I\u00f0:\u00de denotes the indicator function, N m is the number of post-burn-in MCMC samples, and h \u00f0i\u00de j is the ith MCMC sample for h j . This probability is easily evaluated in Win-BUGS/OpenBUGS through the logical function step(.) that takes the value 1 when its argument is larger than zero and the value zero otherwise. For more details on this, see supporting information, File S1.", "cite_spans": [], "ref_spans": []}, {"section": "The novel QTL detection rule", "text": "We next report on two simulation studies designed to investigate the performance of our new QTL detection rule under different scenarios. We subsequently utilize our decision rule to reanalyze the genetic basis of time to heading in barley (Hordeum vulgare L.), using real-world data from the North American Barley Genome Mapping project (Tinker et al. 1996) .", "cite_spans": [], "ref_spans": []}, {"section": "Report on simulation studies", "text": "To evaluate the performance of our new decision rule for QTL detection, we carried out two simulation studies, hereafter simulation study 1 and simulation study 2. Simulation study 1 involved two replicated analyses based, respectively, on the moderately dense barley marker data and on a computer-simulated dense marker data set. Simulation study 2 was based on a very dense and particularly challenging marker data set generated through computer simulation.", "cite_spans": [], "ref_spans": []}, {"section": "Report on simulation studies", "text": "Simulation study 1: This simulation study is based on the following two marker data sets differing in both the marker density and the n-to-p ratio:", "cite_spans": [], "ref_spans": []}, {"section": "Report on simulation studies", "text": "1. The real-world marker data set from the North American Barley Genome Mapping project (Tinker et al. 1996) , which involves 145 DH lines and 127 biallelic markers covering seven chromosomes, the distance between consecutive markers being 10.5 cM: We refer to Tinker et al. (1996) for more details on this data set. The few missing genotypes were imputed with random draws from Bernoulli(0.5) before the analysis. A more appropriate approach to missing genotype imputation would be to utilize their genotype probabilities given the genotypes of flanking markers with regard to a genetic map (see Jiang and Zeng 1997 In both cases, the phenotypic trait values were simulated assuming sparse underlying biology with only four QTL at loci 4, 25, 50, and 65, with respective effects 2.5, 22.5, 4, and 24. In the data simulation process, the intercept was set to zero without loss of generality. The residual variance, s 2 0 , was set to 2 and 1 under the barley marker data and the simulated dense marker data, respectively, yielding an approximate heritability of 0.80 in both cases. Our analyses are based on data with high heritabilities and small sample sizes. Sillanp\u00e4\u00e4 and Hoti (2007) pointed out that, with regard to power analysis, similar results arise under small heritabilities and large samples.", "cite_spans": [{"start": 597, "end": 616, "text": "Jiang and Zeng 1997", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Report on simulation studies", "text": "One hundred phenotype replicates were simulated under each marker data set. The R codes for generating the replicated phenotypic data are provided in File S1, along with the simulated dense marker data and a realization of the simulated phenotypes under the parameter setting described above. A typical vector of simulated phenotypes under the barley marker data is provided as well.", "cite_spans": [], "ref_spans": []}, {"section": "Report on simulation studies", "text": "The model specification was completed with the following (essentially noninformative) prior specification: b 0 N\u00f00; 100\u00de; and s 2 0 Inv-Gamma \u00f00:01; 0:01\u00de, d Uni\u00f00; 100\u00de, and h j Uni\u00f00; w\u00de for j \u00bc 1; . . . ; p independently. Finally, w was set to 10, yielding a prior probability Pr\u00f0h j , 1\u00de \u00bc 0:1 of QTL presence at any locus j \u00f01 # j # p\u00de.", "cite_spans": [], "ref_spans": []}, {"section": "Report on simulation studies", "text": "We used MCMC simulation, through the Bayesian freeware OpenBUGS (Thomas et al. 2006) , to sample from the joint posterior of the model parameters. The BUGS code is available in File S1. All computations were carried out on an AMD Turion X2 Dual, with a 64-bit operating system and 4 GB of RAM. We initially ran three Markov chains for 100,000 iterations to assess, through visual inspection of traceplots, the time to convergence and the quality of the mixing of the chains. The Markov chains reached apparently their target distributions after 500 and 2000 iterations under the barley data and the simulated dense marker data set, respectively. The 100,000 iterations of three Markov chains took 7 hr under the barley data and 2 hr under the simulated dense marker data set.", "cite_spans": [], "ref_spans": []}, {"section": "Report on simulation studies", "text": "We then fitted the model to the 100 replicated data sets, running a single Markov chain for 7000 iterations after a burn-in period of 3000 iterations and thinning the remainder to each 10th sample. The model fitting to each replicated data set took 770 sec under the barley marker data and 420 sec under the simulated dense marker data set. Figure 1 shows the Bayes factors for QTL presence at each marker locus on a natural logarithmic scale, averaged over the 100 replicated data sets plotted against the marker genomic positions for simulations based on the barley marker data ( Figure 1A ) and the simulated dense marker data set ( Figure 1B ). In Figure 1 , A and B, the threshold, log\u00f03\u00de 1:1, above which QTL are declared is indicated by a horizontal shaded dashed line.", "cite_spans": [], "ref_spans": [{"start": 341, "end": 349, "text": "Figure 1", "ref_id": "FIGREF1"}, {"start": 582, "end": 591, "text": "Figure 1A", "ref_id": "FIGREF1"}, {"start": 636, "end": 645, "text": "Figure 1B", "ref_id": "FIGREF1"}, {"start": 652, "end": 660, "text": "Figure 1", "ref_id": "FIGREF1"}]}, {"section": "Report on simulation studies", "text": "From the results plotted in Figure 1 , the four \"true\" QTL are clearly singled out with BFs far larger than the cutoff value log\u00f03\u00de 1:1, in contrast to the non-QTL candidate loci. The four QTL were also the only loci with BFs exceeding the detection threshold under the barley marker data set, implying a false discovery rate of 0%. The BFs for QTL presence at non-QTL loci were consistently ,1 and did not even approach the selection threshold in the few cases where they happened to exceed 1. In analyses based on the simulated dense marker data set, some loci close to the actual QTL locations could occasionally have BFs .1 due to linkage disequilibrium, but these should not be considered as false positives.", "cite_spans": [], "ref_spans": [{"start": 28, "end": 36, "text": "Figure 1", "ref_id": "FIGREF1"}]}, {"section": "Report on simulation studies", "text": "We also evaluated the performance of the permutationbased method for QTL detection under the EBL with the parameter setting described above, using 100 phenotype permutations. For each permuted data set, we ran 15,000 iterations of a single Markov chain and discarded the first 4000 iterations as burn-in, thinning the remainder to each 10th sample. Figure 2 shows the posterior mean genetic effects averaged over the 100 replicated data sets, plotted against the marker numbers for analyses based on the barley marker data ( Figure 2A ) and for those based on the simulated dense marker data set ( Figure 2B ). The horizontal shaded dashed lines therein represent the permutation-based effect size thresholds for declaring QTL.", "cite_spans": [], "ref_spans": [{"start": 349, "end": 357, "text": "Figure 2", "ref_id": "FIGREF2"}, {"start": 525, "end": 534, "text": "Figure 2A", "ref_id": "FIGREF2"}, {"start": 598, "end": 607, "text": "Figure 2B", "ref_id": "FIGREF2"}]}, {"section": "Report on simulation studies", "text": "It seems that QTL 25 could be missed under a number of data replicates. From Figures 1B and 2B , one can realize that the correlation among markers is high in the vicinity of QTL 25. On the other hand, we know that the effect of QTL 25 was simulated to be relatively small. This suggests that the permutation-based method may be ineffective at detecting small-effect size QTL in the presence of strongly correlated markers, in contrast to the method proposed here (Figure 1) .", "cite_spans": [], "ref_spans": [{"start": 77, "end": 94, "text": "Figures 1B and 2B", "ref_id": "FIGREF1"}, {"start": 464, "end": 474, "text": "(Figure 1)", "ref_id": "FIGREF1"}]}, {"section": "Report on simulation studies", "text": "One a priori for this may be that in MCMC-based Bayesian replicated data analysis, permutation thresholds are often, as is also the case here, based on a single realization so that its behavior may heavily depend on the particular data realization under consideration. Moreover, Churchill and Doerge (1994) emphasized that a large number of phenotype permutations are required to produce a more accurate estimate of the critical value. With the MCMC-based Bayesian approach, one should also ensure that the MCMCs are run long enough under each phenotype permutation and not rely on a small number of permutations. With the approach proposed here, the MCMCs are run only once, with no extra computational cost required for variable selection that is a by-product of the model-fitting effort, rather than the result of a post-model-fitting exercise as is the case for the permutation-based counterpart.", "cite_spans": [{"start": 279, "end": 306, "text": "Churchill and Doerge (1994)", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Report on simulation studies", "text": "Simulation study 2: In simulation study 1 we simulated dense markers with 3-cM intervals, mimicking a realistic inbred line cross situation where recombination occurs rarely between adjacent markers. Although it is unnecessary for researchers to screen their BC or DH populations at each centimorgan, we simulate a marker map with 1 cM distance between consecutive markers to investigate how well our method would perform when faced with such a situation where the dependency between markers is very high. Mutshinda and Sillanp\u00e4\u00e4 (2012) simulated marker maps of inbred line-cross data with 1-cM intervals to evaluate the performance of their procedures.", "cite_spans": [], "ref_spans": []}, {"section": "Report on simulation studies", "text": "The marker data set was simulated through the WinQTL Cartographer 2.5 program (Wang et al. 2006 ) and involved 50 BC progeny and 200 markers (i.e., four times as many markers as individuals), with just 1 cM between consecutive markers.", "cite_spans": [], "ref_spans": []}, {"section": "Report on simulation studies", "text": "The phenotypic trait values were simulated assuming seven QTL, namely at loci 6, 12, 71, 75, 120, 185, and 192 , with respective effects 22.5, 21.5, 3, 23, 4, 21.5, and 25. The residual variance was set to 8 in the data simulation process, yielding an approximate heritability of 0.80.", "cite_spans": [], "ref_spans": []}, {"section": "Report on simulation studies", "text": "Note that in extremely oversaturated regression models, the intercept may fluctuate greatly and capture most of the signal since no shrinkage is imposed on it, which may erode the model's ability to discriminate the effects of different predictors (loci). This is more so when no prior covariance structure is assumed for the regression coefficients (genetic effects) as is the case here (cf. Mutshinda and Sillanp\u00e4\u00e4 2012) . It would be worth checking whether this problem would be less acute under a different genotype coding e.g., 21 and 1 rather than the 0 and 1 coding used here. Anyway, we found that this problem can be mitigated by centering the response variable (phenotype) before the analysis (i.e., subtracting its mean from individual values) and forcing the intercept to be zero during estimation. We adopted this approach here without rescaling the phenotypic values to unit variance to maintain the estimated genetic effects on the scale of the simulated values so that we can appreciate the extent of the model-induced shrinkage on individual locus effects.", "cite_spans": [], "ref_spans": []}, {"section": "Report on simulation studies", "text": "As a word of caution, the prior inclusion probability should not be selected to be too small in extremely oversaturated regression models (i.e., when p n) or when the correlation among predictors (markers) is very high, to preserve the good mixing property. A similar problem has been pointed out to occur in spike-and-slab methods (e.g., O'Hara and Sillanp\u00e4\u00e4 2009). Recall that Pr \u00f0h j , 1\u00de is controlled by the prior setting of h j or, more specifically in our case, by the value of w. In analyzing this particularly challenging data set, we set the hyperparameter w to 4, yielding a prior inclusion probability Pr \u00f0h j , 1\u00de = 0.25 for each marker, which is comparable to prior inclusion probabilities typically used in spike-and-slab variable selection methods.", "cite_spans": [], "ref_spans": []}, {"section": "Report on simulation studies", "text": "The simulated marker data set is provided in File S1, along with a typical vector of simulated phenotypic values and the R code for phenotype generation.", "cite_spans": [], "ref_spans": []}, {"section": "Report on simulation studies", "text": "In MCMC-based Bayesian shrinkage QTL analysis, when a QTL is correlated with nearby markers, the posterior kernel density plots of its genetic effect typically display a two-component mixture (bimodal) structure. One of the two mixture components is clustered around zero (the prior mode). As more Markov chain iterations are run, a second mode emerges by the actual QTL effect, and the mixture component concentrated around zero becomes increasingly peaked at its mode. It is crucial in such circumstances that MCMC samplers be run much longer to generate enough samples from the emerging mixture components in the posteriors of QTL effects.", "cite_spans": [], "ref_spans": []}, {"section": "Report on simulation studies", "text": "We ran 200,000 iterations of two MCMC chains. The chains seemed to reach their target distribution after 7000 iterations. We discarded the first 25,000 iterations as burn-in and thinned the remaining MCMC draws to each 25th sample. The 200,000 iterations of two Markov chains took 12 hr.", "cite_spans": [], "ref_spans": []}, {"section": "Report on simulation studies", "text": "The performance of our method on this challenging data set is illustrated in Figure 3A , where the Bayes factors for QTL presence at each marker locus are plotted on a natural logarithmic scale against the marker position for a singlephenotype realization. The horizontal shaded dashed line indicates the threshold above which QTL are declared.", "cite_spans": [], "ref_spans": [{"start": 77, "end": 86, "text": "Figure 3A", "ref_id": "FIGREF3"}]}, {"section": "Report on simulation studies", "text": "To verify the ability of the phenotype permutation-based method to identify QTL in the presence of highly correlated markers, we required 100 phenotype permuted data sets. For each permutated data set, we ran 25,000 iterations of a single Markov chain, discarding the first 8000 samples as burn-in and thinning the remainder by a factor of 10. The 25,000 iterations took 2122 sec. Figure 3B shows the posterior means of genetic effects with the permutation threshold indicated by the overlaid horizontal shaded dashed line.", "cite_spans": [], "ref_spans": [{"start": 381, "end": 390, "text": "Figure 3B", "ref_id": "FIGREF3"}]}, {"section": "Report on simulation studies", "text": "It can be seen from Figure 3A that a few adjacent loci to actual QTL positions were also selected, due to linkage disequilibrium. The BFs for QTL presence at actual QTL positions were much larger, making them plainly distinguishable from non-QTL loci through our decision rule (except locus 6). The posterior means of genetic effects for a single phenotype realization are shown in Figure 3B , where the horizontal shaded dashed lines therein indicate the effect size thresholds for declaring QTL, based on 100 phenotype permutations.", "cite_spans": [], "ref_spans": [{"start": 20, "end": 29, "text": "Figure 3A", "ref_id": "FIGREF3"}, {"start": 382, "end": 391, "text": "Figure 3B", "ref_id": "FIGREF3"}]}, {"section": "Real data analysis", "text": "We utilized our new decision rule for QTL detection to reanalyze the genetic basis of the time to heading in barley, using real-world data from the North American Genome Mapping project (Tinker et al. 1996) . As mentioned above, the mapping population comprises 145 doubled haploid lines after 5 individuals with missing phenotype have been omitted. Each progeny was scored at 127 markers covering seven chromosomes. The phenotypic trait of interest is the number of days to heading, averaged over 25 different environments. The phenotypic trait values were standardized to have mean zero and unit variance, and the few missing genotypes were imputed with random draws from Bernoulli(0.5) before the analysis.", "cite_spans": [], "ref_spans": []}, {"section": "Real data analysis", "text": "The model fitting to the data was carried out by MCMC simulation through OpenBUGS under the same prior specification as in simulation study 1. We ran 20,000 iterations of two MCMC chains after a burn-in period of 5000 iterations and applied a thinning factor of 10, which resulted in 4000 draws. Figure 4 , A and B, shows, respectively, the BFs for QTL presence and the posterior mean genetic effects at different loci. The horizontal shaded dashed line in Figure 4A represents the log(BF) threshold, log\u00f03\u00de 1:1, above which QTL are declared, whereas the ones in Figure 4B represent the permutation-based thresholds above which to declare QTL. These cutoff values are based on 100 phenotype permutations.", "cite_spans": [], "ref_spans": [{"start": 296, "end": 304, "text": "Figure 4", "ref_id": "FIGREF4"}, {"start": 457, "end": 466, "text": "Figure 4A", "ref_id": "FIGREF4"}, {"start": 563, "end": 572, "text": "Figure 4B", "ref_id": "FIGREF4"}]}, {"section": "Real data analysis", "text": "The results shown in Figure 4 imply that the genetic basis of the time to heading in barley is sparse. Five loci only, namely loci 6, 9, 12, 63, and 86, emerged as actual QTL, with BFs for QTL presence exceeding the cutoff value of 3. All loci with BFs for QTL presence .1 are listed in Table 1 , wherein boldface type is used to indicate the BFs exceeding the QTL detection threshold. We also performed a randomization test for QTL discovery, using the highest posterior inclusion probability, and hence the highest BF, as a test statistic. The posterior marker inclusion probabilities are shown in Figure 5 . Therein, the permutation-based cutoff value for QTL selection based on 100 phenotype permutations, 0.15, corresponding to a BF of 1.588 is indicated by the horizontal shaded dashed line. The solid dashed line indicates the QTL inclusion probability 0.25, which corresponds to our rule-of-thumb threshold BF \u00bc 3 for QTL selection under the prior inclusion probability Pr \u00f0h j , 1\u00de \u00bc 0:10 adopted here.", "cite_spans": [], "ref_spans": [{"start": 21, "end": 29, "text": "Figure 4", "ref_id": "FIGREF4"}, {"start": 287, "end": 294, "text": "Table 1", "ref_id": "TABREF2"}]}, {"section": "Real data analysis", "text": "The randomization approach has led to the selection of some additional loci, namely loci, 3, 5, 33, 40, 47, 78, 119 , and 120, which are mostly among the loci with BFs .1 under our decision rule. Kn\u00fcrr et al. (2011) also analyzed the time to heading in barley, using the same data set, and identified 12 markers, 10 of which are among the loci with Bayes factors for inclusion .1, which are given in Table 1 . The BFs for the two other loci, namely locus 44 and locus 55, were ,1 in our analysis.", "cite_spans": [{"start": 196, "end": 215, "text": "Kn\u00fcrr et al. (2011)", "ref_id": "BIBREF12"}], "ref_spans": [{"start": 400, "end": 407, "text": "Table 1", "ref_id": "TABREF2"}]}, {"section": "Discussion", "text": "In this article, we proposed a fully Bayesian decision rule for QTL detection under the EBL introduced by Mutshinda and Sillanp\u00e4\u00e4 (2010) . In simulation studies (Mutshinda and Sillanp\u00e4\u00e4 2010; Fang et al. 2012; K\u00e4rkk\u00e4inen and Sillanp\u00e4\u00e4 2012; Li and Sillanp\u00e4\u00e4 2012) , the EBL has proved to be among the top LASSO-type shrinkage methods with regard to QTL detection, owing presumably to its ability to explicitly distinguish the overall model sparsity from the degree of shrinkage idiosyncratically experienced by the regression coefficients. Since true QTL effects are expected to experience less shrinkage than assumed by the overall model sparsity level, their individual shrinkage hyperparameters should consistently be ,1. Consequently, QTL detection can be based on whether a locus-specific shrinkage hyperparameter is ,1. If these hyperparameters are assigned suitable (uniform) priors that can be understood in terms of marker inclusion/ exclusion, QTL detection can rely on their posterior distributions. The posterior inclusion probabilities of different loci, and hence the corresponding Bayes factors, can be used to evaluate the strength of evidence for QTL presence at different loci with regard to a suitable cutoff value. This is what our QTL detection rule is all about.", "cite_spans": [{"start": 106, "end": 136, "text": "Mutshinda and Sillanp\u00e4\u00e4 (2010)", "ref_id": "BIBREF15"}, {"start": 161, "end": 191, "text": "(Mutshinda and Sillanp\u00e4\u00e4 2010;", "ref_id": "BIBREF15"}, {"start": 192, "end": 209, "text": "Fang et al. 2012;", "ref_id": "BIBREF4"}, {"start": 210, "end": 240, "text": "K\u00e4rkk\u00e4inen and Sillanp\u00e4\u00e4 2012;", "ref_id": "BIBREF10"}, {"start": 241, "end": 263, "text": "Li and Sillanp\u00e4\u00e4 2012)", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Discussion", "text": "Simulation results (Figures 1-3 ) demonstrated the effectiveness of our new detection rule to identify QTL, including in very challenging situations. For example, in simulation study 2, the QTL 71 and 75 simulated to be physically close, but with opposite signs were effectively detected (Figure 3 ), although this is generally difficult in practice as pointed out by Wang et al. (2005) .", "cite_spans": [], "ref_spans": [{"start": 19, "end": 31, "text": "(Figures 1-3", "ref_id": "FIGREF1"}, {"start": 288, "end": 297, "text": "(Figure 3", "ref_id": "FIGREF3"}]}, {"section": "Discussion", "text": "It has been noted earlier that under the MCMC estimation context where uniform priors can be easily assumed, EBL shows no need for tuning of hyperparameters (Mutshinda and Sillanp\u00e4\u00e4 2010) while in a maximum a posteriori estimation context, tuning of the Gamma hyperparameters is critical (K\u00e4rkk\u00e4inen and Sillanp\u00e4\u00e4 2012; Li and Sillanp\u00e4\u00e4 2012; Mutshinda and Sillanp\u00e4\u00e4 2012) . Accordingly, our results were robust to the values of u and w defining the range of the uniform prior imposed on the hyperparameters h j , j \u00bc 1; . . . ; p. However, the Bayes factors may in some cases be sensitive to the choice of u and w, and the suitable BF threshold for detecting QTL may be data dependent as pointed out by Kn\u00fcrr et al. (2011) . A sensitivity analysis is therefore necessary.", "cite_spans": [{"start": 157, "end": 187, "text": "(Mutshinda and Sillanp\u00e4\u00e4 2010)", "ref_id": "BIBREF15"}, {"start": 288, "end": 319, "text": "(K\u00e4rkk\u00e4inen and Sillanp\u00e4\u00e4 2012;", "ref_id": "BIBREF10"}, {"start": 320, "end": 342, "text": "Li and Sillanp\u00e4\u00e4 2012;", "ref_id": "BIBREF14"}, {"start": 704, "end": 723, "text": "Kn\u00fcrr et al. (2011)", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Discussion", "text": "In cases where the model is excessively overparameterized, or when the level of correlation between markers is extremely high, one may proceed stepwise by first filtering the data by discarding all loci with BFs for QTL presence ,1 and then refitting the mapping model to the reduced data set. The model fitting to a filtered data set generally results in improved accuracy of the estimated genetic effects (see, e.g., Mutshinda and Sillanp\u00e4\u00e4 2011). One may alternatively proceed by placing pseudomarkers in every interval of a prespecified length (e.g., every 5 cM as in Che and Xu 2010) and base the mapping analysis on these pseudomarkers, with their genotypes inferred (or imputed) using, for example, the multipoint method (Jiang and Zeng 1997).", "cite_spans": [{"start": 572, "end": 588, "text": "Che and Xu 2010)", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Discussion", "text": "In our evaluation, we used the permutation-based method as proposed by Churchill and Doerge (1994) . The within-MCMC permutation-based method of Che and Xu (2010) is just a more computationally efficient approach to the original method of Churchill and Doerge (1994) and should ideally lead to similar results. On the other hand, the method of Che and Xu (2010) builds on the Bayesian shrinkage regression model of Xu (2003) as extended by Ter Braak et al. (2005), which does not involve the separation feature of the EBL on which our method is based. Hoti and Sillanp\u00e4\u00e4 (2006) (2003) under highly correlated predictors (markers and gene expressions) and small sample size, which is apparently not the case for EBL.", "cite_spans": [{"start": 71, "end": 98, "text": "Churchill and Doerge (1994)", "ref_id": "BIBREF2"}, {"start": 145, "end": 162, "text": "Che and Xu (2010)", "ref_id": "BIBREF1"}, {"start": 239, "end": 266, "text": "Churchill and Doerge (1994)", "ref_id": "BIBREF2"}, {"start": 344, "end": 361, "text": "Che and Xu (2010)", "ref_id": "BIBREF1"}, {"start": 552, "end": 577, "text": "Hoti and Sillanp\u00e4\u00e4 (2006)", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Discussion", "text": "It would be interesting to examine whether the introduction of the separation feature in Xu's (2003) et al. (2005) would alleviate these problems and to further investigate how well the QTL detection method proposed here would perform under such a model. Figure 5 Posterior marker inclusion probabilities for the number of days to heading in barley. The cutoff posterior probability for QTL selection based on 100 phenotype permutations, 0.15, is indicated by the horizontal shaded dashed line. This probability corresponds to a BF of 1.588 under the prior inclusion probability Pr\u00f0h j , 1\u00de \u00bc 0:10 adopted here. The horizontal solid dashed line indicates the probability 0.25, which corresponds to our rule-of-thumb Bayes factor 3 for QTL detection under our prior QTL inclusion probability. and monitoring its MCMC--based mean value. The BUGS function step(.) takes the value 1 if its argument is larger than zero and is zero otherwise. 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1,  1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1,  1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1,  1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1,  1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 0 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 0, 0, 0, 0, 1, 1, 1, 1, 0 1, 1, 1, 1, 1,  1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1,  1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1,  1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1 1, 1, 1, 1, 1, 1, 1,  1, 1, 1, 1, 1, 1, 1, 0 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1,  1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1,  1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 0 1, 1, 1, 1, 1, 1, 1, 1,  1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1 1, 1, 1, 1, 1, 1, 1, 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The horizontal shaded dashed line indicates the log(BF) threshold, log\u00f03\u00de 1:1, above which QTL are declared.", "type": "figure"}, "FIGREF2": {"text": "Figure 2 (A and B) Posterior mean genetic effects averaged over 100 replicated data sets against the marker numbers for simulations based on the barley marker data (A) and the simulated dense marker data set (B). The horizontal shaded dashed lines represent the effect size thresholds for declaring QTL, based on 100 phenotype permutations.", "type": "figure"}, "FIGREF3": {"text": "Figure 3 (A) Natural logarithms of the Bayes factors for QTL presence at each marker, plotted against the marker number for a single-phenotype realization under the very dense marker data, with the horizontal shaded dashed line indicating the log(BF) threshold, log\u00f03\u00de 1:1, above which QTL are declared. (B) Posterior means of genetic effects for a single-phenotype realization under the very dense marker data. The horizontal shaded dashed lines represent the effect size thresholds for declaring QTL, based on 100 phenotype permutations.", "type": "figure"}, "FIGREF4": {"text": "Figure 4 (A) Natural logarithms of the Bayes factors for QTL presence at each marker with regard to the phenotypic trait \"number of days to heading,\" using the North American Barley data, plotted against marker numbers. The horizontal shaded dashed line indicates the log(BF) threshold, log\u00f03\u00de 1:1, above which QTL are declared. (B) Posterior means of genetic effects on the time to heading in North American barley. The horizontal shaded dashed lines represent the effect size thresholds for declaring QTL, based on 100 phenotype permutations.", "type": "figure"}, "FIGREF5": {"text": "the BUGS code (see above)", "type": "figure"}, "FIGREF26": {"text": "0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 1, 1, 1, 1, 1, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0, 0,", "type": "figure"}, "FIGREF35": {"text": ".M., and M.J. SILLANP\u00c4\u00c4, 2010 Extended Bayesian LASSO for multiple quantitative trait loci mapping and unobserved phenotype prediction. Genetics 186: 1067--1075.", "type": "figure"}, "TABREF2": {"text": "List of loci with Bayes factors for QTL presence .1, with boldface type indicating BFs that exceed the QTL detection threshold of 3", "type": "table"}, "TABREF3": {"text": "Hara, R. B., and M. J. Sillanp\u00e4\u00e4, 2009 A review of Bayesian variable selection methods: what, how and which. Bayesian Anal. 4: 85-118. Park, T., and G. Casella, 2008 The Bayesian Lasso. J. Am. Stat. Assoc. 103: 681-686. Schervish, M. J., 1995 Theory of Statistics, Springer-Verlag, New-York. Sillanp\u00e4\u00e4, M. J., and F. Hoti, 2007 Mapping quantitative trait lociTinker, N. A., D. E Mather, B. G. Rosnagel, K. J. Kasha, and A. Kleinhofs, 1996 Regions of the genome that affect agro- nomic performance in two-row barley. Crop Sci. 36: 1053- 1062. Wang, H., Y-M. Zhang, X. Li, G. L. Masinde, and S. Mohan et al.,Supporting Information http://www.genetics.org/content/early/2012/09/14/genetics.111.130278/suppl/DC1 A Decision Rule for Quantitative Trait Locus Detection Under the Extended Bayesian LASSO Model Crispin M. Mutshinda and Mikko J. Sillanp\u00e4\u00e4", "type": "table"}, "TABREF4": {"text": "Simulated phenotype under the barley marker dataThe simulated dense marker dataset involving 50 individuals and 102 markers", "type": "table"}}}
{"paper_id": "213461097", "_pdf_hash": "6ac3675103fc5c78c48e2e569b70520632513373", "abstract": [{"section": "Abstract", "text": "The downy rose-myrtle berry is regarded as a healthy food due to its high content of anthocyanin and other antioxidant phytochemicals. The berries are sometimes dried, ground into a powder and used as a natural food coloring agent or functional food additive. This study aimed to determine the physicochemical properties and anthocyanin bioaccessibility of superfine ground downy rose-myrtle powders. Compared with shear pulverized coarse particles, the superfine ground particles of berry powders had decreased bulk density and fluidity while improved water-holding capacity and solubility. In addition, the amounts of polyphenols and anthocyanins released from the superfine powders were significantly higher than those from coarse powders during in vitro gastrointestinal digestion. These results indicate that after superfine grinding treatment, downy rose-myrtle powder could serve as a potential resource of natural bioactive compounds for food and nutraceutical applications.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "ARTICLE HISTORY", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Downy rose-myrtle, scientifically named Rhodomyrtus tomentosa (Ait.) Hassk, is a well-known edible and medicinal plant, and is mainly found in south-east Asian countries, such as Thailand, Japan, and China. [1] The juicy downy rose-myrtle berry turns dark purple when ripe, and is historically regarded as a healthy food that has been used for making traditional wine, jams and beverages. Anthocyanin pigments confer the purple color and are considered the active components of downy rose-myrtle. [2] These pigments are located in the vacuole of plant cells, and are released following cell rupture during eating or processing. Generally, bioaccessibility is defined by the fraction of bioactive substance that is released from the food matrix after digestion and solubilized in the gut lumen for uptake across the intestinal mucosa. [3] The cell wall breakage ratio is a key factor limiting anthocyanin bioaccessibility during food digestion, since the approximate diameter of a plant cell ranges from 10 to 50 \u03bcm, [4] which is too small to be broken by chewing and grinding with teeth. Anthocyanins remaining within intact cells are inaccessible during upper gut digestion. [5] Superfine grinding is a new technology that can reduce the particle size of food ingredients to 0.01-25 \u03bcm. Compared with traditional mechanically ground particle materials, superfine food powder has outstanding characteristics including high solubility, dispersion, adsorption, chemical reactivity, and fluidity. [6] [7] [8] [9] This is because superfine grinding can increase the particle surface area and break down cell walls. Ni et al. found that superfine grinding markedly increases the extraction of polyphenols from green tea, leading to more potent free radical scavenging capacity. [10] Tang et al.", "cite_spans": [{"start": 497, "end": 500, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 834, "end": 837, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 1016, "end": 1019, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 1494, "end": 1497, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 1498, "end": 1501, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 1502, "end": 1505, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 1506, "end": 1509, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 1773, "end": 1777, "text": "[10]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Introduction", "text": "found that the antioxidant activity of red grape pomace powder increases with decreasing particle size after superfine grinding. [7] Superfine grinding can break the plant cell wall and promote the release of active components from the food matrix. [9] Therefore, it is interesting to study the physicochemical and morphological properties of superfine powder derived from downy rosemyrtle and its bioaccessible anthocyanin as a functional ingredient.", "cite_spans": [{"start": 129, "end": 132, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 249, "end": 252, "text": "[9]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Introduction", "text": "In vitro gastrointestinal digestion procedures have been extensively used to assess the bioaccessibility of food constituents because they are rapid, safe and do not have the same ethical restrictions as in vivo approaches. The in vitro gastrointestinal digestion method has already been used for the study of triturated foods rich in anthocyanins such as chokeberry, [11] mulberry, [12] pomegranate, [13] and red cabbage. [14] There were a mass of controversial findings about the effects of in vitro gastrointestinal digestion on the bioaccessibility and stability of anthocyanin in the previous research. The degree of pulverization may impact the anthocyanin release from food matrix. Till date, little is known about the anthocyanin bioaccessibility and antioxidant activity of super finely ground food powder during digestion.", "cite_spans": [{"start": 368, "end": 372, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 383, "end": 387, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 401, "end": 405, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 423, "end": 427, "text": "[14]", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Introduction", "text": "In this study, we compared the morphological and physicochemical properties of superfine powders and coarse particles derived from downy rose-myrtle. In addition, the digestibility of phenolics and anthocyanins, as well as the antioxidant activity of digested compounds of downy rose-myrtle powder were determined using an in vitro gastrointestinal digestion model.", "cite_spans": [], "ref_spans": []}, {"section": "Materials and methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Materials", "text": "Fresh mature fruits of downy rose-myrtle were obtained in September 2016 from a local market in Shaoguan, Guangdong Province, China. HPLC certified syringe filters, formic acid, and acetonitrile were purchased from Dikma Technologies Inc. (Beijing, China). The standard of cyanidin-3-glucoside was provided by Polyphenol AS (Sandnes, Norway). Folin-Ciocalteu's reagent was obtained from Sinopharm Chemical (Shanghai, China). The enzymes used for in vitro digestion were supplied by Sigma Aldrich (St Louis, MO, USA).", "cite_spans": [], "ref_spans": []}, {"section": "Sample preparation", "text": "The downy rose-myrtle berries were put in a forced convection oven and incubated at 60\u00b0C for 8 h and then dried in a chamber under a vacuum with heated air at 60\u00b0C until the moisture content reached less than 8%. The moisture content was determined by weighing the sample after drying at 105\u00b0C for 24 h. The dried fruits were milled into raw material powders by a DLF18 disc mill (Dingli Medical Instrument, Wenzhou, China). Some of the raw material powders were screened through sieves with bore diameters <96 \u03bcm, 96-120 \u03bcm and 120-180 \u03bcm to separate granulates to yield three different particle sizes of coarse powders (CP), denoted as CP96, CP120, and CP180, respectively. The remaining RMPs were re-milled at 20,000 r/min for 3 min with a YF2-2 micronizer (Yongli Pharmaceutical Machinery, Ruian, China) to obtain superfine powder.", "cite_spans": [], "ref_spans": []}, {"section": "Particle size and specific surface area measurements", "text": "The particle size distribution and specific surface area were measured using a LS-POP9 laser diffraction particle size analyzer (Omec Instruments, Zhuhai, China) at room temperature with deionized water as the solvent. Particle size distribution was characterized by the median diameter (D 50 ) and span factor [(D 90 -D 10 )/D 50 ], where D 10 , D 50 , and D 90 represent 10%, 50% and 90% cumulative percentiles of particles, respectively. [15] Scanning electron microscope (SEM) Downy rose-myrtle powder (DRMP) samples were spread on a conductive adhesive carbon tape that was pasted on a sample stub. The morphological characteristics of different sized DRMPs were determined using a Hitachi TM3030 model SEM (Hitachi, Japan) at 15 kV accelerated voltage and 10-15 mm working distance.", "cite_spans": [{"start": 441, "end": 445, "text": "[15]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Color difference analysis", "text": "The color of different sized DRMPs was determined using a WR-10 automatic chromameter (Wave Optoelectronics Technology Co., Ltd, Shenzhen, China). The color values represented whiteness/ darkness (L/-L), redness/greenness (a/-a) and yellowness/blueness (b/-b). [16] Bulk density", "cite_spans": [{"start": 261, "end": 265, "text": "[16]", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "Color difference analysis", "text": "The bulk density of a powder is the ratio of the mass of an untapped powder sample to its volume including pores and interparticle voids. 10.0 g powder samples were poured into a 50-mL volumetric cylinder using a funnel and the volume of the powder was taken. The bulk density of the downy rose-myrtle powder was calculated using the following formula:", "cite_spans": [], "ref_spans": []}, {"section": "Color difference analysis", "text": "Bulk density g=mL \u00f0 \u00de\u00bc Weight of powder=Volume of powder", "cite_spans": [], "ref_spans": []}, {"section": "Angle of repose and slide", "text": "Angle of repose is the tan inverse of the angle between the height of the powder pile and the radius of the base of the conical pile. The angle of repose of downy rose-myrtle powder was measured using a funnel method. [6] First, a funnel was vertically fixed above the graph paper so that the distance of the paper from the outlet of the funnel (H) was 4 cm. Then, four types of downy rose-myrtle powders were poured into the funnel till the tip of the powder cone touched the outlet of the funnel. The radius (R) of the cone was measured for each type of powder. Results were only considered valid when a symmetrical cone of powder was formed. The angle of repose (\u00b0) was calculated as follows:", "cite_spans": [{"start": 218, "end": 221, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Angle of repose and slide", "text": "The slide angle was determined as previously described. [8] Briefly, 3.0 g powder samples with different sizes were poured on a glass plate with a length (L) of 150 mm and a width of 100 mm. The top of the glass plate was gradually lifted until the surface of the downy rose-myrtle powder began to slide. The vertical distance (H) between the top of the inclined glass plate and the horizontal was estimated to calculate the angle of slide using the following formula:", "cite_spans": [{"start": 56, "end": 59, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Water-holding capacity (WHC)", "text": "WHC represents the ability of a powder to absorb and retain bound, hydrodynamic, capillary, and physically entrapped water against gravity. The WHC of downy rose-myrtle powder was determined as previously described with some modifications. [6] First, 2.0 g powder was weighed in preweighed 50 mL plastic centrifuge tube. Then, the sample was dispersed in 40 mL distilled water and placed in a water bath at 37\u00b0C for 10 min. The mixture was centrifuged at 5000 r/min for 15 min. The supernatant liquid was carefully removed and the centrifuge tubes with the powders were weighed again. WHC (g water/g powder) was calculated as: WHC = total water mass/dry powder mass.", "cite_spans": [{"start": 240, "end": 243, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Water solubility index (WSI)", "text": "This parameter was measured according to the method reported by Zhao et al. with some modifications. [6] 1.000 g (W 1 ) sample was measured and dispersed in tubes with 50 mL of distilled water. The mixture was incubated at 37\u00b0C in a shaking water bath for 30 min at a speed of 100 r/min. Then, the tubes were centrifuged at 5000 r/min for 15 min. The clear supernatant solution was drained off by evaporation, and the samples were dried at 105\u00b0C and weighed (W 2 ). The WSI was calculated as: WSI (%) = W 2 /W 1 \u00d7 100%.", "cite_spans": [{"start": 101, "end": 104, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "In vitro simulated gastrointestinal digestion", "text": "The digestion procedure mimicking the physiological situation of the stomach and small intestine was carried out as previously described with some modifications. [17] 40 mL distilled water was added to 5.0 g downy rose-myrtle powder. To simulate gastric digestion, 60,000 units pepsin (EC 2.4.23.1) was added to the samples, and the pH was adjusted to 2 with 1 M HCl (final incubation volume 50 mL). The mixture was incubated with gently shaking at a 37\u00b0C for 2 h in the absence of light. After post-gastric digestion, aliquots of 10 mL samples were taken and frozen for analysis of anthocyanins and phenolics. The remainder was diluted with 30 mL water adjusted to pH 7.4 with 1 M NaHCO 3 . Then, a stock solution of pancreatin from porcine pancreas (final trypsin activity 100 U/mL) and bile salts containing a mixture of sodium cholate and sodium deoxycholate (final concentration of bile acid 10 mM) were added for a final volume of 80 mL. The resulting mixtures were incubated for an additional 2 h at 37\u00b0C. After pancreatic digestion, the aliquots of the digested samples were rapidly acidified to pH 2.0 and stored at \u221280\u00b0C until use.", "cite_spans": [{"start": 162, "end": 166, "text": "[17]", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Determination of total polyphenols and anthocyanins", "text": "One gram of different sized downy rose-myrtle powders was dispersed in 16 mL of 70% aqueous methanol or the same amount of distilled water and put into centrifuge tubes, placed in a water bath at 37\u00b0C and shaken for 4 h. The extracts were then centrifuged at 5000 g for 10 min, and supernatants were collected. The obtained methanolic and aqueous extracts, as well as supernatants of the gastric and pancreatic digestion samples, were assayed for total polyphenol and anthocyanin content. Results obtained for methanolic extracts were assumed to be 100% of polyphenols or anthocyanins contained in the downy rose-myrtle powders. The bioaccessibility of polyphenols and anthocyanins, defined as the fraction of an external dose released from their matrix in the gastrointestinal tract, [18] was calculated as follows:", "cite_spans": [{"start": 785, "end": 789, "text": "[18]", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "Determination of total polyphenols and anthocyanins", "text": "where AD is the amount of polyphenols or anthocyanins present in the digesta post gastric and pancreatic digestion, and AE is the amount of polyphenols or anthocyanins extracted from downy rose-myrtle powders using methanol as extractant. Total phenolics content was determined by the Folin-Ciocalteu method. [19] An aliquot of 0.5 mL of sample was mixed with 2.5 mL of Folin-Ciocalteu's reagent (FCR; 1:10 dilution), and incubated at 50\u00b0C for 30 min to allow for the FCR to react completely with the oxidizable phenolates. To destroy the residual reagent, 2 mL of Na 2 CO 3 (20% solution in water) was added. The absorbances were measured at 760 nm using a spectrophotometer. Quantification was done using a standard curve of gallic acid and expressed as milligrams of catechin equivalents per 100 g of powder.", "cite_spans": [{"start": 309, "end": 313, "text": "[19]", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Determination of total polyphenols and anthocyanins", "text": "The anthocyanin profiles of nondigested or digested samples were analyzed by a Shimadzu 20A HPLC System equipped with a UV-Vis detector and a Diamonsil C18 column (250 mm \u00d7 4.6 mm; 5 \u03bcm). All samples before injection were passed through a 0.45 \u03bcm filter. The binary mobile phase consisted of water/formic acid (95:5, v/v) (solvent A) and acetonitrile, according to our previous study. [2] The system was run with a flow rate of 1 mL/min and under the following gradient program: 0 min: 85% A + 15% B, 5 min: 75% A + 25% B, 15 min: 65% A + 35% B, 20 min: 55% A + 45% B, and 30 min: 50% A + 50% B. Anthocyanins were detected at 520 nm and their content was expressed as cyanidin 3-glucoside equivalents. [20] ABTS radical cation scavenging activity Experiments were performed according to a procedure described in our previous study. [21] ABTS radical cation was produced by mixing the 7 mM ABTS solution with 2.45 mM potassium persulfate aqueous solution and leaving the mixture to stand for 12-16 h in the dark at room temperature before use. The stock solution was diluted with phosphate buffer to the absorbance of 0.70 \u00b1 0.05 at 734 nm. Each sample solution (0.1 mL) was added to 1.9 mL of diluted ABTS + solution and incubated at 37\u00b0C for 5 min before the absorption was measured at 734 nm. In the blank, 0.1 mL distilled water was used instead of the sample. Trolox (6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxylic acid) was used as a standard and results were expressed in mmol Trolox equivalents (TE)/g of powder.", "cite_spans": [{"start": 385, "end": 388, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 702, "end": 706, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 832, "end": 836, "text": "[21]", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Statistical analyses", "text": "All data are expressed as 'mean \u00b1 standard deviation' from at least three replicates. Statistical comparisons were made using one-way analysis of variance (ANOVA) followed by Tukey-Kramer post hoc test for multiple comparisons. Statistically significant difference was defined as P< .05. All analyses were performed with the Statistical Package for the Social Sciences software (version 19.0, SPSS Inc., Chicago, IL).", "cite_spans": [], "ref_spans": []}, {"section": "Results and discussion", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Micromeritic properties of downy rose-myrtle powder", "text": "The particle size of the superfine downy rose-myrtle powder ranged from 0.79 to 41.57 \u03bcm, with a median particle size of 16.41 \u03bcm ( Table 1 ). The particle size distributions of the coarsely ground powder fractions of CP180, CP120, and CP96 were much wider, ranging from 1.52 to 218.94 \u03bcm, with median particle sizes of 86.93, 73.19 and 46.56 \u03bcm, respectively. In addition, the superfine powder had a significantly narrower particle size distribution (span factor = 2.20) than the coarsely ground downy rose-myrtle powders. Thus, compared to the traditional shear pulverization grinding process, superfine grinding brings much more energy with higher reduction efficiency, making the samples easy to reduce to sub-micron size powders.", "cite_spans": [], "ref_spans": [{"start": 132, "end": 139, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Micromeritic properties of downy rose-myrtle powder", "text": "The specific surface area values of the different particle-sized powders ranged from 1.82 to 3.14 m 2 /g. These parameters varied significantly between the downy rose-myrtle particles with different sizes (P < .05). Furthermore, the specific surface area increased as the particle size decreased. These results indicate that the surface parameters of downy rose-myrtle powders are directly related to the projected size of the corresponding fruit granules. The data are mean \u00b1 standard deviation, n = 3. Values in the same column with different letters are significantly different (P < 0.05).", "cite_spans": [], "ref_spans": []}, {"section": "Morphology of downy rose-myrtle powder", "text": "SEM images at 600 times magnification were obtained for the four downy rose-myrtle powder sizes (Figure 1) , and the SEM results are highly consistent with the particle size analysis data. After superfine grinding, the particle size was significantly reduced and uniformity was greatly improved. Partial aggregation was observed in the superfine downy rose-myrtle powder, which may attribute to its high specific surface area and electrostatic interaction. [22] Color difference of downy rose-myrtle powders", "cite_spans": [{"start": 457, "end": 461, "text": "[22]", "ref_id": "BIBREF21"}], "ref_spans": [{"start": 96, "end": 106, "text": "(Figure 1)", "ref_id": "FIGREF0"}]}, {"section": "Morphology of downy rose-myrtle powder", "text": "In addition to particle size, color is an important quality character for food powders. A previous study by Hu et al. indicated that particle size has a significant effect on the color characteristics of green tea powder. [10] The effect of superfine grinding on the color properties of downy rose-myrtle powder is shown in Table 1 . The results show that the values of lightness, redness, and yellowness of the superfine ground powder were significantly higher than those of CP180 and CP120 (P < 0.05). Thus, superfine grinding can yield downy rose-myrtle powders with bright red and yellow colors.", "cite_spans": [{"start": 222, "end": 226, "text": "[10]", "ref_id": "BIBREF9"}], "ref_spans": [{"start": 324, "end": 331, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Basic physical properties of downy rose-myrtle powder", "text": "We next characterized some physical properties of downy rose-myrtle powder with different sizes ( Table 2 ). The bulk density of the superfine ground powder was significantly lower than that of the other powders (P < 0.05). This suggests that the superfine ground power has larger interparticle voids, which would offer a larger contact surface with the surroundings. Bulk density can also help determine whether a raw material should be mixed or a final product is packed in a predetermined container. As with other powders of the same weight, the finer downy rose-myrtle powder should be packed in a relatively large container.", "cite_spans": [], "ref_spans": [{"start": 98, "end": 105, "text": "Table 2", "ref_id": "TABREF2"}]}, {"section": "Basic physical properties of downy rose-myrtle powder", "text": "The change in the fluidity of the downy rose-myrtle powder can be shown through the angles of repose and slide, which were found to increase dramatically with a decreasing particle size ( Table 2 ). The superfine powder displayed the highest repose and slide angles. As the angle of repose and slide increased, the fluidity of the particle worsened. This result is inconsistent with the results of super finely ground ginger and pomegranate peel powders. [6, 8] However, Zhao et al. showed that the fluidity of red grape pomace powders increased with increasing particle size. [7] Similarly, this could be explained by the fact that the finer downy rose-myrtle powder is easily agglomerated due to its oil content or absorbance of water from the air. The aggregates tended to arrange in a cone with an angle that was much higher than expected. As a result, the fluidity of the finer powder decreased.", "cite_spans": [{"start": 455, "end": 458, "text": "[6,", "ref_id": "BIBREF5"}, {"start": 459, "end": 461, "text": "8]", "ref_id": "BIBREF7"}, {"start": 577, "end": 580, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": [{"start": 188, "end": 195, "text": "Table 2", "ref_id": "TABREF2"}]}, {"section": "Basic physical properties of downy rose-myrtle powder", "text": "The different particle-sized powders had different WHC and WSI. Compared with the coarse downy rose-myrtle particles, the superfine powder possessed higher WHC and WSI ( Table 2) . This may be due to improved surface properties of the superfine powders, such as an increase in surface area and surface energy. [9] In addition, the hydrophilic groups in the cellulose and hemicellulose of the downy rose-myrtle may have been exposed, resulting in easy integration with water and ultimately increasing the WHC and WSI values. The results indicate that the finer downy rose-myrtle powder could be dispersed better in water than coarser particles and may increase the solubility of water-soluble ingredients. The dispersibility and dissolution of the superfine powder were exceptional and the functional components increased after superfine grinding, which could be applied in food processing as a new value-added product with healthpromoting benefits.", "cite_spans": [{"start": 310, "end": 313, "text": "[9]", "ref_id": "BIBREF8"}], "ref_spans": [{"start": 170, "end": 178, "text": "Table 2)", "ref_id": "TABREF2"}]}, {"section": "Release of polyphenols and anthocyanins from downy rose-myrtle powder before and after gastrointestinal digestion", "text": "Absorption of phenolic compounds is dependent on release from the food matrix. [23] To understand the potential bioaccessibility of phenolic compounds in downy rose-myrtle powder after digestion, the release of polyphenols (Table 3 ) and anthocyanins ( The data are mean \u00b1 standard deviation, n = 3. Values in the same column with different letters are significantly different (P < 0.05). WHC, water-holding capacity; WSI, water solubility index. The data are mean \u00b1 standard deviation, n = 3. Values in the same column with different letters are significantly different (P < 0.05). GAE = gallic acid equivalents.", "cite_spans": [{"start": 79, "end": 83, "text": "[23]", "ref_id": "BIBREF22"}], "ref_spans": [{"start": 223, "end": 231, "text": "(Table 3", "ref_id": "TABREF3"}]}, {"section": "Release of polyphenols and anthocyanins from downy rose-myrtle powder before and after gastrointestinal digestion", "text": "anthocyanins can both be extracted efficiently using methanol, so the amounts of polyphenols and anthocyanins extracted by methanol were considered to be 100%. [13] Aqueous extracts were also measured to assess the bioaccessibility of these phytochemicals in the digestive system. In the nondigested aqueous extracts of the coarse powders, the polyphenol content varied from 514 \u00b1 16 to 570 \u00b1 12 mg GAE/100 g, while in the superfine powder, the polyphenol content significantly increased to 662 \u00b1 21 mg GAE/100 g. Similarly, the amount of anthocyanins released from the coarse powders was lower than that released from the superfine powders. After gastric digestion, both the released polyphenol and anthocyanin content increased markedly, which is consistent with previous studies. [13, 24] During the gastric phase, pepsin digestion and low pH favored the inseparable phenolic compounds, which could be released by diffusion from the food matrix to the aqueous phase due to reduced ionic interactions. Compare with polyphenols release after gastric digestion, pancreatic treatment of the coarse powders significantly enhanced the amounts of polyphenols released, but this parameter of the superfine powder was unchanged (Table 3 ). However, transition of samples from the acidic gastric (pH 2.0) to the mild alkaline intestinal environment (pH 7.4) caused a slight decrease in the amounts of anthocyanins relative to the initial samples ( Table 4 ). The phenolic compounds of the downy rose-myrtle powders were found to be more stable to gastrointestinal digestion than anthocyanin, and losses were greater during pancreatic digestion than gastric digestion. Losses of anthocyanins during pancreatic digestion were likely due to an increase in pH. [25] Overall, we found that the bioaccessibility of either polyphenols or anthocyanins bioaccessibility of the superfine powder was higher than that of the other powders (all P < 0.05; Figure 2 ). The data are mean \u00b1 standard deviation, n = 3. Values in the same column with different letters are significantly different (P < 0.05). CGE = cyanidin 3-glucoside equivalent. ", "cite_spans": [{"start": 160, "end": 164, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 783, "end": 787, "text": "[13,", "ref_id": "BIBREF12"}, {"start": 788, "end": 791, "text": "24]", "ref_id": "BIBREF23"}, {"start": 1750, "end": 1754, "text": "[25]", "ref_id": "BIBREF24"}], "ref_spans": [{"start": 1222, "end": 1230, "text": "(Table 3", "ref_id": "TABREF3"}, {"start": 1441, "end": 1448, "text": "Table 4", "ref_id": "TABREF1"}, {"start": 1935, "end": 1943, "text": "Figure 2", "ref_id": "FIGREF1"}]}, {"section": "Influence of in vitro digestion on antioxidant capacity", "text": "The health benefits of downy rose-myrtle berries are partly attributed to their antioxidant activity. The antioxidant capacities of the initial and digested samples were evaluated with the ABTS free radical scavenging method, which is widely used to evaluate the free radical scavenging capacities of natural compounds. The radical scavenging activities of the aqueous downy rose-myrtle powder extract were found to be significantly lower than those of the methanolic extract ( Figure 3 ). Among all tested aqueous extracts, the superfine powder extract exhibited the strongest ABTS free radical scavenging activity, while the crude powder extract with the largest particle size showed the lowest antiradical activity. After the gastric phase of digestion, although there was no change in the order of the activities, the activities of all powder digesta significantly increased. After the intestinal phase of digestion, the antiradical activities of the crude powder samples were further increased, while those of the superfine powder remained unchanged. Interestingly, a high positive correlation was also observed between the antiradical activity and the total polyphenolic content (r = 0.9316, P < 0.01) or the total anthocyanin content (r = 0.8956, P < 0.01) of the downy rose-myrtle powder extracts. A possible explanation for this is that anthocyanins and phenolic compounds may directly contribute to the antioxidant capacity of the digestion samples. [26] ", "cite_spans": [{"start": 1460, "end": 1464, "text": "[26]", "ref_id": "BIBREF25"}], "ref_spans": [{"start": 478, "end": 486, "text": "Figure 3", "ref_id": "FIGREF2"}]}, {"section": "Conclusion", "text": "Our research dried and ground downy rose-myrtle berries into superfine powder form with a median particle size of 16.41 \u03bcm. Compare with coarsely ground powders, the superfine powders have many significant characteristics including narrow and uniform particle size distribution, strong specific surface energy, remarkable dispersibility and solubility, polyphenol and anthocyanin bioaccessibility, and ABTS radical scavenging activity. These findings indicate that superfine grinding has a great potential to improve the physicochemical and functional properties of downy rose-myrtle powders, which is helpful to promote the overall quality and healthy effect of foods containing downy rose-myrtle powders. ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF1": {"title": "Optimization of the Extraction of Anthocyanins from the Fruit Skin of Rhodomyrtus Tomentosa (Ait.) Hassk and Identification of Anthocyanins in the Extract Using High-performance Liquid Chromatography-electrospray Ionization-mass Spectrometry (HPLC-ESI-MS)", "authors": [{"first": "G", "middle": [], "last": "Liu", "suffix": ""}, {"first": "H", "middle": [], "last": "Guo", "suffix": ""}, {"first": "Y", "middle": [], "last": "Sun", "suffix": ""}], "year": 2012, "venue": "Int. J. Mol. 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Values in the same group with different letters are significantly different (P < .05).", "type": "figure"}, "FIGREF2": {"text": "Evaluation of the antioxidant capacities of extracts from downy rose-myrtle powders as determined by ABTS radical scavenging effect. Values in the same group with different letters are significantly different (P < .05).", "type": "figure"}, "TABREF0": {"text": "Micromeritic and color properties of downy rose-myrtle powder. Superfine 0.79 \u00b1 0.10 c 16.41 \u00b1 0.23 d 41.57 \u00b1 0.25 d 2.20 \u00b1 0.03 c 3.14 \u00b1 0.02 d 49.54 \u00b1 2.71 c 18.99 \u00b1 0.66 b 6.28 \u00b1 1.26 c", "type": "table"}, "TABREF1": {"text": "was measured. Polyphenols and", "type": "table"}, "TABREF2": {"text": "Physical properties of downy rose-myrtle powder.", "type": "table"}, "TABREF3": {"text": "The release of polyphenols (mg GAE/100 g powder) from downy rose-myrtle powders before and after in vitro gastrointestinal digestion.", "type": "table"}, "TABREF4": {"text": "The release of anthocyanins (mg CGE/100 g powder) from downy rose-myrtle powders before and after in vitro gastrointestinal digestion.", "type": "table"}}}
{"paper_id": "213461798", "_pdf_hash": "58404977c47830b861edaae9e79ccf3588b042e3", "abstract": [{"section": "Abstract", "text": "OBJECTIVE: This longitudinal study investigated psychosocial mediators in the association between minority sexual orientation (e.g., identifying as lesbian, gay, or bisexual) and depressive symptoms in young people. METHOD: Data from the Avon Longitudinal Study of Parents and Children (ALSPAC) UK birth cohort were analyzed. Sexual orientation was assessed at 15 years and depressive symptoms were assessed at 18 years. Mediators were assessed at 17 years: unhelpful assumptions (i.e., dysfunctional attitudes about the self and others), hypothesized to be vulnerability factors in cognitive theories of depression; selfesteem; and family relationships measured with four items. Multiple mediation analysis of 14,814 individuals utilized structural equation models estimated via full information maximum likelihood, with family relationships entered as a latent variable. Sex at birth was examined as a moderator. RESULTS: Sexual minority youth had higher risk for depressive", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "symptoms at 18 years than heterosexual youth. They also had poorer relationships with their family and more unhelpful assumptions, with weaker evidence for lower self-esteem, especially those who were male sex at birth. Poorer family relationships and unhelpful assumptions mediated the relation between sexual minority status and depressive symptoms, with weaker evidence for self-esteem as a mediator. There was no evidence to suggest that sex at birth moderated these relations. CONCLUSIONS: Poorer family relationships, more unhelpful self-beliefs, and possibly lower self-esteem may contribute to sexual orientation disparities in depressive symptoms, indicating possible areas for prevention and intervention.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "more profound in girls. More evidence of the importance of family relationships as a mediator was provided by a longitudinal study of adolescents that demonstrated that selfreports of family satisfaction at 17 years mediated the relation between sexual orientation reported at 17 years and depressive symptoms in later adolescence and early adulthood (Luk, Gilman, Haynie, & Simons-Morton, 2018) . Similarly, Rosario et al. (2014) demonstrated that less secure attachments attenuated the relation between sexual orientation and depressive symptoms in a longitudinal sample of young adults. Such findings are consistent with evidence from cross-sectional studies of young adults (Needham & Austin, 2010; Ueno, 2010) .", "cite_spans": [{"start": 351, "end": 395, "text": "(Luk, Gilman, Haynie, & Simons-Morton, 2018)", "ref_id": "BIBREF31"}, {"start": 678, "end": 702, "text": "(Needham & Austin, 2010;", "ref_id": "BIBREF40"}, {"start": 703, "end": 714, "text": "Ueno, 2010)", "ref_id": "BIBREF58"}], "ref_spans": []}, {"section": "Cognitive Vulnerabilities", "text": "According to the psychological mediation model (Hatzenbuehler, 2009) , sexual minority individuals are more susceptible to developing cognitive vulnerability factors for depression due to their stigma experiences. Beck and colleagues' (1979) work on depression suggests that key cognitive vulnerability factors for depression include certain types of cognitive structures or underlying beliefs. Such beliefs contain unhelpful attitudes towards themselves, others, and the future (e.g., \"I should be always happy\"; \"If I make a mistake then I'm a failure.\") These depressogenic attitudes typically involve negative beliefs about the self or others that are excessive and rigid. Beck suggests that when they are activated, such underlying attitudes result in more \"negative automatic thoughts\" that contribute to depressed mood. Research has demonstrated their predictive role in the onset and maintenance of depression (e.g., Alloy et al., 2006) .", "cite_spans": [{"start": 47, "end": 68, "text": "(Hatzenbuehler, 2009)", "ref_id": "BIBREF23"}, {"start": 925, "end": 944, "text": "Alloy et al., 2006)", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Cognitive Vulnerabilities", "text": "There has been limited research exploring whether there are disparities between different sexual orientations in cognitive vulnerabilities and whether such disparities may help explain the increased rates of depression in sexual minority individuals. Kirsch, Conley, and Riley (2015) found the sexual minority individuals had higher scores on a composite measure of cognitive vulnerabilities, that included unhelpful assumptions, suppression, and avoidant coping. Hart et al. (2017) found that unhelpful attitudes and negative automatic thoughts mediated the relation between adverse childhood experiences and depression outcomes in gay and bisexual men. Their results suggested that the role of these general cognitive factors as mediators was stronger than internalized homophobia, a sexual minorityspecific vulnerability.", "cite_spans": [{"start": 464, "end": 482, "text": "Hart et al. (2017)", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "Self-Esteem", "text": "Another psychological process hypothesized by Hatzenbuehler (2009) to be related to sexual orientation disparities in mental illness is self-esteem. Self-esteem has been shown to be a risk factor for the development of depression in prospective general population studies (Sowislo & Orth, 2013) and there is evidence that sexual minority adolescents and young adults have lower self-esteem than heterosexuals (e.g., Jager & Davis-Kean, 2011) . Crosssectional mediation studies have suggested that self-esteem may mediate the association between sexual orientation and depression. Martin-Storey and Crosnoe (2012) for example, found that poorer self-concept (a construct very closely related to self-esteem; Baumeister, 1997 ) was a significant mediator of the association between sexual orientation and depression. Similarly, Ueno (2010) showed evidence that controlling for self-esteem, along with mastery and a sense of mattering, attenuated the association between same-sex contact and depressive symptoms. To our knowledge, no prospective studies have examined selfesteem as a mediator in a between-group study.", "cite_spans": [{"start": 46, "end": 66, "text": "Hatzenbuehler (2009)", "ref_id": "BIBREF23"}, {"start": 272, "end": 294, "text": "(Sowislo & Orth, 2013)", "ref_id": "BIBREF54"}, {"start": 416, "end": 441, "text": "Jager & Davis-Kean, 2011)", "ref_id": "BIBREF27"}, {"start": 707, "end": 723, "text": "Baumeister, 1997", "ref_id": "BIBREF10"}, {"start": 826, "end": 837, "text": "Ueno (2010)", "ref_id": "BIBREF58"}], "ref_spans": []}, {"section": "Limitations of Previous Studies", "text": "A mediation hypothesis implies a causal chain of events in which the independent variable causes change in the mediator, which in turn causes change in the dependent variable. Therefore, longitudinal studies in which the independent variable, mediator, and dependent variable are measured at three consecutive timepoints allow time for causal effects to manifest themselves and ensure that presumed causes precede effects. Consequently, they are considered to be more appropriate in the context of mediation compared to cross-sectional studies. Existing studies examining mediators of the disparities in depression between sexual minority and heterosexual individuals are largely based on cross-sectional data which do not fully support causal inferences about mediators (Cole & Maxwell, 2003; Goldsmith et al., 2017) . Even the studies in the literature that had longitudinal designs either measured sexual minority status and mediators at time 1 and depression at time 2, or sexual minority status at time 1 and mediators and depression at time 2. Moreover, many studies used retrospective accounts to assess mediators (e.g., family relationships) which can suffer from recall biases.", "cite_spans": [{"start": 794, "end": 817, "text": "Goldsmith et al., 2017)", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Limitations of Previous Studies", "text": "Another limitation of previous studies is that they have often failed to examine the possible moderating effect of sex when investigating mediational pathways. It is welldocumented that women report higher depression (e.g., Salk, Petersen, Abramson, & Hyde, 2016 ) and lower self-esteem (e.g., Bleidorn et al., 2016) than men and that such differences are present as early as in adolescence. Both biologically-based and psychologically-based explanations for the emergence of greater rates of depression in women after puberty have been proposed, such as genetic factors, ovarian and adrenal hormonal changes at puberty, gender intensification and adherence to traditional gender roles, greater female exposure to negative life experiences of rape and child sexual abuse, female body dissatisfaction, greater cognitive vulnerability in women, female reliance on relationships, and greater ruminative coping (Hyde, Mezulis, & Abramson, 2008) . Moreover, there is some evidence that potential mediating factors between minority sexual orientation and increased depression may be different for boys than for girls (e.g., la Roi et al., 2016) . Given the potential differences in the mediators, outcome, and mediation relations among males and females, sex differences should be investigated in mediational studies in this area.", "cite_spans": [{"start": 224, "end": 262, "text": "Salk, Petersen, Abramson, & Hyde, 2016", "ref_id": "BIBREF48"}, {"start": 294, "end": 316, "text": "Bleidorn et al., 2016)", "ref_id": "BIBREF12"}, {"start": 907, "end": 940, "text": "(Hyde, Mezulis, & Abramson, 2008)", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "The Current Study", "text": "A better understanding of the intermediate factors contributing to increased depression symptom rates in sexual minority individuals would be instrumental in designing and refining effective prevention, early intervention, and therapeutic programs for sexual minority youth. Research with general population samples has demonstrated the effectiveness of cognitive-behavioral interventions (CBT) in modifying unhelpful rules about the self or others (Sankar et al., 2015) and self-esteem (Taylor & Montgomery, 2007) , whilst family therapy and community approaches are often used to help improve family relationships.", "cite_spans": [{"start": 487, "end": 514, "text": "(Taylor & Montgomery, 2007)", "ref_id": "BIBREF55"}], "ref_spans": []}, {"section": "The Current Study", "text": "Establishing the importance of these factors for sexual minority youth could lead to improved evidence-based and targeted intervention approaches for sexual minority youth.", "cite_spans": [], "ref_spans": []}, {"section": "The Current Study", "text": "The present study used existing data from the UK Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort to investigate disparities in depression between sexual minority young people and heterosexual participants while examining psychosocial factors that mediate them. To do so, temporally ordered data were used with sexual minority status measured at age 15, mediators measured at age 17, and depressive symptoms measured at age 18. Structural equation modelling (SEM) was used to assess the extent to which sexual minority status was related to increased depressive symptoms via family relationships, unhelpful assumptions, and self-esteem. The moderating effect of sex (male/female) at birth on these pathways was also tested. Gender identity had not been assessed in this birth cohort study therefore the terms male sex at birth (MSAB) and female sex at birth (FSAB) are used to refer to sex as reported by mothers at birth.", "cite_spans": [], "ref_spans": []}, {"section": "Method", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Participants", "text": "The sample comprised participants from ALSPAC, an observational cohort prospective study Fraser et al., 2013) . The study invited all pregnant women who were expected to give birth between April 1, 1991 and December 31, 1992 in Avon, UK, to enroll, resulting in a cohort of 14,541 pregnancies. Of these pregnancies, there was a total of 14,676 fetuses, resulting in 14,062 live births and 13,988 children alive at age one. The sample was increased by an additional 713 children during a second and third enrollment phase when the children were seven years old by sending invites to eligible families that had not previously responded. The total sample size following Phases II and III of enrollment was therefore 15,247 pregnancies, resulting in 15,458 fetuses. Of this sample, 14,775 were live births and 14,701 were alive at age one. Compared with the 1991 UK Census data, the ALSPAC sample is slightly more affluent and more likely to be white. Data collection included self-report questionnaires by the young person or their carer and direct assessment at clinics. The study website contains details of all the data that is available through a fully searchable data dictionary and variable search tool (http://www.bris.ac.uk/alspac/researchers/dataaccess/data-dictionary/). Ethical approval for the study was obtained from the ALSPAC Ethics and Law Committee and the Local Research Ethics Committees. Ethical approval for the analysis of secondary data for this study was obtained from [removed for blinding].", "cite_spans": [{"start": 89, "end": 109, "text": "Fraser et al., 2013)", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "Measures", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Sexual orientation.", "text": "At age 15 (in 2006-2007) , adolescents were asked to choose the \"description that best fits how you think about yourself\" with seven response options provided regarding sexual orientation. A total of 5154 participants responded to this item. Responses were: \"100% heterosexual\" (n = 4470), \"mostly heterosexual\" (n = 441), \"bisexual\" (n = 86), \"mostly homosexual\" (n = 27), \"100% homosexual\" (n = 20), \"not sure\" (n = 93), or \"not attracted to either sex\" (n = 17). Participants who responded either \"not sure\" or \"not attracted to either sex\" were excluded from the analyses. Due to small subgroup sizes, and in line with previous studies using the ALSPAC cohort (Jones, Robinson, Oginni, Rahman, & Rimes, 2017; Oginni, Robinson, Jones, Rahman, & Rimes, 2018; Pesola, Shelton, & van de Bree, 2014) \"mostly heterosexual,\" \"bisexual,\" and \"mostly homosexual\" responses were combined to define the sexual minority group (n = 574) whilst the \"100% heterosexual\" responses defined the heterosexual group (n = 4470).", "cite_spans": [{"start": 664, "end": 712, "text": "(Jones, Robinson, Oginni, Rahman, & Rimes, 2017;", "ref_id": "BIBREF28"}, {"start": 713, "end": 760, "text": "Oginni, Robinson, Jones, Rahman, & Rimes, 2018;", "ref_id": "BIBREF41"}], "ref_spans": []}, {"section": "Depression.", "text": "Depressive symptoms were measured using the Short Mood and Feelings Questionnaire (SMFQ; Angold et al., 1995) administered to young people at the clinic at 13 (in 2004-2005) and 18 years (in 2009-2010) . The self-report measure consists of 13 statements, each of which can be rated as \"not true,\" \"sometimes true,\" or \"true.\" The total scores range from 0 to 26, with higher scores indicating higher depressive symptoms. The SMFQ was demonstrated to have high validity (Turner, Joinson, Peters, Wiles, & Lewis, 2014) . Internal consistency in the current study was very good (\u03b1 = 0.91).", "cite_spans": [{"start": 89, "end": 109, "text": "Angold et al., 1995)", "ref_id": "BIBREF5"}, {"start": 469, "end": 516, "text": "(Turner, Joinson, Peters, Wiles, & Lewis, 2014)", "ref_id": "BIBREF57"}], "ref_spans": []}, {"section": "Family relationships.", "text": "Family relationships were assessed with a latent factor that was measured by the following four items that participants completed at age 17 years (in 2008-2009): (1) \"How close do you feel to your parents\"; (2) \"How close do you feel to your siblings?\"; (3) \"How easy do you find it to discuss your problems with anyone in your family?\"; and (4) \"How well have you been getting along with your family in the past few months?\". Responses were rated on Likert scales ranging from 1 (very close to at least one) to 4 (not close at all to any) for items 1 and 2, from 1 (very easy) to 5 (very difficult) for item 3, and from 1 (very close) to 5 (not close at all) for item 4.", "cite_spans": [], "ref_spans": []}, {"section": "Unhelpful assumptions.", "text": "Unhelpful assumptions were assessed at 17 years with an abbreviated nine-item version of the Dysfunctional Attitudes Scale derived from a factor analysis (Andrews, Lewinsohn, Hops, & Roberts, 1993) . The Dysfunctional Attitudes Scale (DAS; Weissman, 1979 ) is a self-report scale assessing rigid, negative, and perfectionist attitudes and unhelpful contingencies for self-evaluation that were proposed by Beck, Rush, Shaw, & Emery (1979) to be vulnerability factors for depression. An example item in this version of the questionnaire is \"My life is wasted unless I am a success.\" Respondents rated their agreement to each of the nine statements on a five-point Likert scale. Scores ranged from 9 to 45, and in the ALSPAC dataset scoring was conducted so that lower scores reflected more unhelpful assumptions. Both the original DAS and the abbreviated version used here have been reported to have good reliability and validity (Andrews et al., 1993; de Graad, Roelofs, & Huibers, 2009) . Internal consistency in the present sample was good (\u03b1 = 0.80).", "cite_spans": [{"start": 154, "end": 197, "text": "(Andrews, Lewinsohn, Hops, & Roberts, 1993)", "ref_id": "BIBREF4"}, {"start": 240, "end": 254, "text": "Weissman, 1979", "ref_id": "BIBREF60"}, {"start": 405, "end": 437, "text": "Beck, Rush, Shaw, & Emery (1979)", "ref_id": "BIBREF11"}, {"start": 928, "end": 950, "text": "(Andrews et al., 1993;", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Self-esteem.", "text": "Self-esteem was measured with the Bachman revision (1970) of the Rosenberg Self-Esteem Scale (1965) at 17 years (RSE-B). The measure consists of 10 statements, which can be rated on a scale from 1 (almost always true) to 5 (never true). The total scores range from 0 to 40, and higher scores indicate higher self-esteem. Good construct validity has been reported for the measure (Bachman & O'Malley, 1977) and internal consistency was very good in the present sample (\u03b1 = 0.89).", "cite_spans": [{"start": 379, "end": 405, "text": "(Bachman & O'Malley, 1977)", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Potential confounders.", "text": "The original model was adjusted for a number of confounding variables and an earlier measure of the outcome variable:", "cite_spans": [], "ref_spans": []}, {"section": "Potential confounders.", "text": "Earlier depressive symptoms. Following recent recommendations (Dunn, Emsley, Liu, Landau, 2013; Landau, Emsley, & Dunn, 2018; Pickles et al., 2015) , baseline measures of the outcome variable were adjusted for in the model using the SMFQ measure assessed at 13 years.", "cite_spans": [], "ref_spans": []}, {"section": "Potential confounders.", "text": "Socioeconomic status. Maternal occupation and maternal education were used as socioeconomic status indicators. Maternal occupation information was collected from mothers at 18 weeks of pregnancy and was dichotomized into \"non-manual\" and \"manual\" work (Dale & Marsh, 1993) . Maternal education information was collected from mothers at 32 weeks of pregnancy and was categorized into \"below O-level,\" \"O-level,\" and \"above Olevel\" (O-levels are school tests previously taken at age 16 in the UK).", "cite_spans": [], "ref_spans": []}, {"section": "Potential confounders.", "text": "Race. Participants' ethnic group was derived from mothers' reports of their ethnic group and that of the children's fathers' ethnic group, taken during pregnancy, as adolescents were not asked about their self-identified race or ethnicity. Race was coded dichotomously in the ALSPAC data (white / non-white). Child race was coded as non-white if either mother or partner race was reported as anything other than white.", "cite_spans": [], "ref_spans": []}, {"section": "Potential confounders.", "text": "Sex at birth. Sex of the child was reported by the mother or healthcare provider at birth. For the main SEM analyses sex at birth was entered as a confounding variable, whilst it was used as a moderator in supplementary analyses to examine \u03b1 paths, b paths, and indirect effects separately by sex at birth and to test for possible sex at birth differences in the indirect effects. Data on gender identity was not available and therefore could not be used in the analysis.", "cite_spans": [], "ref_spans": []}, {"section": "Statistical Analyses", "text": "Preliminary analyses were conducted in SPSS using Pearson's chi-squared tests and ttests to compare heterosexual participants and sexual minority participants on all variables.", "cite_spans": [], "ref_spans": []}, {"section": "Statistical Analyses", "text": "Intercorrelations were assessed using Pearson's correlation coefficients. The descriptive statistics, correlations, chi-squares, and t-tests are based on complete cases. Main analyses were conducted using MPlus Version 8 (Muth\u00e9n & Muth\u00e9n, 2017) .", "cite_spans": [{"start": 221, "end": 244, "text": "(Muth\u00e9n & Muth\u00e9n, 2017)", "ref_id": "BIBREF39"}], "ref_spans": []}, {"section": "Missing data.", "text": "Large longitudinal studies like ALSPAC generally suffer from significant attrition and hence missing follow-up data. Listwise deletion analyses of such data would result in diminished statistical power and may give biased results if data are not missing completely at random (MacKinnon, 2008) . In the ALSPAC data it is known that factors such as household income and being male predict missingness . For the present study, Full Information Maximum Likelihood (FIML) was used as it is often used to deal with missing data in large datasets (Enders & Bandalos, 2001) and has been used in other ALSPAC studies (Li, Kung, & Hines, 2017) . FIML assumes the data are missing at random (MAR) (Enders & Bandalos, 2001; Rubin, 1976) . FIML was implemented here by conditioning on the covariates, including confounders.", "cite_spans": [{"start": 275, "end": 292, "text": "(MacKinnon, 2008)", "ref_id": "BIBREF33"}, {"start": 540, "end": 565, "text": "(Enders & Bandalos, 2001)", "ref_id": "BIBREF15"}, {"start": 608, "end": 633, "text": "(Li, Kung, & Hines, 2017)", "ref_id": "BIBREF29"}, {"start": 686, "end": 711, "text": "(Enders & Bandalos, 2001;", "ref_id": "BIBREF15"}, {"start": 712, "end": 724, "text": "Rubin, 1976)", "ref_id": "BIBREF47"}], "ref_spans": []}, {"section": "Missing data.", "text": "Multiple Imputation (Rezvan, Lee, & Simpson) was also implemented as an alternative method. This was not presented as the main analysis because percentile bootstrap confidence intervals and multiple group analysis by sex at birth were not available for multiple imputation in MPlus. Information on the missing data model and results based on analyses ran after MI can be found in Supplemental Materials.", "cite_spans": [], "ref_spans": []}, {"section": "Missing data.", "text": "Cases that had missing data on all the model variables were excluded (n = 521). The final sample used for both types of missing data analyses was n = 14,814.", "cite_spans": [], "ref_spans": []}, {"section": "SEM Analyses.", "text": "The SEM framework allows for fitting multiple regression equations simultaneously.", "cite_spans": [], "ref_spans": []}, {"section": "SEM Analyses.", "text": "The mediation hypotheses in this study were assessed using SEM with the three mediators (family relationships, unhelpful assumptions, and self-esteem) examined in parallel. Family was entered as a latent variable. The model was used to test the hypothesis that on average sexual minority adolescents exhibit poorer relationships with their family, higher unhelpful assumptions, and lower self-esteem (a paths) which may lead to depressed symptoms (b paths).", "cite_spans": [], "ref_spans": []}, {"section": "SEM Analyses.", "text": "The strength of the effects of sexual orientation via each of the mediators on depressed symptoms was estimated by calculating the specific indirect effect of interest. The indirect effects were calculated using SEM path tracing rules, which is sometimes referred to specifically in the mediation context as the product of coefficients method (a path \uf0b4 b path) (MacKinnon, 2001 (MacKinnon, , 2008 Wright, 1921) . The total indirect effect was calculated as the sum of the three specific indirect effects. Note that the b paths in the model are each adjusted for the other mediators, as would occur in any regression model. As recommended, 95% percentile bootstrap confidence intervals were estimated for indirect effects (Fritz, Taylor, & MacKinnon, 2012) , using 1,000 repetitions.", "cite_spans": [{"start": 361, "end": 377, "text": "(MacKinnon, 2001", "ref_id": "BIBREF32"}, {"start": 378, "end": 396, "text": "(MacKinnon, , 2008", "ref_id": "BIBREF33"}, {"start": 397, "end": 410, "text": "Wright, 1921)", "ref_id": "BIBREF63"}, {"start": 721, "end": 755, "text": "(Fritz, Taylor, & MacKinnon, 2012)", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "SEM Analyses.", "text": "Model fit was assessed using the Root Mean Square Error of Approximation (RMSEA), the Comparative Fit Index (CFI), and the Standardized Root Mean Square Residual (SRMSR) as recommended for SEM (Hooper, Coughlan, & Mullen, 2008) .", "cite_spans": [{"start": 193, "end": 227, "text": "(Hooper, Coughlan, & Mullen, 2008)", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "SEM Analyses.", "text": "To investigate whether there was differential mediation between MSAB and FSAB participants, a multiple-group analysis of the mediated model was also conducted. This assesses evidence for sex at birth -specific direct, indirect, and total effects. The differences between the indirect effects of the two groups were compared in model constraint statements in MPlus, to examine the presence of moderated mediation. The multiple group analysis for sex at birth was conducted using FIML with bootstrapped confidence intervals.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Descriptive Statistics and Preliminary Results", "text": "The demographic characteristics of heterosexual and sexual minority groups are listed in Table 1 and their scores on the rest of the variables in the hypothesized model are presented in Table 2 , with the results of chi-square or t-test comparisons. Intercorrelations between variables can be found in Supplemental Materials. As can be seen in Table 2 , sexual minority young people reported poorer family relationships, more unhelpful beliefs, lower self-esteem, and higher depression symptoms at both 13 and 18 years compared to heterosexuals.", "cite_spans": [], "ref_spans": [{"start": 89, "end": 96, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "SEM Analyses", "text": "The confirmatory factor analysis showed that the measurement model fit the data adequately [CFI = .987; RMSEA = 0.076, (90% CI: 0.058, 0.095), SRMR = .017]. In this model, the factor loadings for the four observed family relationships items were statistically significant at p < .001 (Item 1 = 0.736, Item 2 = 0.464, Item 3 = 0.676, Item 4 = 0.726). As the results of the model indicated that the observed items were adequate indicators of their corresponding latent construct, structural models were fitted.", "cite_spans": [], "ref_spans": []}, {"section": "SEM Analyses", "text": "The fit indices for the hypothesized model were mostly adequate [CFI = 0.87, RMSEA = 0.041, (90% CI: 0.039, 0.043), SRMR = 0.06]. According to Hu and Bentler's (1999) recommended cut-off guidelines, the RMSEA (recommended cut-off < .06) and the SRMR indexes (recommended cut-off < .08) suggested good fit whilst the CFI index (recommended cut-off > .95) cast some doubt on the adequacy of the model.", "cite_spans": [{"start": 143, "end": 166, "text": "Hu and Bentler's (1999)", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "SEM Analyses", "text": "The unstandardized estimates, bootstrapped standard errors, p-values, and CIs of all the a paths, b paths, indirect, and total effects are summarized in Table 3 and Figure 1 .", "cite_spans": [], "ref_spans": []}, {"section": "SEM Analyses", "text": "Sexual minority status was associated with depressive symptoms (\u03b2 = 1.07, 95% CI: 0.26, 1.86). Sexual minority status was associated with poorer family relationships (\u03b2 = 0.17, 95% CI: 0.08, 0.25) and unhelpful assumptions (\u03b2 = -0.89, 95% CI: -1.61, -0.18), but for selfesteem evidence for an association was weak (\u03b2 = -0.70, 95% CI: -1.49, 0.05); (a paths).", "cite_spans": [], "ref_spans": []}, {"section": "SEM Analyses", "text": "Poorer family relationships (\u03b2 = 0.81, 95% CI: 0.34, 1.36), unhelpful assumptions (\u03b2 = -0.11, 95% CI: -0.16, -0.07), and lower self-esteem (\u03b2 = -0.28, 95% CI: -0.32, -0.24) at 17 years were all associated with more depressive symptoms at 18 years (b paths). Evidence was found for specific indirect paths from sexual minority status to depressive symptoms via poorer family relationships (\u03b2 = 0.13, 95% CI: 0.04, 0.26) and more unhelpful assumptions (\u03b2 = 0.10, 95% CI: 0.02, 0.17). Suggestive evidence for an indirect path via lower self-esteem was also found (\u03b2 = 0.20, 95% CI: -0.01, 0.42). Combined, there was evidence for a total indirect path from sexual minority status to depressive symptoms via all the mediators in the model (\u03b2 = 0.43, 95% CI: 0.12, 0.75).", "cite_spans": [], "ref_spans": []}, {"section": "Estimates by Sex at Birth", "text": "Evidence of an association between sexual minority status and poorer family relationships was found for both MSAB (\u03b2 = 0.17, 95% CI: 0.05, 0.30) and FSAB participants (\u03b2 = 0.17, 95% CI: 0.05, 0.28). Sexual minority status was associated with unhelpful assumptions in MSAB participants (\u03b2 = -1.35, 95% CI: -2.32, -0.33) but there was no such evidence for FSAB participants (\u03b2 = -0.72, 95% CI: -1.56, 0.18). Although there was weak evidence for an association between sexual minority status and self-esteem for MSAB participants (\u03b2 = -1.35, 95% CI: -2.50, 0.01), there was no evidence of such an association for FSAB (\u03b2 = -0.46, 95% CI: -1.38, 0.50).", "cite_spans": [], "ref_spans": []}, {"section": "Estimates by Sex at Birth", "text": "Whilst strong evidence of an association between family relationships and depressive symptoms was found for FSAB participants (\u03b2 = 0.99, 95% CI: 0.37, 1.65), no such evidence was found for MSAB participants (\u03b2 = 0.33, 95% CI: -0.29, 1.14). Unhelpful assumptions were found to be related with depressive symptoms for MSAB (\u03b2 = -0.08, 95% CI: -0.15, -0.02) and FSAB participants (\u03b2 = -0.12, 95% CI: -0.17, -0.06). Strong evidence for an association of self-esteem with depressive symptoms was found for both MSAB (\u03b2 = -0.19, 95% CI: -0.25, -0.14) and FSAB participants (\u03b2 = -0.32, 95% CI: -0.38, -0.27).", "cite_spans": [], "ref_spans": []}, {"section": "Estimates by Sex at Birth", "text": "Evidence was found for a total effect of sexual minority status on depressive symptoms for MSAB participants (\u03b2 = 1.44, 95% CI: 0.26, 2.53), whilst this was not strongly supported for FSAB participants (\u03b2 = 0.89, -0.11, 1.84). There was some evidence to suggest an indirect effect of sexual minority status on depressive symptoms via family for FSAB participants (\u03b2 = 0.16, 95% CI: 0.04, 0.35), whilst such evidence was weak for MSAB participants (\u03b2 = 0.06, 95% CI: -0.05, 0.26). Evidence for an indirect effect of sexual minority status on depressive symptoms via unhelpful assumptions was moderate for both MSAB participants (\u03b2 = 0.11, 95% CI: 0.01, 0.26) and weak for FSAB participants (\u03b2 = 0.09, 95% CI: -0.02, 0.19). Finally, whilst there was suggestive evidence that self-esteem mediated the relation between sexual minority status in MSAB participants (\u03b2 = 0.26, 95% CI: 0.00, 0.56), there was no such evidence of mediation in FSAB participants (\u03b2 = 0.15, 95% CI: -0.16, 0.45). Detailed results on separate analyses by sex at birth can be found in Supplemental Materials.", "cite_spans": [], "ref_spans": []}, {"section": "Sex at Birth Differences", "text": "No evidence was found for differences between MSAB and FSAB participants regarding the specific indirect paths from sexual minority status to depressive symptoms via self-esteem (\u03b2 = -0.11, 95% CI: -0.55, 0.31), unhelpful assumptions (\u03b2 = -0.03, 95% CI: -0.22, 0.15), or family relationships (\u03b2 = 0.11, 95% CI: -0.14, 0.31). Similarly, the total indirect effect was not found to differ significantly between MSAB and FSAB participants (\u03b2 = -0.03, 95% CI: -0.65, 0.55). Finally, there was no evidence of difference in the direct (\u03b2 = -0.52, 95% CI: -1.99, 1.01) or the total effects (\u03b2 = -0.55, 95% CI: -2.17, 1.06) either. These results suggest no evidence of sex at birth as a moderator. Detailed results on moderation by sex at birth can be found in Supplemental Materials.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "The present study tested family relationships, unhelpful assumptions, and self-esteem as mediators of the relation between minority sexual orientation and depressive symptoms.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "As expected, youth who reported sexual minority status at 15 years reported higher depressive symptom scores than heterosexual youth at 18 years. This difference was present as early as age 13. The SEM results suggested that family relationships and unhelpful assumptions at 17 years mediated the association between sexual minority status and depressive symptoms. The results for self-esteem were inconclusive; suggestive evidence for self-esteem as a mediator was provided by the FIML analysis presented, whilst stronger evidence was found using multiple imputation (Supplemental Materials). This is the first published study of which we are aware that used temporally-ordered prospective data at three timepoints to conduct mediation analysis, which is recommended as it provides stronger evidence for possible causal relations (Maxwell & Cole, 2007) . It is the also first published study that we could identity that tests unhelpful assumptions as a mediator, and the first UK study to investigate family relationships and self-esteem as mediators. The inclusion of sociodemographic confounding variables as well as the baseline confounder of the outcome variable is an important strength of this study as the importance of the adjusting for confounding variables has been extensively discussed in literature (Goldsmith, Chalder, White, Sharpe, & Pickles, 2016; MacKinnon, 2008; Pickles et al., 2015) .", "cite_spans": [{"start": 831, "end": 853, "text": "(Maxwell & Cole, 2007)", "ref_id": "BIBREF36"}, {"start": 1313, "end": 1365, "text": "(Goldsmith, Chalder, White, Sharpe, & Pickles, 2016;", "ref_id": "BIBREF19"}, {"start": 1366, "end": 1382, "text": "MacKinnon, 2008;", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "Discussion", "text": "In general, the findings of this study are in line with the psychological mediation framework (Hatzenbuehler, 2009 ) that suggests that general psychological processes known to confer risk for mental health problems in the general population are elevated in sexual minority individuals compared to their heterosexual counterparts and are causally related to later depressive disparities. In accordance to Hatzenbuehler's model, both unhelpful attitudes and self-esteem can be thought as cognitive psychological processes, while perceptions of family relationships can be conceptualised as a social/interpersonal mediator. The current study demonstrated how these proximal mediators mediate the relation between minority status and depressive symptomatology. Minority stress theories (Meyer, 2003; Hatzenbuehler, 2009) propose that these psychological vulnerability factors are increased in sexual minority individuals due to stigma-related stressors, but this was not directly tested in the present study. Hatzenbuehler's (2009) mediation model suggests that minority status leads to stigma-related stressors that then lead to individual psychological processes which in turn lead to increased risk for mental health problems. Future studies can therefore attempt to test this full mediation model, by using for instance serial mediation pathways to demonstrate how sexual minority status leads to increased exposure to prejudice events which may lead to increased levels of these psychological mediation processes and with these processes then contributing to the increased rates of depression symptomatology.", "cite_spans": [{"start": 94, "end": 114, "text": "(Hatzenbuehler, 2009", "ref_id": "BIBREF23"}, {"start": 783, "end": 796, "text": "(Meyer, 2003;", "ref_id": "BIBREF37"}, {"start": 797, "end": 817, "text": "Hatzenbuehler, 2009)", "ref_id": "BIBREF23"}, {"start": 1006, "end": 1028, "text": "Hatzenbuehler's (2009)", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Discussion", "text": "The finding that poorer family relationships may contribute to the depression disparities between sexual minority and heterosexual young people is in line with evidence supporting the role of parental rejection, family satisfaction, and parental closeness and support as intermediate mechanisms found in three longitudinal studies in samples of Dutch and American adolescents (la Roi et al., 2016; Luk et al., 2018; Pearson & Wilkinson, 2013) .", "cite_spans": [{"start": 398, "end": 415, "text": "Luk et al., 2018;", "ref_id": "BIBREF31"}, {"start": 416, "end": 442, "text": "Pearson & Wilkinson, 2013)", "ref_id": "BIBREF45"}], "ref_spans": []}, {"section": "Discussion", "text": "The present study is the first study of which we are aware that has provided support for this mechanism in a UK youth sample using a full longitudinal mediation design. Evidence from general population research indicates that poorer family relationships in adolescence are associated with not only depression but a range of other outcomes and can have long-lasting effects (e.g., Laursen & Collins, 2009; Sander & McCarty, 2006) . Family relationships should therefore be a factor to look at when considering designing prevention and intervention programs for sexual minority youth. This is the first study that we could identify showing that unhelpful assumptions mediate the relation between minority sexual orientation and increased depressive symptoms.", "cite_spans": [{"start": 405, "end": 428, "text": "Sander & McCarty, 2006)", "ref_id": "BIBREF49"}], "ref_spans": []}, {"section": "Discussion", "text": "These results are consistent with Beck and colleagues' (1979) Cross-sectional studies have provided evidence for self-esteem as a mediator in the relation between sexual minority status and depression (Martin-Storey & Crosnoe, 2012; Ueno, 2010) . This is the first longitudinal study examining self-esteem as a mediator in a between-group sample of young people. In line with previous research (Sowislo & Orth, 2013) , self-esteem was associated with subsequent depression, however results were inconclusive regarding the link between sexual orientation and self-esteem, with weak evidence provided for MSAB participants and no link supported for FSAB participants. In the alternative whole sample analysis presented in Supplemental Materials however, both these links were supported. Consequently, there is suggestive evidence of self-esteem as a mediator. As self-esteem rates differed between sexual minority and heterosexual youth in preliminary analyses (see Table 2 ), it seems that controlling for earlier levels of depression and demographic characteristics attenuated the relation between sexual orientation and selfesteem. Indeed, depressive symptoms are more strongly associated with self-esteem than with family relationships or unhelpful assumptions, so it is not surprising that adjusting for prior depression may have had more impact on this association. It is worth noting the potential conceptual overlap between depression and self-esteem as theoretical and measurement constructs, with low self-esteem also being a symptom of depression. We therefore suggest despite the weak evidence in our study that future research should continue to investigate positive self-esteem as a possible resilience factor for depression in sexual minority youth, as well as the possibility that sexual minority boys in particular are at increased risk for low self-esteem.", "cite_spans": [{"start": 233, "end": 244, "text": "Ueno, 2010)", "ref_id": "BIBREF58"}, {"start": 394, "end": 416, "text": "(Sowislo & Orth, 2013)", "ref_id": "BIBREF54"}], "ref_spans": []}, {"section": "Discussion", "text": "There was no evidence to support sex at birth as a moderating factor of any of the pathways. Uncertainty around parameter estimates was considerable however and confidence intervals for differences between indirect effects in MSAB and FSAB participants were relatively large. Consequently, whilst no evidence was provided that effects differ between MSAB and FSAB participants, it was still the case that evidence was found for some associations in one sex at birth whilst there was too much uncertainty to provide evidence for associations (or lack thereof) in the other. Whilst sexual minority status was related with poorer family relationships for both MSAB and FSAB participants, poorer family relationships were associated with depressive symptoms in FSAB participants, whereas this relation was not shown in MSAB participants. Therefore, family relationships emerged as a mediator for FSAB participants but not for MSAB participants. This is consistent with findings of other longitudinal research with Dutch and American adolescents, suggesting that family-related variables such as parental rejection or parental closeness, support, and involvement appear to be stronger mediators of the relation between sexual orientation and depressive symptoms for girls than for boys (la Roi et al., 2016; Pearson & Wilkinson, 2013) . This is the opposite pattern that was found for self-esteem, where evidence suggested that self-esteem was a weak mediator for MSAB participants, but was not a mediator for FSAB participants, as self-esteem was related with sexual minority status only for MSAB. It has been reported that attitudes are often more negative toward sexual minority men than women (Kite & Whitley, 1996) and that sexual minority men may experience sexual-orientation related victimization more than sexual minority women (e.g., Almeida, Johnson, Corliss, Molnar, & Azrael, 2009 ). However, sexual minority young women report more sexual victimization than sexual minority men (Rothman, Exner, & Baughman, 2011) . It could be argued that the impact of minority stressors relating to sexual orientation on self-esteem may be less apparent in the young women because self-esteem is generally lower in women than men (Bleidorn et al., 2016) , presumably due to sexism and gender-based victimization.", "cite_spans": [{"start": 1303, "end": 1329, "text": "Pearson & Wilkinson, 2013)", "ref_id": "BIBREF45"}, {"start": 1839, "end": 1888, "text": "Almeida, Johnson, Corliss, Molnar, & Azrael, 2009", "ref_id": "BIBREF2"}, {"start": 1987, "end": 2021, "text": "(Rothman, Exner, & Baughman, 2011)", "ref_id": "BIBREF46"}, {"start": 2224, "end": 2247, "text": "(Bleidorn et al., 2016)", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Discussion", "text": "Indeed, self-esteem was lower in FSAB participants in the present study (data available upon request).", "cite_spans": [], "ref_spans": []}, {"section": "Clinical Implications", "text": "The findings have important implications in terms of primary and secondary prevention. Firstly, these UK findings support many other studies (e.g., King et al., 2008) indicating that sexual minority youth should be recognized as an at-risk population for depression. Depression disparities were already present at 13 years indicating that prevention efforts need to begin at a young age.", "cite_spans": [], "ref_spans": []}, {"section": "Clinical Implications", "text": "Secondly, knowledge of psychosocial processes that act as vulnerability factors provides specific targets for preventative and therapeutic efforts. The current findings suggest that psychological interventions for sexual minority youth should attend to unhelpful rules for living and conditional beliefs about self-worth. Addressing these beliefs is a core component of CBT for depression. Future research should investigate whether sexual minority youth in the UK are accessing evidence-based treatments such as CBT in line with their increased need. Unfortunately, access to mental health services for children and young people in the UK is currently poor (Care Quality Commission, 2019). Pilot studies have investigated a computerized CBT program specifically adapted for sexual minority teenagers with depression (Lucassen, Merry, Hatcher, & Frampton, 2015) , group CBT for sexual minority youth (Craig & Austin, 2016) , and LGB affirmative CBT for gay and bisexual men (Pachankis, Hatzenbuehler, Rendina, Safren, & Parsons, 2015) . Such interventions address minority stress processes not investigated in the current study but show promising results and require further research.", "cite_spans": [{"start": 817, "end": 861, "text": "(Lucassen, Merry, Hatcher, & Frampton, 2015)", "ref_id": "BIBREF30"}], "ref_spans": []}, {"section": "Clinical Implications", "text": "Recently, research and practice has been focused on resilience as a protective factor for sexual minority individuals (Mustanski, Newcomb, & Garofalo, 2011) . Although resilience is a poorly understood process, self-esteem has been shown to be an important aspect of it (Anderson, 1998) . There is some evidence that CBT specifically focused on selfesteem may be effective in the general population (Waite, McManus, & Shafran, 2012) although this has not been tested in sexual minority youth. The presence of community and school-based programs that facilitate positive identity development (e.g., Asakura, 2010) as well as interventions that focus on building sexual minority young people's self-esteem (e.g., Craig, McInroy, Austin, Smith, & Engle, 2012) are also likely to be protective for this population.", "cite_spans": [{"start": 118, "end": 156, "text": "(Mustanski, Newcomb, & Garofalo, 2011)", "ref_id": "BIBREF38"}, {"start": 270, "end": 286, "text": "(Anderson, 1998)", "ref_id": "BIBREF3"}, {"start": 399, "end": 432, "text": "(Waite, McManus, & Shafran, 2012)", "ref_id": "BIBREF59"}, {"start": 598, "end": 612, "text": "Asakura, 2010)", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Clinical Implications", "text": "Furthermore, the finding that poorer family relationships may have contributed to the greater depressive symptoms in sexual minority youth highlights the need for research evaluating the impact of interventions that facilitate awareness, normalization, and education to parents and families. Research on interventions that focus on the family relationships of sexual minority youth is scarce (Diamond et al., 2012; Willoughby & Doty, 2010) . Although recommendations for family interventions exist (Woodward & Willoughby, 2013) , they are not based on a solid evidence base. Young people who come out to their families (or who are \"outed\" without their consent) may also need support coping with any adverse reactions including the possibility that they will be made homeless. Young people who experience concealment stigma (Pachankis, 2007) and do not come out due to fears of negative family reactions require a different kind of support, that takes into account that they may be correct in their anticipated family rejection.", "cite_spans": [{"start": 415, "end": 439, "text": "Willoughby & Doty, 2010)", "ref_id": "BIBREF61"}, {"start": 498, "end": 527, "text": "(Woodward & Willoughby, 2013)", "ref_id": "BIBREF62"}, {"start": 824, "end": 841, "text": "(Pachankis, 2007)", "ref_id": "BIBREF42"}], "ref_spans": []}, {"section": "Limitations", "text": "Like most longitudinal cohort studies, ALSPAC suffers from significant attrition which may lead to biased estimates. Two different methods were used to deal with missing data, both of which are known to reduce statistical bias when data can be assumed to be missing at random, as well as to increase power. These two methods led to similar results.", "cite_spans": [], "ref_spans": []}, {"section": "Limitations", "text": "One of the strengths of this study is that it used a mediational design with three timepoints. However, it should be noted that it is very difficult to infer causal relationships based solely on one observational study, and results obtained from SEM will be biased if causal structures are misspecified or there are unobserved confounders. Hence, analyses such as the ones presented here do not provide conclusive evidence of some causal structure. Instead, they examine whether a causal theory is consistent with observational data, and presupposing that this causal structure is correct, perform inference for the parameters of the causal model. Further, as previously discussed, mediation studies with a longitudinal design are methodologically superior to cross-sectional mediation studies in that they acknowledge that mediation processes unfold over time. However, in the present study assumptions are necessarily being made about the timing of the effects of sexual minority status on the mediators, and of the mediators on depressive symptoms. Ideally, when the hypothesized timings of the effects are unknown as they are in this model, multiple measures should be collected at different timepoints so that the nature of how the causal process unfolds could be better modelled. This was not possible in this study as more measures were not administered to the ALSPAC participants and they were therefore not available to us for analysis.", "cite_spans": [], "ref_spans": []}, {"section": "Limitations", "text": "In the present study, a self-report measure assessing the number of depressive symptoms was used rather than a diagnostic tool for major depression. Future studies should investigate whether similar results are found when using clinical structured assessment of major depression as an outcome variable. Moreover, the family relationships variable was not assessed by a validated questionnaire thus this construct requires further research with alternative measures. In addition, sexual orientation was measured at a single time-point using a simple measure of sexual orientation; participants were not asked about sexual attraction or sexual behavior. Sexual orientation was only assessed at one time point (15 years) and we were not able to account for the stability of sexual orientation across time.", "cite_spans": [], "ref_spans": []}, {"section": "Limitations", "text": "Particularly at this developmental stage, sexual identity is likely to shift over time for some individuals.", "cite_spans": [], "ref_spans": []}, {"section": "Limitations", "text": "Different sexual minority subgroups were grouped together due their small sizes. This has been a common approach used in sexual minority research; however, it represents an important limitation as it fails to capture differences in the experiences among different sexual minority subgroups. Research indicates that some groups such as bisexual people may be at more risk than others (Ross et al., 2018) . There is also evidence that suggests that \"mostly heterosexual\" youth can be considered a separate group (Savin-Williams & Vrangalova, 2013 ) that may also be vulnerable compared to heterosexuals (Corliss et al., 2009 ). Participants who responded \"not sure\" or \"not attracted to either sex\" were excluded and these individuals require research in their own right. In addition, it is very likely that selfreported sexual orientation would have changed for some young people in the timespan of the study. It is important for future research to investigate mechanisms contributing to depression disparities in sexual minority subgroups and in those who report changing identities.", "cite_spans": [{"start": 510, "end": 544, "text": "(Savin-Williams & Vrangalova, 2013", "ref_id": "BIBREF52"}, {"start": 601, "end": 622, "text": "(Corliss et al., 2009", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Limitations", "text": "Data on gender identity was not collected for the ALSPAC birth cohort and therefore could not be included in the analysis. However, it is highly likely that the sample includes transgender, gender fluid, or other gender expansive young people. Future longitudinal studies should include measures of gender identity.", "cite_spans": [], "ref_spans": []}, {"section": "Limitations", "text": "Although we used a few potential confounding variables in our analysis, these were not without limitations. A crude measure of race was used (dichotomized as white/non-white) that fails to capture different non-white racial and ethnic identities. Similarly, SES was measured on data of the mother's education and occupation, which do not take into account the background of the father or other factors that contribute to the SES make-up of the young people in the sample. Future studies should use more inclusive and nuanced demographic variables and also investigate a broader range of confounding variables, (e.g., victimization experiences).", "cite_spans": [], "ref_spans": []}, {"section": "Limitations", "text": "There may be limits to the generalizability of the findings: firstly, the sample exclusively consisted of participants from Avon, UK, a relatively affluent and mostly white community, and therefore it is unclear whether the present findings translate to other populations and cultures. Moreover, societal attitudes about sexual orientation are rapidly and continuously changing and it is therefore possible that, with measures administered between 2006 and 2010, the results of this study are already limited in their generalizability to present day youth.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "The study is unique in using a longitudinal design in which the sexual minority status, proposed mediators, and depressive outcomes are measured at different timepoints. Results provide evidence for the importance of family relationships and unhelpful assumptions in explaining disparities in depressive symptoms between heterosexual and sexual minority youth, and there is weaker support that self-esteem may also help explain the disparities. The results do not provide conclusive evidence for sex at birth differences in these mediational pathways. Future studies should further investigate such differences, along with differences across sexual minority subgroups.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "adolescents: prospective birth cohort study. Journal of Child Psychology and Psychiatry, 58, 1201 -1209 . doi: 10.1111 /jcpp.12757. King, M., Semlyen, J., Tai, S. S., Killaspy, H., Osborn, D., Popelyuk, D., & Nazareth, I. (2008 . A systematic review of mental disorder, suicide, and deliberate self-harm in lesbian, gay and bisexual people. Note: 1,000 bootstrap samples were drawn for each imputed dataset and used to obtain standard errors (SEs) of the estimates. The estimates and their SEs were combined using Rubin's rules.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "Confidence intervals were then constructed based on asymptotic normal theory, in contrast to the quantile method used in the presented analysis with FIML which is recommended in the literature (Fritz, Taylor, & MacKinnon, 2012) . This methodology is recommended in recent literature (Schomaker & Heumann, 2018) as an alternative. 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For example, sexual minority youth show elevated rates of childhood abuse as well as victimization and stigma relating to their sexual orientation or associated precursors such as childhood gender nonconformity(Roberts et al., 2013;Toomey, Ryan, Diaz, Card, & Russell, 2010). These experiences may contribute to the development of unhelpful beliefs which may then become activated by other life stressors.", "type": "figure"}, "FIGREF1": {"text": "BMC Psychiatry, 8, 70. doi:10.1186/1471 70 Kirsch, A. C., Conley, C. S., & Riley, T. J. (2015). Comparing psychosocial adjustment across the college transition in a matched heterosexual and lesbian, gay, and bisexual sample. Journal of College Student Development, 56, 155-169. doi: 10.1353/csd.2015.0017 Kite, M. E., & Whitley, B. E. (1996). Sex differences in attitudes toward homosexual persons, behaviors, and civil rights: a meta-analysis. 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Journal of Youth Adolescence, 5, 440-56. doi: 10.1007/s10964-015-0403-0", "type": "figure"}, "TABREF0": {"text": "Frequencies, percentages, and chi-square tests of demographic variables.*p <.05. **p <.01. ***p <.001.Means, standard deviations (SD), and t-test differences based on summary scores for respondents with complete information on each variable.Results of mediation for FIML with bootstrapped CIs(n = 14,814). Mediation diagram. Estimates of factor loadings, specific indirect effects (under each mediator variable), and direct effect are shown.", "type": "table"}, "TABREF1": {"text": "SUPPLEMENTAL MATERIALS D -SEM ESTIMATES BY SEX AT BIRTH (WITH FIML) MODERATION RESULTS. ESTIMATES OF SEX AT BIRTH DIFFERENCES IN EFFECTS BETWEEN MALE SEX AT BIRTH AND FEMALE SEX AT BIRTH PARTICIPANTS a Higher scores indicate lower unhelpful assumptions.", "type": "table"}}}
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{"paper_id": "213467351", "_pdf_hash": "a2690a97545cafd2b9887411f68d9ca390b4c549", "abstract": [{"section": "Abstract", "text": "Nowadays, there are many graduates who are not directly employed after receiving bachelor's degree. The graduates who are not employed seem largely unaware of career opportunities and unsure of how to apply their skills in the workforce. This indicates a lack of career guidance, coaching and counselling. This research aims to study people's preferences on determining their jobs by using conjoint analysis. Four factors are evaluated: (1) income, (2) suitability of the workplace with educational background, (3) field of works, and (4) working hours, which has different level category values. Monotonic analysis of variance is used to analyze the data and the results are (1) utility value which is useful to know the most desirable level of each attribute and (2) its relative importance value to know the most considered attribute on determining their jobs. The full profile method of conjoint analysis shows that income is the most considered attribute value.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Conjoint analysis was introduced for the first time by the mathematical psychology in 1964 [1] , then developed according to the need of the researcher. In the beginning, this analysis is more widely used by research companies in developing their product, but over the times, conjoint analysis can also be applied to other fields of study.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "In its application, conjoint analysis can be used by the university to determine the preferences of its college students on the factors or attributes that are considered in choosing a job. Salary, the work field, the suitability of educational background to the workplace, and distance of the workplace, are some of the many things that they consider in choosing a job.", "cite_spans": [], "ref_spans": []}, {"section": "Conjoint analysis", "text": "Conjoint analysis is a multivariate technique that is specifically used to study consumers' product or service preferences by measuring utility of each level of each attribute and relative importance value of various attributes [2] .", "cite_spans": [{"start": 228, "end": 231, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Conjoint analysis", "text": "In general, conjoint analysis model can be formulated as follows [3] :", "cite_spans": [], "ref_spans": []}, {"section": "Conjoint analysis", "text": "in practical, intercept is usually added to the conjoint analysis model so that the model becomes: \u2022 ! ! = total utility \u2022 ! !\" = part-worth or utility value of the i-th attribute, j-th level", "cite_spans": [], "ref_spans": []}, {"section": "Conjoint analysis", "text": "The utility value is used to determine the importance of a level relative to another level in an attribute. Utility value is derived from the dummy variable for the level of an attribute that constructed conjoint model, where the value of the dummy variable for the other attribute is fixed or zero. The best product or service is a combination of a level attribute that has the highest utility value. Relative importance value is used to know the importance of an attribute to another attribute. Relative importance is formulated as follows:", "cite_spans": [], "ref_spans": []}, {"section": "Conjoint analysis", "text": "where:", "cite_spans": [], "ref_spans": []}, {"section": "Conjoint analysis", "text": "\u2022 !\" = relative importance \u2022 !\" ! = highest utility score i-th attribute \u2022 !\" ! = lowest utility score i-th attribute \u2022 ! = total attribute.", "cite_spans": [], "ref_spans": []}, {"section": "Conjoint analysis", "text": "The following are the steps in conjoint analysis:", "cite_spans": [], "ref_spans": []}, {"section": "Conjoint analysis", "text": "\u2022 Designing stimulus Stimulus is a combination of each level from different attribute. Respondents are asked to evaluate these stimuli, so that the researcher could know about their preferences. Conjoint analysis used full factorial design to construct stimulus. However, as the number of attributes and level increases, there are many stimuli to evaluate. This condition will make respondents difficult and inconsistent to trade-offs, so it is necessary to reduce stimulus, and then this is called fractional factorial design.", "cite_spans": [], "ref_spans": []}, {"section": "\u2022 Choosing a Conjoint method", "text": "There are three methods that can be used in conjoint analysis:", "cite_spans": [], "ref_spans": []}, {"section": "\u2022 Choosing a Conjoint method", "text": "a. Traditional conjoint analysis Traditional conjoint analysis is the simplest method of conjoint analysis where data analyze single or full profile can be done manually or computerized. Estimation of utility score in traditional conjoint analysis if the data is metric (rating data) then used OLS (Ordinary Least Square), and if the data is nonmetric (ranking data) then used monotone regression.", "cite_spans": [], "ref_spans": []}, {"section": "\u2022 Choosing a Conjoint method", "text": "b. Adaptive conjoint analysis ACA (Adaptive Conjoint Analysis) is developed specifically to accommodate a large number of factors (many rimes up to 30), which would not be feasible in traditional conjoint analysis. The term \"adaptive\" means that the interview is employed computerized process and the question must be different for each respondent. Previous answer is used to determine which questions will be presented to respondents to obtain the most dominant information on respondent preferences. When ACA was introduced, the utility was estimated using OLS (Ordinary Least Square). But as the times goes by, ACA has grown and improved, which ACA-Hierarchical Bayes has been widely used to estimate the utility value of a product.", "cite_spans": [], "ref_spans": []}, {"section": "\u2022 Choosing a Conjoint method", "text": "c. Choice based conjoint The CBC (Choice Based Conjoint) is a new method in the conjoint study, which has been very popular in recent years. Compared to other method, CBC allows respondents to choose one preference profile from a set of profiles or not choosing at all. The estimation of utility is obtained in aggregate by using multinomial logit. As the time goes by, Hierarchical Bayes Estimation have been found for CBC that make it possible to calculate the utility of each respondent. a. Multidimensional scaling [4] , commonly used to provide an overview of the pair attributes performed in the measurement pairwise comparison. This method is limited to a small number of attributes.", "cite_spans": [], "ref_spans": []}, {"section": "\u2022 Choosing a Conjoint method", "text": "b. Regression analysis with dummy variables widely used for metric and nonmetric data types. Metrics are scaled-up interval or ratio data that gives ratings or values to each stimulus. While nonmetric are data in the form of nominal, ordinal or category, rank or sort the stimulus.", "cite_spans": [], "ref_spans": []}, {"section": "\u2022 Interpreting the result", "text": "The most commonly used interpretation method is to make a utility score (part-worth) estimate for each attribute. The part-worth estimates are usually scaled, so that the higher the part-worth value the more it gives more impact to the total utility. Conjoint analysis can also measure the relative importance of each attribute. Since usually part-worth estimates are converted to a general scale, the greatest contribution to the total utility and the most considered attributes is the attribute with the largest part-worth range.", "cite_spans": [], "ref_spans": []}, {"section": "Data and methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Data", "text": "The data of this research is the data preference of determining jobs study on college students of University of Indonesia, majoring Statistics. The data is used for the application of the traditional conjoint analysis method. The number of respondents taken is 96 respondents.", "cite_spans": [], "ref_spans": []}, {"section": "Data", "text": "The result of previous research shows that salary, suitability of educational background to the workplace, and work fields affect college student in choosing a job. Here are four attributes with each attribute consisting of three levels that affect college student in choosing a job in this research; the attributes can be seen in table 1.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "These are some steps in this research as follows:", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "1. Determine the purpose of the research, determine the attributes and levels, and construct stimulus design. 2. Choose the conjoint method (table 2) and construct the questionnaire. 3. Data collection is done by spreading questionnaires directly to respondent. In this method, respondents were asked to give ranking to each stimulus in questionnaire. 4. Monotonic analysis of variance is used to analyse the data. MONANOVA is used to fit data to an additive model by way of a nonmetric scaling procedure [5] . There are two parallel processes. First, ranking data from questionnaire will be transformed to numeric data and second, ordinary least square between variable independent X (attributes) and variable dependent Y (transformed data). Profile  A  B  C  D  1  1  1  1  1  2  1  2  2  3  3  1  3  3  2  4  2  1  2  2  5  2  2  3  1  6  2  3  1  3  7  3  1  3  3  8  3  2  1  2  9 3 3 2 1 4. Results and study Data analysis is done by using monotonic analysis of variance. MONANOVA is used to estimate utility value of each level of each attribute [6] . Level of attribute that has high value is the most desirable level of determining jobs. There are two parallel processes in this estimation. First, ranking data transforms to numeric data by monotone transformation, which ranking data is close enough with numeric data. Second, ordinary least square variable independent X and variable dependent Y so that we get coefficient regression which is utility value. We also can obtain relative importance value of each attribute by using equation (3), attribute that has high importance relative value is the most considered attribute. Table 3 is the result of utility value estimation and importance relative value of this research: Based on the result of parameter estimation, hence can be determined the utility of each levels and relative importance each attributes. Salary and allowance attribute gives the highest relative importance compared to other attributes, which is 47.35 %. The suitability of educational background to the workplace has a relative importance of 23.77 %, which is less than the relative importance value of the salary and allowance attribute, which means that the student puts salary and allowance as the most considered attribute when they choose a job. The work fields and working hours attribute have their respective relative importance of 16.99 % and 11.89 %, this indicates that these two attributes are less than the relative importance value of suitability background, but work fields attribute gives more contribution to students' preferences than working hours attribute.", "cite_spans": [{"start": 1053, "end": 1056, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": [{"start": 743, "end": 885, "text": "Profile  A  B  C  D  1  1  1  1  1  2  1  2  2  3  3  1  3  3  2  4  2  1  2  2  5  2  2  3  1  6  2  3  1  3  7  3  1  3  3  8  3  2  1  2  9", "ref_id": "TABREF1"}, {"start": 1639, "end": 1646, "text": "Table 3", "ref_id": "TABREF4"}]}, {"section": "Methods", "text": "Then for the highest utility of each levels from each attribute will be described as follows: the highest utility on salary and allowance attributes are at the high salary and low allowance that is equal to 1.5249, that level is the most desirable level compared to other levels. Then on the suitability of educational background to the workplace, students prefer a workplace that suits the background of education that is statistics with utility of 0.6374. Then the highest utility on work fields and working ", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "By using conjoint analysis method, we get found the preference of determining jobs study on college students of University of Indonesia majoring Statistics. Based on the result, it shows that the most considered attributes by the student is salary and allowance attributes, followed by suitability of educational background to the workplace attribute which land in the second place. Attributes that are in the third position are work fields and in the last position is working hours. At the salary and allowance attribute, the most considered level is the high salary and low allowance. The suitability of educational background to the workplace attribute, the most considered is suitable with educational background, which is statistics. The most considered level on works fields and working hours attribute is government companies and flexible working hours.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF1": {"title": "Multivariate Data Analysis", "authors": [{"first": "J F", "middle": [], "last": "Hair", "suffix": ""}, {"first": "W C", "middle": [], "last": "Black", "suffix": ""}, {"first": "B", "middle": [], "last": "Babin", "suffix": ""}, {"first": "Anderson R E", "middle": [], "last": "", "suffix": ""}], "year": 2010, "venue": "", "link": null}, "BIBREF5": {"title": "Conjoint and Graphical Techniques 9", "authors": [{"first": "W", "middle": [], "last": "Kuhfeld", "suffix": ""}], "year": 2005, "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Basic and Applied Sciences Interdisciplinary Conference 2017 Journal of Physics: Conference Series 1442 (2020) 012040 IOP Publishing doi:10.1088/1742-6596/1442/1/012040 5 hours is government companies and flexible working hour with each utility value is 0.4437 and 0.4499.", "type": "figure"}, "TABREF1": {"text": "Attributes and levels in this research", "type": "table"}, "TABREF3": {"text": "Fractional factorial design", "type": "table"}, "TABREF4": {"text": "Utility and relative importance", "type": "table"}}}
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{"paper_id": "213345224", "_pdf_hash": "ca1fd95e4bbbb0b2df3d887c90eb8bf3dd945ff5", "abstract": [{"section": "Abstract", "text": "The microtubule-associated protein Tau is implicated in the pathogenesis of several neurodegenerative disorders, including Alzheimer's disease. Increasing evidence suggests that post-translational modifications play critical roles in regulating Tau normal functions and its pathogenic properties in Tauopathies. Very little is known about how phosphorylation of tyrosine residues influences the structure, aggregation, and microtubule-and lipid-binding properties of Tau. In this work, we aimed to address this knowledge gap and determine the relative contribution of phosphorylation of one or several of the five tyrosine residues in Tau (Y18, Y29, Y197, Y310 and Y394) to the regulation of its biophysical, aggregation and functional properties. Towards this goal, we used a combination of site-specific mutagenesis and in vitro phosphorylation by c-Abl kinase to generate Tau species phosphorylated at all tyrosine residues, all tyrosine residues except Y310 or Y394 (pTau-Y310F, pTau-Y394F) and Tau phosphorylated only at Y310 or Y394 (4F\\pY310 or 4F\\pY394). Our results show that phosphorylation at all five tyrosine residues, multiple Nterminal tyrosine residues (Y18, Y29 and Y197) or site-specific phosphorylation at residue Y310, itself located in the microtubule-binding and aggregation-prone domain of Tau, was sufficient to abolish Tau aggregation and inhibit its microtubule-and lipid-binding properties. NMR studies demonstrated that these effects were mediated by a local decrease in \u03b2\u2212sheet propensity of the PHF6 domain. Our findings underscore the unique role of Y310 phosphorylation in the regulation of Tau aggregation, microtubule and lipid interactions and highlight the importance of conducting further studies to elucidate its role in the regulation of Tau normal functions and its pathogenic properties.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "The misfolding and aggregation of the microtubule (MT)-associated protein Tau have been linked to the pathogenesis of several neurodegenerative disorders (1) , including Alzheimer disease (AD) (2) , corticobasal degeneration (CBD) (3), progressive supranuclear palsy (PSP) (3, 4) , Pick's disease (PiD), argyrophilic grain disease (AGD) (5) , chronic traumatic encephalopathy (CTE) (6) and frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) (7) . In the brain of individuals affected by AD, aggregated and abnormally hyper-phosphorylated and modified forms of Tau, such as paired helical filaments (PHFs) and straight filaments (SFs), are found as the main component of the neurofibrillary tangles (NFTs), one of the key diagnostic pathological hallmarks of AD, in addition to amyloid plaques (8) .", "cite_spans": [{"start": 154, "end": 157, "text": "(1)", "ref_id": "BIBREF0"}, {"start": 193, "end": 196, "text": "(2)", "ref_id": "BIBREF1"}, {"start": 273, "end": 276, "text": "(3,", "ref_id": "BIBREF2"}, {"start": 277, "end": 279, "text": "4)", "ref_id": "BIBREF3"}, {"start": 337, "end": 340, "text": "(5)", "ref_id": "BIBREF4"}, {"start": 382, "end": 385, "text": "(6)", "ref_id": "BIBREF5"}, {"start": 466, "end": 469, "text": "(7)", "ref_id": "BIBREF6"}, {"start": 818, "end": 821, "text": "(8)", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Introduction", "text": "Tau is extensively post-translationally modified (PTM) with phosphorylation being one of the predominant modifications (9) . Although many phosphorylation sites of Tau identified in NFTs are also found in healthy neurons, at advanced disease stages Tau aberrant hyperphosphorylation (10) encompasses more than 39 potential sites (11, 12) , leading to a total phosphorylation level of Tau that is three to four times higher than that of normal Tau (13, 14) . The presence of hyper-phosphorylated Tau in both soluble cytosolic forms and highly aggregated and insoluble forms within NFTs (13, 15) suggests that the pattern of hyperphosphorylation or site-specific phosphorylation may play key roles in regulating its normal function(s) and/or pathogenic properties.", "cite_spans": [{"start": 119, "end": 122, "text": "(9)", "ref_id": "BIBREF8"}, {"start": 329, "end": 333, "text": "(11,", "ref_id": "BIBREF10"}, {"start": 334, "end": 337, "text": "12)", "ref_id": "BIBREF11"}, {"start": 452, "end": 455, "text": "14)", "ref_id": "BIBREF14"}, {"start": 590, "end": 593, "text": "15)", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "Introduction", "text": "Serine and threonine residues greatly outnumber tyrosine residues in the Tau sequence, which explains why phosphorylation at these residues has received predominant attention. Tau contains five tyrosine residues ( Fig. 1 ), located at positions Y18, Y29, Y197, Y310 and Y394, which are all susceptible to phosphorylation. Tau phosphorylation on tyrosine residues has been described only recently and remains understudied. A few tyrosine kinases have been shown to phosphorylate tyrosine residues in Tau both in vitro, in cell culture and in vivo. For example, Fyn (16, 17) and Lck (17) , members of the Src kinase family, phosphorylate Tau on all five tyrosine residues, however somewhat preferentially on residue Y18; while members of the c-Abl kinase family (c-Abl and Arg) were reported to phosphorylate Tau on Y394 (18, 19) and to a lesser extent on Y197 and Y310. Other non-SH3-containing tyrosine kinases have also been reported to phosphorylate Tau on residue Y18, such as Syk (20) and Pyk2, the focal adhesion kinase (FAK) (21) ; and on residue Y197 by TTBK1 (22) . Additionally, it was shown that an increase in Tau tyrosine phosphorylation correlated with the formation of Tau aggregates (23) . Furthermore, several reports have established that Abelson tyrosine kinase (c-Abl) becomes active in a variety of neurodegenerative diseases, including Parkinson's disease (PD) and several Tauopathies (24) (25) (26) , suggesting a likely role in the regulation of Tau tyrosine phosphorylation levels in disease.", "cite_spans": [{"start": 564, "end": 568, "text": "(16,", "ref_id": "BIBREF16"}, {"start": 569, "end": 572, "text": "17)", "ref_id": "BIBREF17"}, {"start": 581, "end": 585, "text": "(17)", "ref_id": "BIBREF17"}, {"start": 819, "end": 823, "text": "(18,", "ref_id": "BIBREF18"}, {"start": 824, "end": 827, "text": "19)", "ref_id": "BIBREF19"}, {"start": 984, "end": 988, "text": "(20)", "ref_id": "BIBREF20"}, {"start": 1031, "end": 1035, "text": "(21)", "ref_id": "BIBREF21"}, {"start": 1067, "end": 1071, "text": "(22)", "ref_id": "BIBREF22"}, {"start": 1198, "end": 1202, "text": "(23)", "ref_id": "BIBREF23"}, {"start": 1406, "end": 1410, "text": "(24)", "ref_id": "BIBREF24"}, {"start": 1411, "end": 1415, "text": "(25)", "ref_id": "BIBREF25"}, {"start": 1416, "end": 1420, "text": "(26)", "ref_id": "BIBREF26"}], "ref_spans": [{"start": 214, "end": 220, "text": "Fig. 1", "ref_id": "FIGREF1"}]}, {"section": "Introduction", "text": "Alternative splicing of exon 2, 3 and 10 exons of Tau produces 6 isoforms from chromosome 17, the splicing results in an assembly domain that contains three or four microtubule-binding repeats (27) . The four repeats form the proteolysis-resistant core of Tau aggregates (28) . PHF6* and PHF6 hexapeptides (Fig. 1, A and B ) are important elements for Tau binding to microtubules and constitute the minimal motif allowing fibrillization (29, 30) . K19 and K18 are fragments of Tau that comprise three and four repeat domains, respectively. These fragments have high aggregation and microtubules-binding propensities (31, 32) . Whereas phosphorylation of serine and threonine residues exhibit a degree of clustering in the N-and C-terminal functional domains encompassing the repeat regions and the MT-binding domains 1 and 2 (Fig. 1, A and B) , there is only one tyrosine phosphorylation site (Y310) within the MT-binding domain. This residue is located in the repeat peptide R3, which has also been shown to play key roles in regulating Tau aggregation, PHF formation, and membrane interactions (33, 34) .", "cite_spans": [{"start": 193, "end": 197, "text": "(27)", "ref_id": "BIBREF27"}, {"start": 271, "end": 275, "text": "(28)", "ref_id": "BIBREF28"}, {"start": 437, "end": 441, "text": "(29,", "ref_id": "BIBREF29"}, {"start": 442, "end": 445, "text": "30)", "ref_id": "BIBREF30"}, {"start": 616, "end": 620, "text": "(31,", "ref_id": "BIBREF31"}, {"start": 621, "end": 624, "text": "32)", "ref_id": "BIBREF32"}, {"start": 1096, "end": 1100, "text": "(33,", "ref_id": "BIBREF33"}, {"start": 1101, "end": 1104, "text": "34)", "ref_id": "BIBREF34"}], "ref_spans": [{"start": 306, "end": 322, "text": "(Fig. 1, A and B", "ref_id": "FIGREF1"}, {"start": 825, "end": 842, "text": "(Fig. 1, A and B)", "ref_id": "FIGREF1"}]}, {"section": "Introduction", "text": "Interestingly, despite the prominent position of Y310 within the aggregation-prone hexapeptide PHF6 (amino acids 306-311), only a handful of studies have specifically investigated the roles of this residue in regulating Tau structure, aggregation, and toxicity. Importantly, none of the previous studies (30, (35) (36) (37) (38) (39) (40) (41) (42) specifically investigated the effects of Y310 phosphorylation in the context of the full-length Tau protein, relying instead on the short PHF6-containing peptides, featuring PHF6-derived sequences as short as 3 amino acids (43) . Santa-Maria et al. (44) showed that phosphorylation of Y310 abolished the aggregation of the PHF6 fragment (amino acids 306-311) in vitro. Conversely, Inoue et al. reported contradictory results, where phosphorylation of Y310 resulted in a marked increase in the propensity of PHF6 peptide to form fibrils (40, 45, 46) . Furthermore, while previous studies have suggested that Tau phosphorylation on tyrosine residues is an important modulator of Tau functions under both normal conditions and in the course of AD pathogenesis (16, 47) , the role of each tyrosine residue in regulating Tau protein aggregation, MT-binding, and lipid-binding propensities has not been systematically investigated.", "cite_spans": [{"start": 304, "end": 308, "text": "(30,", "ref_id": "BIBREF30"}, {"start": 309, "end": 313, "text": "(35)", "ref_id": "BIBREF35"}, {"start": 314, "end": 318, "text": "(36)", "ref_id": "BIBREF36"}, {"start": 319, "end": 323, "text": "(37)", "ref_id": "BIBREF37"}, {"start": 324, "end": 328, "text": "(38)", "ref_id": "BIBREF38"}, {"start": 329, "end": 333, "text": "(39)", "ref_id": "BIBREF39"}, {"start": 334, "end": 338, "text": "(40)", "ref_id": "BIBREF40"}, {"start": 339, "end": 343, "text": "(41)", "ref_id": "BIBREF41"}, {"start": 344, "end": 348, "text": "(42)", "ref_id": "BIBREF42"}, {"start": 572, "end": 576, "text": "(43)", "ref_id": "BIBREF43"}, {"start": 598, "end": 602, "text": "(44)", "ref_id": "BIBREF44"}, {"start": 885, "end": 889, "text": "(40,", "ref_id": "BIBREF40"}, {"start": 890, "end": 893, "text": "45,", "ref_id": "BIBREF45"}, {"start": 894, "end": 897, "text": "46)", "ref_id": "BIBREF46"}, {"start": 1106, "end": 1110, "text": "(16,", "ref_id": "BIBREF16"}, {"start": 1111, "end": 1114, "text": "47)", "ref_id": "BIBREF47"}], "ref_spans": []}, {"section": "Introduction", "text": "This knowledge gap combined with the location of Y310 within the PHF6 domain of Tau prompted us to conduct more detailed investigations to 1) determine the effects of tyrosine phosphorylation on the regulation of the normal function and pathogenic properties of full-length Tau; 2) elucidate the relative contribution of phosphorylation at each tyrosine residue; and 3) investigate the effect of phosphorylation at Y310 on the structure, aggregation and microtubule-binding of the fulllength Tau and microtubule-binding domaincontaining Tau K18 fragment. Towards achieving these goals, we utilized a combination of mutagenesis and in vitro phosphorylation using the c-Abl kinase to produce milligram quantities of Tau phosphorylated at single or multiple tyrosine residues. Our findings show that phosphorylation of Y310 is sufficient to inhibit Tau aggregation and plays a key role in regulating Tau microtubule-binding properties and interactions with the membrane, thus underscoring the importance of further studies to elucidate the role of phosphorylation at this residue in regulating Tau function under normal and pathological conditions.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "c-Abl phosphorylates Tau on multiple tyrosine residues in vitro.", "text": "To investigate the role of tyrosine phosphorylation in regulating Tau structure, aggregation and MT-binding properties, we first sought to develop conditions that allow for efficient phosphorylation of Tau in vitro. Towards this goal, we assessed the phosphorylation efficiency and specificity of c-Abl kinase for Tau. Recombinant full-length Tau was subjected to in vitro phosphorylation using recombinant c\u2212Abl and the extent of phosphorylation and number of phosphorylation sites was systematically followed by LC/MS. Fig.  2 , A shows that c-Abl phosphorylated Tau at multiple sites, up to 5 sites after 4 h of incubation in reaction buffer. Increasing the amount of kinase or incubation time did not cause a shift towards species with a higher number of phosphorylated tyrosine residues or relative phosphorylation levels (data not shown). Although RP\u2212HPLC allowed the separation of the kinase from the phosphorylated Tau proteins, it was not possible to achieve separation of the different phosphorylated Tau species, which eluted in one peak as observed by the UPLC and a single band by SDS-PAGE (Fig. 2 , B and C).", "cite_spans": [], "ref_spans": [{"start": 521, "end": 528, "text": "Fig.  2", "ref_id": "FIGREF3"}, {"start": 1103, "end": 1110, "text": "(Fig. 2", "ref_id": "FIGREF3"}]}, {"section": "c-Abl phosphorylates Tau on multiple tyrosine residues in vitro.", "text": "To determine the exact tyrosine phosphorylation profile of Tau, the purified mixture of pTau was digested by trypsin and the resulting peptides were analyzed by LC/MS/MS. The analysis of the phosphorylated sites was performed using the Scaffold software (http://www.proteomesoftware.com/) which determines the abundance of phosphorylated peptides based on the spectral counting (SP). As shown in Fig. 2 , D and E, c\u2212Abl phosphorylated Tau on Y18, Y29, Y197, Y310 and Y394, with Y310 and Y394 being the major phosphorylation sites.", "cite_spans": [], "ref_spans": [{"start": 396, "end": 402, "text": "Fig. 2", "ref_id": "FIGREF3"}]}, {"section": "c-Abl phosphorylation of Tau significantly delays its aggregation.", "text": "To determine the effect of tyrosine phosphorylation on Tau aggregation, we carried out in vitro phosphorylation of Tau using the c-Abl kinase and purified the mixture of Tau phosphorylated proteins using RP-HPLC. Next, we compared in vitro aggregation of the non-phosphorylated to c-Abl-phosphorylated Tau (Fig. 3 ) by incubating and monitored the aggregation of both proteins (at10 \u00b5M) over two days at 37\u00b0C under shaking conditions, in presence of 2.5 \u00b5M heparin. We found that phosphorylated Tau (pTau) was unable to form canonical \u03b2\u2212sheet-containing fibrils, as demonstrated by 1) electron microscopy (Fig.  3A) ; 2) the absence of conversion of Tau conformation to \u03b2\u2212sheet structure as discerned by circular dichroism (CD) ( Fig. 3, B) ; and 3) the fact that the ThT fluorescence remained at baseline levels ( Fig. 3 , C). However, large oligomers were discernible by electron microscopy at 12 h, and longer fibrils were apparent only after 24-48 h incubation. These observations were further confirmed by the fact that the sedimentation assay showed an increase of the SDS-resistant oligomeric species overtime in the pTau sample, but not for the unmodified protein ( Fig. 3 , A, D).", "cite_spans": [], "ref_spans": [{"start": 306, "end": 313, "text": "(Fig. 3", "ref_id": "FIGREF4"}, {"start": 605, "end": 615, "text": "(Fig.  3A)", "ref_id": "FIGREF4"}, {"start": 730, "end": 740, "text": "Fig. 3, B)", "ref_id": "FIGREF4"}, {"start": 815, "end": 821, "text": "Fig. 3", "ref_id": "FIGREF4"}, {"start": 1174, "end": 1180, "text": "Fig. 3", "ref_id": "FIGREF4"}]}, {"section": "c-Abl phosphorylation of Tau significantly delays its aggregation.", "text": "It is likely that oligomeric species observed in the unmodified Tau sample were ON-pathway to fibril formation and represent intermediate species that disappeared by the end of the reaction through equilibrium shift towards fibrillar structures. In contrast, the oligomers formed by pTau might represent OFF-aggregation-pathway species that did not proceed to form fibrils and remained in the sample at 96h (Fig 3, D) . These results demonstrate that phosphorylation of Tau at multiple tyrosine residues significantly delays its aggregation and fibril formation and results in the accumulation of phosphorylated Tau oligomers.", "cite_spans": [], "ref_spans": [{"start": 407, "end": 417, "text": "(Fig 3, D)", "ref_id": "FIGREF4"}]}, {"section": "c-Abl-mediated inhibitory effects on Tau aggregation depend on the site of tyrosine phosphorylation.", "text": "To determine the relative contribution of each tyrosine residue to the c-Abl phosphorylation-mediated inhibition of Tau aggregation, we generated Tau proteins that were phosphorylated or not at one or a selected number of tyrosine residues focusing on Y394 and Y310. To allow site-specific phosphorylation of these residues, we mutated all tyrosine residues except Y310 (4F\\Y310) or Y394 (4F\\Y394) to phenylalanine. In addition, we generated Y310 and Y394 residue-specific phosphorylation deficient Tau mutants, where each of these residues is mutated to phenylalanine to allow phosphorylation of all other tyrosine residues except at Y310 (Y310F) or Y394 (Y394F) ( Fig.  4 , A, hollow circles). These Tau variants were subjected to in vitro phosphorylation using c-Abl ( Fig. 4 , A, red circles) and the phosphorylated proteins were purified and their aggregation properties were compared to that of the corresponding non-phosphorylated variants. For the 4F\\Y310 and 4F\\Y394 mutants, which could only be phosphorylated at Y310 and Y394, complete phosphorylation was achieved, whereas a mixture of up to four phosphorylation sites was observed for the single Y310F and Y394F mutants (see LC/MS spectra in Table 1 ). We next investigated the kinetics of aggregation of Tau Y\u2212>F mutants using the same experimental conditions as for full-length Tau (Fig. 4 ). We observed that 4F\\pY310, pTau\u2212Y310F and pTau\u2212Y394F were unable to aggregate, as demonstrated by the lack of increase in the ThT fluorescence for these samples (Fig. 4, B) , while 4F\\pY394 retained its capacity to form \u03b2\u2212sheetcontaining species. These findings were supported by EM data (Fig. 4, D) , where only the 4F\\pY394 sample was found to contain Tau of fibrillar morphology, whereas all other phosphorylated mutants only showed the presence of oligomeric species (Fig. 4 , D, arrows). These results were further supported by the sedimentation assay, whereupon removal of fibrillar species by ultracentrifugation monomeric Tau species showed time-dependent decrease in soluble Tau in all non-phosphorylated mutants ( Fig. 4 , C) that paralleled the increase in ThT fluorescence signal ( Fig. 4, B ), signifying the recruitment of monomeric Tau into \u03b2\u2212sheetcontaining species. A time-dependent decrease in monomeric Tau over time was also observed for phosphorylated Tau mutants. However, in contrast to their non-phosphorylated counterparts or mutant 4F\\pY394, higher molecular weight Tau bands were apparent for phosphorylated Tau mutants 4F\\pY310, pTau\u2212Y310F and pTau\u2212Y394F ( Fig. 4 , C, red boxes), suggesting the presence of Tau oligomeric species, which agrees with EM and ThT data. These findings suggest that phosphorylation at Y310, but not Y394 is sufficient to inhibit the fibrillization of Tau, as 4F\\pY394 was able to aggregate to the same extent as its non\u2212phosphorylated version. Interestingly, phosphorylation of the Y310F mutant also suppressed Tau fibril formation, even though in this mutant the residue Y310 was not available for phosphorylation, indicating that phosphorylation of multiple N-terminal tyrosine residues (Y18, Y29 and Y197) may also play important role in inhibiting Tau aggregation These results show that although Y310 phosphorylation is sufficient to suppress the aggregation of the full-length Tau, the interplay between phosphorylation of the other tyrosine residues is also of critical importance in modulating Tau oligomerization and fibril formation.", "cite_spans": [], "ref_spans": [{"start": 666, "end": 673, "text": "Fig.  4", "ref_id": "FIGREF5"}, {"start": 772, "end": 778, "text": "Fig. 4", "ref_id": "FIGREF5"}, {"start": 1347, "end": 1354, "text": "(Fig. 4", "ref_id": "FIGREF5"}, {"start": 1519, "end": 1530, "text": "(Fig. 4, B)", "ref_id": "FIGREF5"}, {"start": 1646, "end": 1657, "text": "(Fig. 4, D)", "ref_id": "FIGREF5"}, {"start": 1829, "end": 1836, "text": "(Fig. 4", "ref_id": "FIGREF5"}, {"start": 2082, "end": 2088, "text": "Fig. 4", "ref_id": "FIGREF5"}, {"start": 2152, "end": 2161, "text": "Fig. 4, B", "ref_id": "FIGREF5"}, {"start": 2543, "end": 2549, "text": "Fig. 4", "ref_id": "FIGREF5"}]}, {"section": "c-Abl-mediated inhibitory effects on Tau aggregation depend on the site of tyrosine phosphorylation.", "text": "Tyrosine 310 phosphorylation underlies the structural basis of the inhibitory effect on Tau aggregation. The strong inhibitory effects of Y310 phosphorylation combined with the fact that it represents the only tyrosine residue within the MT-binding domain of full-length Tau and K18 fragment prompted us to investigate the molecular and structural bases by which Y310 phosphorylation inhibits Tau aggregation propensity. Towards this goal, we performed nuclear magnetic resonance (NMR) studies on the K18 peptide, which encompasses the MTbinding region (residues 244-368 of Tau-441 sequence) and includes the highly amyloidogenic PHF6 and PHF6* hexapeptides, the former of which contains Y310 ( Fig. 1 ). K18 is also known for its high propensity to aggregate in vitro and in cells (48) .", "cite_spans": [{"start": 782, "end": 786, "text": "(48)", "ref_id": "BIBREF48"}], "ref_spans": [{"start": 695, "end": 701, "text": "Fig. 1", "ref_id": "FIGREF1"}]}, {"section": "c-Abl-mediated inhibitory effects on Tau aggregation depend on the site of tyrosine phosphorylation.", "text": "To this end, we produced recombinant 13C 15Nlabelled K18 and subjected it to in vitro phosphorylation using recombinant c\u2212Abl under the same experimental conditions as for fulllength Tau. Given that there is only one tyrosine residue in K18, we were able to achieve complete K18 phosphorylation on Y310 within 4 h and obtained highly pure Y310-specifically modified pK18 ( Fig. 5 , A-C). Next, to determine the effect of tyrosine 310 phosphorylation on the structural properties of K18, we performed NMR analysis of 15N-labeled pK18. The proton\u2212nitrogen HSQC spectrum of pK18 compared to that of K18 showed that phosphorylation at residue Y310 induced local effects on the structure of the peptide, as indicated by chemical shift changes for signals originating from residues surrounding Y310 ( Fig. 5, D) . Interestingly, signals that were affected in the spectrum of pK18 consistently moved towards lower 15N chemical shifts. Because increases/decreases in NMR 15N chemical shifts correlate with increases/decreases in local \u03b2-strand structure (49) , the observed decrease in 15N chemical shifts upon Y310 phosphorylation indicated a local decrease in \u03b2sheet propensity for the PHF6 region as well as the subsequent ~10 residues ( Fig. 5, E ). This effect likely results from the added negative charges of the phosphate group. Notably, the affected region adopts \u03b2-sheet conformations in all known Tau fibril structures. Thus, the local decrease in \u03b2-sheet propensity may have important implications in the context of Tau fibrillization, especially as the PHF6 hexapeptide exhibits the strongest intrinsic \u03b2-sheet propensity in the Tau sequence (50) and is critical for the aggregation of the protein (30, 51) .", "cite_spans": [{"start": 1046, "end": 1050, "text": "(49)", "ref_id": "BIBREF49"}, {"start": 1647, "end": 1651, "text": "(50)", "ref_id": "BIBREF50"}, {"start": 1703, "end": 1707, "text": "(30,", "ref_id": "BIBREF30"}, {"start": 1708, "end": 1711, "text": "51)", "ref_id": "BIBREF51"}], "ref_spans": [{"start": 373, "end": 379, "text": "Fig. 5", "ref_id": "FIGREF6"}, {"start": 795, "end": 805, "text": "Fig. 5, D)", "ref_id": "FIGREF6"}, {"start": 1233, "end": 1242, "text": "Fig. 5, E", "ref_id": "FIGREF6"}]}, {"section": "c-Abl-mediated inhibitory effects on Tau aggregation depend on the site of tyrosine phosphorylation.", "text": "To further test whether Y310 phosphorylation impacted K18 aggregation, we compared the in vitro aggregation of Y310 phosphorylated K18 to that of WT K18 (Fig. 6 ). As shown in Fig. 6 A and B, the aggregation of pK18 was significantly delayed compared to unmodified K18. In fact, both the ThT (Fig. 6 , A) and the sedimentation assays ( Fig. 6 , D) showed a delay of about 2 h in the fluorescence increase and loss of soluble protein, respectively. Interestingly, the final absolute value of the plateau ThT signal of the phosphorylated K18 was consistently about two to three times higher than that of WT K18, suggesting a difference in fibril structure, packing of the fibrils or susceptibility to fragmentation ( Fig. 6 ,C), which may affect ThT binding capacity and thus the end-point ThT value.", "cite_spans": [], "ref_spans": [{"start": 153, "end": 160, "text": "(Fig. 6", "ref_id": "FIGREF7"}, {"start": 176, "end": 182, "text": "Fig. 6", "ref_id": "FIGREF7"}, {"start": 292, "end": 299, "text": "(Fig. 6", "ref_id": "FIGREF7"}, {"start": 336, "end": 342, "text": "Fig. 6", "ref_id": "FIGREF7"}, {"start": 715, "end": 721, "text": "Fig. 6", "ref_id": "FIGREF7"}]}, {"section": "c-Abl-mediated inhibitory effects on Tau aggregation depend on the site of tyrosine phosphorylation.", "text": "To further investigate the effect of phosphorylation at Y310 on the early formation of \u03b2-sheet-containing species of K18, we monitored changes in K18 secondary structure overtime under aggregation conditions by CD spectroscopy. K18 displayed significantly higher ThT fluorescence signal than pK18 ( Fig. 6 , A) and sedimented more rapidly than pK18 (Fig 6,  B ). In addition, K18 fully converted to \u03b2\u2212sheet within 1 h, whereas pK18 clearly showed markedly delayed conformational shift toward \u03b2\u2212sheet spectra during 4 h of incubation ( Fig. 6 , C). As shown in Fig. 6 D, EM studies confirmed that fibril formation by pK18 was also delayed and showed significant accumulation of oligomeric amorphous aggregates at early and intermediate time points (Fig. 6 , D, 0.5 h, 1 h, 6 h: arrows), and accumulation of fragmented and fully mature fibrillar morphologies, in addition to some oligomers at later time points ( Fig. 6 , D, 6 and 24 h). These findings suggest that Y310 phosphorylation results in delayed formation of \u03b2\u2212sheet-rich K18 fibrillar structures ( Fig. 6, A, B ) and plays an inhibitory role during the nucleation phase of K18 aggregation, as demonstrated by attenuation of the pK18 conformational change ( Fig. 6 , C).", "cite_spans": [], "ref_spans": [{"start": 299, "end": 305, "text": "Fig. 6", "ref_id": "FIGREF7"}, {"start": 349, "end": 359, "text": "(Fig 6,  B", "ref_id": "FIGREF7"}, {"start": 535, "end": 541, "text": "Fig. 6", "ref_id": "FIGREF7"}, {"start": 560, "end": 566, "text": "Fig. 6", "ref_id": "FIGREF7"}, {"start": 747, "end": 754, "text": "(Fig. 6", "ref_id": "FIGREF7"}, {"start": 911, "end": 917, "text": "Fig. 6", "ref_id": "FIGREF7"}, {"start": 1057, "end": 1069, "text": "Fig. 6, A, B", "ref_id": "FIGREF7"}, {"start": 1216, "end": 1222, "text": "Fig. 6", "ref_id": "FIGREF7"}]}, {"section": "Phosphorylation on tyrosine residues reduces", "text": "Tau affinity for MTs. In light of the prominent direct association of Tau with MTs, we next asked whether Tau tyrosine phosphorylation, especially on residues Y310 and Y394, influence Tau microtubule-binding propensity. To address this question, we used full-length Tau phosphorylated by c\u2212Abl, taking advantage of the preferential phosphorylation of Y310 and Y394 among other residues, as demonstrated by mass spectrometry SP counts (Figure 2 , D). We first assessed the binding propensity of pTau to the MTs by quantifying the percent of protein pelleted when incubated with pre\u2212formed paclitaxel\u2212stabilized MTs at a single concentration (250 \u00b5g/ml Tau and 100 \u00b5g/ml of tubulin) ( Fig. 7, A) . We observed, as previously reported (16) , that Tau bound to tubulin with about 50% efficiency, while this efficiency was decreased to approximately 30% in the case of pTau. As a negative control, the BSA was found to bind MTs with low efficiency of 12%, and as a positive control, the Microtubule\u2212Associated Protein Fraction (MAPF) showed a high binding of 78% ( Fig. 7, A) , as expected. These results were further confirmed by the SDS-PAGE, where band corresponding to the molecular weight of non-phosphorylated Tau was enriched in the pellet fraction ( Fig. 7 , C, solid red arrows), whereas pTau remained predominantly in the soluble fraction. EM data showed no morphological differences for MTs bound to Tau or pTau ( Fig. 7, B ).", "cite_spans": [{"start": 732, "end": 736, "text": "(16)", "ref_id": "BIBREF16"}], "ref_spans": [{"start": 434, "end": 443, "text": "(Figure 2", "ref_id": "FIGREF3"}, {"start": 683, "end": 693, "text": "Fig. 7, A)", "ref_id": "FIGREF8"}, {"start": 1060, "end": 1070, "text": "Fig. 7, A)", "ref_id": "FIGREF8"}, {"start": 1253, "end": 1259, "text": "Fig. 7", "ref_id": "FIGREF8"}, {"start": 1420, "end": 1429, "text": "Fig. 7, B", "ref_id": "FIGREF8"}]}, {"section": "Phosphorylation on tyrosine residues reduces", "text": "Our results confirm the negative impact of tyrosine phosphorylation on the interaction of Tau with MTs, likely mediated by the large shift towards the negative electrostatic potential as well as structural rearrangements of MT-binding region through the phosphorylation of C-terminal tyrosine residues Y310 and Y394, with a possible contribution from other phosphorylated tyrosine residues requiring further investigation.", "cite_spans": [], "ref_spans": []}, {"section": "Phosphorylation on tyrosine residues reduces Tau affinity for and binding of lipid vesicles.", "text": "We have previously shown that both Tau and K18 interact with brain phosphatidylserine (BPS) vesicles resulting in vesicle disruption and the formation of highly stable oligomeric protein/phospholipid complexes (52) . Therefore, we sought to assess whether phosphorylation on tyrosine residues influenced Tau interaction with membranous vesicles and the formation of such Tau-phospholipid complexes.", "cite_spans": [{"start": 210, "end": 214, "text": "(52)", "ref_id": "BIBREF52"}], "ref_spans": []}, {"section": "Phosphorylation on tyrosine residues reduces Tau affinity for and binding of lipid vesicles.", "text": "To address this question, we incubated Tau and K18 and their respective tyrosine-phosphorylated forms with BPS vesicles at a molar Tau to phospholipid ratio of 1 to 20 and performed sedimentation assay. We found that Tau and K18 incubated with BPS vesicles co\u2212sedimented with vesicles to a larger extent compared to their phosphorylated counterparts. This is demonstrated by the reduction of phosphorylated Tau and K18 in the pellet fractions ( Fig. 8 , A, red box), signifying reduced Tau affinity and binding to lipids.", "cite_spans": [], "ref_spans": [{"start": 445, "end": 451, "text": "Fig. 8", "ref_id": "FIGREF10"}]}, {"section": "Phosphorylation on tyrosine residues reduces Tau affinity for and binding of lipid vesicles.", "text": "Next, to confirm the formation of oligomeric Tau-and K18-phospholipid complexes, Native gel analysis was performed, and showed the formation of oligomeric species by both nonphosphorylated and phosphorylated Tau and K18 ( Fig. 8, B , red boxes). These findings were further supported by CD spectroscopy (Fig. 8, D) , and EM, where oligomeric complexes were detected for all proteins without discernible morphological differences ( Fig. 8, C) , indicating no major differences in the absolute capacity of pTau and pK18 to form oligomeric structures compared to their non-phosphorylated counterparts.", "cite_spans": [], "ref_spans": [{"start": 222, "end": 231, "text": "Fig. 8, B", "ref_id": "FIGREF10"}, {"start": 303, "end": 314, "text": "(Fig. 8, D)", "ref_id": "FIGREF10"}, {"start": 431, "end": 441, "text": "Fig. 8, C)", "ref_id": "FIGREF10"}]}, {"section": "Phosphorylation on tyrosine residues reduces Tau affinity for and binding of lipid vesicles.", "text": "Next, to verify the formation of the Tau/K18 phospholipid-oligomer complexes by the nonphosphorylated and phosphorylated Tau and K18, size exclusion chromatography (SEC) was performed. pTau and pK18 complexes peaks ( Fig. 8 , E, red) systematically eluted later compared to their non-phosphorylated counterparts ( Fig. 8 , E, blue; dashed lines indicate peaks of the elution profiles, arrows indicate the direction of elution profile shift) ( Fig. 8 , E, dashed). These data are well in line with biochemical data (Fig. 8, A, B ) and suggest that Tau-lipid complex formation is affected by tyrosine phosphorylation of Tau and K18, resulting in oligomeric Tau-and K18phospholipid complexes of smaller size, either through the reduction of the number of protein and/or phospholipid molecules per complex, through complex compaction. The differences in the pattern of the SDS-resistant oligomers formed by Tau and pTau oligomer suggests that they exhibit distinct biophysical properties and/or stability.", "cite_spans": [], "ref_spans": [{"start": 217, "end": 223, "text": "Fig. 8", "ref_id": "FIGREF10"}, {"start": 314, "end": 320, "text": "Fig. 8", "ref_id": "FIGREF10"}, {"start": 443, "end": 449, "text": "Fig. 8", "ref_id": "FIGREF10"}, {"start": 514, "end": 527, "text": "(Fig. 8, A, B", "ref_id": "FIGREF10"}]}, {"section": "Phosphorylation on tyrosine residues reduces Tau affinity for and binding of lipid vesicles.", "text": "Tau and K18 were reported to undergo the structural transitions upon binding to lipid membranes (28, (53) (54) (55) . Therefore, to investigate the effects of tyrosine-phosphorylated Tauphospholipids interactions, we monitored changes in Tau and K18 secondary structures by CD spectroscopy. Interestingly, the conformational transitions towards more structured forms of the proteins in the presence of BPS vesicles were markedly more pronounced for non-phosphorylated Tau and K18 ( Fig. 8, D) .", "cite_spans": [{"start": 96, "end": 100, "text": "(28,", "ref_id": "BIBREF28"}, {"start": 101, "end": 105, "text": "(53)", "ref_id": "BIBREF53"}, {"start": 106, "end": 110, "text": "(54)", "ref_id": "BIBREF54"}, {"start": 111, "end": 115, "text": "(55)", "ref_id": "BIBREF55"}], "ref_spans": [{"start": 482, "end": 492, "text": "Fig. 8, D)", "ref_id": "FIGREF10"}]}, {"section": "Phosphorylation on tyrosine residues reduces Tau affinity for and binding of lipid vesicles.", "text": "Our results demonstrate that phosphorylated Tau and K18 had reduced lipid vesicle binding affinity and formed oligomers that showed less pronounced structural conformation transitions and SEC elution profiles that were shifted towards smaller species compared to nonphosphorylated Tau and K18 in the presence of BPS vesicles. However, the capacity to associate with lipids was still preserved in the phosphorylated variants. Interestingly, the reduction of monomeric pTau protein band observed in BPS sample was concomitant with an increase of oligomeric bands of slightly different profile compared to those observed for nonphosphorylated Tau (Fig. 8, B ). This observation combined with the differences in the SEC and CD profiles of phosphorylated Tau and K18 compared to the unmodified proteins suggest that the oligomers formed by the phosphorylated proteins exhibit distinct conformational and size properties.", "cite_spans": [], "ref_spans": [{"start": 644, "end": 654, "text": "(Fig. 8, B", "ref_id": "FIGREF10"}]}, {"section": "Phosphorylation on tyrosine residues reduces Tau affinity for and binding of lipid vesicles.", "text": "Tyrosine 310 phosphorylation attenuates Tau affinity for and binding of lipid vesicles. Next, we sought to determine the underlying structural basis for the reduced lipid-binding affinity of tyrosine-phosphorylated Tau. Previously, we showed that the core of the highly-stable oligomeric Tau-phospholipid complexes was comprised of both the PHF6* and PHF6 hexapeptide motifs, the latter in a \u03b2\u2212sheet conformation (52) . Since the Y310 residue is located in the PHF6 hexapeptide, part of the R3 repeat peptide (Fig. 1) , which plays an important role in mediating the interaction between Tau and membranes (52, 56) , we set out to assess the effect of R3 Y310 phosphorylation on the lipidmediated formation of fibrils by R3 and its interaction with membranes in vitro.", "cite_spans": [{"start": 413, "end": 417, "text": "(52)", "ref_id": "BIBREF52"}, {"start": 605, "end": 609, "text": "(52,", "ref_id": "BIBREF52"}, {"start": 610, "end": 613, "text": "56)", "ref_id": "BIBREF56"}], "ref_spans": [{"start": 509, "end": 517, "text": "(Fig. 1)", "ref_id": "FIGREF1"}]}, {"section": "Phosphorylation on tyrosine residues reduces Tau affinity for and binding of lipid vesicles.", "text": "First, we incubated R3 and pR3 peptides with BPS vesicles at a molar peptide to phospholipid ratio of 1 to 1 and monitored fibril formation using EM ( Fig. 9, A) . We observed a very rapid formation of large fibrils by R3, whereas the pR3 peptide exhibited a significant delay in fibril formation ( Fig. 9, A, 1h ). Furthermore, whereas R3 formed long fibrils at a later time point, pR3 formed fibrils relatively shorter than R3 ( Fig. 9 , A, 24h, insets).", "cite_spans": [], "ref_spans": [{"start": 151, "end": 161, "text": "Fig. 9, A)", "ref_id": "FIGREF11"}, {"start": 299, "end": 312, "text": "Fig. 9, A, 1h", "ref_id": "FIGREF1"}, {"start": 431, "end": 437, "text": "Fig. 9", "ref_id": "FIGREF11"}]}, {"section": "Phosphorylation on tyrosine residues reduces Tau affinity for and binding of lipid vesicles.", "text": "Our in vitro aggregation studies suggested that the phospholipids become incorporated within the fibrils during the fibrilization of R3. Therefore, we sought to assess the effects of Y310 phosphorylation influence R3 binding and incorporation of phospholipids into R3 fibrills. To this end, we co\u2212incubated the R3 and pR3 peptides with vesicles containing 1% NBD\u2212labelled fluorescent phospholipids (fPS). Under these conditions, we observed the formation of fluorescent fibrils in the case of R3, suggesting that R3 bound to and incorporated phospholipids within the fibril matrix. No fluorescent signal was observed in the case of the fibrils formed by pR3, suggesting that they were devoid of phospholipids ( Fig. 9, B ).", "cite_spans": [], "ref_spans": [{"start": 711, "end": 720, "text": "Fig. 9, B", "ref_id": "FIGREF11"}]}, {"section": "Phosphorylation on tyrosine residues reduces Tau affinity for and binding of lipid vesicles.", "text": "To further confirm the interaction of R3 and pR3 with the phospholipids, we performed a peptidelipid sedimentation assay based on free lipid vesicle flotation. R3 and pR3 were incubated for 24 h with BPS vesicles containing 1% NBD\u2212labelled fluorescent phospholipids, subsequently centrifuged, and run on SDS\u2212PAGE and imaged with a fluorescent scanner, that detects fluorescent lipid signal ( Fig.  9 , C). In this assay, vesicles alone floated and remained in the supernatant ( Fig. 9 , C, fPS, sup.) and did not pellet to a high extent. However, upon association with the R3 peptide, a fluorescent signal could be observed in the pellet fractions. The signal present in the pellet fraction of R3-fPS at ~30 min was likely due to the very aggregation and fibrillization of R3 that occurred during the short period of time required to aliquot and process the sample. We observed that phospholipids in the R3 sample were solely present in the pellet fraction after 24 h incubation, but that only a small fraction of the phospholipids in the pR3 sample were found in the pellet (Fig.  9, C) . These results further confirm our EM and fluorescence microscopy data and indicate that the capacity of R3 to form fibrils that contain phospholipids in the presence of BPS vesicles was significantly diminished by phosphorylation of residue Y310. These findings are in line with data obtained with the full-length Tau and K18 data (Fig. 8) , and further suggest that lipid incorporation into the fibrillar matrix is mediated by the aggregation\u2212prone PHF6 peptide.", "cite_spans": [], "ref_spans": [{"start": 392, "end": 399, "text": "Fig.  9", "ref_id": "FIGREF11"}, {"start": 478, "end": 484, "text": "Fig. 9", "ref_id": "FIGREF11"}, {"start": 1075, "end": 1087, "text": "(Fig.  9, C)", "ref_id": "FIGREF11"}, {"start": 1421, "end": 1429, "text": "(Fig. 8)", "ref_id": "FIGREF10"}]}, {"section": "Discussion", "text": "Despite the presence of tyrosine residues in domains that regulate Tau interactions with microtubules and its aggregation propensity, the role of Tau tyrosine phosphorylation in regulating Tau functions, structure, aggregation and toxicity remain generally understudied. For example, tyrosine 310 residue is located in the PHF6 motif of Tau protein, which has been identified as forming \u03b2-sheet structure in the core of Tau fibrils and is necessary for Tau aggregation in vitro. Despite consistent findings implicating PHF6 in the initiation of Tau aggregation, stabilization of Tau fibrils and the importance of the interaction of Y310 and I308 for Tau filament formation (35) , there are no reports in the literature examining the potential impact of phosphorylation at this residue on the physiological and/or pathogenic properties of biologically-relevant full-length Tau proteoforms. This is possibly due to the lack of well-characterised pY310 specific antibodies and until recently the lack of methods for site-specific phosphorylation of Tau (57) (58) (59) .", "cite_spans": [{"start": 673, "end": 677, "text": "(35)", "ref_id": "BIBREF35"}, {"start": 1050, "end": 1054, "text": "(57)", "ref_id": "BIBREF57"}, {"start": 1055, "end": 1059, "text": "(58)", "ref_id": "BIBREF58"}, {"start": 1060, "end": 1064, "text": "(59)", "ref_id": "BIBREF59"}], "ref_spans": []}, {"section": "Discussion", "text": "We speculated that modifications, such as the addition of bulky negatively-charged phosphogroup to Y310 and/or other tyrosine residues would significantly alter the biophysical, aggregation and MT binding properties of Tau. In addition, the stoichiometry and localization of Tau tyrosine phosphorylation may confer differential effects on either N-terminal domain (Y18, Y29), that is implicated in Tau secretion (60) and regulation of microtubule stabilization (61) , or on mid-and C-terminal domains (Y197, Y310, Y394), that are implicated in the modulation of Tau aggregation, microtubule-and lipid-binding properties (for a recent review see (62) ). Furthermore, recent studies using cryoelectron microscopy of Tau filaments from human brain confirmed the PHF6 motif as a core component of Tau filaments, with Y310 buried within the interior of Tau filament in Pick's disease, as well as in PHFs and SFs in AD, and Tau filaments in CTE (63-65) ( Fig. 10) , supporting our initial rationale for initiating the studies outlined in this manuscript. Although the extrapolations of in vitro studies' results to in vivo conditions have obvious limitations and must be applied cautiously, the phosphorylation of Y310 residue, which is buried inside the core of Tau filaments in some Tauopathies, may have implications for some forms of disease featuring specific Tau strains.", "cite_spans": [{"start": 461, "end": 465, "text": "(61)", "ref_id": "BIBREF61"}, {"start": 645, "end": 649, "text": "(62)", "ref_id": "BIBREF62"}], "ref_spans": [{"start": 949, "end": 957, "text": "Fig. 10)", "ref_id": "FIGREF1"}]}, {"section": "Discussion", "text": "Our results indicate that a) phosphorylation of Tau at multiple tyrosine residues inhibits Tau aggregation through cumulative effects of phosphorylation at multiple or all tyrosine residues, and that b) phosphorylation at residue Y310 is a key determinant of Tau aggregation in vitro. We show that Y310 phosphorylation appears to be sufficient to significantly delay Tau aggregation in vitro and reduces the propensity of the microtubule-binding region of Tau to aggregate through attenuation of the PHF6 hexapeptide propensity to adopt \u03b2-sheet rich structure in the context of the full-length Tau. Structural studies by NMR revealed that phosphorylation at Y310 induced local structural modifications in the PHF6 region of K18, thereby decreasing its propensity to adopt a \u03b2-sheetcontaining secondary structure, contributing to the decreased aggregation propensity.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Y310 is the only tyrosine residue located in the MT-binding region of Tau, which highlights the potential role of Y310 in regulating Tau affinity for MTs. Our work here shows that phosphorylation on tyrosine residues affects fulllength Tau affinity for MTs, in contrast to previous reports where Tau phosphorylated by Fyn (16) , Arg (19) or c-Abl (18) in vitro was found to bind to MTs with an efficiency similar to that of the non-phosphorylated protein. These findings suggest that tyrosine phosphorylation of Tau on either Y18 (i.e. by Fyn) or Y394 (by c-Abl or Arg) did not significantly alter its affinity for MTs. Our data point toward residue Y310 as an important regulator of Tau/MTs interactions. One notable difference to previous reports is that our studies relied on the use of pTau proteins that are site-specifically phosphorylated at residues Y310 or Y394 (Figure 2, D) . To the best of our knowledge, this is the first report demonstrating the role of tyrosine phosphorylation and Y310 in particular in regulating Tau MT-binding domain.", "cite_spans": [{"start": 322, "end": 326, "text": "(16)", "ref_id": "BIBREF16"}, {"start": 333, "end": 337, "text": "(19)", "ref_id": "BIBREF19"}, {"start": 347, "end": 351, "text": "(18)", "ref_id": "BIBREF18"}], "ref_spans": [{"start": 871, "end": 884, "text": "(Figure 2, D)", "ref_id": "FIGREF3"}]}, {"section": "Discussion", "text": "The fact that the MT-binding domain of Tau is also responsible for Tau-lipid interactions also points to the potential role of Y310 in regulating Tau affinity for lipid membranes. We have previously demonstrated that the PHF6 hexapeptide located within R3 interacts with negatively charged vesicles, resulting in the formation of \u03b2\u2212strand-rich mixed phospholipid/peptide fibrils (52) . In this work, we show that tyrosine phosphorylation, at least at residue Y310, reduced Tau binding to negativelycharged lipid membranes, which may have important implications for Tau functions at the cell plasma membrane. Our findings are especially relevant in the light of reports demonstrating that Tau tyrosine phosphorylation occurs in the human brain under both physiological and pathological conditions. Although aberrant serine and threonine phosphorylation of Tau is well-established in the pathology of AD and other Tauopathies (66), the contributions of tyrosine phosphorylation to Tau pathology and Tau-mediated toxicity in these disorders remain poorly understood . Several lines of evidence suggest that Tau tyrosine phosphorylation is an early event in the development of AD (67) . In 1991, Wood and Zinmeister used pan anti-phosphotyrosine antibodies to demonstrate the increase of nonspecific tyrosine phosphorylation in AD patient's brain tissue of NFT-bearing neuronal somatodendritic and dystrophic neurite compartments, as well as microglia-resembling cells within neuritic plaques, whereas predominantly neurite staining was observed in non-AD tissue (68) . Similarly, Shapiro et al. reported increased non-specific phosphotyrosine immunoreactivity in the frontal cortex and hippocampus of AD patients (69) . Since then, several reports based on antibody recognition or mass spectrometry have shown that Tau is phosphorylated on residues Y18, Y197 and Y394 (16, 18, 19, 70) in AD and in foetal brain, whereas phosphorylation at positions Y18 (71) and Y394 (18) have been clearly shown to occur under physiological conditions. Furthermore, in the P301L transgenic mouse model, Vega et al. showed that Tau phosphorylation at residues Y197 and Y394 correlated with the formation of Tau aggregates and occurred concurrently with serine and threonine phosphorylation (detected by PHF1 antibody at residues S396/S404 and by CP13 at residues S202/T205) known to be implicated in AD pathogenesis (70) . Moreover, two tyrosine kinases, Fyn and c-Abl, which are known to phosphorylate Tau, have been shown to colocalize with Tau in NFTs (18, 72) . Interestingly, treatment with A\u03b2 increased the activity of both kinases and led to a subsequent increase in Tau tyrosine phosphorylation and cell death, which could be prevented by treatment with tyrosine kinase inhibitors (73) . In addition, Tau tyrosine phosphorylation may be involved in regulating several cellular activities of Tau linked to signalling events at the cell membrane, in lipid rafts and/or in the neuron growth cone (16, 18) . Overall, these findings strongly suggest that Tau tyrosine phosphorylation plays important roles in both the healthy state and in neurodegenerative disease conditions (74) , and further studies investigating the specific role of Tau residue Y310 modifications are warranted.", "cite_spans": [{"start": 379, "end": 383, "text": "(52)", "ref_id": "BIBREF52"}, {"start": 1176, "end": 1180, "text": "(67)", "ref_id": "BIBREF67"}, {"start": 1559, "end": 1563, "text": "(68)", "ref_id": "BIBREF68"}, {"start": 1710, "end": 1714, "text": "(69)", "ref_id": "BIBREF69"}, {"start": 1865, "end": 1869, "text": "(16,", "ref_id": "BIBREF16"}, {"start": 1870, "end": 1873, "text": "18,", "ref_id": "BIBREF18"}, {"start": 1874, "end": 1877, "text": "19,", "ref_id": "BIBREF19"}, {"start": 1964, "end": 1968, "text": "(18)", "ref_id": "BIBREF18"}, {"start": 2535, "end": 2539, "text": "(18,", "ref_id": "BIBREF18"}, {"start": 2540, "end": 2543, "text": "72)", "ref_id": "BIBREF72"}, {"start": 2769, "end": 2773, "text": "(73)", "ref_id": "BIBREF73"}, {"start": 2981, "end": 2985, "text": "(16,", "ref_id": "BIBREF16"}, {"start": 2986, "end": 2989, "text": "18)", "ref_id": "BIBREF18"}, {"start": 3159, "end": 3163, "text": "(74)", "ref_id": "BIBREF74"}], "ref_spans": []}, {"section": "Discussion", "text": "In conclusion, our findings show that Tau phosphorylation on multiple tyrosine residues may have additive effects on inhibiting Tau fibril formation, and attenuating its MT-and lipidbinding affinity. In addition, our findings underscore the unique role of Y310 phosphorylation in regulating these properties of tau, which is consistent with its position within the aggregation-prone PHF6 hexapeptide, itself located in the MT-binding domain of the protein.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "We show that phosphorylation at Y310 is sufficient to significantly delay the fibrillization of full-length Tau and K18, and of the R3 repeat fragment. Our results strongly implicate tyrosine phosphorylation of Tau as a novel target for disease-modifying therapies of proteopathic disorders driven by Tau aggregation. Furthermore, our results underscore the critical importance of developing the new tools to assess the extent of Tau tyrosine phosphorylation in different Tauopathies and enable investigations of the role of tyrosine phosphorylation in regulating Tau function in health and disease.", "cite_spans": [], "ref_spans": []}, {"section": "Experimental procedures", "text": "DNA constructs and mutagenesis. The K18 fragments were synthesized by GeneArt Gene Synthesis (Life Technologies) and cloned into the pT7-7 for bacterial expression. Tau 2N4R in pCMV6-XL5 vectors was obtained from OriGene Technologies, Inc. and cloned in pET-15b for bacterial expression. Single site mutagenesis was performed in the pET-15b using the QuikChange Site-Directed Mutagenesis Kit (Stratagene), as per manufacturer's instructions. pET21d SH2-CD c-Abl T231R and pCDFDuet-1 YopH for bacterial expression were kindly donated by Prof. Oliver Hantschel (ISREC Institute, EPFL).", "cite_spans": [], "ref_spans": []}, {"section": "Peptides.", "text": "The R3 (306-VQIVYKPVDLSKVTSKCGSLGNIHHK-331and the pY-R3 (306-VQIV(pY)KPVDLSKVTSKCGSLGNIHHK-331) corresponding to the third microtubulebinding repeat without/with phosphorylation at Y310 were purchased from CS Bio Co.", "cite_spans": [], "ref_spans": []}, {"section": "Peptides.", "text": "Other compounds. Tubulin protein isolated from porcine brain (97% or >99 % pure), provided as a lyophilized powder was purchased from Cytoskeleton Inc. Paclitaxel from the pacific yew tree, Taxus brevifolia (purity of >99.5%), used inhibit microtubule depolymerization, provided as a lyophilized powder and resuspended at 2 mM anhydrous DMSO was purchased from Cytoskeleton Inc. (U.S.A). Guanosine triphosphate (GTP) provided as a lyophilized powder, resolubilized at 100 mM with ice-cold MilliQ water was purchased from Cytoskeleton Inc. (U.S.A). Microtubule (MT) associated protein fraction (MAPF) isolated from bovine brain, used as positive control for the MT binding assay, supplied as lyophilized powder was purchased from Cytoskeleton Inc. (U.S.A). Phosphatidylserine isolated from porcine brain (BPS) and fluorescently labeled phospholipid 1-oleoyl-2-{6-[(7-nitro-2-1,3-benzoxadiazol-4yl)amino]hexanoylM-sn-glycero-3phosphoserine (fPS) were purchased from Avanti Polar Lipids, Inc. Heparin sodium salt was from Applichem GmbH. K18) . Tau isoforms 2N4R in pET-15b, K18 in pT7-7 were expressed in E. coli strain BL21. The purification protocol of Tau 2N4R Tau was adapted from (75) . Cells were pelleted and broken by sonication in lysis buffer (3 M urea in 10 mM MES, pH 6.5, 1 mM DTT, 1 mM EDTA, 1 mM PMSF). After centrifugation at 150,000 g for 1 h at 4\u00b0C, 1% (w/v) of streptomycin sulfate was added to the supernatant, and the solution was stirred for 90 min at 4\u00b0C. After centrifugation at 27,000 g for 1 h at 4\u00b0C, the supernatant was dialyzed overnight at 4\u00b0C in ion exchange (IEX) buffer A (10 mM MES, pH 6.5, 20 mM NaCl, 1 mM DTT, 1 mM EDTA). The supernatant was filtered and loaded on a cation-exchange column (MonoS, GE Healthcare) and the protein was eluted using a salt gradient (increasing the NaCl concentration of IEX buffer A from 20 mM to 1 M NaCl over 20 column volumes). Fractions containing the proteins were dialyzed overnight against acetic buffer (5% acetic acid in water) and loaded on a reverse-phase HPLC C4 column (PROTO 300 C4 10 \u00b5m, Higgins Analytical; buffer A: 0.1% TFA in water, buffer B: 0.1% TFA in acetonitrile), and the protein was eluted using a gradient from 30 to 40% buffer B over 40 min (15 ml/min). K18 in pT7-7 was purified following a protocol adapted from (76) . Briefly, cells were broken by sonication in IEX buffer B (10 mM HEPES, pH 6.5, 1 mM MgCl2, 20 mM NaCl, 1 mM DTT, 1 mM PMSF). After centrifugation at 40,000 g for 30 min, the supernatant was boiled until the solution became cloudy (~5 min) and centrifuged again for 30 min. The supernatant was filtered and loaded on a cation-exchange column (MonoS, GE Healthcare), and the protein was eluted using a salt gradient (increasing the NaCl concentration of IEX buffer B from 20 mM to 1 M NaCl over 20 column volumes). Fractions containing the K18 fragment were immediately loaded on a reverse-phase HPLC C4 column (PROTO 300 C4 10 \u00b5m, Higgins Analytical; buffer A: 0.1% TFA in water, buffer B: 0.1% TFA in acetonitrile), and the protein was eluted using a gradient from 30 to 40% buffer B over 40 min (15 ml/min).", "cite_spans": [{"start": 1183, "end": 1187, "text": "(75)", "ref_id": "BIBREF75"}, {"start": 2307, "end": 2311, "text": "(76)", "ref_id": "BIBREF76"}], "ref_spans": [{"start": 1035, "end": 1039, "text": "K18)", "ref_id": "FIGREF1"}]}, {"section": "Protein expression and purification (Tau and", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "SH2-CD c-Abl expression and purification.", "text": "Recombinant SH2-CD c-Abl, T231R and YopH were co-overexpressed and SH2-CD c-Abl purified from E.coli as previously described (77) . Briefly, cells were grown in 2 L of TB media, until the OD reached 1.0, after which the cultures were cooled down and induced overnight at 18\u00b0C, with 0.2 mM IPTG. The cells were then lysed by sonication in HisTag binding buffer HA (50 mM Tris pH 8, 500 mM NaCl, 5% Glycerol, 25 mM imidazole) and centrifuged twice at high speed (50 000 g, 20 min, 4\u00b0C), before being injected in 5 mL HisTag columns (histrap 5mL column, GE Healthcare, buffer HA: same as above, buffer HB: same as HA with 0. Preparation and characterization of heparininduced Tau and K18 fibrils. Fibrils of WT, mutants and phosphorylated Tau and K18 were formed by incubating monomeric protein in 10 mM phosphate, pH 7.4, 50 mM NaF and 0.5 mM DTT with heparin sodium salt (Applichem GmbH,Activity 204.7 I.U./mg MW: 8000-25000 g/mol) at a molar heparin:protein ratio of 1:4 under constant orbital agitation (1000 rpm, Peqlab, Thriller) at 37\u00b0C for up to 72 hours.", "cite_spans": [{"start": 125, "end": 129, "text": "(77)", "ref_id": "BIBREF77"}], "ref_spans": []}, {"section": "SH2-CD c-Abl expression and purification.", "text": "R3 and pY-R3 peptide aggregation. 100 \u00b5M R3 or pY-R3 peptide were dissolved in 10 mM Tris, 50 mM NaF,0.5 mM DTT and pH-adjusted to 7.4. The solution was then vortexed, centrifuged for 20 min at 14000 rpm and the supernatant was incubated in absence or presence of 25 \u00b5M heparin sodium salt (Applichem GmbH) at 37 \u00b0C, with constant orbital agitation (1000 rpm, Peqlab, Thriller).", "cite_spans": [], "ref_spans": []}, {"section": "Vesicle preparations.", "text": "Vesicles were prepared using the extrusion method. Briefly, individual phospholipids or phospholipid mixtures in chloroform were dried using an argon stream to form a thin film on the wall of a glass vial. Potentially remaining chloroform was removed by placing the vial under vacuum overnight. The phospholipids were resolubilized in 10 mM HEPES, pH 7.4, 100 mM NaCl and 2.5 mM DTT to the desired final concentration by sonication. The solution was then passed through an Avestin LiposoFast extruder (Avestin Inc.) (membrane pore size: 0.1 \u00b5m), and the size and homogeneity of the resulting vesicles were assessed by EM. For the preparation of fluorescently labeled vesicles, fluorescent and non-fluorescent phospholipids in chloroform were mixed at a molar ratio of 1:99 prior to the initial drying step.", "cite_spans": [], "ref_spans": []}, {"section": "Vesicle preparations.", "text": "Preparation of mixed protein/phospholipid complexes. Protein/phospholipid complexes were prepared by incubating BPS vesicles with Tau or K18 at a molar protein:phospholipid ratio of 1:20 in 10 mM HEPES, pH 7.4, 100 mM NaCl, 2.5 mM DTT for 48 h at 37\u00b0C. The resulting protein/phospholipid complexes were separated from the remaining vesicles and soluble protein by SEC using a Superose 6 column (GE Healthcare).", "cite_spans": [], "ref_spans": []}, {"section": "Preparation of mixed R3 and pY-R3", "text": "peptides/phospholipid fibrils. 100 \u00b5M of R3 and pY-R3 peptides were incubated with BPS vesicles at a molar ratio of 1:1. For fluorescence microscopy, the peptides were incubated with vesicles containing 1% fluorescent NBDphospholipids, imaged with confocal laserscanning microscope (LSM 700, Zeiss) and analyzed using Zen software.", "cite_spans": [], "ref_spans": []}, {"section": "Preparation of Microtubules.", "text": "Tubulin was dissolved at a concentration of 5 mg/ml in icecold General tubulin buffer (80 mM PIPES, 0.5 mM EGTA, 2 mM MgCl2, pH 6.9) supplemented with 1 mM GTP and snap-frozen as 10 \u00b5l aliquots in liquid nitrogen and stored at -80\u00b0C. Microtubules were assembled by defrosting an aliquot of 10 \u00b5l tubulin stock in a RT water bath, immediately placed on ice and incubated for 20 min at 35\u00b0C in 100 \u00b5l pre-warmed (35\u00b0C) General tubulin buffer supplemented with 1 mM GTP and 5% glycerol. Then the solution was diluted with 100 \u00b5l General tubulin buffer supplemented with 1 \u00b5l of paclitaxel (Taxol\u00a9, stock at 2 mM), gently mixed and kept at RT. Microtubule morphology was systematically verified by electron microscopy.", "cite_spans": [], "ref_spans": []}, {"section": "Preparation of Microtubules.", "text": "Microtubule binding assay. Pre-formed paclitaxel-stabilized MTs were incubated for 30 min at RT with Tau, pTau, MAPF or bovine serum albumin (BSA) (250 \u03bcg/ml protein and 100 \u03bcg/ml of tubulin) in General tubulin buffer supplemented with 1 mM GTP and 5% glycerol (total of 50 \u03bcl per sample). The samples were placed on top of a 100 \u03bcl Cushion buffer (i.e. General tubulin buffer containing 60 % glycerol) in 1.5 ml tubes. The tubes were centrifuged at 100'000 g for 40 min at RT. The top 50 \u03bcl of each tube was mixed with 10 \u03bcl of 5x Laemmli buffer (supernatant) and the pellet was resuspended in 50 \u03bcl 1x Laemmli buffer (pellet). The samples were run on SDS-PAGE gels. The relative amount of Tau, pTau, MAPF or BSA in the supernatant and in the pellet were estimated by measuring the band intensity using Fiji software (National Institute of Health) over 5 repeats, and represented as mean +/-SD.", "cite_spans": [], "ref_spans": []}, {"section": "Preparation of Microtubules.", "text": "Monitoring of c-Abl Tau/K18 phosphorylation by mass spectrometry. 100 or 200 \u03bcg of WT Tau or K18 were incubated with 5 or 10 \u03bcg of recombinant c-Abl in 50 mM Tris, 5 mM MgCl2, 1 mM DTT, 20 mM Na3VO4 (phosphatase inhibitor), 3 mM MgATP at a pH of 7.5. Reactions were performed for 4 h at 30\u00b0C without agitation. The reactions were followed using ESI-MS on a Thermo LTQ ion trap system.", "cite_spans": [], "ref_spans": []}, {"section": "Tandem MS/MS of in vitro c-Abl phosphorylated recombinant Tau.", "text": "Tau phosphorylated with C-Abl as described above were run on an SDS-PAGE and stained using Simply Blue Safe Stain (Life Technologies). The bands corresponding to Tau were excised, destained with 50% ethanol in 100 mM ammonium bicarbonate, pH 8.4, and dried. The proteins were digested in gel by covering gel pieces with a trypsin solution (12.5 ng/\u00b5l in 50 mM ammonium bicarbonate (pH 8.4), 10 mM calcium chloride) at 37\u00b0C overnight. The digested peptides were subjected to TiO2 phosphopeptide enrichment, concentrated to dryness, resuspended in acetonitrile and dried again. After repeating this step, the dried peptides were resuspended in 20 \u03bcl of 20% formic acid, and 2% acetonitrile, desalted on C18 OMIX tips (Agilent Technologies), and analyzed by a capillary LC-ESI-MS system (Thermo Scientific LTQ Orbitrap instrument). The collected MS/MS spectra were matched against human and scored using Mascot and Sequest algorithms. The data were then analyzed using Scaffold version 4.0 (Proteome Software, http://www.proteomesoftware.com/). Transmission electron microscopy. Samples (3.5 \u03bcl) were applied onto glow-discharged Formvar/carbon-coated 200-mesh copper grids (Electron Microscopy Sciences) for 1 min. The grids were blotted with filter paper, washed twice with ultrapure water and once with staining solution (uranyl formate 0.7% (w/V)), and then stained with uranyl formate for 30 sec. The grids were blotted and dried. Specimens were inspected with a Tecnai Spirit BioTWIN operated at 80 kV and equipped with an LaB6 filament and a 4K x 4K FEI Eagle CCD camera.", "cite_spans": [], "ref_spans": []}, {"section": "Tandem MS/MS of in vitro c-Abl phosphorylated recombinant Tau.", "text": "Circular dichroism (CD) spectroscopy. CD spectra were recorded on a Jasco J-815 CD spectrometer operated at 20\u00b0C. To minimize buffer absorption, the buffer was modified to 10 mM phosphate buffer, pH 7.4, with 50 mM NaF and 0.5 mM DTT. CD spectra were acquired from 195 nm to 250 nm at a scan rate of 50 nm/min and in increments of 0.2 nm. For each sample, five spectra were averaged and smoothed using binomial approximation.", "cite_spans": [], "ref_spans": []}, {"section": "Nuclear", "text": "Magnetic Resonance (NMR) spectroscopy. 1 H-15 N HSQC spectra were collected at 25 o C on a Bruker Avance 600 MHz spectrometer using samples containing 500 \u03bcM K18 or pK18 peptide in 10 mM Na2HPO4, 100 mM NaCl, 1 mM DTT, 10% D2O buffer at pH 7.4. Resonance assignments are based on the previously published assignments of the K18 spectrum (66) .", "cite_spans": [{"start": 39, "end": 40, "text": "1", "ref_id": "BIBREF0"}, {"start": 337, "end": 341, "text": "(66)", "ref_id": "BIBREF66"}], "ref_spans": []}, {"section": "Sedimentation assay.", "text": "Taking advantage of the fact that high-speed centrifugation sediments fibrils but not monomeric or soluble oligomeric species, the sedimentation assay makes it possible to assess the ratio of fibrillised-tosoluble protein. 20 \u00b5l of WT Tau, K18 or Y->F mutants aggregation reactions were pelleted by ultracentrifugation at 200'000 g of 2 h at 4\u00b0C. The supernatant was mixed with 2x Laemmli buffer and run on 15% SDS-PAGE. When stated, the amount of soluble material was quantified by measuring the band intensity using Fiji software (National Institute of Health) and averaged over at least three independent repeats.", "cite_spans": [], "ref_spans": []}, {"section": "Thioflavin T fluorescence measurements.", "text": "Thioflavin T (ThT) fluorescence reading (excitation wavelength of 450 nm, emission wavelength of 485 nm) was performed in triplicate with a ThT concentration of 60 \u03bcM and a peptide concentration of 60 \u03bcM or a protein concentration of 3 \u03bcM in 50 mM glycine, pH 8.5, using a Bucher Analyst AD plate reader without shaking.", "cite_spans": [], "ref_spans": []}, {"section": "Thioflavin T fluorescence measurements.", "text": "Vesicle binding assay. The co-sedimentation assay was used to assess initial binding of protein to vesicles. Tau or K18 WT, or tyrosine phosphorylated (10 \u00b5M) were mixed with BPS vesicles (200 \u00b5M) to a total volume of 20 \u00b5l and immediately centrifuged at 200,000 g for 2 h at 4\u00b0C. At this speed, the vesicles pellet, and protein bound to them co-sediment with the vesicles. Both the supernatant, containing unbound protein, and the resuspended pellet, containing vesicles with bound protein, were run on 15% SDS-PAGE gels. The binding propensity of pTau to the MTs was quantified as the percent of protein pelleted when incubated with pre\u2212formed paclitaxel\u2212stabilized MTs at a single concentration (250 \u00b5g/ml pTau and 100 \u00b5g/ml of tubulin). Tau bound to tubulin with about 50 % efficiency, while this efficiency was decreased to about 30% in the case of pTau. As a negative control, we used BSA, which showed low MT binding efficiency of 12%. As a positive control, the Microtubule\u2212Associated Protein Fraction (MAPF) was used and showed a high binding of 78%. The averaged quantification from 5 repeats, represented as mean +/-SD with individual points plotted. Two-tailed ANOVA with Tukey's multiple comparisons test, significance values are denoted by: * p < 0.05; **, ## and $$ p < 0.001. 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Selected fractions were desalted using two HiPrep 26/10 desalting columns (GE Healthcare) in series (Desalting buffer: 20 mM Tris pH 8, 50 mM NaCl, 5 % Glycerol, 1 mM DTT), combined and further purified by anion-exchange chromatography using a MonoQ 5/50 GL column (GE Healthcare, buffer A: 20 mM Tris, 5% Glycerol, 1 mM DTT, pH 8.0, buffer B: same as buffer A with 1 M NaCl). The final concentration of the c-Abl kinase was determined using the UV absorbance at 280 nm (M = 46797 g.mol-1 and \u03b5280 = 80010 M-1.cm-1). Large scale preparation of phosphorylated K18, Tau and Y-> F mutants by c-Abl. The large-scale phosphorylation of 10 mg K18, Tau and Tau Y-> F mutants were performed for 4 h in 50 mM Tris, 5 mM MgCl2, 1 mM DTT, 20 mM Na3VO4 (phosphatase inhibitor) in the presence of 3 mM MgATP, pH,7.5 at 30\u00b0C. We used c-Abl kinase at a mass to mass ratio of 1:20 (kinase:Tau). The reaction mixture was followed by ESI-MS to verify the completion of the phosphorylation. Additional kinase and MgATP were added when needed. Phosphorylated K18, Tau and Y-> F mutants were purified by reversephase HPLC preparative C4 column (PROTO 300 C4 10 \u00b5m Higgins Analytical; buffer A: 0.1% TFA in water, buffer B: 0.1% TFA in acetonitrile) using a linear gradient of 30 to 40 % of B in 40 min for Tau or 20 to 35 % of B in 40 min for K18. The HPLC fractions were analyzed by LC-MS and once pure were pooled and lyophilized.", "type": "figure"}, "FIGREF1": {"text": "The abbreviations used are: Abl Abelson murine leukemia viral oncogene homolog FTDP-17 frontotemporal dementia with parkinsonism linked to chromosome 17 GTP guanosine triphosphate HSCQS heteronuclear single quantum coherence spectroscopy LC/MS liquid chromatography-mass spectrometry MAPF microtubule\u2212associated protein fraction MS/MS tandem mass spectrometry MT microtubule MTBD microtubule-binding domain MTBR microtubule-binding region NBD nitrobenzoxadiazole NFT neurofibrillary tangle NMR nuclear magnetic resonance PD Parkinson's disease pS phospho-serine PSP progressive supranuclear palsy pT phospho-threonines PTM post-translational modification pY phospho-tyrosine RP\u2212HPLC reversed phase high-performance liquid chromatography RT room temperature SD standard deviation SDS-PAGE sodium dodecyl sulphate-polyacrylamide gel electrophoresis SP spectral count ssi secondary shift index Syk Spleen tyrosine kinase ThT thioflavin T TTBK1 Tau tubulin kinase 1 UPLC ultra performance liquid chromatography WT wild-type", "type": "figure"}, "FIGREF2": {"text": "Schematic depiction of the sequence and different domains in Full-length Tau-441. (A) Map and domains of full-length Tau with known post-translational modification sites (grey); phospho-tyrosines (pY, magenta), phospho-serines (pS, dark grey) and phospho-threonines (pT, dark grey). Furthermore, Tau contains different functional domains: N-terminal sites (N1 aa 45-74, N2 aa 75-103), a proline-rich region (aa 151-224), and four repeat domains (R1 aa 244-274; R2 aa 275-305; R3 aa 306-336; R4 aa 337-368). Microtubule-binding region (MTBR) contains 2 hexapeptide domains PHF6* (aa 275-280, purple) and PHF6 (aa 306-311, purple). Adapted from http://www.Tauptm.org (78). (B) The annotated sequence of full-length Tau. Tau possesses 5 tyrosine residues, as indicated in red, at positions Y18, Y29, Y197, Y310 and Y394. Y18 and Y29 are localized in the N-terminal region of Tau (orange, N-terminal repeats N1 and N2 underlined), Y197 in the proline-rich domain (green), Y310 in the third repeat of the MTBR of Tau (blue) and Y394 in the C-terminal part of the protein (black). PHF6 and PHF6* hexapeptides are indicated in purple.", "type": "figure"}, "FIGREF3": {"text": "c-Abl-mediated in vitro phosphorylation and characterization of Tau (pTau); phosphorylation was performed for 4 h, which leads to a mixture of Tau phosphorylated on two to five residues. Characterization of the RP-HPLC purified Tau and the pTau mixtures by LC-MS (A), UPLC (B) and SDS-PAGE (C). (D and E) Tandem LC/MS/MS of RP-HPLC purified pTau following trypsin digestion and peptides enrichment using a TiO2 resin. The analysis of the phosphopeptides was performed using the Scaffold version 4.0 (Proteome Software), and the number of phosphopeptides detected per phosphorylation site was reported as the spectral count (SP).Table 1. A list of the phosphorylated proteins used in this study, including how they were prepared and the LC/MS data for each protein before and after in vitro phosphorylation with c-Abl.", "type": "figure"}, "FIGREF4": {"text": "Comparison of the aggregation properties of WT Tau and purified c-Abl phosphorylated Tau, pTau. 10 \u00b5M Tau and pTau were incubated for 48 hours at 37\u00b0C under shaking conditions, in presence of 2.5 \u00b5M heparin and the extent of aggregation was monitored by EM (scale bar = 100 nm for all images) (A), CD spectroscopy (B) ThT fluorescence (C), and sedimentation assays (D). Quantification of the supernatant band intensity could not be performed due to the presence of soluble non\u2212pelletable oligomeric species in the pTau sample. In (C) Two-tailed ANOVA with Sidak's multiple comparisons test, significance values are indicated by *** p<< 0.001; time points at 0h and 1h were not significantly different.", "type": "figure"}, "FIGREF5": {"text": "Comparison of the aggregation behavior of non-phosphorylated and phosphorylated Y->F Tau mutants. (A) Schematic depiction showing the position of Tau tyrosine residue Y\u2212> F mutations (filled circle: Y; hollow circle: F) and the tyrosine sites phosphorylated by c-Abl (red circles). For the aggregation studies, 10 \u00b5M non-and phosphorylated Y\u2212>F Tau mutants were incubated for 48 hours at 37\u00b0C under shaking conditions, in the presence of 2.5 \u00b5M heparin and the extent of aggregation was monitored by ThT fluorescence (B), EM (scale bar = 100 nm for all images) (C), and sedimentation assays (D). (B) Kinetics of aggregation of the Y\u2212>F Tau mutants monitored by changes in ThT fluorescence at different time points (graphs show one representative experiment for each mutant). Of the phosphorylated proteins only the 4F\\pY394 was able to form fibrils, as detected by the increase in ThT fluorescence over time. Two-tailed ANOVA with Sidak's multiple comparisons test, significance values are indicated by * p<0.05, ** p< 0.01 and *** p<< 0.001. (C) At several time points, an aliquot of the aggregation was taken and centrifuged. The supernatants were run on SDS\u2212PAGE. All of the non\u2212phosphorylated mutants showed a significant reduction of the soluble fraction over time. Out of the phosphorylated proteins, only the 4F\\pY394 presented a similar reduction in the amount of soluble protein over time, while the 4F\\pY310, pTau\u2212Y310F and pTau\u2212Y394F formed non\u2212pelletable oligomeric structures (red dashed rectangles). (D) EM micrographs of non-phosphorylated (top panels) and phosphorylated (bottom panels) Tau Y\u2212>F mutants at 24 h. Of the phosphorylated proteins only the 4F\\pY394 was able to form fibrils, while 4F\\pY310, pTau\u2212Y310F and pTau\u2212Y394F formed many oligomeric and amorphous structures (arrows).", "type": "figure"}, "FIGREF6": {"text": "Detailed characterization of phosphorylated K18 at Y310 (pK18) and NMR analysis of 15N pK18 compared to the non-phosphorylated K18. LC/MS spectra (A), UPLC profile and SDS-PAGE (B) of reverse-phase HPLC of purified pK18 following phosphorylation by c\u2212Abl (phosphorylation was performed for 4 h). K18 phosphorylated by c\u2212Abl leads to the complete phosphorylation at residue Y310. (C) The analysis of the phosphopeptides was performed using the Scaffold version 4.0 (Proteome Software), and the number of phosphopeptides detected per phosphorylation site was reported as the spectral count (SP). (D) Proton\u2212nitrogen HSQC spectrum of unmodified K18 (red) compared to that of pK18 (black). Phosphorylation on Y310 induced local effects on the structure of pK18, as shown by chemical shift changes to annotated signals. (E) Decreased values of nitrogen chemical shifts (plotted as pK18 minus K18) indicate that phosphorylation decreases the \u03b2\u2212sheet propensity of K18 in the PHF6 region, as well as for the subsequent ~10 residues, all of which are found in a \u03b2-sheet conformation in Tau fibrils.", "type": "figure"}, "FIGREF7": {"text": "Comparison of the aggregation behavior of non-phosphorylated and phosphorylated K18. 10 \u00b5M non-and phosphorylated Y\u2212>F Tau mutants were incubated for 48 hours at 37\u00b0C under shaking conditions, in the presence of 2.5 \u00b5M heparin and the extent of aggregation was monitored by ThT fluorescence (A), sedimentation assays (B), circular dichroism (C) and EM (scale bar = 100 nm for all images) (D). Together, the results from these different assay show that phosphorylation at Y310 plays an inhibitory role during the nucleation phase of K18 aggregation, and delays formation of \u03b2\u2212sheet-rich K18 fibrils. In (A) Two-tailed ANOVA with Sidak's multiple comparisons test, significance values are indicated by * p < 0.05, ** p < 0.01, *** p<< 0.001. (B) At several times points, an aliquot of the aggregation reaction was taken and centrifuged. The supernatants were run on an SDS\u2212PAGE (inlet). The supernatant band intensity from four independent experiments was quantified and reported as the percent of protein remaining in the supernatant (mean +/-SD).", "type": "figure"}, "FIGREF8": {"text": "Tau/microtubule binding assay. (A)", "type": "figure"}, "FIGREF9": {"text": "(B) EM micrographs of paclitaxel\u2212stabilized MTs alone and incubated with Tau or pTau. Scale bar = 100 nm for all images. (C) Representative total protein SDS-PAGE illustrating less pTau protein in pellet fraction compared to Tau (solid red arrows). sup. = supernatant, pel. = pellet.", "type": "figure"}, "FIGREF10": {"text": "Phosphorylation on tyrosine residues reduces Tau affinity for and binding of lipid vesicles. (A) Co\u2212sedimentation assay of BPS vesicles with 10 \u03bcM Tau, K18, pTau and pK18 at a molar ratio 1:20 (protein:phospholipid). (B) Native PAGE analysis of protein/phospholipid complexes formed by Tau, pTau (left) and K18, pK18 (right) after 24 h of incubation with BPS vesicles at a molar protein:phospholipid ratio of 1:20. The monomer bands are indicated by * and the presence of higher molecular weight bands indicated by red dashed rectangles. (C) EM micrographs showing that both WT and phosphorylated proteins were able to form phospholipid/protein complexes. Scale bar = 100 nm for all images. (D) CD spectra of proteins incubated for 2h alone (blue) or in presence of BPS vesicles at a molar protein:phospholipid ratio of 1:20 (red). (E) Assessment of the extent of Tau/K18-pTau/pK18-phospholipids complex formation using size\u2212exclusion chromatography under the same conditions used in (A). Dotted lines demarcate the elution peaks, arrows show the direction of the peak shift.", "type": "figure"}, "FIGREF11": {"text": "Tyrosine 310 phosphorylation attenuates R3 peptide affinity for and binding of lipid vesicles (A) EM and (B) fluorescence microscopy images of 100 \u03bcM R3 and pR3 peptides incubated with BPS vesicles at a molar ratio of 1:1. For fluorescence microscopy, R3 or pR3 peptides were incubated with vesicles containing 1% fluorescent NBD\u2212labelled phospholipids (fPS). Scale bar in (A) = 200 nm, in insets = 1 \u03bcm. Scale bar in (B) = 20 \u03bcm for all images. (C) SDS\u2212PAGE gel analysis of the fluorescent lipid signal detection of the lipid vesicle flotation and peptide-lipid complex sedimentation assays. ~30 min sample represents aliquots taken immediately after addition of peptides to fPS vesicles. Presence of faint signal in the pellet fraction of R3-fPS sample is likely due to fast association of peptide with lipids that occurred during the short period of time required to take and process the sample (estimated time ~30min).", "type": "figure"}, "FIGREF12": {"text": "Schematic representations of Tau filament core fold from recently published Cryo-EM structures of brain-derived and in vitro-generated Tau filaments . Y310 residue is buried in the interior (red) of the Tau single filament fold in structures derived from AD, PiD, CTE and CBD-Tau, or exposed in the exterior (green) in in vitro-derived Tau structures. Adapted from(63)(64)(65)79,80).", "type": "figure"}}}
{"paper_id": "147010463", "_pdf_hash": "06813a7aa8731e24877c1f8e1aed2f4d5ceb411a", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "147011029", "_pdf_hash": "70404c727e07db3335e97b5bf7b6ef2e4e53020c", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "147013892", "_pdf_hash": "8c67a8b5cbf03826714435a3c6f09c22eb971d31", "abstract": [{"section": "Abstract", "text": "This article confirms what others have argued about the bifurcated representation of Amerindian women in the Jesuit Relations (aggressive, insubordinate, prideful, and licentious on the one hand and docile, obedient, humble, and chaste, on the other) but extends the analysis of gendered discourse at work in the text to argue that the Relations persist in characterizing both types of Amerindian women as virile in excess of the limits of prescribed femininity. Attention to the stubborn persistence of the virile in Jesuit representations of Amerindian women suggests that the encounter between French Jesuit gender norms and the gendered ideals native to the indigenous populations of colonial Canada is best understood as an encounter between a range of competing discourses about gender and gestures toward a polyvalence of gendered discourses at play in colonial texts more generally.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Once upon a time, there was a woman, a \"noble Huron woman,\" who had \"as much goodness and gentleness for others as she had rigor for herself.\" She disciplined herself so severely (inspired by Christ's own sufferings) that \"the marks of it remained for a long time engraven on her shoulders.\" She visited journal of jesuit studies 3 (2016) [179] [180] [181] [182] [183] [184] [185] [186] [187] [188] [189] [190] [191] [192] [193] [194] [195] [196] There is, however, another sort of Amerindian woman who abides in the pages of the Jesuit Relations-or rather, not another sort of Amerindian woman, but the negative counterpart of the good Huron woman described by Lalemant. This sort of Amerindian woman is the personification of vice: full of wrath, sharp of tongue, wanton, and lascivious. She indulges her children and loves them too passionately. She mocks the faith and stands in the way of conversions, demanding that husbands, sons, daughters, and others stick with their own kind-a demand she makes with particular urgency when her loved ones are in their final moments and in need, she insists, of local shamans who will \"sing on [them] , blow on [them] and juggle for [them] with their drums.\"3", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Mediating between the virtuous Amerindian woman and her vicious counterpart within the discursive context of the Jesuit Relations is the moment of conversion. Consistent with a Jesuit conviction that God's grace was available to everyone, conversion to Christianity made possible the transformation of vice into virtue, infidelity into devotion, pride into humility. Take, for example, Barth\u00e9lemy Vimont's (1594-1667) account of the conversion of Charles Meiaskawat's wife in the Relation of 1642-44: before his own baptism, Charles \"had taken a wife who was of a very arrogant and violent temper, and who had no inclination toward the Faith.\" Despite his conversion, she \"stubbornly persisted in her unbelief\" until, worn down by her husband's patience persistence, she \"urgently asked for Baptism and obtained it.\" On the eve of their marriage, which was to take place according to the laws of the church, Charles demanded to know if his wife would \"continue to be proud, disobedient, and ill-tempered, as in the past.\" \"Answer me,\" he went on, \"for, if thou wilt not behave better, I will not take thee for my wife,-I shall easily find another.\" \"She was quite abashed,\" reports Vimont, \"and replied that she would conduct herself better in future.\" \"Speak louder,\" Charles cried, \"I do not hear thee. When thou art angry, thou screamest like a mad woman; and now thou wilt not open thy mouth.\" \"The poor woman,\" concludes Vimont, \"had to shout aloud, and protest publicly that she would be obedient to her husband, and live with him in gentleness and in the utmost humility.\" And, indeed, \"God has visibly blessed this marriage, and we have never seen a greater change than in this woman, who has now become truly a lamb, and has very deep and affectionate feelings of devotion.\"4 In this account and in others like it, it is conversion to Christianity that tips the scales from the vicious to the virtuous, enabling the transformation of the ungodly, disobedient, and lecherous Amerindian woman into her devout, submissive, and chaste counterpart.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The bifurcated rendering of Amerindian women-ungodly, disobedient, and lecherous on the one hand and devout, submissive, and chaste on the other-is not unique to the Jesuit Relations. A conspicuous and well-studied feature of early modern colonial texts more generally, representations of the indigenous other split between the binary poles of virtue on the one hand and vice on the other confirm what Edward Said argued nearly forty years ago about the systematicity of colonial discourse.5 The structure of colonial discourse, Said contended, is dichotomous, dependent on the articulation of absolute and essential difference between West and East, buttressed by a host of binary distinctions between, among others, male and female, health and disease, rationalism and sensuality. The Orient produced by colonial discourse, moreover, has a \"reality and presence in and for the West. The two geographical entities thus support and to an extent reflect each other.\"6 Although Said's analysis applied particularly to the ways in which Europeans sought to \"manageand even produce-the Orient politically, sociologically, militarily, ideologically, scientifically, and imaginatively during the post-Enlightenment period,\" his broader points about the way colonial discourse operates to constitute the self by means of a binary dialectic illuminates the discursive strategies of seventeenth-century French Jesuit writings about Canada, too-a point that has been made and developed by Olive Dickason, Pierre Hurtubise, and others.7", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "To argue that the Jesuit Relations operates on the mutually constitutive binaries of self and other, savage and civilized, the West and the rest to represent colonial subjects (and their European counterparts) discursively is, therefore, to till no new scholarly ground, but rather to tread a path charted by Said and traveled by generations of postcolonial scholars since. In what follows, however, Seventeenth-Century New France (New York: Routledge, 1993 ). Anderson contends that over the course of just three decades, Jesuit missionaries succeeded in so thoroughly altering both relations between the sexes and gendered identities among the Huron and the Montagnais that indigenous women-once vocal, independent, and empowered-were \"silenced, supervised, and subdued.\"9 On the basis of missionary reports gleaned from the Relations, Anderson argues that by 1650 the traditional complementarity between the sexes gave way to hierarchy in the wake of the collapse of indigenous institutions and in conformity with French Jesuit ideals of feminine obedience and submission.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Or did it? In the years since the publication of Chain Her by One Foot Anderson's critics have accused her of confusing Jesuit rhetoric with historical reality. Although the Jesuits \"may have claimed that [Amerindian] women became 'like lambs,'\" attention to the ways in which the Relations function as a species of colonial discourse, operating within a particular discursive context and according to particular discursive rules and strategies, should persuade us to approach the Relations with a healthy dose of skepticism.10 Attention to the discursive dimensions of the Relations illuminates the ways in which representations of both the vicious Amerindian woman and her virtuous counterpart alike served the rhetorical purposes of the Jesuits who sought, by means of the publication and distribution of the Relations, to attract support for their missionary efforts in Canada. Understanding the Relations as a species of colonial discourse primes us to see, in other words, how both kinds of Amerindian women function as an argument in defense of the Jesuit mission-the former as an argument about Canada's ongoing need for the mission, the latter as an argument about its success.11", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Were Amerindian Christian women converts really as docile, submissive, and chaste as the Relations suggest? Were their traditionalist counterparts really as aggressive, insubordinate, and promiscuous? There is reason to be skeptical on both counts-and not only because of the Relations' discursive agenda. Even presuming (albeit incorrectly) that the Relations faithfully report the observed behavior of Amerindian women (sans embellishment, elision, or emendation), we ought to be careful not to assume that Amerindian women and their Jesuit witnesses understood such behavior in the same way. The insight of recent work on the Canadian martyrs, after all, is that events in colonial New France were informed by a \"range of perspectives\" and subject to \"multiple interpretations,\" 10 Olive journal of jesuit studies 3 (2016) [179] [180] [181] [182] [183] [184] [185] [186] [187] [188] [189] [190] [191] [192] [193] [194] [195] [196] such that Jesuit and Amerindian interpretations of the same historical event were, more often than not, largely incommensurate.12 In what follows, I provide a corrective to Anderson's analysis-one founded on a sensitivity to the structures and strategies of colonial discourse. I argue that the encounter between French Jesuit gender norms and the gendered ideals native to the indigenous populations of colonial Canada is best understood not as an encounter between one kind of discourse about gender and its opposite-\u00e0 la Said-but rather as an encounter between a range of competing discourses about gender. When the Jesuits arrived in the woodlands of seventeenth-century New France, they did not just bring with them Aristotelian and Thomistic ideas about gender, which colluded to render women irrational, weak, passive, and properly subject to the supervision of men, but other ideas, too, informed by the figures of the Amazon, femme forte, and holy virago whose feminine fortitude and aggressive autonomy chafed against early modern French gendered conventions. Although my own read of the Jesuit Relations confirms, by and large, what Anderson argues about the bifurcated representation of Amerindian women, attention to the ways in which the Relations subtly persist in characterizing Amerindian women on both sides of the conversion divide as virile in excess of the limits of prescribed femininity destabilizes a dichotomous reading and gestures toward a polyvalence of gendered discourses at play in the Relations and in colonial texts more generally.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Representations of Amerindian women in the Jesuit Relations are, indeed, largely bifurcated between descriptions of indigenous women, on the one hand, whose \"fury and cruelty\" astounds, whose disobedience to their husbands matched only their inordinate attachment to their children, whose haughtiness and pride present frustrating and persistent obstacles to the conversions of their families and friends, whose sexual license appalls the prudish sensibilities of the Jesuit fathers, and descriptions of indigenous women, on the other hand, whose utter lack of \"savage tendencies,\" \"refinement,\" and \"admirable modest bearing\" impress, whose compliance, obedience, and humility elicits admiration, whose severity toward their children and commitment to perpetual virginity astound, whose incredible devotion, eloquent speeches in defense of the faith, and assiduous efforts to compel the conversions of their husbands and children were absolutely critical in the success of the seventeenth-century Jesuit mission in New France.13 In nearly all respects, these two types of Amerindian women are almost perfect mirror images of each other: the one aggressive, insubordinate, prideful, and licentious, the other docile, obedient, humble, and chaste. And yet, a close reading of the Relations reveals a troubling inconsistency that belies the easy symmetry between the one type of Amerindian woman and the other. Read with an open receptivity to the evidence on its own terms, unencumbered by a Saidian hermeneutic, the Relations betray a decided ambivalence toward what the Jesuits persisted in seeing as the ineradicable virility (or commendable masculinity) of Amerindian women. If, for the Jesuits, conversion to Christianity transformed aggression into docility, pride into humility, lechery into modesty, it did not-or could not-eradicate the manliness that Jesuits noticed (and sometimes admired) in Amerindian women, whether Christian or not. As early as 1634, Jesuit impressions of Amerindian women suggest something of an ambivalence about gender. In winter, Paul le Jeune (1591-1664) reported that there is \"no difference at all\" in what men and women wear: \"anything is good, provided it is warm.\"14 The following year, Julien Perrault (1602-47) confirmed and extended le Jeune's observation, commenting that \"the women cannot be distinguished\" from the men since both have long hair and neither have beards.15 In the Relation of 1657-58, another Jesuit went so far as to describe \"savage women\" as having \"mustaches\" in the backs of their heads, presumably referring to the conspicuous style in which some Amerindian women wore their hair. 16 And it was not just in matters of appearance that Amerindian women confounded French expectations about gender difference. Amerindian women (at least in the eyes of the Jesuits) acted like men, too. They displayed a manly fortitude, engineering daring and courageous escapes from their captors that obliged them to employ every trick of survival as they navigated their way independently back to their own countries, enduring days and nights in the woods without food or shelter, even \"in the midst of the snow.\"17 Take, for example, a group of Algonquin captives who, in 1642, \"crept away into the deep forest [at a distance from their Iroquois captors] [\u2026] the better to find their way home again. They had no food for the first ten days, after which they found journal of jesuit studies 3 (2016) [179] [180] [181] [182] [183] [184] [185] [186] [187] [188] [189] [190] [191] [192] [193] [194] [195] [196] some wild animals that a band of Iroquois on their way to war, had killed and half-consumed. They cut off long strips of flesh from these, [\u2026] produced fire by means of fire-sticks made of cedar wood, [\u2026] caught some Beavers, and crossed great rivers, enduring sufferings and hardships sufficient to kill men.\"18 They also exercised \"great power\" within their homes and had total freedom over whom to marry and when. Writing in the Relation of 1633, le Jeune wondered at the deference Amerindian men showed their wives. In response to le Jeune's request that he hand over his son to be educated-and fed and clothed-by the Jesuits, an Algonquin chief replied \"that he would be very glad to give us his son, but that his wife did not wish to do so.\" Here in North America, le Jeune continued, a \"man may promise you something, and, if he does not keep his promise, he thinks he is sufficiently excused when he tells you that his wife did not wish to do it. I told him then that he was the master, and that in France women do not rule their husbands.\"19 In the eyes of the Jesuits, Amerindian women enjoyed such a degree of sexual freedom, too, that \"it is very difficult for a young man [\u2026] Amerindian women, too, held public positions of authority alongside men, serving on councils and giving indispensable advice to tribal elders. Claude d' Ablon (1619-97) described in the Relation of 1669-71 a woman from the nation of Anni\u00e9 who had come to Quebec \"this spring with two little children of hers, [from] her own Country, where she was highly esteemed\" as Otiander-a title merited by the woman's \"intelligence, prudence, and discreet conduct.\" \"Women of this rank,\" D' Ablon explained, \"are much respected; they hold councils, and the Elders decide no important affair without their advice.\"21 In the Relation of 1696-1702, Jacques Gravier (1651-1708) even reported on a woman chief among the Natchez who \"is very intelligent, and enjoys greater influence than one thinks.\"22 In the eyes of the Jesuits, even after the moment of conversion Amerindian women continued to exhibit tendencies toward what, in an exclusively French context, might have been considered masculine behavior. Amerindian women converts continued to act with a manly fortitude-only now, inspired by their ardent devotion. Take, for example, the \"poor woman helplessly crippled in her legs\" described by Lalemant in the Relation of 1662-64 who nonetheless \"had the courage to undertake a long journey full of rapids and precipices\" in order to bring her companions to receive the sacrament of baptism.23 Amerindian women converts continued to exercise \"great power\" within their homesonly now, this power was wielded for the purpose of securing the salvation of their children and others (and this, sometimes in opposition to the wishes and intentions of their husbands, to whom Christianity, paradoxically, subordinated them under ordinary circumstances). Take, for example, the Christian woman who, having once been an Otiander, now turned her social standing and rhetorical abilities to securing the conversion of her countrymen, beseeching \"her whole nation to rid itself of all that prevented it from listening to the Preachers of the Gospel.\"24 And they continued to enjoy a surprising degree of public authority-only now, this authority was a religious authority that mimicked what was theoretically (and in a European context) the exclusive preserve of clerical men.25", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Moreover, frustrating a tidy reading of the Relations as either the documentary evidence of the successful imposition of a gendered binary that subordinated women to men or the discursive construction of a colonial regime founded on the same, the Relations represent Amerindian women as not just the helpmeets of the Jesuit missionaries, recasting and repeating to their families and friends the catechetical lessons they had learned from the Jesuits, but as preachers whose occasional sacramental authority was not just tolerated, 23 Ibid., 48:67. 24", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Ibid., 55:263. 25 There is room here for thinking about the sort of religious authority exercised by Amerindian women within the interpretative framework provided by Homi Bhabha, although a sustained inquiry is beyond the scope of this paper. The concept of mimicry, by which Bhabha refers to the displacement of the authoritative discourse of the colonizer to the site of the colonized is a central one within Bhabha's postcolonial theory. The sign of a double articulation, mimicry proves at once the means by which colonial authority attempts to \"reform, regulat[e], and discipline\" the colonial subject and at the same time a strategy that \"poses an imminent threat to both 'normalized' journal of jesuit studies 3 (2016) [179] [180] [181] [182] [183] [184] [185] [186] [187] [188] [189] [190] [191] [192] [193] [194] [195] [196] but admired.26 Against the gendered norms of a post-Tridentine Catholicism that, if anything, shored up the boundaries between the sexes, the Relations bear witness to Amerindian women who preached, heard confessions, and even administered baptism. Sometimes the Relations are careful to describe the eloquent speeches of converted women as instances of instruction or catechesis, as in the case of a \"good Christian woman\" from the Neutral Nation who so thoroughly \"instructed\" a Sonnontoueronnon captive that he immediately asked to be baptized.27 At other times, though, the Relations betray a curious sort of slippage, attributing to the female Amerindian converts the authority to preach, as in the case of an Algonquin convert named Monique who so ably \"instructed, catechized, encouraged, and taught\" her fellow captives that Paul Ragueneau (1608-80) was forced to admit that \"God enabled her to perform, in that land of horror and darkness, the office of a dogique or preacher.\"28 Elsewhere in the Relations, Amerindian women converts not only urge their family and friends to go and confess to an ordained priest, but in at least one instance a fervent old woman named Genevi\u00e8ve exhorted her dying husband \"earnestly, and constantly made him perform acts of Contrition, so that, as a result of her fervent admonitions, he died a good Christian.\"29 Finally, there are accounts in the Relations not just of women who labor vigorously to ensure that their compatriots seek out baptism from the Jesuits but the occasional story, too, of women who themselves administer the sacrament-not, admittedly, in direct contravention of gendered norms, but in decided tension with an ecclesial sacramental system that under ordinary circumstances reserved sacramental authority to a male clerical elite.30 Take, for example, the story of Th\u00e9r\u00e8se Oionhaton who admitted to a Jesuit priest that she herself had baptized her child with these words, \"Jesus, take pity on my child. The persistence of the virile in Jesuit representations of Amerindian women confounds a dichotomous reading of the Relations, suggesting that the history of the encounter between seventeenth-century French Jesuits and their Amerindian counterparts is not one of the collision between two opposing sets of gender norms that ended in the inversion of sexed relations and the conversion of gendered identities. This persistence suggests, rather, that the gendered discourses at work in the Relations are richly polyvalent. When the Jesuits came to New France in the early part of the seventeenth century, they imported with them not just Aristotelian and Thomistic ideas about gender, but a set of discourses already fractured by competing ideals of femininity, inclusive of the figures of the honn\u00eate fille, the Amazon, the femme forte, and the virago, as well as an equal diversity of negative counterparts. The encounter consequent to the Jesuit arrival in early modern Canada, then, was not so much between one set of gender norms and its opposite, but between a diversity of discourses about gender that alternately challenged, confirmed, and subtly inflected relations between the sexes and gendered identities among Amerindian and French alike. Domna Stanton's recent intervention in the field of French literary and cultural studies illuminates the heterogeneous variety of gendered discourses at work in early modern France. It is true, Stanton admits, that seventeenthcentury French women struggled under the heavy weight of gendered presumptions borrowed from classical philosophy and ancient medical texts. Early modern French writers \"perpetuated tropes [\u2026] that opposed male to female as mind to matter, reason to unreason, spirituality to carnality,\" at once enabling and legitimating women's legal incapacitation and professional marginalization.32 Even into the seventeenth century, a gendered discourse rooted in the humoral system and women's unfortunate association with the cold and wet elements influenced cultural convictions in women's sensitivity, impulsivity, and passivity, and justified women's subordination to men (who were, by nature, more rational, steadfast, and active). Indeed, Stanton argues, women's status in seventeenth-century France deteriorated, if anything, under the pressure of a broader cultural preoccupation with the threat of chaos and decay. Anxieties about national, cultural, and religious identity-at a fever pitch in seventeenth-century France-were, Stanton argues, displaced onto the gendered figures of the coquette and the libertine whose presumed insatiable sexuality was cultural shorthand for deviance and disorder. Thus, Stanton concludes, Ma\u00eft\u00e9 Albistur and Daniel Armogathe could argue for the \"generalized journal of jesuit studies 3 (2016) [179] [180] [181] [182] [183] [184] [185] [186] [187] [188] [189] [190] [191] [192] [193] [194] [195] [196] repression\" of women after 1653, a period known in early modern French historiography as \"the great confinement of women.\"33 Alongside stereotypes of the coquette and the libertine that justified the strict imposition of a gendered hierarchy, however, early modern French writers also made room for countervailing ideals of femininity, suggestive of a multiplicity of gendered discourses in seventeenth-century France. Although they condemned the sexually rapacious coquette and libertine, early modern French writers celebrated not just the honn\u00eate fille (whose modesty and silence fit comfortably with conventional gendered ideals) but also the Amazon and the femme forte whose aggressive heroism and public virtue pushed against traditional gendered expectations in important ways.34 By the middle of the seventeenth century, the figure of the Amazon had become a prominent one in French literature. Boldly heroic and possessed of both military and political prowess, the Amazon of mid-century French literature was a profoundly menacing figure, threatening to overturn gendered norms and upset the natural hierarchy of the sexes in ways that found real-world expression in the example of French women who fought valiantly in the Fronde.35", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Closely related to the Amazon-although considerably less frighteningwas the femme forte, whose incarnation in seventeenth-century France was the paradox of womanly fortitude.36 At once feminine and virile, the femme forte lived in the contradictory interstices between womanly weakness and masculine strength, confounding the neat binary between male and female. In contrast to the literary figure of the Amazon who tended to elicit anxiety rather than admiration for threatening to invert the gendered status quo, the femme forte seemed to belie early modern stereotypes about femininity and at the same time to confirm them. Although as patriotic, resolute, and heroic as any man (and sometimes more so), the femme forte was at the same time invariably beautiful and unfailingly compassionate.", "cite_spans": [], "ref_spans": []}, {"section": "33", "text": "Ibid., 13. 34", "cite_spans": [], "ref_spans": []}, {"section": "33", "text": "Stanton contends that in some ways the figures of the Amazon and the femme forte actually confirmed traditional gender roles, cohering with the ideals of the good wife of Proverbs 31 and functioning rather to \"embolden\" traditional female virtues. Ibid., 21. If we consider, in conjunction with the literary figures of the Amazon and the femme forte, the Christian hagiographic ideal of the virago, the range of competing discourses about gender in early modern France extends still further. The subject of extensive scholarly analysis, the virile woman (or virago) of hagiographic tradition testifies to the ways in which for early Christians manliness and holiness were intimately connected.37 Despite the fact, as Elizabeth Clark has argued, that some degree of gender fluidity characterizes early Christian saints in general-both male and female-the promise of gender reversal seems to have held particular spiritual potential for women with saintly aspirations. By the fifth century, the female transvestite had become a familiar figure in Christian hagiography with no comparable male counterpart. A testament, perhaps, to the tight bind between masculinity and virtue (virtue's etymological roots, after all, are in the Latin vir, or \"man\"), the virago deserved admiration for having triumphed over her sex and the temptations of her fleshy femininity. As Valerie Hotchkiss puts it, the virago in hagiographic tradition stands \"alternately (and sometimes simultaneously) [\u2026] as a sign of the power of Christianity to transform, a sign of woman's commitment to asceticism, and disregard for her own body, a glorified escape from the sinfulness of womanhood, and a sacrificial and self-effacing choice that only the most pious of women would make.\"38 (New York: Garland, 1996) , 19. In a striking counterpoint to my broader argument about the polyvalence of gendered discourses at work in the Jesuit Relations, it is worth noting here that the hagiographic figure of the virago is an ambivalent one. Neither entirely feminine (obviously) nor entirely masculine (perhaps less obviously), the virago belies the supposition of a neatly bifurcated gendered universe at work in Christian hagiography. At once feminine (in some respects) and at the same time masculine (in other respects), the virago straddles the boundary between the sexes. Take, for instance, the example of Perpetua who fought heroically in the gladiatorial ring like a man and yet \"drew [her robe] journal of jesuit studies 3 (2016) [179] [180] [181] [182] [183] [184] [185] [186] [187] [188] [189] [190] [191] [192] [193] [194] [195] [196] Given the insights of decades of colonial discourse analysis, it is, of course, difficult to accept the argument that sexed relations and gendered identities among the Amerindians of New France were actually transformed by the Jesuits. But what the polyvalence of discourses about gender operative in seventeenth-century France suggests, however, is that it is also difficult to contend that the Jesuits wanted to transform sexed relations and gendered identities among Amerindian women.39 The virility that the Jesuits persisted in seeing in Amerindian women, whether Christian or not, was arguably just as foreign as it was familiar. It is true that the Jesuits might have interpreted the manliness of Amerindian women as deviant, symptomatic of a transgressive femininity in need \"of constant vigilance and supervision.\"40 But they might just as readily have interpreted such manliness as consistent with what they knew about the eminent Amazons, femmes fortes, and viragos of French literature and Christian hagiography.", "cite_spans": [], "ref_spans": []}, {"section": "33", "text": "up to cover her thigh, more mindful of her modesty than her suffering.\" Or St. Wilgefortis who grew a beard like a man but whose disfigurement ensures the preservation of her virginity. Or even Teresa of \u00c1vila whose Spanish devotees praised her Amazonian capacities and at the same time admired her feminine obedience and humility. Indeed, it was precisely the virago's femininity that rendered her masculinity spiritually meaningful. The virago deserved admiration not as a woman who had become a man but as a woman who-despite being a woman-could act like a man. Thomas J. Heffernan, The Passion of Perpetua and Felicity (New York: Oxford University Press, 2012) Indeed, evidence from the Relations suggests they did so. Although allusions to the literary figure of the femme forte and to the hagiographic model of the virago are only implicit in the Relations, Jesuit observers explicitly invoked the figure of the Amazon to make sense of Amerindian women whose fortitude and authority pushed provocatively against conventional European standards of femininity and threatened to invert traditional gender hierarchies.41 Take, for example, the account of an Algonquin woman in the Relation of 1654-56 \"who, when she saw her husband surprised and bound by five Iroquois, seized a hatchet and with two blows-struck right and left, with astounding rapidity [\u2026] killed two of those Barbarians outright on the spot; then, having promptly unbound her husband, she advanced to do the same to the three others, who, dismayed at that Amazon's furious onslaught, retained only sense enough to seek safety in flight.\"42 Or the woman described by Jean de Quen (1603-59) in the Relation of 1657 who \"displayed the courage of an Amazon in an attack made by a Frenchman upon her chastity from which she came forth victorious.\"43 Or, finally, the Natchez chief that Gravier identified as \"an Amazon\" who \"had so distinguished herself by the blows that she inflicted upon their enemies, having in person led several war-parties, that she was looked upon [\u2026] as the mistress of the whole village.\" True to Amazonian form, this woman enjoyed a public esteem that surpassed even that due to the great chief, \"for she occupied the 1st place in all the Councils, and, when she walked about, was always preceded by four young men, who sang and danced the Calumet to her.\" She dressed, too, \"as an Amazon; she painted her face and Wore her Hair like the men.\"44 Like their textual counterparts in the literature of seventeenth-century France, these real-life women were heroically aggressive and possessed of a military and political prowess in ways that at once fascinated and frightened their Jesuit witnesses.", "cite_spans": [], "ref_spans": []}, {"section": "33", "text": "Tellingly, implicit in Jesuit descriptions of the (virile) strength, independence, and authority of Amerindian Christian women is not resigned toleration but genuine admiration. When le Jeune reported on the \"poor Huron woman who [\u2026] ran and plunged twice into the water, in very cold weather, in 41 The only direct appeal to the figure of the femme forte in the Relations is made by the Relation of 1672 in connection to Marie de l'Incarnation who arrived in Quebec from Tours, France in 1639 to found the first Ursuline community in Canada. Thwaites, Jesuit Relations, 56:285. Elsewhere in the Relations, Marie and her Ursulines sisters are described as Amazons (ibid., 16: 7; 18:75; 147 knowledge,\" \"piety,\" and \"virtue\" enabled her \"to assume and ever to maintain a certain ascendancy over all the other Christians\" such that even \"the men themselves willingly listen to her as their teacher,\" he did not censure her for having upset a gendered hierarchy that recognized men as the natural superiors of women but commended her (albeit implicitly) for having actively and publicly promoted the faith.47 Jesuit admiration for Amerindian women who did not passively accept governance by another (but actively pursued the things of the faith), who did not obediently submit their husbands (but boldly instructed them instead), who were not modest and docile (but publicly outspoken in defense of Christianity) belies any claim about a gendered binary at work in the seventeenth-century Jesuit missionary project in New France. A close reading of the Relations reveals not the encounter between one kind of gendered discourse and its opposite-and surely not the inversion of sexed relations and the conversion of gendered identities-but rather the encounter between a diversity of discourses about gender, which perhaps did not so much clash and collide as play together in alternating harmony and dissonance.", "cite_spans": [], "ref_spans": []}, {"section": "33", "text": "Thinking about the Jesuit Relations as a species of colonial discourse fractured by a range of competing discourses about gender has implications not only for our understanding of the history of the seventeenth-century encounter between Jesuit missionaries and their Amerindian interlocutors but also for the way we read colonial discourse more generally. Colonial discourse is not, contrary to what Said had presumed, (always) neatly structured according to the conceptual binaries of self and other, savage and civilized, the West and 45", "cite_spans": [], "ref_spans": []}, {"section": "33", "text": "Ibid., 47:55. 46 Ibid., 58:197. the rest. It is true, of course, that much of colonial discourse does make use of essentialized dichotomies like these to draw the boundaries between colonizer and colonized, but in the years since Orientalism's publication postcolonial theorists have illuminated the ways in which \"alterity and ambivalence\" persistently threaten to undermine the discursively constructed binaries that undergird colonial authority.48 Homi Bhabha, one of Said's most vocal critics, argues for example that although \"the exercise of colonial power through discourse demands an articulation of forms of difference-racial and sexual,\" colonial discourse remains conspicuously ambivalent as it attempts to render the colonial subject at once knowable and at the same time different.49 The effect of this ambivalent discourse is not, as Said had suggested, to shore up the boundaries between colonizer and colonized but rather to produce what Bhabha calls hybrid colonial identities that confound the neat binaries of colonized and colonizer and expose the fact that colonial discourse always slips the grasp of the colonized. What my analysis of the representation of Amerindian women in the Jesuit Relations suggests, however, is that perhaps even Bhabha's theoretical tools are in need of a whetstone. If the Relations are any indication, perhaps what is going on in colonial discourse is neither simply the encounter between one thing and its opposite that ends in the preservation of difference (even if it also makes room for the transformation of the one into the other) nor simply the encounter between one thing and its opposite that ends in the production of a hybrid third thing, but the messier and more fluid encounter between a wide range of ideas, norms, and conceptual structures that were fractured and polyvalent long before the moment of colonial encounter.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "The Other Question [\u2026] Homi Bhabha Reconsiders the Stereotype and Colonial Discourse", "authors": [{"first": "Homi", "middle": [], "last": "Bhabha", "suffix": ""}], "year": 1983, "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "The Death and Afterlife of the North American Martyrs (Cambridge: Harvard University Press, 2013), 370. See also Timothy G. Pearson, Becoming Holy in Early Canada (Montreal: McGill-Queen's University Press, 2014), who argues that the death of the Canadian Jesuit martyrs \"took place within and as a result of indigenous ritual prac- tices of warfare, captivity, and adoption [and] became reinscribed as performances of the drama of Christian martyrdom.\" Ibid., 37.", "type": "figure"}, "FIGREF1": {"text": "to parry [the] blows\" of \"women and girls [who] have nothing to restrain them.\" Sounding a note in harmony with hagio- graphic descriptions of virgin women who admirably and persistently resist the advances of their many male suitors, Lalemant tells the story of a young Arendaenhronon convert's struggle to preserve his chastity: \"In vain did [the girls] solicit him; he refused presents, and trembled with fear [\u2026] when he fled from the danger of losing what Faith alone had taught him to cherish above pleasure and above life.\"20", "type": "figure"}, "TABREF0": {"text": "5 Edward W. Said, Orientalism (New York: Vintage Books, 1978). 6 Ibid., 5. 7 Ibid., 3. Olive Patricia Dickason, The Myth of the Savage and the Beginnings of FrenchI turn my attention to the question of gender, looking closely at how represen- tations of Amerindian women in the Relations actually confound and compli- cate the presumptive binaries that discursively distinguish between self and other in ways that have broader implications for our understanding of the way colonial discourse works.8 I admit that I am not the first to inquire into representations of Amerindian women in the Jesuit Relations. Nearly thirty years ago, Karen Anderson broke this ground with the publication of Chain Her by One Foot: The Subjugation of Native Women in", "type": "table"}, "TABREF8": {"text": ", 134. For an analysis of the gender ambivalence in the passion of Perpetua as well as in other early Christian martyr accounts, see L. Stephanie Cobb, Dying to be Men: Gender and Language in Early Christian Martyr Texts (New York: Columbia University Press, 2008); Lewis Wallace, \"Bearded Woman, Female Christ: Gendered Transformations in the Legends and Cult of Saint Wilgefortis,\" Journal of Feminist Studies in Religion 30, no. 1 (2014): 43-63; Erin Kathleen Rowe, \"The Spanish Minerva: Imagining Teresa of \u00c1vila as Patron Saint in Seventeenth- century Spain,\" The Catholic Historical Review 92, no.Chain Her by One Foot, 98.", "type": "table"}, "TABREF9": {"text": "order to cross two rivers and hasten\" to receive the sacrament of penance from a newly-arrived Jesuit, he did not rebuke the woman for her indelicacy, but found in her example an instructive counterpoint to the tepid devotion of even the \"best Christians\" of France.45 When, similarly, Fran\u00e7ois le Mercier (1604-90) reported that C\u00e9cile Gannend\u00e2ris had \"made [her husband] go through all the ceremonies which it is customary to have the sick observe under those circum- stances\" and so \"clearly convinced [him] of the truth of our Mysteries [\u2026] dur- ing an exhortation that she made him,\" he did not reprove her for her insubordinate impudence vis-\u00e0-vis the husband to whom she owed an unques- tioning obedience but praised her for having lived \"so exemplary a life and [having possessed] such recognized ability.\"46 Finally, when Pierre Millet (1635-1708) described a Christian woman named F\u00e9licit\u00e9 whose \"sound [\u2026]", "type": "table"}}}
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{"paper_id": "147015620", "_pdf_hash": "db48b0444687b1c67df8a133e7b948f17d43af67", "abstract": [], "body_text": [{"section": "", "text": "conversation. If the obstacles to a global conversation remain, the intended results will not ensue even if tools are precise, energy is abundant, and intentions are noble. Accordingly, we seek to locate the impediments to such a conversation. As we see it, the query 'how do we start a meaningful conversation that engages the diversity of IPE?' requires a prior question: 'How have we remained unaware of or insensitive to the diversity that already exists?' John Hobson (2012 Hobson ( , 2013a produces a powerful answer to the latter question. He argues that racism, imperialism and Eurocentrism disallow a western-dominated social science from engaging with diverse viewpoints. We find Hobson's arguments and the evidence he marshals compelling. Yet good arguments and weighty evidence may not be convincing unless we begin to understand the 'how': how exactly do those who profess to pursue value-free science nevertheless produce it in a manner that is racist, imperialist, and Eurocentric? We argue that they do it via a disciplinary bias towards a unit-level or atomistic understanding of social science. It is this habit that precludes and disallows epistemological encounters in which actual diversity might be harnessed. Our task is to substantiate this answer.", "cite_spans": [{"start": 466, "end": 478, "text": "Hobson (2012", "ref_id": "BIBREF11"}, {"start": 479, "end": 495, "text": "Hobson ( , 2013a", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "", "text": "Our presentation contrasts accounts that favour unit-level characteristics with those that foreground the culture, history, and context of the actions in question. We refer to the latter as social explanation. 1 This dichotomous contrast between atomistic, explanation foregrounding culture, history and the context of action justifies atrocious conduct. In his reflections on the social science of suicide bombing, Ghassan Hage (2003) calls this discomfort exigophobia: the fear that social explanation inadvertently justifies horrendous actions, and humanises perpetrators. Exigophobia activates what we call the condemnation imperative: an eagerness to condemn an individual or group act, of fierce violence for example, before one has tried to understand or explain it. Specifically, the condemnation imperative is triggered when explanations of social phenomena seem to excuse actions that are ethically reprehensible, and is especially tricky for those whose profession it is to explain such acts. The logic of contextual explanation, the presence of exigophobia, and the condemnation imperative work together to produce the individualism imperative: a tendency to favour explanations tied to the characteristics of individualised units, and to devalue explanations that rely on social, historical or institutional context.", "cite_spans": [{"start": 210, "end": 211, "text": "1", "ref_id": "BIBREF0"}, {"start": 424, "end": 435, "text": "Hage (2003)", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "", "text": "We can say all this in simpler language: theorists and lay people alike worry that understanding and explaining horrendous acts also mean defending, rationalising, affirming, or justifying them. To push away this fear, they condemn such acts before they explore their making, defaulting to explanations that place the blame and responsibility upon individuals (whether persons or larger units) rather than upon those that point to the larger context. In this way, exigophobia, the condemnation imperative, and the individualism imperative work together to produce what Hobson calls the racism, imperialism and Eurocentrism of western social science, and therefore of much of IR/IPE.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "One more remark before we begin our investigation. As we expose the usual habits of dominant forms of western social science, we also affirm a standard through which we develop our critique. We refer to this ideal as the ethics of social explanation. Such an ethic abandons strategies that either reject or assimilate the other, and instead require regarding the other as both universal and particular. When the other's humanity is restored in this way, the other's similarity and difference appear first and foremost as resources for self-understanding and dialogue. Overcoming the individualism imperative may help us move in directions envisaged by Cohen's call.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Hage: social explanation, exigophobia, and the individualist imperative", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Hage explains the emergence of Palestinian 'suicide bombers' in his journal article '\"Comes a time we are all enthusiasm\": understanding Palestinian suicide bombers in times of exigophobia ' (2003) . Simultaneously, he deciphers why his explanation of suicide bombing falls foul of his students and fellow academics. He discovers, much to his annoyance, that commentary on Palestinian suicide bombers must begin with a moral condemnation. Prior to saying anything about their motives, tactics and circumstances, one must first reject 'suicide bombers' as beyond the pale, as absolute otherness outside the realm of explanation. Hage confesses that this 'condemnation imperative' places him in a performative contradiction: before he can explain or assess the actions of Palestinian suicide bombers, he must first judge their actions to be reprehensible and barbaric (2003: 67) . He must give the science before the science, as Marx might say. Hage accepts this predicament in order to cast light on the situation. He humanises 'suicide bombers' by proposing a hypothetical sociological/anthropological project which he ties to the term 'social determinism', 2 but which we will refer to as social explanation.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Along the way, he produces three intriguing insights. He discovers: More is at stake, however, than a familiarity with and an understanding of 'suicide bombers'. The more dangerous implication is that any society put in such a situation will respond in a similar fashion. It is this inference we may fear as we shift locating the cause of an event from the individuated unit to that actor's social and historical context. The worry produced by a contextual social explanation is that they and we are made of similar stuff, and that, when placed in similar situations, we would respond in similar fashion. We resist this movement, argues Hage, because we fear seeing ourselves in them. Our fear of their difference (they perform suicide bombings, we do not) is secretly a fear of our similarity (we might do the same when put in their situation). 4 The truthfulness or actuality of this claim may not be germane. What is important is the anxiety itself that can be fully activated by the mere possibility. Assimilating the other's difference erases the particularity of the other; rejecting others' similarity to us overlooks their universality. Both moves deny the other's humanity. Social explanation can humanise others by embracing both similarity and difference. This process, Hage points out, is not an impartial act: 'In taking the side of social explanation, one is clearly not inhabiting a politically neutral position ' (2003: 88) . Such partiality, he quickly asserts, does not preclude our ability to condemn the very actions we are trying to explain. Having retrieved the humanity of perpetrators, we can still oppose their actions, so long as we are willing to admit that by so doing we also condemn our own potential actions, should we find ourselves in a similar situation. As we condemn their actions, we condemn our own -as forgotten past, denied present, or potential future.", "cite_spans": [{"start": 846, "end": 847, "text": "4", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "", "text": "Pulling these elements together, we might say that social explanation highlights particular actions in particular situations via generalisation, and that doing so requires regarding the other as both universal and particular. Simultaneously, social explanation reveals an ethics that resists both the assimilation and rejection of the other. This is the standard by which we assess western social science, and through which we hope it can live up to its own ideals.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Despite this logic, most social theorists hesitate to embrace such an ethics. We resist the humanising move, the acceptance of the vilified as 'ordinary people'. Why? Perhaps we fear a loss of judgment, an inability to take a stand, and the dissolution into a relativist quagmire. The tension between the logic of social explanation and our difficulty in accepting its consequences may be described as a hesitation, or a stuttering -a seemingly involuntary disruption of speech and thought, or a deep-seated phobic reaction (exigophobia, in Hage's terms) to the humanising role of explanation. Our desire to override such hesitation expresses itself as the 'condemnation imperative'. As Eagleton (2010: 8-11 ) notes: 'No western politician today could afford to suggest in public that there are rational motivations behind the dreadful things that terrorists do. \"Rational\" might too easily be translated as \"commendable\".' And, as Hage (2003: 66-7) argues, the failure to condemn in scholarly discussions makes you 'a morally suspicious person', associated with, if not culpable for, the malevolence itself. Both Hage and Eagleton suggest that pursuing social explanation -explanation that humanises the other, that refuses to locate the other as absolute difference -associates the scholar with nefarious purposes. This would seem to foreclose social explanation altogether, replacing it with the cant of the condemnation imperative.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "But this resistance to social explanation as a humanising strategy does not simply foreclose social enquiry; it channels it in certain directions. The condemnation of individuals or groups as evil presumes and invokes the idea of autonomous and responsible individuals whose motives and actions are separable from ours. William Connolly (1991: 1-2, 99) emphasises that the language of evil is 'bound up with the issue of responsibility ... some agent must be responsible for it'. If others are responsible for evil acts, then no further social enquiry is required; the motive of individuals or groups or the context of their action is mooted. And, he stresses, by intensifying 'our search for responsible agents at the level of individual or group, we 'exclude some injuries from the category of evil ' (1991: 1) . More precisely, as Eagleton (2010: 143) suggests, we exclude those injuries for which an account in terms of individual responsibility is difficult to sustain, such as where 'wickedness is institutional ... the result of vested interests and anonymous processes, not of the malign acts of individuals'. These 'forms of wickedness are built into our social systems, within which individuals are deeply conditioned by their circumstances' and in which we may be implicated (2010: 144-5). Connolly and Eagleton are pointing to the kind of social explanation advocated by Hage (2003: 86-7) that attends to 'the social conditions of action and the historical conditions of formation of the acting self'. They suggest that explanation which humanises others produces a resistance that prevails not only in Hage's seminars and at scholarly conventions, but also in public debate and in social theorising more generally. They also suggest that resistance is intimately interwoven with a focus on the individual or group as a separable unit, and a unique locus of agency.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "The hints provided by Hage, Connolly and Eagleton imply that we can link this stutter or involuntary disruption in our political/ethical sensibilities to the individualism imperative: the tendency to ignore all levels of analysis in favour of the individual level. Here, actions emerge not from context or structure, but from the autonomous will (or traits) of the individual unit. The individual unit is the locus of the action, and this will or these traits must be 'blamed' for an insufficient reading of what is good, right, and proper in the world. The western social scientist is thereby caught between the humanising ethics of social explanation and the ready opportunities to blame the individual or group for poor decisions. Hence the hesitation, or stuttering.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "To foreshadow our point of arrival, we see two responses to this stutter. One can discount the role of individual will or traits, and move towards a full ethics of explanation. Or one can emphasise the individual unit by disavowing the ethics of explanation, or disavowing it in the last instance. 5 In the latter case, one moves to a kind of essentialism, or atomism. This is the individualism imperative. This imperative, as we shall see, goes hand in hand in IR and IPE with a refusal and rejection of the global 'level'. This refusal also facilitates the Eurocentric myths that keep self and other separated, that produce the stutter, and resist the humanising move of social explanation. We trace the work of the individualism imperative in the following section, showing how it has come to define conventional international relations as a positive, supposedly value-free science.", "cite_spans": [{"start": 298, "end": 299, "text": "5", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Levels, the individualism imperative, and Eurocentric condemnation", "text": "We think with metaphors; indeed, we cannot think without them (Lakoff and Johnson 1980) . For example, in thinking about the planet, we use visual metaphors that organise space. We imagine its three-dimensional oneness via satellite pictures of the earth as a blue globe, and we see differences within and across that oneness via maps that show how the various continents are divided into states. IR arranges these images via the metaphor of 'levels'. But IR's general bias is towards the unit or actor level. This emphasis on unit-level explanations leads international theory to neglect the very processes that produce relations of global inequality and domination. Our wager in this section is that a focus on levels helps us locate the deeper root of how IR/IPE becomes racist, imperialist, and Eurocentric, thereby undermining its own desire to engage other, more diverse viewpoints.", "cite_spans": [{"start": 62, "end": 87, "text": "(Lakoff and Johnson 1980)", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "Levels, the individualism imperative, and Eurocentric condemnation", "text": "In his classic paper on levels of analysis in IR, J David Singer begins by admitting that levels create a problem of choice:", "cite_spans": [], "ref_spans": []}, {"section": "Levels, the individualism imperative, and Eurocentric condemnation", "text": "In any area of scholarly inquiry, there are always several ways in which the phenomena under study may be sorted and arranged for purposes of systemic analysis. Whether in the physical or social sciences, the observer may choose to focus upon the parts or upon the whole, upon the components or upon the system (1961: 77, emphasis added).", "cite_spans": [], "ref_spans": []}, {"section": "Levels, the individualism imperative, and Eurocentric condemnation", "text": "According to Singer, the word 'choose' suggests opportunities for a pluralism of scholarly perspectives: 'For a staggering variety of reasons, a scholar may be more interested in one level than another (in parts as opposed to the whole) at any given time, and will undoubtedly shift his orientation according to his research needs' Onuf (1995: 35) notes, Singer boils the choices down to 'two levels -the behavioral and the systematic,' and scholars' research problems dictate whether they highlight parts or whole and therefore the level they select.", "cite_spans": [], "ref_spans": []}, {"section": "6", "text": "Robert Cox shifts the language somewhat by emphasising the role of habit or convention in disciplinary practice:", "cite_spans": [], "ref_spans": []}, {"section": "6", "text": "Academic conventions divide the seamless web of the real social world into separate spheres, each with its own theorising; this is a necessary and a practical way of gaining understanding. Contemplation of undivided totality may lead to profound abstractions and mystical revelations, but practical knowledge \u2026 is always partial or fragmentary in origin.", "cite_spans": [], "ref_spans": []}, {"section": "6", "text": "Whether the parts remain as limited, separated objects of knowledge, or become the basis of constructing a structured and dynamic view of larger wholes is a major question of purpose and method. Either way, the starting point is some initial subdivision of reality, usually dictated by convention (1986: 204, emphasis added).", "cite_spans": [], "ref_spans": []}, {"section": "6", "text": "Cox seems to suggest that one's orientation towards parts and whole is not so much chosen but acquired through disciplinary socialisation. To further invert Singer's claims, we might say that levels schemes choose the scholar, and -having been selected (or initiated into disciplinary conventions) -scholars organise their work according to a pre-decided understanding of levels. 7 And, Cox stresses, our 'choice' of analytic stance is not innocent. We can read him to say that a discipline organised around 'parts' tends to support a 'problem-solving' mentality that takes existing structures of world order for granted. Only when scholars are disciplined to focus on the whole can they adopt a critical stance towards world orders (1986: 207-10).", "cite_spans": [{"start": 380, "end": 381, "text": "7", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "6", "text": "A problem with levels: how to engage a diverse IPE", "cite_spans": [], "ref_spans": []}, {"section": "6", "text": "We follow Cox's lead by exploring the political and ethical implications of being selected by a level. We read along with Nicholas Onuf (1995: 43) , who has done the most thorough and sophisticated work on levels: 'Levels schemes are all members of a family of pictures, or framed spaces, within which we see the contents of the field of study we call international relations.' Pushing against Singer's notion of the choice of levels following from our selected problem, Onuf seems to indicate that the levels scheme precedes that selection. As he puts it, 'the \"level\" is just one in a family of spatial metaphors for ways of seeing. They tell us how we see, and not what we see ' (1995: 41 but also how we make our disciplines, and how we make the world. As he puts it:", "cite_spans": [], "ref_spans": []}, {"section": "6", "text": "Levels are not just a taxonomic convenience for scholars, or a methodological convenience. They are a potent metaphor, an ancient convention, for marking, and thus making, wholes. In our culture, as in our field, we would have difficulty getting along without the language of levels. In other cultures people make wholes of their own \u2026 and mark their significance with conventions we may not even recognise (1995: 53).", "cite_spans": [], "ref_spans": []}, {"section": "6", "text": "For example, Onuf reports that Aristotle locates the 'complete good' in the self-sufficient community that stands above its many parts. Similarly, Christian cosmology associates the complete or final good with 'with God and the heavenly city' that stand above the 'social arrangements' which order the human beings who reside below that social order. The cosmos was visualised as a 'great chain of being ...", "cite_spans": [], "ref_spans": []}, {"section": "6", "text": "[o]rdering all things from least to greatest, lowest to highest ' (1995: 48-9) . As individuals, we look up to locate the good -towards God, and the social order sanctified by God. Here, up is good.", "cite_spans": [], "ref_spans": []}, {"section": "6", "text": "But, by the 17 th and 18 th centuries, 'an alternative visualisation gained favour': 'After Kant, metaphorically, the great chain tipped over -levels became stages ' (1995: 49) . In place of God's order and God's goodness (descending from on high), we come to see nature as governed by its own laws. So too with humans: God's laws are replaced by those humans make for themselves. And a notion of sovereignty follows, as Onuf (1995) explains: 'If nature's design fosters horizontal representation in space, so also does the emergence of autonomous sovereignties' ... ; the 'flat territorialities of states' come to replace 'overarching claims to hierarchical authority'. A modern cosmology challenges the notion that we locate the good above. The locus of the good now shifts downward to a lower rung on the great chain -to individual members of the community, and the independent states that now govern this horizontal space. Down is good. Social order, which is up, appears not as a realisation of the good of individuals, but as a potential constraint on the autonomy and responsibility of individual or sovereign actions.", "cite_spans": [{"start": 421, "end": 432, "text": "Onuf (1995)", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "6", "text": "Thus the 'flat territorialities' of states suggest an IR of 'like units'. The claim of sovereignties suggests an IR of independent actors that appear, in principle, as formally equal. Where the units are privileged as the locus of the good and of creative action, explanatory emphasis is placed on the actions of the units as opposed to the determining effects of the structuring of the whole. Singer captured this opposition in his own discussion of parts and wholes: looking at the world from the level of the individual unit emphasises the concrete, and moves away from abstraction. Looking from the system or the whole, 'we tend to move ... away from notions implying much national autonomy and independence of choice and towards a more deterministic orientation ' (1961: 80-1) . We catch a hint of favouritism: an emphasis on the whole smacks of the kinds of historical arguments made by dependency theories that so violated the commonsense notion of the world as looked at from below -from the point of view of the behaviour (and freedom) of individual actors.", "cite_spans": [], "ref_spans": []}, {"section": "9", "text": "The flat map of formally 'like units' does not preclude the assumption of graded selves or states, however. The flat map of sovereignties coexists with inequalities of position within a capitalist division of labour emphasised by theories of dependency and underdevelopment. But although those inequalities are taken to indicate 'higher' and 'lower', where higher suggests more civilised, more developed, and so on, the individual units retain the status granted by the flat map. They remain sovereign units, ungoverned or undetermined by any social arrangements that might be located at a higher level. Looking from above, however, we see how colonial rule and imperial domination produce an unequal grading of western and non-western peoples as natural. Our modern scholarly socialisation now disfavours the view from above, from the point of view of the patterned inequality. Seeing from above has been stigmatised in conventional IR because it suggests the primacy of the patterned inequality of the whole, violating the imperative to condemn or assign responsibility to the individual or group. Where seeing from below, from the level of the units, is idealised, patterned inequality is treated as secondary -as an effect, not a cause.", "cite_spans": [], "ref_spans": []}, {"section": "9", "text": "Thus, even if Onuf is correct that the up and down of levels do not connote good or evil in the sense suggested by a Christian cosmos, levels schemes are not politically and ethically neutral. Rather, a levels scheme that privileges looking from below dovetails with Eurocentrism in IR. Hobson (2012: 224-5 ) explains that seeing from the level of individual actors, in this case Europe or the west, as 'self-constituting and exceptional', we 'thereby deny the dialogical notions of an \"other-generated Europe\" and the poly-civilization \"logic of confluence\" that a non-Eurocentric approach would focus upon'. When one neglects the structuring features of the whole, neglects colonial rule and imperial domination, and assumes western 'pioneering agency', it is easy to treat non-western inferiority (irrationality, backward culture, and so on) as an explanation for the relative successes and failures of a flattened planet of autonomous units.", "cite_spans": [], "ref_spans": []}, {"section": "9", "text": "Though explicitly universal and value-free in its aspirations, much of contemporary IPE proudly displays the individualism imperative that reproduces and reinforces the political content of this racist Eurocentrism. The claimed scientific achievements of dominant strains of IPE, Benjamin Cohen (2008: 143) claims, have come via a focus on individuated units -'actor behaviour' -and how those actors, usually states, manage the interdependence generated by their interactions. Cohen's story of IPE begins with the post-war recognition of growing independence among 'national' economies, including newly independent countries (2008: 21-3). International institutions (GATT and the IMF, in his account) appear as mechanisms for managing disputes among independent states. In an advance over the work of economists, Cohen announces a new era of enquiry in which '[t]he world economy could be depoliticised no longer'. Yet, as he acknowledges (2008: 42-3) , the tremendous gains in knowledge production involved imitation of the 'technical sophistication and intellectual elegance' of economists -a kind of 'reductionism' (in his terms) that 'comes at a price in descriptive and practical credibility'. The explicit contrast is with earlier Marxist theories of imperialism, dependency theory, and a contemporary 'British School' that harks 'back to the tradition of classical political economy, [where a] broad comprehension of \"society\" -the social context of IPE -is valued more ' (2008: 18-9, 44 ). Cohen seems to suggest that we can simply add some of the 'social' to an inadequate science of IPE focused on unit-level behaviour.", "cite_spans": [], "ref_spans": []}, {"section": "9", "text": "However, as we have seen, 'levels' are not neutral, or simply abandoned or expanded at will, and they foreclose the kind of conversational diversity that Cohen (2014) now seeks. To return to Hobson, the continued embrace of Eurocentric myths by international theory in the 21 st century need not be taken only as the resurgence of latent racism/Eurocentrism on the part of scholars or a discipline. It is not only western ignorance or discrimination that leads to the marking of the non-west as legally recognised but relatively failed states or quasi-sovereigns. The west also turns to data. The non-west's failure to develop is 'evidence' that reveals and confirms an underlying hierarchy of capacities and potentialities. Civilizational hierarchy or graduated sovereignty merely names this underlying differential in the capacity of the autonomous units. Given an ontological individualism that rules out thinking of the whole as the context within which parts and their relations emerge, this naturalised hierarchy can only be re-enforced by the continuing 'evidence' of the relative failure of the non-west to develop or live up to civilised standards of governance.", "cite_spans": [], "ref_spans": []}, {"section": "9", "text": "Thus the political and ethical possibilities of modern life rest upon a tension between wholes and parts within the theory of progress. On the one hand, political and economic development is seen as isomorphic with modern western civilization. Here, modernity is more than just a model; it foretells the future of all cultural spaces. On the other, political and economic development is also linked to the principle of sovereignty; a principle that separates political and economic spaces, and putatively allows each state to find its own version of meaningful development. IR theory proper concentrates exclusively on one side of this tension by focusing on the spatial demarcation of the world into separable nations or peoples or states of civilizations who follow (or not) or are capable of following (or not) the path pioneered by modern western states and the international institutions they have created. This atomistic vision posits that realising the promises of modernity (in other words, political and economic development) depends upon the character of the developing (or not) units themselves. In this way, dominant strains of international theory suppress from our thinking the larger context of historical structures/interactions that follow from seeing down from the whole -suppress a fuller comprehension of the structuring of the whole. If the western theorist 'chooses' the individual level, he seems preordained to do so. It serves his belief that he and his state do not exist in deterministic and hierarchical order; that he and his state have earned their status. Conversation ends here, precisely where it needs to begin.", "cite_spans": [], "ref_spans": []}, {"section": "Closing remarks", "text": "As we have tried to show, the dread of contextual/structural explanation, the condemnation imperative, and the individualism imperative exhibit a fear of similarity -an anxiety that we may be just A problem with levels: how to engage a diverse IPE like them. We cannot allow ourselves to imagine how the other sees the world lest we admit that her vision is already within us -that ordinary human beings, like us, might use our bodies as weapons, or might find our sagging prospects in a culture of competition attributed to our genes, or our deficient culture. Such sameness threatens to undermine our own space/time/cultural distinctions, and weakens claims to our development and our advanced culture. Similarity challenges our specificity, exclusivity and uniqueness, and, in Hobson's terms, a sense of our 'pioneering agency'. As long as we don't allow ourselves to see the other as an other within, we will be tempted to explain their actions as resulting from their (projected) status as 'evil', 'backward,' 'underdeveloped', 'yet to be civilized' -in a nutshell, 'the still lacking'. And, to extend Hobson, these hesitations, stutters, erasures -all produced by the individualism imperative -are the most entrenched instantiations of Eurocentrism, Orientalism and racism.", "cite_spans": [], "ref_spans": []}, {"section": "Closing remarks", "text": "If we cannot allow the other to be the same, we also cannot seem to bear the other's difference. Difference is always a latent critique, and we are apprehensive about what it may purport. Learning from the other inverts the usual hierarchy wherein the other must always learn from us. It is, nevertheless, no small miracle that this relationship remains reversible; that we can still learn from the other's difference. Fear of difference, then, is resistance to the need to know beyond oneself to know oneself; particularly learning that none of us can become whole on our own, that our feeling of being unique or self-sufficient depends on repressing the similarities and overlaps that make us the same. In this way, fear of similarity and fear of difference entwine.", "cite_spans": [], "ref_spans": []}, {"section": "Closing remarks", "text": "Where we adopt a position of social explanation, sameness and difference have more to offer than destabilising our position in a hierarchy. When the other's humanity is restored, her similarity and difference appear also as resources. To recognise and accept our intimacy with difference is also to embrace the simultaneous teacher/student status of both self and other. To recognise and accept our intimacy with sameness is also to desire entering the world of the other for the sake of learning. But we hesitate, we stutter, we resist the turn to social explanation. Our trepidation exhibits itself as a fear of systematic explanation, a fear of regarding parts as always in relation to wholes.", "cite_spans": [], "ref_spans": []}, {"section": "Closing remarks", "text": "In IR/IPE, we often translate holism as an emphasis on the global or systemic level, as we saw in Singer and Cohen. But, in this closing section, we wish to translate the global less as a level and more as a system in which whole and parts are simultaneous moments in process. Looking from above, from the system as a whole, does not exclude the parts; indeed they constitute the whole. But the parts -in this case as individuated units -do not exist apart from 'the social conditions of action and the historical conditions of formation of the acting self' (Hage 2003: 86-7) . Still, the usual preference is to see from the other direction -from the parts upward. Conventional IR/IPE scholars have not produced much of a symmetrical countermove. Though unit-level analysis may require attention to context, so that explanations incorporate 'constraints,' units are treated as if they can exist apart from the whole. Here we have parts without any account of the whole, or as Schwartz (2007, 132) would have it, 'incomplete knowledge' that is filled by a 'belief in the virgin birth' of the units.", "cite_spans": [], "ref_spans": []}, {"section": "Closing remarks", "text": "Overcoming the individualism imperative requires us to make two opposed moves: to invert the usual bias, and then to negate that very inversion. Inversion of the bias towards unit-level means emphasising the whole, the global level. But we also repudiate the dichotomy that separates parts from wholes, and unit-level from global level. This repudiation requires us to move past the language of the 'mutual constitution' of 'wholes and parts, and of different 'levels', and towards the claim that such language reifies what might be described as simultaneous and continuous processes. Taken to its logical conclusion, this means there are no parts, no wholes, and no levels. There are only simultaneous and continuous processes whose seeming mystical flow our descriptions cannot but freeze.", "cite_spans": [], "ref_spans": []}, {"section": "10", "text": "Regardless of our speculations in this closing section, two conclusions emerge from our analysis. We find laudable Cohen's desire to seek out and invite diverse others to the IPE conversational summit. However, Cohen and his colleagues have yet to confront why that diversity has not already been embraced. 10. Robert Cox (1986: 204) , in a passage we have referred to, speaks of the 'seamless web' of the social world, about how 'contemplating \u2026 undivided totality may lead to profound abstractions and mystical revelations', and about the need to construct a 'structured and dynamic view of larger wholes'.", "cite_spans": [], "ref_spans": []}, {"section": "10", "text": "remained unaware of or insensitive to the diversity that already exists? We follow John Hobson's claim that racism, imperialism and Eurocentrism disallow a western-dominated social science from engaging with diverse viewpoints. We argue further that a disciplinary bias towards a unit-level or atomistic understanding of social science precludes and disallows epistemological encounters in which actual diversity might be harnessed. We support this claim in two steps. First, we draw on Ghassan Hage's analysis of exigophobia, or the fear that social explanation inadvertently justifies horrendous actions and humanises their perpetrators. Exigophobia activates what we call the condemnation imperative: an eagerness to condemn an individual or group act, of fierce violence, for example, before one has tried to understand or explain it. Second, building on Nicholas Onuf's work on levels, we show that the disciplinary bias towards explanations which 'see' from the level of individual actors treats Europe or the west, in Hobson's terms, as 'self-constituting and exceptional'. When one neglects the structuring features of the whole, and assumes western 'pioneering agency', it is easy to treat non-western inferiority (irrationality, backwards culture, and so on) as an explanation of the relative successes and failures of a flattened planet of autonomous units. Though we endorse forms of social explanation that start from the whole as opposed to the parts, we favour the view that there are only simultaneous and continuous processes whose seeming mystical flow our descriptions cannot but freeze. We suggest that there are no levels, simply parts and wholes in process.", "cite_spans": [], "ref_spans": []}, {"section": "10", "text": "Keywords: Eurocentrism -Condemnation Imperative -ExigophobiaAtomism -Social Explanation -Levels -Parts and Wholes -Process A problem with levels: how to engage a diverse IPE", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "We recognise that unit-level strategies are the epitome of the so-called social sciences in the United States, but we mean to disrupt that characterisation. 2. 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We turn to this more nuanced position in the conclusion", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF4": {"title": "92) does argue that the development of 'systematic' generalisations about IR depends on resolving the problem of parts and wholes, though he does not settle on any particular resolution", "authors": [{"first": "", "middle": [], "last": "Singer", "suffix": ""}], "year": 1961, "venue": "", "link": null}, "BIBREF5": {"title": "How a disciplinary schema or a social context 'selects' the scholar results perhaps from the scholar's location and movement within the global political Naeem Inayatullah and David L. Blaney References Abufarha, Nasser. 2009. The making of the human bomb", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF6": {"title": "International political economy: an intellectual history. 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Economic geography, causal mechanisms, and logic in the understanding of development'", "authors": [{"first": "Herman", "middle": [], "last": "Schwartz", "suffix": ""}], "year": 2007, "venue": "Studies in Comparative International Development", "link": "59504308"}, "BIBREF18": {"title": "The levels of analysis problem in international relations", "authors": [{"first": "David", "middle": ["J"], "last": "Singer", "suffix": ""}], "year": 1961, "venue": "World Politics", "link": null}}, "ref_entries": {"TABREF3": {"text": "Onuf implies that levels schemes show us how to see the contents of the world. Put more starkly than Onuf might like, we can say the level selects the scholar, and then conditions how that scholar can see, and what counts as enquiry.", "type": "table"}, "TABREF4": {"text": "We have suggested some of what is required in this confrontation. Absent such an effort, the good intentions of Cohen and his colleagues risk becoming empty gestures.economy, what we otherwise call her/his biography. See Inayatullah (2011: 1-12). 8. In recent correspondence, Onuf has agreed that levels scheme are not value-neutral. 9. Patrick Jackson (2011) challenges the presumption of neopositivists in IR that science requires the testing of proposition based on the observable behavior of individual units. Other, context-dependent, forms of explanation have equal claim to scientific status.", "type": "table"}}}
{"paper_id": "147016405", "_pdf_hash": "af7b11a6068b4db29e72eecc1a1dac2f85ab13b7", "abstract": [], "body_text": [{"section": "", "text": "tion' (Beck 2002) . Perhaps in no other area in the social sciences has sociology been so pro minent in the field of research and yet much work has to be done on both conceptual clarifi cation and empirical inquiry. The topic has already produced a number of major publications offering an overview of the internal diversity of the field (Ritzer 2010; Turner 2010) . However, the key issue within the globalization literature is quite specific, namely what are the forms of culture or consciousness that offer a normative framework for these global processes? Can a global consciousness that has been orchestrated around human rights, environmentalism and cosmopolitanism counter-balance the otherwise bleak and depressing picture of what George Ritzer (2003) has called 'the globalization of nothing' -the world-wide dystopia of empty consumerism that gouges out the significance of human culture. While the intensification of global inequality may well be the inevitable outcome of the current financial crisis (Martell 2010 ), many sociologists and social philosophers have identified cosmopolitan ethics as a promising response to the global movement, or more accurately displacement, of people around the world (Appiah 2006) . What comes after globalization may either be the emergence of a feral society to be characterized by urban decay, water wars, over-population and pandemics, or the construction of new social bonds around a shared cosmopolitan ethic. In short, the sociology of globalization has produced an important discussion of post-national sociology around an emerging 'cosmopolitan imagination' (Delanty 2009 ).", "cite_spans": [{"start": 338, "end": 351, "text": "(Ritzer 2010;", "ref_id": "BIBREF24"}, {"start": 746, "end": 759, "text": "Ritzer (2003)", "ref_id": "BIBREF23"}, {"start": 1013, "end": 1026, "text": "(Martell 2010", "ref_id": "BIBREF20"}, {"start": 1216, "end": 1229, "text": "(Appiah 2006)", "ref_id": "BIBREF1"}, {"start": 1616, "end": 1629, "text": "(Delanty 2009", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "", "text": "Many of the key issues in the field of globalization and cosmopolitan sociology have been explored by Ulrich Beck, whose recent sociological work attempts to provide a systematic theory of these diverse developments (Beck / Sznaider 2006) .There is no need here to comment in any depth on the sociology of cosmopolitanism that Beck has developed in the years follow ing the publication of his seminal work on risk society (Beck [1986 (Beck [ ] 1992 1999) . His theory is adequately described in this edition of Soziale Welt with Edgar Grande ('Jenseits des me thodologischen Nationalismus'). Suffice it to say that, building on the theory of risk society, he has proposed a new periodization of modernity in which the second modernity refers to a world that has moved beyond a system of nation states with the penetration of society by diverse globalizing processes. As a result he has raised some profound issues about the epistemological assumptions of conventional national sociologies (Beck 2000) . Beck has also given some pro minence to the question of human rights as the quintessential expression of law in such a post national environment. Finally, and perhaps most importantly, he has explored the idea of a new type of world consciousness in the notion of 'banal cosmopolitanism'.", "cite_spans": [{"start": 216, "end": 238, "text": "(Beck / Sznaider 2006)", "ref_id": "BIBREF6"}, {"start": 449, "end": 454, "text": "1999)", "ref_id": "BIBREF10"}, {"start": 989, "end": 1000, "text": "(Beck 2000)", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "", "text": "The collection of articles in this special issue of Soziale Welt is a clear and vigorous testimony to the importance of these ideas and to the originality of Beck's current sociological project. These articles can also be seen as a response to some of the criticisms raised against globa lization theory in general. One obvious criticism of most versions of globalization is that they fail conspicuously to examine the development of Asian societies or indeed whether Asian globalization is separate from or prior to western developments (Turner / Khondker 2010 China' provide a welcome addition to the current debate around the limitations of an exclusi vely western view of globalization.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "While recognizing Beck's attempts to develop a systematic general theory of globalization, I shall raise some general criticisms of his theory, all of which revolve around the issue of religion in modernity. I raise some empirical problems for Beck's historical characterization of modernity and thereby bring into focus some difficulties with his theory. There is no need here to dwell on the fact that religion in the classical sociology of Weber, D\u00fcrkheim and Simmel was crucial to the sociological understanding of the origins and character of the modern. Before dealing with these empirical issues, we need to consider Beck's position of 'methodological nationalism'.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "One problem with the early position of both Beck and Anthony Giddens is that they want to argue that, since both Weber and D\u00fcrkheim based their sociology on the notion of bounded nation-states, we need to break out of these limiting assumptions in order to create a post national sociology. I have elsewhere questioned whether the generic notion of the 'social' in Weber, D\u00fcrkheim and Simmel was ever unambiguously 'national' (Turner 2006 a) . It is cer tainly difficult to assume that in his sociology of capital accumulation Marx made any as sumptions about the national character of capital.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "This issue of the national and the social also emerges in a problematic way with respect to human rights. I have in my own work argued that we need to develop a normative sociological notion of 'cosmopolitan virtue' in order to come to terms with modern globalization in Vul nerability and Human Rights (Turner 2006 b) , but I have severe reservations about the feasi bility in the real world of what we might call post-national sovereign jurisdictions. We have to take account of the paradox that in a global world human rights are typically enforced by nation states in the absence of world government. With the current development of global securitization, we should not exaggerate the demise of the nation state and hence the imple mentation of human rights is severely limited. In analytical terms, the construction of a socio logy of human rights remains underdeveloped (Morgan / Turner 2009 ).", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "These opening comments bring me to the core of my objections, which hinge on the pro blematic nature of religion to modernity. It has been often observed that, given the emphasis on economic globalization, the role of religion in the history of globalization has been neglected and that religious globalization predated contemporary secular forms of globalization by many centuries (Beckford / Demerath 2007). Early contributions to the globalization debate were explored some decades ago by sociologists of religion such as Roland Robertson. The rela tionship between religion, the concept of humanity and the origins of human-rights conscious ness had been explored in the 1980 s (Robertson / Chirico 1985) . Some aspects of the sociology of globalization arose out of Robertson's interest in 'intra-civilizational analysis' (Robertson 1982) . The influential volume on Globalization (Robertson 1992 ) was a collection of essays that reflected a decade of work on religion and globalization. These foundations were followed by contributions from Peter Beyer (1994) (Hodgson 1974) . In these examples, the theory of world history had already gone well beyond the tradition of national methodologies of history. These empirical examples from the sociology of religion begin to raise difficulties for Beck's account of the second modernization.", "cite_spans": [{"start": 682, "end": 708, "text": "(Robertson / Chirico 1985)", "ref_id": "BIBREF27"}, {"start": 827, "end": 843, "text": "(Robertson 1982)", "ref_id": "BIBREF25"}, {"start": 886, "end": 901, "text": "(Robertson 1992", "ref_id": "BIBREF26"}, {"start": 1054, "end": 1066, "text": "Beyer (1994)", "ref_id": "BIBREF8"}, {"start": 1067, "end": 1081, "text": "(Hodgson 1974)", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "", "text": "Of course, the growth of these global networks for the pre-modern transmission and ex change of both material goods and cultures does not raise any necessary or fatal difficulty for Beck's argument about a second modernization. We need to demonstrate, in addition to these trade and cultural networks, the emergence of a cosmopolitan consciousness in the pre-modern period. While one can produce ample evidence about inter-connectedness through trade, cul tural exchange and religious conversion, we need also to demonstrate the emergence of an openness to the outside world. Robert Holton (2009: 101) is surely correct to insist that 'to qualify as cosmopolitan, such inter-personal milieux need to exhibit some sense of inter-cul tural openness'. Travel and trade do not automatically produce cosmopolitanism.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "My argument is that any evangelical religion with a universalistic set of assumptions must confront the problem of the Other and out of that dialogue with alterity an early form of cosmopolitan consciousness can emerge. My first example would be the problem that con fronted Saint Paul when faced by the conflicts between Jewish Christians and Gentile Chris tians over the relevance of the Law to the primitive Church. In claiming that there was neither Gentile nor Jew, slave nor free man, man or woman, Paul laid down a universalistic doctrine that challenged any allegiance based on blood and kinship (Badiou 2003) . It is for this reason that Jacob Taubes (2004) can claim Paul as our contemporary. My argument is that Pauli ne 'political theology' contains a reflexive understanding of Otherness and an incipient cosmo politan grasp of the problem of 'the world'. Similar arguments can be presented about the early history of Islam. When Mohammed the Prophet came to construct an early polity, he was also presented with a social situation that was deeply divided between pagan, Christian and Jewish tribes. In searching for a solution to these conflicts, the Constitution of Medina is an early document that outlines a political solution to social divisions, but one that also recognized, albeit implicitly, an Other. The dialogue with other 'people of the book' has had a long history in the evolution of Islam.", "cite_spans": [{"start": 604, "end": 617, "text": "(Badiou 2003)", "ref_id": "BIBREF2"}, {"start": 653, "end": 666, "text": "Taubes (2004)", "ref_id": "BIBREF28"}], "ref_spans": []}, {"section": "", "text": "There is currently ample literature on modern Islamic fundamentalism and its global reach (Mandaville 2001) . Unfortunately this literature often neglects the equally important spread of less radical forms of Islam such as Sufism and the association between peaceful trade and Muslim growth (Diouf 1999) . The division between a pure Islam and the hostile outside world -the world of the ignorant -is relatively modern and in particular a product of the theology of Syed Abul Ala Maududi in the 1940 s (Ahmad 2009 ). But fundamentalism is not the whole story. The global spread of Islam in the modern period has produced a Muslim cosmopolitanism that is in part the legacy of the traditional ummah, but which also responds to the modern development of a global diaspora (Iqtidar 2010) .", "cite_spans": [{"start": 90, "end": 107, "text": "(Mandaville 2001)", "ref_id": "BIBREF19"}, {"start": 291, "end": 303, "text": "(Diouf 1999)", "ref_id": "BIBREF10"}, {"start": 502, "end": 513, "text": "(Ahmad 2009", "ref_id": "BIBREF0"}, {"start": 770, "end": 784, "text": "(Iqtidar 2010)", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "", "text": "The history of religious conflict and co-operation produced a traditional consciousness about the Other and in turn one can therefore detect an early reflection on these religio-cultural differences that created an ecumenical consciousness. It may however be an exaggeration to call this 'reflexive cosmopolitanism' and it is certainly not 'reflexive modernization'. These early forms of awareness of the Other were for one thing not epistemologically open; they were based on the assumption that other traditions were either defective or false. They could be tolerated but they were nevertheless departures from an absolute revealed Truth. The inter faith tolerance that is often associated with Islamic Spain or the millet system of the Ottoman Empire was still based on an assumption about the superiority of Islam. Tolerance of difference has had a slow, fragile and uncertain development, and in my view we have to wait for Leibniz to give a plausible philosophical justification for taking other beliefs seriously (Turner 2005) .", "cite_spans": [{"start": 1020, "end": 1033, "text": "(Turner 2005)", "ref_id": "BIBREF30"}], "ref_spans": []}, {"section": "", "text": "However, I follow Holton (2009: 81) in rejecting the assumption that 'cosmopolitanization and the cosmopolitan outlook are essentially very recent phenomena'. If the empirical validity of the idea of a second modernity is in doubt, the theoretical structure of Beck's argument may be insecure.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "We can in thinking about these pre-modern foundations of cosmopolitanism refer to them as examples of 'reflexive traditionalism'. In Christianity and Islam, this reflexivity emerged out of a world of cultural contact (through global trade) and as a result of global evangelical competition for world influence. Nevertheless, because both New Testament and Qur'an were and continue to be treated as revelations of a singular Truth, there were certain limitations on these early forms of world consciousness. We can claim through this brief commentary that the conditions for such a reflexive traditionalism were mobility and exchange, an evangelical religious culture that undermined the idea that a religious community ('church' or ummah) is merely an extension of kinship relations, the presence of alternative religious traditions in a competitive relationship, and a theological critique of idolatry. Reflexive traditionalism did not however generate what we might call a 'vernacular hermeneutics of doubt' in that these religions assumed an unquestioned notion of revealed Truth that had exclusionary consequen ces. These elementary forms of cosmopolitanism could not cope easily with the possibility of apostasy.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "These historical problems create significant empirical problems for Beck's claims about a second modernization. However, the development of religion in the modern world does appear to verify one important feature of Beck's theory about modernity, namely the idea of 'indivi dualization'. There is widespread agreement in the sociology of religion that one major trend in contemporary religious life is towards 'spirituality' which is defined as post-institutional, global, hybrid, and post-orthodox (Hunt 2005) . It is partly a result of the growth of online religion, and partly a consequence of consumer youth cultures that have an experimental atti tude towards religion (Hulsether 2000) . These self-consciously post-orthodox hybrid trends in personal religiosity are not confined to Christianity, but are widespread in Asia where there is a powerful mixture of traditional practice and the commodification of religion (Kitiarsa 2008) . Although Beck's periodization of modernity is not entirely supported by the historical evi dence, the notion of religious individualization provides an important insight into changing subjectivities in the modern period.", "cite_spans": [{"start": 499, "end": 510, "text": "(Hunt 2005)", "ref_id": "BIBREF15"}, {"start": 674, "end": 690, "text": "(Hulsether 2000)", "ref_id": "BIBREF14"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Islamism and Democracy in India. The transformation of Jamaat-e-Islami", "authors": [{"first": "Irfan", "middle": [], "last": "Ahmad", "suffix": ""}], "year": 2009, "venue": "", "link": "162009066"}, "BIBREF1": {"title": "Cosmopolitanism. Ethics in a World of Strangers", "authors": [{"first": "Kwame", "middle": ["A"], "last": "Appiah", "suffix": ""}], "year": 2006, "venue": "", "link": "145582537"}, "BIBREF2": {"title": "Saint Paul. The Foundation of Universalism", "authors": [{"first": "Alain", "middle": [], "last": "Badiou", "suffix": ""}], "year": 2003, "venue": "", "link": "170687667"}, "BIBREF4": {"title": "The cosmopolitan perspective: sociology in the second age of modernity", "authors": [{"first": "Ulrich", "middle": [], "last": "Beck", "suffix": ""}], "year": 2000, "venue": "British Journal of Sociology", "link": null}, "BIBREF6": {"title": "Unpacking cosmopolitanism for the social sciences: a research agenda", "authors": [{"first": "Beck", "middle": [], "last": "Ulrich / Nathan", "suffix": ""}, {"first": "", "middle": [], "last": "Sznaider", "suffix": ""}], "year": 2006, "venue": "British Journal of Sociology", "link": "145420885"}, "BIBREF7": {"title": "The Sage Handbook of Sociology of Religion", "authors": [], "year": 2007, "venue": "", "link": "141525907"}, "BIBREF8": {"title": "Religion and Globalization", "authors": [{"first": "Peter", "middle": [], "last": "Beyer", "suffix": ""}], "year": 1994, "venue": "", "link": "147374358"}, "BIBREF9": {"title": "The Cosmopolitan Imagination. 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A Basic Text", "authors": [{"first": "George", "middle": [], "last": "Ritzer", "suffix": ""}], "year": 2010, "venue": "", "link": "153043013"}, "BIBREF25": {"title": "Societies, individuals and sociology: intra-civilizational themes", "authors": [{"first": "Roland", "middle": [], "last": "Robertson", "suffix": ""}], "year": 1982, "venue": "", "link": null}, "BIBREF26": {"title": "Globalization. Social Theory and Global Culture", "authors": [{"first": "Roland", "middle": [], "last": "Robertson", "suffix": ""}], "year": 1992, "venue": "", "link": "157616372"}, "BIBREF27": {"title": "Humanity, globalization and worldwide religious resurgence", "authors": [{"first": "Roland / Joann", "middle": [], "last": "Robertson", "suffix": ""}, {"first": "", "middle": [], "last": "Chirico", "suffix": ""}], "year": 1985, "venue": "", "link": null}, "BIBREF28": {"title": "The Political Theology of Paul", "authors": [{"first": "Jacob", "middle": [], "last": "Taubes", "suffix": ""}], "year": 2004, "venue": "", "link": null}, "BIBREF29": {"title": "Cosmopolitan Virtue, Globalization and Patriotism", "authors": [{"first": "Bryan", "middle": ["S"], "last": "Turner", "suffix": ""}], "year": 2002, "venue": "", "link": "146168050"}, "BIBREF30": {"title": "Leibniz, Islam and Cosmopolitan Virtue", "authors": [{"first": "Bryan", "middle": ["S"], "last": "Turner", "suffix": ""}], "year": 2005, "venue": "", "link": "144062827"}}, "ref_entries": {"TABREF0": {"text": "). The various articles in this collection such as the contributions to the family and 'the individua lization of relationships in Japan' and David Tyfield and John Urry's article on 'Cosmopolitan", "type": "table"}, "TABREF1": {"text": "Religion and Globalization and more recently by Mark Juergensmeyer's edited collection on Global Religions (2003) and by David Martin (2002) on Pentecostalism. There are several issues here. Perhaps the least important is the fact that globalization appears to have been explored originally by reference to religion, but the sociology of religion is often neglected in contemporary sociological contributions to globalization theory from David Har vey and Anthony Giddens. Secondly, there is considerable neglect of the historical aspects of the globalization of religion and its interconnections with pre-modern world trade. One obvious example can be taken from the history of the Silk Routes that lasted for some 3000 years. These intercontinental trade routes connected Ancient China and the Mediterranean. Designated as This content downloaded from 203.10.41.180 on Wed, 07 Jun 2017 03:17:17 UTC All use subject to http://about.jstor.org/terms the Silk Road (Seidenstrasse) by the German geographer Ferdinand von Richthofen in 1877, these routes played a major role in the early transmission of Buddhism to China in the first century CE. These routes also contributed to the growing dominance of Islam in Central Asia in the seventh century. In the sociology of globalization, these examples from the ancient world are almost never seriously considered. By contrast, in religious studies and the historical re search on world religions, these global formations have been the topic of major investigations. In particular we can refer to the work of Marshall G.S. Hodgson (1993) who developed a post national epistemology and theory of the world in Rethinking World History and developed the idea of a world oikoumene in his three volume The Venture of Islam exploring 'Islamicate history' from the perspective of an integrated Mediterranean system", "type": "table"}}}
{"paper_id": "147016420", "_pdf_hash": "f73f9510110ca020b7f33ff381051d38e4e2fc99", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Intercultural Education: Teacher Training and School Practice", "authors": [{"first": "T", "middle": [], "last": "Aguado", "suffix": ""}, {"first": "B", "middle": [], "last": "Malik", "suffix": ""}], "year": 2006, "venue": "Intercultural Education", "link": null}, "BIBREF1": {"title": "Intercultural Experience and Education. 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{"paper_id": "147018376", "_pdf_hash": "6cc99b7ca607804ee6f9e46e886696fba6836bd3", "abstract": [], "body_text": [], "bib_entries": {"BIBREF1": {"title": "Foundation Against Trafficking in Women et al. 2001:6. 64 UNODC 2006:154; US Department of State 2007:28, 35; US Department of State 2008:32, 34; US Department of State", "authors": [{"first": "-", "middle": [], "last": "Gajic", "suffix": ""}, {"first": "", "middle": [], "last": "Veljanoski", "suffix": ""}, {"first": ";", "middle": [], "last": "Stewart", "suffix": ""}, {"first": "", "middle": [], "last": "Silverman", "suffix": ""}], "year": 2006, "venue": "", "link": null}, "BIBREF3": {"title": "b) and (c) of the Australian Criminal Code of 1995 goes even further by defining deception in the context of sex trafficking to include deceit about the extent to which a person will be free to leave the place where services are provided or even to cease to provide the sexual services", "authors": [], "year": 2009, "venue": "Section", "link": null}, "BIBREF6": {"title": "placing of a child\", usually from poor, rural areas, with more affluent people, is an acceptable practice. Human traffickers, pretending to be trustworthy agents, facilitate the placing of children, but actually sell these children to their new \"owners\". Parents usually do not receive payment for giving up their children, because the agents promise schooling for them, a luxury many parents cannot afford. In reality, the restav\u00e8cs, or the so-called \"stay-withs\", are child slaves who are forced to work long hours without payment, are often sexually abused and rarely have the privilege of attending school", "authors": [], "year": 2008, "venue": "Haiti and also in Haitian communities across the United States of America, the \"restav\u00e8c\" custom, involving the", "link": null}, "BIBREF11": {"title": "For a discussion of gender discrimination, see Kruger", "authors": [], "year": 2010, "venue": "", "link": null}, "BIBREF14": {"title": "The Future Group 2007b:2. 84 Kreston 2007:38; US Department of State", "authors": [{"first": "U", "middle": ["N"], "last": "Gift", "suffix": ""}], "year": 2007, "venue": "", "link": null}, "BIBREF15": {"title": "in footnote 12; UNODC 2004:269. The UNODC Model Law provides more than one definition of the \"abuse of a position of vulnerability", "authors": [{"first": "", "middle": [], "last": "Un General Assembly", "suffix": ""}], "year": 2000, "venue": "", "link": null}, "BIBREF16": {"title": "Article 3(a)", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF17": {"title": "Shelley reports that this method of offering money to parents for their child has been used in Russia in some cases where the parents are alcoholics and drug addicts", "authors": [], "year": 2007, "venue": "Article", "link": null}, "BIBREF18": {"title": "In the South African context, these methods of controlling victims are well known -Brown", "authors": [], "year": 2010, "venue": "", "link": null}, "BIBREF19": {"title": "For a discussion of the various methods that traffickers use to exercise control over their victims, see Kruger", "authors": [], "year": 2005, "venue": "", "link": null}, "BIBREF20": {"title": "Article 3(a)", "authors": [], "year": 2004, "venue": "", "link": null}, "BIBREF21": {"title": "The exploitation part distinguishes human trafficking from kidnapping, in that kidnapping entails the deprivation of a person's freedom of movement, usually by means of forceful or deceptive movement. However, exploitation of the victim is not a requirement of the crime of kidnapping -Rijken", "authors": [], "year": 2003, "venue": "IOM 2007:23", "link": null}, "BIBREF22": {"title": "Article 3(a)", "authors": [], "year": 2010, "venue": "", "link": null}, "BIBREF24": {"title": "Article 3(a); see also Gallagher 2010:34; UNODC 2006:xii. 104 UNODC 2006:xii; Kamidi", "authors": [], "year": 2001, "venue": "in footnote 72. 105 UNODC 2006:xii; Weissbrodt and Anti-Slavery International", "link": null}, "BIBREF25": {"title": "Gallagher explains that these two concepts have been intentionally left undefined to allow countries to sign and ratify the Palermo Protocol, even though their approach to voluntary adult sex work in their respective legal systems varies", "authors": [{"first": "Jordan", "middle": [], "last": "", "suffix": ""}], "year": 2002, "venue": "UNODC", "link": null}, "BIBREF27": {"title": "However, research indicates that cases of trafficking for labour purposes outnumber sex trafficking where trafficking is committed within a country's borders -US Department of State", "authors": [], "year": 2002, "venue": "Rijken", "link": null}, "BIBREF28": {"title": "Weissbrodt and Anti-Slavery International 2002:29; US Department of State", "authors": [], "year": 2001, "venue": "", "link": null}, "BIBREF29": {"title": "For a further discussion of this Convention and \"the worst forms of child labour", "authors": [{"first": "", "middle": [], "last": "Kruger", "suffix": ""}], "year": 2010, "venue": "", "link": null}, "BIBREF30": {"title": "Slavery, servitude and forced labour are prohibited in almost all major international human rights instruments, but, since none of them define these terms, definitions are only found in subsidiary instruments -Haysom 1997:88; Devenish 1998:54; Haysom 2002:176; Bales and Robbins 2001:26. For a discussion of \"practices similar to slavery\", including debt bondage, serfdom, servile forms of marriage and the provision of children for exploitation", "authors": [], "year": 2010, "venue": "", "link": null}, "BIBREF31": {"title": "Haysom 2002:176 points out that, although slavery was abolished more than a century ago in many countries, such as Britain in 1807 and the United States of America in 1862, the Slavery Convention was the first international", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF33": {"title": "For a more detailed discussion of slavery and its relationship to human trafficking, see Kruger", "authors": [{"first": "Weissbrodt", "middle": [], "last": "Dottridge", "suffix": ""}], "year": 1999, "venue": "", "link": null}, "BIBREF35": {"title": "Dottridge and Weissbrodt 1999:248 explain that traditional slavery was referred to as \"chattel slavery\", because owners were entitled to treat their slaves like any moveable possession (chattel) by buying or selling them", "authors": [], "year": 2004, "venue": "Allain", "link": null}, "BIBREF38": {"title": "Several countries, such as Taiwan, recognise trafficking for the purpose of forced marriage as a significant problem and have adopted more stringent prevention measures to combat this type of exploitation by traffickers", "authors": [], "year": 1999, "venue": "SALRC 2006:33; Wijers and Lap-Chew", "link": null}, "BIBREF39": {"title": "Vietnamese -They Don't Run Away! -International Marriage Specialist\" -US Department of State 2007:17; see also GAATW 1999a:15; Weissbrodt and Anti-Slavery International", "authors": [], "year": 2002, "venue": "", "link": null}, "BIBREF40": {"title": "For a discussion on women advertised for marriage, usually under the description \"mail-order brides\", and their vulnerability in becoming victims of trafficking, see Dottridge and Weissbrodt", "authors": [], "year": 1999, "venue": "", "link": null}, "BIBREF42": {"title": "US Department of State 2009:260; US Department of State", "authors": [{"first": "", "middle": [], "last": "Mcquoid-Mason", "suffix": ""}], "year": 2009, "venue": "", "link": null}, "BIBREF43": {"title": "For a discussion of the violation of the various constitutional rights as a result of ukuthwala being abused to force a woman into marriage, see McQuoid", "authors": [], "year": 2009, "venue": "", "link": null}, "BIBREF45": {"title": "This provision of the Palermo Protocol links up with the Optional Protocol to the Convention of the Rights of the Child on the Sale of Children, Child Prostitution and Child Pornography, which prohibits", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF46": {"title": "However, it must be noted that the removal of an organ from a child, with the valid consent of a parent, for legitimate medical or therapeutic reasons is not considered exploitation -UN General Assembly 2000: paragraph 65", "authors": [{"first": "Anti-Slavery", "middle": [], "last": "Weissbrodt", "suffix": ""}], "year": 2002, "venue": "", "link": null}, "BIBREF47": {"title": "When an organ is illegally removed from a deceased person and sold for profit, this is an example of organ trafficking, but it does not constitute human trafficking unless the person was killed for the purpose of removing the organ -UN.GIFT 2008a:6; Weissbrodt and Anti-Slavery International", "authors": [{"first": "U", "middle": ["N"], "last": "Gift", "suffix": ""}], "year": 2002, "venue": "", "link": null}, "BIBREF48": {"title": "It is reported that a distinguishing feature of this type of trafficking is that \"traffickers and organ 'brokers' come from atypical sectors and include doctors and other health-care practitioners, ambulance drivers and mortuary workers", "authors": [{"first": "Newell", "middle": [], "last": "Hodgkin", "suffix": ""}], "year": 2002, "venue": "", "link": null}, "BIBREF49": {"title": "US Department of State 2010:8; UN.GIFT 2008a:2; SALRC 2006:30; Dottridge and Weissbrodt", "authors": [], "year": 1999, "venue": "", "link": null}, "BIBREF50": {"title": "also confirms the worldwide shortage of body organs available for life-saving transplants. 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{"paper_id": "147018674", "_pdf_hash": "ace005f4bacbb345d214d095a8226ec0b3360ecc", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "116980417", "_pdf_hash": "8296d7b3f89d24936ea57160641ec7fe5dc0e9b0", "abstract": [{"section": "Abstract", "text": "Abstract. We prove some vector-valued inequalities for fractional integrals defined in the context of two different orthonormal systems of Laguerre functions. Our results are based on estimates of the corresponding kernels with precise control of the parameters involved. As an application, mixed norm estimates for the fractional integrals related to the harmonic oscillator are deduced.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Consider the fractional integral I \u03c3 f (x) = R n f (y) |x \u2212 y| n\u2212\u03c3 dy, x \u2208 R n , 0 < \u03c3 < n, defined for any function f for which the above integral is convergent. Then, with an appropriate constant c \u03c3 ,", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "where \u2206 is the standard Laplacian in R n , and the negative power is defined in L 2 (R n , dx) by means of the Fourier transform, see [22, Ch. 5] .", "cite_spans": [{"start": 134, "end": 138, "text": "[22,", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "Introduction", "text": "The classical Hardy-Littlewood-Sobolev inequality (see, e.g., [8, 22] ) establishes that n n\u2212\u03c3 a weak type inequality holds. A weighted version of the Hardy-Littlewood-Sobolev was given in [23] .", "cite_spans": [{"start": 62, "end": 65, "text": "[8,", "ref_id": "BIBREF8"}, {"start": 66, "end": 69, "text": "22]", "ref_id": "BIBREF22"}, {"start": 189, "end": 193, "text": "[23]", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Introduction", "text": "Numerous analogues of the Euclidean fractional integral operator were investigated in various settings for the last decades. For instance, B. Muckenhoupt and E. M. Stein analyzed the topic for ultraspherical expansions in [16] . The one dimensional Hermite and Laguerre function expansions have been considered in [12, 13, 14] . Recently, B. Bongioanni and J. L. Torrea [3] obtained estimates for the negative powers of the multidimensional harmonic oscillator. Fractional integrals for the multidimensional Laguerre expansions (or negative powers of the corresponding second order differential operators) have been treated by A. Nowak and K. Stempak in [18, 19] . They analyzed L p \u2212 L q estimates (with and without weights) for the expansions related to Laguerre functions of Hermite type and Laguerre functions of convolution type (this nomenclature is used by S. Thangavelu in [24] ). Sharp bounds for the kernel of potential operators in the case of the Laguerre functions of convolution type have been obtained very recently in [18] . Also, a complete and exhaustive study of fractional integrals for Jacobi and Fourier-Bessel expansions has been developed in [17] . Moreover, a vector-valued extension in the Jacobi case was done in [5] . The aim of this paper is the extension of L p \u2212L q mapping properties concerning fractional integrals (or negative powers) related to two second order differential operators of Laguerre type. Namely, our target will be the proof of vector-valued extensions of some results given in [19] . We will deal with vector-valued inequalities of the form", "cite_spans": [{"start": 222, "end": 226, "text": "[16]", "ref_id": "BIBREF16"}, {"start": 314, "end": 318, "text": "[12,", "ref_id": "BIBREF12"}, {"start": 319, "end": 322, "text": "13,", "ref_id": "BIBREF13"}, {"start": 323, "end": 326, "text": "14]", "ref_id": "BIBREF14"}, {"start": 370, "end": 373, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 654, "end": 658, "text": "[18,", "ref_id": "BIBREF18"}, {"start": 659, "end": 662, "text": "19]", "ref_id": "BIBREF19"}, {"start": 881, "end": 885, "text": "[24]", "ref_id": "BIBREF24"}, {"start": 1034, "end": 1038, "text": "[18]", "ref_id": "BIBREF18"}, {"start": 1166, "end": 1170, "text": "[17]", "ref_id": "BIBREF17"}, {"start": 1240, "end": 1243, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 1528, "end": 1532, "text": "[19]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "Introduction", "text": ", where {T j } j\u22650 is a sequence of operators defined on a measure space (X, d\u00b5). We will also consider weighted vector-valued inequalities.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "If we denote, respectively, by (L \u2212\u03c3 } j\u22650 , where a is positive real parameter. The meaning of \u03b1 + aj will be explained below. For Laguerre expansions of Hermite type we will consider the space (R n + , dx), with dx the Lebesgue measure and our approach will be similar to [19] . But in our case, we will prove an estimate for the kernels of the operators (L H \u03b1+aj )", "cite_spans": [{"start": 274, "end": 278, "text": "[19]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "Introduction", "text": "\u2212\u03c3 independent of the parameter j. Then a general result of vector-valued extensions will do the work. We will also include some potential weights. On the other hand, we will deal with fractional integrals related to Laguerre expansions of convolution type, where the space considered will be (R + , d\u00b5 \u03b1 ) with d\u00b5 \u03b1 = x 2\u03b1+1 dx. However, the way to prove the corresponding vector-valued inequality will be close to the ideas in [3] . Observe that in [3] , the authors consider Hermite expansions. The argument given in [19] to treat the convolution type setting is based on a very useful convexity principle. Unfortunately, we cannot apply the convexity principle here. The reason is the following: the constants appearing in this case involve Gamma functions whose log-convexity makes these constants increase with no control at all. The new estimates given in [18] for (L \u03b1 ) \u2212\u03c3 are not appropriate for our target either: these estimates, applied to (L \u03b1+aj ) \u2212\u03c3 , yield constants depending on the parameter j and in that case we could not deduce the vector-valued extension.", "cite_spans": [{"start": 429, "end": 432, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 451, "end": 454, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 520, "end": 524, "text": "[19]", "ref_id": "BIBREF19"}, {"start": 863, "end": 867, "text": "[18]", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Introduction", "text": "As an application of our result on Laguerre expansions of convolution type, we will analyze the fractional integral operator related to spherical eigenfunctions of the harmonic oscillator. Observe that the result in [3] deals with eigenfunctions of the harmonic oscillator in cartesian coordinates. In our situation we consider the eigenfunctions obtained by using spherical coordinates (this is the reason for the name spherical eigenfunctions). In the spherical case, the eigenfunctions are products of Laguerre functions and spherical harmonics. We consider the mixed norm spaces L p,2 (R n , r n\u22121 dr d\u03c3) (see Section 3 for definition). These spaces were first sistematically studied by A. Benedek and R. Panzone in [2] . They arise frequently in harmonic analysis when the spherical harmonics are involved, see [21, 6, 4, 1] .", "cite_spans": [{"start": 216, "end": 219, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 720, "end": 723, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 816, "end": 820, "text": "[21,", "ref_id": "BIBREF21"}, {"start": 821, "end": 823, "text": "6,", "ref_id": "BIBREF5"}, {"start": 824, "end": 826, "text": "4,", "ref_id": "BIBREF3"}, {"start": 827, "end": 829, "text": "1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Introduction", "text": "The organization of the paper is the following. In Section 2 we introduce some definitions related to Laguerre systems and establish our results about boundedness of the fractional integrals related. Section 3 contains our analysis of the fractional integrals for the harmonic oscillator in mixed norm spaces. In Section 4 and Section 5 we give the proofs of the results given in Section 2. Finally, in Section 6 we show the proofs of some technical results used along the paper.", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and main results", "text": "Let \u03b1 = (\u03b1 1 , . . . , \u03b1 n ) \u2208 (\u22121, \u221e) n be a multi-index and x, y \u2208 R n + , n \u2265 1. The Laguerre function on R n + is the tensor product", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and main results", "text": "where \u03d5 \u03b1i ki (x i ) are the one dimensional Laguerre functions", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and main results", "text": "and L \u03b1i ki denotes the Laguerre polynomial of degree k i \u2208 N and order \u03b1 i > \u22121, see [15, p. 76] . We consider the differential operator ; by |\u03b1| and |k| we denote |\u03b1| = \u03b1 1 + \u00b7 \u00b7 \u00b7 + \u03b1 n (thus |\u03b1| may be negative) and the length |k| = k 1 + \u00b7 \u00b7 \u00b7 + k n . We will refer to \u03d5 ", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and main results", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and main results", "text": "With these notations, our result related to the fractional integrals for the Laguerre expansions of Hermite type is the following.", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and main results", "text": ", then there exists a constant depending only on \u03c3 and \u03b1 such that", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and main results", "text": "(ii) If \u03c3 < n/2, then the same boundedness holds under the additional condition", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and main results", "text": "Remark 2.2. In the previous theorem, the sequence \u03b1+aj has to be understood as (\u03b1 1 +aj, . . . , \u03b1 n + aj). It will be clear after the proof that this sequence can be changed into (\u03b1 1 + a 1 (j), . . . , \u03b1 n + a n (j)) where {a i (j)} j\u22650 , for i = 1, . . . , n, are positive, increasing and unbounded sequences such that a i (0) = 0 and a i (1) \u2265 1.", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and main results", "text": "Let us focus on the second setting. We consider now the differential operator given by (2.2)", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and main results", "text": "This is a symmetric operator on R n + equipped with the measure", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and main results", "text": "The Laguerre functions \u2113 ", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and main results", "text": "where \u2113 \u03b1i ki are the one dimensional Laguerre functions", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and main results", "text": "The functions \u2113 ", "cite_spans": [], "ref_spans": []}, {"section": "4\u00d3. CIAURRI AND L. RONCAL", "text": "For the expansions of Laguerre functions of convolution type we define the fractional integrals as", "cite_spans": [], "ref_spans": []}, {"section": "4\u00d3. CIAURRI AND L. RONCAL", "text": "where \u03c3 > 0 and", "cite_spans": [], "ref_spans": []}, {"section": "4\u00d3. CIAURRI AND L. RONCAL", "text": "Our result in this case is the following.", "cite_spans": [], "ref_spans": []}, {"section": "4\u00d3. CIAURRI AND L. RONCAL", "text": "Then there exists a constant depending only on \u03c3 and \u03b1 such that", "cite_spans": [], "ref_spans": []}, {"section": "4\u00d3. CIAURRI AND L. RONCAL", "text": ", if and only if p and q satisfy", "cite_spans": [], "ref_spans": []}, {"section": "4\u00d3. CIAURRI AND L. RONCAL", "text": "with exclusion of the cases p = 1 and q = \u03b1+1 \u03b1+1\u2212\u03c3 , and p = \u03b1+1 \u03c3 and q = \u221e. Remark 2.4. In the case of Theorem 2.3, we deduce from our proof that the sequence \u03b1 + aj can be changed into \u03b1 + a(j) where {a(j)} j\u22650 , is a positive, increasing and unbounded sequence such that a(0) = 0 and a(1) \u2265 1.", "cite_spans": [], "ref_spans": []}, {"section": "4\u00d3. CIAURRI AND L. RONCAL", "text": "3. An application of Theorem 2.3", "cite_spans": [], "ref_spans": []}, {"section": "4\u00d3. CIAURRI AND L. RONCAL", "text": "As we commented in the previous section, the results in Theorem 2.1 and Theorem 2.3 are extensions of some known inequalities for fractional integrals for Laguerre expansions. However, the inequality (2.3) appears in a natural way in the study of fractional integrals related to the harmonic oscillator. Indeed, the eigenfunctions of the harmonic oscillator in R n verify", "cite_spans": [], "ref_spans": []}, {"section": "4\u00d3. CIAURRI AND L. RONCAL", "text": "where E is the corresponding eigenvalue. There are two complete sets of eigenfunctions for this equation. Using cartesian coordinates, one obtains the functions", "cite_spans": [], "ref_spans": []}, {"section": "4\u00d3. CIAURRI AND L. RONCAL", "text": ", and H j denote the Hermite polynomials of degree j \u2208 N (see [15, p. 60] ). In this case E k = 2|k| + d. The system of functions {\u03c6 k } k\u2208N n is orthonormal and complete in L 2 (R n , dx). The fractional integrals for this system have been studied in [3] and [19] . Vector-valued extensions of the results in both papers for sequences of functions {f j (x)} j\u2208N , with x \u2208 R n , are trivial. But the situation is completely different if we analyze the eigenfunctions of the harmonic oscillator by using spherical coordinates. Let H j be the space of spherical harmonics of degree j in n variables. Let {Y j,\u2113 } \u2113=1,...,dim Hj be an orthonormal basis for H j in L 2 (S n\u22121 , d\u03c3). Then the eigenfunctions of the harmonic oscillator, see [7] , are given b\u1ef9", "cite_spans": [{"start": 252, "end": 255, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 260, "end": 264, "text": "[19]", "ref_id": "BIBREF19"}, {"start": 736, "end": 739, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "4\u00d3. CIAURRI AND L. RONCAL", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "4\u00d3. CIAURRI AND L. RONCAL", "text": ", and L b j are Laguerre polynomials of order b and degree j \u2208 N. This system is orthonormal and complete in L 2 (R n , dx) and the eigenvalues are E m,j,\u2113 = (n + 2m). Moreover", "cite_spans": [], "ref_spans": []}, {"section": "4\u00d3. CIAURRI AND L. RONCAL", "text": "For each \u03c3 > 0, we define the fractional integrals for the harmonic oscillator as", "cite_spans": [], "ref_spans": []}, {"section": "4\u00d3. CIAURRI AND L. RONCAL", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "4\u00d3. CIAURRI AND L. RONCAL", "text": "The most appropriate spaces in order to analyze this kind of operators are the mixed norm spaces, defined as", "cite_spans": [], "ref_spans": []}, {"section": "4\u00d3. CIAURRI AND L. RONCAL", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "4\u00d3. CIAURRI AND L. RONCAL", "text": "with the obvious modification in the case p = \u221e. The main characteristic of these spaces is that we consider the L 2 -norm in the angular part and the L p -norm in the radial. They are very different from", "cite_spans": [], "ref_spans": []}, {"section": "4\u00d3. CIAURRI AND L. RONCAL", "text": "These spaces are suitable when spherical harmonics are involved. Indeed, if a function f on R n is expanded in spherical harmonics,", "cite_spans": [], "ref_spans": []}, {"section": "4\u00d3. CIAURRI AND L. RONCAL", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "4\u00d3. CIAURRI AND L. RONCAL", "text": "we have", "cite_spans": [], "ref_spans": []}, {"section": "4\u00d3. CIAURRI AND L. RONCAL", "text": ".", "cite_spans": [], "ref_spans": []}, {"section": "4\u00d3. CIAURRI AND L. RONCAL", "text": "From this and using Theorem 2.3, we can prove the following result.", "cite_spans": [], "ref_spans": []}, {"section": "4\u00d3. CIAURRI AND L. RONCAL", "text": "Theorem 3.1. Let n \u2265 2, 0 < \u03c3 < n/2, and 1 \u2264 p, q \u2264 \u221e. Assume that p and q satisfy", "cite_spans": [], "ref_spans": []}, {"section": "4\u00d3. CIAURRI AND L. RONCAL", "text": "with exclusion of the cases p = 1 and q = n n\u22122\u03c3 , and p = n 2\u03c3 and q = \u221e. Then there exists a constant depending only on \u03c3 such that", "cite_spans": [], "ref_spans": []}, {"section": "4\u00d3. CIAURRI AND L. RONCAL", "text": "Proof. Consider the decomposition", "cite_spans": [], "ref_spans": []}, {"section": "4\u00d3. CIAURRI AND L. RONCAL", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "4\u00d3. CIAURRI AND L. RONCAL", "text": "We start analyzing O 1 . After some elementary algebraic manipulations, we have", "cite_spans": [], "ref_spans": []}, {"section": "4\u00d3. CIAURRI AND L. RONCAL", "text": "By (3.1), we can deduce the following identity immediately", "cite_spans": [], "ref_spans": []}, {"section": "4\u00d3. CIAURRI AND L. RONCAL", "text": "where we used the notation in the previous section for Laguerre expansions of convolution type. Then", "cite_spans": [], "ref_spans": []}, {"section": "4\u00d3. CIAURRI AND L. RONCAL", "text": "In a similar way, we conclude that", "cite_spans": [], "ref_spans": []}, {"section": "4\u00d3. CIAURRI AND L. RONCAL", "text": "So, the inequality (3.2) is equivalent to", "cite_spans": [], "ref_spans": []}, {"section": "4\u00d3. CIAURRI AND L. RONCAL", "text": ", which is a consequence of Theorem 2.3. This has been pointed out to us by G. Garrig\u00f3s in a personal communication.", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.1", "text": "The heat semigroup related to L", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.1", "text": "and by f, g we denote", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.1", "text": "We can write the heat semigroup {T H \u03b1,t } t>0 as an integral operator", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.1", "text": "The Laguerre heat kernel is given by", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.1", "text": "The explicit expression for Laguerre heat kernel is known and it can be found in [15, (4.17.6) ]:", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.1", "text": ", ", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.1", "text": "where the measure d\u03a0 \u03bd (u) is given by", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.1", "text": "In the limit case \u03bd = \u22121/2, we put", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.1", "text": "n , the kernel can be expressed as", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.1", "text": "Meda's change of variable", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.1", "text": "The following technical lemma can be found in [19, Lemma 2.1].", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.1", "text": "Lemma 4.1. Let a \u2208 R be fixed and T > 0. Then", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.1", "text": "and for 0 < T < 1", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.1", "text": "with C independent of \u03b1.", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.1", "text": ". . , n. From this identity and (4.2), it follows that q \u00b1 (x, y, s) = n i=1 q \u00b1,i (x i , y i , s i ). Observe that (4.5)", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.1", "text": "so it suffices to deal with the integral in dimension one. The case \u03b1 i = \u22121/2 is elementary, so we obtain the estimate for \u03b1 i > \u22121/2. We write", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.1", "text": "With the change of variable s i = 2u \u2212 1 we have", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.1", "text": "It is easy to check that", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.1", "text": "and then", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.1", "text": "From (4.1), (4.4) and (4.5), the estimate in the proposition follows.", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.1", "text": "For each \u03c3 > 0, we define the potential operator", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.1", "text": "is the potential kernel. Define the auxiliary convolution kernel K \u03c3 (x), x \u2208 R n \\ {0}, by", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.1", "text": "and for |x| < 1,", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.1", "text": "Proof. By (4.6), Meda's change of variable (4.3), (4.4), and Proposition 4.2, we have", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.1", "text": "Concerning I 1 , observe that there exists C such that log 1+\u03be 1\u2212\u03be < C\u03be, for \u03be \u2208 (0, 1/2). Then, we apply Lemma 4.1 with a = \u2212\u03c3 + 1 + n/2 and T = |x \u2212 y| 2 /4, and we obtain", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.1", "text": "for |x \u2212 y| < 2, and", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.1", "text": "for |x \u2212 y| \u2265 2, which is equivalent to the required bound. Now we deal with I 2 . By using that \u03be \u2212n/2 \u223c 1, for \u03be \u2208 (1/2, 1), and reverting Meda's change of variable yield", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.1", "text": "which is enough for our purposes.", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.1", "text": "On the other hand, we will use the following result about vector-valued extensions of bounded operators. This result is a version of [11, Ch. 5, Theorem 1.12] in the setting of \u2113 r spaces.", "cite_spans": [], "ref_spans": []}, {"section": "be a bounded linear operator which is positive (i.e. g(x)", "text": "\u2265 0 implies T g(x) \u2265 0), 1 \u2264 p, q \u2264 \u221e, with norm |T |. Then T has an \u2113 r -valued extension for 1 \u2264 r \u2264 \u221e and", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.1. First we have to prove that (L", "text": ". This is obtained by showing that both operators, being bounded in L 2 (R n + , dx), coincide on the linear span of the functions \u03d5 \u03b1 k which is a dense subspace of", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.1. First we have to prove that (L", "text": "Application of Fubini's theorem in the second identity was possible since H", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.1. First we have to prove that (L", "text": ". Now we observe that, by Proposition 4.3, there exists a constant C \u03c3 depending only on \u03c3 such that for a nonnegative function f ,", "cite_spans": [], "ref_spans": []}, {"section": "10\u00d3. CIAURRI AND L. RONCAL", "text": "By [19, Theorem 2.5] and Lemma 4.4 (note that K \u03c3 (x \u2212 y) is positive), there exists a constant C depending only on \u03c3, s and t such that", "cite_spans": [], "ref_spans": []}, {"section": "10\u00d3. CIAURRI AND L. RONCAL", "text": ", and the proof is complete.", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.3", "text": "Recall the differential operator L \u03b1 given in (2.2). The heat semigroup related to", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.3", "text": "and by f, g d\u00b5\u03b1 we denote R n + f (x)g(x) d\u00b5 \u03b1 (x). We can write the heat semigroup {T \u03b1,t } t>0 as an integral operator", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.3", "text": "The Laguerre heat kernel in this case is given by", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.3", "text": "Observe that", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.3", "text": "We define the potential operator", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.3", "text": "is the potential kernel. Due to (5.1),", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.3", "text": "For, n = 1, which is the case in which we are interested from now on, by using the estimates in the previous section for H H \u03b1,\u03c3 and the relation (5.4), we obtain that", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.3", "text": "If one uses this estimate to attain L p \u2212 L q inequalities, then it turns out that we need an extra restriction on the parameters. In fact, the condition", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.3", "text": "2\u03b1+1 arises in the estimate of H \u03b1+aj,\u03c3 (x, y) due to the presence of the factor (xy) \u2212\u03b1\u22121/2 and the measure d\u00b5 \u03b1 . So, in order to take out such restriction on p and q, one has to get suitable estimates for the kernel. In this way, the proof of Theorem 2.3 is based on the estimates collected in Propositions 5.1 and 5.6. Proposition 5.1. Let \u03b1 \u2265 \u22121/2, a \u2265 1, j \u2208 N, and 0 < \u03c3 < \u03b1 + 1. Then", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.3", "text": "where C depends on \u03b1 and \u03c3, but not on j, and", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.3", "text": "for some constant c > 0, with", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.3", "text": "The two following lemmas will provide us the main tools to prove the previous proposition.", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.3", "text": "Lemma 5.2. Let c > \u22121 and \u2113 be such that 0 < \u03c3 < c + \u2113 and a > 0. Then", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.3", "text": "where C is independent of c.", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.3", "text": "Lemma 5.3. Let \u03b1 \u2265 \u22121/2, \u03bb \u2208 R, b \u2265 1, 0 < B < A, and", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.3", "text": "Then, for \u03bb > 0,", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.3", "text": "and, for \u03bb < 0,", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.3", "text": "Aditionally, for the case |x \u2212 y| < 1, x + y > 2, and \u03c3 > 1/2 we will use the following result.", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.3", "text": "Lemma 5.4. Let \u03b1 \u2265 \u22121/2, a \u2265 1, and j \u2208 N. Then", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.3", "text": "with C a constant independent of j.", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.3", "text": "Also, in the case |x \u2212 y| \u2265 1, the result will follow from an appropriate estimate of the heat kernel.", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.3", "text": "Lemma 5.5. Let \u03b1 \u2265 \u22121/2, a \u2265 1, and j \u2208 N. Then", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.3", "text": "with C a constant independent of j.", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.3", "text": "The previous lemmas are rather technical and their proofs will be given in the last section. ", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.3", "text": "Finally, we conclude by using Lemma 5.3 with b = aj, \u03bb = 1/2 \u2212 \u03c3, A = (x + y) 2 , and B = 4xy. Indeed, for \u03c3 < 1/2,", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.3", "text": "and, for \u03c3 > 1/2,", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.3", "text": "The previous estimate for H \u03b1+aj,\u03c3 , in the case \u03c3 > 1/2, will be used when max{x, y} \u2264 2 and |x \u2212 y| < 1. For max{x, y} > 2 and |x \u2212 y| < 1, we obtain a sharper inequality by using Lemma 5.4. Indeed,", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.3", "text": "where we have used that in this region xy \u223c x 2 + y 2 and that the integral is convergent because \u03c3 > 1/2.", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.3", "text": "To bound the kernel in the case |x \u2212 y| \u2265 1, we use (5.3), Meda's change of variable (4.3), and Lemma 5.5 to obtain that", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.3", "text": "The last integral can be controlled by a constant by applying Lemma 5.2 with c = \u03b1 and \u2113 = 1, and the condition |x \u2212 y| \u2265 1. Then", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.3", "text": "and the proof is finished.", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.3", "text": "The next auxiliary result will be used in the proof of Theorem 2.3.", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.3", "text": "Proposition 5.6. Let \u03b1 \u2265 \u22121/2, a \u2265 1, j \u2208 N \u222a {0}, and 0 < \u03c3 < \u03b1 + 1. Then,", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.3", "text": "where C is independent of j and", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.3", "text": "Moreover, for x > 2,", "cite_spans": [], "ref_spans": []}, {"section": "Proof of Theorem 2.3", "text": "The proof of the necessity of the condition (2.4) in Theorem 2.3 is an immediate consequence of Theorem 2.2 in [18] where the boundedness of (L \u03b1 ) \u2212\u03c3 is characterized. The sufficiency of (2.4) will be obtained from the following result and the Riesz-Thorin interpolation theorem.", "cite_spans": [{"start": 111, "end": 115, "text": "[18]", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Proof of Theorem 2.3", "text": ".", "cite_spans": [], "ref_spans": []}, {"section": "c) If", "text": ". e) If p > 1, q < \u221e and", "cite_spans": [], "ref_spans": []}, {"section": "c) If", "text": ".", "cite_spans": [], "ref_spans": []}, {"section": "c) If", "text": "The proof of e) is a consequence of a classical result for the Hardy operator (see [10, Theorem 1] ) and another result about the boundedness of local one-dimensional fractional integrals (see [9, Corollary 5.4] ). These results are stated below.", "cite_spans": [{"start": 83, "end": 87, "text": "[10,", "ref_id": "BIBREF10"}, {"start": 193, "end": 196, "text": "[9,", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "c) If", "text": "Theorem 5.9. Let f be a nonnegative function defined on (0, +\u221e). Let 0 < \u03b2 < 1 and consider the local fractional integral in (0, +\u221e): Proof of Theorem 5.7 . As in the proof of Theorem 2.1, it can be checked easily that (L \u03b1 ) \u2212\u03c3 = I \u03b1,\u03c3 so we omit the details.", "cite_spans": [], "ref_spans": []}, {"section": "c) If", "text": "In the five parts of the proof we will analyze u j (L \u03b1+aj ) \u2212\u03c3 (u \u22121 j f j ) for j \u2265 1. The case j = 0 can be deduced from Theorem 2.2 in [18] . By (5.2) and Proposition 5.1, it is clear that", "cite_spans": [{"start": 139, "end": 143, "text": "[18]", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "c) If", "text": "where K \u03b1,\u03c3 is that in (5.5).", "cite_spans": [], "ref_spans": []}, {"section": "Proof of a)", "text": "The inequality in a) will be deduced from the estimate", "cite_spans": [], "ref_spans": []}, {"section": "Proof of a)", "text": "and Lemma 4.4. Applying Minkowski inequality, the previous inequality is a consequence of the estimate", "cite_spans": [], "ref_spans": []}, {"section": "Proof of a)", "text": "To prove the previous bound, we consider the cases |x \u2212 y| < 1 and |x \u2212 y| \u2265 1. For |x \u2212 y| < 1 we distinguish three cases: Case \u03c3 < 1/2. For y \u2265 1, we have", "cite_spans": [], "ref_spans": []}, {"section": "Proof of a)", "text": "When y < 1, it is verified that |x\u2212y|<1", "cite_spans": [], "ref_spans": []}, {"section": "Proof of a)", "text": "where in the last step we used that 1 \u2212", "cite_spans": [], "ref_spans": []}, {"section": "Proof of a)", "text": "And the last integral can be controlled as follows", "cite_spans": [], "ref_spans": []}, {"section": "Proof of a)", "text": "where in the last step we have used a standard estimate for the incomplete Gamma function. For y < 1, it holds that", "cite_spans": [], "ref_spans": []}, {"section": "Proof of a)", "text": "Case \u03c3 > 1/2. For y \u2265 1, we have", "cite_spans": [], "ref_spans": []}, {"section": "Proof of a)", "text": "where we use the condition 1 \u2212 \u03c3 \u03b1+1 < 1", "cite_spans": [], "ref_spans": []}, {"section": "Proof of a)", "text": "q . We pass to analyze (5.8) for |x \u2212 y| \u2265 1. We have", "cite_spans": [], "ref_spans": []}, {"section": "Proof of a)", "text": "In this region, the inequality", "cite_spans": [], "ref_spans": []}, {"section": "Proof of a)", "text": "and the proof of (5.8) is completed.", "cite_spans": [], "ref_spans": []}, {"section": "Proof of b)", "text": ". By using an argument analogous to a), it is enough to prove that", "cite_spans": [], "ref_spans": []}, {"section": "Proof of b)", "text": "Now, by H\u00f6lder inequality, the result will follow from (5.8) and the symmetry of the kernel K \u03b1,\u03c3 , by using the condition", "cite_spans": [], "ref_spans": []}, {"section": "Proof of c).", "text": "We consider x \u2208 (0, 2) and x \u2265 2 separately. In the first case, by Proposition 5.1 and Lemma 4.4, the inequality is reduced to prove", "cite_spans": [], "ref_spans": []}, {"section": "Now, taking into account that", "text": "we will conclude by showing that When x \u2265 2, by (5.6) and Lemma 4.4, it will be enough to prove that", "cite_spans": [], "ref_spans": []}, {"section": "Now, taking into account that", "text": "By applying (5.7), we obtain that", "cite_spans": [], "ref_spans": []}, {"section": "Now, taking into account that", "text": "where in the last step we have used the restriction", "cite_spans": [], "ref_spans": []}, {"section": "Proof of d).", "text": "We distinguish between y \u2208 (0, 2) and y \u2265 2. In the first case, by Proposition 5.1 and Lemma 4.4, the inequality is reduced to prove", "cite_spans": [], "ref_spans": []}, {"section": "16\u00d3. CIAURRI AND L. RONCAL", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "By Fubini's theorem and H\u00f6lder inequality", "text": "where in the last step we used (5.8).", "cite_spans": [], "ref_spans": []}, {"section": "By Fubini's theorem and H\u00f6lder inequality", "text": "In the case y \u2265 2, by (5.6) and Lemma 4.4, it will be enough to prove that", "cite_spans": [], "ref_spans": []}, {"section": "By Fubini's theorem and H\u00f6lder inequality", "text": "Applying Fubini's theorem, H\u00f6lder inequality and (5.7), we obtain that", "cite_spans": [], "ref_spans": []}, {"section": "By Fubini's theorem and H\u00f6lder inequality", "text": "where in the last step, we used that 1 \u2212", "cite_spans": [], "ref_spans": []}, {"section": "By Fubini's theorem and H\u00f6lder inequality", "text": "Proof of e). By using Proposition 5.1 we have to distinguish three cases in terms of \u03c3. Case \u03c3 < 1/2. In this case", "cite_spans": [], "ref_spans": []}, {"section": "By Fubini's theorem and H\u00f6lder inequality", "text": ", where", "cite_spans": [], "ref_spans": []}, {"section": "By Fubini's theorem and H\u00f6lder inequality", "text": "f (x), and", "cite_spans": [], "ref_spans": []}, {"section": "By Fubini's theorem and H\u00f6lder inequality", "text": "For I 1 the required bound follows from Theorem 5.8 and for I 2 is an immediate consequence of Theorem 5.9. For I 3 , we can prove the boundedness for the pairs (1/q, 1/p) = (1\u2212\u03c3/(\u03b1+1), 1) and (1/q, 1/p) = (0, \u03c3/(\u03b1+1)) as we did in a) and c). Indeed, the result will follow by applying Minkowski or H\u00f6lder inequalities and taking into account that |x\u2212y|\u22651 e \u2212c(x\u2212y) 2 (x + y) r(2\u03b1+1) d\u00b5 \u03b1 (y) \u2264 C, for any r \u2265 1. The complete result is obtained by interpolation. Case \u03c3 = 1/2. Now, it is verified that 1/p \u2212 1/q = 1/2(\u03b1 + 1) =: \u03b4 < 1. Then (since \u2212 log t \u2264 Ct 1\u2212\u03b4 , for 0 < t < C < 1)", "cite_spans": [], "ref_spans": []}, {"section": "By Fubini's theorem and H\u00f6lder inequality", "text": ", where 2 (x + y) 2\u03b1+1 f (y) d\u00b5 \u03b1 (y). The operator J 1 can be analyzed by using Theorem 5.8 and for J 2 we proceed analogously as for I 3 in the case \u03c3 < 1/2.", "cite_spans": [], "ref_spans": []}, {"section": "Proofs of technical results", "text": "Proof of Lemma 5.2. First, observe that (6.1) log 1 + \u03be 1 \u2212 \u03be \u223c \u03be, for 0 < \u03be \u2264 1/2, \u2212 log(1 \u2212 \u03be 2 ), for 1/2 < \u03be < 1.", "cite_spans": [], "ref_spans": []}, {"section": "Proofs of technical results", "text": "Then, denoting by J the integral to be estimated, we have In order to control J 2 , we start by using the estimate Finally, by Stirling's approximation, we conclude the bound for J 2 .", "cite_spans": [], "ref_spans": []}, {"section": "Proofs of technical results", "text": "Proof of Lemma 5.3 . With the obvious bound .", "cite_spans": [], "ref_spans": []}, {"section": "Proofs of technical results", "text": "In the case \u03bb = 0, we have ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "The convergence of multidimensional Fourier-Bessel series", "authors": [{"first": "P", "middle": [], "last": "Balodis", "suffix": ""}, {"first": "A", "middle": [], "last": "C\u00f3rdoba", "suffix": ""}], "year": 1999, "venue": "J. 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Mech", "link": "124506972"}, "BIBREF24": {"title": "Lectures on Hermite and Laguerre expansions", "authors": [{"first": "S", "middle": [], "last": "Thangavelu", "suffix": ""}], "year": 1993, "venue": "", "link": "126139733"}}, "ref_entries": {"FIGREF0": {"text": "Moreover, in the case (p, q) = 1,", "type": "figure"}, "FIGREF1": {"text": "and (L \u03b1 ) \u2212\u03c3 the fractional operators for Laguerre expansions of Hermite type and for Laguerre expansions of convolution type (see Section 2 for definitions), we are interested in the analysis of vector-valued inequalities for the sequences of operators {(L H \u03b1+aj ) \u2212\u03c3 } j\u22650 and {(L \u03b1+aj )", "type": "figure"}, "FIGREF3": {"text": "Laguerre functions of Hermite type. For each \u03c3 > 0, the fractional integrals for expansions in Laguerre functions of Hermite type are given by", "type": "figure"}, "FIGREF5": {"text": "\u03b1 k are eigenfunctions of the differential operator (2.2). Indeed, we have L \u03b1 \u2113 \u03b1 k = (4|k| + 2|\u03b1| + 2n)\u2113 \u03b1 k . We will refer to the functions \u2113 \u03b1 k as Laguerre functions of convolution type.", "type": "figure"}, "FIGREF6": {"text": "c = \u03b1 + aj, \u2113 = 1 and a = q + , and the change of variable s = 1 \u2212 2u, we have", "type": "figure"}, "FIGREF7": {"text": "AND L. RONCAL holds for 1 \u2264 p \u2264 q < \u221e if and only if (b + 1)/p \u2212 (a + 1)/q = \u03b2 and either 1/p \u2212 1/q \u2264 \u03b2 for p > 1, or 1/p \u2212 1/q < \u03b2 for p = 1.", "type": "figure"}, "FIGREF8": {"text": "but this is true by (5.8) with q = 1.", "type": "figure"}, "FIGREF9": {"text": "(x), and I 3 is as in the previous case. In this way, to obtain the estimate we proceed analogously as for \u03c3 < 1/2 by applying Theorem 5.8 and Theorem 5.9. Case \u03c3 > 1/2. Now, we have u j (x)(L \u03b1+aj )(\u00b7)f j )(x) d\u00b5 \u03b1 (x) \u2264 C(J 1 f (x) + J 2 f (x)), where J 1 f (x) = \u03c7 [0,2] (x)x \u22122(\u03b1+1\u2212\u03c3) x 0 f (y) d\u00b5 \u03b1 (y) + \u03c7 [0,2] (x) 2 x y 2\u03c3\u22121 f (y) dy,", "type": "figure"}, "FIGREF10": {"text": "Now, for J 1 , the change of variable s = q+ 4\u03be produces the required bound. Indeed,", "type": "figure"}, "FIGREF12": {"text": "A \u2212 Bs) b+\u03bb ds.", "type": "figure"}, "FIGREF14": {"text": "The proof of Lemma 5.4 and Lemma 5.5 follow a same scheme. We provide the proof of Lemma 5.5. The details of the proof of Lemma 5.4 are left to the reader.", "type": "figure"}, "TABREF0": {"text": "Remark 3.2. We have just proved that Theorem 3.1 is a consequence of the vector-valued estimates in Theorem 2.3. An alternative proof could be obtained by using the boundedness of the fractional integrals given in [3, Theorem 8] and an observation due to Rubio de Francia in [21, Remark (a)].", "type": "table"}, "TABREF1": {"text": "the modified Bessel function of the first kind and order \u03bd, see [15, Chapter 5]. We use Schl\u00e4fli's integral representation of Poisson's type for modified Bessel function, see [15, (5.10.22)],", "type": "table"}}}
{"paper_id": "116981782", "_pdf_hash": "01e33fdf30e0421c1e6e6e52b552262ec6fd0c52", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
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{"paper_id": "116983052", "_pdf_hash": "605dcdcae0daedd0b5f1ee3ad9316a8ed324235d", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "About the calculation of the photon power", "authors": [], "year": 2004, "venue": "S. Reissig, Bulletin of the APS", "link": "118858613"}}, "ref_entries": {}}
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{"paper_id": "116985841", "_pdf_hash": "960e67cb3a6afe355a68855ea9f21758e821e7d2", "abstract": [{"section": "Abstract", "text": "The next-to-leading-order (NLO) term in the operator product expansion (OPE) of the quark propagator vector part Z and the vertex function g 1 of the vector current in the Landau gauge should be dominated by the same hA 2 i condensate as in the gluon propagator. On the other hand, the perturbative part has been calculated to a very high precision thanks to Chetyrkin and collaborators. We test this on the lattice, with both clover and overlap fermion actions at 6:0, 6.4, 6.6, 6.8. Elucidation of discretization artifacts appears to be absolutely crucial. First hypercubic artifacts are eliminated by a powerful method, which gives results notably different from the standard democratic method. Then, the presence of unexpected, very large, nonperturbative, O4 symmetric discretization artifacts, increasing towards small momenta, is demonstrated by considering Z MOM V , which should be constant in the absence of such artifacts. They impede in general the analysis of OPE. However, in two special cases with overlap action -(1) for Z ; (2) for g 1 , but only at large p 2 -we are able to identify the hA 2 i condensate; it agrees with the one resulting from gluonic Green functions. We conclude that the OPE analysis of quark and gluon Green function has reached a quite consistent status, and that the power corrections have been correctly identified. A practical consequence of the whole analysis is that the renormalization constant Z ( Z \u00ff1 2 of the momentum-subtraction (MOM) scheme) may differ sizably from the one given by democratic selection methods. More generally, the values of the renormalization constants may be seriously affected by the differences in the treatment of the various types of artifacts, and by the subtraction of power corrections.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "I. INTRODUCTION", "text": "The study of the quark propagator and vertex functions in momentum space has been extensively pursued in the literature starting in the 70's with analytical considerations [1] [2] [3] , later completed by the discovery of the presence of a contribution of the A 2 operator, due to gauge fixing [4] . Numerical lattice QCD has more recently treated this issue [5] [6] [7] [8] [9] [10] [11] [12] [13] . The scalar part of the quark propagator is related via axial Ward identities to the pseudoscalar vertex function. The role of the Goldstone boson pole in the latter has been thoroughly discussed [14 -17] .", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "In our paper Ref. [18] , we have initiated a new study of the propagator and of the vector vertex function, which we pursue here. This paper has been devoted to an improved treatment of hypercubic artifacts. Now we present the whole of the work, which also includes the analysis of the other types of artifacts and the extraction of the power corrections.", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "We mainly study the vector part of the inverse quark propagator, the one which is proportional to 6 p, Z , and the vector vertex function g 1 related to it by the Ward identity, or, equivalently, on the ratio", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": ". One of the reasons is to check for the effect of the hA 2 i condensate which has been discovered via power corrections to the gluon propagator and three point Green functions at large momenta [19] [20] [21] [22] (let us recall that, in order to perform trustable perturbative calculations, we take always p > 2:6 GeV). OPE shows that the effect of the hA 2 i condensate should have almost the same magnitude in the Z p 2 of the quark as in the gluon propagator. Moreover, the perturbative-QCD corrections are known to be varying especially slowly (the anomalous dimension being zero at one loop in the Landau gauge), as we shall recall later. This should give a favorable situation to display the power corrections (recall that in the gluon case, it was difficult to disentangle the power and the logarithmic corrections, which were moreover very sensitive to the value of QCD ). Now, for the clover action, the crude values plotted in literature (with only a selection of democratic points) for Z p 2 are extremely flat above 2 GeV [23] . This was formerly considered as being natural, as a consequence of the vanishing of the one-loop anomalous dimension. However, thinking more about it, it must be considered on the contrary as very worrying since it means that the decrease predicted both by the perturbative-QCD corrections and the hA 2 i condensate would not be seen. This leads us to start a very systematic study of the problem, with the following series of improvements on earlier works: (i) We reach an energy of 10 GeV by matching several lattice spacings so that we are in a better position to eliminate lattice artifacts and also to identify power corrections, which requires a large momentum range. (ii) We make use of a very efficient way of eliminating hypercubic artifacts. A first version was used to study gluon Green functions [24, 25] . In Ref. [18] , this method has been improved for the specific case of the quark Green functions, where such artifacts are huge, especially in Z and for the overlap action. Hypercubic artifacts have often been cured by the ''democratic'' method which considers only momenta with equilibrated values of the components. This method points in the right direction but, as we shall discuss in more details, is by far insufficient when the hypercubic artifacts reach such a level as illustrated in this article. In fact, we are then led to qualitatively different conclusions. (iii) We make systematic use of Ward-Takahashi identities relating the quark propagator and the vertex function. According to these Ward identities, Z MOM V should be independent of p 2 up to artifacts. Then, Z MOM V is a very sensitive test of the presence of artifacts. The fact that we observe a strong dependence of the lattice Z MOM V on p 2 shows unambiguously the existence of large remaining discretization artifacts, this time respecting O4 symmetry, and decreasing with negative power of momentum. We can also check the consistency of Z MOM V with other determinations of Z V . (iv) The above mentioned O4 symmetric artifacts could constitute a very serious problem, since we do not know how to eliminate them, and they would hide the OPE power corrections. Fortunately, in the case of overlap fermions (with s 0), we find that for Z , there remains only very small O4 artifacts. Then, we can obtain a satisfactory estimate of the 1=p 2 correction due to the hA 2 i condensate. For this reason, we consider mainly overlap fermions (with s 0), although they have some specific inconveniences (for example very large perturbative corrections). This work, as well as the preceding one, clearly shows that lattice artifacts are overwhelming at the start, both the hypercubic and O4 ones. The hypercubic ones have been shown to be cleanly eliminated by our method. The remaining O4 ones, on the other hand, cannot, and we do not foresee the possibility of a similarly efficient method, wherefrom we have to rely on situations where they are small for reasons which are not known, so that their smallness appears accidental. In that respect, it may seem worrying; but, on the other hand, we are very happy to have found that the OPE can be checked to a good accuracy and power corrections are found consistent with the gluon analysis. It must be noted that on the whole, the main body of the analysis relies on the overlap data, because we have found that they exhibit smaller O4 artifacts.", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "Another obvious interest of the study is then to improve the determination of the momentum-subtraction (MOM) renormalization constants, by taking into account both continuum power corrections and artifacts; and, indeed it indicates that much care must be exerted in using the MOM renormalization approach when high precision will be required, a point which has already been illustrated by the Goldstone contribution to Z MOM P . In Sec. II, we will recall theoretical premises; in Sec. III we will indicate the lattice conventions and the simulations which we have performed, as well as recall the general problems of the improvement; the three following sections are devoted to artifacts, with a large development justified by the importance of the topic: in Sec. IV, we will recall the method to eliminate hypercubic lattice artifacts, and emphasize the difference with the democratic method; in Secs. V and VI, we discuss the other artifacts (Lorentz scalar artifacts, volume effects); in Sec. VII, we will give the results of the overlap action; in Sec. VIII, we perform several consistency checks: chiral symmetry of the overlap action VIII A; comparison with clover action VIII B; finally, we note the agreement with the previous gluon analysis, Subsection VIII C. In Sec. IX, we will give our conclusions and further discussions.", "cite_spans": [], "ref_spans": []}, {"section": "II. THEORETICAL PREMISES", "text": "We work in the Landau gauge. Let us first fix the notations that we will use in the continuum, the precise lattice definitions being given later. We will use all along the Euclidean metric. The continuum quark propagator is a 12 12 matrix Sp for 3-color and 4-spinor indices. The inverse propagator is expanded according to:", "cite_spans": [], "ref_spans": []}, {"section": "II. THEORETICAL PREMISES", "text": "where a, b are the color indices. Z p 2 being a standard lattice notation (for the precise lattice definition, see below, Sec. III). Obviously, one has in the continuum, with trace on spin and color:", "cite_spans": [], "ref_spans": []}, {"section": "II. THEORETICAL PREMISES", "text": "Sometimes one uses the alternative quantity:", "cite_spans": [], "ref_spans": []}, {"section": "II. THEORETICAL PREMISES", "text": "to describe the scalar part of the propagator. Let us consider a colorless vector current q q. The three point Green function G is defined by", "cite_spans": [], "ref_spans": []}, {"section": "II. THEORETICAL PREMISES", "text": "The vertex function is then defined by \u00ff p; q S \u00ff1 pG p; qS \u00ff1 p q:", "cite_spans": [], "ref_spans": []}, {"section": "II. THEORETICAL PREMISES", "text": "In the whole paper, we will restrict ourselves to the case where the vector current carries a vanishing momentum transfer q . In the following we will omit to write q 0 and we will understand \u00ff p as the bare vertex function computed on the lattice. From Lorentz covariance and discrete symmetries", "cite_spans": [], "ref_spans": []}, {"section": "II. THEORETICAL PREMISES", "text": "which should be obeyed approximately on the lattice, as we checked.", "cite_spans": [], "ref_spans": []}, {"section": "A. Renormalization and Ward-Takahashi (WT) identities", "text": "The renormalized vertex function is then Z 2 Z V \u00ff p. Here we must say something of conventions for renormalization constants. The standard definition of renormalization constants has been to divide the bare quantity by the renormalization constant to obtain the renormalized quantity (except for photon or gluon vertex renormalizations Z 1 which we do not use). Z 2 is the standard renormalization of fermions bare", "cite_spans": [], "ref_spans": []}, {"section": "A. Renormalization and Ward-Takahashi (WT) identities", "text": "In principle renormalization of composite operators, for instance Z V , should be defined similarly. We have followed this convention in our works on gluon fields. But, in the case of quark operators, an opposite convention has become standard in lattice calculations:", "cite_spans": [], "ref_spans": []}, {"section": "A. Renormalization and Ward-Takahashi (WT) identities", "text": "O O R ; we feel compelled to maintain this convention for the sake of comparison with parallel works on the lattice. This explains our writing of the renormalized vertex function. In the continuum Z V 1 (conserved current). We keep Z V since the local vector current on the lattice is not conserved, and the discrepancy, which is of course an artifact, generates however finite effects in graphs due to additional divergencies multiplying the a terms (which have higher dimension).", "cite_spans": [], "ref_spans": []}, {"section": "A. Renormalization and Ward-Takahashi (WT) identities", "text": "The Ward identity in the renormalized form tells us that at infinite cutoff:", "cite_spans": [], "ref_spans": []}, {"section": "A. Renormalization and Ward-Takahashi (WT) identities", "text": "After multiplying both sides by Z \u00ff1 2 to return to bare quantities", "cite_spans": [], "ref_spans": []}, {"section": "A. Renormalization and Ward-Takahashi (WT) identities", "text": "which from (1)-(6) implies", "cite_spans": [], "ref_spans": []}, {"section": "A. Renormalization and Ward-Takahashi (WT) identities", "text": "We note that the first Eq. (9) implies that Z V is independent of the renormalization scheme up to artifacts (it is a ratio of bare quantities). Of course, this will hold up to terms vanishing as inverse powers of the cutoff at infinite cutoff, which are called artifacts in the lattice language. It must be recalled that, on the lattice, the Ward identity is not exact, but holds only up to artifacts, because we work at finite cutoff, and the deviation will be found very large in some cases. A very important consequence of the Ward identity for our study is that the ratio g 1 p 2 =Z p 2 is constant up to artifacts, or that deviations of this ratio from a constant are pure artifacts.", "cite_spans": [], "ref_spans": []}, {"section": "A. Renormalization and Ward-Takahashi (WT) identities", "text": "Defining analogously the vertex function of the pseudoscalar ( q 5 q) density", "cite_spans": [], "ref_spans": []}, {"section": "A. Renormalization and Ward-Takahashi (WT) identities", "text": "the axial Ward identity implies", "cite_spans": [], "ref_spans": []}, {"section": "A. Renormalization and Ward-Takahashi (WT) identities", "text": "where m q is 1=2a1= \u00ff 1= c .", "cite_spans": [], "ref_spans": []}, {"section": "B. MOM renormalization; radiative corrections", "text": "To perform renormalization on the lattice, we appeal as usual to the convenient MOM schemes, which does not refer to a specific regularization. To speak technically, the precise renormalization scheme that we use is the one called RI' by Chetyrkin, Eq. (26) in Ref. [26] . This is in fact the most standard MOM scheme in the continuum, developed a long time ago by Georgi, Politzer, and Weinberg. It consists of setting the renormalized Green functions to their tree approximation at the renormalization point p 2 i 2 , in the chiral limit. The inverse bare propagator S \u00ff1 p is normalized through:", "cite_spans": [], "ref_spans": []}, {"section": "B. MOM renormalization; radiative corrections", "text": "Making p 2 2 shows that ", "cite_spans": [], "ref_spans": []}, {"section": "B. MOM renormalization; radiative corrections", "text": "which recalls that Z MOM V , which should be in fact independent of p 2 in the limit where the cutoff a \u00ff1 is infinite, is not so at finite a \u00ff1 -i.e. there are artifacts. The Ward identity implies that Z p and g 1 p have, in particular, the same perturbative p scale dependence. From the calculations of Chetyrkin et al. [26, 27] , we may express, for example, the perturbative running of Z at large p as a function of the running MOM p. This is our main choice throughout this paper, although we discuss the effect of substituting an expansion in MS p. More precisely, we will always choose to use the definition of MOM p by the symmetric three-gluon vertex. The advantage of quarks is that we can reach an accuracy of four loops in the renormalization group (RG) expansion, because we do not need MOM 3 (for symmetric MOM p), since the dimension of the fermion is 0 at lowest order in the Landau gauge. Since the expression is lengthy and not necessary for present understanding, we refer the reader to Appendix A. Of course, even with such accuracy, such an expression cannot be expected to hold for too small p; we esteem the lower bound to be p min 2:6 GeV, from our experience in the case of gluons; indeed, we must avoid going down too close to the ''bumps'' which manifest clearly that the gluon Green functions become nonperturbative.", "cite_spans": [], "ref_spans": []}, {"section": "B. MOM renormalization; radiative corrections", "text": "The perturbative calculation requires a value of QCD ; in order to compare with existing values from a different origin, it is convenient to reexpress all values in terms of the equivalent MS , whatever the scheme employed to make the perturbative expansion of the Green functions. One advantage of Z p 2 is that it is not as sensitive to the QCD value as the gluon quantities, because of the vanishing of the LO fermion anomalous dimension in the Landau gauge; we choose MS 0:237 GeV from a previous analysis [19] , not far from the ALPHA estimate [28] , MS 0:23819 GeV; we will discuss in the end the sensitivity of our results to this choice.", "cite_spans": [], "ref_spans": []}, {"section": "B. MOM renormalization; radiative corrections", "text": "Z p 2 and g 1 p 2 should have also the same nonperturbative power corrections, up to a constant. We consider them now.", "cite_spans": [], "ref_spans": []}, {"section": "C. Power correction from the hA 2 i condensate", "text": "An OPE analysis as those performed in Refs. [19] [20] [21] [22] leads to consider a hA 2 i condensate coupled to the quark propagator and vertex in Landau gauge. Let us recall that such a condensate could not contribute to gauge-invariant Green functions, and is present only in (gauge fixed) gauge-noninvariant Green functions. The meaning and magnitude of such a condensate has been extensively discussed in the recent literature. Our aim here is to detect its effect on the Green functions through OPE, which provides a way of testing theoretical ideas on its existence and magnitude.", "cite_spans": [], "ref_spans": []}, {"section": "C. Power correction from the hA 2 i condensate", "text": "For the propagator, we can write", "cite_spans": [], "ref_spans": []}, {"section": "C. Power correction from the hA 2 i condensate", "text": "where we only keep the leading term in 6 p. The calculation of the coefficients of the OPE has been performed in the chiral limit, and therefore one has as far as possible to stay near this limit.", "cite_spans": [], "ref_spans": []}, {"section": "C. Power correction from the hA 2 i condensate", "text": "In the renormalization prescription denoted by ''RI''' in Chetyrkin papers (which amounts to the standard MOM of Georgi and Politzer in the chiral limit), and expanding everywhere in terms of MOM s , we obtain from Eq. (15) (see Appendix B) from the Ward identity (9), up to artifacts; then it cannot receive any power correction from A 2 , and therefore g 1 receives exactly the same contribution from the condensate as Z . We will use this as a very useful test.", "cite_spans": [], "ref_spans": []}, {"section": "C. Power correction from the hA 2 i condensate", "text": "The essential step is then to fit this formula on the lattice data to extract hA 2 i. The renormalization constants at each , Z 2 ; will enter in the fit as free parameters to be determined, although they would be expected a priori to be close to lattice perturbation theory predictions. Of course, in general, we have to add lattice artifacts to Eq. (16) , and one of the main problems we will discuss is how to determine them accurately.", "cite_spans": [], "ref_spans": []}, {"section": "C. Power correction from the hA 2 i condensate", "text": "An important warning must be made here, concerning the low accuracy in the perturbative calculation of the Wilson coefficient of A 2 written above, namely, it is only tree order with renormalization group improvement. Expanding in terms of MOM s , although it may seem natural, is completely arbitrary, and one would wish the results to be the same with MS s . While this is the case to a good precision for Z pert , this is obviously not the case here, due to the low order of the expansion: s p is quite different in the two schemes. At p 2:6 GeV, the ratio MOM=MS is around 2 and decreases slowly down to 1.4 at 10 GeV; taking into account the anomalous dimension amounts roughly to replace s p by s , then the ratio of coefficients in terms of the two coupling constants is only slightly closer to 1: it is 1.5 in average over the whole range. This means that the coefficient is reduced by 50% when using", "cite_spans": [], "ref_spans": []}, {"section": "MS", "text": "s . This is due to the fact that the ratio of coupling constants decreases only very slowly up to the largest available momenta. As a consequence, the determination of hA 2 i obtained by fitting the lattice data will be automatically affected by the same amount. We will give the results with the convention of using everywhere MOM s , as we have done for gluons. We shall first show that the power correction is indeed present and well determined, and then express it in terms of the condensate value, which suffers from the above uncertainty. We also note that the ratio of condensates fitted from gluons and quark Green functions, which should be 1 ideally, is not affected by this uncertainty, since the Wilson coefficients relative to the various Green functions differ mainly by purely algebraic numbers (the anomalous dimensions differ only slightly). ", "cite_spans": [], "ref_spans": []}, {"section": "III. LATTICE CALCULATIONS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "A. Actions and parameters", "text": "We have first used Sheikholeslam-Wohlert improved Wilson quarks (here called clover) with the c SW coefficients computed in [30] . 100 quenched gauge configurations have been computed at 6:0, 6.4, 6.6, 6.8 with volumes 24 4 , 16 4 , and 8 4 . We have performed the calculation for five quark masses but in practice, for what is our concern in this paper, the quark mass dependence has not surprisingly proven to be negligible; anyway, since the theoretical calculations are performed in the chiral limit, we have to work as close as possible to the chiral limit; then, we present only for simplicity the results for the lightest quark mass, about 30 MeV, i.e. ", "cite_spans": [], "ref_spans": []}, {"section": "A. Actions and parameters", "text": "It should also be mentioned that all the results presented for clover action refer to the 24 4 lattices unless stated otherwise.", "cite_spans": [], "ref_spans": []}, {"section": "A. Actions and parameters", "text": "In addition to clover fermions, the use of overlap fermions [31] has been revealed to be necessary, and even crucial, to obtain a good determination of the power correction, because the most embarrassing type of artifacts, the O4 invariant ones, have been found to be smaller in certain cases with the overlap action (see Sec. VII). We have used approximately the same physical masses, i.e. as in the clover case am 0 0:03; 0:016 67; 0:0125; 0:01 for 6:0; 6:4; 6:6; 6:8", "cite_spans": [], "ref_spans": []}, {"section": "A. Actions and parameters", "text": "with s 0 and volumes of 16 4 . The bare mass m 0 and s are defined from", "cite_spans": [], "ref_spans": []}, {"section": "A. Actions and parameters", "text": "where D w \u00ff1 s is the Wilson-Dirac operator with a (negative) mass term \u00ff1 \u00ff s,", "cite_spans": [], "ref_spans": []}, {"section": "A. Actions and parameters", "text": "We use s 0. s 0:4 is considered preferable from locality requirements [32] , however the difference is slight as soon as is larger than 6.0. The reason for using only the small lattice 16 4 is well known; it is due to limitation in the special treatment needed for small eigenvalues of the Neuberger operator. In practice, as for clover action, we discuss only the lightest quark mass, roughly corresponding to the same 30 MeV.", "cite_spans": [], "ref_spans": []}, {"section": "A. Actions and parameters", "text": "We express everywhere quantities in physical units. Throughout this paper we will use for the lattice spacings the values in the following Table I which follow the dependence found in Ref. [33] , Appendix C, Formule C.1.", "cite_spans": [], "ref_spans": [{"start": 139, "end": 146, "text": "Table I", "ref_id": "TABREF2"}]}, {"section": "B. Improvements", "text": "The propagators Sx; 0 from the origin to point x have been computed and their Fourier transform is defined as:", "cite_spans": [], "ref_spans": []}, {"section": "B. Improvements", "text": "They have been averaged among all configurations and all momenta p within one orbit of the hypercubic symmetry group of the lattice, exactly as for gluon Green functions in [24] . The two actions are Oa improved; however, this is not sufficient to improve the propagator itself, which is an off shell quantity. In the case of overlap quarks, the propagator and other Green functions can be improved according to a standard and exact procedure [34] which should eliminate Oa discretization errors in Green functions, at large p, in the perturbative regime ", "cite_spans": [], "ref_spans": []}, {"section": "B. Improvements", "text": "On the other hand, such a well-defined improvement recipe for the propagator with the clover action does not exist: we would have to fix the counterterms necessary to eliminate the Oa terms from the numerical study of the propagator itself. Note that the standard contact term with a perturbative evaluation of the coefficient leads to subtract from Z p a term of the type a=p 2 . Indeed, it subtracts a term of the type a mp 2 , where mp 2 is the continuum mass term, vanishing at large p, with a rather small absolute value less than 30 MeV for p > 2:6 GeV, i.e. in the region where we are working. But this term happens to be much smaller than the observed artifacts. We indeed find a decreasing artifact: a 1:9 GeV 3 =p 2 Eq. (40), which amounts to a 280 MeV at p 2:6 GeV. This suggests that the standard perturbative improvement is rather ineffective. Anyway, the analysis of the artifacts is included in our discussion of remaining O4 invariant artifacts, and in fact, as we shall see, this is not feasible with accuracy.", "cite_spans": [], "ref_spans": []}, {"section": "B. Improvements", "text": "From now on, the notation Sp will represent the improved quark propagator in the case of overlap quarks and the standard one in the case of clover quarks. Now there are still various ways to define the Z p and mp of Eq. (1) on the lattice.", "cite_spans": [], "ref_spans": []}, {"section": "B. Improvements", "text": "In both cases we fit the inverse quark propagator by", "cite_spans": [], "ref_spans": []}, {"section": "B. Improvements", "text": "according to Eq. (1) and where p 1 a sinap . We write Z p and mp because of the loss of the Lorentz invariance. Z p can then be written as:", "cite_spans": [], "ref_spans": []}, {"section": "B. Improvements", "text": "We could have chosen instead of p any other definition equivalent to p up to terms of order Oa 2 , for example p or 2=a sinap =2. It is important to stress that after eliminating the hypercubic artifacts as explained in Sec. IV, the different definitions give similar results; however, the definition we choose here permits to reach the final result with smaller hypercubic corrections. Note that in our first gluon papers, we did not extract the hypercubic artifacts in this manner, and therefore the choice of an appropriate definition for the lattice gluon propagator was very important, as well as the one of the gluon vertex function.", "cite_spans": [], "ref_spans": []}, {"section": "B. Improvements", "text": "The three point Green functions with vanishing momentum transfer are computed by averaging analogously over the thermalized configurations and the points in each orbit", "cite_spans": [], "ref_spans": []}, {"section": "B. Improvements", "text": "where the identity S0; x 5 S y x; 0 5 has been used. The vertex function is then computed according to Eq. (5) and we choose for the lattice form factor g 1", "cite_spans": [], "ref_spans": []}, {"section": "B. Improvements", "text": "where the trace is understood over both color and Dirac indices. Finally, according to the Ward identity (9) we compute Z MOM V simply from Eq. (14) where any effective p 2 dependence of Z V should come only from lattice artifacts.", "cite_spans": [], "ref_spans": []}, {"section": "C. Classification of remaining artifacts", "text": "The question of eliminating lattice artifacts has been perhaps our main difficulty in this work. Let us stress that the discretization artifacts we will discuss are all due to the QCD interaction. Indeed, our definition of Z p 2 is such that it is equal to 1, as in the continuum limit, when interaction is switched off, and we have also g 1 1 in that case. This illustrates that, in general, it may not be sufficient, by far, to extract the free case artifacts, or to use such prescriptions as replacing p by p . Note that we have used Oa improved actions. But of course, there still remains artifacts of higher order in the lattice spacing, and furthermore, the Green functions are not thereby improved. In the overlap case, a simple definite recipe exists, as we have explained above, to improve exactly the propagator and the other Green functions at large p, but obviously Oa artifacts at small p and Oa 2 remain.", "cite_spans": [], "ref_spans": []}, {"section": "C. Classification of remaining artifacts", "text": "Since we will have a detailed discussion, it is useful first to remind of the main species of artifacts which are expected. First, we have discretization artifacts, 3 which themselves split into two:", "cite_spans": [], "ref_spans": []}, {"section": "C. Classification of remaining artifacts", "text": "(i) hypercubic artifacts, treated in Sec. IV which are the most visible because they break the elementary O4 symmetry; they are seen, as we plot invariants of Green functions as a function of p 2 , as a large discrepancy between the value for different orbits at the same p 2 . With some simple democratic treatment, it is easy to get a relatively regular function of p 2 . Nevertheless, in general, there remain nonanalytic oscillations, and to eliminate them will be shown to be very important to obtain the final physical result, and requires sophisticated methods.", "cite_spans": [], "ref_spans": []}, {"section": "C. Classification of remaining artifacts", "text": "(ii) O4 invariant discretization artifacts, which remain after elimination of the hypercubic ones, and which will be discussed in Sec. V. Let us say that this is the weakest point, because we do not have theoretical principles to determine their form, neither is there a systematical empirical method to determine them. Second, there may be finite volume artifacts which will be discussed in Sec. VI, and very shortly since they do not seem sizable.", "cite_spans": [], "ref_spans": []}, {"section": "IV. ELIMINATION OF HYPERCUBIC LATTICE ARTIFACTS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "A. Generalities", "text": "Since we use hypercubic lattices our results are invariant under a discrete symmetry group H 4 , a subgroup of the continuum Euclidean O4, but not under O4 itself. This implies that lattice data for momenta which are not related by an H 4 transformation but are by a O4 rotation will in principle differ. Of course this difference must vanish in the continuum limit, i.e. when a ! 0. It must be considered as one species of the so-called discretization effects, or ultraviolet artifacts. They also may be termed as ''anisotropy artifacts.'' The hypercubic artifacts turned out to be particularly striking for Z . The results, including overlap-computed quantities, have already been presented in [18] . The raw lattice data for Z and Z MOM V exhibit dramatically the ''half-fishbone'' structure which is a symptom of strong hypercubic artifacts, and we recall that these effects are especially strong in the overlap case.", "cite_spans": [], "ref_spans": []}, {"section": "A. Generalities", "text": "Altogether we would like to recall the following hierarchy: first, the hypercubic artifacts are 1 order of magnitude larger for overlap quarks than for clover ones. Second, for both types of quarks the hypercubic artifacts for Z are 1 order of magnitude larger than those for g 1 .", "cite_spans": [], "ref_spans": []}, {"section": "A. Generalities", "text": "These hypercubic artifacts have been of course a long standing problem in lattice calculations, and methods have been devised for a long time to handle them. A general idea has been the so-called democratic one: the hypercubic effects are minimal when the four components of the momentum for a given p 2 do not differ too much (this is democracy between components; ideal democracy is for diagonal p / 1; 1; 1; 1). Then the question is how to make this criterion quantitative, the rationale being to find a compromise between two contradictory requirements: (1) to be as democratic as possible, which tends to reduce the number of points and (2) to retain enough points to have a real curve.", "cite_spans": [], "ref_spans": []}, {"section": "A. Generalities", "text": "The precise criterion is often something of a secret recipe, not communicated in papers. On studying the gluon propagator, the authors of Ref. [35] have made explicit a selection method, keeping only the orbits having a point within a cylinder around the diagonal. Several other similar criteria have been written. As it can be seen, the compromise is never very good, leaving rather large oscillations in Green functions. Moreover, it is not suitable for a precision treatment.", "cite_spans": [], "ref_spans": []}, {"section": "A. Generalities", "text": "The alternative idea which we propose, on the contrary, relies on the use of all the orbits, and a method to extract the physical point from an extrapolation of the different orbits. 4 A first successful application of this idea was for the gluon propagator [36] .", "cite_spans": [], "ref_spans": []}, {"section": "B. Our method: the p 2n extrapolation method", "text": "We use here the final refined form of the method, the socalled p 2n extrapolation method, presented in [18] , and which has been shown to be necessary to obtain satisfactory results for Z .", "cite_spans": [], "ref_spans": []}, {"section": "B. Our method: the p 2n extrapolation method", "text": "In order to perform a global fit, we start from the remark that we are dealing with dimensionless quantities g 1 and Z . It is thus natural to expect that hypercubic artifacts contribute via dimensionless quantities times a constant. 5 Next we assume that there is a regular continuum limit. We denote the generic Green function as Q; it depends a priori on p 2 , but also a 2 p 4 , a 4 ; we Taylor expand it around the O4 symmetric limit Qp 2 ; 0; 0; 0; . Of course we must truncate this Taylor expansion of Q in a and we choose to expand it up to a 4 . Note that at this stage, the function Qp 2 ; 0; 0; 0; may still depend on a through terms of the form a 2 p 2 , etc., but we do not consider presently this further dependence; it will be discussed in the next sections.", "cite_spans": [], "ref_spans": []}, {"section": "B. Our method: the p 2n extrapolation method", "text": "As a conclusion, we have fitted our results over the whole range of p 2 according to the following formula, where the c i 's are constants independent of p 2 :", "cite_spans": [], "ref_spans": []}, {"section": "B. Our method: the p 2n extrapolation method", "text": "with indeed small 2 's. We have also checked the validity of this expansion for the free propagator. The functional form used for Qp 2 ; 0; 0 does not influence significantly the resulting artifact coefficients. We can even avoid using any assumption about this functional form by taking the value for Qp 2 ; 0; 0 at each p 2 as an independent parameter to be fitted. ", "cite_spans": [], "ref_spans": []}, {"section": "C. Quantitative comparison with the democratic method", "text": "We would like now to recall the quantitative comparison of our '' p 2n extrapolation method'' Eq. (28) with the more common ''democratic selection'' methods; the latter method is carefully defined in [35] . This comparison is important, since almost all works up to now are using some variant of the democratic method, and since the difference with this method is crucial, as we show, to extract power corrections.", "cite_spans": [], "ref_spans": []}, {"section": "C. Quantitative comparison with the democratic method", "text": "Let us consider the overlap case. If we try to select [35] the orbits which are in a cylinder around the diagonal with a radius 2=L, this is too restrictive anyway for our 16 4 4 The initial idea is due to Claude Roiesnel. 5 We neglect a possible logarithmic dependence on p 2 . 6 We have enough data for that.", "cite_spans": [], "ref_spans": []}, {"section": "C. Quantitative comparison with the democratic method", "text": "overlap case, where we have only 22 orbits at the start. In order to have a less restrictive democratic criterion and to make a bridge with our own method, we will use the p 2n 's defined above. In our language, democracy can be translated as having a small enough ratio p 4 =p 2 2 . Momenta proportional to (1, 1, 1, 1) and (1, 0, 0, 0) have ratios 1=4 (minimum ratio, maximally democratic) and 1 (maximum, totally undemocratic), respectively. We then retain the democratic orbits defined by an intermediate p 4 =p 2 2 :5. This leaves already only 7 orbits out of 22 for every .", "cite_spans": [], "ref_spans": []}, {"section": "C. Quantitative comparison with the democratic method", "text": "In Fig. 1 we plot for Z the result of this selection, as compared with our own method. Figure 1 clearly shows visible oscillations in the democratic curve demonstrating that the hypercubic artifacts have not been totally eliminated, while after applying the p 2n extrapolation method, Eq. (28), the curves are perfectly smooth; they do not either exhibit the oscillations which remain in previous methods.", "cite_spans": [], "ref_spans": []}, {"section": "C. Quantitative comparison with the democratic method", "text": "We prefer our own method for this reason and also because of the loss of information due to the rejection of ''undemocratic'' points, which leaves one with very few points. This appears crucial in the overlap case, where one is constrained to use small lattices.", "cite_spans": [], "ref_spans": []}, {"section": "C. Quantitative comparison with the democratic method", "text": "Then another very important aspect appears: while completely eliminating the hypercubic oscillations, we also considerably modify the mean value of the curve, as defined by an analytic fit; for the present case, as seen in the figure, our curve is considerably lower, with a quite steeper descent than the democratic one.", "cite_spans": [], "ref_spans": []}, {"section": "C. Quantitative comparison with the democratic method", "text": "We will return later to the fact that Z", "cite_spans": [], "ref_spans": []}, {"section": "MOM V", "text": "remains not at all constant in p after this treatment.", "cite_spans": [], "ref_spans": []}, {"section": "D. The importance of optimizing the elimination of hypercubic artifacts", "text": "Let us stress then that, as is particularly visible from this comparison, the difference of the a 2 p 2n method with the standard democratic method is not at all academic in the context of the study of power corrections and renormalization constants. The difference with the previous versions of our method is also not negligible, as we have found.", "cite_spans": [], "ref_spans": []}, {"section": "D. The importance of optimizing the elimination of hypercubic artifacts", "text": "(1) It is obvious that with the standard democratic method, we would obtain quite different results for power corrections and O4 symmetric artifacts, and therefore for the resulting perturbative contribution. In fact, it has not even been really considered that Z could be affected by such power corrections. (2) Moreover, we observe that the power corrections, as well as the residual O4 symmetric discretization artifacts, extracted by the previous variants of our method for treating the hypercubic artifacts are not the same; indeed, when using a previous cruder treatment for overlap action, we have found an important a 2 p 2 artifact, which disappears with the more refined treatment, and we were also finding different power corrections (with a weaker condensate). The clover case shows similar spurious issues. This means that for a too crude treatment, some hypercubic artifacts can be spuriously mimicked as part of O4 symmetric discretization artifacts or continuum power corrections. This does not imply that the determination of power corrections is uncertain in this respect, but rather that it is very important to push hypercubic artifact elimination to the best to obtain the genuine continuum power corrections. Let us finally mention an interesting consequence; as is well known, the values of Green functions at different momentum points in a Monte Carlo lattice calculation are highly correlated, which should lead to very small 2 =d:o:f: for fits describing the p dependence by smooth analytic expressions (by small, we mean well below one). It is not found so with too crude treatments of the hypercubic artifacts, because of the erratic oscillations which always remain in the latter methods mimicking statistical deviations. We observe however an impressive decrease of the 2 down to its expected small value when we improve the treatment of the data, showing that we are now obtaining indeed very smooth functions as physically expected.", "cite_spans": [], "ref_spans": []}, {"section": "D. The importance of optimizing the elimination of hypercubic artifacts", "text": "Another encouraging fact is that, after having eliminated consistently hypercubic artifacts, the different definitions of Z on the lattice converge to the same final result (see the comments around Eq. (24)).", "cite_spans": [], "ref_spans": []}, {"section": "V. PROOF OF THE PRESENCE OF O4 SYMMETRIC ''NONCANONICAL'' DISCRETIZATION ARTIFACTS", "text": "We now start, in the rest of the discussion, from the data obtained through the above treatment of the hypercubic artifacts. They still differ from the continuum by renor- 1 (color online) . Comparison between the democratic method and our refined treatment for the overlap Z p 2 at 6.0 and 6.4. Above 2 GeV, precisely where one must study the power corrections, the difference is striking. malization and by O4 symmetric discretization artifacts. It happens that the determination of these artifacts is still harder in general than for hypercubic ones (as for finite volume artifacts, which we estimate to be weak, see the corresponding short section below).", "cite_spans": [], "ref_spans": []}, {"section": "V. PROOF OF THE PRESENCE OF O4 SYMMETRIC ''NONCANONICAL'' DISCRETIZATION ARTIFACTS", "text": "Indeed, in practice, there is no similar unambiguous method to determine the O4 symmetric discretization artifacts. True, they manifest themselves by a residual variation with , and, in principle, we could study the variation with at each momentum, and then extrapolate to the continuum. However, this requires too many momenta and too much accuracy, if we want really to extract the power correction from the extrapolation to the continuum.", "cite_spans": [], "ref_spans": []}, {"section": "V. PROOF OF THE PRESENCE OF O4 SYMMETRIC ''NONCANONICAL'' DISCRETIZATION ARTIFACTS", "text": "(a) A possible general method for treating O4 scalar artifacts. Then, a more practical method consists in assuming a prescribed analytical form for both the continuum and the artifacts, with some unknown parameters to be determined by the 2 adjustment. One has therefore to appeal to our a priori knowledge (a) of the continuum, as a function of p; (b) of the structure of O4 symmetric artifacts, as a function of p and a, so that we could make fits with prescribed functions depending on a limited number of free parameters. For the continuum, this is exactly what is provided by the OPE, with the renormalization constants z b and hA 2 i as free parameters. For O4 symmetric artifacts, a standard idea is to recourse to lattice perturbation theory, in which the structure of artifacts is easily explicited. After all, this is what we have invoked for the hypercubic artifacts. As for O4 symmetric artifacts, the result is quite simple: in the case of a scalar function, and in the chiral limit, where there is no other dimensioned parameters than a and p, there can be no other artifacts than a n p n , with n > 0. Then we could work with a few parameters only. (b) Why it fails.", "cite_spans": [], "ref_spans": []}, {"section": "V. PROOF OF THE PRESENCE OF O4 SYMMETRIC ''NONCANONICAL'' DISCRETIZATION ARTIFACTS", "text": "But now, there appears a very unfortunate circumstance. It is seen that this usual assumption of a perturbative structure of artifacts does not work at all, at least in general. We observe undoubtedly O4 symmetric artifacts decreasing with p, i.e. for instance of the form 1=p n and n > 0 times some positive power of a. To show it, the best way is to consider the p dependence of Z MOM V g 1 =Z , which should be momentum independent close to the continuum limit. Any p dependence is therefore to be attributed to artifacts. Now, the lattice data show quite clearly a very strong p dependence of Z MOM V except at large p. This is true for clover action, and for overlap action as well, see Fig. 2 for overlap fermions. The artifacts are similar; they decrease monotonously with increasing p for 6:4, 6.6, 6.8; they could be fitted by negative powers of the momentum squared; for the overlap case, this is also true for 6:0. (c) Consequences for determination of power corrections.", "cite_spans": [], "ref_spans": [{"start": 692, "end": 698, "text": "Fig. 2", "ref_id": "FIGREF2"}]}, {"section": "V. PROOF OF THE PRESENCE OF O4 SYMMETRIC ''NONCANONICAL'' DISCRETIZATION ARTIFACTS", "text": "The necessity of taking into account such negative powers of p is very embarrassing because, as we explained, we cannot distinguish the O4 symmetric discretization artifacts by the sole dependence; we have to rely on the p dependence. Now it is clear that we will have much difficulty in distinguishing the power corrections and the artifacts decreasing with p, and therefore to determinate the condensate.", "cite_spans": [], "ref_spans": []}, {"section": "V. PROOF OF THE PRESENCE OF O4 SYMMETRIC ''NONCANONICAL'' DISCRETIZATION ARTIFACTS", "text": "One of the problems is that when increasing the number of negative power terms in the description of the artifact, the tendency is to get alternating signs, and therefore rather unstable results. There is no rationale as to where we should stop. In addition, we must consider that we have also as parameters in the fit the renormalization constants z b , which are practically chosen as an independent parameter at each . To add to the uncertainty, we observe that within the precision of the data, we can obtain equivalently good solutions by modifying the O4 artifacts with a correlative change in the z b 's. as a function of momentum, respectively, for 6:0 and 6.4, and 6:6 and 6.8, for the overlap action. The huge momentum dependence which is displayed must be entirely attributed to discretization artifacts. exploiting particular circumstances, to which we devote the rest of the analysis, after a few words on finite volume artifacts.", "cite_spans": [], "ref_spans": []}, {"section": "VI. FINITE VOLUME ARTIFACTS", "text": "A priori, finite volume artifacts are not expected to be important in this study because we work at large momentum with respect to the inverse lattice size. Let us recall that in the clover case [18] , we have found only very small volume artifacts, after a careful study with 8 4 , 16 4 , 24 4 lattices. Only the first points with smallest n 2 were showing some effect.", "cite_spans": [], "ref_spans": []}, {"section": "VI. FINITE VOLUME ARTIFACTS", "text": "We have not performed the same tests for the overlap action because of the slowness of numerical calculation; we have only ran on a 16 4 lattice. We are conscious that this is a possible weak point, since this volume is small, and we rely mainly on the analysis of overlap results for the determination of the condensate. So we are thinking of extending this analysis to larger volume as soon as possible. It would, in particular, be interesting to test the possibility of a chiral-symmetry restoration at small physical volumes (see further comments in Subsection VIII A).", "cite_spans": [], "ref_spans": []}, {"section": "VI. FINITE VOLUME ARTIFACTS", "text": "We stress however that the consistency which is obtained for the continuum power corrections between the overlap results and the clover ones with a greater volume 24 4 (see Subsection VIII B), is a further proof that the volume effects are not crucial for our purpose of determining the condensate.", "cite_spans": [], "ref_spans": []}, {"section": "VI. FINITE VOLUME ARTIFACTS", "text": "We must also observe that we can determine the condensate mainly from our large p data (p > 4-5 GeV) (see VII A), with large Lp, where volume artifacts are expected to be even smaller.", "cite_spans": [], "ref_spans": []}, {"section": "A. Discretization or volume artifacts?", "text": "The fact that the above O4 symmetric artifacts are observed at small p-and only at small p-is deserving of a special discussion, since it is so counter to usual expectation. Our ears are indeed accustomed to the dictum: ''artifacts at small p, finite volume artifacts,'' ''artifacts at large p, finite spacing artifacts.'' Why are they not volume artifacts? Since it is one important finding of our study, we collect here our arguments.", "cite_spans": [], "ref_spans": []}, {"section": "A. Discretization or volume artifacts?", "text": "Let us stress that, in the overlap case, the use of a small volume 16 4 at large , to which we are constrained, is not the reason for our finding of large O4 symmetric artifacts at small p. The first argument is that they are also seen in the clover case where we have tested in detail the smallness of volume artifacts; to reiterate, we have seen that only one or two of the smallest momenta seem affected by a volume dependence, while the artifacts we are discussing now are present over a large number of points.", "cite_spans": [], "ref_spans": []}, {"section": "A. Discretization or volume artifacts?", "text": "Moreover, let us stress that they have the typical behavior of discretization artifacts, i.e. they decrease at large and fixed p: indeed, Z V (which should be flat in the continuum limit) is flatter and flatter as the beta increases at a fixed number of sites 16 4 , i.e. as the physical volume decreases. More precisely, we observe that, as the volume decreases, we have more and more points where it is flat, i.e. where it has small artifacts: the respective number of points is 0 at 6:0, 3 at 6:4, 9 at 6:6, 14 at 6:8. This is exactly counter to a volume effect, for which the flatness should be obtained for n 2 larger that some fixed number. In other terms, for a volume effect, we would expect the artifacts to vanish at smaller and smaller values of p as decreases (i.e. when the physical volume increases). Instead, we find that they vanish around 4 -5 GeV irrespective of 6:4, 6.6, 6.8; even more, at 6:0, with the largest volume, Z V never becomes flat.", "cite_spans": [], "ref_spans": []}, {"section": "A. Discretization or volume artifacts?", "text": "On the other hand, we have no understanding of why Z MOM V seems devoid of sizeable artifacts at large p: it must be regarded as an accident. But it must be underlined that this is not an accident specific to our particular problem. It is a well-known fact, on which any MOM practitioner is relying without being able to explain it: one measures the Z's in regions of large p, assuming that artifacts are small, although they would be expected to be large precisely there from lattice perturbation theory.", "cite_spans": [], "ref_spans": []}, {"section": "VII. CASES WITH SMALL O4 SYMMETRIC ARTIFACTS WITH THE OVERLAP ACTION-DETERMINATION OF THE CONDENSATE", "text": "As we have underlined as the conclusion of Sec. V, paragraph (c), the O4 symmetric artifacts we have found, when present, impede a clear determination of the power correction. It is fortunate that they seem absent or small in some cases. All correspond to overlap action; then the results are convincingly consistent. Therefore, we concentrate on the overlap fermions in the present and following Secs. VII and VIII A. As concerns the clover action, we will not be able to have such compelling conclusions, but we show that they are at least compatible (see Sec. VIII B).", "cite_spans": [], "ref_spans": []}, {"section": "A. Large p (p * 5 GeV)", "text": "At this point, we notice that the above difficulties may disappear first at large p, above roughly 5 GeV (therefore at 6:4, 6.6, 6.8), because Z V is constant in this region, especially for the overlap action; therefore it is suggestive that the artifacts of Z and g 1 are small there, barring for the unprobable eventuality that Z and g 1 would happen to have exactly the same artifacts. We then fit Z and g 1 with a formula containing no O4 artifact, i.e. we take only the continuum expression times the renormalization factor z b , at fixed , and we obtain then a very encouraging conclusion. Choosing the window of p within which Z V is well constant, we obtain at each 6:4, 6.6, 6.8, and for Z and g 1 , i.e. for six independent data, almost the same condensate value; we quote a common fit (see Fig. 3 ) to the three Z , with p min 5, 5, 4 GeV, respectively, corresponding to the respective p where Z V is beginning to be flat:", "cite_spans": [], "ref_spans": []}, {"section": "A. Large p (p * 5 GeV)", "text": "large and positive, with a rather small error, and quite consistent with what is found in the gluon sector (see below). The 2 =d:o:f: 0:07 is very small as expected from very correlated data. Let us recall that this value of hA 2 i is obtained with the convention that the Wilson coefficient of the operator is expressed in terms of MOM s . A remarkable feature of this region of momentum is that both Z and g 1 , and therefore Z V too, are almost independent of . We take it as a further indication that artifacts are accidentally small there.", "cite_spans": [], "ref_spans": []}, {"section": "A. Large p (p * 5 GeV)", "text": "Let us reinsist that the value of the condensate given in Eq. (29) corresponds to the convention, always followed in this paper, that the Wilson coefficient of the operator, calculated only at leading order, is expressed in terms of MOM . The choice of MS , would lead to an appreciably higher value (larger by around 70%). However, what is important is that the power correction by itself is well determined by our analysis, almost independently of such a change. Indeed, let us replace the OPE expression for the power correction by a simple power, without logarithms corresponding to s , while maintaining the full perturbative expressions for the perturbative part. The fit then gives for the coefficient c of the power term c=p ", "cite_spans": [], "ref_spans": []}, {"section": "A. Large p (p * 5 GeV)", "text": "when using MS instead, a small change indeed, of only 10%, reflecting the small change of the perturbative part, which is calculated by theory to a great accuracy.", "cite_spans": [], "ref_spans": []}, {"section": "B. Z over the whole allowed range of p", "text": "In addition, we observe another fact: Z -but not g 1 -is strikingly independent of over the full range of p. We have no explanation for that, but we can at least interpret this as meaning that Z is free of O4 symmetric artifacts over all this range. And indeed, we can fit Z on the full range p > 2:6 GeV allowed for the perturbative calculation, and the four 's with:", "cite_spans": [], "ref_spans": []}, {"section": "B. Z over the whole allowed range of p", "text": "see Fig. 4 .", "cite_spans": [], "ref_spans": []}, {"section": "B. Z over the whole allowed range of p", "text": "We thus obtain a remarkable similarity of the condensate with the previous value. We also obtain similar results by varying the window of the momenta, provided the lower limit is not pushed beyond 5 GeV, and also by selecting various triplets of values. This seems to support the consistency of our assumptions about artifacts. Note that Z is still far from being flat. It has a monotonous decrease, of around 6% over the range, mainly due to the condensate. The dotted line is the purely perturbative result, clearly inconsistent with the data. Normalization is made at 10 GeV. g 1 is described by a similar fit. If we want to still improve the agreement with the large p analysis, we can introduce a further 1=p 4 term, accounting for the possibility that we may not be sufficiently asymptotic to have a good description with the 1=p 2 condensate alone. For the full window, and the four 's, we obtain a very good fit with:", "cite_spans": [], "ref_spans": []}, {"section": "B. Z over the whole allowed range of p", "text": "and with a small subleading term:", "cite_spans": [], "ref_spans": []}, {"section": "B. Z over the whole allowed range of p", "text": "with a minus sign which explains that the value of hA 2 i is slightly higher than in the preceding fits. It is then closer to the large p fit. is not yet flat at the highest momentum. Let us repeat that it is remarkable, and perhaps surprising, to observe such a constancy with , while one-loop perturbation theory would predict a strong variation with .", "cite_spans": [], "ref_spans": []}, {"section": "D. Comparison with lattice perturbation theory", "text": "The fact that Z and Z V are very different from 1 (in fact not far from 2) in the overlap case with s 0 may seem surprising. But in fact, already in lattice perturbation theory, the tendency is that the one-loop corrections to Z and Z V are large because of a very large tadpole contribution to the self-energy [37, 38] (while g 1 remains close to 1 as we find nonpertubatively). The net effect is already large at 6:0, for the usual s 0:4: Z V 1:247, and still larger for our s 0: Z V 1:444; we use Table 1 of Ref. [37] for the analytical expressions (the definition of Z is different, but by a negligible amount); the numbers are quoted assuming a boosted perturbation theory (BPT) boosted coupling with g 2 BPT 1:68 (see Ref. [38] under Eq. (44)). Of course, what is surprising is first that the nonperturbative determination (35) is still much larger, and, second, that it is almost independent of over a large range.", "cite_spans": [], "ref_spans": []}, {"section": "D. Comparison with lattice perturbation theory", "text": "Note that the value found by Ref. [39] for Z A at 6:0, Z A 1:55, which should equate Z V , is also much larger than BPT; however, this is not Z MOM A as measured directly; it is the Z A deduced from hadronic WT identities. One may think of large artifacts which render different the results from various definitions of Z A , Z V ; our study below, Sec. VIII A 2, shows indeed the presence of such effects, very large at 6:0; but they are decreasing rapidly at larger , and our finding is that, at 6:8, Z MOM V is still much larger than the boosted lattice perturbation theory.", "cite_spans": [], "ref_spans": []}, {"section": "VIII. CONSISTENCY CHECKS", "text": "A. Z V and Z A with the overlap action-complementary studies on chiral symmetry and artifacts", "cite_spans": [], "ref_spans": []}, {"section": "VIII. CONSISTENCY CHECKS", "text": "To ascertain the soundness of our analysis, which may be surprising in several respects, we also perform several consistency checks of general nature in the overlap case; indeed, some strong statements deriving from chiral symmetry can be formulated.", "cite_spans": [], "ref_spans": []}, {"section": "Z A =Z V in the nonperturbative MOM scheme", "text": "The overlap action has an exact chiral symmetry, discovered by Luescher, which, combined with the choice of the improved current, or equivalently, of improved Green functions, should lead to Z MOM A =Z MOM V 1 without any artifact. However, let us note that this is true only if one assumes the symmetry of the vacuum state, and therefore the absence of spontaneous symmetry breaking. In the presence of spontaneous symmetry breaking, one expects (1) a physical effect from the Goldstone boson, (2) discretization artifacts, both vanishing with inverse powers of momentum. Therefore this result only holds at large momenta.", "cite_spans": [], "ref_spans": []}, {"section": "Z A =Z V in the nonperturbative MOM scheme", "text": "We find indeed Z", "cite_spans": [], "ref_spans": []}, {"section": "Z A =Z V in the nonperturbative MOM scheme", "text": "1 to a high accuracy, Fig. 5 , above 2.4 GeV, for the four 's. On the other hand, we see that for lower momentum: (i) the ratio differs from 1, and (ii) it depends on . Observation (i) has also been made for domain wall fermions at 6:0 [40] .", "cite_spans": [], "ref_spans": []}, {"section": "Z A =Z V in the nonperturbative MOM scheme", "text": "At 6:0, there is a rather abrupt change of regime slightly below p 2 GeV. At higher 6:4, 6.6, the values below p 2 GeV differ both from 6:0 and, slightly, from 1. Unhappily, we have no point in this region at 6:8. Therefore, at the two or three lowest , we have a combination of discretization artifacts and perhaps a not well-determined physical effect; on the other hand, at 6:8, all the known points being at large p, it is impossible to conclude whether the flat result 1 is due to restoration of chiral symmetry at small volume or to extinction of spontaneous symmetry breaking effects at large p; working with larger volumes would allow the question to be settled.", "cite_spans": [], "ref_spans": []}, {"section": "Z A from a hadronic WT identity against Z", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "MOM V", "text": "In principle, once artifacts and power corrections have been eliminated, the various ways of defining the renormalization constants can be related by perturbation theory. In the case of Z V or similar cases, for the same action, implying identical finite parts, they should even be equal.", "cite_spans": [], "ref_spans": []}, {"section": "MOM V", "text": "Moreover, Z A should be equal to Z V from the chiral symmetry of the overlap action.", "cite_spans": [], "ref_spans": []}, {"section": "MOM V", "text": "We verify this statement, as a highly nontrivial consistency check of our treatment, by measuring Z A from a standard hadronic Ward-Takayashi identity Z WI A m q =, where: is indeed a discretization artifact, as it should be, and one of the most canonical species, since we expect precisely chiralsymmetry breaking to be at most Oa 2 . Indeed, on hadron states, the Ward identity is valid up to Oa 2 , and Green functions at large p, where we measure Z MOM; large p V , we have also only Oa 2 artifacts from chiral-symmetry arguments, in the chiral limit.", "cite_spans": [], "ref_spans": []}, {"section": "B. Check through the clover Z", "text": "In view of the rather paradoxical situation which allows us to determine hA 2 i from the s 0 overlap action, it is important to reascertain this analysis by a study of the standard clover action, to check whether we can obtain a similar continuum result. Let us stress indeed that from renormalizability, the whole continuum function must be the same up to an overall constant for all the versions of the action. A priori, as we have said, the clover case may seem hopeless because there are large O4 artifacts even in Z ; and even at large p, Z V is not so flat.", "cite_spans": [], "ref_spans": []}, {"section": "B. Check through the clover Z", "text": "However, one can benefit from the knowledge gained in the overlap case. In the end, the situation appears in fact somewhat similar for the clover action as concerns O4 symmetric artifacts: the main burden of noncanonical artifacts appears to concern g 1 , and we can obtain a good description of Z with a minimal a 2 p 2 canonical artifact, and just one a=p 2 term. Let us insist that one should consider this structure as a very empirical fitting form. One should not take literally the power exponents in p and a, since the artifacts are very large. The important point is that one has both canonical increasing artifacts and noncanonical decreasing artifacts. We obtain:", "cite_spans": [], "ref_spans": []}, {"section": "B. Check through the clover Z", "text": "with artifacts \u00ff 0:005 0:0015a 2 p 2 \u00ff 1:", "cite_spans": [], "ref_spans": []}, {"section": "B. Check through the clover Z", "text": "In the present case, the role of these artifacts is crucial to obtain the condensate. In fact, before extraction of these artifacts, the clover data show a rather flat behavior at large p, or even a small increase at 6.8. The very large term a=p 2 considerably improves the fit, with a 2 divided by 3, and brings in a value of the condensate quite close to the one obtained with overlap fermions. These results seem to be a signal that we have obtained a rather accurate treatment of artifacts. Of course, one may be worried of having introduced a noncanonical artifact, which was not necessary in the overlap case; yet, we must remember that there is no logical reason why such terms should be absent (in the overlap case, they are present anyway in g 1 ).", "cite_spans": [], "ref_spans": []}, {"section": "B. Check through the clover Z", "text": "With a subleading term", "cite_spans": [], "ref_spans": []}, {"section": "B. Check through the clover Z", "text": "we obtain a still somewhat better agreement with the overlap condensate,", "cite_spans": [], "ref_spans": []}, {"section": "B. Check through the clover Z", "text": "The subleading term is also of the same sign and comparable magnitude as for overlap action, for overlap fermions and small quark mass at the four 6:0, 6.4, 6.6, 6.8. The ratio is 1 above 2 GeV, but differs from 1 and depends on below 2 GeV.", "cite_spans": [], "ref_spans": []}, {"section": "B. Check through the clover Z", "text": "Note that the consistency of the clover 24 4 results with the overlap analysis is comforting the idea that the volume effects are not too important in the overlap case, although certainly they are less compelling because of the need to introduce the a=p 2 artifact.", "cite_spans": [], "ref_spans": []}, {"section": "C. Consistency with the gluon analysis", "text": "To stress the overall consistency of the analysis, one has also to consider the agreement with the previous gluon analysis. We quote the result of a combined fit of hA 2 i and QCD to the gluon propagator and the symmetric threegluon vertex [21] : (30)). The coincidence of the values of hA 2 i with the quark value is highly significant since it concerns the continuum function, extracted by a series of various, independent, manipulations committed on the gluon and quark Green functions, and since these continuum functions are related only thanks to the OPE.", "cite_spans": [], "ref_spans": []}, {"section": "C. Consistency with the gluon analysis", "text": "The quark measurement has much smaller statistical errors. This is simply due to the fact that in the gluon case, we have left free the value of QCD , and moreover, the value of the condensate depends strongly on this value, whence the large errors in the gluon case. On the contrary, in the quark case, we have chosen a fixed MS 0:237 GeV. Indeed, in this case, the dependence on QCD is rather weak. Then it is useless to try to determine QCD from the fit, and on the other hand the value obtained for hA 2 i remains well determined if we allow some variation in QCD . Another advantage of quarks is that we can reach the accuracy of four loops in the theoretical expression for the purely perturbative part. In the gluon case, such an accuracy is only possible for the asymmetric vertex, but in that case, the leading term in OPE is not given by hA 2 i [22] .", "cite_spans": [], "ref_spans": []}, {"section": "IX. CONCLUSIONS AND DISCUSSIONS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "A. Physical results and evidences of various artifacts", "text": "Let us summarize our results in the following few points:", "cite_spans": [], "ref_spans": []}, {"section": "A. Physical results and evidences of various artifacts", "text": "(i) First of all, and this is the main point, let us stress that we have finally obtained a rather nontrivial confirmation of the validity of the OPE in the nongauge-invariant sector of lattice QCD (treated numerically). The virtue of OPE is that one can describe the departure of all the various Green functions from the perturbative approximation at large momenta with the same set of expectation values. We have now obtained consistency not only between gluon Green functions, but also with the quark sector. This is highly nontrivial. Let us recall that there is often some doubt raised about OPE itself, and the possibility is sometimes considered that power corrections could be present not corresponding to an operator vacuum expectation value (v.e.v.). The final consistency of the determination of the condensate from three distinct types of Green functions strongly suggests that this is not the case, at least for leading power 1=p 2 corrections. We do identify an OPE power correction, consistently related to A 2 . hA 2 i is found consistently large and positive. The precise magnitude of hA 2 i is affected by an important uncertainty, due to the low accuracy of the theoretical calculation of the Wilson coefficient. But the power correction (i.e. the product of the coefficient and the condensate) is well determined by the lattice analysis, and the ratio of the power corrections in the various Green functions is actually as expected from lowest order OPE.", "cite_spans": [], "ref_spans": []}, {"section": "A. Physical results and evidences of various artifacts", "text": "(ii) It turns out that the lattice discretization artifacts are unusually sizable in the quark propagator Z , but a clear-cut distinction must be made between hypercubic artifacts, which are gigantic, but can be efficiently eliminated, and the O4 symmetric ones, which are not so catastrophic, but that we have not been able to handle systematically. (iii) We believe that we have been really efficient in getting rid of the hypercubic artifacts thanks to our (improved) method of ''restoration of O4 symmetry.'' (iv) Once these artifacts have been subtracted, the overlap Z V p 2 Z p 2 =g 1 p 2 , which should be independent of p except for artifacts, is very close to a constant at large p > 5 GeV. This is far from trivial and supports the statement that we have no remaining O4 symmetric artifacts in this specific region. This is directly supported by the near constancy of the quantities as a function of . Moreover, also in the overlap case, but for Z p 2 only, the same statement of constancy with extends down to the lowest momenta; this leads one to suspect that O4 symmetric artifacts are small in this case over the whole range of p. We are unable to explain these two special situations. Let us recall that a certain flatness Z V p 2 at large p is also observed with the clover quark action, although it is not so good. Let us recall also that this region is the basis for the standard determi-nations of MOM renormalization constants, usually with the clover quark action (see for example [41] , which presumes that discretization artifacts are not large there. Let us then recall that we have no theoretical argument supporting the statement that they are not large. Quite the contrary. If any, the theoretical arguments would suggest for them to increase with p. The support is purely empirical. This is embarrassing if we aim at precision determinations.", "cite_spans": [], "ref_spans": []}, {"section": "A. Physical results and evidences of various artifacts", "text": "(v) Z V of the overlap action at s 0 is large, around 1.8, in qualitative agreement with BPT perturbation theory which finds large self-energy contributions in Z p. But it is still much larger than the expectation, and the lack of dependence on is not understood from perturbation theory. (vi) Considering the cases where the O4 symmetric artifact-free results are suspected to be small, we try to fit them by OPE, i.e. by the four-loop perturbative contribution plus the hA 2 i condensate contribution computed to leading logarithm. The overlap Z and g 1 at large p > 5 GeV allows for a good fit for 6:4, 6.6, 6.8, leading to a consistent hA 2 i not far from 3 GeV 2 . The overlap Z also allows for a good fit for the whole range p > 2:6 GeV, including in addition 6:0. The hA 2 i condensate is consistent with the former value. A very small 1=p 4 term still improves the consistency.", "cite_spans": [], "ref_spans": []}, {"section": "A. Physical results and evidences of various artifacts", "text": "(vii) In the other cases, namely, in g 1 and Z V for p lower than p 5 GeV, the O4 symmetric artifacts become large, especially at small p, and in fact, they increase regularly from large to small p. This trend, which is also contrary to the expectation of lattice perturbation theory, clearly indicates a nonperturbative origin. In fact, one important conclusion of our study is the existence of these very large nonperturbative artifacts at small p due to discretization. These are very embarrassing for any analysis of the Green functions, as we comment below. Let us repeat our strong conviction that these low p effects (under 2 GeV) are indeed discretization artifacts and not volume artifacts. They behave quite counter to volume effects, as we have extensively argued.", "cite_spans": [], "ref_spans": []}, {"section": "A. Physical results and evidences of various artifacts", "text": "shows that similar artifacts are still present in a ratio where they would be expected to cancel if one applies naively the exact chiral symmetry of the lattice action. They are clearly seen as being discretization artifacts because they are reduced at larger . They seem to be present on top of an actual continuum effect, small but visible, which could be due to continuum chiral symmetry spontaneous breaking. One can suspect that the artifacts themselves are connected with the spontaneous breaking of chiral symmetry. It seems logical that such chiral-symmetry violating artifacts, as well as the continuum effect, be only forbidden at large p, if they are connected with spontaneous breaking effects. Indeed, it is there and only there that such effects fade away. Therefore, it is consistent with this interpretation that we find Z MOM A =Z MOM V 1 at large p to a high precision, without dependence. (ix) Of course, the clover action has the great advantage that it does not present the same very constraining limit in volume as the overlap one; however, it leads to less compelling results than the overlap one, because we have not found here the same particular situations where O4 artifacts can be neglected; the small p artifacts, which render so difficult the determination of power corrections, are present in Z and not only in g 1 . As explained above, by including more and more terms to describe these artifacts, we destabilize the numerical value of hA 2 i. Stopping with the first term a=p 2 , we obtain consistency with the overlap results. (x) In comparison with other works on the quark propagator, the question of the presence and magnitude of power corrections is a crucial test of the precision obtained in the treatment of Green functions: the condensate value hA 2 i should be independent of the action and of with due renormalization. In our opinion, safe and accurate extraction of power corrections requires a very large range of momenta, and therefore a large range of 7 ; indeed, to use a rather large range of momenta at a fixed would be dangerous because of the periodicity of the lattice; the large p behavior would then be highly dependent on empirical redefinitions of the momenta, aiming to remove empirically lattice artifacts at very large p ' 10 GeV. Of course, a crucial question is whether one can work with a as large as 6.8 with our lattice size 16 4 -the possible size is indeed strongly restricted for the overlap action. It is our conviction, for reasons which have been explained in detail. Another concern is that, according to our experience, to extract the real power corrections, one needs a particularly careful elimination of hypercubic artifacts. (xi) The resulting value of hA 2 i from the OPE analysis of lattice QCD data should be compared to tenta- 7 The lattice group in Adelaide has performed extensive studies of the quark propagator (see references above). Recently, the same group has extended its analysis to overlap action [11] and a special gauge action, with several 's, corresponding to a \u00ff1 1 GeV \u00ff1 -2 GeV \u00ff1 , yet notably lower than our largest cutoffs.", "cite_spans": [], "ref_spans": []}, {"section": "A. Physical results and evidences of various artifacts", "text": "tive estimates made by various authors within analytical approaches. One will find abundant references in the paper of Dudal et al., Ref. [42] . It is clear that this comparison must take care of the precise definition of the condensate, as regarding instance renormalization.", "cite_spans": [], "ref_spans": []}, {"section": "B. Systematic errors on hA 2 i", "text": "Of course, we are making many assumptions which introduce uncertainty in the value of hA 2 i. Recall that we do not claim to determinate it only from the present study, since we have several previous determinations from the gluonic sector. So we can also appreciate systematic errors from the consistency we obtain with these previous estimates (see above, Sec. VIII C). In fact, as we have observed in Sec. VIII C, the gluon propagator determination and the one from s are notably different, but the values are affected by very large errors, and are compatible with the present ones. From all the determinations, we could conclude that the systematic errors do no seem to exceed 1 GeV 2 . But there is in fact an important source of the systematic error, which is explained below, and which cannot be estimated by comparison with gluons because it is present in both: it is the fact that the Wilson coefficient is calculated only at low order. Then, it remains useful to discuss the sources of errors inside the quark sector itself, for which anyway the conditions are intrinsically very favorable.", "cite_spans": [], "ref_spans": []}, {"section": "B. Systematic errors on hA 2 i", "text": "Since we do not claim to do phenomenology, but rather an exercise in quenched QCD, we have not bothered with the quenched approximation, which is also supposed for gluons. Chiral limit is assumed on the theoretical side, for instance to calculate the Wilson coefficients. Now, of course, we do not work at zero quark mass on the lattice. We have not tried to do a systematic chiral extrapolation on the lattice data, which would only lead to increase the statistical errors. We observe that Z seems very weakly dependent on our set of masses, which means that this limit is not a priori a problem at the smallest mass (at which we have made all our OPE analysis). Anyway, we can discard any catastrophic effect at very low quark masses through the consistency with the quenched gluon data.", "cite_spans": [], "ref_spans": []}, {"section": "B. Systematic errors on hA 2 i", "text": "Let us now pass to more relevant effects. Some come from the treatment of artifacts, for which we lack theoretical basis, some are relative to our description of the continuum, which, although based on a much stronger theoretical basis, involves necessarily approximations.", "cite_spans": [], "ref_spans": []}, {"section": "B. Systematic errors on hA 2 i", "text": "We do not return to finite volume artifacts, since we have nothing quantitative to say about their magnitude in the overlap case. For what concerns hypercubic artifacts, we may have an idea on the error remaining in their treatment by the variation observed with two variants, with a slightly different description of the continuum limit: 10 GeV, and more for the smaller momenta; whence a reduction of the Wilson coefficient by 50% in average. Through a conspiracy with the smaller change in the perturbative contribution, this change amounts to an increase of the resulting condensate by 70%. Of course, similar effects are present for gluons, and, as we have explained, the ratio of condensates obtained from quarks and gluons will remain the same. More importantly, one must be aware that the power correction by itself remains well determined; what is not well determined is the translation of the power correction into a hA 2 i condensate value. Indeed, this translation depends on the theoretical evaluation of the Wilson coefficient, which is not accurate at present. As to the properly nonperturbative aspect, we may think of two sources of uncertainties in determining hA 2 i. The one stems from other operators which could enter with the same power in the OPE expansion. However, we do not find any such operator contribution in Z in the chiral limit. We could have some contamination since we are not exactly in the chiral limit, but it must be small, since we observe a very weak quark mass dependence. The other could be the possibility that p is not sufficiently large for the leading correction 1=p 2 to completely dominate over the next ones. This possibility is represented by the 1=p 4 term and the fact that it is small but nonzero in the fits shows indeed that we are not completely asymptotic at such large momenta; although it is very small, around 1% at 3 GeV, it leads to a change of around 15% in hA 2 i. On the other hand, with this term included, we find a very good stability of hA 2 i over the large range 2:6 GeV < p < 10 GeV, when varying the fitting window, which suggests that we have correctly accounted for the small subasymptotic effects. Actually, this term could also mimic a neglected logarithmic dependence; indeed, passing from MOM to MS as expansion parameter as explained above, the 1=p 4 term passes from \u00ff1:1=p 4 GeV 4 to \u00ff0:65 0:34 GeV 4 =p 4 , therefore there is an appreciable variation, although the sign and order of magnitude are encouragingly stable.", "cite_spans": [], "ref_spans": []}, {"section": "B. Systematic errors on hA 2 i", "text": "On the whole, the dependence of the Wilson coefficient on the scheme for s seems to be the most worrying source of uncertainty, yet it can be solved soon.", "cite_spans": [], "ref_spans": []}, {"section": "B. Systematic errors on hA 2 i", "text": "Another concern is the value we use for QCD , conventionally converted to the MS scheme. Let us vary by 10% our MS 0:237 GeV. We find: ", "cite_spans": [], "ref_spans": []}, {"section": "B. Systematic errors on hA 2 i", "text": "a quite moderate change indeed. There is naturally an increase for decreasing QCD because the larger power correction compensates for the slower falloff of the perturbative part.", "cite_spans": [], "ref_spans": []}, {"section": "C. General consequences for the nonperturbative MOM renormalization approach", "text": "True, the direct object of this study has been to verify the consistency of our OPE analysis of lattice data by extending it to the quark sector, and then comparing with the previous analysis of the gluon sector; and thereby to assess the soundness of our statement of large power corrections in ''elementary'' Green functions as well as of their interpretation in terms of the nongauge-invariant condensate hA 2 i. Now, one must also be aware of the strong consequences of this study, as well as of the preceding ones, on other problems, especially in precision studies of physical quantities. These consequences should be then reexamined in unquenched calculations.", "cite_spans": [], "ref_spans": []}, {"section": "C. General consequences for the nonperturbative MOM renormalization approach", "text": "A first example is the determination of QCD in the gluonic sector; a purely perturbative fit leads to a first determination of QCD ; the necessary inclusion of a 1=p 2 power correction induces a striking modification in the value of QCD , as was found some years ago [19] . In general, important consequences are expected on quantities requiring a renormalization procedure. Very commonly, the renormalization is performed in the MOM method, which uses elementary Green functions in momentum space to calculate the renormalization factors. The naive MOM method would just start from raw lattice data, with minimal improvements such as a democratic selection and choice of an optimal momentum window. Then, our study makes clear the difficulties of this naive method, which render impossible to get accurate results at the precision of a few percents. The present study allows some improvements, but fails in extracting the O4 artifacts. Let us enumerate the obstacles in the naive method and those who remain in spite of our attempts to improve it:", "cite_spans": [], "ref_spans": []}, {"section": "C. General consequences for the nonperturbative MOM renormalization approach", "text": "(1) Power corrections.-First, we have a problem independent of the discretization of the action: the presence of the power corrections has the effect of modifying the lattice estimate of the renormalization constants defined in the perturbative regime. Indeed, only perturbative renormalization schemes can be connected between one another by analytical calculations (e.g. the MS quark mass), and also connected to Wilson coefficients in order to produce physical quantities (e.g. weak four-fermion interaction). Now, the lattice measurement can be performed only at rather small momenta, where power corrections are present. These corrections must be subtracted, especially if one requires a good precision. This extraction is not performed in the naive method. Such power corrections affect Z and various vertex functions. From the Ward identity, it happens that for quantities like Z V , the A 2 power corrections cancel between the vertex function and Z . But this is not true in general: in Z S and Z P for instance, this cancellation does not occur. In such cases, the power corrections must be subtracted, in principle. Of course, one may wonder whether this is practically important. It depends on the accuracy we want to obtain. If we aim at a precision of a few percent, certainly we do require to take them into account, since they reach several percent around 4 GeV, 5% on Z in the clover case. Now, one often claims to go below 10% with dynamical quarks; then, such effects are deserving of consideration. What simplifies somewhat the problem raised by power corrections is that not only are they independent of the chosen discretization of the action, but they are often related to the same hA 2 i condensate, at least as regards the dominant power. Once hA 2 i has been confidently determined by one analysis, it can be used for other Green functions.", "cite_spans": [], "ref_spans": []}, {"section": "C. General consequences for the nonperturbative MOM renormalization approach", "text": "(2) the discretization artifacts that we have found set a more general difficulty, and one which is more embarrassing, in view of our lack of theoretical control. We have no reason to suppose that the special case we have studied is especially cata-", "cite_spans": [], "ref_spans": []}, {"section": "C. General consequences for the nonperturbative MOM renormalization approach", "text": "strophic. Yet, it shows already an embarrassing situation. -The first step is to have control on hypercubic artifacts to a good accuracy. It is deserving of mention that this accuracy cannot be obtained by the naive method of selecting democratic points; since the determination of renormalization constants relies on measures at large p, the error is particularly large. Moreover, the simplest version of our alternative method of ''restoration of O4 symmetry,'' the old ''p 4 '' method, has not allowed one to get a good accuracy. We have had to go further with the p 2n method. This requires already a good deal of work. But, finally, it seems that we are able to produce a systematic and accurate procedure.", "cite_spans": [], "ref_spans": []}, {"section": "C. General consequences for the nonperturbative MOM renormalization approach", "text": "-On the other hand, we have a clear proof from Z V that there are large O4 invariant artifacts at small p. This type of large artifacts seems to be a problem specific to the quark sector: we had not found similar evidence for gluonic Green functions. We do not have any theoretical mastering about the magnitude of these artifacts. It is also surprising that Z V becomes relatively flat at large p. This suggests, but does not prove, that these artifacts are small at large p. All this is counter to the expectation of perturbation theory which would predict artifacts increasing with p. This lack of theoretical understanding will remain a problem for all the MOM determinations of renormalization constants.", "cite_spans": [], "ref_spans": []}, {"section": "C. General consequences for the nonperturbative MOM renormalization approach", "text": "Indeed, we have not obtained on the other hand an empirical method which would be safe and systematic, to eliminate this new type of artifacts. This is disastrous. It also renders difficult the extraction of the power corrections, as we have observed in the clover case. The choice of the overlap action may help somewhat, but does not offer a general solution. Indeed, for Z , the overlap action seems to present small O4 invariant artifacts. It introduces larger hypercubic artifacts, but this is not a decisive obstacle, as we have explained how to eliminate them accurately. Then one would conclude that all in all, the overlap action has an important advantage. Yet, it is weakened by our lack of theoretical understanding of the underlying reasons why it is so, which precludes any estimation of accuracy (calculations with other values of 1 s may reveal instructive in this respect). Moreover, the problem remains entire for Z V and other vertex renormalization constants.", "cite_spans": [], "ref_spans": []}, {"section": "C. General consequences for the nonperturbative MOM renormalization approach", "text": "Taking into account the large uncertainties coming from O4 invariant artifacts, the MOM method for renormalization, even with the improvements we have proposed, may reveal not very practicable for precision calculations, although it is appealing by its simplicity, and quite efficient for ordinary purposes. Of course, at this point, one may think of the method of the ALPHA collaboration as a complementary one, technically difficult, but which allows a very clean treatment of discretization artifacts by using on shell quantities, and also allows to work at a very high energy scale, therefore eliminating power corrections (see, for example, for Z V , [43] ). 8 ", "cite_spans": [], "ref_spans": []}], "bib_entries": {}, "ref_entries": {"FIGREF2": {"text": "", "type": "figure"}, "FIGREF4": {"text": "FIG. 1 (color online). Comparison between the democratic method and our refined treatment for the overlap Z p 2 at 6.0 and 6.4. Above 2 GeV, precisely where one must study the power corrections, the difference is striking.", "type": "figure"}, "FIGREF6": {"text": "FIG. 3 (color online). Renormalized overlap Z at 6:4, 6.6, 6.8, and large p, compared with the purely perturbative result. The fit of the solid line is made with the perturbative part and only the condensate term, in the windows where the respective Z MOM V become flat (solid line). One finds hA 2 i 3:1 0:3. Note that Z is still far from being flat. It has a monotonous decrease, of around 6% over the range, mainly due to the condensate. The dotted line is the purely perturbative result, clearly inconsistent with the data. Normalization is made at 10 GeV. g 1 is described by a similar fit.", "type": "figure"}, "FIGREF7": {"text": "FIG. 4 (color online). Overlap Z at 6:0, 6.4, 6.6, 6.8, renormalized at 10 GeV. The fit for Z extends to the full allowed range of momentum, with 6:0 included, and a close value of the condensate hA 2 i 2:75 0:2. The dotted line is the purely perturbative result.", "type": "figure"}, "FIGREF9": {"text": "FIG. 5 (color online). Z MOM A =Z MOM V", "type": "figure"}, "FIGREF10": {"text": "GeV, and three-loop anoma- lous dimensions (the use of our present MS 0:237 GeV would lower somewhat the condensate values). The fit has been done with the same convention as for quarks, that the Wilson coefficient (calculated only to one loop) is ex- pressed in terms of MOM s . (We could get free from this convention by comparing the magnitude of power correc- tions themselves as in Eq.", "type": "figure"}, "TABREF0": {"text": "MOM V 2 is the ratio Z 2 =g 1 2 up to artifacts, but as remarked above, this must be nothing but the scheme independent Z V : therefore this ratio Z MOM", "type": "table"}, "TABREF2": {"text": "", "type": "table"}, "TABREF3": {"text": "p 6 : Qp 2 ; a 2 p 4 ; a 4 p", "type": "table"}, "TABREF4": {"text": "Then, in spite of many efforts, we have in fact not been able to extract stable and accurate values of hA 2 i by this method, although we have gotten a clear signal that it is positive and sizable. Then we have been able to fix the continuum power corrections only by", "type": "table"}, "TABREF5": {"text": "''large p'' superscript is to recall that we have selected the value at large p, where we hope to have small O4 artifacts, in view of the observed flatness; the precise value is obtained by a fit. For 6:0, we quote Z", "type": "table"}, "TABREF7": {"text": "Whenever large O4 symmetric artifacts are present, we are compelled, as we have seen, to rather arbitrary assump- tions on their structure, since we have concluded that we cannot rely on lattice perturbation theory. The correlated errors in our determination of the ''nonperturbative'' arti- facts and of the condensate seem very large, as judged from the range of values obtained in various fits, to such a point that we have renounced to extract any number in this case. Therefore, we consider only the case where we have strong hints that the artifacts are small, in which case we have mainly to consider uncertainties in the continuum descrip- tion. They are themselves of two origins: the perturbative calculation of Wilson coefficients; the nonperturbative aspect, i.e. the relevance of the OPE expansion, the enu- meration of operators, etc. As to uncertainties in perturba- tive calculations: (i) We have checked that computing the perturbative contribution to third or fourth order in perturbation does not change significantly the estimated conden- sate (only 7% of change). Another test is to reex- press the series in terms of MS instead of MOM . Z changes by less than 1% with various prescriptions. We can thus assume that the perturbative contribu- tion has been expanded far enough. (ii) As we have explained in Subsection II C, the prob- lem is much more important for the Wilson coeffi- cient of the A 2 operator which has, on the contrary, only been computed to leading logarithm. A sign of this problem is seen by changing MOM into MS . A change of MOM into MS reduces it by 40% s", "type": "table"}}}
{"paper_id": "116986054", "_pdf_hash": "21adea0095b8309776484c57c89cf40260e43608", "abstract": [], "body_text": [], "bib_entries": {"BIBREF1": {"title": "Technical Digest of 3rd OEC", "authors": [{"first": "H", "middle": [], "last": "Asano", "suffix": ""}], "year": 1990, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "116987449", "_pdf_hash": "80527bf4a29f681bccbb09e728e578b8671d530f", "abstract": [{"section": "Abstract", "text": "Eclipsing millisecond pulsars in close (P b < 1 day) binary systems provide a different view of pulsar winds and shocks than do isolated pulsars. Since 2009, the numbers of these systems known in the Galactic field has increased enormously. We have been systematically studying many of these newly discovered systems at multiple wavelengths. Typically, the companion is nearly Roche-lobe filling and heated by the pulsar which drives mass loss from the companion. The pulsar wind shocks with this material just above the surface of the companion. We discuss various observational properties of this shock, including radio eclipses, orbitally modulated X-ray emission, and the potential for \u03b3-ray emission. Redbacks, whose companions are likely non-degenerate and significantly more massive, generally have more luminous shocks than black widows which have very low mass companions. This is expected since the more massive redback companions intercept a greater fraction of the pulsar wind. We also compare these systems to accreting millisecond pulsars, which may be progenitors of black widows and in some cases can pass back and forth between redback and accretion phases.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "In 1986, the first binary pulsar to exhibit radio eclipses, PSR B1957+20, was discovered at the Arecibo observatory (Fruchter et al. 1988a ). This 1.61 ms pulsar is in a 9.2 hr orbit around a very low mass (M c \u223c 0.02M \u2299 ) companion. Regular radio eclipses were observed for \u223c 10% of the orbit when the companion was at inferior conjunction. During the ingress and egress of the eclipse, delays in the pulse arrival times were observed which, along with the eclipse duration, suggested that the eclipses were due to excess ionized gas within the system (although the exact physical mechanism of the eclipses was and still is unclear eg. Thompson 1995) . Optical studies showed large orbital variations in the light from the companion, suggesting the emission was primarily due to illumination by the pulsar (Fruchter et al. 1988b) . H\u03b1 (Kulkarni et al. 1988 ) and X-ray (Stappers et al. 2003) imaging showed unambiguous evidence for a pulsar wind nebula around the pulsar, and observations of the non-thermal X-ray point source showed evidence for orbital modulation as well (eg. Huang and Becker 2007) . Long term timing has shown that there are orbital period variations which are much larger in magnitude than would be expected from gravitational wave emission, with an orbital period derivative that can even change sign over time (Arzoumanian et al. 1994) . These have no easy interpretation, but mass loss from the system and an induced quadrapole moment of the companion could contribute to the measured changes in orbit (Applegate & Shaham 1994) .", "cite_spans": [{"start": 637, "end": 651, "text": "Thompson 1995)", "ref_id": "BIBREF32"}], "ref_spans": []}, {"section": "Introduction", "text": "The inference drawn from these various observations is that PSR B1957+20 is ablating material off of its companion which shocks with the pulsar wind. Such systems had been proposed as a stage in the formation of isolated millisecond pulsars by Ruderman et al. (1989) . Since the pulsar seemed to be in the process of destroying its companion, it was dubbed the \"black widow\" pulsar. Early models of the shock emission expected from the original Black Widow pulsar were developed by Arons and Tavani (1993) and Raubenheimer et al (1995) . These predicted electrons could be accelerated to \u223c 3 TeV and that orbital modulation could arise from obscuration by the companion of part of the shock, intrinsic beaming of the emission by the magnetic field in the shock, or by doppler boosting. The high energy luminosity could depend on the distance to the shock, the magnetic field of the pulsar, the ion fraction, the optical emission of the companion (in the case of inverse Compton emission), and the magnetization of the wind. However, the overall scaling should be primarily due to spin-down power of the pulsar\u0116, the fraction of the wind involved in the shock f , and the distance to the system d.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "No unambiguous detection of \u03b3-ray emission arising from the shock in PSR B1957+20 has yet been made (although there has been an intriguing suggestion of GeV emission in F ermi data, see Wu et al. 2012) . However, the ability of a pulsar wind to produce emission from radio frequencies up to TeV energies in an intrabinary shock has been demonstrated by observations of the PSR B1259\u221263 system (Johnston et al. (1999) ; Abdo et al. (2011) ; H.E.S.S. Collaboration et al. (2013) ) which consists of a young pulsar in an highly eccentric 3.4 year orbit around a main sequence Be star. Near periastron the radio pulses of PSR B1259\u221263 are obscured as it enters the region of the dense equatorial outflow of the Be star, and unpulsed radio, X-ray, GeV and TeV emission is observed. While th\u0117 E of PSR B1259\u221263 is somewhat higher and a larger fraction of the pulsar wind is shocked by the stellar wind than in PSR B1957+20, the total shock luminosity should not be much more than an order of magnitude greater. However, near periastron, PSR B1259\u221263 is a few hundred times brighter in X-rays than PSR B1957+20, despite being at similar distances.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The big difference between the Black Widow shock and those in PSR B1259-63 and the termination shocks of young pulsar wind nebulae is the scale of the systems. In terms of light cylinder radii R lc , the companion of the Black Widow pulsar is on the order of 10 4 R lc rather than the more typical 10 8 R lc to the inner torii of young pulsar wind nebulae. This forces the shock to be in the region where, if the pulsar wind is magnetically dominated at the light cylinder, the magnetization fraction \u03c3 should still be relatively high. This may allow direct observational tests of proposed solutions to the \"sigma problem\" of pulsar wind shocks where the inferred magnetization at the termination shock from models of the X-ray emission is very low despite the expectation that at the light cylinder it should be very high (Arons (2012) ). Other potential advantages of studying the shocks in black widow type systems are that pulsar timing and optical observations allow us to determine the geometry of the system very well, and short orbits (< 1 d) allow for many repeated observations of the shock as viewed from different orientations.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "For many years it seemed that eclipsing systems in the Galactic field might be quite rare. In the 20 years following the discovery of PSR B1957+20, only 2 other systems were discovered, both of which had spin-down fluxes\u0116/d 2 much smaller than that of the original Black Widow (see Roberts 2011 and references therein). Observations of globular clusters, however, revealed that a significant fraction of their millisecond pulsars either eclipsed and/or had very low companion masses. Freire (2005) listed 18 such systems. 11 have very low mass companions (M c 0.04M \u2299 )like PSR B1957+20, but 7 have masses more typical of helium white dwarfs. Optical observations of these latter systems tended to indicate the companions were, in fact, non-degenerate. Were these then systems where the pulsar was spun up by one companion, then exchanged the original companion for a non-degenerate one in the very crowded core of the globular cluster? If this were the case, then it would be natural that most such systems would be found in globular clusters.", "cite_spans": [{"start": 484, "end": 497, "text": "Freire (2005)", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "PSR J1023+0038 the Canonical Galactic Field Redback", "text": "During a drift scan survey for radio pulsars with the Green Bank Telescope, a 1.69 ms pulsar was discovered in a 4.8 hr orbit around a \u223c 0.2M \u2299 companion coincident with the radio source FIRST J102347.6+003841 ). This source had been noted previously as a possible cataclysmic variable (Bond et al. (2002) ) whose optical spectrum had undergone a drastic change \u223c 2001 \u2212 2002 (Wang et al. (2009) ) from a source with strong, broad, double-peaked emission lines implying an accretion disk to one more consistent with that of a G-type star with no emission lines but strong orbital modulation (Thorstensen & Armstrong (2005) ). Modeling of the photometric light curve along with radial velocity measurements implied a hidden companion with a mass more in line with a neutron star that a white dwarf. The radio pulsations not only confirmed the neutron star nature of the primary, but also showed regular, frequency dependent orbital eclipses. This was reminiscent of both the Black Widow pulsar and the systems in globular clusters with non-degenerate companions, the first of which was discovered with the Parkes telescope. However this source is in the Galactic field and there was evidence for a recent accretion phase, suggesting that these systems with non-degenerate companions represented a phase in the life of system still undergoing the recycling process where the accretion is only temporarily interrupted and goes into a temporary phase where the freshly revealed radio pulsar ablates its companion. As more such systems were found in the Galactic field, they were given the moniker \"redback\", after the Australian cousin to the North American black widow spider.", "cite_spans": [], "ref_spans": []}, {"section": "PSR J1023+0038 the Canonical Galactic Field Redback", "text": "Further optical studies and VLBI studies of PSR J1023+0038 combined with radio timing studies allowed for an accurate estimate of the intrinsic spin down, the distance, the inclination angle, and the companion's Roche lobe filling factor (Deller et al. (2012) ). They also showed the neutron star to be massive, likely to be 2M \u2299 , implying a moment of inertia significantly larger than the canonical 10 45 gm cm 2 derived from an assumed mass of 1.4M \u2299 and radius of 10 km. PSR J1023+0038 so far is the only Galactic field redback with a VLBI determined parallax and proper motion as well as optical observations implying a massive neutron star with a Roche lobe filling companion. Since dispersion measure distances determined from the NE2001 free electron model (Cordes & Lazio (2002) ) often underestimate the true distance by as much as a factor of 2 for mid Galactic latitude pulsars (as was the case for PSR J1023+0038), and relative motion of the source to us can strongly affect the observed spin-down rate through the Shklovskii effect (Shklovskii (1970) ) and the interaction region depends on the angle distended by the companion and hence the mass ratio and Roche lobe filling factor, any interpretation of shock emission from these systems should take into account these areas of uncertainty and ideally all would be observationally constrained.", "cite_spans": [], "ref_spans": []}, {"section": "PSR J1023+0038 the Canonical Galactic Field Redback", "text": "In the case of PSR J1023+0038, fairly extensive X-ray observations have been made showing clear evidence of emission from the shock (Archibald et al. (2010) ). Bogdanov et al. (2011) have modelled the X-ray lightcurve and find that the evidence points towards an emission region very near the companion and that the orbital variations primarily come from partial obscuration of the shock region by the companion. Given the level of X-ray emission and assuming it is primarily synchrotron, they infer a fairly strong magnetic field of \u223c 40 G at the shock. If this is the magnetic field carried by the wind to the shock, it would indicate a very high magnetization fraction in the wind, and that pulsar winds out to at least \u223c 10 4 light cylinder radii are still magnetically dominated (i.e. have a high \u03c3). An upper limit on the TeV flux from VERITAS supports a scenario with a moderately strong magnetic field at the shock (Aliu et al. in preparation). However, it is not clear that the inferred magnetic field is necessarily due to the pulsar wind and not the magnetosphere of the companion. For example, if the dipole moment of the companion is similar to that of the Sun, then it's surface field would be on \u223c 25 G, which could significantly influence the emission of electrons accelerated in a shock near the star's surface. PSR J1023+0038 has also been weakly detected by F ermi, but it is not yet clear if this emission is pulsed (Tam et al. (2010) ).", "cite_spans": [], "ref_spans": []}, {"section": "The New Population of Black Widows and Redbacks Associated with Fermi Sources", "text": "Since the discovery of PSR J1023+0038, both large scale surveys and targeted searches of unassociated F ermi \u03b3-ray sources have resulted in a swarm of new black widow and redback discoveries (Roberts (2013) ). Currently, there are \u223c 17 black widows and \u223c 7 redbacks known in the Galactic field. Typically, they have spin-down powers (uncorrected for Shklovskii effect)\u0116 \u223c 10 34\u221235 erg s \u22121 , distances between \u223c 0.5 \u2212 3.5 kpc (based on dispersion measures), and orbital periods much shorter than a day. Those with long term timing solutions, especially redbacks, show orbital period variations similar to what is seen in the original black widow. The vast majority of these new systems are associated with F ermi sources. However, in almost all cases once a good timing solution is obtained, pulsed GeV emission can be detected while there is little evidence for any \u03b3-ray emission coming from the shock. The pulse period distribution is on average shorter than the general radio MSP population, and similar to what is seen in accreting X-ray millisecond pulsars (AXMSPs) (Patruno & Watts (2012) ). Comparison of orbital period-companion mass relationship of redbacks and black widows to AXMSPs show that the latter appear to bridge the two populations. Accreting sources with similar companion masses to redbacks also have similar orbital periods, while those with companion masses similar to black widows tend to have shorter orbital periods. This suggests that accretion may turn on and off when the companion has not yet fully shed its non-degenerate envelope, and so can either be a redback or an AXMSP, but for very light companions, once the pulsar turns on the accretion phase has ended. The ability to pass back and forth between a redback phase and an AXMSP phase has been spectacularly demonstrated by the globular cluster redback M28I. This system was observed to briefly go into an accretion phase and become an AXMSP in Spring 2013 (Papitto et al. (2013a) ) and then turned back into a radio pulsar within a few months (Papitto et al. (2013b) ). While interruptions in the accretion process are expected on the evolutionary timescale of the companion, the mechanism for such rapid switching back and forth is currently not understood. (2012)). The lines are from various binary evolution models considered by Tauris & Savonije (1999) which result in a Helium white dwarf companion. Since we plot minimum companion masses, we expect systems which evolved according to standard evolutionary scenarios be just to the left of these lines. Non-spider MSPs (plus signs) are from the ATNF pulsar catalog http://www.atnf.csiro.au/research/pulsar/psrcat A number of the new systems have been studied in the optical. Most seem to be nearly Roche lobe filling, but at least one black widow (PSR J0023+0923) and possibly a second (PSR J2256\u22121024) significantly underfill their Roche lobes (Breton et al. (2013) ). There is also one system (PSR J1816+4510) which shows eclipses and has a companion mass from timing > 0.16M \u2299 like a redback (Kaplan et al. (2012) ), but optical studies show that its companion is a very hot, metal rich, low-gravity star which significantly un-derfills its Roche lobe and is spectrally similar to a proto-white dwarf. It therefore may just be ending its redback phase (Kaplan et al. (2013) ).", "cite_spans": [], "ref_spans": []}, {"section": "The New Population of Black Widows and Redbacks Associated with Fermi Sources", "text": "Several of the new systems have also had X-ray observations covering at least one orbit (Gentile et al. (2013) ), although none have been as extensively studied in X-rays as PSR B1957+20 and PSR J1023+0038. Their Xray spectra mostly seem to be a mixture of thermal and non-thermal emission. Some show strong evidence for orbital variation, while others show hints of orbital variation. An exception is PSR J0023+0923, which is in keeping with the companion underfilling its Roche lobe and hence intersect with a smaller fraction of the pulsar wind. In Figure 2 , we plot the measured X-ray flux as a function of the quantity (\u0116/d 2 )(R L /2a) 2 where R L is the average Roche lobe radius of the companion and a is the semi-major axis of the orbit. Hence this quantity should be proportional to the total potential flux from any intrabinary shock, assuming the companion fills its Roche lobe. Note we assume the standard formula for\u0116 and do not try to take into account differences in moment of inertia and in most cases there are no proper motion constraints and hence no correction for the Shklovskii effect. The distances, other than for PSR J1023+0038, are from the pulsar dispersion measure. For cases where there is evidence for underfilling of the Roche lobe and/or a different distance, we have indicated the effect on the inferred shock flux with arrows of varying length. The measured values do seem to roughly correlate to the expected total flux from the intrabinary shock. Such a relationship will hopefully become clearer once more sources have more reliable estimates of their intrinsic spin-downs, true distances and Roche lobe filling factors, and also have good enough statistics in their X-ray spectra to clearly separate non-thermal flux emitted by the shocked wind from thermal emission emitted by the neutron star surface. None of the newer sources has yet to show evidence of extended nebular emission as seen around PSR B1957+20. Interesting information about the intrabinary shocks in black widows and redbacks as a class is beginning to emerge. Deeper X-ray observations covering multiple orbits and better optical constraints on the companions and the system geometries are needed to model the X-ray light curves and extract information about the pulsar wind. More TeV constraints and a clear detection of orbital modulation at GeV energies would also be very helpful, as would detections at radio wavelengths. These systems give us a different view into the ultrarelativistic winds accelerated in pulsars and the shocks they produce that complements studies of pulsar wind nebulae around young, isolated pulsars.", "cite_spans": [], "ref_spans": []}, {"section": "Shock Flux [(E/d", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Acknowledgements", "text": "Portions of this work were supported by NASA's Fermi Guest Investigator Program, including grant number NNG10PB13P and the Chandra Guest Observer Program including grant numbers GO1-12061B and GO2-13056X.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF12": {"title": "Binary Radio Pulsars", "authors": [{"first": "P", "middle": ["C C"], "last": "Freire", "suffix": ""}], "year": 2005, "venue": "", "link": null}, "BIBREF23": {"title": "The Astronomer's Telegram", "authors": [{"first": "A", "middle": [], "last": "Papitto", "suffix": ""}, {"first": "J", "middle": ["W T"], "last": "Hessels", "suffix": ""}, {"first": "M", "middle": [], "last": "Burgay", "suffix": ""}], "year": 2013, "venue": "", "link": null}, "BIBREF26": {"title": "American Institute of Physics Conference Series", "authors": [{"first": "M", "middle": ["S E"], "last": "Roberts", "suffix": ""}], "year": 2011, "venue": "", "link": "198099532"}, "BIBREF32": {"title": "Millisecond Pulsars. A Decade of Surprise", "authors": [{"first": "C", "middle": [], "last": "Thompson", "suffix": ""}], "year": 1995, "venue": "", "link": "117452422"}}, "ref_entries": {"FIGREF0": {"text": "Fig. 1.-Minimum companion mass vs. orbital period of fast (P < 8 ms) binary MSPs in the Galactic field, showing the positions of Redbacks (blue stars), Black Widows (green crosses) and AXMSPs (pink boxes) (Roberts (2013); Patruno & Watts (2012)). The lines are from various binary evolution models considered by Tauris & Savonije (1999) which result in a Helium white dwarf companion. Since we plot minimum companion masses, we expect systems which evolved according to standard evolutionary scenarios be just to the left of these lines. Non-spider MSPs (plus signs) are from the ATNF pulsar catalog http://www.atnf.csiro.au/research/pulsar/psrcat", "type": "figure"}, "FIGREF1": {"text": "Fig. 2.-0.3-8 keV X-ray flux vs. \"Shock Flux\" (see text) for black widows and spiders with X-ray observations, assuming the NE2001 distance (except for the case of PSR J1023+0038) and a Roche lobe filling companion. Arrows point to what positions on the plot certain sources would move to in cases where optical observations suggest the companions underfill their Roche lobes.", "type": "figure"}}}
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{"paper_id": "118860777", "_pdf_hash": "62fca669e2e10ea2e3ade485129d9cbc330cb528", "abstract": [{"section": "Abstract", "text": "Entanglement, which quantifies non-local correlations in quantum mechanics, is the fascinating concept behind much of aspiration towards quantum technologies. Nevertheless, directly measuring the entanglement of a many-particle system is very challenging. Here we show that via supervised machine learning using a convolutional neural network, we can infer the entanglement from a measurable observable for a disordered interacting quantum many-particle system. Several structures of neural networks were tested and a convolutional neural network akin to structures used for image and speech recognition performed the best. After training on a set of 500 realizations of disorder, the network was applied to 200 new realizations and its results for the entanglement entropy were compared to a direct computation of the entanglement entropy. Excellent agreement was found, except for several rare region which in a previous study were identified as belonging to an inclusion of a Griffiths-like quantum phase. Training the network on a test set with different parameters (in the same phase) also works quite well.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Recently there has been a growing interest in understanding quantum entanglement [1] [2] [3] [4] [5] . The concept of entanglement lies at the heart of quantum mechanics [6] and its application in the emerging field of quantum technologies [7] .", "cite_spans": [{"start": 81, "end": 84, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 85, "end": 88, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 89, "end": 92, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 93, "end": 96, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 97, "end": 100, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 170, "end": 173, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 240, "end": 243, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Abstract", "text": "In many-particle systems, entanglement is traditionally quantified by the entanglement entropy [1-5], i.e., the measure of the amount of information in the reduced density matrix of part of the system when the degrees of freedom of the remainder of the system are traced out. This entanglement entropy is used e.g. to identify phases of many-body systems such as insulator or metallic phases [8] [9] [10] [11] , or topological phases [12] [13] [14] .", "cite_spans": [{"start": 392, "end": 395, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 396, "end": 399, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 400, "end": 404, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 405, "end": 409, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 434, "end": 438, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 439, "end": 443, "text": "[13]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Abstract", "text": "Nevertheless, in contrast to few-particle systems, measurement of entanglement for many-particle systems turns out to be very challenging. Despite the growing importance of entanglement in theoretical physics, current condensed matter experiments do not have a direct probe with which to measure entanglement. One can quantify the entanglement through the measurement of the second R\u00e9nyi entropy, which measures the overlap between the ground state of two identical copies of a system when a region is swapped between them [15, 16] . It was realized that this could be actually measured through coupling between two identical copies of cold atom systems [17, 18] . This measurement has indeed been performed on such systems [19, 20] . Another way, which has recently been proposed [21] , involves repeatedly applying time dependent disorder potentials and projective measurement. After statistical analysis, the second R\u00e9nyi entropy may be extracted. This method avoids the need for cloning copies of the system, which is difficult even for cold atom systems and impossible for condensed matter systems, nonetheless, applying this method raises its own set of challenges.", "cite_spans": [{"start": 523, "end": 527, "text": "[15,", "ref_id": "BIBREF14"}, {"start": 528, "end": 531, "text": "16]", "ref_id": "BIBREF15"}, {"start": 654, "end": 658, "text": "[17,", "ref_id": "BIBREF16"}, {"start": 659, "end": 662, "text": "18]", "ref_id": "BIBREF17"}, {"start": 724, "end": 728, "text": "[19,", "ref_id": "BIBREF18"}, {"start": 729, "end": 732, "text": "20]", "ref_id": "BIBREF19"}, {"start": 781, "end": 785, "text": "[21]", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Abstract", "text": "Here, a different tack on extracting the entanglement entropy of a region in a many-particle system is taken. The method is based on utilizing the apparent correlation between the variance of the number of particles in the sub-system and the entanglement entropy. A connection between the summation of a weighted series of cumulants of the number of particles in the sub-system and the entanglement entropy was established by Klich and Levitov [22, 23] for non-interacting free fermions. This theory was extended to include disordered systems by Burmistrov et al. [24]. These relations are no longer exact for interacting fermions [25] . Nevertheless, since here interactions do not change the phase of the system which remains an Anderson insulator, and by looking at the number variance vs. the entanglement entropy (see Fig. 1 ), it is clear that even for disordered interacting systems there is a strong correlation between the two quantities. This indicates that within the chaotic-like data of the particle variance data on the entanglement is embedded. Since experimentally the variance in the number of particles is accessible and the entanglement entropy is not, and for many numerical procedures it is computationally simpler to calculate the number of particles in a sub-region than the entanglement of that region, it would be very useful to extract one from the other. In order to do so, machine learning will be utilized in order to train a convolution neural network (the term will be explained later) on a finite number of realizations of disorder and evaluate its performance on a different set of realizations. It will be shown that after such training, the neural network is able to map the number variance to the entanglement entropy of a given realization with a very good accuracy. Moreover, training the network on a set of realizations with different parameters than the test realizaitions, but which are nevertheless in the same physical phase, can also result in a network which can extract a reasonable entanglement entropy for the test realization. Thus, it is proposed that one train an artificial neural network on a system for which both an easily measured quantity and the entanglement may be measured or numerically calculated, then apply the network to infer the entanglement arXiv:1810.00346v1 [cond-mat.dis-nn] 30 Sep 2018", "cite_spans": [{"start": 449, "end": 452, "text": "23]", "ref_id": "BIBREF22"}, {"start": 631, "end": 635, "text": "[25]", "ref_id": "BIBREF24"}], "ref_spans": []}], "body_text": [{"section": "", "text": "Recently there has been a growing interest in understanding quantum entanglement [1] [2] [3] [4] [5] . The concept of entanglement lies at the heart of quantum mechanics [6] and its application in the emerging field of quantum technologies [7] .", "cite_spans": [{"start": 81, "end": 84, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 85, "end": 88, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 89, "end": 92, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 93, "end": 96, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 97, "end": 100, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 170, "end": 173, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 240, "end": 243, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "", "text": "In many-particle systems, entanglement is traditionally quantified by the entanglement entropy [1] [2] [3] [4] [5] , i.e., the measure of the amount of information in the reduced density matrix of part of the system when the degrees of freedom of the remainder of the system are traced out. This entanglement entropy is used e.g. to identify phases of many-body systems such as insulator or metallic phases [8] [9] [10] [11] , or topological phases [12] [13] [14] .", "cite_spans": [{"start": 95, "end": 98, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 99, "end": 102, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 103, "end": 106, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 107, "end": 110, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 111, "end": 114, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 407, "end": 410, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 411, "end": 414, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 415, "end": 419, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 420, "end": 424, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 449, "end": 453, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 454, "end": 458, "text": "[13]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "", "text": "Nevertheless, in contrast to few-particle systems, measurement of entanglement for many-particle systems turns out to be very challenging. Despite the growing importance of entanglement in theoretical physics, current condensed matter experiments do not have a direct probe with which to measure entanglement. One can quantify the entanglement through the measurement of the second R\u00e9nyi entropy, which measures the overlap between the ground state of two identical copies of a system when a region is swapped between them [15, 16] . It was realized that this could be actually measured through coupling between two identical copies of cold atom systems [17, 18] . This measurement has indeed been performed on such systems [19, 20] . Another way, which has recently been proposed [21] , involves repeatedly applying time dependent disorder potentials and projective measurement. After statistical analysis, the second R\u00e9nyi entropy may be extracted. This method avoids the need for cloning copies of the system, which is difficult even for cold atom systems and impossible for condensed matter systems, nonetheless, applying this method raises its own set of challenges.", "cite_spans": [{"start": 523, "end": 527, "text": "[15,", "ref_id": "BIBREF14"}, {"start": 528, "end": 531, "text": "16]", "ref_id": "BIBREF15"}, {"start": 654, "end": 658, "text": "[17,", "ref_id": "BIBREF16"}, {"start": 659, "end": 662, "text": "18]", "ref_id": "BIBREF17"}, {"start": 724, "end": 728, "text": "[19,", "ref_id": "BIBREF18"}, {"start": 729, "end": 732, "text": "20]", "ref_id": "BIBREF19"}, {"start": 781, "end": 785, "text": "[21]", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "", "text": "Here, a different tack on extracting the entanglement entropy of a region in a many-particle system is taken. The method is based on utilizing the apparent correlation between the variance of the number of particles in the sub-system and the entanglement entropy. A connection between the summation of a weighted series of cumulants of the number of particles in the sub-system and the entanglement entropy was established by Klich and Levitov [22, 23] for non-interacting free fermions. This theory was extended to include disordered systems by Burmistrov et al. [24] . These relations are no longer exact for interacting fermions [25] . Nevertheless, since here interactions do not change the phase of the system which remains an Anderson insulator, and by looking at the number variance vs. the entanglement entropy (see Fig. 1 ), it is clear that even for disordered interacting systems there is a strong correlation between the two quantities. This indicates that within the chaotic-like data of the particle variance data on the entanglement is embedded. Since experimentally the variance in the number of particles is accessible and the entanglement entropy is not, and for many numerical procedures it is computationally simpler to calculate the number of particles in a sub-region than the entanglement of that region, it would be very useful to extract one from the other. In order to do so, machine learning will be utilized in order to train a convolution neural network (the term will be explained later) on a finite number of realizations of disorder and evaluate its performance on a different set of realizations. It will be shown that after such training, the neural network is able to map the number variance to the entanglement entropy of a given realization with a very good accuracy. Moreover, training the network on a set of realizations with different parameters than the test realizaitions, but which are nevertheless in the same physical phase, can also result in a network which can extract a reasonable entanglement entropy for the test realization. Thus, it is proposed that one train an artificial neural network on a system for which both an easily measured quantity and the entanglement may be measured or numerically calculated, then apply the network to infer the entanglement arXiv:1810.00346v1 [cond-mat.dis-nn] 30 Sep 2018 entropy from the measured quantity.", "cite_spans": [{"start": 444, "end": 448, "text": "[22,", "ref_id": "BIBREF21"}, {"start": 449, "end": 452, "text": "23]", "ref_id": "BIBREF22"}, {"start": 564, "end": 568, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 632, "end": 636, "text": "[25]", "ref_id": "BIBREF24"}], "ref_spans": [{"start": 824, "end": 830, "text": "Fig. 1", "ref_id": "FIGREF0"}]}, {"section": "", "text": "Artificial neural networks have garnered a tsunami of publicity due to their application to a diverse set of tasks from speech recognition [26] to autonomous cars [27] and molecular synthesis design [28] . In quantum manyparticle physics, there are several applications of machine learning [29] . Some are related to classifying different phases of matter [30] [31] [32] [33] [34] [35] [36] [37] [38] , others to designing new materials [39] [40] [41] [42] , and also to representing the essence of many-particle states by neural network structures [43] [44] [45] . Very recently, machine learning was used to recognize order appearing in seemingly chaotic experimental data of cuprate Mott insulators in order to identify the physics behind the pseudo gap phenomenon [46] . Here, machine learning will be used for a different task, namely predicting one physical quantity based on the measurement of another, where there is no exact theoretical prescription to rely on. In this, we take advantage of the power of deep neural networks to learn from examples, i.e., after training the network on a set of realizations where both quantities (in this case primarily the number variance and entanglement entropy) are provided, the network is applied to other realizations for which it receives only one quantity and must infer the other. As we shall see, the training could be performed also on a non-interacting systems for which the calculation of the entanglement is much simpler than for the interacting target realizations.", "cite_spans": [{"start": 139, "end": 143, "text": "[26]", "ref_id": "BIBREF25"}, {"start": 163, "end": 167, "text": "[27]", "ref_id": "BIBREF26"}, {"start": 199, "end": 203, "text": "[28]", "ref_id": "BIBREF27"}, {"start": 290, "end": 294, "text": "[29]", "ref_id": "BIBREF28"}, {"start": 356, "end": 360, "text": "[30]", "ref_id": "BIBREF29"}, {"start": 361, "end": 365, "text": "[31]", "ref_id": "BIBREF30"}, {"start": 366, "end": 370, "text": "[32]", "ref_id": "BIBREF31"}, {"start": 371, "end": 375, "text": "[33]", "ref_id": "BIBREF32"}, {"start": 376, "end": 380, "text": "[34]", "ref_id": "BIBREF33"}, {"start": 381, "end": 385, "text": "[35]", "ref_id": "BIBREF34"}, {"start": 386, "end": 390, "text": "[36]", "ref_id": "BIBREF35"}, {"start": 391, "end": 395, "text": "[37]", "ref_id": "BIBREF36"}, {"start": 396, "end": 400, "text": "[38]", "ref_id": "BIBREF37"}, {"start": 437, "end": 441, "text": "[39]", "ref_id": "BIBREF38"}, {"start": 442, "end": 446, "text": "[40]", "ref_id": "BIBREF39"}, {"start": 447, "end": 451, "text": "[41]", "ref_id": "BIBREF40"}, {"start": 452, "end": 456, "text": "[42]", "ref_id": "BIBREF41"}, {"start": 549, "end": 553, "text": "[43]", "ref_id": "BIBREF42"}, {"start": 559, "end": 563, "text": "[45]", "ref_id": "BIBREF44"}, {"start": 768, "end": 772, "text": "[46]", "ref_id": "BIBREF45"}], "ref_spans": []}, {"section": "", "text": "One of the most popular quantification of entanglement is the entanglement entropy (EE), and its generalization, the R\u00e9nyi entropy. These entropies measure the entanglement in a many-body system by dividing it into two regions A and B. For a system in a pure state |\u03a8 , the entanglement between regions A and B is related to the eigenvalues of the reduced density matrix of area A, \u03c1 A (or B, \u03c1 B ). Specifically, \u03c1 A is defined as: \u03c1 A = Tr B |\u03a8 \u03a8|, where the degrees of freedom of region B are traced out. The eigenvalues \u03bb A i of \u03c1 A are used to calculate the EE:", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Here, we illustrate these ideas for a 1D wire of length L = 700 half-filled by spinless electrons with nearestneighbor interactions and an on-site disordered potential. The Hamiltonian is given by:", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "where\u0109 \u2020 j is the creation operator for a spinless electron at site j, and t = 1 is the hopping matrix element. Since we want to test the case which the simple connection between number variance and EE is expected to fail, strong interaction (U = 2.4) and weak disorder (where j ,the on-site energy, is drawn from a uniform distribution of width 0.7, corresponding to a localization length, \u03be \u223c 14) [47] were chosen for the targets. The eigenvalues, \u03bb i , for different sizes of region A between 3 < L A < L \u2212 3, as well as the probability p i (N i A ) of measuring a specific number of particles N A i in the region, was calculated for 700 realizations of disorder using DMRG [48] [49] [50] [51] , with a block size of 392 and two sweeps through the system. The EE, S A , and the variance in number of particles, and \u03b4 2 N A , are calculated using \u03bb i , N A i , and p i (N i A ). A detailed description of the computational method can be found in Ref. [47] and references therein.", "cite_spans": [{"start": 399, "end": 403, "text": "[47]", "ref_id": "BIBREF46"}, {"start": 677, "end": 681, "text": "[48]", "ref_id": "BIBREF47"}, {"start": 682, "end": 686, "text": "[49]", "ref_id": "BIBREF48"}, {"start": 687, "end": 691, "text": "[50]", "ref_id": "BIBREF49"}, {"start": 953, "end": 957, "text": "[47]", "ref_id": "BIBREF46"}], "ref_spans": []}, {"section": "", "text": "In Fig. 1 , the entanglement entropy S A , and the number variance,", "cite_spans": [], "ref_spans": [{"start": 3, "end": 9, "text": "Fig. 1", "ref_id": "FIGREF0"}]}, {"section": "", "text": ", for a typical realization of disorder are presented. It is obvious that the two quantities fluctuate as a function of the size L A of region A, and that there are sections for which there are strong even-odd fluctuation while other segments are rather smooth. Nevertheless, both quantities have a strong correlation between them. The simplest assumption would be a linear relation, which as we shall see, works reasonably well for the smooth regions, but fails for the strongly fluctuating one. Therefore, it looks plausible that by using machine learning which will identify the features of the region in the vicinity of L A which may enable the network to determine S A from \u03b4 2 N A . A rather simple neural network structure will be used in order to achieve this goal. Three main network structures were tested for this study, and as described in the supplementary material the network illustrated in Fig. 2 was chosen . Thus, here a convolutional neural network (CNN), similar to the ones used in speech recognition ", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "The neural network which showed the best performance for reproducing the entanglement entropy, SA, from the number variance \u03b4 2 NA (labeled network C in the supplementary material). The lower (input) layer of neurons are the L values of \u03b4 2 NA for a given realization and size of area A,, LA, denoted by e (1) , and the top layer are the output values of the entanglement entropy SA, denoted by e (3) . This network is a convolution neural network where the hidden layer is composed of M neurons termed e (2) , each of them connected to M input neurons in the vicinity of output neuron LA. The same weights W 1,2 and W 2,3 are used for all output neurons.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "and image processing is used [26] . The basic unit is a neuron e", "cite_spans": [{"start": 29, "end": 33, "text": "[26]", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "", "text": "j , where l is the layer number (l = 1 the input layer, l = 2 hidden layer, and l = 3 output layer). Each e (l) j can attain in principal any value. The size of the input layer is L, the size of the hidden layer is M , and the size of the output layer is L \u2212 M . There are two convolutional weight matrices connecting between consecutive layers W l,l+1 , where W 1,2 is a M \u00d7 M matrix, and W", "cite_spans": [], "ref_spans": []}, {"section": "2,3", "text": "is a M \u00d71 matrix. The matrices do not depend on the position of the output neuron j. Initially the matrices have random values between 0 and 0.1, while e", "cite_spans": [], "ref_spans": []}, {"section": "2,3", "text": "is the input layer. The higher layers are calculated by", "cite_spans": [], "ref_spans": []}, {"section": "2,3", "text": "where f (x) is a non-linear differentiable function, which here is taken as the Fermi function, f (x) = (1 + exp(\u2212x)) \u22121 . As can be seen from the summation indices in Eq. (3), both layers are shifted according to the output neuron.", "cite_spans": [], "ref_spans": []}, {"section": "2,3", "text": "After generating the output, one should update the weights W (l,l+1) according to the discrepancy between the output e S A (L A )) 2 /L, the goal of the deep learning algorithm is to minimize q by adjusting the weights.", "cite_spans": [], "ref_spans": []}, {"section": "2,3", "text": "The backpropagation algorithm is used. Essentially a partial differentiation of q as a function of each weight is performed, and the weights are updated accordingly. Specifically,", "cite_spans": [], "ref_spans": []}, {"section": "2,3", "text": "and the weights are updated accordingly:", "cite_spans": [], "ref_spans": []}, {"section": "2,3", "text": "\u2206W is summed over all realizations in the learning set and for different locations of the relevant weight W in the network. After completing the sweep, one updates the weights. The procedure continues until the desired accuracy q is obtained or until a preset number of training steps is reached. As a test of the ability of the network to predict the entanglement entropy for realizations on which it was not trained, q is calculated also for a set of different realizations of disorder, but no update of W is performed for those realizations. In Fig. 3 , the error, q, in the computed entanglement entropy as a function of the number of training steps is shown for the test set (realizations not included in the training). The value of the number variance, \u03b4 2 N A , is used in order to generate the entanglement entropy S A (L A ) as an output. The network show an initial plateau in q, followed by a decrease of q, i.e., the network has \"learned\" to produce a better correspondence between the observable and S A (L A ). It is interesting to note that there is an initial short period (around 10 3 training steps) where a steep improvement in the error occurs, i.e., a period of accelerated learning. This period is followed by periods of slower decrease sometimes punctuated by additional accelerated learning periods. Examining closely a typical realization of disorder from the test set (Fig. 4) , for the number variance as an input, the superiority of the results obtained by the CNN compared to a simple assumption", "cite_spans": [], "ref_spans": [{"start": 548, "end": 554, "text": "Fig. 3", "ref_id": "FIGREF2"}, {"start": 1394, "end": 1402, "text": "(Fig. 4)", "ref_id": "FIGREF3"}]}, {"section": "2,3", "text": "It is very impressive that CNN can identify regions with enhanced even-odd fluctuations in \u03b4 2 N A (L A ) and regions with more moderate fluctuations and respond accordingly.", "cite_spans": [], "ref_spans": []}, {"section": "2,3", "text": "Nevertheless, a questions remains: If the CNN works so well (as is evident from Fig. 4) what is the factor limiting the q value? The answer lies in some rare regions appearing in a few realizations of disorder for which the network fails to reproduce the EE. Such a rare region is presented in Fig. 5 . One can see that the CNN results fits quite well the value of S A anywhere except for 150 < L A < 250. Such behavior has been seen for about five samples out of the 200 in the test set. In all cases, the regions for which network fails are regions with anomalously high values of S A , in the ballpark of the values expected for a clean system. Such rare regions, which exhibit metal-like behavior within an insulating phase, have been identified in a previous study [47] . These \"microemulsion\" metallic regions may be connected to the rare thermalizing inclusions postulated to drive the Griffiths phase close to the many-body localization transition [52, 53] , to phase separation in two-dimensional systems [54] , and to rare occurrences of enhancement of the per- sistent current in disordered interacting systems [55] .", "cite_spans": [{"start": 770, "end": 774, "text": "[47]", "ref_id": "BIBREF46"}, {"start": 956, "end": 960, "text": "[52,", "ref_id": "BIBREF51"}, {"start": 961, "end": 964, "text": "53]", "ref_id": "BIBREF52"}, {"start": 1014, "end": 1018, "text": "[54]", "ref_id": "BIBREF53"}, {"start": 1122, "end": 1126, "text": "[55]", "ref_id": "BIBREF55"}], "ref_spans": [{"start": 80, "end": 87, "text": "Fig. 4)", "ref_id": "FIGREF3"}, {"start": 294, "end": 300, "text": "Fig. 5", "ref_id": "FIGREF4"}]}, {"section": "2,3", "text": "The fact that the CNN network learns almost perfectly to calculate S A from \u03b4 2 N A in the insulating phase and fails for the metallic like microemulsion is very interesting, and may lead one to argue that during the training the CNN has \"learned\" the features of the insulating phase. On the other hand, it can not infer the entanglement entropy of regions governed by different physics, i.e., the rare metallic regions. Thus, we have a computational procedure to calculate the entanglement entropy from the number variance which was created by supervised learning of a deep CNN, which seems to capture the physics of the majority phase of the system for the given parameters, but can not reproduce the entanglement for the rare regions belonging to a different phase.", "cite_spans": [], "ref_spans": []}, {"section": "2,3", "text": "Nonetheless, one remains with the problem that one must supply a training set for which both the observable and the entanglement entropy is known. For numerical studies where a direct calculation of the entanglement entropy might be computational expensive, but still doable, training such a network may show clear advantages. Success in extracting the entanglement from an observable for a numerical model also provides motivation to try to develop a theory connecting these quantities and may furnish clues towards its structure.", "cite_spans": [], "ref_spans": []}, {"section": "2,3", "text": "The question remains of how to train a system when the entanglement entropy is not known. One solution recently proposed is to try to extract the wavefunction out of the measurement of an observable(s), and use the wavefunction to extract the EE [56] . This is a promising method, but at the moment limited to small systems (of order of 20 sites). A different strategy for extracting the entanglement is to train the CNN on a set corresponding to a system for which it is easier to obtain the entanglement and then apply it to the system we are interested in. As an example we tried training the CNN on a set of 300 samples for which W = 0.7 and U = 0 (non-interacting), and then test them on the 200 samples of the previous test set of the interacting system (w = 0.7,U = 2.4). Since interactions here do not change the phase of the system (it remains an Anderson insulator), this might be expected to work. Nevertheless, using network C, although giving a better fit to the S A than the proportionality to \u03b4 2 N A , leaves much to be desired. Inserting an additional processing layer (see supplementary material, network D), which actually worsens somewhat the fit to a test set with the same parameters improves the fit to the interacting case. Network D results for the error are shown in Fig. 3 , while the fit for the same realization which exhibits the rare region is shown on the bottom part of Fig. 5 . For network D over training appears after \u223c 310 4 training steps. Thus, if the system can be reasonably represented by a numerically solvable model which can capture its main physical features, a situation common for cold-atom and for some solid-state systems, one could train the CNN using the calculation of the observable and entanglement entropy and then apply the network to the experimentally measured observable in order to extract the entanglement measure.", "cite_spans": [{"start": 246, "end": 250, "text": "[56]", "ref_id": "BIBREF56"}], "ref_spans": [{"start": 1293, "end": 1299, "text": "Fig. 3", "ref_id": "FIGREF2"}, {"start": 1403, "end": 1409, "text": "Fig. 5", "ref_id": "FIGREF4"}]}, {"section": "2,3", "text": "In conclusion, here it was shown that by using supervised machine learning it is possible to extract the entanglement between two regions of a disordered interacting many-particle system, a quantity which is very difficult to measure directly, by measuring more accessible observables. By training a neural network on several hundred realizations of disorder for which the entanglement as well as other observables are computed, it is then possible to apply the network on a new realization, for which the network has not been trained, and predict accurately the entanglement. It would be very useful to expand this method to higher dimensions.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Entanglement in many-body systems", "authors": [{"first": "L", "middle": [], "last": "Amico", "suffix": ""}, {"first": "R", "middle": [], "last": "Fazio", "suffix": ""}, {"first": "A", "middle": [], "last": "Osterloh", "suffix": ""}, {"first": "A", "middle": [], "last": "Vedral", "suffix": ""}], "year": 2008, "venue": "Rev. Mod. 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These quantities show strong non-monotonic dependence on LA, but nevertheless, there is a strong correspondence between them.", "type": "figure"}, "FIGREF2": {"text": "FIG. 3: The development of the error in the computed entanglement entropy q as functions of the number of training steps, measured for an ensemble of 200 realizations not included in the training set (test set), for the number variance, \u03b4 2 NA as an input. Two different cases are shown: (black) A training set of 500 realizations with the same interaction parameter (U = 2.4, network C); (cyan) A training set of 300 non-interacting realizations (U = 0, network D).", "type": "figure"}, "FIGREF3": {"text": "FIG. 4: The correspondence between the value of the entanglement entropy calculated directly by DMRG and by the deep CNN for a typical realization in the test set. The simplest assumption (SA(LA) \u221d \u03b4 2 NA(LA)) is indicated by the red curve. It is clear that the CNN gives an almost perfect fit. Left inset: Zoom into an area with strong even-odd fluctuations. Right inset: A region with weaker even-odd fluctuations.", "type": "figure"}, "FIGREF4": {"text": "FIG. 5: (Top) The correspondence between the value of the entanglement entropy calculated directly by DMRG (black) and by CNN (cyan) for a rare realization in the test set. The variance is indicated in green. It can be seen that even for this rare realization the network does a decent job except for the region between sites 150 and 250. (Bottom) The same realization where the CNN was trained on a non-interacting (U = 0) training set. Although the overall fit is not as good as in the case above, it is surprisingly decent.", "type": "figure"}}}
{"paper_id": "118861293", "_pdf_hash": "ffed2c9f60a6f4eb2244f9f78287cbc048e9df45", "abstract": [{"section": "Abstract", "text": "The MACHO Project generated two-colour photometric lightcurves for 73 million stars in the LMC, SMC, and the Galactic bulge during its 8 years of observing. This photometry, along with all images from the over 100 thousand observations from which it was derived, and an associated catalogue of 21 thousand LMC variable stars, is now available via webservices which comply with standards defined by the International Virtual Observatory Alliance (IVOA).", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "The MACHO Project (Alcock et al. 2000) had as its principal goal the detection of gravitational microlensing in the LMC, the SMC and the Galactic bulge. The 50\" Great Melbourne Telescope at Mt. Stromlo Observatory in Australia collected the observations 1 Supercomputer Facility, Australian National University, Canberra, ACT 2600, Australia.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Email: Jon.Smillie@anu.edu.au via a CCD mosaic camera comprising 8 2k x 2k chips generating images in two passbands simultaneously. In excess of 100 thousand observations were taken between 1992 and 2000. Approximately 8TB of raw images resulted, from which photometric lightcurves were constructed for approximately 73 million stars. Subsequently, a catalogue of 21 thousand variable stars in the LMC was distilled from these lightcurves.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Since its formation in June 2002, the International Virtual Observatory Alliance (IVOA) has published a range of data and service standards intended to facilitate the construction of an integrated international virtual observatory. These standards define services such as ConeSearch and Simple Image Access (SIA), which enable a data set to be searched based on user-defined sky regions, and VOTable, which is a data exchange format intended to facilitate the interoperation of disparate astronomical data sets and compatible tools.", "cite_spans": [], "ref_spans": []}, {"section": "IVOA Compliant MACHO Services", "text": "Recent work at the Australian National University Supercomputer Facility (ANUSF) has resulted in the implementation of a range of IVOA compliant services which enable users to search and retrieve data from the full MACHO data set. The complete MACHO image metadata can be searched via both ConeSearch and SIA protocols, and the corresponding images can be downloaded directly to the user's desktop. Similarly, the macho star catalogue, including entries for 21 thousand LMC variable stars, can be searched via ConeSearch, and any of the lightcurves for the 73 million stars in the catalogue can be downloaded.", "cite_spans": [], "ref_spans": []}, {"section": "IVOA Compliant MACHO Services", "text": "Services defined by IVOA protocols are in general intended to be accessed via compatible software tools, rather than by direct browser interaction. However simple form-based webpages have also been implemented which allow users to directly query the MACHO services. Alternatively, a range of VO-compliant software tools are now available, such as TOPCAT (TOPCAT), which are able to directly access IVOA compliant data services, such as those discussed here. ", "cite_spans": [], "ref_spans": []}, {"section": "MACHO Service URLs", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Available Documentation", "text": "Some documentation for these services, and their usage, has been provided. This includes a user guide (https://dc2.apac.edu.au/trac/macho/browser/trunk/macho/doc/user_guide.txt) and a guide regarding how to perform some typical operations using these services (https://dc2.apac.edu.au/trac/macho/browser/trunk/macho/doc/how_to.txt).", "cite_spans": [], "ref_spans": []}, {"section": "Service Compliance", "text": "At the time of writing, the ConeSearch services described here comply with IVOA Searching these results by the centre code \"ANU\" will yield the validation results for the services discussed here.", "cite_spans": [], "ref_spans": []}, {"section": "Service Registration", "text": "All services have been registered with the NVO service registry (http://nvo.stsci.edu/vor10/), and will thus be available to all tools which utilize this registry. A search on this registry using the terms \"macho anusf\" will yield the registry entries for the services described here.", "cite_spans": [], "ref_spans": []}, {"section": "Compatibility with Earlier Services", "text": "The services described here are intended to functionally replace the services described in Allsman et al. (Allsman et al. 2001) which have been in constant use now for approximately eight years.", "cite_spans": [], "ref_spans": []}], "bib_entries": {}, "ref_entries": {"TABREF0": {"text": "The IVOA compliant MACHO services can be accessed via the server at http://macho.anu.edu.au. Four services are available from this page, namely observation metadata search via ConeSearch and SIA protocols (http://macho.anu.edu.au/image), observation image download (http://macho.anu.edu.au/image_download), star catalogueThe underlying IVOA compliant services are accessed directly via the following URLs. The image metadata catalogue can be searched via ConeSearch at http://macho.anu.edu.au/image/conesearch, or SIA at http://macho.anu.edu.au/image/sia. The VOTable results returned by these two services include URLs which enable thehttp://macho.anu.edu.au/photometry/conesearch. It is these URLs to which compliant software tools should be directed, rather than the URLs accessing search forms described above. Interaction with these services is as per the associated protocol definition.", "type": "table"}, "TABREF1": {"text": "All services have been validated with the US National Virtual Observatory (NVO) validation services at http://nvo.ncsa.uiuc.edu/dalvalidate/csvalidate.html (ConeSearch) and http://nvo.ncsa.uiuc.edu/dalvalidate/siavalidate.html (SIA), and found to comply fully with the above protocol standards. They have also been validated by the NVO automatic validation service, whose results are available at http://heasarc.gsfc.nasa.gov/vo/validation/.", "type": "table"}}}
{"paper_id": "118862592", "_pdf_hash": "b8d880abfaf314e828ce5fc508b32983316b4145", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Multiplicity as a function of primary mass", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF1": {"title": "Comparison of separation distributions", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF3": {"title": "Companions and the unexplained X-ray detection of B6 -A7 stars 107", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF4": {"title": "X-ray emission of Main Sequence stars", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF5": {"title": "108 7.2.2 High-resolution imaging companion searches", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF11": {"title": "Comparison of measured and expected X-ray luminosities", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF13": {"title": "Orbital motion monitoring of A-type star multiples 136", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF19": {"title": "Continued study of A-type binaries", "authors": [], "year": "", "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "118862686", "_pdf_hash": "1fc795d702d419ed29fbba5007dea004d94a8b63", "abstract": [{"section": "Abstract", "text": "We consider a general stationary solution and derive the general laws for accretion of rotating perfect fluids. For non-degenerate and degenerate Fermi and Bose fluids we derive new effects that mimic the center-of-mass-energy effect of two colliding particle in the vicinity of horizons. Nondegenerate fluids see their chemical potential grow arbitrarily and ultra-relativistic Fermi fluids see their specific enthalpy and Fermi momentum grow arbitrarily too while the latter vanishes gradually for non-relativistic Fermi fluids. For degenerate Bose fluids two scenarios remain possible as the fluid approaches a horizon: a) The Bose-Einstein condensation ceases or b) the temperature drops gradually down to zero. The critical flow is also investigated.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Given a metric solution of spacetime, a geodesic motion is the process by which a massive or massless test particle \"falls\" freely. The fall motion may be bounded (circular motion or else) or unbounded (scattering motion). The free fall of the test particle does not disturb, affect, or modify the given geometry: No back reaction effects are taken into consideration. Moreover, no group motion is treated in geodesic motion. Back reaction effects are present in the calculation of gravitational self forces where the motion of the \"small\" body is still seen as geodesic in the perturbed metric.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Accretion is an advanced state of motion. It describes group motion with and without back reaction and it is generally non-geodesic. By group motion it is meant that the accreting matter is modeled by a fluid and that each fluid element encompasses a) a sufficiently large number of particles to be described statistically by an average pressure, average temperature, average particle number density, and average energy density; b) a sufficiently small number of particles compared to the whole system (accreting matter, atmosphere, etc). These conditions are easily met in astrophysics and atmospheric motion. The presence of a gradient of pressure, which is a sort of fluid group self force, renders the accretion motion non-geodesic.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "In accretion motion back reaction effects are taken into consideration in numerical and simulation analyses [1] [2] [3] . Full analytical treatments [4-8] drop back reaction effects for simplicity and cognitive treatments [9-15] may include emission effects and neglect back reaction too.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "All the above-mentioned treatments make common simplificative physical assumptions of symmetry concerning both the given background geometry and the fluid. They assume the background metric to remain stationary and time-independent during accretion [16] . The analysis remains valid for accretion time, larger than free-fall time, and much smaller than the ratio mass/(mass rate change) of the star.", "cite_spans": [{"start": 249, "end": 253, "text": "[16]", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "Abstract", "text": "In this work we will keep using the standard set of simplificative assumptions to describe the accretion of rotating perfect fluids onto rotating black holes with no back reaction or emission effects. In Sec. II we present the accretion model and in sec. III we derive the general equations for accretion of a perfect fluid onto a stationary rotating black hole. We keep using a general stationary metric throughout the paper. In Sec. IV we investigate the end-behavior of accretion as the fluid approaches horizons and other end-points. Sec. V is devoted to important applications concerning the accretion of non-degenerate as well as degenerate Fermi and Bose fluids. In Sec. VI we derive the conditions of a critical flow and the corresponding critical points. An appendix section has been added to complete the discussion of, and to derive some equations pertaining to, Sec. IV. We conclude in Sec. VII.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Consider a stationary rotating generic metric of the form", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "admitting two Killing vectors, one is timelike \u03be \u00b5 t = (1, 0, 0, 0) and the other is spacelike \u03be \u00b5 \u03c6 = (0, 0, 0, 1). The metric components g \u00b5\u03bd are functions of the radial and polar coordinates (r, \u03b8) and g t\u03c6 vanishes identically if rotation is suppressed. We do not assume any specific asymptotic end-behavior (asymptotic flatness, de Sitter, or anti-de Sitter behavior), for the analysis we intend to give in this work applies whatever the end-behavior of the black hole is.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "The metric may have an event horizon, a cosmological horizon, and possibly other horizons all denoted by r h . In any case we will be concerned with the regions of the three-space where the Killing vector \u03be \u00b5 t is timelike. These are the regions accessible to the fluid flow and to observers.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "We choose the signature (\u2212, +, +, +) for (1). In all our mathematical expressions we will keep using absolute values so that the formulas remain valid if the signature (+, \u2212, \u2212, \u2212) is adopted.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "Given a metric solution of spacetime, a geodesic motion is the process by which a massive or massless test particle \"falls\" freely. The fall motion may be bounded (circular motion or else) or unbounded (scattering motion). The free fall of the test particle does not disturb, affect, or modify the given geometry: No back reaction effects are taken into consideration. Moreover, no group motion is treated in geodesic motion. Back reaction effects are present in the calculation of gravitational self forces where the motion of the \"small\" body is still seen as geodesic in the perturbed metric.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Accretion is an advanced state of motion. It describes group motion with and without back reaction and it is generally non-geodesic. By group motion it is meant that the accreting matter is modeled by a fluid and that each fluid element encompasses a) a sufficiently large number of particles to be described statistically by an average pressure, average temperature, average particle number density, and average energy density; b) a sufficiently small number of particles compared to the whole system (accreting matter, atmosphere, etc). These conditions are easily met in astrophysics and atmospheric motion. The presence of a gradient of pressure, which is a sort of fluid group self force, renders the accretion motion non-geodesic.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "In accretion motion back reaction effects are taken into consideration in numerical and simulation analyses [1] [2] [3] . Full analytical treatments [4] [5] [6] [7] [8] drop back reaction effects for simplicity and cognitive treatments [9] [10] [11] [12] [13] [14] [15] may include emission effects and neglect back reaction too.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "All the above-mentioned treatments make common simplificative physical assumptions of symmetry concerning both the given background geometry and the fluid. They assume the background metric to remain stationary and time-independent during accretion [16] . The analysis remains valid for accretion time, larger than free-fall time, and much smaller than the ratio mass/(mass rate change) of the star.", "cite_spans": [{"start": 249, "end": 253, "text": "[16]", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "", "text": "In this work we will keep using the standard set of simplificative assumptions to describe the accretion of rotating perfect fluids onto rotating black holes with no back reaction or emission effects. In Sec. II we present the accretion model and in sec. III we derive the general equations for accretion of a perfect fluid onto a stationary rotating black hole. We keep using a general stationary metric throughout the paper. In Sec. IV we investigate the end-behavior of accretion as the fluid approaches horizons and other end-points. Sec. V is devoted to important applications concerning the accretion of non-degenerate as well as degenerate Fermi and Bose fluids. In Sec. VI we derive the conditions of a critical flow and the corresponding critical points. An appendix section has been added to complete the discussion of, and to derive some equations pertaining to, Sec. IV. We conclude in Sec. VII.", "cite_spans": [], "ref_spans": []}, {"section": "II. MODEL FOR ANALYTICAL ACCRETION", "text": "Consider a stationary rotating generic metric of the form", "cite_spans": [], "ref_spans": []}, {"section": "II. MODEL FOR ANALYTICAL ACCRETION", "text": "admitting two Killing vectors, one is timelike \u03be \u00b5 t = (1, 0, 0, 0) and the other is spacelike \u03be \u00b5 \u03c6 = (0, 0, 0, 1). The metric components g \u00b5\u03bd are functions of the radial and polar coordinates (r, \u03b8) and g t\u03c6 vanishes identically if rotation is suppressed. We do not assume any specific asymptotic end-behavior (asymptotic flatness, de Sitter, or anti-de Sitter behavior), for the analysis we intend to give in this work applies whatever the end-behavior of the black hole is.", "cite_spans": [], "ref_spans": []}, {"section": "II. MODEL FOR ANALYTICAL ACCRETION", "text": "The metric may have an event horizon, a cosmological horizon, and possibly other horizons all denoted by r h . In any case we will be concerned with the regions of the three-space where the Killing vector \u03be \u00b5 t is timelike. These are the regions accessible to the fluid flow and to observers.", "cite_spans": [], "ref_spans": []}, {"section": "II. MODEL FOR ANALYTICAL ACCRETION", "text": "We choose the signature (\u2212, +, +, +) for (1) . In all our mathematical expressions we will keep using absolute values so that the formulas remain valid if the signature (+, \u2212, \u2212, \u2212) is adopted.", "cite_spans": [], "ref_spans": []}, {"section": "A. Zero-angular-momentum observers", "text": "we bring the metric (1) to the following useful form", "cite_spans": [], "ref_spans": []}, {"section": "A. Zero-angular-momentum observers", "text": "One can always make it such that \u03c9 > 0 (for instance, by changing the positive direction of the z axis, which coincides with the axis of symmetry). However, the inequalities in (2) are supposed to hold in the regions of the three-space where the Killing vector \u03be \u00b5 t is timelike. It is straightforward to show that \u03c9 is the angular velocity of the zero-angular-momentum observers (ZAMOs) [17] . We choose a reference frame (e t , e r , e \u03b8 , e \u03c6 ) dual to the 1-forms defined in (3):", "cite_spans": [], "ref_spans": []}, {"section": "A. Zero-angular-momentum observers", "text": "The frame (e t , e r , e \u03b8 , e \u03c6 ) is given by", "cite_spans": [], "ref_spans": []}, {"section": "A. Zero-angular-momentum observers", "text": "Consider a ZAMO with four-velocity\u016b \u00b5 = e \u00b5 t (4). Relative to the\u016b \u00b5 frame, the four-velocity vector of the fluid,", "cite_spans": [], "ref_spans": []}, {"section": "A. Zero-angular-momentum observers", "text": "with \u03c4 being the proper time, expands as", "cite_spans": [], "ref_spans": []}, {"section": "A. Zero-angular-momentum observers", "text": "where we have set", "cite_spans": [], "ref_spans": []}, {"section": "A. Zero-angular-momentum observers", "text": "On comparing (5) and (6) and using (4) it is easy to establish that (v,\u00fb, u) are the three-dimensional linear components of the three-velocity of the fluid relative to th\u0113 u \u00b5 reference frame and V is the (relative) three-speed. The components (v,\u00fb, u) along with u t are given by", "cite_spans": [], "ref_spans": []}, {"section": "A. Zero-angular-momentum observers", "text": "where \u2126 \u2261 d\u03c6/dt is the differential angular velocity of the fluid.", "cite_spans": [], "ref_spans": []}, {"section": "B. The stress-energy tensor", "text": "From now on, we consider an accreting perfect fluid containing a single particle species.", "cite_spans": [], "ref_spans": []}, {"section": "B. The stress-energy tensor", "text": "In arbitrary coordinates, we consider a general observer (not necessarily co-moving with the fluid) with four-velocity U \u00b5 . We reserve the notation with large characters to physical and geometrical entities measured by, or pertaining to, this observer. Such a general observer can decompose the stress-energy tensor (SET) of the fluid in the form", "cite_spans": [], "ref_spans": []}, {"section": "B. The stress-energy tensor", "text": "where E = U \u00b5 U \u03bd T \u00b5\u03bd is the relativistic energy density as measured by the observer with four-velocity U \u00b5 , \u03a0 \u00b5\u03bd is the traceless anisotropic pressure tensor satisfying U \u00b5 U \u03bd \u03a0 \u00b5\u03bd = 0, and P = \u2212(g \u00b5\u03bd \u2212 U \u00b5 U \u03bd )T \u00b5\u03bd /3 is the average relativistic isotropic pressure as measured by this observer. In the rest frame of the perfect fluid we assume the latter to be isotropic; that is, the observer comoving with the fluid (U \u00b5 = u \u00b5 ) measures a vanishing anisotropic pressure tensor \u03c0 \u00b5\u03bd \u2261 0 and decomposes the SET of the fluid as", "cite_spans": [], "ref_spans": []}, {"section": "B. The stress-energy tensor", "text": "where \u01eb and p are the energy density and pressure in the rest frame of the perfect fluid. The assumption of being isotropic holds in the u \u00b5 frame only. It is easy to show that in the\u016b \u00b5 frame the transverse pressure of the fluid is not isotropic and splits into two components p \u03b8 = p \u03c6 defined as e \u00b5 \u03b8 e \u03bd \u03b8 T \u00b5\u03bd and e \u00b5 \u03c6 e \u03bd \u03c6 T \u00b5\u03bd , respectively. In the latter frame, the SET splits as", "cite_spans": [], "ref_spans": []}, {"section": "B. The stress-energy tensor", "text": "and, for instance,", "cite_spans": [], "ref_spans": []}, {"section": "B. The stress-energy tensor", "text": "It is clear from these relations and\u016b \u00b5\u016b\u03bd\u03c0 \u00b5\u03bd = 0 that \u03c0 \u00b5 \u00b5 = 0.", "cite_spans": [], "ref_spans": []}, {"section": "C. Assumptions and choice of a ZAMO", "text": "It is usually assumed that the accreting matter moves within a narrow planar disk that one chooses to be the \u03b8 = \u03c0/2 plane [18] . The rotation concentrates the streamlines in the equatorial plane [19] so that the thickness of the disk is assumed to be much smaller than its extent in the \u03b8 = \u03c0/2 plane, in that, we neglect any variation with respect to \u03b8:", "cite_spans": [{"start": 123, "end": 127, "text": "[18]", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "C. Assumptions and choice of a ZAMO", "text": "where F represents some physical or geometrical entity. The disk is supposed to surround the black hoke in such a way that one generally drops any dependence on the azimuthal angle \u03c6.", "cite_spans": [], "ref_spans": []}, {"section": "C. Assumptions and choice of a ZAMO", "text": "To perform analytical treatment of accretion, it is also commonly assumed that the fluid is in a steady state for most of the accretion time. Thus, the four-velocity vector and the thermodynamic properties of the fluid and related physical entities are considered to be independent of time.", "cite_spans": [], "ref_spans": []}, {"section": "C. Assumptions and choice of a ZAMO", "text": "These last two paragraphs ensure that the fluid motion is endowed with the same symmetry properties of the spacetime.", "cite_spans": [], "ref_spans": []}, {"section": "C. Assumptions and choice of a ZAMO", "text": "If the metric (1) describes a black hole, it has a number of horizons all denoted by r h where (in the \u03b8 = \u03c0/2 plane, r h is a constant)", "cite_spans": [], "ref_spans": []}, {"section": "C. Assumptions and choice of a ZAMO", "text": "that is, the metric is regular at r = r h . Since the absolute value of the determinant |g| is given by |g| = g rr g \u03b8\u03b8 D (3), D must go to zero as 1/g rr in the limit r \u2192 r h to ensure that |g| remains regular there", "cite_spans": [], "ref_spans": []}, {"section": "C. Assumptions and choice of a ZAMO", "text": "where we have introduced the notation F(r h ) \u2261 F h with F being some physical or geometrical entity. The metric (1) may admit a static limit, which is the 2-surface on which the timelike Killing vector \u03be \u00b5 t becomes null, corresponding to", "cite_spans": [], "ref_spans": []}, {"section": "C. Assumptions and choice of a ZAMO", "text": "Observers can remain static only for g tt < 0. 1 Whether such a static limit exists or not, a convenient reference frame for describing the fluid flow in the regions of the three-space where the Killing vector \u03be \u00b5 t is timelike is a ZAMO O \u2022 with four-velocity\u016b \u00b5 = e \u00b5 t (4) located at a constant radius r = const and a constant angle \u03b8 = \u03c0/2, as is always the case in accretion problem [16, p. 114 ]. Relative to this stationary observer O \u2022 ,\u00fb \u2261 0 and (v, u) are given by (8) where the rhs's are evaluated at \u03b8 = \u03c0/2.", "cite_spans": [], "ref_spans": []}, {"section": "III. GENERAL EQUATIONS FOR ACCRETION OF ROTATING FLUIDS", "text": "We define the current density by J \u00b5 = nu \u00b5 where n is the particle density, precisely the baryon number density in the fluid rest frame (recall that we consider an accreting perfect fluid containing a single particle species). From the particle conservation law, we have that the divergence of the current density is conserved", "cite_spans": [], "ref_spans": []}, {"section": "III. GENERAL EQUATIONS FOR ACCRETION OF ROTATING FLUIDS", "text": "where \u2207 \u00b5 is the covariant derivative. In the \u03b8 = \u03c0/2 plane, this reduces using (11) to \u2202 r ( |g|nu r ) = 0 or, upon integrating, to", "cite_spans": [], "ref_spans": []}, {"section": "III. GENERAL EQUATIONS FOR ACCRETION OF ROTATING FLUIDS", "text": "where we have used |g| = g rr g \u03b8\u03b8 D. It is understood that (n, u r ) are evaluated at \u03b8 = \u03c0/2. Here C 1 is a numerical constant of integration. Reversing (8) (or, equivalently, using the normalization condition u \u00b5 u \u00b5 = 1), we obtain", "cite_spans": [], "ref_spans": []}, {"section": "III. GENERAL EQUATIONS FOR ACCRETION OF ROTATING FLUIDS", "text": "A theorem of relativistic hydrodynamics [20] states that the scalar hu \u00b5 \u03be \u00b5 is conserved along the trajectories of the fluid,", "cite_spans": [{"start": 40, "end": 44, "text": "[20]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "III. GENERAL EQUATIONS FOR ACCRETION OF ROTATING FLUIDS", "text": "where \u03be \u00b5 is a Killing vector of spacetime (in the case of the metric (1),", "cite_spans": [], "ref_spans": []}, {"section": "III. GENERAL EQUATIONS FOR ACCRETION OF ROTATING FLUIDS", "text": "and h is the specific enthalpy (enthalpy per particle) defined by", "cite_spans": [], "ref_spans": []}, {"section": "III. GENERAL EQUATIONS FOR ACCRETION OF ROTATING FLUIDS", "text": "This theorem stems from the fact that the fluid motion is endowed with the same symmetry properties of the spacetime (see assumptions made in the first two paragraphs of Sec. II C). Consider the timelike Killing vector \u03be \u00b5 t of the metric (1), Eq. (18) yields \u2202 r (hu t ) = 0 (where we have used (11) and u \u03b8 = 0 on the \u03b8 = \u03c0/2 plane).", "cite_spans": [], "ref_spans": []}, {"section": "this finally yields", "text": "where C 2 is a numerical constant of integration. On considering the spacelike Killing vector \u03be \u00b5 \u03c6 , we obtain", "cite_spans": [], "ref_spans": []}, {"section": "this finally yields", "text": "where C 3 is a numerical constant of integration. In Eqs. (20) and (21) it is understood that all the physical and geometrical entities are evaluated at \u03b8 = \u03c0/2.", "cite_spans": [], "ref_spans": []}, {"section": "this finally yields", "text": "The meaning of the constants (C 2 , C 3 ) is as follows. If accretion were a geodesic motion, we would have h = m, where m is the baryonic mass, and (C 2 , C 3 ) would reduce to (mu \u00b5 \u03be \u00b5 t , mu \u00b5 \u03be \u00b5 \u03c6 ) that are the usual energy and angular momentum conservation laws, respectively. The constants (hu \u00b5 \u03be \u00b5 t , hu \u00b5 \u03be \u00b5 \u03c6 ) are their generalizations to the case where the fluid is subject to acceleration, which takes place when the pressure throughout the fluid is not uniform.", "cite_spans": [], "ref_spans": []}, {"section": "this finally yields", "text": "Since the transverse three-velocity is subject to u 2 < 1 (8), this restricts the values of \u2126 by", "cite_spans": [], "ref_spans": []}, {"section": "this finally yields", "text": ". (22) It is easy to show that \u2126 \u2212 is greater than \u2212g tt /g t\u03c6 ensuring C 2 < 0 (20) for all 2 r. It is also easy to show that \u2126 \u2212 < 0, \u2126 + > 2\u03c9 > 0 outside the ergoregion, \u2126 \u2212 = 0, \u2126 + = 2\u03c9 on the boundary of the ergoregion, and", "cite_spans": [], "ref_spans": []}, {"section": "this finally yields", "text": "On combining (20) and (21) we obtain, setting", "cite_spans": [], "ref_spans": []}, {"section": "this finally yields", "text": "The value C 4 = 0 yields \u2126 = \u03c9 corresponding to the case where the fluid is only being dragged by the rotating solution. This results in u \u2261 0 (8) . We see that the fluid flow is characterized by three angular velocities: the one equals the angular velocity of the ZAMO's, \u03c9(r), corresponding to C 4 = 0 and the other two are \u2126 \u2212 (r) and \u2126 + (r) corresponding to the maximum value and minimum value of C 4 if r = r h , respectively. Note that the derivative of the rhs in (23) with respect to", "cite_spans": [], "ref_spans": []}, {"section": "this finally yields", "text": ", is negative for r = r h and vanishes for r = r h . The three angular velocities are equal on the horizons.", "cite_spans": [], "ref_spans": []}, {"section": "this finally yields", "text": "If the solution is static (nonrotating with \u03c9 \u2261 0), it is apparent from (23) that the angular velocity of the fluid elements is function of the ratio g tt /g \u03c6\u03c6", "cite_spans": [], "ref_spans": []}, {"section": "this finally yields", "text": "On inserting (17) into (16), (20) and (21) we obtain", "cite_spans": [], "ref_spans": []}, {"section": "this finally yields", "text": "where we have used another expression for D = \u2212|g \u03c6\u03c6 |(g tt + \u03c9g t\u03c6 ) and (8) . Notice that the case C 1 = 0 corresponds either to v \u2261 0 (circular flow) or to n \u2261 0 (no fluid). We drop this case from our analysis and focus on the case C 2 1 > 0.", "cite_spans": [], "ref_spans": []}, {"section": "IV. END-BEHAVIOR FLOW", "text": "In this section we consider the fluid flow in the vicinity of the horizons and the flow as the fluid extends to spatial infinity.", "cite_spans": [], "ref_spans": []}, {"section": "A. Flow in the vicinity of the horizons", "text": "In equations (20) and (21), u t is given by (17) and it diverges by (13) as the fluid approaches a horizon. One of the factors in each of Eq. (20) and Eq. (21) has to go to zero to keep the value of the lhs constant. For ordinary matter, h has a lower limit m, the only option is to have in (20) \u2126(r h ) = \u2212g tt (r h )/g t\u03c6 (r h ), which is by (2) and (13)", "cite_spans": [], "ref_spans": []}, {"section": "A. Flow in the vicinity of the horizons", "text": "This is the same equation derived from (21) . This results in u h = 0 (8) and by (7) in", "cite_spans": [], "ref_spans": []}, {"section": "A. Flow in the vicinity of the horizons", "text": "The fluid is doomed to rotate at ZAMO's angular velocity as it approaches a horizon. Particularly, if the black hole is static, the fluid reaches a horizon with a vanishing angular velocity. Based on our previous conclusions, D h = 0 and \u2126 h = \u03c9 h , it is easy to show that the fluid reaches, or emanates from, a horizon with a three-dimensional radial velocity |v h | = 0 (subsonic velocity on the horizons) or |v h | = 1 (luminal velocity on the horizons) [15] . In fact, since", "cite_spans": [], "ref_spans": []}, {"section": "A. Flow in the vicinity of the horizons", "text": ", which is the case we dropped from our analysis and we only considered the case C 1 > 0. In the former case, |v h | = 0, the particle density n h \u2192 \u221e. Note that this conclusion, |v h | = 0 or |v h | = 1, is solely based on the continuity equation (15) and the assumptions made in the first two paragraphs of Sec. II C. This conclusion applies to non-perfect fluids too provided we adopt the so-called Eckart frame or particle frame for defining the four-velocity vector of the fluid [20, 21] . In this frame, J \u00b5 and u \u00b5 are parallel and (15) is still valid.", "cite_spans": [{"start": 484, "end": 488, "text": "[20,", "ref_id": "BIBREF19"}, {"start": 489, "end": 492, "text": "21]", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "A. Flow in the vicinity of the horizons", "text": "The case |v h | = 1 is physically more interesting. The case |v h | = 0 has been discussed in the literature too [7, 13-15, 22, 23] . In Ref. [7] the cases with subsonic velocities at the horizon [22, 23] were described as unphysical and in Refs. [13] [14] [15] it has been shown that if v h \u2192 0 then the pressure increasingly diverges as the fluid approaches a horizon yielding a divergent gradient of pressure opposing the flow motion and pushing the fluid backward. There are no available empirical data to support such a conclusion nor are there data to refute it. In this work we too drop this case from our analysis and focus only on the case |v h | = 1. Now back to Eqs. (25-a) and (25-c). In the limit r \u2192 r h , we have respectively", "cite_spans": [], "ref_spans": []}, {"section": "A. Flow in the vicinity of the horizons", "text": "For most known nonextremal black holes D \u223c |r \u2212 r h | as r \u2192 r h . To include in the investigation other types of black holes, including phantom [24] [25] [26] and regular [27] [28] [29] black holes, we consider the case", "cite_spans": [{"start": 172, "end": 176, "text": "[27]", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "A. Flow in the vicinity of the horizons", "text": "where x is a measure of the horizon degeneracy. It is understood that r approaches r h from within the region of the three-space where the Killing vector \u03be \u00b5 t = (1, 0, 0, 0) is timelike.", "cite_spans": [], "ref_spans": []}, {"section": "A. Flow in the vicinity of the horizons", "text": "In the vicinity of a horizon we set", "cite_spans": [], "ref_spans": []}, {"section": "A. Flow in the vicinity of the horizons", "text": "with z \u2265 y to ensure that h 2 > 0 (29); if z = y we further restrict C v and C u by C v /C 2 u > 1 to have h 2 > 0. This yields", "cite_spans": [], "ref_spans": []}, {"section": "A. Flow in the vicinity of the horizons", "text": "where C v > 0, C u > 0, C n > 0, and C h > 0 are finite constant values (C h = h h if z = y and C v /C 2 u > 1). The third line in (31), corresponding to z > y, has been derived by first rewriting (29) as", "cite_spans": [], "ref_spans": []}, {"section": "A. Flow in the vicinity of the horizons", "text": "For z > y, the first term diverges in the limit r \u2192 r h , so we can drop 1 and have h \u221d (r\u2192r h ) \u221a 1 \u2212 v 2 /u yielding the third line in (31) . Using the law of motion [20, 37] ", "cite_spans": [{"start": 168, "end": 172, "text": "[20,", "ref_id": "BIBREF19"}, {"start": 173, "end": 176, "text": "37]", "ref_id": "BIBREF36"}], "ref_spans": []}, {"section": "A. Flow in the vicinity of the horizons", "text": "where a \u03bd \u2261 u \u00b5 \u2207 \u00b5 u \u03bd is the four-acceleration vector, we arrive at (see Appendix)", "cite_spans": [], "ref_spans": []}, {"section": "A. Flow in the vicinity of the horizons", "text": "Two physical cases emerge depending on the value of y \u2212 1 \u2212 (x + z)/2. For a reason that will become clear in Sec. V, we impose the \"physical\" constraint that the pressure has no logarithmic divergence as the fluid approaches a horizon", "cite_spans": [], "ref_spans": []}, {"section": "A. Flow in the vicinity of the horizons", "text": "where the upper sign yields a finite pressure and the lower sign a divergent pressure as r \u2192 r h . In both cases the pressure behaves generically as", "cite_spans": [], "ref_spans": []}, {"section": "A. Flow in the vicinity of the horizons", "text": "where C p and p h are constants. By a generic behavior we mean that the constraints (34) do not depend on the metric value on the horizons; they just depend on the parameters (x, y, z). In a non-generic behavior it would be possible, as shown in the last paragraph of the Appendix, to fix C p = 0 by imposing constraints relating (x, y, z) to the metric value on the horizons. In that case the pressure would behave as p \u2243", "cite_spans": [], "ref_spans": []}, {"section": "A. Flow in the vicinity of the horizons", "text": "(r\u2192r h ) p h +C p |r \u2212 r h | 1+y\u2212(x+z)/2 whereC p is a constant, provided y \u2212 (x + z)/2 = \u22121. To keep the discussion as generic as possible we drop this case from our consideration. Two physical cases emerge from the above discussion:", "cite_spans": [], "ref_spans": []}, {"section": "A. Flow in the vicinity of the horizons", "text": "1. Finite pressure in the vicinity of the horizons. This case with the upper sign in (34) yields, using the fact that z \u2265 y,", "cite_spans": [], "ref_spans": []}, {"section": "A. Flow in the vicinity of the horizons", "text": "This implies that n \u2192 0 (31) as r \u2192 r h . We distinguish two subcases:", "cite_spans": [], "ref_spans": []}, {"section": "A. Flow in the vicinity of the horizons", "text": "(a) Non-geodesic flow in the vicinity of the horizons -This corresponds to", "cite_spans": [], "ref_spans": []}, {"section": "A. Flow in the vicinity of the horizons", "text": "Since in this case the pressure gradient (33) is nonzero, the flow is non-geodesic in the vicinity of the horizons.", "cite_spans": [], "ref_spans": []}, {"section": "A. Flow in the vicinity of the horizons", "text": "(b) Geodesic flow in the vicinity of the horizonsThis corresponds to", "cite_spans": [], "ref_spans": []}, {"section": "A. Flow in the vicinity of the horizons", "text": "In this case \u2202 r p \u2192 0 as r \u2192 r h resulting in a geodesic flow in the vicinity of the horizons. Note that the pressure (35) falls to a constant value, as r \u2192 r h , in a way faster than in the previous subcase.", "cite_spans": [], "ref_spans": []}, {"section": "A. Flow in the vicinity of the horizons", "text": "2. Divergent pressure in the vicinity of the horizons. This case with the lower sign in (34) yields", "cite_spans": [], "ref_spans": []}, {"section": "A. Flow in the vicinity of the horizons", "text": "This, for instance, may be satisfied if we take z > y and x > y or z = y and x > y, in which cases the number density n diverges as r \u2192 r h .", "cite_spans": [], "ref_spans": []}, {"section": "B. Asymptotic Flow", "text": "If the fluid flow may extend to spatial infinity (this concerns solutions with no cosmological horizon), the flow is said to be global. ", "cite_spans": [], "ref_spans": []}, {"section": "B. Asymptotic Flow", "text": "On performing similar end-behavior evaluations on (25-b) we arrive at", "cite_spans": [], "ref_spans": []}, {"section": "B. Asymptotic Flow", "text": "In all cases, we have", "cite_spans": [], "ref_spans": []}, {"section": "V. APPLICATIONS: NON-DEGENERATE AND DEGENERATE GASES", "text": "What distinguishes a black hole from a star is the presence of horizons in the vicinity of which interesting physical phenomena may occur due to strong gravitational attraction. It is worth mentioning that the Hawking radiation occurs there. Another well instance and established fact concerns the efficiency of emission due to accreting matter onto a black hole that is few orders smaller than that due to accreting matter onto a neutron star [31] . These two instances show that the investigation of physical phenomena in the vicinity of horizons is of great importance.", "cite_spans": [{"start": 444, "end": 448, "text": "[31]", "ref_id": "BIBREF30"}], "ref_spans": []}, {"section": "V. APPLICATIONS: NON-DEGENERATE AND DEGENERATE GASES", "text": "In this section we focus more on accretion, as well as particle jets, in the vicinity of horizons. We will show that the accretion model we have developed in the previous sections applies to a variety of non-degenerate and degenerate gases. The applications mostly concern ultra-and non-relativistic flows (at least in the vicinity of the horizons) where the ansatz (31) 1 holds 3 .", "cite_spans": [], "ref_spans": []}, {"section": "V. APPLICATIONS: NON-DEGENERATE AND DEGENERATE GASES", "text": "The statistics of non-degenerate and degenerate gases result in different one-particle distribution functions [20, 30, 31] . Non-degenerate gases obey Maxwell-Boltzmann statistics and degenerate gases obey either Fermi-Dirac statistics, if they have half-integral spin, or Bose-Einstein statistics, if they have integral spin.", "cite_spans": [{"start": 110, "end": 114, "text": "[20,", "ref_id": "BIBREF19"}, {"start": 115, "end": 118, "text": "30,", "ref_id": "BIBREF29"}, {"start": 119, "end": 122, "text": "31]", "ref_id": "BIBREF30"}], "ref_spans": []}, {"section": "V. APPLICATIONS: NON-DEGENERATE AND DEGENERATE GASES", "text": "We are not interested in the equilibrium distribution function corresponding to each of the three cases mentioned above; rather, we are concerned with the expressions of the fields in equilibrium, which are the number and energy densities (n, \u01eb), enthalpy h and entropy s per particle, pressure p, and chemical potential \u00b5, and we seek to apply them to the regions adjacent to the horizons where the Killing vector \u03be", "cite_spans": [], "ref_spans": []}, {"section": "V. APPLICATIONS: NON-DEGENERATE AND DEGENERATE GASES", "text": "Applications of equilibrium distribution functions are well-known in the literature [32] and include application to white dwarf stars [33] . We intend to extend their realm to accretion onto black holes.", "cite_spans": [{"start": 84, "end": 88, "text": "[32]", "ref_id": "BIBREF31"}, {"start": 134, "end": 138, "text": "[33]", "ref_id": "BIBREF32"}], "ref_spans": []}, {"section": "V. APPLICATIONS: NON-DEGENERATE AND DEGENERATE GASES", "text": "It is according to the limiting values of the dimensionless parameter \u03b6 \u2261 mc 2 /k B T (coldness), where T is the temperature of the fluid and k B is the Boltzmann constant, that one defines the ultra-relativistic (\u03b6 \u226a 1) and non-relativistic (\u03b6 \u226b 1) cases. So, the ultra-relativistic limit corresponds generally to high temperatures and the non-relativistic limit corresponds generally to low temperatures. It has become customary to let the speed of light c appear explicitly in \u03b6 and the expressions of the fields of this section. As to the states of non-degeneracy (\u03b1 f \u226a 1) and degeneracy (\u03b1 f \u226b 1) of the fluid are defined by the limiting values of the fugacity \u03b1 f \u2261 \u00b5/k B T, which is a dimensionless parameter expressing the tendency of volatility [34] .", "cite_spans": [{"start": 755, "end": 759, "text": "[34]", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "V. APPLICATIONS: NON-DEGENERATE AND DEGENERATE GASES", "text": "A. Non-degenerate fluids: \u03b1 f \u226a 1", "cite_spans": [], "ref_spans": []}, {"section": "V. APPLICATIONS: NON-DEGENERATE AND DEGENERATE GASES", "text": "In terms of the modified Bessel function of second kind K \u03bd [35] , the expressions of (n, p, h, \u01eb) are given by (see, for instance, [20, 30, 31] )", "cite_spans": [{"start": 60, "end": 64, "text": "[35]", "ref_id": "BIBREF34"}, {"start": 132, "end": 136, "text": "[20,", "ref_id": "BIBREF19"}, {"start": 137, "end": 140, "text": "30,", "ref_id": "BIBREF29"}, {"start": 141, "end": 144, "text": "31]", "ref_id": "BIBREF30"}], "ref_spans": []}, {"section": "V. APPLICATIONS: NON-DEGENERATE AND DEGENERATE GASES", "text": "where h P is the Planck constant.", "cite_spans": [], "ref_spans": []}, {"section": "V. APPLICATIONS: NON-DEGENERATE AND DEGENERATE GASES", "text": "1. Ultra-relativistic limit: \u03b6 \u226a 1", "cite_spans": [], "ref_spans": []}, {"section": "V. APPLICATIONS: NON-DEGENERATE AND DEGENERATE GASES", "text": "The ultra-relativistic limit of h is to the leading terms", "cite_spans": [], "ref_spans": []}, {"section": "V. APPLICATIONS: NON-DEGENERATE AND DEGENERATE GASES", "text": "which is large and remains finite. This corresponds to the case z = y (31). Non-degenerate fluids are subject to \u03b1 f \u226a 1 resulting in e \u00b5/k B T \u226a 1 and n \u226a 1 (43). The pressure, proportional to n (43), goes to zero as n does. This corresponds to y > x (31) and p h = 0 (35) so that both p and n behave as |r \u2212 r h | (y\u2212x)/2 in the limit r \u2192 r h . Using the above expressions we obtain p \u2243 \u01eb/3, which implies that \u01eb \u2192 0 as r \u2192 r h ; the energy per particle, however, does not go to zero as r \u2192 r h and it is given by \u01eb/n \u2243 3k B T.", "cite_spans": [], "ref_spans": []}, {"section": "V. APPLICATIONS: NON-DEGENERATE AND DEGENERATE GASES", "text": "2. Non-relativistic limit: \u03b6 \u226b 1", "cite_spans": [], "ref_spans": []}, {"section": "V. APPLICATIONS: NON-DEGENERATE AND DEGENERATE GASES", "text": "In this limit we have", "cite_spans": [], "ref_spans": []}, {"section": "V. APPLICATIONS: NON-DEGENERATE AND DEGENERATE GASES", "text": "and this again yields z = y, h h = mc 2 , y > x (31) and p h = 0 (35) so that both p and n behave as |r \u2212 r h | (y\u2212x)/2 in the limit r \u2192 r h . We have thus shown that ultra-relativistic, as well as non-relativistic, non-degenerate fluids reach horizons in a state of a very dilute matter and vanishing pressure and energy density as measured by a local Lorentz rest frame that moves with the fluid velocity. Equation (43) shows that the chemical potential diverges logarithmically as r \u2192 r h . This effect mimics that of the centerof-mass-energy (CME) of two colliding particles in the vicinity of a horizon by which the CME attains an arbitrarily large value [36] . This may signal the necessity of introducing quantum effects in the vicinity of the horizons.", "cite_spans": [], "ref_spans": []}, {"section": "V. APPLICATIONS: NON-DEGENERATE AND DEGENERATE GASES", "text": "Recall that the chemical potential measures the change in the internal energy (the energy in the fluid's rest frame) as one particle is added to the system. Since the chemical potential becomes arbitrarily large and negative as the fluid approaches a horizon, the addition of one particle results in an arbitrarily large decrease in the internal energy. Conversely the extraction of one particle would require an increasingly large amount of energy as the fluid approaches a horizon. Thus, the black hole ensures cohesion and stability of the accreting matter.", "cite_spans": [], "ref_spans": []}, {"section": "B. Completely degenerate Fermi fluids", "text": "The \"exact\" expressions of (n, p, \u01eb) for the FermiDirac fluids, as for the Bose-Einstein fluids, are available in the literature (see, for instance, [20, 30, 31, 34] ). We content here to give only their ultra-and non-relativistic limits.", "cite_spans": [{"start": 149, "end": 153, "text": "[20,", "ref_id": "BIBREF19"}, {"start": 154, "end": 157, "text": "30,", "ref_id": "BIBREF29"}, {"start": 158, "end": 161, "text": "31,", "ref_id": "BIBREF30"}, {"start": 162, "end": 165, "text": "34]", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "Ultra-relativistic limit: p F \u226b mc", "text": "Fermi fluids are characterized by the presence of a limiting momentum value called Fermi momentum p F all the quantum states with | p| < p F are filled by fermions and the states with | p| > p F are empty. Since the fields do not depend (explicitly) on the temperature the coldness parameter \u03b6 is no longer convenient for discussing the limiting ultra-and non-relativistic cases. These two limits correspond to p F \u226b mc and p F \u226a mc, respectively.", "cite_spans": [], "ref_spans": []}, {"section": "Ultra-relativistic limit: p F \u226b mc", "text": "Rather, the fields (\u01eb, p, h) depend only on n. To the leading term in n, which is supposed to be large enough to allow for series expansions in powers of 1/n, the expressions of (\u01eb, p) read", "cite_spans": [], "ref_spans": []}, {"section": "Ultra-relativistic limit: p F \u226b mc", "text": "from which we derive", "cite_spans": [], "ref_spans": []}, {"section": "Ultra-relativistic limit: p F \u226b mc", "text": "This corresponds to the case", "cite_spans": [], "ref_spans": []}, {"section": "Ultra-relativistic limit: p F \u226b mc", "text": "where the pressure (39), the number density and enthalpy per particle (31) all attain arbitrarily large values in the vicinity of the horizons. The Fermi momentum p 3 F = 3h 3 P n/(4\u03c0g s ) also attains an arbitrarily large value. This effect mimics the classical CME effect and may be ruled out, as well as the CME effect, by the introduction of quantum corrections.", "cite_spans": [], "ref_spans": []}, {"section": "Ultra-relativistic limit: p F \u226b mc", "text": "From (31) and the first equation in (48) we derive", "cite_spans": [], "ref_spans": []}, {"section": "Ultra-relativistic limit: p F \u226b mc", "text": "Since z > y, this implies x > z. Thus, as the flow of the ultra-relativistic Fermi fluid approaches a horizon, the parameters (y, z) adjust their values to remain smaller than x (x > z > y) while subject to the constraint (50).", "cite_spans": [], "ref_spans": []}, {"section": "Non-relativistic limit: p F \u226a mc", "text": "In this limit n is supposed to be small enough to allow for series expansions in powers of n. To the leading order of approximation the expression of (\u01eb, p) read The progressive vanishing of the Fermi momentum as r \u2192 r h has the following physical interpretation. All the quantum states filled with fermions, having | p| < p F , form progressively a continuum of energy as r \u2192 r h , that is, as p F \u2192 0. The momentum particle density 4 dN/dp 1 dp 2 dp 3 \u221d p Here again we give only the limiting expressions of (n, p, \u01eb) for the Bose-Einstein fluids (see, for instance, [20, 30, 31, 34] for more details).", "cite_spans": [{"start": 569, "end": 573, "text": "[20,", "ref_id": "BIBREF19"}, {"start": 574, "end": 577, "text": "30,", "ref_id": "BIBREF29"}, {"start": 578, "end": 581, "text": "31,", "ref_id": "BIBREF30"}, {"start": 582, "end": 585, "text": "34]", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "Non-relativistic limit: p F \u226a mc", "text": "The Bose-Einstein condensation occurs for the ultraand non-relativistic limits at the well-known temperatures", "cite_spans": [], "ref_spans": []}, {"section": "Non-relativistic limit: p F \u226a mc", "text": "respectively. Here \u03b6 R (i) = \u2211 \u221e j=1 j \u2212i is the Riemann zeta function. Condensation means that some fraction n cond of n occupies the level with zero energy. This fraction v 2 c = \u03b1 2 . Thus, the conclusions and results of the static case do not generalize to the rotating configurations. The three-speed V 2 c is also different from \u03b1 2 and reduces to it in the static limit (\u03c9 \u2261 0) only. This is evaluated from (8) and (65) ", "cite_spans": [], "ref_spans": []}, {"section": "Non-relativistic limit: p F \u226a mc", "text": "This equation generalizes Eq. (13) of Ref. [15] to the case of rotating solutions and rotating fluids. Equations (65) and (68) cannot be handled further unless a stationary metric and an equation-of-state for the fluid are prescribed. This generally leads to a numerical analysis [13] [14] [15] to solve the non-linear system of equations (65) and (68) for the unknowns r c and v c . We postpone this task to a subsequent work.", "cite_spans": [], "ref_spans": []}, {"section": "VII. CONCLUSION", "text": "The accretion of non-degenerate and degenerate Fermi and Bose fluids have been modeled by the flow of a perfect fluid sharing with the stationary background metric the same symmetric properties. Conservation laws impose restrictions on the fluid flow at the endpoints of the accessible region(s) to the fluid flow.", "cite_spans": [], "ref_spans": []}, {"section": "VII. CONCLUSION", "text": "We have shown that the sort of \"critical exponents\" (x, y, z) determine the behavior of the thermodynamic fields of the fluid as it approaches a horizon from within the region of the three-space where the Killing vector \u03be \u00b5 t = (1, 0, 0, 0) is timelike. This behavior is characterized by the presence of divergencies in the expressions of some fields along with the nullity of some other fields.", "cite_spans": [], "ref_spans": []}, {"section": "VII. CONCLUSION", "text": "With the exception of the ultra-relativistic limit of the completely degenerate Fermi fluids, the presence of a power-law divergence in the expression of the pressure (39) seems not consistent with the other statistical models where the pressure either converges to a constant value or vanishes in the limit r \u2192 r h .", "cite_spans": [], "ref_spans": []}, {"section": "VII. CONCLUSION", "text": "Critical flow in this model occurs for stationary black holes if initially the fluid rotates retrograde and for static black holes if initially the fluid is not rotating. At the critical point(s) the sound speed is larger than the radial three-velocity and smaller that the three-speed of the fluid element there.", "cite_spans": [], "ref_spans": []}, {"section": "VII. CONCLUSION", "text": "The results apply to jets of particles too. We have not assumed any theory of relativity, that is, we have just considered a general stationary metric with two Killing vectors. Hence the results apply to all black holes of all theories of gravitation, provided their metrics are endowed with the same properties of the general stationary metric we considered in this work.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF15": {"title": "Accretion discs, jets and high energy phenomena in astrophysics", "authors": [{"first": "V", "middle": [], "last": "Beskin", "suffix": ""}, {"first": "G", "middle": [], "last": "Henri", "suffix": ""}, {"first": "F", "middle": [], "last": "Menard", "suffix": ""}, {"first": "G", "middle": [], "last": "Pelletier", "suffix": ""}, {"first": "J", "middle": [], "last": "", "suffix": ""}], "year": 2003, "venue": "Les Houches Session LXXVIII, Series", "link": null}, "BIBREF17": {"title": "Accretion Power in Astrophysics", "authors": [{"first": "J", "middle": [], "last": "Frank", "suffix": ""}, {"first": "A", "middle": [], "last": "King", "suffix": ""}, {"first": "D", "middle": [], "last": "Raine", "suffix": ""}], "year": 2002, "venue": "", "link": "117737951"}, "BIBREF19": {"title": "Relativistic Hydrodynamics", "authors": [{"first": "L", "middle": [], "last": "Rezzolla", "suffix": ""}, {"first": "O", "middle": [], "last": "Zanotti", "suffix": ""}], "year": 2013, "venue": "", "link": null}, "BIBREF20": {"title": "Relativistic Cosmology", "authors": [{"first": "G", "middle": ["F R"], "last": "Ellis", "suffix": ""}, {"first": "R", "middle": [], "last": "Maartens", "suffix": ""}, {"first": "M", "middle": ["A H"], "last": "Maccallum", "suffix": ""}], "year": 2012, "venue": "", "link": null}, "BIBREF26": {"title": "Non-singular general relativistic gravitational collapse", "authors": [{"first": "J", "middle": ["M"], "last": "Bardeen", "suffix": ""}], "year": 1968, "venue": "Proceedings of the 5th International Conference on Gravitation and the Theory of Relativity", "link": "118932717"}, "BIBREF29": {"title": "Rational Extended Thermodynamics", "authors": [{"first": "I", "middle": [], "last": "M\u00fcller", "suffix": ""}, {"first": "T", "middle": [], "last": "Ruggeri", "suffix": ""}], "year": 1998, "venue": "", "link": "117099863"}, "BIBREF30": {"title": "The Relativistic Boltzmann Equation", "authors": [{"first": "C", "middle": [], "last": "Cercignani", "suffix": ""}, {"first": "G", "middle": ["M"], "last": "Kremer", "suffix": ""}], "year": 2002, "venue": "Theory and Applications", "link": null}, "BIBREF31": {"title": "The Boltzmann equation and its applications", "authors": [{"first": "C", "middle": [], "last": "Cercignani", "suffix": ""}], "year": 1988, "venue": "", "link": "125973037"}, "BIBREF32": {"title": "An introduction to the study of stellar structure", "authors": [{"first": "S", "middle": [], "last": "Chandrasekhar", "suffix": ""}], "year": 1958, "venue": "", "link": null}, "BIBREF33": {"title": "Statistical Mechanics", "authors": [{"first": "K", "middle": [], "last": "Huang", "suffix": ""}], "year": 1987, "venue": "", "link": null}, "BIBREF34": {"title": "Handbook of Mathematical Functions: with Formulas, Graphs, and Mathematical Tables", "authors": [], "year": 1972, "venue": "", "link": "124717216"}, "BIBREF36": {"title": "Gravitation", "authors": [{"first": "C", "middle": ["W"], "last": "Misner", "suffix": ""}, {"first": "K", "middle": ["S"], "last": "Thorne", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Wheeler", "suffix": ""}], "year": 1973, "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "For stars \u03c9 \u223c 1/r 3 as r \u2192 \u221e. If the metric (1) is asymptotically flat (as. flat), g tt \u223c 1 and g \u03c6\u03c6 \u223c r 2 as r \u2192 \u221e, and if the flow is global, then by (23) we have \u2126 \u223c 1/r 2 as r \u2192 \u221e. This applies to \u2126 stat (24) too. If the metric (1) is asymptotically anti-de Sitter (as. adS), g tt \u223c r 2 and g \u03c6\u03c6 \u223c r 2 as r \u2192 \u221e, and if the fluid flow is global, we have that \u2126 \u223c const and \u2126 stat \u223c const as r \u2192 \u221e. Using this in (25-a) along with g t\u03c6 \u223c 1/r, D \u223c r 2 (as. flat), D \u223c r 4 (as. adS) (2), and u \u223c 1/r 2 (as. flat), u \u223c 1/r 4 (as. adS) (8) as r \u2192 \u221e, we obtain", "type": "figure"}, "FIGREF1": {"text": "(p i ) 2 = | p| and N being the fermions number, assumes an arbitrarily large value in the vicinity of the horizons. C. Degenerate Bose fluids: \u03b1 f \u226b 1", "type": "figure"}, "TABREF0": {"text": "This corresponds to the case z = y, y > x, h h = mc 2 (31), and p h = 0 (35). We see that the non-relativistic Fermi fluid behaves in the vicinity of the horizons as does the non-relativistic, non-degenerate fluid behave with van- ishing pressure and energy density. Moreover, the Fermi momentum, p 3 F = 3h 3 P n/(4\u03c0g s ), attains an arbitrarily small value.", "type": "table"}, "TABREF1": {"text": "as 1 > VThe unconstrained expression of H r is sizeable. How- ever, using the already determined extreme values (64) and (66) to eliminate (\u2126, V 2 ), this reduces after some al- gebra to H r = + h 2 g tt 1 \u2212 \u03b1 2 [(ln |g tt |) r \u2212 \u03b1 2 (ln |g \u03b8\u03b8 |D) r ](ln |g \u03b8\u03b8 |D) r r=r c .", "type": "table"}}}
{"paper_id": "118862984", "_pdf_hash": "9a848622d7827635caa98d73e622a987e4a589e3", "abstract": [{"section": "Abstract", "text": "Integrated Information Theory (IIT) has emerged as one of the leading research lines in computational neuroscience to provide a mechanistic and mathematically well-defined description of the neural correlates of consciousness. Integrated Information (\u03a6) quantifies how much the integrated cause/effect structure of the global neural network fails to be accounted for by any partitioned version of it. The holistic IIT approach is in principle applicable to any information-processing dynamical network regardless of its interpretation in the context of consciousness. In this paper we take the first steps towards a formulation of a general and consistent version of IIT for interacting networks of quantum systems. A variety of different phases, from the dis-integrated (\u03a6 = 0) to the holistic one (extensive log \u03a6), can be identified and their cross-overs studied.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Introduction.-Over the last decade Integrated Information Theory (IIT), developed by G. Tononi and collaborators, has emerged as one of the leading research lines in computational neuroscience. IIT aims at providing a mechanistic and mathematically well-defined description of the neural correlates of consciousness [1][2][3][4].", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "The idea is to quantify the amount of cause/effect power in the neural network that is holistic in the sense that goes beyond and above the sum of its parts. This is done in a bottom-up approach by quantifying how arbitrary parts of the network (\"mechanisms\"), in a given state, influence the future and constrain the past of other arbitrary parts (\"purviews\"), in a way that is irreducible to the separate (and independent) actions of parts of the mechanism over parts of the purview. Iterated at the global network level this process gives rise to a so-called conceptual structure, comprising a family of mechanisms and purviews, where the latter represent the integrated core causes/effects of the former [2]. A suitable measure of the distance between this conceptual structure with the closest one obtainable from a partitioned network (where the connections between the two subsystems are \"noised\") quantifies how much of the cause/effect structure of dynamical newtwork fails to be reducible to the sum of its parts. This minimal distance is the Integrated Information (\u03a6) of the network.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "In IIT it is then boldly postulated that the larger \u03a6, the higher is the degree of consciousness of the network in the given state. The irreducibility of the causal informationprocessing structure of the network measured by \u03a6 is independent of the specific \"wetware\" implementing the brain circuitry. It follows that the IIT approach to consciousness seems to unavoidably lead to panpsychist, and a rather controversial [5] view of the world [4].", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Importantly, besides (and irrespective of) the applications to consciousness, the IIT approach is in principle applicable to any information-processing dynamical network. For example, applications of IIT to Elementary Cellular Automata and Adapting Animats have been discussed [6]. Furthermore, potential extensions of IIT", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "Introduction.-Over the last decade Integrated Information Theory (IIT), developed by G. Tononi and collaborators, has emerged as one of the leading research lines in computational neuroscience. IIT aims at providing a mechanistic and mathematically well-defined description of the neural correlates of consciousness [1] [2] [3] [4] .", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "The idea is to quantify the amount of cause/effect power in the neural network that is holistic in the sense that goes beyond and above the sum of its parts. This is done in a bottom-up approach by quantifying how arbitrary parts of the network (\"mechanisms\"), in a given state, influence the future and constrain the past of other arbitrary parts (\"purviews\"), in a way that is irreducible to the separate (and independent) actions of parts of the mechanism over parts of the purview. Iterated at the global network level this process gives rise to a so-called conceptual structure, comprising a family of mechanisms and purviews, where the latter represent the integrated core causes/effects of the former [2] . A suitable measure of the distance between this conceptual structure with the closest one obtainable from a partitioned network (where the connections between the two subsystems are \"noised\") quantifies how much of the cause/effect structure of dynamical newtwork fails to be reducible to the sum of its parts. This minimal distance is the Integrated Information (\u03a6) of the network.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "In IIT it is then boldly postulated that the larger \u03a6, the higher is the degree of consciousness of the network in the given state. The irreducibility of the causal informationprocessing structure of the network measured by \u03a6 is independent of the specific \"wetware\" implementing the brain circuitry. It follows that the IIT approach to consciousness seems to unavoidably lead to panpsychist, and a rather controversial [5] view of the world [4] .", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Importantly, besides (and irrespective of) the applications to consciousness, the IIT approach is in principle applicable to any information-processing dynamical network. For example, applications of IIT to Elementary Cellular Automata and Adapting Animats have been discussed [6] . Furthermore, potential extensions of IIT to more general systems, including quantum ones, have been investigated in [7, 8] by M. Tegmark (see also [9] ).", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "In this paper we shall make an attempt at formulating a general and consistent version of IIT for interacting networks of finite-dimensional quantum systems (qudits). Naturally, classical probability distributions are being replaced by (non-commutative) density matrices and probability transition matrices by completely positive (CP) maps [10] . We would like to emphasize that 1) our goal is not to account for potential quantum features of consciousness 2) the quantum extension that we are going to discuss differs in some essential ways from its classical counterpart and it is not claimed to be unique [11] .", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Quantum IIT.-Let \u039b be a set of cardinality |\u039b| < \u221e. For each j \u2208 \u039b there is an associated d\u2212dimensional quantum system with Hilbert space h j \u223c = C d . Given any \u2126 \u2282 \u039b we define H \u2126 = \u2297 j\u2208\u2126 h j , with dimension d |\u2126| . We will denote by L(H \u039b ) (S(H \u039b )) the associated operatoralgebra (state-space). One has that H \u039b \u223c = H \u2126 \u2297 H \u2126 , where \u2126 denotes the complement of \u2126 (in \u039b). Let the dynamics be described by a unital CP-map U: L(H \u039b ) \u2192 L(H \u039b ) with U(1) = 1. This map has to be thought of as the one-step evolution of a discrete time process. Adopting the IIT jargon we will refer to subsets M of \u039b as to mechanisms). Given \u2126 \u2282 \u039b we define the noising CP-", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "The first step of is to define a quantum version of the cause/effect repertoires of classical IIT [3, 4] .", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Definition 1a: cause/effect Repertoires: Given the unital U, the state \u03a8 \u039b \u2208 L(H \u039b ), (\u03a8 \u039b \u2265 0, Tr \u03a8 \u039b = 1) and the mechanisms M, P \u2282 \u039b, we define the effect (e) and cause (c) repertoire of M over the purview P , by [12] ", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "U (e) = U and U (c) = U * (Hilbert-Schmidt dual of U). The set of density matrices \u03c1 (e) (P |M ) (\u03c1 (c) (P |M )) encode how the dynamics constrain the future (past) of P , given that the system is initialized in \u03a8 M and noised over M . Note, \u03c1 (e/c) (\u2205|M ) = 1 (\u2200M ), by trace normalization.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "The second step is to define the cause/effect information by the information-theoretic distance between the conditioned and the un-conditioned repertoire \u03c1 (x) (P |\u2205). In classical IIT the distance between repertoires (and related objects) is usually taken to be the Wasserstein distance [3] . In this paper, in view of its salient quantuminformation theoretic properties and simplicity, we will adopt the trace distance between density matrices \u03c1 and \u03c3 as a natural measure of statistical distinguishability, i.e., D(\u03c1, \u03c3) :=", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "cause/effect Information: The cause/effect information of M over P is given by", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Since U and U * are unital \u03c1 (e/c) (P |\u2205) = 1 P d |P | ; these are the unconditioned repertoires.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Remarks: 1) Since pure states have the maximum distance from the maximally mixed state and by distance monotonicity under partial traces xi(", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "2) From (2) and distance monotonicity under partial traces and unitary invariance follows Q \u2282 P \u21d2 xi(Q|M ) \u2264 xi(P |M ) (x = e, c). 3) For unitary U's generated by a local Hamiltonian xi(P |M ), (x = e, c) fulfill a Lieb-Robinson type inequality [13] , see [12] .", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Definition 2: Integrated information for mechanismsGiven the mechanism M and the purview P we consider all possible bi-partitions of them {M 1 , M 2 } and {P 1 , P 2 }, where", "cite_spans": [], "ref_spans": []}, {"section": "c).", "text": "In this definition the minimum is taken over all the 2 |P |+|M |\u22121 \u2212 1 possible pairings (P i , M i ) (i = 1, 2) different from the trivial one (\u2205, \u2205), (P, M ), which would make any repertoire factorizable. Notice that, since the \u03c1 (x) (P i |M i )'s (i = 1, 2) are not the reduced density matrices of \u03c1 (x) (P |M ), the factorizability of the latter is a necessary, but not sufficient condition for the vanishing of \u03d5 (x) (P |M ). If (P 1 , P 2 ) is the partition of P , which achieves the minimum, then the entanglement of \u03c1 (x) (P |M ), measured by its distance from the set of separable states over H P1 \u2297 H P2 , provides a lower-bound to \u03d5 (x) (P |M ). Moreover, cause/effect information gives an upper bound to the integrated information [14]", "cite_spans": [], "ref_spans": []}, {"section": "c).", "text": "In particular, Eq. (3) and remark 3) above imply that integrated information obeys a Lieb-Robinson type bound for U's generated by local-Hamiltonians. This shows that \u03d5 obeys locality in the usual sense allowed in nonrelativistic quantum theory [13] . Definition 3: Core causes, effects.-The purview P (e/c) * is a core effect/cause of M , if P (e/c) * = arg max P \u03d5 (e/c) (P |M ). The corresponding value of \u03d5 will be denoted by", "cite_spans": [], "ref_spans": []}, {"section": "c).", "text": "In the first (second) case, the mechanism M fails to constrain the future (past) on any purview P in an integrated fashion. Either way, such a mechanism is not regarded as an integrated part of the network and it is dropped out of the picture.", "cite_spans": [], "ref_spans": []}, {"section": "c).", "text": "Definition 4: Conceptual Structure operators.-For any mechanism M \u2282 \u039b the triple (\u03c1 c (M ), \u03c1 e (M ), \u03d5(M )) with \u03d5(M ) > 0 is called a concept. The totality of concepts forms a conceptual structure (CS) [3] . Formally one can encode a CS on a positive semi-definite operator over ( (4) where M \u2282 \u039b, \u03b1 = e, c, and we have made explicit the U-dependence (but kept implicit the \u03a8 \u039b one). Given two CS's, C 1 and C 2 associated to U 1 and U 2 , respectively, we define the distance between them as the (trace-norm) distance bewteen the associated CS opera-", "cite_spans": [], "ref_spans": []}, {"section": "c).", "text": "In words: two conceptual structures are the same iff all the core effects/causes repertoires and the associated integratedinformation coincide for all concepts [15] .", "cite_spans": [], "ref_spans": []}, {"section": "c).", "text": "The key idea in IIT is to quantitatively compare the global cause/effect structure, encoded in (4), with the one associated to the factorized maps. In this way one wants to asses how the \"whole goes beyond and above the sum of its parts\". The standard way in classical IIT to produce factorized maps is by bi-partitioning the total set \u039b and by \"cutting the connections between the two halves by injecting them with noise\" [3] . We adopt here a natural quantum version of this procedure.", "cite_spans": [], "ref_spans": []}, {"section": "c).", "text": "Formally, given the (non-trivial) partition", "cite_spans": [], "ref_spans": []}, {"section": "c).", "text": "), (i = 1, 2). Now we define the fundamental global quantity of the paper: the Integrated Information of the whole network. Qualitatively, \u03a6 measures how the integrated cause/effect structure of the quantum network fails to be described by any factorized version of it.", "cite_spans": [], "ref_spans": []}, {"section": "c).", "text": "Definition 5: Integrated Information.-We define the Integrated Information (II) by", "cite_spans": [], "ref_spans": []}, {"section": "c).", "text": "The minimum here is taken over the set of 2 |\u039b|\u22121 \u2212 1 bipartitions of \u039b [17] . If \u03a6(U) = 0, we say that the network is dis-integrated.", "cite_spans": [], "ref_spans": []}, {"section": "c).", "text": "It is important to stress that, in spite of the simplified notation, II depends crucially on \u03a8 \u039b as well. In this paper we focus on completely factorized pure states \u03a8 \u039b = \u2297 i\u2208\u039b |\u03c8 i \u03c8 i |. Different state choices, e.g., entangled, may result in dramatically different results [18] , and will be considered elsewhere [19] . Notice that \u03a6 obeys a sort of time-reversal symmetry \u03a6(U * ) = \u03a6(U) [20] . The bi-partition P M IP , for which the minimum in Eq. (6) occurs, is referred to as the Maximally Irre-", "cite_spans": [], "ref_spans": []}, {"section": "c).", "text": "Of course factorizability of U is a sufficient (but not necessary [21] ) condition for vanishing II. More in general, if the network is dis-integrated C(U) = C(U P M IP ), namely there exists a \"cut and noising\" of the network in two halves that does not affect its global (integrated) cause/effect structure. The system does not exist as a whole per se, but fragments into causally decoupled parts.", "cite_spans": [], "ref_spans": []}, {"section": "c).", "text": "Permutational networks.-In order to illustrate the above definitions and ideas we will now discuss the simple case of Permutational networks, in which \u03a8 \u039b = \u2297 i\u2208\u039b |\u03c8 i \u03c8 i | and U(X) = U \u03c3 XU \u2020 \u03c3 , where U \u03c3 acts as the permutation \u03c3 \u2208 S |\u039b| over", "cite_spans": [], "ref_spans": []}, {"section": "c).", "text": "The same equations hold, with \u03c3 \u22121 replacing \u03c3, for the cause repertoires. From this totally factorized form one sees that the only irreducible (M, P ) pairs are given by (i, \u03c3 \u00b11 (i)) [and that the core effect", "cite_spans": [], "ref_spans": []}, {"section": "c).", "text": "From these results and (4) one has", "cite_spans": [], "ref_spans": []}, {"section": "c).", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "c).", "text": ". Now given the partition P = (\u2126, \u2126 ), (\u2126 = \u2205), from the Proposition in [12] it follows that the concepts which are dis-integrated are those whose core effects or/and causes lie on the complementary set. Any permutation can be factorized in disjoint cycles, if the number of cycles is larger than one, one can choose a partition the of \u039b that gives rise to the same CS and, therefore \u03a6(\u03c3) = 0. If there is just one cycle (and |\u039b| > 2) the MIP is anyone of the form P = {{i}, {i} } in which the three concepts associated with i, \u03c3(i), \u03c3 \u22121 (i) are dis-integrated and all the others left intact. It follows from (6) that \u03a6(\u03c3) = ) the network is in the \"identity\" (\"swap\") phase. The discontinuities at t = cos \u22121 ( 2/3) and t = cos \u22121 (1/ \u221a 3) are due to a jump and delocalization of the core cause/effect repertoires. The dashed red curve shows the average of \u03a6 where U = exp(i t HGUE) and HGUE is sampled from the Gaussian unitary ensemble (GUE) with unit variance.", "cite_spans": [], "ref_spans": []}, {"section": "c).", "text": "Partial Swap.-To investigate quantum effects on \u03a6 we now consider a basic network with", "cite_spans": [], "ref_spans": []}, {"section": "c).", "text": ", where S is the permutation operator swapping the two qubits. One has three mechanisms/purviews M, P = {1}, {2}, \u039b = {1, 2}. A direct computation shows that:", "cite_spans": [], "ref_spans": []}, {"section": "c).", "text": ". Identical expressions hold for the repertoires \u03c1 (x) (P |2), (c t = cos t, s t = sin t). Finally, \u03c1(1|\u039b) = \u03c1(2|\u039b) = \u03a8 and \u03c1 (x) (\u039b|\u039b) = \u03a8 \u2297 2 . One can then obtain \u03d5 for each mechanism (i = 1, 2)", "cite_spans": [], "ref_spans": []}, {"section": "c).", "text": "2 )}. It follows that for small (near to \u03c0 2 ) t's the core effect/cause of {1} is itself ({2}) (analogously for {2}), whereas the core effect/cause of \u039b is itself \u2200t. Moreover, there is a window around t = \u03c0 4 in which the core effect/cause of {1} and {2} delocalize and comprise the full \u039b. The corresponding discontinuities of \u03a6(t) are illustrated in Fig. 1 . The existence of the intermediate, high \u03a6, delocalized phase originates from the commutator term in \u03c1 (e/c) (\u039b|1). It can be regarded as a genuine quantum feature, i.e., it would disappear if the dynamics were a just probabilistic mixture of identity and swap.", "cite_spans": [], "ref_spans": [{"start": 354, "end": 360, "text": "Fig. 1", "ref_id": "FIGREF3"}]}, {"section": "c).", "text": "Low-integration and Holistic Phases.-As customary in statistical mechanics one can consider families of increasingly large networks (\u039b, U \u039b , \u03a8 \u039b ) and study how \u03a6 For HXX (H XXfc ) the fit gives log 2 (\u03a6) = 2.38 log 2 |\u039b| \u2212 3.15 (log 2 (\u03a6) = 2.03 log 2 |\u039b| \u2212 2.58), illustrating a polynomial growth of the integrated information \u03a6 with the system size |\u039b| (low-integration). The same behavior is also observed for the Heisenberg XXX model [12] . Inset: holistic phase for the |\u039b|-local interaction Z. The fit shows log 2 (\u03a6) = 1.04|\u039b|\u22122.35, consistent with an exponential scaling \u03a6 \u223c 2 |\u039b| . The timestep t for the different system sizes |\u039b| is fixed by the \"constant action\" prescription t H \u221e = 2.5 [22] . Results for other prescriptions are discussed in [12] . > 0, we say that the network is the holistic phase in the TDL. The quantity O(U) can be referred to as the holistic parameter and it is at most one [23] . In the holistic phase the system shows the maximal level of integration and intrinsic existence as an irreducible causal whole.", "cite_spans": [], "ref_spans": []}, {"section": "c).", "text": "To study the different integration phases it is useful to consider the following upper bound to \u03a6 [24]", "cite_spans": [], "ref_spans": []}, {"section": "c).", "text": "where (8), it follows that the holistic parameter is vanishing:", "cite_spans": [], "ref_spans": []}, {"section": "c).", "text": "On the other hand, in order to be in the holistic phase, the network needs to have a number of concepts asymptotically lower bounded by 2 a|\u039b| (1 \u2265 a > 0). Whence, if the concepts are supported only on mechanisms M , such that |M | = \u03ba = O(1), then the network is necessarily in the non-holistic (low II) phase, e.g., permutational networks. Now we discuss a sufficient condition for a network to be in the holistic phase and provide a physical example. First, Eqs. (5) and (6) imply the bound:", "cite_spans": [], "ref_spans": []}, {"section": "c).", "text": "2 , where [25] . Notice that |\u2202P M IP | \u2265 2 |\u039b|\u22121 \u2212 1, therefore, in view of the lower bound above, one is guaranteed to be in the holistic phase if \u03d5 0 is lower-bounded by a non-zero constant. This situation can be realized by a |\u039b|-local interaction. Let us consider a qubit network with", "cite_spans": [], "ref_spans": []}, {"section": "c).", "text": "Since, by definition, \u03d5 Ut (M ) \u2265 \u03d5 Ut (M |M ) by setting, e.g., t = \u03c0 4 , one finds \u03d5 0 \u2265 1 2 . This argument also shows that the holistic parameter O(U t ) is one for all t = 0, \u03c0/2, where it is ill-defined as \u03a6 = 0. Turning on the global interaction Z (or mixing it with the identity) results in a direct transition from the dis-integrated phase to the holistic one. In general, one may speculate that k-local (k = O(1)) interactions will give rise to low-integration networks with sub-extensive log 2 \u03a6 [19] . Preliminary numerical results are shown in Fig. 2 .", "cite_spans": [], "ref_spans": [{"start": 557, "end": 563, "text": "Fig. 2", "ref_id": "FIGREF5"}]}, {"section": "c).", "text": "Conclusions.-The main goal of classical Integrated Information Theory (IIT) [1] [2] [3] [4] is to provide a mathematical and conceptual framework to study the neural correlates of consciousness. In this paper we took the first steps towards a possible quantum version of IIT irrespective of its applications to consciousness.", "cite_spans": [], "ref_spans": []}, {"section": "c).", "text": "Our approach is a quantum information-theoretic one, where neural networks are being replaced by networks of qudits, probability distributions by non-commutative density matrices, and markov processes by completely positive maps. The irreducible cause/effect structure of the global network is encoded by a so-called conceptual structure operator. The minimal distance of the latter from those obtained by factorized versions of the network, defines the quantum Integrated Information \u03a6.", "cite_spans": [], "ref_spans": []}, {"section": "c).", "text": "We have studied quantum effects in small qubit networks and provided examples, analytical and numerical, of families of low integration networks. Also, we have demonstrated sufficient conditions for the existence of highly integrated ones and given illustrations.", "cite_spans": [], "ref_spans": []}, {"section": "c).", "text": "The scaling of \u03a6 with the network size defines different phases distinguished by a different level of integration of their global cause/effect structure. The study of those phases and cross-overs, their relation to locality and entanglement, and in general the question whether the quantum IIT discussed in this paper has any direct bearing on standard quantum information processing, are challenging tasks for future investigations.", "cite_spans": [], "ref_spans": []}, {"section": "c).", "text": "Acknowledgements.-P.Z. thanks the \"Waking up Podcast\" of Sam Harris for the inception and Giulio Tononi for useful input. [3] G. ", "cite_spans": [], "ref_spans": []}, {"section": "c).", "text": ", (x = e, c). Also, when |M | = |P | = 1, the partition above is the only possible and ii and cause/effect information conflate.", "cite_spans": [], "ref_spans": []}, {"section": "c).", "text": "[15] It is important to notice that if the repertoires depend continuously on some parameter, e.g., through the map U, then \u03d5(M ) will be a continuous function as well. However, core effects/causes may change dis-continuously and this will be reflected by CS operators and functions thereof, e.g., the distance (5).", "cite_spans": [], "ref_spans": []}, {"section": "c).", "text": "[16] Alternatively, a CS can be also be seen a \"constellation\" of triples", "cite_spans": [], "ref_spans": []}, {"section": "c).", "text": "The latter compact set may be referred to as the quantum \"Qualia Space\" [3] .", "cite_spans": [], "ref_spans": []}, {"section": "c).", "text": "[17] At the quantum level one might define the minimization (6) over all possible virtual bi-partitions of H\u039b [26] . This would provide a lower bound to \u03a6 and a much more stringent, and uniquely quantum, definition of integration.", "cite_spans": [], "ref_spans": []}, {"section": "c).", "text": "[18] For example, even factorized maps, e.g., identity may have non-vanishing \u03a6.", "cite_spans": [], "ref_spans": []}, {"section": "c).", "text": "[19] P. Zanardi et al, (to be published).", "cite_spans": [], "ref_spans": []}, {"section": "c).", "text": "[20] From Eq. (1) one sees that causes and effects are exchanged by replacing U with its dual U * , moreover \u03d5(M ) is symmetric under this exchange (\u2200M ). Therefore, C(U * ) = XC(U * )X \u2020 , where X := 1 \u2297 \u03c3 x \u2297 1. Since the distance D in Eq. (6) is unitarily-invariant one gets \u03a6(U * ) = \u03a6(U).", "cite_spans": [], "ref_spans": []}, {"section": "c).", "text": "[21] For a given \u03a8\u039b, vanishing \u03a6 is a weaker property than factorizability of the dynamical map. Take, e.g., any nonfactorizable unitary U that is diagonal in a tensor product basis and \u03a8\u039b to be a basis element. One has that U(\u03a8M \u2297", "cite_spans": [], "ref_spans": []}, {"section": "c).", "text": "The action of U, for this \u03a8\u039b, is the same of the identity map and therefore \u03a6(U) = 0. A different \u03a8\u039b, would generally lead to \u03a6 = 0.", "cite_spans": [], "ref_spans": []}, {"section": "c).", "text": "[22] If the maps U\u039b are associated with unitaries U\u039b = e \u2212it \u039b H \u039b one has to choose how to scale with the system size |\u039b| both the times t\u039b as well as the Hamiltonians H\u039b. For the former three natural options are given by: a) t = O(1); b) \"constant action\" t\u039b H\u039b = O(1); c) t\u039b := argmax t \u03a6\u039b(t), where the maximum overtime is taken at fixed |\u039b| (see [12] ", "cite_spans": [], "ref_spans": []}, {"section": "c).", "text": "Here we have used the fact that the number of concepts Nc(UP ) of the partitioned network is always not larger than the one Nc(U) of the un-partitioned one \u2200P. In the same way one proves \u03a6(U) \u2264 M \u2282\u039b \u03d5U (M ).", "cite_spans": [], "ref_spans": []}, {"section": "c).", "text": "[25] Given a (non-trivial) bi-partition P := {\u039b1, \u039b2 = \u039b 1 } we define \u2202P := {S \u2282 \u039b / S \u2229 \u039b1 = \u2205 \u2227 S \u2229 \u039b2 = \u2205}. This is the \"boundary of the partition\" and it contains |\u2202P| = 2 |\u039b| \u2212 2 Supplemental Material for the paper \"Quantum Integrated Information Theory\" by P. Zanardi, M. Tomka, and L. Campos Venuti QUANTUM CAUSE/EFFECT REPERTOIRES Effects.-We will denote by p (p ) the degrees of freedom (DOFs) associated with the purview P at time t + 1 (its complement P ) and by m (m ) the DOFs associated to the mechanism M at time t (its complement M ). On purely classical probabilistic grounds one can write , and for t = 0 and t = \u03c0/2 we obtain \u03a6 = 0. Fig. S3 (b) shows the holistic behaviour of the network, i.e., the exponential scaling of \u03a6 with the system size |\u039b|. In particular, we observe an exponential scaling of \u03a6 for all the three natural prescriptions for fixing the timescale: a) for t = 0.5 (solid blue line) we get log 2 \u03a6 = 1.05|\u039b| \u2212 2.64, b) for t Z \u221e = 2.5 (dashed orange line), log 2 \u03a6 = 1.04|\u039b| \u2212 2.35 and c) for t = argmax t \u03a6 \u039b (t) (dotted green line), log 2 \u03a6 = 1.04|\u039b| \u2212 2.29. The fits obtained using all the three different prescriptions are consistent with a scaling of the form \u03a6 \u223c 2 |\u039b| . The fit of case b) (dashed orange line), which corresponds to the fixed action case t Z \u221e = 2.5, is also shown in the inset of Fig. 2 from the main text.", "cite_spans": [], "ref_spans": [{"start": 1345, "end": 1351, "text": "Fig. 2", "ref_id": "FIGREF5"}]}, {"section": "LOW-INTEGRATION EXAMPLES", "text": "In this section we numerically calculate \u03a6 for four different qubit networks of sizes up to |\u039b| = 7. We use U(X) = e \u2212it\u039bH Xe it\u039bH , but now the dynamics are described by a two-body Hamiltonian H. Namely, the dynamics are governed i) by the XX Hamiltonian on a ring H XX = |\u039b| i=1 (\u03c3 First, in Fig. S4 we plot the scaling of the timescale t \u039b , used in the evolution operator of the network U(X) = e \u2212it\u039bH Xe it\u039bH . The timescale t \u039b for the different system sizes |\u039b| is determined by fixing the \"action\" to a constant value, i.e., t \u039b ||H|| \u221e = 2.5. Figure S4 (a) shows the scaling of the resulting t \u039b with the system size on a log 2 scale for the XX Hamiltonian on a ring H XX . The blue dots show it for an odd number of qubits (|\u039b| odd) and the orange squares for an even number of qubits (|\u039b| even) in the network. The same is shown in Fig. S4 (b) , (c) and (d) for the XX Hamiltonian on a fully connected graph, the XXX Hamiltonian on a ring and the XXX Hamiltonian on a fully connected graph. The dashed blue line and the dotted orange line show the fits for |\u039b| odd and even, respectively.", "cite_spans": [], "ref_spans": []}, {"section": "LOW-INTEGRATION EXAMPLES", "text": "We observe that for the the XX and the XXX Hamiltonians on a ring, there is a marked even/odd effect in the scaling of t \u039b with |\u039b|. This is due to the fact that for the ring geometry the (sup) norm of the Hamiltonian is given by |E 0 |, where E 0 is the ground state of the corresponding antiferromagnetic Hamiltonian. As such especially ||H XXX || \u221e shows a marked even-odd effect, since for odd chains one cannot have a singlet ground state. (Color online) Scaling of the t \u03bb with the system size |\u039b| given by fixing action t\u039b||H||\u221e = 2.5, for the XX Hamiltonian on a ring (a), the XX Hamiltonian on a fully connected graph (b), the XXX Hamiltonian on a ring (c), and the XXX Hamiltonian on a fully connected graph. Note the more pronounced even-odd effect for HXXX as discussed in the text.", "cite_spans": [], "ref_spans": []}, {"section": "LOW-INTEGRATION EXAMPLES", "text": "The scaling of the Integrated Information \u03a6 with the system size and different prescriptions for fixing the timescale t \u039b is shown in Fig. S5 . Panels (a) and (d) show holistic (exponential) behavior consistent with \u03a6 \u223c 2 |\u039b| , whereas in panel (b) and (c) the best fit is obtained with \u03a6 \u223c |\u039b| \u03b1 for some positive \u03b1 (see figure) .", "cite_spans": [], "ref_spans": []}, {"section": "LOW-INTEGRATION EXAMPLES", "text": "\u2022 i) Compute \u03c1 (e/c) (P |M ) for all non empty M, P \u2282 \u039b (# of repertoires: 2 (2 2|\u039b| \u2212 2 |\u039b|+1 + 1))", "cite_spans": [], "ref_spans": []}, {"section": "LOW-INTEGRATION EXAMPLES", "text": "ii) For each non-trivial \u03c1 (e/c) (P |M ) compute \u03d5 (# of pairings of (P, M ): (2 |M |+|P |\u22121 \u2212 1))", "cite_spans": [], "ref_spans": []}, {"section": "LOW-INTEGRATION EXAMPLES", "text": "iii) For each M = \u2205 find its core effect/cause P (x) * and associated integrated-information \u03d5 (x) (M ) = max P \u03d5 (x) (P |M ) = \u03d5 (x) (P (x) * |M ), (x = e, c). Now the CS (4) is defined for the given U.", "cite_spans": [], "ref_spans": []}, {"section": "LOW-INTEGRATION EXAMPLES", "text": "iv) For each partition P of \u039b compute \u03a6 by using (6) (# partitions of \u039b: (2 |\u039b|\u22121 \u2212 1)).", "cite_spans": [], "ref_spans": []}, {"section": "LOW-INTEGRATION EXAMPLES", "text": "The total number of steps (for a fixed partition) is As in the classical IIT case, the actual computation of \u03a6 is exponentially costly (in |\u039b|) and therefore provides a challenging task even for networks of moderate size.", "cite_spans": [], "ref_spans": []}], "bib_entries": {}, "ref_entries": {"FIGREF0": {"text": "FIG. 1. (Color online) Two qubit network. Solid blue curve: U = exp(i t S). For small t (near \u03c0 2", "type": "figure"}, "FIGREF1": {"text": "FIG. 2. (Color online) Low-integrated and holistic networks: Numerical simulations of \u03a6, for the two-body Hamiltonian on a ring HXX = |\u039b| i=1 (\u03c3 x i \u03c3 x i+1 + \u03c3 y i \u03c3 y i+1 ), and on a fully connected graph H XXfc = |\u039b| i<j (\u03c3 x i \u03c3 x j + \u03c3 y i \u03c3 y j ), as well as for a |\u039b|-local interaction Z = |\u039b| i=1 \u03c3 z i , are depicted. For HXX (H XXfc ) the fit gives log 2 (\u03a6) = 2.38 log 2 |\u039b| \u2212 3.15 (log 2 (\u03a6) = 2.03 log 2 |\u039b| \u2212 2.58), illustrating a polynomial growth of the integrated information \u03a6 with the system size |\u039b| (low-integration). The same behavior is also observed for the Heisenberg XXX model [12]. Inset: holistic phase for the |\u039b|-local interaction Z. The fit shows log 2 (\u03a6) = 1.04|\u039b|\u22122.35, consistent with an exponential scaling \u03a6 \u223c 2 |\u039b| . The timestep t for the different system sizes |\u039b| is fixed by the \"constant action\" prescription t H \u221e = 2.5 [22]. Results for other prescriptions are discussed in [12].", "type": "figure"}, "FIGREF2": {"text": "behaves in the \"thermodynamical limit\" (TDL) |\u039b| \u2192 \u221e [22]. If O(U) := lim |\u039b|\u2192\u221e log 2 \u03a6(U\u039b) |\u039b|", "type": "figure"}, "FIGREF3": {"text": "G. Tononi, BMC Neuroscience 5, 42 (2004). [2] M. Oizumi, L. Albantakis, and G. Tononi, PLOS Com- putational Biology 10, 5 (2014).", "type": "figure"}, "FIGREF5": {"text": ". The initial state was chosen to be \u03a8 \u039b = i\u2208\u039b |\u2191 \u2191| i , whereas in the main text and for the holistic example with Z = \u2297 i\u2208\u039b \u03c3 z i , we used the state \u03a8 \u039b = i\u2208\u039b |+ +| i , where |+ = 1|\u2191 + |\u2193 ) with |\u2191 = (1, 0) T and |\u2193 = (0, 1) T .", "type": "figure"}, "FIGREF6": {"text": "FIG. S3. (Color online) (a) Numerical computation of the Integrated Information \u03a6 as a function of the parameter t, for different system sizes |\u039b| = 3, 4, 5, with \u03a8\u039b = \u2297i\u2208\u039b|+ +|i. The red dashed line shows 2s 2 t c 2 t . (b) Scaling of \u03a6 with the system size |\u039b|, for the three options to fix the time scale a) t = 0.5 (solid blue line) log 2 \u03a6 = 1.04|\u039b| \u2212 2.60, b) t Z \u221e = 2.5 (dashed orange line) log 2 \u03a6 = 1.04|\u039b| \u2212 2.35 and c) t = argmax t \u03a6\u039b(t) (dotted green line) log 2 \u03a6 = 1.04|\u039b| \u2212 2.29.", "type": "figure"}, "FIGREF7": {"text": "FIG. S4. (Color online) Scaling of the t \u03bb with the system size |\u039b| given by fixing action t\u039b||H||\u221e = 2.5, for the XX Hamiltonian on a ring (a), the XX Hamiltonian on a fully connected graph (b), the XXX Hamiltonian on a ring (c), and the XXX Hamiltonian on a fully connected graph. Note the more pronounced even-odd effect for HXXX as discussed in the text.", "type": "figure"}, "FIGREF8": {"text": "FIG. S5. (Color online) Scaling of Integrated Information \u03a6 as a function of the system size |\u039b| for the three different scenarios fixing the timescale t\u039b, i.e., (a) t\u039b = 0.5, (b) and (c) fixed \"action\" t\u039b||H||\u221e = 2.5 and (d) t\u039b = argmax t \u03a6\u039b(t), for the four different two-body Hamiltonians HXX, H XXfc , HXXX, H XXXfc . The initial state was chosen to be \u03a8\u039b = i\u2208\u039b |\u2191 \u2191|i.", "type": "figure"}, "FIGREF9": {"text": "|M | 2 |P | \u2212 2) = O(3 2|\u039b| /2).", "type": "figure"}}}
{"paper_id": "118863125", "_pdf_hash": "0898878388a76a869b0bc120f9260c82ee994b54", "abstract": [{"section": "Abstract", "text": "We present the emission H\u03b1 line images for 40 galaxies of the Local Volume based on the observations at the 6-meter BTA telescope. Among them there are eight satellites of the Milky Way and Andromeda (M 31) as well as two companions to M 51. The measured H\u03b1 fluxes of the galaxies are used to determine their integral (SFR) and specific (sSFR) star formation rates. The values of log sSFR for the observed galaxies lie in the range of (\u22129, \u221214) [yr \u22121 ]. A comparison of SFR estimates derived from the H\u03b1 flux and from the ultraviolet FUV flux yields evidence that two blue compact galaxies MRK 475 and LV J1213+2957 turn out to be at a sharp peak of their star-burst activity.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION", "text": "This work is a continuation of papers [1] [2] [3] [4] [5] [6] [7] [8] determining the rate of star formation in the galaxies of the Local Volume measuring their integral flux in the emission H\u03b1 Balmer line. Our program provides measurements of the H\u03b1 flux at the 6-m telescope of the Special Astrophysical Observatory for all galaxies of the northern sky with distances within D \u2264 11 Mpc which were not covered by observations at other telescopes.", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "The latest version of the Updated Nearby Galaxy Catalog (UNGC) [9] contains 869 objects with distance estimates within D < 11 Mpc or with the line-of-sight velocities relative to the centroid of the Local Group V LG < 600 km s \u22121 .", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "During 2014 this sample has been supplemented with forty new galaxies included in the database [10] , which is available at http://www.sao.ru/lv/lvgdb. In total the current database of the Local Volume contains H\u03b1 flux measurements for approximately 550 galax-* Electronic address: skai@sao.ru ** Electronic address: ikar@sao.ru ies, where the fluxes for more than 350 galaxies were measured with the 6-m BTA telescope.", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "The H\u03b1 line images of nearby galaxies make it possible to study the distribution of the centers of star formation that formed in the galaxies over the past 10-30 myr. A comparison of the H\u03b1-emission map of the galaxy with the distribution of atomic and molecular hydrogen in it allows a detailed study of the conditions under which a transformation of the gas component in the galaxy into stars takes place.", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "Of particular interest in this respect are the dwarf galaxies with their shallow gravitational wells, owing to which dwarf systems easily lose their gas component under the effect of the supernova burst or during the motion through the halo of hot gas around a massive neighboring galaxy. Being sensitive to the environment, dwarf galaxies are often used as \"test particles\" for the analysis of the dynamical evolution of both galaxy clusters and the population of the general field.", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "Below we present the H\u03b1 images, the H\u03b1 flux values, and the star formation rate (SFR) estimates for forty galaxies of the Local Volume and one object, KKR 9, which turned out to be an interstellar cirrus. All but two galaxies are dwarf systems of late or early types.", "cite_spans": [], "ref_spans": []}, {"section": "OBSERVATIONS AND DATA REDUCTION", "text": "The images in the H\u03b1 line and in the neighboring continuum were obtained in the period from February to December 2013. The observations were carried out at the prime focus of the BTA with the SCORPIO focal reducer [11] equipped with a 2048 \u00d7 2048 pixel CCD, in the 2\u00d7 2 binning mode. The optical system provided a field of view of 6. \u2032 1 \u00d7 6. \u2032 1 at the scale of 0. \u2032\u2032 185 per pixel.", "cite_spans": [], "ref_spans": []}, {"section": "OBSERVATIONS AND DATA REDUCTION", "text": "The images in the H\u03b1 + [N II] lines were obtained using a narrowband interference filter with the effective wavelength of 6555\u00c5 and the full width at half maximum of 75\u00c5. The images in the continuum were taken with midband filters SED 607 (\u03bb e = 6063\u00c5, \u2206\u03bb = 167\u00c5) and SED 707 (\u03bb e = 7036\u00c5, \u2206\u03bb = 207\u00c5). Owing to a small range of lineof-sight velocities of the galaxies, all the objects were observed with one and the same filter set. The typical total exposure in the H\u03b1 line was 1200 s.", "cite_spans": [], "ref_spans": []}, {"section": "OBSERVATIONS AND DATA REDUCTION", "text": "For processing the observed data, standard procedures were used: bias subtraction, flat-field correction, removing cosmic ray hits, sky background subtraction. The images in the continuum were normalized to the H\u03b1 images using the non-overexposed stars and were then subtracted. Integral H\u03b1 fluxes of galaxies were measured from the H\u03b1 images with subtracted continuum. To calibrate the flux, the images of the spectrophotometric standard stars [12] were used which were observed at the same night with the objects. A typical H\u03b1 flux logarithm measurement error in our images is \u00b10.1 [8] .", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS OF OBSERVATIONS", "text": "The mosaic image of forty-one observed objects is given in the Appendix, where the lefthand-side images correspond to the total exposure in the H\u03b1 line and the continuum, and the right-hand-side images are the H\u03b1 line images after subtracting the continuum. The image scale and their \"north-east\" orientation are marked at the bottom of the right-hand-side images. After the continuum subtraction many images reveal residual \"caverns\" caused by the saturation of stellar images in high-brightness stars. Another reason may be an abnormal color index of stars or different image quality in the H\u03b1 filter and in the continuum. In fact, it is the presence of such residual components that determines the accuracy limit when detecting the H\u03b1 flux of the galaxy, especially if it has a low surface brightness and large size or is located in a dense stellar field at a low galactic latitude.", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS OF OBSERVATIONS", "text": "Following [13] , we determine the integral star formation rate in the galaxy using the relation log SFR = log F c (H\u03b1) + 2 log D + 8.98, where F c (H\u03b1) is the integral flux in the H\u03b1 line in the units of erg cm \u22122 s \u22121 , corrected for the absorption of light in the Galaxy according to [14] , D is the distance in Mpc, and SFR is expressed in M \u2299 /year. We have ignored the internal absorption of light in the galaxy as well as the contribution of the emission [N II] doublet, since both effects are negligibly small for dwarf galaxies [15, 16] .", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS OF OBSERVATIONS", "text": "The table contains the main data on the observed galaxies. Its columns show: (1) the name of the galaxy, (2) equatorial coordinates for the epoch (J2000.0), (3) integral apparent B magnitude from the UNGC catalog [9] , (4) morphological type by the de Vaucouleurs scale, (5) distance to the galaxy in Mpc according to the UNGC catalog data [9] , (6) logarithm of the observed galaxy flux in the H\u03b1 line in the units of erg cm \u22122 s \u22121 , (7) logarithm of the integral star formation rate in M \u2299 /year, (8) specific star formation rate sSFR = SFR/M * , where M * is the stellar mass of the galaxy from catalog [9] , determined from the K-band luminosity. The last column shows for comparison the integral starburst rate of the galaxy [16] log SFR = log F c (FUV) + 2 log D \u2212 6.78 determined by its flux in the far ultraviolet (\u03bb e = 1539\u00c5, FWHM = 269\u00c5), measured by the GALEX satellite [17] , corrected for the extinction of light in the Galaxy.", "cite_spans": [], "ref_spans": []}, {"section": "FEATURES OF SOME OBSERVED GALAXIES", "text": "With the exception of two late-type spiral galaxies MCG +09-16-010 (Sm) and UGC 5047 (Sdm), all the remaining observed objects are dwarf galaxies of late (Ir, Im, BCD) or early (dSph) type. Note the most remarkable among them.", "cite_spans": [], "ref_spans": []}, {"section": "FEATURES OF SOME OBSERVED GALAXIES", "text": "And XXXII = Cas III, And XXXIII = Perseus I, And XXXI = Lacerta I. These three dSph companions of M 31 were recently detected within the 3\u03c0 Pan-STARRS1-survey [18, 19] . All three objects do not reveal any signs of emission. The table lists for them only the upper limits of the integral H\u03b1 flux. We should, however, note that the angular diameters of these nearby dwarf systems are quite large: 13. \u2032 0 (Cas III), 3. \u2032 4 (Pers I), and 8. \u2032 4 (Lac I), and in two cases they exceed the field of view of our detector.", "cite_spans": [], "ref_spans": []}, {"section": "FEATURES OF SOME OBSERVED GALAXIES", "text": "P And AS-48. A distant globular cluster at the far periphery of M 31 [20] .", "cite_spans": [], "ref_spans": []}, {"section": "FEATURES OF SOME OBSERVED GALAXIES", "text": "DGSAT-I. A dwarf spheroidal galaxy in the neighborhood of M 31 [21] . Its radial velocity is not known, and the distance, measured as 8.0 Mpc, is very unreliable.", "cite_spans": [], "ref_spans": []}, {"section": "FEATURES OF SOME OBSERVED GALAXIES", "text": "Segue 2, UMa I, CVn I, Segue 3. Four dShp companions of the Milky Way, detected in [22] [23] [24] [25] respectively. The table lists for them only the upper value of the H\u03b1 flux. It should be borne in mind that the angular dimensions of UMa I (18. \u2032 0) and CVn I (14. \u2032 3) significantly exceed the field of view of the SCORPIO focal reducer.", "cite_spans": [], "ref_spans": []}, {"section": "FEATURES OF SOME OBSERVED GALAXIES", "text": "NGC 1400. An elliptical galaxy in the Eridanus group at the distance of 24.9 Mpc [26] . It formally makes it into the sample of the Local Volume by its line-of-sight velocity V LG = 496 km s \u22121 . Its peculiar line-of-sight velocity relative to the Eridanus group is \u22121320 km s \u22121 . The presence of H\u03b1 emission in its central part is not typical for the E galaxies in the groups, but the GALEX data [17] indicate active star formation in the center of NGC 1400.", "cite_spans": [], "ref_spans": []}, {"section": "FEATURES OF SOME OBSERVED GALAXIES", "text": "NGC 1592. A knotty dIr galaxy with a high specific star formation rate.", "cite_spans": [], "ref_spans": []}, {"section": "FEATURES OF SOME OBSERVED GALAXIES", "text": "HIPASS J0705-20. This radio source with the radial velocity V LG = 528 km s \u22121 [27] has no optical identification, although the magnitude of the Galactic extinction in its direction is not too large, A B = 2. m 71 [14] . The H\u03b1 image we have obtained reveals one diffuse spot with the coordinates 070546.95-205932.6 and two point knots with the coordinates 070543.31-205935.1 and 070545.87-205837.7, which can belong to an irregular galaxy of low surface brightness. Radial velocity measurement for these objects will be a crucial test for the accuracy of radio source identification.", "cite_spans": [], "ref_spans": []}, {"section": "FEATURES OF SOME OBSERVED GALAXIES", "text": "Leo P. A very nearby dIr galaxy with radial velocity of V LG = 135 km s \u22121 [28] . The main H\u03b1 flux comes from a compact H II region near the center of the object.", "cite_spans": [], "ref_spans": []}, {"section": "FEATURES OF SOME OBSERVED GALAXIES", "text": "LV J1213+2957. A compact blue H II region detected in the SDSS [29] . Having a 212131.0+190702 15.9 \u22123 0.02 < \u221215.37 < \u22129.86 < \u221213.06 < \u22129.67 And XXXI = Lac I 225816.3+411728 14.0 \u22123 0.76 < \u221215.28 < \u22126.42 < \u221213.77 -small radial velocity, V LG = 196 km s \u22121 , it is probably part of the group of five galaxies around NGC 4150 at a distance of approximately 16 Mpc, which has a collective peculiar velocity of about \u2212700 km s \u22121 [30] .", "cite_spans": [], "ref_spans": []}, {"section": "FEATURES OF SOME OBSERVED GALAXIES", "text": "KKH 78. An irregular galaxy of low surface brightness with no signs of H\u03b1 emission, a probable companion of the NGC 4395 galaxy.", "cite_spans": [], "ref_spans": []}, {"section": "FEATURES OF SOME OBSERVED GALAXIES", "text": "DDO 120 = UGC 7408. A bluish Magellanictype irregular galaxy with no H II regions. A very weak diffuse H\u03b1 emission gives the 300 times lower star formation rate than that from the FUV flux measured by the GALEX.", "cite_spans": [], "ref_spans": []}, {"section": "FEATURES OF SOME OBSERVED GALAXIES", "text": "GR 34 = VCC 530, KDG 215. Two dIr galaxies in front of the Virgo Cluster, the distances to which were measured in [31] . KDG 215 shows only a very weak diffuse emission.", "cite_spans": [], "ref_spans": []}, {"section": "FEATURES OF SOME OBSERVED GALAXIES", "text": "UGCA 361, MCG +08-25-028. These are the dSph and dIr companions of M 51. KKR 9. This object proved to be not a dwarf galaxy but a fragment of an interstellar cirrus.", "cite_spans": [], "ref_spans": []}, {"section": "FEATURES OF SOME OBSERVED GALAXIES", "text": "MRK 475. A blue compact galaxy of high surface brightness. One of the most active objects of the Local Volume. Judging by the specific star formation rate log(sSFR) = \u22129.14 [yr \u22121 ], this dwarf system is at the peak of its starburst activity.", "cite_spans": [], "ref_spans": []}, {"section": "FEATURES OF SOME OBSERVED GALAXIES", "text": "UGC 9660, UGC 9992. Both dwarf galaxies have vigorous centers of star formation. Their distances, determined by the Tully-Fisher relation [32] , 7.4 Mpc and 7.3 Mpc, almost coincide with the distance to M 101 (7.38 Mpc). Both galaxies can be associated with the group M 101, although their radial velocities +745 km s \u22121 and +638 km s \u22121 are significantly larger than that of M 101 (+378 km s \u22121 ).", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION AND CONCLUSIONS", "text": "As we can see from the last column of the table, thirty out of forty galaxies we have observed have independent SFR estimates from the ultraviolet flux measured by the GALEX satellite. A fairly clear correlation is noticeable between the SFR estimates by the H\u03b1 flux and FUV flux, which is smeared in weak fluxes. For twenty galaxies with the log SFR(H\u03b1) > \u22124.0 estimates, the average difference between the values is log SFR(H\u03b1) \u2212 log SFR(FUV) = \u22120.16 \u00b1 0.08 with a standard deviation of 0.35. This difference is somewhat larger than the typical measurement error of the H\u03b1 flux (\u00b10.10) logarithm and the FUV flux logarithm (\u00b10.04).", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION AND CONCLUSIONS", "text": "The reasons of the differences between the SFR estimates based on the H\u03b1 line emission and the ultraviolet flux of the galaxies were discussed by many authors, in particular, in [16] and [32] . As it was noted in [33] , the star formation rate by the H\u03b1 flux relative to the FUV flux for the dwarf galaxies of very low luminosity may be underestimated by ten or more times. The empirical mutual normalization of SFR(H\u03b1) \u2243 SFR(FUV) was made by the spiral galaxies. It is not well suited to the dwarf systems, where the initial stellar mass function at its bright end may be substantially different than that of the spiral galaxies. It should also be remembered that the SFR estimation based on the H\u03b1 flux corresponds to the characteristic time of about 10 7 yr, whereas the SFR determined by the FUV flux covers the range of approximately 10 8 yr. In the presence of star formation bursts, especially noticeable in dwarf galaxies, the SFR(H\u03b1)/SFR(FUV) ratio indicates the phase of activity in which the galaxy dwells. For example, blue compact galaxies MRK 475 and LV J1213+2957 are obviously observed at the peak of their starburst activity. On the other hand, dwarf galaxies DDO 120 and KDG 215 with bluish but aged stellar population are at the stage of long-term relaxation after the activity peaks. Therefore, the SFR estimate ratio from the H\u03b1 and FUV fluxes can be a useful indicator of the flare activity phase of a dwarf galaxy.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION AND CONCLUSIONS", "text": "As noted in [34, 35] , specific star formation rate log sSFR = log(SFR/M * ) of the galaxies in the present epoch has an upper limit expressed as \u22129.4 [yr \u22121 ]. Not less than 98-99% of all galaxies are subject to this restriction. It obviously means that a too vigorous star formation leads to the depletion of gas reserves in the galaxy. Among the objects of the table there is only one galaxy, MRK 475 with log sSFR = \u22129.14 [yr \u22121 ], which exceeds the specified limit. It should be noted, however, that the error in the determining the stellar mass in blue compact galaxies is quite large about 50%, and this Markarian galaxy may actually not be violating the general pattern.", "cite_spans": [], "ref_spans": []}, {"section": "ACKNOWLEDGMENTS", "text": "This work was supported by the RFBR grants 13-02-92960-Ind-f and 13-02-00780. The observations at the 6-meter BTA telescope were carried out with the financial support of the Ministry of Education and Science of the Russian Federation (state contracts No. 14.518.11.7070, 16.518.11.7073).", "cite_spans": [], "ref_spans": []}, {"section": "APPENDIX", "text": "", "cite_spans": [], "ref_spans": []}], "bib_entries": {}, "ref_entries": {"TABREF0": {"text": "Parameters of the observed galaxieslog SFR log sSFR log SFR FUV And XXXII =C as III 003559.4+513335 13.7 \u22123 0.78 < \u221215.28 < \u22126.35 < \u221213.92", "type": "table"}}}
{"paper_id": "118863370", "_pdf_hash": "81466d0c8c21314798f498483548496329059db9", "abstract": [{"section": "Abstract", "text": "We study the strangeness production in hot and dense nuclear medium, by requiring the conservation of the baryon density, electric charge fraction and zero net strangeness. The hadronic equation of state is investigated by means of an effective relativistic mean field model, with the inclusion of the full octet of baryons and kaon mesons. Kaons are considered taking into account of an effective chemical potential depending on the self-consistent interaction between baryons. The obtained results are compared with a minimal coupling scheme, calculated for different values of the anti-kaon optical potential and with non-interacting kaon particles. In this context, we also consider the possible onset of the kaon condensation for a wide range of temperatures and baryon densities.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "In the last years there has been a growing interest in the study of the kaons and anti-kaons proprieties in finite nuclear matter as well as in compact stars. Many studies have shown the possibility that these particles may condensate in neutron stars, whereas the situation seems to be more uncertain in the physical conditions reachable in relativistic heavy ion collision 1,2,3,4,5,6,7 . This uncertainty is mainly due to the difficulty of finding out from the experimental results an estimation of the real part of the anti-kaon optical potential at the nuclear saturation density. A stronger attractive potential depth should in fact favor the formation of the condensation, but, on the other hand, a stiffer or softer equation of state (EOS) should help or not the condensation itself. At this regard, the analysis of kaonic atom data leads to the real part of anti-kaon optical potential close to U K \u2212 = \u2212180 \u00b1 20 MeV at the saturation nuclear matter density 5,8,9,10,11,12 . Contrariwise, chiral-models and coupled-channel G-matrix theory, seem to suggest a strength of the optical potential close to U K \u2212 = \u2212(50 \u00f7 80) MeV 13, 14, 15 . These uncertainties in the estimation of the anti-kaon potential depth, imply some difficulties in the calculation of the effective kaon mass in-medium. Moreover, different mean field models predict negative or imaginary effective kaon mass at sufficiently large values of the \u03c3-meson field, responsible of the medium range attraction 11, 12, 16 . At this regard, the future CBM (Compressed Baryonic Matter) experiment of FAIR (Facility of Antiproton and Ion Research) at GSI Darmstadt, will be of great importance to create compressed baryonic matter with a high net baryon density and finite temperature 17, 18, 19, 20 and make possible an accurate analysis of the proprieties of kaons and, more in general, of the strangeness production at high baryon density.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "In this work, we are going to investigate the strangeness production at finite isospin density and zero net strangeness, using two different approaches for what concern the kaon degrees of freedom. The first one consists in a relativistic mean field model, with the introduction of an effective meson chemical potential, obtained through a self consistent interaction between baryons 21 . The second one is based on a minimal coupling scheme, where kaons are directly coupled with the scalar and vectors meson fields (\u03c3, \u03c9 and \u03c1) through coupling constants related to the anti-kaon optical potential 5,11,12,22 . We focalize our analysis in the range of temperature and baryon density reachable in high energy heavy ion collisions with particular attention to the physical conditions relevant for the future CBM experiment at FAIR. At this stage, we do not take in consideration the possible formation of a mixed phase or deconfinement phase transition to a quark-gluon plasma. We point our attention in exploring the strangeness production of a hadronic system and the possible onset of the kaon condensation for the two aforementioned models. In this context, other strangeless mesons are not considered in our analysis, because they do not sensibly affect the strangeness production but they contribute mainly to the total pressure and energy density.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The paper is organized as follow. In the Sect. 2, we introduce the hadronic equation of state and the two frameworks (minimal coupling scheme and effective relativistic mean field model) with which we analyze the kaons behavior in the nuclear medium, for various values of the anti-kaon optical potential. In Sect. 3, we report and discuss our major results obtained in this comparative study, and finally in Sect. 4 we summarize our conclusions.", "cite_spans": [], "ref_spans": []}, {"section": "Hadronic equation of state", "text": "The relativistic mean field model (RMF), first introduced by Walecka and BogutaBodmer 23,24 , is widely successful used for describing the properties of finite nuclei as well as hot and dense nuclear matter 25, 26, 27, 28, 29, 30, 31, 32 . In this context, the total baryon Lagrangian density can be written as", "cite_spans": [], "ref_spans": []}, {"section": "Hadronic equation of state", "text": "where L octet stands for the full octet of baryons (p, n, \u039b, \u03a3 was originally studied by Glendenning with the following standard Lagrangian 26", "cite_spans": [], "ref_spans": []}, {"section": "Hadronic equation of state", "text": "where the sum runs over all the baryons octet, m i is the vacuum baryon mass of index i, \u03c4 = 2 t denotes the isospin operator which acts on the baryon and U (\u03c3) is the nonlinear self-interaction potential of \u03c3 meson", "cite_spans": [], "ref_spans": []}, {"section": "Hadronic equation of state", "text": "introduced by Boguta and Bodmer to achieve a reasonable compressibility for equilibrium normal nuclear matter 24,25,27 . ", "cite_spans": [], "ref_spans": []}, {"section": "Hadronic equation of state", "text": "Because we are going to describe finite temperature and density nuclear matter with respect to strong interaction, we have to require the conservation of three \"charges\": baryon number, electric charge and strangeness number. As a consequence, we have to consider three independent chemical potentials: \u00b5 B , \u00b5 C and \u00b5 S , respectively, the baryon, the electric (isospin) charge and the strangeness chemical potentials of the system 38,39 . Hence, the chemical potential of particle of index i can be written as", "cite_spans": [], "ref_spans": []}, {"section": "Hadronic equation of state", "text": "where b i , c i and s i are, respectively, the baryon, the electric charge and the strangeness quantum numbers of the i-th hadronic species. Kaons degrees of freedom are treated here in two distinct approaches: the first one, well known in literature, considers the interaction between kaons and nucleons by means of a direct minimal coupling scheme with the meson fields (\u03c3, \u03c9, \u03c1) In the first case, we can write the kaon Lagrangian density in terms of minimal coupling scheme, as follow 5,11,12,22", "cite_spans": [], "ref_spans": []}, {"section": "Hadronic equation of state", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "Hadronic equation of state", "text": "the effective kaon mass and \u03c4 3K is the third component of the isospin operator.", "cite_spans": [], "ref_spans": []}, {"section": "Hadronic equation of state", "text": "The kaon-meson vector coupling constant are obtained in the usual way, from the quark model and isospin counting rules, setting g \u03c9K = g \u03c9N /3 and g \u03c1K = g \u03c1N . Whereas the scalar g \u03c3K coupling constant is determined from the study of the real part of the anti-kaon optical potential, at the saturation nuclear density, in a symmetric nuclear matter, by setting", "cite_spans": [], "ref_spans": []}, {"section": "Hadronic equation of state", "text": "In this investigation we set the anti-kaon optical potential equal to U K \u2212 = \u221250 MeV, \u2212100 MeV and \u2212160 MeV, based on recent theoretical calculations and experimental measurements 5,8,10,11,12,13,14,15,40 . For these values of the anti-kaon potential depth, we obtain the following kaon optical potentials (U K + = \u2212g \u03c3K \u03c3 + g \u03c9K \u03c9, where the sign + in the \u03c9-field, is due to the G-parity): U K + = 47 MeV, \u22123 MeV and \u221263 MeV, respectively for U K \u2212 = \u221250 MeV, \u2212100 MeV and \u2212160 MeV, at the saturation nuclear density. In this approach we neglect the contribution of the neutral kaons (K 0 and K 0 ) because of the large uncertainty in literature on their coupling constants with the meson fields. The field equation are obtained in the usual way, from the minimization of the thermodynamic potential \u2126 H = \u2126 B + \u2126 K , with respect to the \u03c3, \u03c9 and \u03c1 meson fields", "cite_spans": [], "ref_spans": []}, {"section": "Hadronic equation of state", "text": "where \u03c3 = \u03c3 , \u03c9 = \u03c9 0 and \u03c1 = \u03c1 where \u03b3 i = 2J i + 1 is the degeneracy spin factor of the i-th baryon (\u03b3 octet = 2), n i (k) and n i (k) are the fermion particle and antiparticle distributions function:", "cite_spans": [], "ref_spans": []}, {"section": "Hadronic equation of state", "text": "The baryon effective energy E * i is defined as E * ", "cite_spans": [], "ref_spans": []}, {"section": "Hadronic equation of state", "text": "The kaons vector and scalar density (\u03c1 K and \u03c1 S K ), are given respectively by 22", "cite_spans": [], "ref_spans": []}, {"section": "Hadronic equation of state", "text": "where we set", "cite_spans": [], "ref_spans": []}, {"section": "Hadronic equation of state", "text": ", \u03be is the order parameter, obtained from the minimization of the thermodynamical potential \u2126 K (naturally for \u03be = 0 we have no condensation). Whereas, the kaon and anti-kaon distribution function are given by", "cite_spans": [], "ref_spans": []}, {"section": "Hadronic equation of state", "text": "where \u03c9 \u00b1 (p) = p 2 + m * K \u00b1 g \u03c9K \u03c9 0 + g \u03c1K \u03c4 3K \u03c1 0 stays respectively for kaons and anti-kaons effective energy and the sign (\u00b1g \u03c9K \u03c9 0 ) is due to the G-parity.", "cite_spans": [], "ref_spans": []}, {"section": "Hadronic equation of state", "text": "The kaon vector density in Eq. (15), can be viewed therefore as the sum of a \"condensate\" and a \"thermal\" contribution:", "cite_spans": [], "ref_spans": []}, {"section": "Hadronic equation of state", "text": "The total pressure and energy density is given as usual by P = P B + P K and \u01eb = \u01eb B + \u01eb K , where", "cite_spans": [], "ref_spans": []}, {"section": "Hadronic equation of state", "text": "and for the kaons one gets", "cite_spans": [], "ref_spans": []}, {"section": "Hadronic equation of state", "text": "The condition for the onset of the kaon condensation, is then given by 22", "cite_spans": [], "ref_spans": []}, {"section": "Hadronic equation of state", "text": "therefore, for a s-wave condensation at p = 0, we obtain, respectively, \u00b5 K + = \u03c9 + for K + and \u00b5 K \u2212 = \u03c9 \u2212 for K \u2212 (naturally when the condensate is not present, \u03be = 0). In the second approach, we use an alternative formulation for what concern kaon degrees of freedom, based on the self-consistent interaction between baryons 21 . In this scheme mesons are treated as a quasi ideal Bose gas with an effective chemical potential \u00b5 * , obtained from the bare one given in Eq. (5) and subsequently expressed in terms of the corresponding effective baryon chemical potentials, respecting the strong interaction. More explicitly, the kaons and anti-kaon effective chemical potential can be written as", "cite_spans": [], "ref_spans": []}, {"section": "Hadronic equation of state", "text": "where x \u03c9\u039b = g \u03c9\u039b /g \u03c9N . Thus, the effective meson chemical potentials are coupled with the meson fields related to the interaction between baryons. This assumption represents a crucial feature in the EOS at finite density and temperature and can be seen somehow in analogy with the hadron resonance gas within the excluded-volume approximation. There the hadronic system is still regarded as an ideal gas but in the volume reduced by the volume occupied by constituents (usually assumed as a phenomenological model parameter), here we have a (quasi-free) meson gas with an effective chemical potential that contains the self-consistent interaction of the meson fields.", "cite_spans": [], "ref_spans": []}, {"section": "Hadronic equation of state", "text": "Following the above scheme, we can evaluate the pressure P K and the energy density \u01eb K as a quasi-particle kaon gas considering the above effective meson potentials depending on the self-consistent interaction between baryons: where n K (p) is the meson particle distribution function, given by", "cite_spans": [], "ref_spans": []}, {"section": "Hadronic equation of state", "text": "where E K (p) = p 2 + m 2 K and the corresponding antiparticle distribution n K is obtained by substituting \u00b5 * K \u2192 \u2212\u00b5 * K . Finally, as before, the total pressure and the total energy density are simply the sum of the mesonic and baryonic components.", "cite_spans": [], "ref_spans": []}, {"section": "Results and discussion", "text": "Let us start our numerical investigation by studying in Fig. 1 the kaon to anti-kaon ratio K + /K \u2212 as a function of baryon density for different values of the anti-kaon optical potential. As expected, the ratio results to be very sensitive to the choices of the anti-kaon potential depth. At fixed temperature and by increasing the baryon density, we observe a continuous growing in the K + /K \u2212 ratio for moderate values of U K \u2212 , whereas in presence of a strong attractive potential, the ratio decreases after reaching the nuclear saturation density, mainly due to the strong reduction of the kaon effective mass. coupled-channel G-matrix theory 13 , are very close to those of the effective relativistic mean field model. Contrariwise, in absence of kaon interaction (dot dashed line) and especially at higher baryon density, we observe a strong increase in the K + /K \u2212 ratio. This effect is mainly due to the absence of an effective kaon mass and chemical potential.", "cite_spans": [], "ref_spans": []}, {"section": "Results and discussion", "text": "In Fig. 2 , we report the variation of the kaon to anti-kaon ratio as a function of the temperature at a fixed baryon density \u03c1 B = \u03c1 0 , where \u03c1 0 is the nuclear saturation density. We observe again a good correspondence between the two approaches for a moderate value of the anti-kaon optical potential. In presence of a free kaons gas, there is a strong enhancement in the K + /K \u2212 , due to the absence of the \u03c3 and \u03c9 fields self-interaction. The contribution of \u03c1-meson field appears to be instead negligible for this choice of parameter set (Z/A = 0.4) and especially at higher temperature, where anti-kaons are abundantly produced and the K + /K \u2212 rapidly decreases. Such a sensible difference in the kaon to anti-kaon ratio can be considered as a relevant feature for the determination of the real part of the anti-kaon optical potential, in the future relativistic heavy ion collision experiments at high baryon density.", "cite_spans": [], "ref_spans": []}, {"section": "Results and discussion", "text": "In Fig. 3 , we show the strangeness concentration Y S of kaons (K + ) and antikaons (K \u2212 ), hyperons (Y ) and anti-hyperons (Y ) as a function of the baryon density. The total strangeness is fixed to zero. As expected, almost all the strangeness fraction is carried by kaons and hyperons, whereas K \u2212 and anti-hyperons play a marginal role, contributing only at low baryon density and high temperatures.", "cite_spans": [], "ref_spans": []}, {"section": "Results and discussion", "text": "The results obtained through the relativistic mean field model, are in very good agreement with the minimal coupling scheme, when we set U K \u2212 = \u221250 MeV. In absence of kaon interaction (free kaon gas, dot dashed lines), at low baryon density, the kaon strangeness concentration is close to that of the relativistic mean field model, whereas, at higher \u03c1 B it converges to that of the effective minimal coupling scheme obtained for U K \u2212 = \u2212160 MeV. Instead, anti-kaons strangeness fraction do not show an appreciable variation in absence of meson-field interaction.", "cite_spans": [], "ref_spans": []}, {"section": "Results and discussion", "text": "In Fig. 4 , we report the strangeness dependence of the system at the nuclear sa-turation density \u03c1 0 for a wide range of temperatures. As we can see, the strangeness concentration is practically negligible below T = 60 MeV. Strange particles start to be abundantly produced above T = 80 MeV and the corresponding anti-particles are produced at higher temperatures. The free kaon gas case is also reported. In this context, it is relevant to note that, for a choice of U K \u2212 = \u221250 MeV, the results obtained in the minimal coupling scheme are very close to those of the relativistic mean field one, because in this case we have an effective kaon mass close to the bare one. At the increasing of the anti-kaon optical potential, the effective kaon mass rapidly decreases, deviating from the behavior of the relativistic mean field model. Before concluding, let us analyze the condition for the onset of the kaon condensation for a wide range of temperatures and baryon densities, in the two aforementioned models, considering U K \u2212 = \u221250 and \u2212160 MeV. At this purpose, in Fig. 5 , we report the threshold condition for the onset of the kaon and anti-kaon condensation (\u03c9", "cite_spans": [], "ref_spans": [{"start": 1070, "end": 1076, "text": "Fig. 5", "ref_id": "FIGREF6"}]}, {"section": "Results and discussion", "text": "at p = 0 (s-wave condensation) as a function of baryon density and at the lower temperature at which strange particles start to be produced (T = 80 MeV). We can see that the kaon/anti-kaon chemical potential \u00b5 K \u00b1 is always lower than the corresponding kaon/anti-kaon threshold energy \u03c9 \u00b1 , therefore the condition for the onset of the condensation is never reached. However, it is interesting to note that, for U K \u2212 = \u2212160 MeV, \u00b5 K + approaches \u03c9 + , but they do not come close enough to allow the formation of the condensation. Note also that for U K \u2212 = \u221250 MeV the minimal coupling curves are perfectly overlapping to that of the effective relativistic one. In absence of the kaon interaction, the effective kaon energy is obviously constant and equal to the kaon mass (\u03c9 \u00b1 = m K ). The chemical potential is close to that of the minimal coupling scheme for U K \u2212 = \u2212160 MeV, hence also in this case the threshold condition for the onset of the condensation is never reached. Analogously, in Fig. 6 , we report the variation of the kaon and anti-kaon effective energy and chemical potential for a very wide range of temperatures at the maximum baryon density explored in this work (\u03c1 B = 4 \u03c1 0 ). It is interesting to observe that both kaon and anti-kaon effective energies seem to be very little affected by variation of the temperature, contrariwise kaon and anti-kaon chemical potentials show a little increase at higher temperature (such a feature persists also by increasing the isospin asymmetry Z/A). This behavior seems to suggest that in relativistic heavy ion collision kaons can never reach the threshold condition for the onset of the condensation. Such a result appears to be in agreement with the predictions of very recent transport models 6 . The situation is of course different in systems like neutron stars, where the total strangeness is not conserved and the kaon condensation can take place 1,2,3,5 .", "cite_spans": [], "ref_spans": [{"start": 997, "end": 1003, "text": "Fig. 6", "ref_id": "FIGREF7"}]}, {"section": "Conclusion", "text": "In this work we have analyzed the strangeness production at fixed isospin density (Z/A = 0.4) and for a zero net strangeness, over a wide range of baryon densities and temperatures. At this scope we have used two different approaches, an effective relativistic mean field model, where kaons are treated as a quasi-ideal Bose gas, but with the introduction of an effective chemical potential depending on the self-consistent interaction between baryons, and a minimal coupling scheme, where kaons are directly coupled with the meson fields (\u03c3, \u03c9 and \u03c1). In this context, we have studied the influence of the kaon in-medium interaction in the determination of the kaon to anti-kaon ratio and in the strangeness production, for different values of the anti-kaon optical potential (U K \u2212 = \u221250, \u2212100 and \u2212160 MeV). The results have been also compared with the case of a noninteracting kaon particles. In this analysis, we have observed a good correspondence between the two models in particular for moderate values of the optical potential (U K \u2212 \u2243 \u221250 MeV), suggested by recent self-consistent calculation based on chiral Lagrangian and G-matrix theory 13, 14, 15 . In this condition, the kaon to anti-kaon ratio and the strangeness fraction become very close to those of the effective relativistic mean field model. Contrariwise, when we take in consideration a stronger potential depth (e.g. U K \u2212 = \u2212160 MeV), the results appear to be different, mainly due to the strong variation in the kaon effective mass in the meson-exchange model.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "We have also seen that, in absence of kaon in-medium interaction, the kaon to anti-kaon ratio rapidly diverges by the results obtained in the meson exchange and the relativistic mean field model, mainly due to the absence of the contribution of the \u03c3 and \u03c9 field into the kaon mass and chemical potential. The kaon strangeness concentration is also sensibly modified taking a behavior intermediate between that of the relativistic mean field model, at low baryon density and the minimal coupling scheme at U K = \u2212160 MeV, for higher values of \u03c1 B . Whereas anti-kaons strangeness fraction do not show an appreciable variation in absence of meson-field interaction. The strong difference in the kaon to anti-kaon ratio could be considered as a relevant feature in the determination of the real part of the anti-kaon optical potential, especially in relativistic heavy ion collisions at high baryon density 17, 19, 20 .", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "Finally, we have also analyzed the possible onset of the kaon condensation in regime of density and temperature reachable in relativistic heavy ion collisions. We have found that the kaons chemical potential is always less then the corresponding kaon threshold energy \u03c9 \u00b1 ). This matter of fact seems to suggest, in agreement with the results obtained within modern transport codes 6 , that kaon condensation does not take place at any temperature and density in those systems in rapid evolution, like the relativistic heavy ion collision, where the zero net strangeness condition is conserved.", "cite_spans": [], "ref_spans": []}], "bib_entries": {}, "ref_entries": {"FIGREF0": {"text": "The meson-nucleon couplings constant (g \u03c3N , g \u03c9N and g \u03c1N ) have been fixed to the parameters set marked as GM3 of Ref. 27 . The implementation of the model with the inclusion of the hyperons requires the determination of the corresponding meson-hyperon coupling constant, that have to be fitted to the hypernuclear pro- prieties. This can be done by fixing the scalar \u03c3-meson hyperon coupling constants to the potential depth of the corresponding hyperon in saturated nuclear matter (U N \u039b = \u221228 MeV, U N \u03a3 = 30 MeV, U N \u039e = \u221218 MeV) 33,34,35 . The obtained ratios x \u03c3Y = g \u03c3Y /g \u03c3N for the GM3 parameter set are: x \u03c3\u039b = 0.606, x \u03c3\u03a3 = 0.328 and x \u03c3\u039e = 0.322. Furthermore, following Ref.s 36,37 , the SU(6) simple quark model can be used to obtain the relations 1 3", "type": "figure"}, "FIGREF1": {"text": "12,22 , the second one considers the meson degrees of freedom as a quasi-ideal Bose gas, with an effective chemical potentials \u00b5 * depending on the self-consistent interaction between baryons 21 .", "type": "figure"}, "FIGREF2": {"text": "respectively the vector and baryon scalar density of the baryon particle of index i:", "type": "figure"}, "FIGREF3": {"text": "the effective baryon mass and the effective chemical potentials \u00b5 * i are defined as", "type": "figure"}, "FIGREF4": {"text": "Fig. 1. Kaon to anti-kaon ratio as a function of baryon density at a fixed temperature T = 120 MeV. The solid lines correspond to the results obtained in the effective relativistic mean field model, the dashed lines correspond to different values of anti-kaon optical potential and the dotdashed lines to a non-interacting free kaon gas.", "type": "figure"}, "FIGREF5": {"text": "Fig. 3. Strangeness concentration as a function of baryon density at a fixed temperature T = 120 MeV. The solid lines correspond to the results obtained in the effective relativistic mean field model, the dashed lines correspond to different values of anti-kaon optical potential and the dotdashed lines to a free kaon gas.", "type": "figure"}, "FIGREF6": {"text": "Fig. 5. Kaon and anti-kaon effective energy \u03c9 \u00b1 (p = 0) and chemical potential as a function of baryon density at T = 80 MeV in the effective relativistic mean field model (solid lines) and in the minimal coupling scheme (dashed lines) for U K \u2212 = \u2212160 and \u221250 MeV.", "type": "figure"}, "FIGREF7": {"text": "Fig. 6. The same of Fig. 5 as a function of the temperature at \u03c1 B = 4\u03c1 0 .", "type": "figure"}, "TABREF0": {"text": "and L K corresponds to the kaon meson degrees of freedom.", "type": "table"}, "TABREF1": {"text": "Strangeness production at finite temperature and baryon density in an effective relativistic mean field model 5", "type": "table"}, "TABREF2": {"text": "Strangeness production at finite temperature and baryon density in an effective relativistic mean field model 7", "type": "table"}}}
{"paper_id": "118864206", "_pdf_hash": "9f6d78b4977bad5ffb10f50b384360052872ae82", "abstract": [{"section": "Abstract", "text": "Context. Precise stellar radial velocities are used to search for massive (Jupiter masses or higher) exoplanets around the stars of the open cluster M67. Aims. We aim to obtain a census of massive exoplanets in a cluster of solar metallicity and age in order to study the dependence of planet formation on stellar mass and to compare in detail the chemical composition of stars with and without planets. This first work presents the sample and the observations, discusses the cluster characteristics and the radial velocity (RV) distribution of the stars, and individuates the most likely planetary host candidates. Methods. We observed a total of 88 main-sequence stars, subgiants, and giants all highly probable members of M67, using four telescopes and instrument combinations. We investigate whether exoplanets are present by obtaining radial velocities with precisions as good as \u224310 m s \u22121 . To date, we have performed 680 single observations (Dec. 2011) and a preliminary analysis of data, spanning a period of up to eight years. After reducing all the observations to the HARPS zero point, the RV measurements for each star are used to evaluate the RV variability along the cluster color magnitude diagram. Results. Although the sample was pre-selected to avoid the inclusion of binaries, we identify 11 previously unknown binary candidates. The RV variance (including the observational error) for the bulk of stars is almost constant with stellar magnitude (therefore stellar gravity) at \u03c3 =20 m s \u22121 . Eleven stars clearly displayed larger RV variability and these are candidates to host long-term substellar companions. The average RV is also independent of the stellar magnitude and evolutionary status, confirming that the difference in gravitational redshift between giants and dwarfs is almost cancelled by the atmospheric motions. We use the subsample of solar-type stars to derive a precise true RV for this cluster (M67 RV = 33.74 \u00b1 0.12 km s \u22121 ) . The velocity dispersion is 0.54 km s \u22121 for giants and 0.68 km s \u22121 for dwarfs, substantially lower than reported in previous works. We finally create a catalog of binaries and use it to clean the color magnitude diagram (CMD). Isochrone fitting confirms an age of around 4 Gyr. Further cleaning of the CMD based on precise RV could establish M67 as a real benchmark for stellar evolutionary models. Conclusions. By pushing the search for planets to the faintest possible magnitudes, it is possible to observe solar analogues in open clusters, and we propose 11 candidates to host substellar companions.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Searching planets in open clusters", "text": "After the discovery of the first exoplanet around 51 Peg about 16 years ago (Mayor and Queloz 1995) , more than 700 planets have been discovered, but a number of very basic questions still await answers, such as: how does the rate of planet formation depend on stellar metallicity and mass? Does planet formation strongly depend on the stellar environment?", "cite_spans": [], "ref_spans": []}, {"section": "Searching planets in open clusters", "text": "Most exoplanets have been found around bright and nearby field stars that cover a very large range of stellar characteristics.", "cite_spans": [], "ref_spans": []}, {"section": "Searching planets in open clusters", "text": "Send offprint requests to: L. Pasquini, e-mail: lpasquin@eso.org \u22c6 Based on observations collected at ESO, La Silla, Chile, OHP and HET.", "cite_spans": [], "ref_spans": []}, {"section": "Searching planets in open clusters", "text": "These studies have many advantages, but the widely differing characteristics of field stars may also limit our capability to derive precise conclusions. For instance, it is puzzling that mainsequence stars hosting giant planets are metal rich (Gonzales et al. 1997 , Santos et al. 2004 , while evolved stars that host giant planets are not (Pasquini et al. 2007) . Is this because of stellar pollution acting on main-sequence stars (e.g. Laughlin & Adams 1997) , or because planet formation favors the birth of planets around more metallic stars (Pollack et al. 1996) ? Or maybe the metal-rich planet-hosting stars belong to an inner disk population, as proposed by Haywood (2009) ? Are planet-hosting stars more depleted in Li than their non-hosting twins, as suggested by e.g. Israelian et al. (2009) (see however Baumann et al. 2010 for a different opinion) ? Or are the volatile elements depleted in the convective zones of stars that created rocky planets, as implied by the findings of Melendez et al. (2009) (see, however Gonzalez-Hernandez et al. 2010 for a different opinion)?", "cite_spans": [], "ref_spans": []}, {"section": "Searching planets in open clusters", "text": "A large number of planets discovered around stars in open clusters would provide the perfect sample to answer all the above questions. Under the very reasonable assumption that open cluster stars have similar ages and chemical compositions , Randich et al. 2005 , De Silva et al. 2007 ), a thorough, detailed chemical analysis of stars with and without planets belonging to the same cluster would provide direct answers to all the questions and hypotheses above, without any need for further speculation.", "cite_spans": [], "ref_spans": []}, {"section": "Searching planets in open clusters", "text": "Similarly, it is now quite clear that stellar mass has a great influence on the frequency of giant planets (Lovis & Mayor 2007 , Johnson et al. 2010 , although the precise dependence of the planet rate on stellar mass is not yet known. In addition, a large number of giant planets around stars of open clusters, which have precisely determined masses, would provide an ideal database to study this dependence.", "cite_spans": [], "ref_spans": []}, {"section": "Searching planets in open clusters", "text": "Finally, although most stars were born in stellar clusters and star associations, very little is known about the frequency of planetary systems in different environments, and on how their survival and evolution changes with it. A lot will be learned about this by directly imaging star forming regions, but the comparison between field and cluster statistics will help us to understand this point.", "cite_spans": [], "ref_spans": []}, {"section": "Previous searches", "text": "In spite of the importance of finding planets in open clusters, the literature on the subject is so far rather limited. The search for planets in open clusters with the RV technique has been limited to the studies of Paulson et al. (2002 Paulson et al. ( , 2004 around main-sequence stars of the Hyades, and the search for planets around evolved stars in a few clusters by Lovis & Mayor (2007) and around the Hyades giants (Sato et al. 2007 ). Paulson et al. did not find any evidence of short-period giant planets around the Hyades dwarfs, and excluded a high rate of hot jupiters in this high metallicity cluster. Several potential long-term candidates were present in their sample, but they did not perform any follow-up for longer periods. Sato et al. (2007) found a long-period giant planet around one of the Hyades clump giants, and that there are only three such stars in this cluster led the authors to conclude that stellar mass has a significant influence on the giant planet rate. Finally, Lovis & Mayor (2007) collected RV observations of evolved stars in open clusters for several years. They found evidence of a couple of sub-stellar mass objects, and used statistical arguments to conclude that a higher stellar mass is more likely to promote the formation of massive planets.", "cite_spans": [], "ref_spans": []}, {"section": "Previous searches", "text": "Although the probability of finding a transiting exoplanet in an open cluster is rather low (van Saders & Gaudi 2011) , open clusters (OC) have been targeted for extensive transit searches in the past few years (Bruntt et al. (2003) , Street et al. (2003 ), von Braun et al. (2005 , Bramich et al. (2005) , Mochejska et al. (2005) , Burke et al. (2006) , Aigrain et al. (2006 ), and Hartman et al. (2009 . However, only a handful of weak, unconfirmed candidates have been so far identified .", "cite_spans": [{"start": 355, "end": 375, "text": "Aigrain et al. (2006", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Previous searches", "text": "Being much richer in stars than OCs, globular clusters (GCs) are of greater statistical significance, particularly in the case of a null detection (which always seems to be the case). Only a few GCs so far have been systematically searched for exoplanet transits. Among these, we may mention the groundbased campaigns targeting 47 Tucanae (Weldrake et al. 2005) and \u03c9 Centauri (Weldrake et al. 2008) , both searching for hotJupiters around upper main-sequence stars in the outskirts of these two clusters, and both providing no significant exoplanet transit candidate.", "cite_spans": [{"start": 377, "end": 399, "text": "(Weldrake et al. 2008)", "ref_id": "BIBREF76"}], "ref_spans": []}, {"section": "Previous searches", "text": "The systematic photometric search that had placed the tightest constraints on the planet-frequency occurrence in a cluster, was that of Gilliland et al. (2000) . This work was based on Hubble Space Telescope (HST) WFPC2 images of the dense core of 47 Tuc, which was monitored for \u223c8.3 days during which about 34,000 upper main-sequence stars were observed. Gilliland et al. (2000) found no exoplanet transits, and concluded that the planet occurrence in 47 Tuc is smaller by a factor of ten than for field stars. Nascimbeni et al. (2012) analyzed a similar HST data set (based this time on ACS/WFC images) in an outer field of the GC NGC 6397. For the first time, this work focused on searching for hot-Jupiters among low mass stars (K and M spectral types). Again, no high-significance planetary candidate was detected, but owing to the lower quality statistics no firm conclusion was reached about the occurrence of giant planets in M and K stars of NGC 6397.", "cite_spans": [], "ref_spans": []}, {"section": "Previous searches", "text": "The cause of the lack of close-in planets in GCs is not fully understood. Presumably the low metallicities and/or the dense environments interfere with planet formation, leading to orbital evolution to close-in positions, and/or planet survival.", "cite_spans": [], "ref_spans": []}, {"section": "Why a search in M67?", "text": "M67 is one of the most well-studied open clusters. It has been comprehensively observed to establish astrometric membership (Sanders 1977 , Girard et al. 1989 , Yadav et al. 2008 , precise photometry (Montgomery et al. 1993 , Sandquist 2004 , and a rather precise RV and binary search , Melo et al. 2001 ). X-ray sources have been identified (Pasquini & Belloni 1998 , Van den Berg et al. 2004 , and was one of the first clusters for which observations of stellar oscillations were attempted (Gilliland et al. 1991) . Its chemical composition and age are very close to solar values (Randich et al. 2006 , Pace et al. 2008 ,\u00d6nehag et al. 2010 and it hosts very good candidates for solar twins (Pasquini et al. ,\u00d6nehag et al. 2010 .", "cite_spans": [], "ref_spans": []}, {"section": "Why a search in M67?", "text": "For an open cluster, M67 is quite rich in stars, and its color magnitude diagram (CMD) is well populated in the main sequence, in the subgiant and red giant (RGB) branches. With a distance modulus of 9.63 ) and a low reddening (E(B-V)=0.041, Taylor 2007), the solar stars have an apparent magnitude of V=14.58 and a (B-V) of 0.69 , and the cluster contains more than 100 stars brighter than this magnitude suitable for a RV planet search.", "cite_spans": [], "ref_spans": []}, {"section": "Sample and Observations", "text": "We selected stars that are proper motion members with a probability higher than 60% from Yadav et al. (2008) and also RV members, and unknown binaries from previous studies. In this context we recall the extended work of Mathieu and coworkers ), who made a very complete RV survey of the evolved stars of M67 with a precision of a few hundred m s \u22121 . The majority of the other stars were selected following Pasquini et al. (2008) , who used several VLT-FLAMES exposures for each star to classify suspected binaries. The full sample includes a total of 88 stars, from solar type (faintest is V\u223c15) to the tip of the RGB. The stars are rather faint for precise radial velocity observations, but a RV precision of \u223c10 m s \u22121 can be obtained for each measurement even for the faintest objects, with observations shorter than one hour at the ESO 3.6m telescope.", "cite_spans": [], "ref_spans": []}, {"section": "Sample and Observations", "text": "The bulk of the observations were carried out with HARPS at the ESO 3.6m telescope (Mayor et al. 2003) , and this instrument is our reference for all the observations. Given the superior performances of HARPS, we concentrated mostly on the faintest objects with this facility.", "cite_spans": [], "ref_spans": []}, {"section": "Sample and Observations", "text": "After the project started, we added the sample of evolved stars observed by CORALIE in the years [2003] [2004] [2005] , as part of a program of planet search of giants in open clusters (cfr. Lovis & Mayor 2007) . One limitation of our program is the sparse sampling frequency of the observations: typically a few nights/yr were awarded in the period January-April, and large gaps, longer than six months, are present between one season of observations and the next. We tried to gather HARPS observations for stars all over the CMD, to have enough points to derive proper zero-point offsets for the other instruments. Figure 1 presents the CMD of M67, using the photometry of Yadav et al. (2008) and stars with at least 60 % membership from proper motions. The sample stars are marked in green, and spectroscopic binaries (see Table 6 ) in red.", "cite_spans": [], "ref_spans": [{"start": 617, "end": 625, "text": "Figure 1", "ref_id": "FIGREF0"}, {"start": 826, "end": 833, "text": "Table 6", "ref_id": "TABREF4"}]}, {"section": "HARPS observations", "text": "HARPS (Mayor et al. 2003 ) is the planet hunter at the ESO 3.6m telescope. In high accuracy mode (HAM) it has an aperture on the sky of one arcsecond, and a resolving power of 115000. The spectral range covered is 380-680 nm. In addition to be exceptionally stable, HARPS achieves the highest precision using the simultaneous calibration principle: the spectrum of a calibration (Th-Ar) source is recorded simultaneously with the stellar spectrum, with a second optical fibre. Since the M67 stars are quite faint for this instrument, we opted to use HARPS in the high efficiency mode: the fibre has a larger aperture on the sky (1.2 arcseconds, corresponding to R=90000) and is not equipped with an optical scrambler. This mode is limited to a precision of a few (5-7) m s \u22121 , but it is 30-40 % more efficient than the HAM mode. For our purposes this precision is sufficient, and the improved efficiency ensures that a high enough signal-to-noise (S/N) ratio can be obtained even for the faintest stars. As a rule of thumb we can consider that the precision of HARPS scales as \u01eb RV \u221d 1/(S /N) (see below). Since the aim of this giant planet survey is a precision of the single measurement of \u223c 10 m s \u22121 , it is possible to reach our goal with limited S/N observations, of on the order of S/N=10 at the peak of the signal. As a consequence, we can limit the integration time to less than one hour even for the faintest stars. Our HARPS spectra have typically a peak S/N of 15 for the faintest stars.", "cite_spans": [], "ref_spans": []}, {"section": "HARPS observations", "text": "HARPS is equipped with a very powerful pipeline that provides on-line RV measurements, which are computed by cross correlating the stellar spectrum with a numerical template mask. This on-line pipeline also provides an associated RV error. For all of our stars, irrespective of the spectral type and luminosity, we used the solar template (G2V) mask. Figure 2 shows the error associated with the HARPS RV measurements versus (vs.) the S/N of the observations computed at the middle of echelle order 50 (555 nm) for the faintest stars of the sample (Vmag >14). The RV precision scales approximately as \u01eb RV \u223c 100/(S /N) when expressed in m s \u22121 and it levels off, as expected, at 8 m s \u22121 for S/N above 13 for this order. In the figure, the uncertainty associated with each RV measurement is also given for SOPHIE (red) and HET (black). The magnitude range of the star sample is between 10.0-14.5 for SOPHIE and 9.8-14.0 for HET.", "cite_spans": [], "ref_spans": [{"start": 351, "end": 359, "text": "Figure 2", "ref_id": "FIGREF1"}]}, {"section": "HARPS observations", "text": "Between January 2008 and March 2011 we gathered 409 observations of 88 stars with HARPS, which represent the bulk of this work.", "cite_spans": [], "ref_spans": []}, {"section": "SOPHIE observations", "text": "SOPHIE is the planet hunter at the 1.93m OHP telescope (Bouchy et al. 2006) . The instrument concept and data reduction is similar to that of HARPS; in high efficiency mode it has an aperture on the sky of three arcseconds with which a resolution of 40000 is obtained. In our first observing runs we observed all M67 stars with SOPHIE, including solar twins, but the smaller telescope diameter and the somewhat more critical weather conditions in winter at OHP than at La Silla, prompted our decision not to use this instrument further for the faintest objects.", "cite_spans": [{"start": 55, "end": 75, "text": "(Bouchy et al. 2006)", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "SOPHIE observations", "text": "We considered 34 M67 stars in common between our targets observed with SOPHIE and HARPS to compute the zero point between the two instruments. The comparison gives RV (SOPHIE)= RV HARPS -12.34\u00b18.0 m s \u22121 , with no dependence on the spectral type. This value is confirmed by the observations of the star 104Tau (HD32923), for which a difference of -11.40\u00b17.0 m s \u22121 between the two instruments is found (for a sample of 11 observations with HARPS and 5 with SOPHIE). We finally adopt a zero-point offset of -11.40 m s \u22121 between SOPHIE and HARPS.", "cite_spans": [], "ref_spans": []}, {"section": "SOPHIE observations", "text": "We analyze 78 SOPHIE observations of M67 stars with an associated precision of \u224312 m s \u22121 . Since the observations with HARPS and the other instruments were not simultaneously acquired, we can assume that the precision with which the offsets are computed also includes the contribution from the intrinsic variability of the stars (and of course the photon and the instrumental noise).", "cite_spans": [], "ref_spans": []}, {"section": "CORALIE observations", "text": "CORALIE is located at the 1.2m Euler Swiss telescope at La Silla (Baranne et al. 1996) . The M67 stars were observed between 2003 and 2005 in the framework of a larger program of search for planets around giants in open clusters (Lovis & Mayor 2007) . The technique used to measure the RV in CORALIE observations is again the same as described for HARPS. As for the other instruments, the zero-point shift to HARPS was computed by using observations of stars in common to both instruments. Since the stars in common are only giants, it is expected that the intrinsic RV variability of these stars is larger than for mainsequence objects (Setiawan et al. 2004) , and not negligible. We used ten stars in common between HARPS and CORALIE to evaluate the offset, obtaining RV(Coralie)= RV HARPS + 26.8 \u00b1 5.0 m s \u22121 . We have so far gathered 123 observations for 17 giants with CORALIE with a precision associated with these observations of \u224320 m s \u22121 .", "cite_spans": [], "ref_spans": []}, {"section": "HET Observations", "text": "HRS, mounted on the 10 m HET telescope (Tull 1998) , was the last instrument used in our survey. We were granted 70 observing runs in service mode between November 2010-April 2011. Each run consisted of two exposures of 1320 s and counts as one observation. The configuration was set to a wavelength range between 407.6 nm and 787.5 nm with a central wavelength at 593.6 nm and a resolving power of R=60000. We were able to observe 13 objects selected from our sample with 9.0\u2264Vmag\u226414.6. The S/N for the faintest stars is \u223c 10. The radial velocities were com- 2008-2011 2008-2011 2010-2011 2003-2005 Table 1 . Table presenting the number of observed stars, the total number of observations, the number of main-sequence (MS), turn-off (TO), giant stars (G) observed for each instrument.", "cite_spans": [], "ref_spans": []}, {"section": "Fig. 3.", "text": "Histogram showing the number of observations/star for our total sample. All observations from HARPS, SOPHIE, CORALIE, and HRS are included in the plot. We have observed each star on average seven times.", "cite_spans": [], "ref_spans": []}, {"section": "Fig. 3.", "text": "puted using a series dedicated routines (Cappetta et al. 2012, in preparation) . The different steps include the wavelength calibration using a Th-Ar lamp exposure performed before and after each stellar spectrum, the normalization of the spectra, the cleaning of cosmic rays and both, telluric and sky lines, the computation of the heliocentric corrections and finally the crosscorrelation of the spectrum with a G2 star template. We used the multiple exposures of the same star to estimate the typical error bar associated with the HET observations, finding an error of \u224325 m s \u22121 . When considering the different analysis used for the HET data with respect to the other instruments, it is unsurprising to find a larger offset with respect to HARPS for HRS than for the other instruments: RV (HRS)= RV(HARPS)+ 242.0 \u00b1 12 m s \u22121 ( eight stars were used for the comparison).", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "Once corrected to the zero points of HARPS, all the observations of each star were collected and analyzed together. Table 5 summarizes the main data for the observed stars. In addition to the basic stellar parameters, the number of observations per star is given, for each spectrograph and as a total. We have obtained, on average, 7 observations/star, but this ranges from a minimum of 2 to more than 20 (see Table 5 ). The histogram showing the number of observations/star is given in Figure 3 . We performed a series of Monte Carlo simulations to establish the minimum number of observations/star that we need to exclude the presence of hot Jupiters at high confidence. The preliminary results indicate that a final number of at least 9 observations/star should be reached (Brucalassi et al. 2012, in preparation) .", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "In the last two columns of Table5 the mean stellar RV of each star is given, together with the RV dispersion. Individual RV measurements will be provided in a forthcoming paper devoted to the detailed discussion of the planets' host candidates and to discussion of the presence of hot Jupiters (Brucalassi et al. 2012, in preparation) .", "cite_spans": [], "ref_spans": []}, {"section": "Binaries and CMD", "text": "One of the first findings of our survey is that, despite all the stars having been previously observed and found to have no evidence of companions, 11 stars in the original sample of 88 (13%) show RV variations that are too large to be produced by an exoplanet, or by a non-stellar object. We considered as binary candidates all the stars displaying a peak-to-peak RV amplitude of at least 1.7 km s \u22121 . Considering half of the difference as a lower limit to the orbital semi-amplitude, this amplitude corresponds to a companion of 15 Jupiter masses on a 30 day period for a circular orbit around a star of 1.2 solar masses. The RV range spanned by these stars is so large that planetary companions can be excluded, as can be seen from Figure 4 , where the RV measurements for 9 of the binary candidates are shown. The binary/long-term RV variable nature of 7 of them was confirmed by D. Latham (private communication) , who is performing a long-term RV monitoring of more than 400 M67 stars (Latham 2006) .", "cite_spans": [{"start": 992, "end": 1005, "text": "(Latham 2006)", "ref_id": "BIBREF26"}], "ref_spans": [{"start": 736, "end": 744, "text": "Figure 4", "ref_id": "FIGREF2"}]}, {"section": "Binaries and CMD", "text": "The measurements are also given in table 2, which is available in electronic form. These stars are binary candidates, and were not observed after a large variation of their RV was measured. Given that these stars are high-probability M67 propermotion members, and that their RV is close to that of the cluster, it is very likely that they are spectroscopic binaries belonging to the cluster.", "cite_spans": [], "ref_spans": []}, {"section": "Binaries and CMD", "text": "Two stars (S815 and S1197, cf Table 5 ) show peak to peak RV variations of the order of 700 /ms ; they are retained in the single star sample, although the amplitude of the RV variation is possibly too high to host a planet.", "cite_spans": [], "ref_spans": []}, {"section": "Binaries and CMD", "text": "In the process of evaluating the effects of binaries in M67 CMD, we found that binaries are identified in many works in the literature and sometimes different names are used; in addition several works have been published after the compilation of Sandquist (2004) . We therefore opted to create a new catalog of binaries in M67 that includes our candidates, binaries from the literature, as well as binary candidates from X-ray observations. The catalog is given in Table 6 , with reference to the original studies.", "cite_spans": [], "ref_spans": [{"start": 465, "end": 472, "text": "Table 6", "ref_id": "TABREF4"}]}, {"section": "Binaries and CMD", "text": "The binary stars from Table6 are plotted in Figure 1 as red points. The high percentage of binaries in M67 is unsurprising, given that to retain the stars for such a long time, M67 has the most massive stars in the core, and some mass segregation has occurred.", "cite_spans": [], "ref_spans": [{"start": 44, "end": 52, "text": "Figure 1", "ref_id": "FIGREF0"}]}, {"section": "Binaries and CMD", "text": "A complete census of the binaries in M67 is helpful because this cluster can be used to test the effects of several mechanisms debated in stellar evolution, such as diffusion and overshooting (see e.g. the discussion in Magic et al. 2010) . Cleaning of the CMD is especially important in the region of the turnoff, because, as is clear in Figure 5 , in that region binaries cannot be photometrically distinguished from single main-sequence stars. They separate more clearly along the main sequence, where a separate, detached binary sequence is present, although several fainter binaries lie on the main sequence and are photometrically indistinguishable from single stars in the CMD.", "cite_spans": [], "ref_spans": [{"start": 339, "end": 347, "text": "Figure 5", "ref_id": "FIGREF3"}]}, {"section": "Binaries and CMD", "text": "In his extensive study of M67, Sandquist (2004) created one table containing the fiducial sample of single stars and a second table with a list of interesting or peculiar stars. In the first list, 11 stars are indicated as possible binaries according to our catalog (S1305, 1458, 990, 1300, 1075, 1201, 982, 1102, 1452, 951, 820) , and one star (S1197) has large RV variations. Among these 11 binary candidates, some have weak evidence coming from a few FEROS or FLAMES multiple spectra, which had a limited precision. For instance star S1305, a low-RGB star, is indicated as a suspected binary in Pasquini et al. 2011 , but is not confirmed by our higher precision measurements (cfr. Table5). Other Sandquist' single-star sequence fiducial stars (e.g. S982, 1201, 1452) are, on the other hand, confirmed to be binaries by our high-precision RV measurements.", "cite_spans": [], "ref_spans": []}, {"section": "Binaries and CMD", "text": "Three stars of the Sandquist 'unusual stars' table are confirmed to be RV multiple candidates according to Table 6 (S1292, S816, S1011).", "cite_spans": [], "ref_spans": [{"start": 107, "end": 114, "text": "Table 6", "ref_id": "TABREF4"}]}, {"section": "Binaries and CMD", "text": "The above results show that, in spite of the large efforts to clean the CMD of M67, a number of unknown binaries are still present and the detailed comparisons required to distinguish between different potential mechanisms (Magic et al. 2010 ) could strongly benefit from additional cleaning, in particular around the turnoff.", "cite_spans": [], "ref_spans": []}, {"section": "Binaries and CMD", "text": "In Figure 5 , we show the observed region of the CMD with the isochrones from Pietrinferni et al.( 2004) , with and without overshooting. In this CMD, we also indicate the position of the solar analog, as determined in Pasquini et al. 2008 , and we impose that the tracks appropriately fit this point, in addition to the rest of the CMD. The 4 Gyr track with moderate overshooting seems to most closely represent the data. In the same figure, we also superimpose the Padova isochrones, with solar metallicity, age 4.47Gyr, and Y=0.26 (Girardi et al. 2000 , as from Girardi web page). The isochrone fits the turnoff very well, but produces a RGB and clump that are too red. The mismatch is not dramatic and may indicate some problem in either the bolometric correction used or some of the free parameters adopted (e.g. mixing length). We note that for both sets of isochrones a slightly lower reddening (E(B-V)=0.02 instead of 0.041 (Taylor 2007) ) is needed to match the colors of the turnoff. We also note that there are a number of stars, apparently with constant RVs, and a high probability of proper motion membership, that are above the main sequence. Yadav et al. 2008 ) for probable members (P \u00b5 > 60%, filled dots). Probable single stars within our sample are indicated with star symbols, and probable binaries with empty dots. The location of the Sun, as if it were within M67, is marked with the \u2299. The 4-Gyr isochrones in red and blue are from the BaSTI library (Pietrinferni et al. 2004 ) for standard models and with overshooting, respectively. The isochrone in green is a 4.47 Gyr from Girardi et al. (2000) .", "cite_spans": [], "ref_spans": [{"start": 3, "end": 11, "text": "Figure 5", "ref_id": "FIGREF3"}]}, {"section": "Binaries and CMD", "text": "This analysis confirms that, in addition to its extraordinarily similar abundance pattern, M67 has an age compatible with that of the Sun.", "cite_spans": [], "ref_spans": []}, {"section": "Binaries and CMD", "text": "Given these similarities and that the solar birthplace has not yet been identified, it is natural to ask whether M67 and the Sun were associated in the past. This problem was exhaustively studied by Pichardo et al.(2012) , who performed a full set of dynamical simulations, excluding that M67 and the Sun were born in the same cloud. This result leaves us therefore with a question mark about the birthplace of the Sun and might challenge the validity of chemical tagging, which associates stars with either clusters or associations based on the similarity of their chemical compositions (see e.g. Freeman and Bland-Hawthorn 2002).", "cite_spans": [], "ref_spans": []}, {"section": "Radial velocity variability", "text": "We first investigate the observed RV variability along the CMD. Since all the stars belong to the cluster with high probability, we have the unique opportunity to study how RV variability changes along the CMD diagram, for a given chemical composition and age. In addition, a diagram with RV variability vs. magnitude would immediately highlight any possible 'outliers', which would be the most obvious hosts of exoplanets. Setiawan et al. (2004) and Hekker and Melendez (2007) shwed that the intrinsic RV variability of giants increases with stellar luminosity and becomes large for bright, low-gravity giants. Since we cover a six magnitude interval, it could be useful to determine for each magnitude or evolutionary status a typical average RV variability. This quantity should depend solely on both, the intrinsic stellar RV variability and the RV measurement error (typical photon errors associated with the bright stars are smaller because faint star observations are limited by photon noise). Figure 6 shows the rms RV vs. V diagram for 75 single stars. Binary candidates have been excluded, and the two stars (S815 and S1197) with high RV variability are not shown.", "cite_spans": [], "ref_spans": [{"start": 1001, "end": 1009, "text": "Figure 6", "ref_id": "FIGREF4"}]}, {"section": "Radial velocity variability", "text": "Some of the stars with very little or no RV variability have very few observational points, and their small scatter is very likely the result of our low data statistics. The increase in RV scatter with stellar luminosity observed in field stars (Setiawan et al. 2004 ) is not evident in our sample. There is a possible hint of an increase in the range of magnitudes 12<V<14, but the RV variability does not increase further for the more luminous stars.", "cite_spans": [], "ref_spans": []}, {"section": "Radial velocity variability", "text": "As a general conclusion, we can say that the RV variability shown in Figure 6 is basically constant at 20 m s \u22121 (\u03c3), indepen- This is likely a combination of larger intrinsic variability for the more luminous stars and larger measurement uncertainty for the faintest ones. The excess of variability seems real, and may indicate that more stars have low mass companions. dent of the stellar magnitude. The bulk of our observations have a RV variability that is well represented by a Gaussian distribution centered at 20 m s \u22121 of width \u03c3 = 10 m s \u22121 . The unexpected flatness of the RV variability with magnitude is most likely due to the combination of two effects. In evolved stars, some measurable stellar RV variability is present, while for the faint main-sequence stars the uncertainty in the measurements increases because of the limited S/N.", "cite_spans": [], "ref_spans": [{"start": 69, "end": 77, "text": "Figure 6", "ref_id": "FIGREF4"}]}, {"section": "Radial velocity variability", "text": "To investigate these points, in Figure 7 we plot the RV variability as a function of the stellar luminosity to mass ratio (L/M). According to Kjelsden and Bedding (1995) the RV jitter induced by solar oscillations is expected to grow according to the law RV \u221d 0.23*L/M (with RV expressed in m s \u22121 ). This law is represented by the continuous line. Figure 7 illustrates the very good agreement between this scaling law and the RV variability of evolved stars in M67. The continuous line remains just below the measurements, but this does not take into account that the measurements, in addition to the stellar intrinsic variability, include measurement uncertainties that are not negligible. A fit to the evolved star data (L/M > 5) gives \u03c3 RV = 0.25 L/M + 9.3 ( m s \u22121 ), which is shown by the dashed line in Figure 7 . The observations and the predictions therefore match quite well, when the measurement errors are considered. We note that this comparison implies that the oscillation RV amplitude and its variations are of comparable size. More precise RV measurements would allow us to quantitatively investigate this point in more detail. We conclude that the M67 evolved stars show signs of intrinsic RV variability and that for most of the evolved stars the observed RV variability is consistent with that expected from the Kjelsen and Bedding (1995) scaling law for solar-type oscillations. As far as the lower main sequence is concerned, the behavior of the faint stars in our sample (which are also the least massive ones) is quite interesting, because if the RV variability observed were induced by substellar companions, this would already indicate a correlation between planet frequency and mass in M67. There are good arguments to believe that an RV variability as large as 20 m s \u22121 cannot be caused by intrinsic stellar noise, because stellar noise for solar stars scales with activity and therefore age, and M67 is almost as old as the Sun (see e.g. Saar et al. 1998 , Dumusque et al. 2011 . On the other hand we have seen that the uncertainties in the RV measurements of faint stars is above 10 m s \u22121 (cfr Figure 2 ) but well below 20 m s \u22121 . We investigated whether other instrumental effects, not included in the data analysis, could affect the RV measurement precision at low count levels. At least two effects could influence the observations, and we investigated whether our measurements depend on observational parameters, such as the observed flux or airmass. A dependence on flux could be induced, for instance, by CCD transfer inefficiency, which has been reported to be high in SOPHIE (Bouchy et al. 2009) . A dependence of RV on airmass could instead indicate that some systematic effects are induced by the HARPS atmospheric dispersion compensator at high airmass or by the guiding system of the telescope. For every solar star, we therefore computed the \u2206RV of each observation with respect to the average stellar radial velocity, and analyzed all the measurements of all stars together, as functions of counts and airmass. No trend is present, as is clear from Figure 8 , where the \u2206RV is plotted vs. the square of the S/N at 550 nm. We conclude therefore that these two quantities do not affect our measurements in an appreciable way. We note that in these comparisons only the HARPS data have been used, because they by far dominate the faint star statistics.", "cite_spans": [], "ref_spans": [{"start": 2126, "end": 2134, "text": "Figure 2", "ref_id": "FIGREF1"}]}, {"section": "Radial velocity variability", "text": "With a RV variability for the whole sample centered at 20 m s \u22121 and a width \u03c3 of 10 m s \u22121 , we can safely assume that stars with a RV variability at or above 50 m s \u22121 are very good candidates for low mass companion hosts. A number of stars (9) stand out clearly from the general constant trend of Figure 3 , showing a \u03c3 RV variability of 50 m s \u22121 or larger. These stars (plus S815, and S1197, which are not included in the figure) are candidates to host giant planets or substellar objects. Another 6 candidates have smaller, but still interestingly large RV variability, and deserve to be investigated further. The list of the most likely 11 candidates is given in Table 3 .", "cite_spans": [], "ref_spans": [{"start": 670, "end": 677, "text": "Table 3", "ref_id": "TABREF2"}]}, {"section": "Radial velocity variability", "text": "Several stars show clear long trends of RV variability compatible with the presence of a planet, but the baseline is not yet long enough to determine the nature of the companion. More RV points are required and are being acquired. A full analysis of the data of our completed survey will be published elsewhere (Brucalassi et al. 2012) . Fig. 7 . Radial velocity variability \u03c3 RV of the observed stars vs. the luminosity/mass ratio. The solid line represents the scaling law proposed by Kjeldsen and Bedding (1995) to extrapolate solar type oscillations to other stars. To plot the scaling law a fixed value (1.2 M \u2299 ) for the mass has been assumed. To first approximation all M67 evolved stars have the same mass. The continuous line is the scaling law, the dashed line is the best fit to the evolved stars data, which is perfectly consistent with the scaling law, when measurement uncertainties are taken into consideration. Fig. 8 . Difference in RV measurement from the average for faint stars in the sample vs. the square of the S/N at 550 nm, a quantity that is roughly proportional to the flux recorded in the spectra. No trend is visible, and this indicates that if detector charge transfer inefficiency is present, it does not affect our measurements in a detectable way.", "cite_spans": [], "ref_spans": []}, {"section": "Radial velocity variability", "text": "The large scatter in the radial velocities, in excess of the measurement errors, may indicate that more stars, in addition to those indicated in Table 3 are suitable candidates for hosting planets.", "cite_spans": [], "ref_spans": [{"start": 145, "end": 152, "text": "Table 3", "ref_id": "TABREF2"}]}, {"section": "Radial velocity variability", "text": "Keeping in mind that we are only sensitive to rather massive planets, we find it interesting that our candidates should all have long orbital periods. Mayor et al. (2011) found clear evidence that the most massive planets tend to have long orbits, which is perfectly in line with our results. Similarly, if all 9 candidates were planets, they would correspond to a frequency of giant planets of \u223c 13%, which agrees with the rate of giant planets found by Mayor et al. (2011) and by D\u00f6llinger et al. (2012, in preparation) around evolved stars.", "cite_spans": [], "ref_spans": []}, {"section": "Radial velocity variability", "text": "3.3. Gravitational redshift in M67 and cluster radial velocity Pasquini et al. (2011) used FEROS and literature observations of M67 stars to investigate whether gravitational redshift could be detected in the stars of this cluster, by comparing the measured RV of the cluster dwarfs and giants. Their adopted technique assumes that the subsamples of cluster stars share the same cluster RV, irrespective of their mass and evolutionary status.", "cite_spans": [], "ref_spans": []}, {"section": "Radial velocity variability", "text": "These authors found that, when using the radial velocities derived from cross correlation masks, there was no evidence of gravitational reddening: giants and dwarfs have, within the RV uncertainties, the same radial velocity. They also showed that this behavior is compatible with the shifts and asymmetries of spectral lines predicted by 3D models. They found in addition that M67 giants are dynamically cooler than dwarfs.", "cite_spans": [], "ref_spans": []}, {"section": "Radial velocity variability", "text": "Although our sample is smaller than the one used by Pasquini et al. (2011) , our RV data are 10-20 times more precise, and, in addition, the many observations acquired have allowed us to eliminate several binaries, which would cause the cluster to appear dynamically hotter and perhaps introduce a skewness in the RV distribution. Since all our newly discovered binaries are on the main sequence, they might have influenced the conclusions about the dynamical status of the cluster, making the dwarfs appear dynamically hotter. Pasquini et al. (2011) derived a \u03c3 giants = 680 m s \u22121 and a \u03c3 dwar f s = 900 m s \u22121 and estimated that their FEROS RV precision is of \u223c300 m s \u22121 . The RV precision of our measurements is more than one order of magnitude more accurate than these values. For the first time we have gathered a sample of stars in M67 whose RV measurement errors are definitely negligible with respect to the cluster dynamics. Figure 9 shows the distribution of stellar RV vs. stellar magnitude, and Figure 10 the same RV but vs. the ratio of stellar mass to radius (see Pasquini et al. 2011 for details) . If gravitational reddening were the only process acting, we would expect a dependence of RV = RV 0 + 0.632(M/R).", "cite_spans": [], "ref_spans": [{"start": 936, "end": 944, "text": "Figure 9", "ref_id": "FIGREF5"}, {"start": 1009, "end": 1018, "text": "Figure 10", "ref_id": "FIGREF0"}]}, {"section": "Radial velocity variability", "text": "There is clearly no significant dependence of RV on either magnitude or M/R, confirming the FEROS results of . A least squares fit to the V-RV diagram gives RV = 33.362 + 0.0295 * V, where the angular coefficient is closely compatible with zero (error is 0.047).", "cite_spans": [], "ref_spans": []}, {"section": "Radial velocity variability", "text": "The average radial velocity of all stars is 33.724 kms \u22121 , with a dispersion of \u00b10.646 km s \u22121 . By dividing the sample into \"giants\" and \"dwarfs\" at B-V=0.7, we find \u03c3 giants = 540 m s \u22121 (\u00b1 90 m s \u22121 , 18 stars, v=33.67) and \u03c3 dwar f s = 680 m s \u22121 (\u00b163 m s \u22121 , 59 stars, v=33.74).", "cite_spans": [], "ref_spans": []}, {"section": "Radial velocity variability", "text": "By computing the ratio mass to radius for each star (cf. Pasquini et al. 2011) we find that RV depends only very slightly on M/R, with an angular coefficient of 0.096 that is much smaller than the 0.6 expected from gravitational reddening (cf. Figure 6 ), confirming the results of Pasquini et al. (2011) .", "cite_spans": [], "ref_spans": [{"start": 244, "end": 252, "text": "Figure 6", "ref_id": "FIGREF4"}]}, {"section": "Radial velocity variability", "text": "In the future we plan to merge all the HARPS spectra acquired for each star to perform a detailed spectroscopic study, including chemical abundance and line-shift analyses.", "cite_spans": [], "ref_spans": []}, {"section": "Radial velocity variability", "text": "Since the present RV measurements are much more precise than in the past, the RV dispersion is smaller than that found by Pasquini et al. (2011) . If we attribute the difference between the giant dispersion found in Pasquini et al. (2011) (680 m s \u22121 ) and that found in this paper (540 m s \u22121 ) entirely to the FEROS RV uncertainty, \u01ebRV Feros \u223c \u221a (680 2 \u2212 540 2 ), this would be approximately 400 m s \u22121 . The value is slightly larger than the FEROS errors estimated by Pasquini et al. (2011) (300 m s \u22121 ), but it is not unreasonable when considering that for most FEROS stars only one observation was available, so some intrinsic stellar RV variability should also contribute to the difference.", "cite_spans": [], "ref_spans": []}, {"section": "Radial velocity variability", "text": "Finally we use the solar-stars radial velocities to compute the true radial velocity of the cluster. We consider that, what is commonly called 'radial velocity' is the measure of the center of the cross-correlation function (CCF) between the stellar lines and a digital mask that in our case is based on the solar spectrum. This implies that the measured Doppler velocity includes the stellar radial velocity, the effects of stellar atmospheres, and the errors in the positioning of the lines in the digital mask (see Lidegren and Dravins 2003) .", "cite_spans": [], "ref_spans": []}, {"section": "Radial velocity variability", "text": "Our observations span the whole cluster and include many solar-type stars. This allows us to properly convert the measured Doppler shifts of the single stars into a measurement of the true radial velocity of the cluster. We therefore analyze only the 36 stars most similar to the Sun, in the range 14.0< V <15. The magnitude of the closest solar analogs is V\u223c14.58 (Pasquini et al. ,\u00d6henaag 2010 . The only two underlying hypotheses are that as a group these stars share the same cluster velocity and that they are representative of the solar spectrum. The average Doppler shifts for the CCF of these 36 stars is M67 Ds =33.83 kms \u22121 , with a \u03c3= 712 m s \u22121 , which implies that the associated uncertainty for M67 Ds is 118 m s \u22121 . To compute the true radial velocity of the cluster, we must correct in addition for the zero-point offset of the G2 mask used. We did this by using the asteroid observations of Ceres obtained by HARPS and described in Molaro et al. (2008) and Molaro & Centurion (2011) . The expected radial velocity of the asteroids with respect to La Silla can be computed rather accurately, and the difference between the computed and the measured radial velocity gives the zero offset of the mask from the solar spectrum. With this procedure, we can pass from Doppler shift measurements to the true radial velocity of solar stars. Table 4 shows the results of the expected vs. measured Ceres radial velocity: the two results are very consistent, to the order of 1 m s \u22121 , indicating a shift for the mask of 94.5 m s \u22121 . This velocity must be subtracted from the measured M67 Ds to obtain the true cluster radial velocity, which is therefore M67 RV = 33.74 \u00b10.12 kms \u22121 .", "cite_spans": [], "ref_spans": [{"start": 1350, "end": 1357, "text": "Table 4", "ref_id": "TABREF3"}]}, {"section": "Radial velocity variability", "text": "We note that the error given by the zero-point correction of the mask is completely negligible compared to the uncertainty introduced by the cluster internal motions. Therefore, by enlarging the sample of solar-type stars, the final error could easily be diminished and very precise measurements of the radial velocity of the cluster could be obtained. This mask offset can also be applied to solar-type field stars to derive their true radial velocities, and this method could be extended to determine precise RV offsets as a function of stellar gravity and temperature for solar metallicity stars. Finally, true radial velocities could then be determined for field stars of different spectral types.", "cite_spans": [], "ref_spans": []}, {"section": "Radial velocity variability", "text": "Our new data confirm that the dwarfs are dynamically hotter (ratio 1.25) than the giants in this cluster. All the derived parameters agree very well with those computed by the maximum likelihood estimation in Pasquini et al. (2011) .", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "We have presented a long-term search program for giant planets in the solar-age, solar-metallicity open cluster M67.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "We have used four different instruments, and, after finding proper zero-point corrections to HARPS, we have analyzed 680 observations for 88 stars. Twelve new binaries have been identified and we have created a catalog of known binaries in M67, which we have used to clean the cluster CMD. We have found that the CMD is well represented by tracks of solar age with some overshooting. The observed RV variability does not depend very strongly on the stellar magnitude. The evolved stars show a RV variability that follows the Kjeldsen and Bedding (1995) scaling law for solar oscillations quite closely, while the RV variability for the main-sequence stars is dominated by the RV measurement uncertainties.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "Eleven stars show long-term RV variability in a range that make them interesting candidates for exoplanet hosts. If confirmed, their long period and fraction would agree with recently derived statistics for field stars (Mayor et al. 2011) .", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "We finally used our precise RV measurements to confirm that no gravitational redshift is measured between M67 giants and dwarfs, confirming that the velocity dispersion of main-sequence stars is larger than that of giants (680 vs. 540 m s \u22121 , respectively). We determined the zero-point shift of the G2 mask of HARPS and by using the solar stars we determined a true M67 radial velocity of 33.74\u00b10.12 kms \u22121 . We have shown that the search for planets in open clusters is a really powerful tool for investigating a large number of questions related to planet formation and stellar evolution. The new generation of spectrographs, such as ESPRESSO (Pasquini et al. 2009 ), will make this search more effective and precise. Table 5 . Observed targets in M67. Stars B \u2212 V colors, apparent V magnitudes, and spectroscopic data. For object identifications, 'S' are from Sanders (1977) ; 'YBP' from Yadav et al. (2008) ", "cite_spans": [{"start": 647, "end": 668, "text": "(Pasquini et al. 2009", "ref_id": "BIBREF52"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Tenth Anniversary of 51 Peg-b: Status of and prospects for hot Jupiter studies", "authors": [{"first": "S", "middle": [], "last": "Aigrain", "suffix": ""}, {"first": "J", "middle": [], "last": "Irwin", "suffix": ""}, {"first": "S", "middle": [], "last": "Hodgkin", "suffix": ""}], "year": 2006, "venue": "", "link": null}, "BIBREF4": {"title": "Tenth Anniversary of 51 Peg-b: Status of and prospects for hot Jupiter studies", "authors": [{"first": "F", "middle": [], "last": "Bouchy", "suffix": ""}], "year": 2006, "venue": "", "link": null}, "BIBREF25": {"title": "Complementary Approaches to Double and Multiple Star Research", "authors": [{"first": "D", "middle": ["W"], "last": "Latham", "suffix": ""}, {"first": "R", "middle": ["D"], "last": "Mathieu", "suffix": ""}, {"first": "A", "middle": ["A E"], "last": "Milone", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Davis", "suffix": ""}], "year": 1992, "venue": "", "link": null}, "BIBREF26": {"title": "Modelling Dense Stellar Systems, 26th meeting of the IAU", "authors": [{"first": "D", "middle": ["W"], "last": "Latham", "suffix": ""}], "year": 2006, "venue": "Joint Discussion", "link": null}, "BIBREF52": {"title": "Science with the VLT in the ELT Era", "authors": [{"first": "L", "middle": [], "last": "Pasquini", "suffix": ""}, {"first": "", "middle": ["A"], "last": "Manescau", "suffix": ""}], "year": 2009, "venue": "Astrophysics and Space Science Proceedings", "link": "109544792"}, "BIBREF66": {"title": "Exoplanet in M67 -I", "authors": [{"first": "L", "middle": [], "last": "Pasquini", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF76": {"title": "VII: New binary candidates from our Sample VIII: Pasquini & Belloni", "authors": [{"first": "David", "middle": ["T F"], "last": "Weldrake", "suffix": ""}, {"first": "P", "middle": ["D"], "last": "Sackett", "suffix": ""}, {"first": "T", "middle": ["J"], "last": "Bridges", "suffix": ""}, {"first": "", "middle": [], "last": "Ii: Pasquini", "suffix": ""}], "year": "", "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Fig. 1. Color-magnitude diagram (CMD) of M67. The photometry is from Yadav et al. 2008. Only stars with a high membership probability (\u226560 %) are shown. Known binaries, either from this work or the literature (cfr. Table 6) are shown in red colors. The stars observed in this survey are marked in green.", "type": "figure"}, "FIGREF1": {"text": "Fig. 2. Errors in the RV measurement of single observations vs. S/N at 550 nm for HARPS (green points, only observations of MS faint stars), SOPHIE (red points, all measurements, typically TO and evolved stars) and HET (black points, all measurements,mostly TO and evolved stars) are presented. The precision of the majority of the measurements for the faint stars is between 10 and 20 m s \u22121 . For HARPS, systematic dominates the uncertainty at 8 m s \u22121 for S/N's above \u223c13 in EGGS mode. For our SOPHIE observations we estimate that systematic effects (not included in the figure) dominate the error below \u223c12 m s \u22121 . The V mag range of the star sample for SOPHIE and HET is brighter than HARPS.", "type": "figure"}, "FIGREF2": {"text": "Fig. 4. Radial velocity curves of 9 binary candidates. The minimum span in RV is about 1.7 km s \u22121 . The error bars are not shown. Different colors refer to HARPS (black), SOPHIE (red), and HET (green) observations. The other two binary stars not shown have double-line CCF, so are double-line spectroscopic binaries.", "type": "figure"}, "FIGREF3": {"text": "Fig. 5. Color-magnitude diagram (CMD) of M67 (photometry from Yadav et al. 2008) for probable members (P \u00b5 > 60%, filled dots). Probable single stars within our sample are indicated with star symbols, and probable binaries with empty dots. The location of the Sun, as if it were within M67, is marked with the \u2299. The 4-Gyr isochrones in red and blue are from the BaSTI library (Pietrinferni et al. 2004) for standard models and with overshooting, respectively. The isochrone in green is a 4.47 Gyr from Girardi et al. (2000).", "type": "figure"}, "FIGREF4": {"text": "Fig. 6. Radial velocity (RV) variability of the observed stars vs. V magnitude. The bulk of the stars show a flat behavior. This is likely a combination of larger intrinsic variability for the more luminous stars and larger measurement uncertainty for the faintest ones. The excess of variability seems real, and may indicate that more stars have low mass companions.", "type": "figure"}, "FIGREF5": {"text": "Fig. 9. M67 stellar magnitude -RV diagram for our observations. No dependence of the stellar RV on the stellar magnitude is present. The data confirm previous findings that the dwarfs are dynamically hotter than giants.", "type": "figure"}, "FIGREF6": {"text": "Fig. 10. M67 radial velocity vs. M/R for all stars. No strong dependence of the stellar RV on M/R is present. Gravitational redshift would predict a 0.6 slope.", "type": "figure"}, "TABREF1": {"text": "The binary candidates of our sample", "type": "table"}, "TABREF2": {"text": "Stars with the largest RV variability, which are candi- dates to host substellar companions", "type": "table"}, "TABREF3": {"text": "Predicted and measured CERES RVs. Mid Julian dates and predicted RVs are taken from Molaro et al. 2008. In the last column, \u2206RV indicates RV measured -expected, and pro- vides the zero-point offset of the HARPS mask for solar stars, in m s \u22121 .", "type": "table"}, "TABREF4": {"text": ". The full table is available in electronic form only. Object B \u2212 V V Obs HARPS Obs SOPHIE Obs CORALIE Obs HET TOT RV( km sBinary candidates in M67. Stars B \u2212 V colors, apparent V magnitudes. For object identifications, 'S' are from Sanders (1977);'YBP' from Yadav et al. (2008). The full table is available in electronic form only.", "type": "table"}}}
{"paper_id": "118865058", "_pdf_hash": "869fba9ed6e731e81671f0b32a2714a4762be48d", "abstract": [{"section": "Abstract", "text": "Abstract. In this work we revisit the MIT bag model to describe quark matter within both the usual FermiDirac and the Tsallis statistics. We verify the effects of the non-additivity of the latter by analysing two different pictures: the first order phase transition of the QCD phase diagram and stellar matter properties. While, the QCD phase diagram is visually affected by the Tsallis statistics, the resulting effects on quark star macroscopic properties are barely noticed.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Although quantum chromodynamics (QCD) is the theory underlying the physics described by the strong interaction, its solution is far from being possible. This fact led to the developments of two complementary theoretical approaches: lattice quantum chromodynamics (LQCD) and effective models, both of them aiming to describe the QCD phase diagram. At this moment, due to computational limitations and numerical difficulties, as the sign problem, for instance, LQCD can only cover a small fraction of the QCD phase diagram, restricted to zero and very low chemical potentials [1] . On the other hand, effective models rely largely on the mean field approximation and not well known hyperonic potentials, depending on which part of the QCD phase diagram one wants to study. Recent investigations taking into account a large number of relativistic models [2] have shown how fragile and model dependent the results can be [3, 4] .", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "In view of these obstacles, alternative phenomenological approaches increase in importance. Among those phenomenological attempts to describe high energy data, the power-law associated to Tsallis statistics is widely used [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] . This approach considers that the highly excited system formed in high energy collisions follows Tsallis statistics instead of Boltzmann statistics, with the entropic index q as a measure of the deviation respect to the latter theory [15] .", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Although the first applications of Tsallis statistics in high energy physics were mainly empirical [16] , it was shown later that a generalisation of the self-consistent thermodynamics [17] exists, as proposed by Hagedorn [18] , but taking into account the non extensive behaviour of the Send offprint requests to: D\u00e9bora P. Menezes Correspondence to: debora.p.m@ufsc.br Tsallis statistics. This non extensive statistics predicts a limiting (or critical) temperature as well as a parameter q o characteristic for all hadrons. Several analyses of transverse momentum distribution from high energy collisions confirmed such predictions [8, 17, [19] [20] [21] [22] [23] , and also an analysis of hadron mass spectrum has shown that the non extensive theory can describe very well the known hadronic states [21] .", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "An important region of the QCD phase diagram is the one where a liquid-gas (type) phase transition is possible and the effects of admitting non-extensivity have already been exploited in [24] . Other important region is the one at low temperatures and high densities, which characterises compact objects, (neutron stars, pulsars, quark stars) one of the aims of the present work.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "More recently, it has been shown that a fractal structure in the thermodynamic functions leads the system to be naturally described by Tsallis statistics [7] . Since the Hagedorn and Frautisch [6, 18] descriptions of hadrons already present such fractal structure, one may conclude that the use of Tsallis statistics for hadronic systems is a consequence of the well-known self-similar characteristics of the hadron structure. Such self-similar feature of hadrons is found in experimental data [9, 10] through different and complementary aspects. The present work presents an attempt to include such self-similarity in the MIT bag model for hadron structure.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "We next concentrate our attention on quark matter described by the simplest possible relativistic model, the MIT bag model [25] , which was developed at the Massachusetts Institute of Technology in the 70s. We first check how the QCD phase diagram is modified once the Fermi statistics is replaced by the Tsallis statistics and then apply the model to the description of quark stars, which are compact stellar objects constituted of deconfined quark matter.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "In previous works [26, 27] , neutron star macroscopic properties have already been investigated with a relativistic model that is popular for this purpose, known as BogutaBodmer [28] or non-linear Walecka model [29] . Within this context, non-extensive statistics can be interpreted as an alternative to account for the not always well justified assumptions underlying mean field approximations [30] . Usually, non-extensivity (or rather non-additivity, as we prefer to put it) is incorporated by simply replacing the usual Boltzmann-Gibbs [31] or Fermi-Dirac statistics [26, 27, 30] without affecting the original structure of the models under investigation. A general conclusion was that a q value larger than one produces families of stars with slightly larger maximum masses. No conclusive statement could be made as far as radii were concerned. In [26] , q values smaller than one were also used and the results went to the opposite direction, i.e., maximum masses were lower. Once the entropy was fixed at one of the commonly used snapshots of the stellar evolution, it was seen that the star internal temperature tended to decrease with the increase of the q parameter. Walecka type models contain two distinct parts in their Lagrangian density: a Fermi kinetic contribution and a part that mimics the strong interaction by coupling mesons to hadrons. It is fair to say that it is not easy to see how non-additivity affects each contribution separately. In [27] , an attempt was made by analysing a free-Fermi gas at a fixed temperature (very academic and unrealistic picture) modified to incorporate Tsallis statistics with q values larger than one and the resulting maximum mass showed a behaviour opposite to the case when the Walecka model was used and based on a fixed entropy picture, an indication that the effects of the non-additivity might be larger in the interaction terms that mimics the strong interaction than in the kinetic part of the EOS.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The model we have chosen to work with in the present study is simple enough to be compared with a free Fermi gas model because all the information on the strong interaction comes from a constant, as will be clearly shown in the next section. Hence, by investigating quark matter with the MIT bag model, our intention is to shed some light to the understanding of the effects of the Tsallis statistics on the QCD phase diagram and also on quark stars. A preliminary calculation of the effects of non--extensivity on relativistic Fermi gas can be seen in [31, 32] .", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Strange (quark) stars were first proposed as a realisation of deconfined quark matter at very high densities, which according to the Bodmer-Witten conjecture, could be the ground state of matter [33] . This state is only attained if strange quarks are present and this assumption led to the name strange star. Since then, the hypothesis of strange matter has been tested with different quark models, mainly the MIT bag model and the Nambu-JonaLasinio model [34] , the last one also investigated within the Tsallis statistics [30] , but in a different perspective.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "We organise our work as follows: section II is devoted to a short review of the the Tsallis statistics and the MIT bag model and section III to the application of the MIT bag model within the non-additivity assumption to the description of the QCD phase diagram and to quark stars. In the last section the final remarks are presented.", "cite_spans": [], "ref_spans": []}, {"section": "The Formalism", "text": "We devote this section to review the formalism underlying the use of the Tsallis statistics and to present the main equations used to describe the MIT bag model. The derivations are not included because they can be obtained from other papers in the literature, whose citations are always given.", "cite_spans": [], "ref_spans": []}, {"section": "Tsallis statistics", "text": "In the following a self-similar bag model is developed by using Tsallis instead of Boltzmann statistics. In this way, the self-similar structure is introduced in the MIT bag model, according to the results presented in [7] .", "cite_spans": [], "ref_spans": []}, {"section": "Tsallis statistics", "text": "The Tsallis statistics [15] was proposed by Constantino Tsallis in 1988 as a generalisation of the Boltzmann-Gibbs Statistics and its associated entropy is given by", "cite_spans": [], "ref_spans": []}, {"section": "Tsallis statistics", "text": "The Tsallis entropy (S q ) is not thought as being an universal function that is given once and for all, but it is a delicate and powerful concept to be carefully constructed for classes of systems characterised by the real parameter \"q\". This entropy satisfies all properties of BoltzmannGibbs entropy (S BG ) , except the additivity, so that (2) in such a way that when q \u2192 1, S BG is recovered.", "cite_spans": [], "ref_spans": []}, {"section": "Tsallis statistics", "text": "According to thermodynamics, entropy needs to be extensive. This means that, for a large number N of elements (probabilistically independent or not) the entropy of the system is (asymptotically) proportional to N . Otherwise, the entropy is non-extensive. For a system whose elements are either independent or weakly correlated, the additive entropy S BG is extensive, whereas the non-additive entropy S q (q = 1) is non-extensive. In contrast, however, for a system whose elements are generically strongly correlated, the additive entropy S BG can be non-extensive, whereas the nonaddictive entropy S q (q = 1) can be extensive for special values of q.", "cite_spans": [], "ref_spans": []}, {"section": "Tsallis statistics", "text": "We next define the q-logarithm function for particles (+) and antiparticles (\u2212) as in [31] :", "cite_spans": [], "ref_spans": []}, {"section": "Tsallis statistics", "text": "is the inverse function of the q-exponential given by", "cite_spans": [], "ref_spans": []}, {"section": "Tsallis statistics", "text": "In this way", "cite_spans": [], "ref_spans": []}, {"section": "Tsallis statistics", "text": "In order to introduce non-extensivity in the EOS of the MIT bag model, the starting point is the partition function [31] for a non extensive ideal quantum gas", "cite_spans": [], "ref_spans": []}, {"section": "Tsallis statistics", "text": "where x = \u03b2(E \u2212 \u00b5), \u03be = \u00b11 for bosons and fermions respectively, and \u0398 is the step function. The distribution and entropy density functions for fermions can be obtained through the relations", "cite_spans": [], "ref_spans": []}, {"section": "Tsallis statistics", "text": "so that, the distribution functions are", "cite_spans": [], "ref_spans": []}, {"section": "Tsallis statistics", "text": "and the entropy density", "cite_spans": [], "ref_spans": []}, {"section": "Tsallis statistics", "text": "It is important to notice that Eq. (9) is consistently obtained from the partition function and by the optimisation of the entropy, as proposed in [31] under the appropriate constraints. An interesting analysis of the several non-extensive versions of a quantum gas has been recently done in ref [32] . Notice that the distribution function n (\u2212) q is a direct result of the application of the usual formalism of thermodynamics, and the exponent 2 \u2212 q results from the usual calculations.", "cite_spans": [], "ref_spans": []}, {"section": "Tsallis statistics", "text": "In this context, the pressure becomes", "cite_spans": [], "ref_spans": []}, {"section": "Tsallis statistics", "text": "the baryonic density reads", "cite_spans": [], "ref_spans": []}, {"section": "Tsallis statistics", "text": "with", "cite_spans": [], "ref_spans": []}, {"section": "Tsallis statistics", "text": "and the energy density is given by:", "cite_spans": [], "ref_spans": []}, {"section": "Tsallis statistics", "text": "and where", "cite_spans": [], "ref_spans": []}, {"section": "MIT Bag Model", "text": "In this subsection we present the equations of state (EOS) used in this work within two different statistical approaches. We describe quark matter with the help of the MIT bag model [25] , which mimics the confinement of quarks in a volume space delimited by a certain pressure. It is interesting, in the present context, to recall that one of the first conjectures about a phase transition between confined and deconfined regimes of hadronic matter was proposed by Cabibbo and Parisi [5] as a way to interpret the Hagedorn limiting temperature. Inside the bag, a constant positive potential energy per unit of volume, the so-called Bag constant and denoted by B is necessary so that the bag can be created and kept in the vacuum. The energy associated with the mere presence of quarks in a volume V is therefore BV . Inside of this volume, the moving quarks have a kinetic energy and no colour currents survive in the surface. Hence, the quarks in the interior of the bag are taken as a Fermi gas whose energy at the border of the bag is negligible when compared with the energies inside it. The Lagrangian density reads", "cite_spans": [], "ref_spans": []}, {"section": "MIT Bag Model", "text": "with", "cite_spans": [], "ref_spans": []}, {"section": "MIT Bag Model", "text": "where R is the radius of the bag and \u2206 s = \u03b4(R \u2212 r) is a Dirac type function. Thus, inside of the bag the quarks are free (asymptotic freedom), and outside of the bag they can no longer exist (confinement). \u03c8(x) is the fermionic field, and m is the quark mass. The role of the B constant is to incorporate the QCD effects at large distances [35, 36] .", "cite_spans": [{"start": 341, "end": 345, "text": "[35,", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "MIT Bag Model", "text": "Assuming a simple relativistic mean filed approximation (RMF), the EOS can then be easily obtained at finite temperature and reads", "cite_spans": [], "ref_spans": []}, {"section": "MIT Bag Model", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "MIT Bag Model", "text": "\u03b3 i refers to the degeneracy of the system and accounts for the number of colours (3) and the spin (2), m i is the quark mass, \u00b5 i the chemical potential and n(k, \u00b1\u00b5 i ) is the statistical distribution for quarks and antiquarks given by:", "cite_spans": [], "ref_spans": []}, {"section": "MIT Bag Model", "text": "When the MIT bag model EOS is calculated with the non-extensive statistical mechanics instead of the usual Fermi-Dirac, the EOS can be rewritten as:", "cite_spans": [], "ref_spans": []}, {"section": "MIT Bag Model", "text": "2 dp log (+)", "cite_spans": [], "ref_spans": []}, {"section": "MIT Bag Model", "text": "The factors of two incorporated in the denominators account for the compensation of the spin degeneracy, already taken into account in eq. (12), but reinserted in the equations above to make them uniform with the notation used in eqs. (17 -20) .", "cite_spans": [], "ref_spans": []}, {"section": "Applications", "text": "We next revisit two situations in which the MIT model has been used in the literature, but now also with the help of the Tsallis statistics. The first one is a simple calculation of the hadronic and quark matter separation boundary in the QCD phase diagram. The second is the calculation of compact objects macroscopic quantities, where neutron stars are assumed to be quark stars, as proposed in [33] . In both cases, only q-values larger than 1 are considered because, from previous works, we already know that lower values make the EOS softer and we are searching for harder EOS.", "cite_spans": [], "ref_spans": []}, {"section": "QCD diagram", "text": "A complete analytical treatment of QCD is still beyond our reach. The only independent intrinsic scale in this theory is the dynamically generated confinement scale \u039b QCD \u223c 1 fm \u22121 . As stated in the Introduction, the most reliable theoretical approach to compute thermodynamic properties of matter at finite temperatures is LQCD [1] . The other possibility is the use of effective models [37, 38] . In both cases, the existence of a transition from a hadronic phase to a quark-gluon plasma phase at a temperature between 150 and 200 MeV is well established. It is worth pointing out that the use of more sophisticated models, as done in [37] may produce different (pseudo)temperatures for the chiral and deconfinement phase transitions (Table I, first line), but the values remain under the range mentioned above. Another important aspect refers to the existence and location of the critical end point (CEP), as discussed in [30, 38] , but this problem is out of the scope of the present paper because the model we are using here can only account for a first order phase transition all the way from high (low) to low (high) chemical potentials (temperatures).", "cite_spans": [], "ref_spans": []}, {"section": "QCD diagram", "text": "If we use the MIT bag model to describe nuclear matter, the increase in density and temperature can make the surfaces of the bags overlap, merging them in a large area where quarks and gluons are allowed to move freely throughout the new volume in a quark-gluon plasma (QGP). A very naive way to obtain the separation limit of the two phases is simply by forcing eq. (17) However, one can also see from Figs1 a) and 1 b) that, for fixed values of B, the shape of the curves are quite different, depending on the statistics used. Moreover, if we vary the value of the parameter q, the critical temperature decreases with the increase of the q value. Another important aspect refers to the behaviour of the curves at low chemical potentials. When q approaches 1, the curves tend to the Fermi-Dirac results, except for chemical potentials smaller than 250 MeV, when the temperatures obtained with non-extensive statistics are slightly larger than the original MIT results. It is interesting to see that the results obtained with the MIT bag model are more sensitive to non-extensivity than the ones obtained with the NJL model, as can be seen in Fig.9 of [30] . We advocate that intrinsic correlations between quarks and gluons not described by the simple MIT within the MFA can be taken into account by the q value. In a previous work [31] , an attempt to describe the QCD transition line with the Tsallis statistics had already been made, by assuming two different conditions, namely, a fixed energy per particle of 1 GeV [40, 41] and a fixed entropy divided by the cubic temperature equal to 5 [42] . In both cases, with q = 1.14 the resulting transition lines were much lower than the expected chemical freeze-out line (see Fig.2 left in [31] ). Here, a somewhat simpler treatment brings the transition line to its correct position and the larger q value (q = 1.14) is the one that produces (pseudo) transition temperatures closer to 155 MeV, the value of the transition temperature most accepted nowadays [1] . However, in the present study, the energy never reaches 1 GeV and it is not a fixed quantity, i.e., it increases with the increase of the chemical potential and decreases with the increase of the temperature. The energy per particle vary between 624 MeV and 640 MeV for the Fermi-Dirac statistics with small variations for the non-extensive statistics, when B 1/4 is 220 MeV. As the energy per particle is given by E/n B and E depends on the B value, the final value also depends on B. It is interesting to see that the values we found with the naive MIT bag model for the energy density and corresponding highest temperature present in the freeze-out line go in line with the values proposed in [43] .", "cite_spans": [], "ref_spans": [{"start": 1725, "end": 1743, "text": "Fig.2 left in [31]", "ref_id": "FIGREF1"}]}, {"section": "Stellar Matter", "text": "As pointed out in the Introduction, previous investigations of the effects of the Tsallis statistics in the description of compact objects have already been performed in [26, 27] . In both cases, neutron stars described by hadronic matter were investigated and in [27] a rapid analyses about its effect on a free gas was also done. We next study quark stars and compare our results with the ones already existing in the literature.", "cite_spans": [], "ref_spans": []}, {"section": "Stellar Matter", "text": "In stellar matter there are two conditions that have to be fulfilled, namely, charge neutrality and \u03b2-stability and they read:", "cite_spans": [], "ref_spans": []}, {"section": "Stellar Matter", "text": "where q type , type = j, l stands for the electric charge of quarks and leptons respectively and", "cite_spans": [], "ref_spans": []}, {"section": "Stellar Matter", "text": "We next use the non extensive statistics also for the leptons, which enter the calculation as free particles obeying the above mentioned conditions. It is important to stress that the spin degeneracy of neutrinos, whenever they are used is 1, in contrast with the degeneracy of the other leptons, which is 2. The number of colours (3) is obviously not part of the degeneracy factor for leptons.", "cite_spans": [], "ref_spans": []}, {"section": "Stellar Matter", "text": "The entropy per particle (baryon) can be calculated through the thermodynamical expression", "cite_spans": [], "ref_spans": []}, {"section": "Stellar Matter", "text": "One common way of studying a compact object history is by looking at three snapshots of the time evolution of a quark star in its first minutes of life, which are given by:", "cite_spans": [], "ref_spans": []}, {"section": "Stellar Matter", "text": "which, according to simulations, can reach Y l 0.3 \u2212 0.4. Let's point out that in snapshot 1, muons are not considered because they are either absent or very few and in snapshot 2, where neutrinos have already left the star (deleptonization era), muons are present.", "cite_spans": [], "ref_spans": []}, {"section": "Stellar Matter", "text": "In the present work we are interested in finite temperature systems and hence, all results refer to the first two snapshots. From this point on, B 1/4 is always taken equal to 145 because this value is known to be inside the stability window that satisfies the Bodmer-Witten conjecture [44] . In Fig.2a we present the EOS obtained for the second snapshot and it is clearly very difficult to distinguish the curves (see the inset). Hence, in Fig.2b we plot the differences from the usual pressure (Fermi-Dirac) obtained with different q values. At very high densities, the larger differences are smaller than 0.025%. We do not display the curves for the first snapshot because the values are different, but the general behaviour is the same.", "cite_spans": [], "ref_spans": [{"start": 296, "end": 302, "text": "Fig.2a", "ref_id": "FIGREF2"}, {"start": 441, "end": 447, "text": "Fig.2b", "ref_id": "FIGREF2"}]}, {"section": "Stellar Matter", "text": "We then analyse the influence of non-additivity on the system temperature in Fig.3 . As q increases, the resulting star internal temperature decreases. This behaviour was already found in [27] , but the temperatures involved in both snapshots are much lower here because the quark matter EOS is softer.", "cite_spans": [], "ref_spans": [{"start": 77, "end": 82, "text": "Fig.3", "ref_id": "FIGREF3"}]}, {"section": "Stellar Matter", "text": "Before we move to macroscopic properties, we observe that the amount of strangeness in the system is barely affected by the Tsallis statistics, as can be seem in Fig.4 for the first snapshot. If the second snapshot were plotted, one could see that the strangeness fraction would be slightly larger (reaches 0.33 at high densities), but the effect of the statistics remains negligible. This fact has consequences in the calculation of the star macroscopic properties, as discussed next.", "cite_spans": [], "ref_spans": []}, {"section": "Stellar Matter", "text": "Once the EOS is computed, it is used as input to the Tolman-Oppenheimer-Volkof equations [45] , which gives the macroscopic properties of interest that are displayed next in Fig. 5 (just the second snapshot) and Table 1 . In the same way as the results obtained in [27] , the final macroscopic properties are practically unchanged, but always tending to larger values for the masses and, in the present work, also for the radii. Therefore, the massive 2 M stars recently observed [46, 47] cannot be described by simply increasing the value of the q-parameter. Table 1 : Stellar macroscopic properties: M max refers to the maximum gravitational mass, M b max to its baryonic counterpart and R to its radius.", "cite_spans": [], "ref_spans": []}, {"section": "Final remarks", "text": "The MIT bag model treats the strong interaction in a very naive way, i.e., through a constant. Hence, due to the sim- plicity of the model, we expected to see more clearly the effects of the Tsallis statistics. In fact, the modifications are always made at the level of a free gas. In contrast with the models used in [26, 27] , where the hadrons are mediated explicitly by mesonic fields, no information about the interaction between quarks and gluons is mimicked in the MIT bag model. The analyses of the first order transition in the QCD phase diagram shows, however, that the model is quite sensitive to non-extensivity. Unfortunately, the model cannot be used to calculate the CEP, as done in [30] , but the influence on the phase transition boundary is larger with the MIT than with the NJL model.", "cite_spans": [], "ref_spans": []}, {"section": "Final remarks", "text": "When the model is extended to incorporate stellar matter conditions and the macroscopic properties are computed, the effects are very small, but corroborate most of the findings obtained for neutron stars described by more sophisticated models in [26, 27] , namely, maximum masses increase and internal stellar temperature decreases with the increase of the q parameter. In the present work, it is also clear that the radii also increase alongside the q parameter, not an obvious result in the previous papers.", "cite_spans": [], "ref_spans": []}, {"section": "Authors contributions", "text": "All the authors were involved in the preparation of the manuscript, read and approved the final version. This work was partially supported by CNPq under grants 300602/2009-0 (DPM), 310982/2014-6 (AD) and 435158/2016-3 (TNdS) and PIBIC scholarship (PHGC). ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF33": {"title": "Models of the Nucleon: From Quarks to Soliton", "authors": [{"first": "R", "middle": ["K"], "last": "Bhaduri", "suffix": ""}], "year": 1988, "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "for Fermi-Dirac statis- tics and eq.(24) for the Tsallis statistics to be identically zero. The quarks masses are taken as 5 MeV for the up and down quarks and 150 MeV for the strange quarks. Common values found in the literature for B 1/4 lie in the range 145 \u2212 235 MeV [39]. From Fig. 1 we see that for B 1/4 = 200 \u2212 235 MeV with the original model and for B 1/4 = 185 \u2212 235 MeV and q = 1.05 with the Tsal- lis statistics, the temperature of QGP transition (T c ) lies within the expected range. This findings mean that a q value larger than one plays the same role as a slightly larger B value.", "type": "figure"}, "FIGREF1": {"text": "Fig. 1: QCD phase diagram using the MIT bag model for a) usual Fermi-Dirac statistics, b) Tsallis statistics with q = 1.05 and c) Fermi-Dirac and Tsallis statistics with B 1/4 = 220 MeV.", "type": "figure"}, "FIGREF2": {"text": "Fig. 2: a) Stellar quark matter equation of state constituted by the three flavours of quarks and electrons and S/n B = 2, \u00b5 \u03bd = 0. b) Differences from the usual Fermi-Dirac pressure obtained with different q values versus energy density for the same snapshot.", "type": "figure"}, "FIGREF3": {"text": "Fig. 3: Temperature as function of density (in units of nuclear matter saturation density) for different values of q and a) S/n B = 1, Y l = 0.3 and b) S/n B = 2, \u00b5 \u03bd = 0.", "type": "figure"}, "FIGREF4": {"text": "Fig. 4: Strange quark fraction obtained for S/n B = 1, Y l = 0.3.", "type": "figure"}}}
{"paper_id": "118866436", "_pdf_hash": "32ce193de69ca95aaf09a7709d40b42cbcc7d378", "abstract": [{"section": "Abstract", "text": "We combined two sets of data to get high-precision time-series for stars in the open cluster NGC 1817. We verified most of the variable stars detected earlier and found some new ones. To the 12 \u03b4 Scuti variables detected prior to this article 4 new \u03b4 Scuti stars and one candidate have been added. In addition 3 \u03b3 Doradus candidates have been detected. The total number of variables and possible variables in NGC 1817, or in the field of view of the cluster is now up to 26. This high number of pulsating stars and especially \u03b4 Scuti variables makes this cluster an interesting asteroseismic target for future study. Using asteroseismology on \u03b4 Scuti stars will hopefully provide us with information that eventually will constrain the theoretical models of stars. This will in the end give us a much greater understanding of the evolution of stellar objects.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Asteroseismic study of pulsating stars is a very interesting field in astronomy nowadays. Results from asteroseismic investigation of oscillation modes of variable stars are helping us to understand fundamental parameters of stars. \u03b4 Scuti variable stars are stars in the range from A to F types and with masses ranging from 1.5 M \u2299 to 2.5 M \u2299 . These stars are main sequence or post-main sequence stars and lie at the bottom of the classical Cephei instability strip. \u03b4 Scuti stars show multiperiodic signals with periods of the order of hours and magnitude variation at the mmag level. Through asteroseismology it is possible to constrain the stellar models, and to test the stellar physics to higher accuracy.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "In the open cluster NGC 1817 different kinds of variable stars are present. A high number of \u03b4 Scuti stars and at least 2 eclipsing binaries make this cluster a prominent target for asteroseismic investigation. Observations of the area including NGC 1817 made detection of at least 16 \u03b4 Scuti variables possible. 12 of these were detected prior to this article Arentoft 1998 and Arentoft et al. 2005 ) but the last 4 are new detections. Another 4 stars are possible candidates. Open clusters are interesting targets for CCD photometry, because of the semicrowded field, which make precise time-series photometry for the individual stars possible. For NGC 1817 the turnoff from the main sequence, due to the exhaustion of Hydrogen in the core of the stars, is located inside the instability strip. This makes NGC 1817 an obvious choice for CCD observations, because the stars in the instability strip, the pulsating candidates, are among the brightest stars in the cluster.", "cite_spans": [], "ref_spans": []}, {"section": "Observations", "text": "Two datasets were used for the analysis of variable stars in the open cluster NGC 1817. The first set of data was taken with the 1.5 m Danish Telescope at La Silla, Chile. The observations were carried out by Lars Glowienka and Henrik Robenhagen Jensen in January 2005. The DFOSC instrument was used to obtain time-series CCD images. A 2048 x 2048 CCD camera was used for the I, B and V filter data. The main part of the total observations were carried out using the B filter and a small part with the V and I filter. In Fig. 1 an image from the La Silla data is shown with the detected variables indicated.", "cite_spans": [], "ref_spans": [{"start": 521, "end": 527, "text": "Fig. 1", "ref_id": "FIGREF0"}]}, {"section": "Observations", "text": "The second dataset was collected using the 2.56 m Nordic Optical Telescope (NOT) at La Palma, Canary Islands. These observations were performed in January 2007 by Lars Glowienka. A mosaic of four 1024 x 1024 CCD cameras were used, and to cover even more, three areas of the cluster were observed. Two images were taken in one area, then the telescope was pointed to a new area where two images were taken, and then pointed to the last area where two images were taken. Then it was moved back to the first area again and so on. One night (13-01-2007) the observations were done with the V filter. The last 3 nights (14,15,16-01-2007) were observed with the B filter.", "cite_spans": [], "ref_spans": []}, {"section": "Data reduction", "text": "The two datasets were reduced separately using the Multi-Object Multi-Frame package (MOMF; Kjeldsen & Frandsen 1992) . The package uses a pointspread function (PSF) and aperture photometry to determine the magnitude of every star in the observed field. In the La Silla data, time-series for 627 stars were obtained. The reduction of the data from NOT was a little more difficult. Because of drift in the position from night to night, every CCD area was reduced separately, which resulted in 12 different MOMF-reductions per night. After the reduction, data for the detected variables were combined by normalizing the magnitude for each night. This affects the analysis of the possible \u03b3 Doradus stars, because of their long variation periods. In the NOT data around 60 stars were present in all of the 12 areas. Time-series of around 650 stars were obtained from the NOT data, because some of the areas were overlapping. Using MOMF, a precision of \u223c2 mmag for the brightest stars was obtained for the La Silla data, and \u223c1 mmag for the NOT data.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Detecting the variables", "text": "The analysis of the time-series was done manually. Every star was checked visually for variability and the interesting stars were analyzed with the program Period04 (Lenz & Breger 2005) . The investigation was done with the B filter data.", "cite_spans": [], "ref_spans": []}, {"section": "Detecting the variables", "text": "In Fig. 2 , a part of the light curves for the new variable stars in NGC 1817 and some candidate variables in the field is shown. The frequency solution for the stars is superimposed with a solid line. These frequencies were determined with Period04, which applies a least square fit of sinusoidals to the data. A criteria of a signal-to-noise ratio (S/N) of 4 for the detected frequencies was used (Breger et al. 1993 & Kuschnig et al. 1997 . Because of the windowfunction this criteria is not sufficient, but gives a rough estimate of the range and number of oscillations present in the stars. Long period variations were subtracted from the data when it was clear that the variations were not intrinsic. In Table 1 basic data for all the variable stars are shown, including candidates. The first 18 variables were detected by Frandsen & Arentoft (1998) and Arentoft et al. (2005) .", "cite_spans": [], "ref_spans": [{"start": 3, "end": 9, "text": "Fig. 2", "ref_id": "FIGREF1"}, {"start": 710, "end": 717, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Detecting the variables", "text": "The V and B-V magnitudes for the variable V20 in Table 1 were determined by comparison of 2 stars in the overlapping region for the La Silla data and the NOT data. Then the transformation was applied to V20, which was done to get an idea about the position of the star in the color-magnitude diagram (CMD). The transformation will be explained in more detail below.", "cite_spans": [], "ref_spans": [{"start": 49, "end": 56, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Frequency analysis", "text": "In Table 2 the frequency solution for the new variables is listed. Only the stars for which a significant solution could be determined are shown. Oscillations with a S/N higher than 4 were used. Because of the low number of detected frequencies, the S/N of every solution is listed as well. The noise level was determined after removing the signals from the table.", "cite_spans": [], "ref_spans": [{"start": 3, "end": 10, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "Frequency analysis", "text": "In Fig. 2 the light curves for the new variables are shown. The solid line is the least square fit solution, with the frequencies from Table 2 . Because of the reduction technique no frequency analysis was possible for the two \u03b3 Doradus variables V23 and V24. The vertical dashed lines in these two plots are to indicate that it is not possible to combine the light curve from the different nights. Therefore no frequency analysis of these stars is possible. V21 is clearly a multiperiodic \u03b4 Scuti star (cf. Fig. 2 ), but the data was not sufficient for a frequency solution. The variable ID for the first 18 stars is that given by Arentoft et al. (2005) and the WIYN-ID is the star number from the WIYN catalog. Right ascension is given in hours, minutes and seconds and declination is given in degrees, arcminutes and arcseconds. The frequencies are given in cycles per day and the S/N ratio is shown for every frequency.", "cite_spans": [], "ref_spans": [{"start": 3, "end": 9, "text": "Fig. 2", "ref_id": "FIGREF1"}, {"start": 135, "end": 142, "text": "Table 2", "ref_id": "TABREF1"}, {"start": 508, "end": 514, "text": "Fig. 2", "ref_id": "FIGREF1"}]}, {"section": "The color-magnitude diagram", "text": "A transformation from the observed V and B data, from La Silla, was done using the WIYN Open Cluster Study (Wisconsin, Indiana, Yale and NOAO) catalog of standardized CCD photometry. 96 stars, which were identified in both WIYN and the La Silla data, were used to obtain the offset transformation. The 14 NGC 1817: the richest population of \u03b4 Scuti stars position of the stars was used to match the different stars in the two data sets. In Fig. 3 the CMD for the stars in the observed field from La Silla is shown. The variable stars are indicated; diamonds indicate \u03b4 Scuti variables, squares indicate binary systems, triangles indicate \u03b3 Doradus variables and circles indicate candidate variables.", "cite_spans": [], "ref_spans": [{"start": 440, "end": 446, "text": "Fig. 3", "ref_id": "FIGREF2"}]}, {"section": "The color-magnitude diagram", "text": "The instability strip (Breger 2000) for NGC 1817 is superimposed with the dashed lines. It is evident that most of the variables are located inside the instability strip. We also see that the stars inside the strip are positioned close to the cluster sequence, which means that most of the stars in the instability strip are likely cluster members. Errors in the CMD are dominated by transformation errors, but the figure is in good agreement with the CMD determined by Arentoft et al. (2005) .", "cite_spans": [{"start": 22, "end": 35, "text": "(Breger 2000)", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Conclusion", "text": "The detection of 17 \u03b4 Scuti variables, 2 eclipsing binaries (one with a component that is also a \u03b4 Scuti) and 8 other possible variables, 4 which could be \u03b3 Doradus variables, one contact binary, one \u03b4 Scuti and 2 other candidates, is at the moment the highest concentration of \u03b4 Scuti variables in any open cluster. This makes NGC 1817 a very interesting asteroseismic target. The combination of \u03b4 Scuti stars and eclipsing binary systems in an open cluster makes this particular target of greatest interest.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "Membership determination of the variables by considering the proper motion, and spectroscopic study of the eclipsing binaries will be the next step. J. Molenda-\u017bakowitz et al. (2009) used spectroscopic observations of 11 variable stars in NGC 1817 to analyze these stars further. In the future a multisite campaign will be needed to get sufficient time-series data to make asteroseismic", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF3": {"title": "Proceedings of Delta Scuti and Related Stars", "authors": [{"first": "M", "middle": [], "last": "Breger", "suffix": ""}], "year": 2000, "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Figure 1: Finding chart for the variable stars (indicated) in NGC 1817. The La Silla field of view is \u223c15'x15' and the inserted bottom image is part of one CCD image from NOT. It is rotated and scaled to match the La Silla image.", "type": "figure"}, "FIGREF1": {"text": "Figure 2: Light curves for the 8 new variables", "type": "figure"}, "FIGREF2": {"text": "Figure 3: Color-Magnitude diagram for stars in i NGC 1817", "type": "figure"}, "TABREF0": {"text": "Basic data for the variable stars in NGC 1817", "type": "table"}, "TABREF1": {"text": "Pulsational data for the new variables in NGC 1817", "type": "table"}}}
{"paper_id": "118866437", "_pdf_hash": "3eff1c870bc72adb9dfa7971e3737c4ed2118833", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Handedness asymmetry of spiral galaxies with z\u00a10.3 shows cosmic parity violation and a dipole axis", "authors": [{"first": "Lior", "middle": [], "last": "Shamir", "suffix": ""}], "year": 2012, "venue": "Physics Letters B", "link": "118477611"}, "BIBREF1": {"title": "Structure and evolution of the Universe", "authors": [{"first": ".", "middle": ["B"], "last": "Zeldovich Ia", "suffix": ""}, {"first": "I", "middle": ["D"], "last": "Novikov", "suffix": ""}], "year": 1975, "venue": "", "link": null}, "BIBREF2": {"title": "Planck 2013 results. I. Overview of products and scientific results -Table 9", "authors": [{"first": "P", "middle": ["A R"], "last": "Ade", "suffix": ""}, {"first": "N", "middle": [], "last": "Aghanim", "suffix": ""}, {"first": "C", "middle": [], "last": "Armitage-Caplan", "suffix": ""}], "year": 2013, "venue": "Astronomy and Astrophysics", "link": null}}, "ref_entries": {}}
{"paper_id": "118867063", "_pdf_hash": "287a4c33cdceb8159874530003575d09b3ce90c0", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Remote wind profiling with a solidstate Nd:YAG coherent lidar system", "authors": [{"first": "M", "middle": ["J"], "last": "Kavaya", "suffix": ""}, {"first": "S", "middle": ["W"], "last": "Henderson", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Magee", "suffix": ""}, {"first": "C", "middle": ["P"], "last": "Hale", "suffix": ""}, {"first": "R", "middle": ["M"], "last": "Huffaker", "suffix": ""}], "year": 1989, "venue": "Opt. Lett", "link": "27817509"}, "BIBREF1": {"title": "Laser Source requirements for coherent lidars based on fiber technology", "authors": [{"first": "J.-P", "middle": [], "last": "Cariou", "suffix": ""}, {"first": "B", "middle": [], "last": "Augere", "suffix": ""}, {"first": "M", "middle": [], "last": "Valla", "suffix": ""}], "year": 2006, "venue": "C. R. Physique", "link": "111011182"}, "BIBREF2": {"title": "ll-Fiber Multifunction Continuous-Wave Coherent Laser Radar at 1.55 \u03bdm for Range, Speed, Vibration, and Wind Measurements", "authors": [{"first": "C", "middle": ["J"], "last": "Karlsson", "suffix": ""}, {"first": "F", "middle": ["\u00c5 A"], "last": "Olsson", "suffix": ""}, {"first": "D", "middle": [], "last": "Letalick", "suffix": ""}, {"first": ".", "middle": ["M"], "last": "Harris", "suffix": ""}], "year": 2000, "venue": "Appl. Opt", "link": "27751979"}, "BIBREF3": {"title": "All-fiber Coherent Doppler LIDAR for Wind Sensing", "authors": [{"first": "S", "middle": [], "last": "Abdelazim", "suffix": ""}, {"first": "D", "middle": [], "last": "Santoro", "suffix": ""}, {"first": "M", "middle": [], "last": "Arend", "suffix": ""}, {"first": "F", "middle": [], "last": "Moshary", "suffix": ""}, {"first": "S", "middle": [], "last": "Ahmed", "suffix": ""}], "year": 2011, "venue": "5th Symposium on Lidar Atmospheric Applications, 91st American Meteorological Society Annual Meeting", "link": "138997345"}, "BIBREF4": {"title": "Wind Velocity Estimate and Signal to Noise Ratio Analysis of an All Fiber Coherent Doppler Lidar System", "authors": [{"first": "S", "middle": [], "last": "Abdelazim", "suffix": ""}, {"first": "D", "middle": [], "last": "Santoro", "suffix": ""}, {"first": "M", "middle": [], "last": "Arend", "suffix": ""}, {"first": "F", "middle": [], "last": "Moshary", "suffix": ""}, {"first": "S", "middle": [], "last": "Ahmed", "suffix": ""}], "year": 2011, "venue": "16th Coherent Laser Radar Conference", "link": "18729627"}, "BIBREF5": {"title": "Field programmable gate array processing of eyesafe all-fiber coherent wind Doppler lidar return signals", "authors": [{"first": "S", "middle": [], "last": "Abdelazim", "suffix": ""}, {"first": "D", "middle": [], "last": "Santoro", "suffix": ""}, {"first": "M", "middle": [], "last": "Arend", "suffix": ""}, {"first": "F", "middle": [], "last": "Moshary", "suffix": ""}, {"first": "S", "middle": [], "last": "Ahmed", "suffix": ""}], "year": 2011, "venue": "SPIE, Remote Sensing", "link": "109727796"}}, "ref_entries": {}}
{"paper_id": "118867393", "_pdf_hash": "e5d2894227a9aa0c649566435f4860c3fcf0a59a", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "d(t))$(t,x(t))dt, x(a) = A,x(b) = B. The following result on the non-occurrence of Lavrentiev's phenomenon was proved in", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF1": {"title": "The Classical Problem of the Calculus of Variations in the autonomous case: Relaxation and Lipschitzianity of solutions", "authors": [{"first": "A", "middle": [], "last": "Cellina", "suffix": ""}], "year": "", "venue": "", "link": "53971102"}, "BIBREF2": {"title": "Reparametrizations and Approximate values of Integrals of the Calculus of Variations", "authors": [{"first": "A", "middle": [], "last": "Cellina", "suffix": ""}, {"first": "A", "middle": [], "last": "Ferriero", "suffix": ""}, {"first": "E", "middle": ["M"], "last": "Marchini", "suffix": ""}], "year": "", "venue": "", "link": "15324658"}, "BIBREF3": {"title": "Existence of solutions to differential inclusions and to time optimal control problems in the autonomous case", "authors": [{"first": "A", "middle": [], "last": "Cellina", "suffix": ""}, {"first": "A", "middle": [], "last": "Ornelas", "suffix": ""}], "year": "", "venue": "", "link": "34377472"}, "BIBREF4": {"title": "On the Minumum Problem for a Class of Non-coercive Functionals", "authors": [{"first": "A", "middle": [], "last": "Cellina", "suffix": ""}, {"first": "G", "middle": [], "last": "Treu", "suffix": ""}, {"first": "S", "middle": [], "last": "Zagatti", "suffix": ""}], "year": 1996, "venue": "Jour. Diff. Equat", "link": null}}, "ref_entries": {}}
{"paper_id": "118868157", "_pdf_hash": "72a02261b50a058b4894caf05aba226c672a8975", "abstract": [{"section": "Abstract", "text": "We describe techniques that simplify the calculation of one-loop QCD amplitudes with many external legs, which are needed for next-to-leading-order (NLO) corrections to multi-jet processes. The constraints imposed by perturbative unitarity, collinear singularities and a supersymmetry-inspired organization of helicity amplitudes are particularly useful. Certain sequences of one-loop helicity amplitudes may be obtained for an arbitrary number of external gluons using these techniques. We also report on progress in completing the set of one-loop helicity amplitudes required for NLO threejet production at hadron colliders, namely the amplitudes with two external quarks and three gluons.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION", "text": "High-p T events in hadronic collisions and high-energy e + e \u2212 annihilations often produce a large number of jets. Quantitative QCD predictions for such multi-jet rates are important, but require at least next-to-leading-order (NLO) calculations. NLO corrections in turn require one-loop amplitudes with many external partons. The analytic complexity of oneloop calculations grows very rapidly with the number of external legs. As a result, complete NLO results are currently available only for processes with up to four external partons or vector bosons, such as e + e \u2212 \u2192 3 jets, and pp (or pp) production of inclusive jets, di-jets, and (W, Z) + 1 jet. To go further requires one-loop QCD amplitudes with five or more external partons or vector bosons. Here we briefly describe some very useful tools for carrying out such calculations, and summarize recent progress.", "cite_spans": [], "ref_spans": []}, {"section": "ORGANIZATIONAL TOOLS", "text": "The basic principle in calculating a complicated one-loop amplitude is to break it up into as many simpler, yet physical, pieces as possible. Traditional Feynman diagrams are not a good way to do this since individual diagrams are gauge-variant, and hence unphysical. Instead one should use the quantum numbers of the external particles, namely their helicities (\u00b1) and color quantum-numbers, to decompose the amplitude into color-ordered helicity subamplitudes, or sub-amplitudes for short. The helicity [1] and color [2] decompositions of multi-parton tree-level amplitudes have been essential to their efficient calculation, and the same is true at one loop. The analytic properties of the one-loop sub-amplitudes -namely their collinear behavior (poles) and their unitarity properties (cuts) -are simpler than those of the full amplitude, yet they provide powerful constraints. They are simpler mainly because they only involve \"color-adjacent\" kinematic invariants such as (k i + k i+1 ) 2 , where k i and k i+1 are adjacent momenta with respect to the color ordering. Consequently the subamplitudes themselves tend to be simple; analytic expressions for each one-loop five-parton sub-amplitude takes up less than a page [3, 4] , whereas the color-summed cross-section would fill hundreds of pages. Thus one should calculate sub-amplitudes analytically, and carry out the squaring of amplitudes and the sum over colors and helicities numerically at the very end.", "cite_spans": [], "ref_spans": []}, {"section": "ORGANIZATIONAL TOOLS", "text": "The analytic properties of the sub-amplitudes can be exploited to simplify their calculation. Consider the constraints from perturbative unitarity. It is well known that the cuts (absorptive parts) of a loop amplitude are much easier to calculate than the full amplitude, because they are given by phase-space integrals of products of tree amplitudes [5] . The phase-space integrals can be performed to obtain integral functions with the correct cuts, omitting the need to do a dispersion integral [6] . Thus the full amplitude is easily reconstructed from the various cuts, up to additive \"polynomial\" terms (lacking branch cuts). It may be possible to determine the polynomial terms recursively using their collinear singularities (there is still a uniqueness question here). If a certain power-counting criterion holds -the degree of the loop-momentum polynomial for each diagram should be two fewer than the maximum possible in gauge theory -then there are actually no polynomial ambiguities and the sub-amplitudes can be completely reconstructed from the cuts [6, 7] . Supersymmetric amplitudes provide examples satisfying the criterion; infinite sequences of \"maximally helicity violating\" n-gluon supersymmetric amplitudes can be efficiently calculated via their cuts [6, 7] .", "cite_spans": [{"start": 498, "end": 501, "text": "[6]", "ref_id": "BIBREF14"}, {"start": 1065, "end": 1068, "text": "[6,", "ref_id": "BIBREF14"}, {"start": 1275, "end": 1278, "text": "[6,", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "ORGANIZATIONAL TOOLS", "text": "Direct calculation of sub-amplitudes can also be simplified using a decomposition based on the internal (spin) quantum numbers of particles going around the loop. For example, in a one-loop n-gluon amplitude the contribution of a gluon propagating around the loop would traditionally lead to a large amount of algebra, due to the complicated non-abelian self-interaction vertex. However, it is possible to rewrite the gluon self-interaction (using either background-field gauge [8] or a string-based approach [9] ) so that the gluon in the loop looks like a scalar in the loop, plus \"a little bit more\". One can rewrite [3] , gluon = scalar", "cite_spans": [{"start": 478, "end": 481, "text": "[8]", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "ORGANIZATIONAL TOOLS", "text": "where all entries correspond to two-component fields circulating in the loop (gluons, Weyl fermions, complex scalars). The \"little bit more\" represented by the last two lines is supersymmetric (the contribution of 4 N = 1 chiral multiplets, and of an N = 4 super-Yang-Mills theory), and is calculable via its cuts. In this way the gluon computation can be traded for the easier scalar case.", "cite_spans": [], "ref_spans": []}, {"section": "ORGANIZATIONAL TOOLS", "text": "Recursive techniques, which were first applied at tree-level by Berends and Giele [10, 11] , are now beginning to show promise at loop-level. Mahlon [12] has recently obtained two infinite sequences of one-loop n-gluon amplitudes by \"sewing up\" recursively determined off-shell tree amplitudes.", "cite_spans": [], "ref_spans": []}, {"section": "EXPLICIT RESULTS", "text": "What are the practical consequences of these tools so far? At the one-loop five-parton level, they have been used to calculate the full set of helicity amplitudes for five external gluons [3] and for two quarks and three gluons (which are almost complete [13] ). In contrast, the calculation of the four-quark one-gluon amplitudes used (of the above tools) only the sub-amplitude decomposition [4] .", "cite_spans": [], "ref_spans": []}, {"section": "EXPLICIT RESULTS", "text": "Here we present one of theqqggg partial amplitudes, A 5;1 (1 (2) where A", "cite_spans": [], "ref_spans": []}, {"section": "EXPLICIT RESULTS", "text": "is the pure super-Yang-Mills amplitude for five external gluons, taken from ref. [3] . In the remaining components, the poles in in D = 4\u22122 dimensional reduction are separated out into \"V \" pieces by", "cite_spans": [], "ref_spans": []}, {"section": "EXPLICIT RESULTS", "text": "where ", "cite_spans": [], "ref_spans": []}, {"section": "EXPLICIT RESULTS", "text": "and", "cite_spans": [], "ref_spans": []}, {"section": "EXPLICIT RESULTS", "text": "The finite terms possess all the analytic complexity, and are given by ", "cite_spans": [], "ref_spans": []}, {"section": "EXPLICIT RESULTS", "text": "where the logarithms and dilogarithms (Li 2 ) are contained in 3 ,", "cite_spans": [], "ref_spans": []}, {"section": "EXPLICIT RESULTS", "text": "(1 \u2212 r 1 \u2212 r 2 ) ,", "cite_spans": [], "ref_spans": []}, {"section": "EXPLICIT RESULTS", "text": "Once the full set ofqqggg helicity amplitudes are available (roughly speaking, six expressions of the above type are required), numerical programs can be constructed for NLO three-jet production at hadron colliders. There are various general formalisms available [14, 15] for combining (n + 1)-parton tree contributions and n-parton loop contributions into a NLO correction; the one of Giele, Glover, and Kosower is convenient because it is in a colorordered framework which meshes well with a color-ordered decomposition of the amplitudes.", "cite_spans": [], "ref_spans": []}, {"section": "FUTURE PROSPECTS", "text": "Projecting into the future, it seems that recently developed tools -especially the combination of unitarity, collinear singularities and recursive techniques -will make the calculation of one-loop six-parton and perhaps even seven-parton amplitudes quite practical within the next couple of years. Indeed, we expect that the bottleneck in getting NLO results out will shift from the analytical to the numerical end of the process. On the analytical side, the emphasis should shift (perhaps fairly soon) to two-loop multi-parton calculations, which are needed for next-to-next-to-leading (NNLO) results, such as the NNLO correction to e + e \u2212 annihilation to 3 jets, a result which could significantly reduce the theoretical error in determining \u03b1 s at the Z pole.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF4": {"title": "The Ubiquitous Photon: Helicity Method for QED and QCD", "authors": [{"first": "R", "middle": [], "last": "Gastmans", "suffix": ""}, {"first": "T", "middle": ["T"], "last": "Wu", "suffix": ""}], "year": 1990, "venue": "", "link": "118030563"}, "BIBREF14": {"title": "preprint SLAC-PUB-6415, hepph/9403226, to appear in", "authors": [{"first": "Z", "middle": [], "last": "Bern", "suffix": ""}, {"first": "D", "middle": ["C"], "last": "Dunbar", "suffix": ""}, {"first": "L", "middle": [], "last": "Dixon", "suffix": ""}, {"first": "D", "middle": ["A"], "last": "Kosower", "suffix": ""}], "year": "", "venue": "Nucl. Phys. B", "link": null}, "BIBREF16": {"title": "Functional and Probabilistic Methods in Quantum Field Theory", "authors": [{"first": "G", "middle": [], "last": "Hooft", "suffix": ""}], "year": 1975, "venue": "", "link": "118872190"}, "BIBREF17": {"title": "Quantum gravity II", "authors": [{"first": "B", "middle": ["S"], "last": "Dewitt", "suffix": ""}], "year": 1981, "venue": "", "link": null}}, "ref_entries": {"TABREF0": {"text": "are gluons. For the gauge group SU (N c ) with n f flavors of quark and n s flavors of scalar quarks, A 5;1 can be decomposed into primitive amplitudes, from which all factors of N c , n f , n s have been extracted, as:", "type": "table"}}}
{"paper_id": "118869140", "_pdf_hash": "01b014c7fa6ee3594f8ed5ee45aae1ce636fd6e3", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Photogrammetry, 4th Ed", "authors": [{"first": "K", "middle": [], "last": "Kraus", "suffix": ""}], "year": 1993, "venue": "", "link": null}, "BIBREF1": {"title": "Basics of Instrumental and Analytical Photogrammetry", "authors": [{"first": "S", "middle": ["E"], "last": "Masry", "suffix": ""}], "year": 1977, "venue": "Lecture Notes", "link": null}, "BIBREF2": {"title": "Analytical Photogrammetric System with Self-Calibration and Its Applications", "authors": [{"first": "H", "middle": [], "last": "Moniwa", "suffix": ""}], "year": 1977, "venue": "", "link": null}, "BIBREF3": {"title": "Construction of Orthogonal Matrices and their Application in Analytical Photogrammetry", "authors": [{"first": "G", "middle": ["H"], "last": "Schut", "suffix": ""}], "year": 1959, "venue": "Photogrammetria", "link": "110921660"}, "BIBREF4": {"title": "The Duality and Critical Condition in the Formulation and Decomposition of a Rotation Matrix", "authors": [{"first": "T", "middle": ["Y"], "last": "Shih", "suffix": ""}], "year": 1990, "venue": "Photogrammetric Engineering & Remote Sensing", "link": null}, "BIBREF5": {"title": "Introduction to the Algebra of Matrices with Some Applications", "authors": [{"first": "E", "middle": ["H"], "last": "Thompson", "suffix": ""}], "year": 1969, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "84880225", "_pdf_hash": "59f3955ad20f5cf6083afb757e5122f888bd99d1", "abstract": [{"section": "Abstract", "text": "Questa \u00e8 la versione dell'autore dell'opera: ", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Over the last few decades, in Italy as in the rest of EU, both the number of wild ungulates and the volume of traffic have increased significantly. Consequently, ungulate-vehicle collisions have increased with significant costs in human death and injury, animal welfare and material damage. In this study we provide information about temporal patterns of collisions in a subalpine Italian region. We analyzed 1110 reports of accidents that occurred in Cuneo district from January 2008 to December 2011. Most of them were caused by roe deer and wild boar, while red deer, fallow deer and chamois were occasionally involved. Monthly distribution of accidents showed two peaks, with a higher risk of collision during spring mainly related to roe deer and a secondary peaking autumn caused by wild boar. No evident daily variations were noticed. In the case of roe deer, we reported the existence of a primary hourly peak at dusk and another secondary peak at dawn. Wild boar were most frequently involved in collisions during dusk and night. We hypothesized that these temporal distributions are the result of a complex interaction of phenological, behavioral and human -related reasons. Information provided in this study allows us to better understand the dynamics and patte rns of wildlife-car collisions and represents an indispensable element for the implementation of any mitigation strategy.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "\"The roe deer survives in some alpine reserves, but is now virtually extinct in the rest of the Italian territory\", and \"the wild boar still exists in some areas of Tuscany, Sardinia and in a few Alpine valleys\": this Italian situation, described by Ghigi and co-workers (Touring Club Italiano 1959, pp. 122-123) has radically changed in the last few decades, when the abundance and distribution of wild ungulates have increased exponentially (Raganella Pelliccioni et al. 2013 ). This growth should be seen as part of a wider and general phenomenon, because ungulates have also been increasing in Western Europe in the last 100 years (Putman et al. 2011 ). Fuller and Gill (2001) individuated six main reasons for this trend: increase of woodland or forested areas, changes in agricultural practices (mainly the proliferation of winter cereals), reduction of livestock husbandry, changes in hunting and management (including reintroduction) practices, presence of a warming climate trend and disappearance of large predators. In Italy in particular, not only the abundance but also the distribution range is rapidly increasing, especially for roe deer (Capreolus capreolus L., 1758) and wild boar (Sus scrofa L., 1758), long diffused in wooded or mountainous regions and at present widespread in cultivated areas (Carnevali et al. 2009 ). In a densely populated territory with well-developed railroad networks and elevated traffic volumes, like many European and North American regions, this has led to an intensification of ungulate -vehicle collisions (Hubbard et al. 2000; Madsen et al. 2002; Cserk\u00e9sz et al. 2013) . Collisions with ungulates are likely to cause serious damage to humans and vehicles, due to the size of these animals, representing an important menace for human health and a source of socio-economic complications (Williams & Wells 2005; Morelle et al. 2013) . Moreover, collisions have important conservation implications, because they represent a direct cause of death for large numbers of animals every year (Trombulak & Frissell 2000) . In the United States, Forman and Alexander (1998) hypothesized that road-kills probably overtook hunting as the principal human cause of terrestrial vertebrate mortality. This problem represents an increasing threat, because conflicts at the road interface will likely increase with the future growth of traffic volume and ungulate populations (Ramp et al. 2005; Langbein 2011 ). Many studies have underlined that this phenomenon responds to non-random patterns in both temporal and spatial aspects, highlighting the importance of behavioural and environmental elements in determining the timing and location of collisions (Madsen et al. 2002; Gunson et al. 2011; Rodriguez-Morales et al. 2013) . Recently, Steiner et al. (2014) reviewed 47 papers about this topic, with the majority originating from North America (n = 37), some from Europe (n = 10) and only one from Italy (Dal Compare et al. 2007 ). Increasing our knowledge about the main factors driving this events is essential to elaborate effective mitigation strategies. The aim of this study is to describe, for me first time in Northwestern Italy, temporal patterns of ungulate-vehicle collisions in a subalpine region.", "cite_spans": [{"start": 443, "end": 477, "text": "(Raganella Pelliccioni et al. 2013", "ref_id": "BIBREF35"}, {"start": 635, "end": 654, "text": "(Putman et al. 2011", "ref_id": "BIBREF35"}, {"start": 658, "end": 680, "text": "Fuller and Gill (2001)", "ref_id": "BIBREF9"}, {"start": 1314, "end": 1336, "text": "(Carnevali et al. 2009", "ref_id": "BIBREF2"}, {"start": 1555, "end": 1576, "text": "(Hubbard et al. 2000;", "ref_id": "BIBREF15"}, {"start": 1577, "end": 1596, "text": "Madsen et al. 2002;", "ref_id": "BIBREF25"}, {"start": 1597, "end": 1618, "text": "Cserk\u00e9sz et al. 2013)", "ref_id": "BIBREF3"}, {"start": 1835, "end": 1858, "text": "(Williams & Wells 2005;", "ref_id": "BIBREF46"}, {"start": 1859, "end": 1879, "text": "Morelle et al. 2013)", "ref_id": "BIBREF27"}, {"start": 2032, "end": 2059, "text": "(Trombulak & Frissell 2000)", "ref_id": "BIBREF43"}, {"start": 2084, "end": 2111, "text": "Forman and Alexander (1998)", "ref_id": "BIBREF8"}, {"start": 2406, "end": 2424, "text": "(Ramp et al. 2005;", "ref_id": "BIBREF37"}, {"start": 2425, "end": 2438, "text": "Langbein 2011", "ref_id": "BIBREF22"}, {"start": 2685, "end": 2705, "text": "(Madsen et al. 2002;", "ref_id": "BIBREF25"}, {"start": 2706, "end": 2725, "text": "Gunson et al. 2011;", "ref_id": "BIBREF12"}, {"start": 2769, "end": 2790, "text": "Steiner et al. (2014)", "ref_id": "BIBREF41"}, {"start": 2937, "end": 2961, "text": "(Dal Compare et al. 2007", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Material and methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Study area", "text": "The study area corresponds to the \"Provincia di Cuneo\", an administrative district of Piemonte (NW Italy). The territory presents a surface of 6903 km\u00b2 and is typically subalpine, with 50.8% occupied by mountains, 26.6% by hills and 22.6% by lowlands. The Cottian, Maritime and Ligurian Alps form a large U -shaped border, which comprises a high alluvial plain crossed by the Po (the longest Italian lotic system) and Tanaro rivers . The human population density is approximately 85 inhabitants per square kilometre. The road density is 1070 km/1000 km\u00b2 (Provincia di Cuneo, Settore Viabilit\u00e0). Ungulate-vehicle collision data We analyzed collision reports collected by Settore Politiche Agricole, Parchi e Foreste of the \"Provincia di Cuneo\" from January 2008 to December 2011. In Italy, it is not mandatory to give info rmation to local or national authorities about accidents involving wildlife, so usually data are scarce and fragmentary. However, in this period, a plan to refund damages caused by wildlife collisions was implemented in Cuneo district, allowing us to produce a homogeneous database of considerable interest. The accident-related information contained in the database included: accident ID, year, month, day, hour, route, kilometre (from control section), day of week and ungulate species. Since we have not verified year effects on monthly (analysis of variance, ANOVA F 3,44 = 0.99, P = ns), daily (ANOVA F 3,24 = 0.13 P = ns (not significant)) and hourly (ANOVA F 3,88 = 0.69, P = ns) distributions, yearly data were pooled. In our study, we performed analysis on the influence of month, day and hour (GMT (Greenwich Mean Time) + 1). Moreover, we also considered the influence of time of day (dawn, day, dusk, night). According to Lagos et al. (2012) , the year was divided into four seasons for roe deer phenology and hunting periods: breeding season (15 April-15 June), mating season (July-August), hunting season (September to January) and the rest of the year. For the analysis involving wild boar, we only differentiated drive-hunting season (September to December) from the rest of the year. A contingency table was used, and \u03c7\u00b2 square test and odd ratio (OR) values were calculated far each risk factor. The OR is a measure of association between an exposure and an outcome. The OR represents the odds that an outcome will occur given a particular exposure, compared to the odds of the outcome occurring in the absence of that exposure.", "cite_spans": [{"start": 1755, "end": 1774, "text": "Lagos et al. (2012)", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "Results", "text": "We analyzed 1110 reports of ungulate vehicle collisions (UVC) in Cuneo. Most of them (92.7%) were caused by roe deer (64.7%) and wild boar (29.5%). Collisions with red deer (Cervus elaphus L., 1758) represented approximately 5%, while fallow deer (Dama dama L., 1758) and chamois (Rupicapra rupicapra L, 1758) were involved occasionally ( Figure 1 ). Figure 2 illustrates monthly, daily and hourly dis tributions of UVC in the study period. Monthly occurrence of collisions was not uniformly distributed (X 2 = 150.4, df (degree of freedom) = 11, P < 0.001), with two distinct peaks (spring and autumn). The number of road casualties varied throughout the week (x 2 = 18.4787, df = 6, P < 0.005), with a maximum on weekends and a minimum on Tuesdays. Regarding hourly occurrence, we noticed a non-random distribution (X 2 = 940.4, df = 23, P < 0.001), with a first peak after dusk and a second, minor peak at dawn. Considering all data together, a higher collision risk was found in March, April and October (odd ratio > 1.0), while in January and February the risk was significantly lower (odd ratio < 1.0; Table I ). Regarding the time of the day, the most dangerous periods were night and dusk, while the safest was daytime (Table II) . Figure 3 illustrates temporal distributions of UVC for the two most involved species, roe deer and wild boar. Monthly collisions showed non-random distributions (roe deer: X 2 = 231.5, df = 11, P < 0.001; wild boar: X 2 = 140.7, df = 11, P < 0.001) and distinct seasonal patterns. Most collisions involving roe deer occurred in springtime (April-May) but also in summertime, while a maximum frequency of wild boar-related accidents was noticed in autumn (September-December; Table I ). Breeding season highly increased the collision risk for roe deer, and hunting season for wild boar (Table III) . At a daily scale, the collision distributions were uniformly distributed for both species. Both species showed a peak of collisions in the evenings, between 19:00 and 23:00, but roe deer collisions have a secondary peak at dawn (Figure 3) . Considering the localized distribution (for red deer: approximately 7.00% of our study area) and the small sample size (for chamois and fallow deer), no significant influences of temporal patterns were found for these species.", "cite_spans": [], "ref_spans": [{"start": 339, "end": 347, "text": "Figure 1", "ref_id": "FIGREF0"}, {"start": 1240, "end": 1248, "text": "Figure 3", "ref_id": "FIGREF1"}, {"start": 2067, "end": 2077, "text": "(Figure 3)", "ref_id": "FIGREF1"}]}, {"section": "Discussion", "text": "The assessment of the main temporal patterns related to ungulate-vehicle collisions is an essential factor to increase road safety and enhance wildlife conservation strategies. Road collisions involving ungulates represent an increasing problem in many developed countries (Conover 2002; Malo et al. 2004; Steiner et al. 2014 ) and, with a few exceptions (Ponzetta et al. 2006; Dal Compare et al. 2007; Primi et al. 2010) , scarce data are available for Italy. This paper covers this blank for a subalpine Italian region where high volumes of traffic overlap with growing populations of ungulates. The rate of ungulate-vehicle collision (UVC/year/1 000 km 2 ) for Cuneo district (40), even if higher than that observed in another subalpine Italian area (Belluno: 18-24; Nardo et al. 2001; Dal Compare et al. 2007) , is lower than those reported in other European countries, such as Slovenia (153; Pokorny 2006), Austria (483; Putman et al. 2011) and Germany (635; Kerzel 2005 ). Comparing to CentraI and Southern European data, the UVC rate is reduced in North America (4.5; Huijser et al. 2009 ) and in Scandinavia (7.2; Haikonen & Summala 2001), likely because of mitigation efforts, but even perhaps b ecause of significantly lower urbanization and road density (Olsson et al. 2008) . Several authors underlined the development of road networks among the main factors affecting UVC increase (Mysterud 2004; Seiler 2004; Langbein 2011) . Our data confirm the findings of studies carried out in similar ecological and environmental conditions, reporting that Cervidae and wild boars represent the main component of UVC (Dal Compare et al. 2007; DiazVarela et al. 2011 ). In our study, an evident non-random temporal distribution was found considering all datasets, and further interesting considerations can be made with a species-pattern approach. The two most frequently involved ungulates, roe deer and wild boar, are the most common species in the area (also in the whole Italian peninsula; Apollonio et al. 1988; Lorenzini et al. 2002) , whereas red deer, chamois and fallow deer have localized distributions and relatively low densities. Monthly UVC showed two peaks, corresponding to spring (April-May) and autumn (October-November). The coincidence of rush hour traffic peaks with twilight in spring and autumn may be important in exacerbating the seasonal peaks in traffic accidents, as suggested by Langbein (1985) . The higher risk of collision during spring months was due to roe deer, according to other studies (i.e. DiazVarela et al. 2011 ). This peak was situated in the period of dispersal of young males and territorial males movements as reported in several studies (Nardo et al. 2001; Pokorny 2006; Lagos et al. 2012) . The dispersion of yearlings from natal ranges to new territories leads to an increased probability to cross main roads, resulting in a greater vulnerability to collision (Langbein & Putman 2006; Langbein 2007) . Moreover, in this period, large wintering groups collapse (Vincent et al. 1995) , males initiate a territorial behaviour (Wahlstr\u00e9im 2013) and many females start important migratory movements ). Another factor is that in this subalpine area, April and May correspond to vegetation renewal, with the availability of new feeding areas (Nilsen et al. 2008) . All these factors increase the probability of roe deer crossing roads. Our results, reporting a significantly lower risk of collision with roe deer in December-February, agree with previous studies, which have reported a typical pattern with a main peak in spring, declining numbers during summer and low values during autumn and winter (Krop-Benesch et al. 2013; Steiner et al. 2014) . The severe climatic conditions, snow cover and reduced food availability probably inhibit or reduce movements, so that roe deer spend most of their time in localized and advantageous wintering areas. Wild boar is the main species involved in the autumn peak (September-November), when the risk of collision was about 2 times higher. Autumn and winter peaks were previously reported for wild boar, and rutting period, longer nights and hunting are frequently used to explain this pattern (Groot Bruinderink & Hazebroek 1996; Primi et al. 2010; Lagos et al. 2012) . Life cycle and seasonal changes in home range size were other factors that should be considered (Diaz-V arela et al. 2011), and even the effect of autumnal outbreak of family groups. Another factor could be represented by winter road conditions, also if the role played by harsh weather is controversial (Hartwig 1993; Garrett & Conway 1999) . Moreover, we could hypothesize that the presence of autumn feeding areas (i.e. related to local chesU1Ut abundance) plays an important role in increasing displacement and, consequently, accidents. Our findings suggest that hunting could have influenced seasonal patterns for wild boar. Indeed, during this period, there was a risk of collision 3.29 times higher than during the rest of the year. Lagos et al. (2012) demonstrated the combined effect of hunting and longer nights on differences in numbers of accidents with wild boar in the autumn-winter months, even if Primi et al. (20 10) reported no correlation between UVC occurrence and drive hunting days. The reduction of wild boar collisions observed in our study after the hunting season could be related to the fact that almost 6000 hogs are harvested every year in Cuneo district, with an important lowering of density (Bonetto D. personal communication, 2014) . The available literature about UVC per day of the week is very scarce. In Spain, two studies (Diaz Varela et al. 2011; Lagos et al. 2012) reported evident weekly patterns with Sunday peaks, probably related to hunting influence. In our study, daily patterns evidenced a non-uniform distribution with a greater rate of accidents during weekends. This distribution was more pronounced for wild boar. Hourly patterns showed a different distribution between the two main species involved. We observed a primary peak at dusk for roe deer: between 19:00 and 22:00, the risk of collision was 3.54 times higher than in other daily periods. Another secondary peak was found at dawn, between 05:00 and 07:00. These findings were comparable to those reported in the Netherlands (Groot Bruinderink & Hazebroek 1996) and in Finland (Haikonen & Summala 2001) . A partially analogous pattern was described for roe deer in Spain (Diaz -Varela et al. 2011; Lagos et al. 2012) and in Siovenia (Pokorny 2006) . This could be related to the activity patterns o f deer that increase during sunrise and sunset (Romin & Bissonette 1996) . Wild boar was most frequently involved in collisions during dusk and night, while dawn and day were periods with a lower risk of accident according to previous studies (Primi et al. 2010; Diaz-Varela et al. 2011; Lagos et al. 2012) . We could hypothesize that the reason for this distribution is mainly behavioural, because the activity of this species is mainly concentrated during sunset and nocturnal periods (Boitani et al. 1994 ).", "cite_spans": [{"start": 273, "end": 287, "text": "(Conover 2002;", "ref_id": "BIBREF3"}, {"start": 288, "end": 305, "text": "Malo et al. 2004;", "ref_id": "BIBREF26"}, {"start": 306, "end": 325, "text": "Steiner et al. 2014", "ref_id": "BIBREF41"}, {"start": 355, "end": 377, "text": "(Ponzetta et al. 2006;", "ref_id": "BIBREF33"}, {"start": 378, "end": 402, "text": "Dal Compare et al. 2007;", "ref_id": "BIBREF4"}, {"start": 403, "end": 421, "text": "Primi et al. 2010)", "ref_id": "BIBREF34"}, {"start": 770, "end": 788, "text": "Nardo et al. 2001;", "ref_id": "BIBREF29"}, {"start": 789, "end": 813, "text": "Dal Compare et al. 2007)", "ref_id": "BIBREF4"}, {"start": 964, "end": 975, "text": "Kerzel 2005", "ref_id": "BIBREF17"}, {"start": 1075, "end": 1094, "text": "Huijser et al. 2009", "ref_id": "BIBREF16"}, {"start": 1265, "end": 1285, "text": "(Olsson et al. 2008)", "ref_id": "BIBREF31"}, {"start": 1394, "end": 1409, "text": "(Mysterud 2004;", "ref_id": "BIBREF28"}, {"start": 1410, "end": 1422, "text": "Seiler 2004;", "ref_id": "BIBREF40"}, {"start": 1423, "end": 1437, "text": "Langbein 2011)", "ref_id": "BIBREF22"}, {"start": 1620, "end": 1645, "text": "(Dal Compare et al. 2007;", "ref_id": "BIBREF4"}, {"start": 1996, "end": 2018, "text": "Apollonio et al. 1988;", "ref_id": "BIBREF0"}, {"start": 2019, "end": 2041, "text": "Lorenzini et al. 2002)", "ref_id": "BIBREF24"}, {"start": 2410, "end": 2425, "text": "Langbein (1985)", "ref_id": "BIBREF20"}, {"start": 2686, "end": 2705, "text": "(Nardo et al. 2001;", "ref_id": "BIBREF29"}, {"start": 2720, "end": 2738, "text": "Lagos et al. 2012)", "ref_id": "BIBREF19"}, {"start": 2911, "end": 2935, "text": "(Langbein & Putman 2006;", "ref_id": "BIBREF23"}, {"start": 2936, "end": 2950, "text": "Langbein 2007)", "ref_id": "BIBREF21"}, {"start": 3011, "end": 3032, "text": "(Vincent et al. 1995)", "ref_id": "BIBREF44"}, {"start": 3286, "end": 3306, "text": "(Nilsen et al. 2008)", "ref_id": "BIBREF30"}, {"start": 3646, "end": 3672, "text": "(Krop-Benesch et al. 2013;", "ref_id": "BIBREF18"}, {"start": 3673, "end": 3693, "text": "Steiner et al. 2014)", "ref_id": "BIBREF41"}, {"start": 4183, "end": 4219, "text": "(Groot Bruinderink & Hazebroek 1996;", "ref_id": "BIBREF11"}, {"start": 4220, "end": 4238, "text": "Primi et al. 2010;", "ref_id": "BIBREF34"}, {"start": 4239, "end": 4257, "text": "Lagos et al. 2012)", "ref_id": "BIBREF19"}, {"start": 4564, "end": 4578, "text": "(Hartwig 1993;", "ref_id": "BIBREF14"}, {"start": 4579, "end": 4601, "text": "Garrett & Conway 1999)", "ref_id": "BIBREF10"}, {"start": 5000, "end": 5019, "text": "Lagos et al. (2012)", "ref_id": "BIBREF19"}, {"start": 5620, "end": 5645, "text": "(Diaz Varela et al. 2011;", "ref_id": "BIBREF5"}, {"start": 5646, "end": 5664, "text": "Lagos et al. 2012)", "ref_id": "BIBREF19"}, {"start": 6294, "end": 6330, "text": "(Groot Bruinderink & Hazebroek 1996)", "ref_id": "BIBREF11"}, {"start": 6346, "end": 6371, "text": "(Haikonen & Summala 2001)", "ref_id": "BIBREF13"}, {"start": 6440, "end": 6466, "text": "(Diaz -Varela et al. 2011;", "ref_id": "BIBREF5"}, {"start": 6467, "end": 6489, "text": "Lagos et al. 2012) and", "ref_id": "BIBREF19"}, {"start": 6615, "end": 6640, "text": "(Romin & Bissonette 1996)", "ref_id": "BIBREF39"}, {"start": 6811, "end": 6830, "text": "(Primi et al. 2010;", "ref_id": "BIBREF34"}, {"start": 6831, "end": 6855, "text": "Diaz-Varela et al. 2011;", "ref_id": "BIBREF5"}, {"start": 6856, "end": 6874, "text": "Lagos et al. 2012)", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "Conclusions", "text": "Information provided by this and similar studies is essential to understand the dynamics and patterns of UV C. The effectiveness of any mitigation strategy strongly depends on the level of our knowledge of this phenomenon. Regarding the presence of distinct temporal peaks, some studies suggested the use of seasonal warning signs (e.g. Dussault et al. 2006) or to realize a campaign of public awareness with local data an d examples, to increase drivers attention in particular periods of the year or day. Thinking to eliminate the prob1em of wildlife-car collisions is absolutely unrealistic. Let us consider that already in his pioneering work, Dickerson (1939, p. 115) wrote that the \"solution of the problem of destruction of wildlife on highways by automobiles is not a search for means of eliminating such destruction entirely but rather of finding means to reduce to a minimum the death toll in each kind of highway environment. It is a subject of investigation that should enlist the cooperation of the w ildlife manager, the landscape engineer, the horticulturist, and the highway engineer.\" With the exponential growth of vehicle traffic and road extension, this problem is still growing enormously. At present, since it is almost impossible to modify ungulates behaviour, the mitigation of this problem should be focused on the modification of human behaviour, changing drivers attitudes and road engineering. 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{"paper_id": "84881263", "_pdf_hash": "877a92903ac86e0f43c04ba06577135fa2e316ac", "abstract": [], "body_text": [{"section": "", "text": "", "cite_spans": [], "ref_spans": []}], "bib_entries": {}, "ref_entries": {"TABREF0": {"text": "Insect Food of the Vesper Sparrow G. F. KNOWLTON and W. P. NYE,l Utah Agriculiura Experiment Station, Logan An examination has been made of 116 stomachs of the western vesper sparrow, Pooecetes gramineus con- finia Baird. The birds were collected throughout Utah during thc seasons of 1934 to 1945, inclusive.Scudder). I, Melanoplus packardi Scudder I, and M. mexicanus Riley 1. Te.ttigoniidae 105158 plant seeds plus numerous seed and plant fragments.-5-4-48. Reprinted January 7, 1949 from JOURNAL OF ECONOMIC ENTOMOLOQY 41: (S) :821", "type": "table"}}}
{"paper_id": "84882675", "_pdf_hash": "75feb7382fc4d7eb1cf58c2f2ab1235df3d90047", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "84882792", "_pdf_hash": "c2b19e580f1ac0971280ed3ae5fcdc43992e468d", "abstract": [], "body_text": [{"section": "", "text": "To elucidate the physiological roles during pregnancy of vascular endothelial growth factor (VEGF), we examined the temporal and spatial expression of VEGF protein and mRNA in the rat uterine and placental tissues throughout pregnancy.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "The uterine tissue of nonpregnant rats, pregnant rats, and the rat placental tissue were examined by Northern blotting, in situ hybridization and immunohistochemistry.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Northern analysis revealed the existence of VEGF mRNA in the uterus and placenta regardless of the stage of estrous cycle or pregnancy. Angiogenesis is the formation of new blood vessels through the sprouting of capillaries from preexisting vessels [13] . During pregnancy, angiogenesis of the placenta and placental vascular bed in the maternal uterus is characterized by the formation of networks of neovasculatures, allowing for the steady increase in fetoplacental blood flow necessary to sustain the growing fetus [17] . Administration of an angiogenesis inhibitor to pregnant mice results in complete failure of embryonic growth due to interference with placenta formation and embryonic vascular development [18] . Although angiogenesis plays a crucial role in fetal development, the stimuli for angiogenesis in the placenta and placental bed throughout gestation are unknown.", "cite_spans": [{"start": 249, "end": 253, "text": "[13]", "ref_id": "BIBREF7"}, {"start": 519, "end": 523, "text": "[17]", "ref_id": "BIBREF11"}, {"start": 714, "end": 718, "text": "[18]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "", "text": "One possible mediator for angiogenesis is vascular endothelial growth factor (VEGF), a potent mitogenic factor for vascular endothelial cells in promoting blood vessel growth [11] . VEGF, also known as vascular permeability factor, is a heparin-binding and highly conserved glycosylated dimetric protein with a molecular weight of 40-45 kDa [11] . VEGF is expressed in a variety of normal and tumor tissues including the placenta [19] , umbilical vein endothelial cells [2] , the pregnant uterus [4, 9] and trophoblasts [4] . Products of two genes, the fms-like tyrosine kinase gene (fit-1), and the kinase insert domain-containing gene (KDR/Flk-1), have been shown to be high-affinity VEGF receptors [10, 21] . The expression of the VEGF receptors was confirmed in decidual beds of mouse uterus in an early stage of pregnancy [4] . Inactivation of one or both VEGF alleles in mice resulted in markedly abnormal blood vessel formation and mid-gestational death [3, 12] . This evidence suggests the involvement of VEGF in the angiogenesis required during pregnancy. However, relatively little is known about the profile of VEGF expression in the uterus and placenta throughout pregnancy. As a part of our overall objective of elucidating the substances that sustain maternal-fetal circulation, we examined the temporal and spatial expression of VEGF protein and mRNA in the rat uterus in the nonpregnant, pregnant and puerperal periods, and in the placenta.", "cite_spans": [{"start": 175, "end": 179, "text": "[11]", "ref_id": "BIBREF5"}, {"start": 341, "end": 345, "text": "[11]", "ref_id": "BIBREF5"}, {"start": 430, "end": 434, "text": "[19]", "ref_id": "BIBREF13"}, {"start": 500, "end": 502, "text": "9]", "ref_id": "BIBREF3"}, {"start": 701, "end": 705, "text": "[10,", "ref_id": "BIBREF4"}, {"start": 706, "end": 709, "text": "21]", "ref_id": "BIBREF15"}, {"start": 965, "end": 968, "text": "12]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "II.", "text": "Materials and Methods", "cite_spans": [], "ref_spans": []}, {"section": "Experimental animals", "text": "Female Wistar rats greater than 10-weeks old were obtained from Japan SLC (Shizuoka, Japan). The rats were acclimated for at least 5 days before determining the estrous cycle, and were housed in a 12-hr on/12-hr off light-dark schedule. The stages of the estrous cycle were checked by vaginal cytology according to the usual methods.", "cite_spans": [], "ref_spans": []}, {"section": "Experimental animals", "text": "Based on these observations, each individual was assigned to a cyclic stage (diestrus, proestrus, estrus or metestrus).", "cite_spans": [], "ref_spans": []}, {"section": "Experimental animals", "text": "Animals were monitored for 10 days before experimentation or mating, and animals not exhibiting a normal 4-to 5-day estrous cycle were excluded from the study. To obtain pregnant animals, rats were cohabited with males overnight and presence of sperm in the vagina was checked the next morning.", "cite_spans": [], "ref_spans": []}, {"section": "Experimental animals", "text": "The day of sperm confirmation was termed day 0 of pregnancy (P0). All animal studies were conducted according to the Guidelines for Animal Experiments approved by the Animal Ethics Committee of Yamanashi Medical University.", "cite_spans": [], "ref_spans": []}, {"section": "Tissue preparation", "text": "The rats were sacrificed by cervical fracture under ether anesthesia on the day of each stage of the estrous cycle, P5, P8, P11, P15, P20 and on the 5th day in the puerperium (PP5). Animals not exhibiting pregnancy on P8, P11, P15, and P20 were excluded from the study. Three animals per each stage or gestational day were used. The uterus was immediately exposed and carefully resected. In P15 and P20 rats, the uterus was dissected, and the fetus with umbilical cord was removed from the placenta and uterus. Consequently, the uterine samples from P5 to P11 animals included all of the conceptus, and those from P15 and P20 included the placenta. Two or three uterine samples for Northern blotting and four for immunohistochemistry and in situ hybridization were obtained from each rat. The placenta and uterus of two uterine samples of the P15 and P20 animals were separated by gentle pulling and stored separately.", "cite_spans": [], "ref_spans": []}, {"section": "Tissue preparation", "text": "For Northern blotting, the samples were immediately frozen in liquid nitrogen and stored at -80\u00b0C.", "cite_spans": [], "ref_spans": []}, {"section": "Tissue preparation", "text": "For immunohistochemistry and in situ hybridization, the samples were fixed in 4% paraformaldehyde (PFA) in phosphate buffered saline (PBS, pH 7.4) overnight at 25\u00b0C and embedded in paraffin.", "cite_spans": [], "ref_spans": []}, {"section": "Northern blotting", "text": "Total RNA was extracted from the tissues by the acid guanidinium-phenol-chloroform system (ISOGEN, NIPPON GENE, Co., Ltd., Toyama, Japan) according to the manufacturer's instructions. The isolated total RNA (20 ,ug) was fractionated by electrophoresis on a 1.5% agarose in 18% formaldehyde gel, then transferred onto a Hybond-N+ nylon membrane (Amersham) and cross-linked by ultraviolet irradiation.", "cite_spans": [], "ref_spans": []}, {"section": "Northern blotting", "text": "After overnight prehybridization at 42\u00b0C in 50% formamide, 5 x saline sodium phosphate-ethylenediaminetetraacetic acid (SSPE), 5 x Denhardt's solution, 0.5% sodium dodecyl sulfate (SDS), and 20pg/ml of denatured salmon sperm DNA, the membranes were hybridized overnight at 42\u00b0C with a 32P deoxycytidine triphosphate (dCTP) labeled DNA hybridization probe encoding rat VEGF. The probe was synthesized by restriction of the pU 18 vector rat VEGF cDNA clone using EcoR I and Hind III according to the method previouly reported [24] . The 500 by fragments encoding exon 1-8 were labeled with a _32P dCTP (NEN) using the BcaBEST Labeling Kit (Takara Shuzo, Co., Ltd., Shiga, Japan). After hybridization, the membranes were washed four times with 2 x SSPE, 0.1% SDS for 5 min at 25\u00b0C and with 0.2 x SSPE, 0.1 \u00b0% SDS for 15 min at 60\u00b0C. The membranes were exposed to Fuji RX film (Fuji Photo Film Co., Ltd., Tokyo, Japan) with intensifying screens for 1 to 3 days. To correct for loading and transfer differences, the membranes were stripped and reprobed with an a32P labeled probe for rat (3-actin (Wako Pure Chemical Co., Ltd., Tokyo, Japan). Total RNA from the rat lung served as a positive control according to the report of Chakraborty et al [4] . Autoradiographs were analyzed with an image analyzer (BAS 2000, Fuji Photo Film Co., Ltd.).", "cite_spans": [{"start": 524, "end": 528, "text": "[24]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "In situ hybridization", "text": "In situ hybridization was carried out using the nonradioactive Genius labeling and detection kit (Boehringer Mannheim GmbH, Mannheim, Germany). The rat VEGF DNA hybridization probes were prepared following the same methods used for the Northern blotting, and were labeled with digoxigenin-dUTP according to the manufacturer's instructions. 501A of Hybridization , and rat lung (Lane 8). To control for transfer efficiency and loading levels, the blots were also hybridized to a p-actin probe.", "cite_spans": [], "ref_spans": []}, {"section": "In situ hybridization", "text": "Solution I (Maxim Biotech, Inc., San Francisco, USA) containing the DNA probe was applied on each slide. Hybridization was performed overnight at 42\u00b0C in a moist chamber. Fab fragments from anti-digoxigenin-alkaline phosphatase antibody (Boehringer Mannheim) in TN solution (100 mM Tris-HC1 pH 7.5, 150 mM NaCl, 1 : 500 dilution) were used to detect the labeled DNA probes. The nuclei were counterstained with methyl green. All tissue sections were stained at the same time and sections without a DNA probe or anti-digoxigenin-alkaline phosphatase antibody were used as negative controls.", "cite_spans": [], "ref_spans": []}, {"section": "Immunohistochemistry", "text": "Paraffin-embedded tissue sections (3,um) were deparaffinized in xylene and substituted gradually in a descending ethanol series ending in water. Endogenous peroxidase activity was destroyed with 3% hydrogen peroxide (H202) for 5 min at 25\u00b0C. Sections were washed with PBS and incubated overnight at 4\u00b0C with a 1: 100 dilution of anti-rat VEGF rabbit IgG (IBL, Gumma, Japan) in 1% bovine serum albumin (BSA) in PBS. Bound primary antibody was detected using the streptavidin-biotin-peroxidase complex method (DAKO Laboratories Ltd., Kyoto, Japan). The secondary antibody was a biotinylated goat anti-rabbit immunoglobulin in 1% BSA (1 : 200 dilution) at 25\u00b0C for 20 min. Positive staining was detected by using peroxidase-conjugated streptavidin in 1% BSA (1:600 dilution) at 25\u00b0C for 20 min. Peroxidase activity was detected using a 3,3'-diaminobenzidine tetrahydrochloride (DAB: Dojindo, Kumamoto) solution containing 0.003% H2O2. The sections were lightly counterstained with hematoxylin to visualize the nuclei. Sections without primary antibody were used as negative controls.", "cite_spans": [], "ref_spans": []}, {"section": "III.", "text": "Results Fig. 1 shows the results of the Northern analysis. Specific hybridization signals were produced by the 32P-dCTP-labeled rat VEGF probe hybridized with the total RNA obtained from the pregnant-and nonpregnant rat uterus and placenta.", "cite_spans": [], "ref_spans": [{"start": 8, "end": 14, "text": "Fig. 1", "ref_id": "FIGREF0"}]}, {"section": "III.", "text": "For P15 and P20 uterine samples, Northern analysis was performed with uterus and placenta in combination (total uterus) or separately. In all tissues studied, 20 ~Cg of total RNA was enough to yield hybridization signals that were detectable after exposure to autoradiography.", "cite_spans": [], "ref_spans": []}, {"section": "III.", "text": "The lung tissue used as a positive control yielded a high signal. The molecular size of the hybridized messenger RNA (mRNA) species, as estimated by comparison with an RNA ladder, was found to occur between the 18S and the 285 ribosomal RNA. The results of rehybridizing the same blot to a 9-actin probe confirmed RNA integrity in this Northern analysis. The levels of VEGF mRNA in total uterus were lower than in the lung tissue, and were almost the same throughout estrus and pregnancy, as well as in the separate placenta and uterus samples on P15 and P20 (data not shown). These results were consistently confirmed in all three experiments. Results of in situ hybridization and immunohistochemistry are shown in Figs. 2 and 3. In situ hybridization for nonpregnant rat specimens showed that VEGF mRNA accumulated in myometrial smooth muscle cells, glandular epithelial cells, stromal cells (Fig. 2-A, E) , and endometrial epithelial cells during each stage of the estrous cycle. With the exception of the myometrial smooth muscle cells, the level of accumulation increased in all of the above mentioned cells upon estrus.", "cite_spans": [], "ref_spans": [{"start": 894, "end": 907, "text": "(Fig. 2-A, E)", "ref_id": "FIGREF1"}]}, {"section": "III.", "text": "During pregnancy, the VEGF mRNA expression in these cells were of the same degree as that during estrus, but fetal compartments such as trophoblasts (Fig. 3-A, E) , vitelline epithelial cells and amnion were labeled more strongly. P8 and P11 sections demonstrated the highly-labeled trophoblasts invading into the endometrium (Fig. 3A) . The vitelline epithelial cells and amnion were also strongly labeled in the P15 and P20 sections. In the puerperal (PP5) uterus, VEGF mRNA was most strongly expressed in the region of mazolysis.", "cite_spans": [], "ref_spans": [{"start": 149, "end": 162, "text": "(Fig. 3-A, E)", "ref_id": "FIGREF2"}, {"start": 326, "end": 335, "text": "(Fig. 3A)", "ref_id": "FIGREF2"}]}, {"section": "III.", "text": "Through immunohistochemistry, cells stained with anti-VEGF antibody were shown to be the same as those with in situ hybridization experiments. The expression of VEGF protein was found in smooth muscle cells, stromal cells, glandular epithelial cells (Fig. 2-B, F) and epithelial cells of the endometrium in nonpregnant and pregnant uterus and trophoblasts (Fig. 3-B, F) , amnion, vitelline epithelial cells, and decidual cells (Fig. 3D) in the pregnant uterus. The highest intensity was observed in fetal compartments such as trophoblasts, vitelline epithelial cells and amnion. VEGF proteins were also detected in vascular endothelial cells, which did not express VEGF mRNA (Fig. 3-E, F) .", "cite_spans": [], "ref_spans": [{"start": 250, "end": 263, "text": "(Fig. 2-B, F)", "ref_id": "FIGREF1"}, {"start": 356, "end": 369, "text": "(Fig. 3-B, F)", "ref_id": "FIGREF2"}, {"start": 427, "end": 436, "text": "(Fig. 3D)", "ref_id": "FIGREF2"}, {"start": 675, "end": 688, "text": "(Fig. 3-E, F)", "ref_id": "FIGREF2"}]}, {"section": "III.", "text": "These results were confirmed in all of the 12 sections from the three animals, and no signals were observed in the control sections (Fig. 2-C, D) . The changes of signal intensity in the above-mentioned cells were summarized in Tables 1 and 2 . The intensity of signals in the myometrial smooth muscle cells was used as a control, since it was relatively constant regardless of the stage in the estrous cycle or pregnancy.", "cite_spans": [], "ref_spans": [{"start": 132, "end": 145, "text": "(Fig. 2-C, D)", "ref_id": "FIGREF1"}, {"start": 228, "end": 242, "text": "Tables 1 and 2", "ref_id": "TABREF2"}]}, {"section": "IV. Discussion", "text": "This study demonstrated both the consistency in spatial expression, and the variation in temporal expression of the VEGF gene and protein in uterine tissue during cyclical changes and pregnancy. This is also the first study to elucidate the profile of VEGF expression in the rat uterus and placenta throughout pregnancy.", "cite_spans": [], "ref_spans": []}, {"section": "IV. Discussion", "text": "We used a DNA probe encoding for 8 exons of VEGF mRNA in Northern analysis since the gene for both human and rat VEGF is organized into 8 exons [14, 15, 22] . The expression of the VEGF gene in the uterus and placenta were consistent with previous results using rats [9] , mice [4] Table 1 . Localization of VEGF mRNA and VEGF protein in the rat uterus during the estrous cycle. and sheep [7] . With regard to the quantitative change of VEGF mRNA during the estrous cycle or pregnancy, Chakraborty et al. [4] reported that the steady-state levels of the major VEGF mRNA transcript (4.2 kb) did not vary much during the pen-implantation period in mice, except for an increase in day-8 decidual samples. We, however, did not find any apparant quantitative difference between stages. This probably means that, since the VEGF mRNA expression occurs not only in the decidua but also in the whole uterine and placental tissues, the quantitative difference can not be detected by comparing the whole-uterine tissues.", "cite_spans": [{"start": 144, "end": 148, "text": "[14,", "ref_id": "BIBREF8"}, {"start": 149, "end": 152, "text": "15,", "ref_id": "BIBREF9"}, {"start": 153, "end": 156, "text": "22]", "ref_id": "BIBREF17"}, {"start": 267, "end": 270, "text": "[9]", "ref_id": "BIBREF3"}, {"start": 389, "end": 392, "text": "[7]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "IV. Discussion", "text": "It is also well known that Northern analysis provides only limited information for quantification of mRNA expression, and a more sensitive method such as an RNase protection assay may be required for this purpose.", "cite_spans": [], "ref_spans": []}, {"section": "IV. Discussion", "text": "To examine the cell type-specific expression of VEGF mRNA and the change throughout pregnancy, we performed in situ hybridization experiments.", "cite_spans": [], "ref_spans": []}, {"section": "IV. Discussion", "text": "Results of in situ hybridization demonstrated that spatial expression of VEGF mRNA in myometrial smooth muscle cells, glandular epithelial cells, stromal cells and endometrial epithelial cells consistently occurred during each stage of the estrous cycle. These signals increased on estrus, except in the myometrial smooth muscle cells. The spatial and temporal expression of VEGF protein as determined by immunohistochemistry was almost the same as that determined with in situ hybridization experiments except for vascular endothelial cells. These results demonstrate that the VEGF gene and protein were specifically expressed in these cells. The lack of VEGF mRNA expression in vascular endothelial cells agrees with previous studies [4, 9, 23] . It has been generally accepted that vascular endothelial cells, a main target of VEGF, do not secrete VEGF protein by themselves [1 1]. The high signals obtained on estrus and during pregnancy can be explained by estrogen regulation of VEGF expression. Estrogen induction of uterine VEGF expression has been generally accepted. Estrogen treatment induces VEGF mRNA in the ovariectomized rat uterus [9] and estradiol increases VEGF mRNA expression in the human endometrial cell line [6] . The estrogen effect may explain why the cyclic change of VEGF mRNA expression in myometrial smooth muscle cells was smaller than in other positive cells, as estrogenreceptor mRNA expression has been reported to be much lower in the human myometrium than in the endometrium [14] . It should be noted, however, that classical estrogen or progesterone response elements are not present in the promotor region of VEGF [23] , suggesting that estrogen may influence VEGF mRNA expression in an indirect fashion.", "cite_spans": [{"start": 740, "end": 742, "text": "9,", "ref_id": "BIBREF3"}, {"start": 743, "end": 746, "text": "23]", "ref_id": "BIBREF18"}, {"start": 1147, "end": 1150, "text": "[9]", "ref_id": "BIBREF3"}, {"start": 1231, "end": 1234, "text": "[6]", "ref_id": "BIBREF0"}, {"start": 1510, "end": 1514, "text": "[14]", "ref_id": "BIBREF8"}, {"start": 1651, "end": 1655, "text": "[23]", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "IV. Discussion", "text": "During pregnancy, the signals from cells of maternal origin were almost the same as those obtained on estrus. But the cells specifically developed during pregnancy, such as trophoblasts and vitelline epithelial cells, showed much stronger signals for VEGF mRNA.", "cite_spans": [], "ref_spans": []}, {"section": "IV. Discussion", "text": "The specific expression of VEGF in these cells subsequently resulted in the strong labeling of the labyrinth which sustains maternal-fetal circulation. The spatial expression of VEGF protein determined by immunohistochemistry was almost the same as that determined by in situ hybridization. A number of authors of histochemical and in situ 8, 19] in trophoblasts throughout pregnancy. VEGF expression by trophoblasts in early gestation is considered to play a principal role in the uterine-vessel remodeling and angiogenesis that occurs, and may influence development of the villous vasculature as well.", "cite_spans": [{"start": 340, "end": 342, "text": "8,", "ref_id": "BIBREF2"}, {"start": 343, "end": 346, "text": "19]", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "IV. Discussion", "text": "We also observed that trophoblasts invading into the endometrium showed a rich accumulation of VEGF mRNA and protein. Expression of VEGF at term (P20), where there is little need for new vessel growth, may signify that a critical level of VEGF is needed to maintain vessel integrity and permeability as demonstrated in other vascular beds. Furthermore, the presence of fit-1, a high-affinity VEGF receptor confirmed on trophoblasts [1, 8] , suggests that trophoblastderived VEGF could act in an autocrine manner to influence trophoblast function at all stages of gestation. The expression of VEGF in the vitelline epithelial cells and amnion might act to maintain permeability in order to sustain amniotic fluid circulation.", "cite_spans": [{"start": 436, "end": 438, "text": "8]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "IV. Discussion", "text": "The VEGF expression seen in the region of mazolysis on the puerperal (PP5) uterus is considered to be involved with wound healing, which is one of the major physiological roles of VEGF.", "cite_spans": [], "ref_spans": []}, {"section": "IV. Discussion", "text": "In conclusion, the spatial expression of VEGF was relatively constant in rat maternal uterus during the estrous cycle and during pregnancy, but there was a temporal change of VEGF expression which might be induced by estrogenic regulation.", "cite_spans": [], "ref_spans": []}, {"section": "IV. Discussion", "text": "During pregnancy, VEGF, which is highly expressed in fetal tissue, especially trophoblastic and amniotic tissue, may act in a paracrine fashion to regulate maternal-fetal vascular growth and permeability changes, and to sustain fetal and placental development.", "cite_spans": [], "ref_spans": []}, {"section": "IV. Discussion", "text": "V. References 1. Ahmed, A., Li, X. F., Dunk, C., Whittle, M. J., Rushton, D. I. ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Identification and localization of alternately spliced mRNAs for vascular endothelial growth factor in human uterus and estrogen regulation in endometrial carcinoma cell lines", "authors": [{"first": "D", "middle": ["S"], "last": "Charnock-Jones", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Sharkey", "suffix": ""}, {"first": "J", "middle": [], "last": "Rajput-Williams", "suffix": ""}, {"first": "D", "middle": [], "last": "Burch", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Schofield", "suffix": ""}, {"first": "S", "middle": ["A"], "last": "Fountain", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Boocock", "suffix": ""}, {"first": "S", "middle": ["K"], "last": "Smith", "suffix": ""}], "year": 1993, "venue": "Biol. 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Northern blot analysis of total RNA (20 ug/lane) extracted from rat uterus on diestrus (Lane 1), uterus on estrus (Lane 2), uterus on P5 (Lane 3), uterus and placenta on P10 (Lane 4), uterus and placenta on P 15 (Lane 5), uterus and placenta on P20 (Lane 6), uterus on PD5 (Lane 7), and rat lung (Lane 8). To control for transfer efficiency and loading levels, the blots were also hybridized to a p-actin probe.", "type": "figure"}, "FIGREF1": {"text": "Fig. 2. In situ localization of VEGF mRNA (A, E) and immunohistochemical staining of VEGF protein (B, F) in estrus uterus. VEGF mRNA and VEGF protein were accumulated in myometrial smooth muscle cells (A, B, arrows), glandular epithelial cells (E, F, arrows) and stromal cells (E, F, arrowheads). A section without probe (C) and a section without primary antibody (D) were used as negative controls for in situ localization and immunohistochemical staining, respectively. x 200.", "type": "figure"}, "FIGREF2": {"text": "Fig. 3. In situ localization of VEGF mRNA and immunohistochemical staining of VEGF protein in P8 (A, B) and P15 uterus (C, D) and in the labyrinth of P15 placenta (E, F). VEGF mRNA and VEGF protein were highly accumulated in trophoblasts (A, B, E, F, arrows). The expression of VEGF mRNA and VEGF protein in decidual cells on P15 (C, D, arrows) were almost as the same level as those in glandular epithelial cells and endometrial epithelial cells on estrus. Vascular endothelial cells did not express VEGF mRNA but VEGF protein (E, F, arrowheads). x 200.", "type": "figure"}, "TABREF2": {"text": "Localization of VEGF mRNA and VEGF protein in the pregnant rat uterus and placenta . PP 5: The 5th day post partum, n.a.: Not available. hybridization studies have reported the expression of VEGF protein [1, 8, 16, 20J and VEGF mRNA [5,", "type": "table"}, "TABREF3": {"text": "Growth Factors 12; 235-243, 1995. 2. Bikfalvi, A., Sauzeau, C., Moukadiri, H., Maclouf, J., Busso, N., Bryckaert, M., Plouet, J. and Tobelem, G.: Interaction of vasculotropin/vascular endothelial cell growth factor with human umbilical vein endothelial cells: binding, internalization, degradation, and biological effects. J. Cell Physiol.149; 50-59, 1991. 3. Carmeliet, P., Ferreira, V., Breier, G., Pollefeyt, S., Kieckens, L., Gertsenstein, M., Fahrig, M., Vandenhoeck, A., Harpal, K., Eberhardt, C., Declercq, C., Pawling, J., Moons, L., Collen, D., Risau, W. and Nagy, A.: Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380; 435-439, 1996. 4. Chakraborty, I., Das, S. K. and Dey, S. K.: Differential ex- pression of vascular endothelial growth factor and its receptor mRNAs in the mouse uterus around the time of implantation. J. Endocrinol. 147; 339-352, 1995. 5. Charnock-Jones, D. S., Sharkey, A. M., Boocock, C. A., Ahmed, A., Plevin, R., Ferrara, N. and Smith, S. K.: Vascular endothelial growth factor receptor localization and activation in human trophoblast and choriocarcinoma cells. Biol. Reprod.", "type": "table"}}}
{"paper_id": "84883819", "_pdf_hash": "81742ac798d85a56bb4c9db391165942ed672c81", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "84885547", "_pdf_hash": "d9841e090f28509294fd60ee05cd97c3f7c9b0f1", "abstract": [{"section": "Abstract", "text": "Potassium sorbate (PS) (0.5%, 1.0% and 1.5% w/w) was included into whey protein 26 concentrate (WPC)/glycerol (Gly) edible films at pH 5.2 and 6.0. The films inhibited or 27 retarded the growth of Shiga toxin producing Escherichia coli (STEC) pathogens in both 28 diffusion and barrier tests. Bacterial growth inhibition was dependent on PS content at both 29 pH values. PS release was not affected by pH. Scanning electron microscopy ( ", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "g/plate) were casted by pipetting the solution into sterile 90 mm diameter plastic plates. Theplates were dried for 2 h at 45 \u00baC plus 24 h at 25 \u00baC and 48 \u00b1 4% relative humidity, after 141 which the films were peeled from the plates and stabilized during 24 h at 25 \u00baC and 48 \u00b1 4% 142 relative humidity. The films used in the different tests were selected based on the lack of 143 physical defects such as cracks, bubbles and holes. 144 145", "cite_spans": [], "ref_spans": []}, {"section": "Film thickness 146", "text": "The thicknesses of three replicates of each film formulation were measured with an electronic 147 digital disk micrometer (Schwyz \u00ae , China) at nine locations on the film to the nearest 0.001 148 mm. Average film thickness was 0.137 \u00b1 0.030 mm. 149 150", "cite_spans": [], "ref_spans": []}, {"section": "Transparency 151", "text": "Film transparency was determined according to ASTM D1746 (ASTM, 1997) with 152 modifications of the method described by Ozdemir & Floros (2008) . The films were cut into 153 rectangular pieces (10 mm x 30 mm) and placed on the internal side of a spectrophotometer 154 cell. Transparency of films was measured using a spectrophotometer Jasco 155 International, Tokyo, Japan) at 560 nm. Five replicates of each film were tested. The 156 transparency (% Transparency) was calculated as the percentual relationship between the lightaccelerating voltage of 20 kV. Magnifications of 500 and 1000 were used. 166 167", "cite_spans": [], "ref_spans": []}, {"section": "Bacterial strains and growth conditions 168", "text": "Eight non-O157 STEC strains isolated from ready-to-eat food samples obtained from 169 supermarkets and shops selling in Rosario (Argentina) were kindly provided by Balagu\u00e9 et al. 170 (2006) as test microorganisms (Table 1 ). E. coli O157:H7 ATCC 43895 from the American 171", "cite_spans": [], "ref_spans": []}, {"section": "Bacterial strains and growth conditions 168", "text": "Type Culture Collection which expresses the Shiga toxin genes stx1 and stx2 was used as a 172 control. All strains were maintained at -70 \u00baC in TSB containing 10% (v/v) glycerol and 173 subcultured overnight in CLDE at 37 \u00baC before use. 174 175", "cite_spans": [], "ref_spans": []}, {"section": "Inhibitory activity of PS in liquid media", "text": "bacterial strain was adjusted to McFarland 0.5 standard in saline solution (approximately 5 x 180 10 7 cfu/ml) and used as test inoculum. One ml of the bacterial inoculum was added and mixed 181 with 1 ml of each PS solution in Mueller-Hinton broth adjusted at pH 5.2 or 6.0. The PS 182 concentrations evaluated were 0.3125, 0.625, 1.25, 2.5, 5.0, 10 and 20 mg/ml. A control tube 183 without PS was inoculated to test microbial growth and a tube containing only broth medium 184 was evaluated to discard possible contaminations. All tubes were overnight incubated (~18 h) 185 at 37\u00b0C. The MIC values were estimated as the lowest concentration of PS that completely 186 inhibits growth of the microorganism in the tubes as detected by the unaided eye. Growth 187 control tubes to assess MIC end points were also evaluated. Hinton agar (pH 5.2). Then, 10 \u00b5l inoculum for each strain were seeded on the film discs. 208", "cite_spans": [], "ref_spans": []}, {"section": "Inhibitory activity of PS in liquid media", "text": "Next, 10 \u00b5l of TTC (30 mg/ml) were added into each well to color the bacterial colonies. 209", "cite_spans": [], "ref_spans": []}, {"section": "Inhibitory activity of PS in liquid media", "text": "Microplates were incubated at 37 \u00baC for 24 h until naked eye observation. Experiments were 210 performed in triplicate. 211 212", "cite_spans": [], "ref_spans": []}, {"section": "Determination of sorbate release from WPC/Gly edible films", "text": "To analyze sorbate release, WPC/Gly films containing 1.5% PS (to enhance detection 214 sensibility) were cut in 12 mm diameter discs using a cork borer. The discs were placed on the 215 surface of Petri dishes containing 10 ml of Mueller-Hinton agar broth acidified to pH 5.2 with 216 1.0 N HCl. After 1 h, 3 h, or 18 h of incubation at 37 \u00baC films disc were removed and the 217 change in PS concentration with time in the film was determined. The initial amount of PS 218 per disc was also evaluated. Each PS-containing WPC/Gly disc was immersed in 4 mL 0.01 N 219", "cite_spans": [], "ref_spans": []}, {"section": "Determination of sorbate release from WPC/Gly edible films", "text": "HCl solution, homogenized (1 min; 20 000 rpm) with an Omni GLH homogenizer (Omni 220", "cite_spans": [], "ref_spans": []}, {"section": "Determination of sorbate release from WPC/Gly edible films", "text": "International Inc., Warrenton, Virginia, U.S.A.) and 10 min sonicated. Samples (30 \u00b5L) were 221 diluted to 3.0 mL with 0.01 N HCl. Potassium sorbate concentration of the collected samples 222", "cite_spans": [], "ref_spans": []}, {"section": "Determination of sorbate release from WPC/Gly edible films", "text": "were measured at 254 nm with a UV-Vis spectrophotometer (Model V-530, Jasco", "cite_spans": [], "ref_spans": []}, {"section": "Results and Discussion", "text": "use as see-through packaging; however, exhibited a slightly yellowish color probably because 240 the presence of contaminants (i.e. lactose, lipids and minerals) in WPC. Their surfaces 241 appeared smooth, without visible pores or cracks. Appearance of the film side facing the 242 casting plate was shiny, while the film side exposed to air was dull; Ramos et al. (2013) 243 reported that this is likely an indication of some phase separation occurring in the solution 244 during drying. Films incorporated with PS, at both pH, were easily separated from the casting 245 plate than control films without preservative. Furthermore, when PS concentration was 246 increased in the film-forming solutions, WPC/Gly films flexibility improved. These 247 observations may be explained because this additive has an additional effect as plasticizer on 248 film matrixes (Fam\u00e1, Rojas, Goyanes & Gerschenson, 2005) . The plasticizer molecules lead 249 to decreases in intermolecular forces along the polymer chains, thus improving flexibility, and 250 allowing an easier removal from the forming support (Karbowiak et al., 2006; Hernandez-251 Izquierdo & Krochta, 2008) . Films showed an average thickness of 0.137 \u00b1 0.030 mm, which 252 is similar to those reported by other authors using similar formulations (Soazo et al., 2010; 253 Ramos et al., 2013) . 254 255", "cite_spans": [], "ref_spans": []}, {"section": "Film transparency 256", "text": "It is important to notice that when an edible film is intended to be used as a superficial layer 257 on food surfaces, transparency is an interesting attribute that contributes to consumer 258 acceptability. In general, films obtained in this study were rather transparent. However, in the 259 absence of PS, films obtained at the acidic pH value of 5.2 were substantially less transparent 260 than films obtained at pH 6.0, presumably due to a partial proteins precipitation when pH is 261 close to the isoelectric point of whey proteins (pI \u2248 5) (Fig. 1) . Film formation from proteinsis believed to proceed through the formation of a three-dimensional network of protein 263 molecules by ionic, hydrogen, hydrophobic, and disulfide bonds. At pH 5.2 proteins are 264 mainly in the zwitterions form; i.e., a neutral molecule with a positive and a negative 265 electrical charge at different locations within that molecule. At this state, near the pI, the 266 solubility of a protein is negligible because its net charge is zero and any electrostatic 267 repulsion disappears. This fact supports the idea that film transparency could decrease at 268 acidic pH due to protein aggregation. Our results correspond well this phenomenon in 269 WPC/Gly films without PS. Interestingly, the addition of 0.5%, 1.0 % and 1.5% of PS 270 significantly improved the transparency of WPC/Gly films when compared to control films 271 without PS at pH 5.2. Under acidic conditions, protein molecules in film-forming solutions 272 are partially unfolded due to the protein denaturation and their hydrophobic groups are 273 exposed (Kristinsson & Hultin, 2003; Hamaguchi, Yin & Tanaka, 2007) . So, the organic 274 sorbate molecule could interact with the amino or hydroxyl groups on non-crosslinked protein 275 through covalent bonds and thus leading to an increase in transparency (Fig. 1) . This effect 276 was also observed in analogous experiments performed by our group where incorporation of 277 sodium benzoate or sodium propionate in WPC/Gly acidic film obtained at pH 5.2 improves 278 transparency (David, 2012; unpublished undergraduate thesis data). So, this phenomenon 279 seems to be independent of the organic salt and its concentration, and is probably more related 280 to hydrophobic interactions between the organic chain and the unfolded protein matrix 281 structure. 282 283", "cite_spans": [], "ref_spans": []}, {"section": "Scanning electron microscopy 284", "text": "Our observations on films transparency are supported by SEM images. As we can see in Fig.  285 surface when compare with that of the acidic control films obtained at pH 5.2. These 287 observations correspond well with the fact that whey protein particles formed at pH values 288 near the pI had a cauliflower-like appearance giving rise to macroscopic gels with 289 heterogeneous microstructure formed of larger pores (Sa\u011flam, Venema, de Vries, Aelst & 290 Linden, 2012) . Langton & Hermansson (1992) showed that whey protein gels formed 291 between pH 4 and 6 were opaque and had a particulate network which can be described as a 292 network consisting of aggregated particles. These authors also reported that the size of those 293 aggregates changed to denser and well-packed aggregates when the pH increased. So, when 294 pH values are far from the pI the microstructure of whey proteins macroscopic gels present a 295 homogeneous surface with relatively small pore sizes distributed regularly through the protein 296 network (Langton & Hermansson, 1992; Sa\u011flam et al., 2012) . SEM images presented in Fig.  297 2 (A and B) agree with these previous experiences, while changes observed in the 298 microstructure of the WPC/Gly films incorporated with PS suggest that interactions between 299 protein chains and the organic acid contribute to improve the structural arrangement of the 300 compounds, and thus could enhance film transparency. 301 302", "cite_spans": [], "ref_spans": []}, {"section": "Inhibitory activity of PS in liquid media 303", "text": "Our MIC data showed that the PS concentration needed to inhibit microbial growth in a liquid 304 medium at pH 6.0 was 2-4 levels higher than at pH 5.2 for all the STEC analyzed (Table 2) . 305", "cite_spans": [], "ref_spans": [{"start": 177, "end": 186, "text": "(Table 2)", "ref_id": "TABREF2"}]}, {"section": "Inhibitory activity of PS in liquid media 303", "text": "These results confirm that the unprotonated-protonated ratio in the liquid medium was 306 relevant for the antimicrobial ability of the organic acid. PS is a weak acid (pKa 4.76) which 307 is more effective in the undissociated form due to its increased capability to penetrate the 308 bacterial plasmatic membrane (Luck & Jager, 1997) is included in a complex matrix, such as an edible film over a solid media (e.g., agar or food), 313 both the pH of the film matrix and the food model system must be considered in order to 314 improve the effectiveness of the antimicrobial film. Therefore, these antimicrobial-containing 315 films would appear to be best suited for foods that have acidic pH values. 316 317", "cite_spans": [], "ref_spans": []}, {"section": "Inhibition zone assay of WPC/Gly films containing PS in agar media 318", "text": "The acidic condition of the media (pH 5.2) for the inhibition zone assay was selected to 319 provide a pH value similar to those reported for several foods, like cheeses and meats (Casp 320 necessity to optimize the formulations of edible films containing antimicrobials for ahave proved that the addition of various lipids or modification of the type and amount of 364 plasticizer used in whey protein films composition can lowered the diffusion coefficients of 365 PS or sorbic acid to release the antimicrobial at a desired rate that would be advantageous in 366 some specific applications (Ozdemir & Floros 2001; Ozdemir & Floros, 2003; Franssen, 367 Rumsey & Krochta, 2004) . Hence, further research are necessary to adequate film coating 368 composition and preservative concentration to obtain films with a satisfactory antimicrobial 369 activity within the accepted policies for food care that ensure microbial control and human 370 safety, in order to reduce the total amount of preservatives in foods. 371", "cite_spans": [], "ref_spans": []}, {"section": "372", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion 373", "text": "The addition of PS to WPC/Gly-based films prepared at two different pH values (5.2 and 6.0) 374 led to inhibit the growth of STEC pathogens obtained from food samples. Our results on real 375 pathogenic isolates correlate well with related studies demonstrating that WPC may be a 376 reliable material for the elaboration of acidic antimicrobial edible films. Antimicrobial 377 effectiveness of WPC/Gly film incorporated with PS seems to be more associated to media 378 pH than to film pH because the acid-base behavior of the organic acid once liberated from 379 films. Acidic status of edible films and foods where coating will be applied are important 380 parameters to consider for optimizing films as food package because some restrictions may 381 exist due to changes in the structural, mechanical or optical properties of whey protein film 382 caused by pH. In our study, WPC/Gly films incorporated with PS proved to be transparent 383 and clear enough to be use as see-through packaging. The utilization of whey proteins and 384 low organic acids concentrations to inactivate post-processing contaminants on ready-to-eat 385 foods may be an effective, safe, ecological and relatively inexpensive alternative. However, 386 formulations of antimicrobial edible films must still be optimized to adequate the preservativeprotein purity and glycerol content upon physical properties of edible films manufactured 512 therefrom. Food Hydrocolloids, 30(1), 110-122. 513 Reilly, A. (1998) ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "AMR 1000", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF1": {"title": "Control of Listeria monocytogenes on ham steaks by 537 antimicrobials incorporated into chitosan-coated plastic films", "authors": [{"first": "M", "middle": [], "last": "Ye", "suffix": ""}, {"first": "H", "middle": [], "last": "Neetoo", "suffix": ""}, {"first": "H", "middle": [], "last": "Chen", "suffix": ""}], "year": 2008, "venue": "Food Microbiology", "link": "20610348"}}, "ref_entries": {"FIGREF0": {"text": "were then aseptically transferred to pour plates containing 10 ml of Mueller-Hinton 193 agar broth acidified to pH 5.2 with 1.0 N HCl, which had been previously seeded with each 194 bacterial suspension adjusted to McFarland 0.5 standard in saline solution. After overnight 195 incubation (~18 h) at 37 \u00baC the diameter of the inhibition zone represented by a clear area of 196 non-growth or a decreased growth around the film disc was measured perpendicularly to the 197 nearest millimeter with a caliper. Control films without antimicrobial were also evaluated. 198 Experiments were performed in triplicate. 199 200 2.9. Barrier assay of WPC/Gly films containing PS in agar media 201 In order to study the film performance to prevent microbial contamination a microplate barrier 202 assay was developed. Mueller-Hinton agar adjusted at pH 5.2 was poured into 24 well 203 microtiter plates (Greiner Bio-One, Frickenhausen, Germany). Inocula were prepared from an 204 overnight culture of each bacterial strain adjusted to McFarland 0.5 standard in saline solution 205 and then diluted 1/10000 (approximately 5 x 10 3 cfu/ml). Discs of 16 mm diameter WPC/Gly 206 films were aseptically cut from and applied on the surface of the wells filled with Mueller- 207", "type": "figure"}, "FIGREF1": {"text": ". Applying the Henderson-Hasselbalch 309 equation (pH = pKa + log [A-]/[HA]) the resulting [sorbate]/[sorbic acid] ratios were 2.75 at 310 pH 5.2 and 17.4 at pH 6.0. These calculations confirm the expected increase of the protonated 311", "type": "figure"}, "FIGREF2": {"text": ". Prevention and control of enterohaemorrhagic Escherichia coli (EHEC) 514 infections: memorandum from a WHO meeting. Bulletin of the World Health Organization, 515 76(3), 245-255. 516 Sa\u011flam, D., Venema, P., de Vries, R., van Aelst, A., & van der Linden, E. (2012). Relation 517 between gelation conditions and the physical properties of whey protein particles. Langmuir, 518 28(16), 6551-6560. 519 Seydim, A.C., & Sarikus, G. (2006). Antimicrobial activity of whey protein based edible 520 films incorporated with oregano, rosemary and garlic essential oils. Food Research 521 International, 39(5), 639-644. 522 Soazo, M., Rubiolo, A. C., & Verdini, R. A. (2010). Effect of drying temperature and 523 beeswax content on physical properties of whey protein emulsion films. Food Hydrocolloids, 524 25(5), 1251-1255. 525 Suppakul, P., Miltz, J., Sonneveld, K., & Bigger, S. W. (2003). Active packaging 526 technologies with an emphasis on antimicrobial packaging and its applications. Journal of 527 Food Science, 68(2), 402-420. 528 Tharanathan, R. N. (2003). Biodegradable films and composite coatings: past, present and 529 future. Trends in Food Science and Technology, 14(3), 71-78.", "type": "figure"}, "FIGREF3": {"text": "Figure 1. Effect of potassium sorbate (PS) and pH (6.0 or 5.2) on the transparency of 550", "type": "figure"}, "TABREF0": {"text": "Characteristics of non-O157 STEC isolates from food samples obtained in Rosario,Minimum inhibitory concentration (MIC) for potassium sorbate (PS) against non- 544 O157 STEC and ATCC 43895 strains. 545Inhibition zone assay of WPC/Gly films containing potassium sorbate (PS) in agar 547 media against non-O157 STEC and ATCC 43895 strains. 548", "type": "table"}, "TABREF1": {"text": "ONT, O serogroup non-typable; stx, shiga toxin genes.", "type": "table"}, "TABREF2": {"text": "Strain number", "type": "table"}}}
{"paper_id": "84886248", "_pdf_hash": "06decb602395df4ac5a57812b0dbfb0a910c6805", "abstract": [{"section": "Abstract", "text": "Abstract Large freshwater contributions to the Arctic Ocean from a variety of sources combine in what is, by global standards, a remarkably small ocean basin. Indeed, the Arctic Ocean receives \u223c11% of global river discharge while accounting for only \u223c1% of global ocean volume. As a consequence, estuarine gradients are a defining feature not only near-shore, but throughout the Arctic Ocean. Seaice dynamics also play a pivotal role in the salinity regime, adding salt to the underlying water during ice formation and releasing fresh water during ice thaw. Our understanding of physical-chemical-biological interactions within this complex system is rapidly advancing. However, much of the estuarine research to date has focused on summer, open water conditions. Furthermore, our current conceptual model for Arctic estuaries is primarily based on studies of a few major river inflows. Future advancement of estuarine research in the Arctic requires concerted seasonal coverage as well as a commitment to working within a broader range of systems. With clear signals of climate change occurring in the Arctic and greater changes anticipated in the future, there is good reason to accelerate estuarine research efforts in the region. In particular, elucidating estuarine dynamics across the near-shore to ocean-wide domains is vital for understanding potential climate impacts on local ecosystems as well as broader climate feedbacks associated with storage and release of fresh water and carbon.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "While the term \"estuary\" typically evokes images of the near-shore environment where continental runoff first mixes with ocean water, the scientific community has also considered estuarine processes over a range of larger spatial scales. Estuarine gradients associated with major river plumes are often studied over the continental shelf domain. Broader still, estuarine qualities of major ocean basins have been considered. For example, Tully and Barber (1960) described the North Pacific as an estuary, and Stigebrandt (1984) described exchange of Pacific and Arctic Ocean waters within an estuarine context. Aagaard and Carmack (1994) considered the estuarine character of the Arctic Ocean more fully, including the importance of freshwater export from the Arctic Ocean to the North Atlantic. Physical, chemical, and biological attributes of the Arctic Ocean estuary are developed further in papers by Macdonald (2000) , Carmack and Wassmann (2006) , and Carmack (2007) . Sea-ice dynamics are an important focal point in all three of these papers. Carmack (2007) also places the Arctic Ocean estuary into a global context, pointing out that stratification of high-latitude seas in both hemispheres is predominantly controlled by salinity (beta oceans) whereas stratification of subtropical seas is predominantly controlled by temperature (alpha oceans). This paper describes the physical and biogeochemical characteristics that define Arctic estuaries (in the classical sense) and the estuarine character of the Arctic Ocean as a whole. It also includes discussion of the strengths and limitations of our current knowledge across the physicalchemical-biological realm and potential changes that we may see in the future. Finally, this paper provides a broad context for four synthesis papers organized around the Arctic Estuary theme. The synthesis papers address biogeochemical export from rivers (Holmes et al. 2011, this issue) , coastal erosion (Lantuit et al. 2011, this issue) , linkages between river-supplied nutrients and productivity (Tank et al. 2011, this issue) , and near-shore ecosystem dynamics (Dunton et al. 2012, this issue) . The first three papers consider the pan-Arctic domain as a whole, while the last one focuses in on the Beaufort and Chukchi Sea regions. Although estuarine ecology is not a major focal point herein, the subject is given significant attention by Dunton et al. (2012, this issue) .", "cite_spans": [{"start": 438, "end": 461, "text": "Tully and Barber (1960)", "ref_id": "BIBREF105"}, {"start": 509, "end": 527, "text": "Stigebrandt (1984)", "ref_id": "BIBREF100"}, {"start": 611, "end": 637, "text": "Aagaard and Carmack (1994)", "ref_id": "BIBREF1"}, {"start": 905, "end": 921, "text": "Macdonald (2000)", "ref_id": "BIBREF58"}, {"start": 924, "end": 951, "text": "Carmack and Wassmann (2006)", "ref_id": "BIBREF10"}, {"start": 954, "end": 972, "text": "and Carmack (2007)", "ref_id": "BIBREF8"}, {"start": 1051, "end": 1065, "text": "Carmack (2007)", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Introduction", "text": "The Arctic Ocean receives massive inputs of fresh water from continental runoff as well as relatively low-salinity Pacific waters delivered through the Bering Strait (Fig. 1) . Net precipitation on the ocean surface and inputs from the Norwegian Coastal Current and Fram Strait deep water also contribute to the freshwater budget of the Arctic Ocean (Serreze et al. 2006 ). These inputs combine in what is, by global standards, a remarkably small ocean basin. While the Arctic Ocean receives \u223c11% of the world's river discharge, it accounts for only about 1% of the world's ocean volume (Menard and Smith 1966; Aagaard and Carmack 1989) . As a consequence, estuarine gradients are a defining feature not only near-shore, but throughout the Arctic Ocean. Seaice dynamics also play a pivotal role in the salinity regime, adding salt to the underlying water during ice formation and releasing fresh water during ice thaw (Macdonald 2000) .", "cite_spans": [{"start": 350, "end": 370, "text": "(Serreze et al. 2006", "ref_id": "BIBREF95"}, {"start": 587, "end": 610, "text": "(Menard and Smith 1966;", "ref_id": "BIBREF77"}, {"start": 611, "end": 636, "text": "Aagaard and Carmack 1989)", "ref_id": "BIBREF0"}, {"start": 918, "end": 934, "text": "(Macdonald 2000)", "ref_id": "BIBREF58"}], "ref_spans": []}, {"section": "River Inputs", "text": "Marked seasonal variations in continental runoff are a defining feature around the pan-Arctic domain (Fig. 2) . Most notably, runoff is relatively low during winter months and peaks with snowmelt in the spring. There are, however, distinct differences in runoff climatology among regions. For example, the winter-spring transition in runoff occurs during the March to May timeframe in the Barents Sea and Hudson Bay regions, whereas the winter-spring transition in runoff occurs in the April to June timeframe in the Kara Sea, Laptev Sea, East Siberian Sea, and Beaufort Sea regions. There are also distinct regional differences in the distribution of runoff among months (Fig. 2) .", "cite_spans": [], "ref_spans": []}, {"section": "River Inputs", "text": "The regional differences in runoff reflect differences in precipitation regimes as well as differences in watershed Fig. 1 The pan-Arctic drainage basin and major freshwater inflows (cubic kilometers per year, as shown in boxes) to the Arctic Ocean and surrounding seas. Red line watershed boundary, A Hudson Bay, B Beaufort Sea, C Chukchi Sea, D East Siberian Sea, E Laptev Sea, F Kara Sea, G Barents Sea. Inputs from land were calculated from the regional runoff estimates of Lammers et al. (2001) . The 2,500 km 3 /year input to the Chukchi Sea is the freshwater content of Bering Sea water flowing into the Arctic Ocean via Bering Strait based on a reference salinity of 34.8 (Serreze et al., 2006) characteristics. The southern and northern boundaries of the pan-Arctic drainage basin vary substantially from region to region (Fig. 1) , and the proportion of annual precipitation falling as rain versus snow in the regional watersheds is, in part, dependent on latitude (i.e., the latitudinal coverage of each drainage basin). Permafrost extent is also related to the latitudinal coverage of each drainage basin (Frey and McClelland 2009 ). For example, less than 20% of the area draining to Hudson Bay is underlain by continuous permafrost, whereas greater than 80% of the area draining to the Laptev Sea is underlain by continuous permafrost. Such differences in permafrost coverage contribute to differences in runoff among regions because drainage basins with permafrost typically have greater surface water flow in comparison to drainage basins without permafrost (McNamara et al. 1997; McNamara et al. 1998) . In drainage basins with large reservoirs, regulation of flow through dams is an additional factor contributing to seasonal patterns in Arctic river discharge. For example, increases in winter discharge from several of the major Eurasian Arctic rivers are largely attributed to release of stored spring/summer runoff from reservoirs during winter months McClelland et al. 2004; Yang et al. 2004 ). Reservoir effects have also been documented in the Mackenzie River basin and the Hudson Bay region (Woo and Thorne 2003; D\u00e9ry and Wood 2005) .", "cite_spans": [{"start": 478, "end": 499, "text": "Lammers et al. (2001)", "ref_id": "BIBREF54"}, {"start": 680, "end": 702, "text": "(Serreze et al., 2006)", "ref_id": "BIBREF95"}, {"start": 1117, "end": 1142, "text": "(Frey and McClelland 2009", "ref_id": "BIBREF30"}, {"start": 1574, "end": 1596, "text": "(McNamara et al. 1997;", "ref_id": "BIBREF73"}, {"start": 1597, "end": 1618, "text": "McNamara et al. 1998)", "ref_id": "BIBREF74"}, {"start": 1974, "end": 1997, "text": "McClelland et al. 2004;", "ref_id": "BIBREF70"}, {"start": 1998, "end": 2014, "text": "Yang et al. 2004", "ref_id": "BIBREF113"}, {"start": 2117, "end": 2138, "text": "(Woo and Thorne 2003;", "ref_id": "BIBREF110"}, {"start": 2139, "end": 2158, "text": "D\u00e9ry and Wood 2005)", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "River Inputs", "text": "While the climatologies shown in Fig. 2 highlight broad similarities and differences in runoff regimes around the pan-Arctic domain, combining multiple rivers and binning the data in monthly increments mask some notable features within regions. A comparison of runoff data from the Laptev Sea and Beaufort Sea regions exemplify variability underlying the regional climatologies (Fig. 3) . In both cases, there is remarkable synchrony in terms of the timing of peak runoff among rivers, but the proportion of runoff occurring during June as compared with other months varies widely among rivers (Fig. 3, top panels) . When considering daily runoff, it is also apparent that the winterspring transition is very abrupt in any given year (Fig. 3 , bottom panels). The more gradual representation of the winter-spring transition shown in the monthly climatologies is a reflection of averaging among years. Although these patterns represent runoff from catchments of vastly different sizes, ranging from 78,800 to 2,430,000 km 2 in the Laptev case and 8,400 to 1,680,000 km 2 in the Beaufort case, it is important to keep in mind that runoff patterns (Kane et al. 2000) . The dominant spring peaks we see in most of the larger Arctic rivers reflect the fact that onset of snowmelt is similar across broad areas whereas rainfall patterns vary substantially over smaller scales.", "cite_spans": [{"start": 1145, "end": 1163, "text": "(Kane et al. 2000)", "ref_id": "BIBREF47"}], "ref_spans": []}, {"section": "River Inputs", "text": "Differences in geomorphology also contribute to variations in runoff patterns among drainage basins within the pan-Arctic watershed. For example, drainage basins in western and eastern Siberia differ substantially with respect to large-scale relief (Gordeev 2006) . Most notably, the Western Siberian Lowlands cover an area of \u223c1.8 million km 2 that accounts for \u223c2/3 of the total area of West Siberia (Kremenetski et al. 2003) . A large proportion of the lowland area lies within the Ob River drainage basin. Smaller proportions lie within the Nadyam, Pur, Taz, and Yenisey drainage basins. The gentle relief in this vast lowland area has a direct impact on flow rates and runoff ratios. In addition, extensive growth of wetland vegetation and build-up of peat deposits within the lowlands mediates water flow through the region. While effects of large-scale topography are emphasized here, it is also important to keep in mind that permafrost has a strong influence on patterns of water flow through the landscape. Indeed local geomorphology related to formation and maintenance of river channel networks differs substantially between areas with and without permafrost (McNamara et al. 1999) .", "cite_spans": [{"start": 249, "end": 263, "text": "(Gordeev 2006)", "ref_id": "BIBREF33"}, {"start": 402, "end": 427, "text": "(Kremenetski et al. 2003)", "ref_id": "BIBREF52"}, {"start": 1171, "end": 1193, "text": "(McNamara et al. 1999)", "ref_id": "BIBREF75"}], "ref_spans": []}, {"section": "River Inputs", "text": "The large seasonal variations in continental runoff in the Arctic are accompanied by large seasonal variations in nutrient and organic matter inputs from rivers to the coastal ocean. Holmes et al. (2011, this issue ) describe these inputs in detail. Here, we highlight some general characteristics of nutrient and organic matter fluxes from Arctic rivers.", "cite_spans": [], "ref_spans": []}, {"section": "River Inputs", "text": "Seasonal changes in water discharge alone account for much of the variation in constituent fluxes. In addition, seasonally varying concentrations of dissolved and particulate material contribute to variations in constituent fluxes. For example, organic matter concentrations increase dramatically during the spring freshet, while nitrate and silica concentrations show the opposite pattern. These concentration changes are tightly coupled to seasonal changes in water flow paths through the landscape (MacLean et al. 1999; Frey and McClelland 2009; Guo and Macdonald 2006; Guo et al. 2007 ). Frozen ground constrains water flow to organic rich surface layers during the spring snowmelt period. As the ground thaws, an increasing proportion of the water moves through mineral soils along deeper flow paths. Where there is permafrost, flow paths are constrained to the seasonally thawed portion of the soil profile (active layer), and deep groundwater contributions (i.e., via springs) are relatively small.", "cite_spans": [{"start": 501, "end": 522, "text": "(MacLean et al. 1999;", "ref_id": "BIBREF66"}, {"start": 523, "end": 548, "text": "Frey and McClelland 2009;", "ref_id": "BIBREF30"}, {"start": 549, "end": 572, "text": "Guo and Macdonald 2006;", "ref_id": "BIBREF36"}, {"start": 573, "end": 588, "text": "Guo et al. 2007", "ref_id": "BIBREF37"}], "ref_spans": []}, {"section": "River Inputs", "text": "Seasonal vegetation growth and microbial activity also contribute to variations in nutrient and organic matter concentrations in arctic rivers. For example, growth of tundra vegetation on the North Slope of Alaska is nitrogenlimited during summer months, and loss of inorganic nitrogen from soils to tundra streams is relatively low during the growing season (Peterson et al. 1992; Rastetter and Shaver 1992; Williams et al. 2000) . Increased microbial activity during summer months provides a source of inorganic nitrogen through mineralization of organic matter, but much of this nitrogen is taken up by the vegetation. Likewise, while decomposition of detritus generates dissolved organic matter, net uptake and mineralization of dissolved organic matter by microbes may be a contributing factor to lower dissolved organic matter concentrations observed in arctic river waters during the summer (Striegl et Fig. 3 Comparison of runoff climatologies, average millimeters per month for 1990-1999, for individual rivers in the Laptev Sea and Beaufort Sea regions (top panels) and daily runoff for 2004, 2005, and 2006 in the Lena and Mackenzie rivers (bottom panels). Data sources are as described for Fig. 2 al. 2005). Higher temperatures and longer residence times (in both soils and stream/river networks) during summer base-flow conditions combine to facilitate microbial decomposition of dissolved organic matter. demonstrated that dissolved organic carbon (DOC) in rivers on the North Slope of Alaska is much more labile during the spring freshet than later in the summer. This finding is consistent with greater net mineralization of dissolved organic matter during watershed transit over the summer months.", "cite_spans": [{"start": 359, "end": 381, "text": "(Peterson et al. 1992;", "ref_id": "BIBREF88"}, {"start": 382, "end": 408, "text": "Rastetter and Shaver 1992;", "ref_id": "BIBREF91"}, {"start": 409, "end": 430, "text": "Williams et al. 2000)", "ref_id": "BIBREF108"}], "ref_spans": []}, {"section": "River Inputs", "text": "In general, river waters entering the Arctic Ocean are rich in organic matter and depleted in inorganic nitrogen. This is demonstrated in Fig. 4 by a comparison of DOC and nitrate concentrations in the six largest rivers draining the pan-Arctic watershed (Ob, Yenisey, Lena, Kolyma, Yukon, and Mackenzie) with several other major rivers around the world (Amazon, Congo, Yangtze, and Mississippi). Ranked by discharge, the Amazon, Congo, and Yangtze are among the five largest rivers in the world. The Mississippi River ranks within the top ten. Nitrate concentrations in the arctic rivers consistently fall toward the lower end of the overall concentration range in this comparison. Furthermore, the nitrate yields (kilograms nitrogen per square kilometer per year) from the drainage basins of the major arctic rivers are much lower than the yields from the Amazon, Yangtze, and Mississippi drainage basins. The relatively low nitrate yields from the arctic drainage basins are a reflection of much lower annual runoff in the arctic basins as compared with the other basins. In contrast with nitrate, DOC concentrations in the arctic rivers fall within the upper half of the overall concentration range, and DOC yields from the arctic basins fall in the middle of the overall yield range (Fig. 4) . In this case, relatively high DOC concentrations in the arctic rivers compensate for low runoff to maintain intermediate yields. The pattern for dissolved inorganic phosphorus is similar to that of nitrate (i.e., low concentra- tion, low yield), and the pattern for dissolved organic nitrogen is similar to that of DOC (i.e., high concentration, intermediate yield). Dissolved silica concentrations in the major arctic rivers are not remarkably different than those found in the other major rivers. While these comparisons between the largest arctic rivers and other major rivers of the world highlight key differences that are important to consider in the development of estuarine research programs in the Arctic, it is also important to keep in mind that unique aspects of smaller arctic rivers may not be wellrepresented. Furthermore, we still have a tremendous amount to learn about the soil and in-stream processes contributing to the unique biogeochemistry of arctic rivers.", "cite_spans": [], "ref_spans": []}, {"section": "River Inputs", "text": "Suspended sediment in the major arctic rivers show a distinct dichotomy between higher concentrations in the North American rivers (Yukon and Mackenzie) and lower concentrations in the Eurasian rivers (Ob, Yenisey, Lena, Kolyma). This dichotomy is primarily a consequence of greater proportional runoff from mountainous terrain in the Yukon and Mackenzie basins as compared with the other basins (Holmes et al. 2002) . In comparison with the Amazon, Congo, Yangtze, and Mississippi, sediment concentrations in the Eurasian arctic rivers are most similar to the Congo River, whereas sediment concentrations in the North American arctic rivers are intermediate between the Amazon and Yangtze rivers (Fig. 4 ). As discussed above for nitrate, lower runoff in the arctic basins leads to markedly lower yields from these basins compared with the Amazon, Yangtze, and Mississippi.", "cite_spans": [], "ref_spans": []}, {"section": "Estuaries within the Arctic", "text": "This section focuses on river-to-shelf salinity gradients, including major river plumes as well as smaller estuaries more intimately associated with the near-shore environment. Classical estuarine studies have been relatively rare in the Arctic. A query of the ISI Web of Science database (done in November 2009) using \"arctic\" and \"estuary\" as search terms returned 256 hits. However, only 65 papers emphasized estuarine processes within the river-to-shelf domain of the Arctic. Out of the 65 papers, 35% dealt with Mackenzie River inputs, 22% dealt with Ob/Yenisey River inputs, and 17% dealt with Lena River inputs. The remaining 26% covered a variety of smaller estuaries around the Arctic. While this query undoubtedly missed some studies, the results do serve to highlight a relative emphasis on estuarine dynamics associated with inputs from a few very large rivers, all of which have large watersheds that extend south of what is typically considered to be \"Arctic\". Furthermore, it should be noted that most of the papers (\u223c2/3) identified in the query emphasized findings from field efforts conducted during mid-to late summer.", "cite_spans": [], "ref_spans": []}, {"section": "Estuaries within the Arctic", "text": "While seasonality has long been recognized as a defining feature in the Arctic, much of the work done on estuaries has been constrained to summer as a consequence of logistical challenges. There has been a major effort to improve our understanding of seasonal variations in the chemistry of river inputs to the Arctic Ocean during recent years ), but additional complexities associated with coastal ocean work in the Arctic make it difficult to conduct parallel studies in estuarine waters. Our current conceptual model of seasonal dynamics in arctic estuaries was largely formed from early studies in the Mackenzie system (Macdonald 2000; Carmack et al. 2004 ). However, more general models based on work in a range of Arctic and sub-Arctic estuaries are beginning to emerge (Kuzyk et al. 2008) . We have also gained important insight (albeit largely during summer) about the transport, fate, and effects of river inputs in coastal and shelf waters from major coordinated efforts such as the Siberian river runoff (SIRRO) project focusing on the Kara Sea system , an earlier German-Russian program in the Laptev Sea system (Kassens et al. 1999) , and the Canadian Arctic Shelf Exchange Study (CASES)/Arctic River-Delta Experiment (ARDEX) focusing on Mackenzie River inputs to the Beaufort Sea (Emmerton et al. 2008; Retamal et al. 2008; Valli\u00e8res et al. 2008 ).", "cite_spans": [{"start": 623, "end": 639, "text": "(Macdonald 2000;", "ref_id": "BIBREF58"}, {"start": 640, "end": 659, "text": "Carmack et al. 2004", "ref_id": "BIBREF12"}, {"start": 776, "end": 795, "text": "(Kuzyk et al. 2008)", "ref_id": "BIBREF53"}, {"start": 1294, "end": 1316, "text": "(Emmerton et al. 2008;", "ref_id": "BIBREF29"}, {"start": 1317, "end": 1337, "text": "Retamal et al. 2008;", "ref_id": "BIBREF92"}, {"start": 1338, "end": 1359, "text": "Valli\u00e8res et al. 2008", "ref_id": "BIBREF106"}], "ref_spans": []}, {"section": "Physical Characteristics of Arctic Estuaries", "text": "While geomorphology and the relative magnitudes of freshwater inflow and tidal mixing are fundamental determinants of estuarine gradients throughout the world, seasonal ice dynamics in coastal waters add to the complexity of Arctic estuaries through effects on wind mixing, buoyancy, and circulation (Macdonald 2000) . During periods of ice cover (\u223c9 months each year around much of the Arctic), coastal waters are not subject to wind mixing and thus stratification associated with river water inputs is enhanced. Ice formation reduces buoyancy by injecting salt into the underlying water column whereas ice melt increases buoyancy by adding fresh water. Some salt is retained as sea-ice forms, but the majority is rejected as brine. Sea-ice melt typically adds back brackish water with a salinity of around 5 (Macdonald et al.1989; Alkire and Trefry 2006) . Freeze/thaw effects on the salt balance are relatively small at the head of the estuary. However, they become more important as salinity increases along the estuarine gradient. The freezing and thawing effects may balance each other over annual timeframes. However, ice and the water from which it was formed are often spatially separated (i.e., the underlying water moves on) during the long winter months so that, when the ice does thaw, it represents a net freshwater source to the local environment. At the same time, the salt that was excluded effectively reduces the freshwater inventory at another location.", "cite_spans": [{"start": 300, "end": 316, "text": "(Macdonald 2000)", "ref_id": "BIBREF58"}, {"start": 833, "end": 856, "text": "Alkire and Trefry 2006)", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Physical Characteristics of Arctic Estuaries", "text": "Ice production is greatest at the interface between landfast ice and drifting ice (Fig. 5) . Open water areas (flaw lead polynyas) are maintained over much of the winter along this interface and thus new ice continues to form throughout the winter. Brine rejected during ice formation at the polynyas can drive deep convection, but the magnitude of this effect (or even whether or not deep convection occurs) depends strongly on the salinity of the water at the site of ice formation. The polynyas typically form over the mid-shelf, and any freshwater contributions from rivers that reach these areas work against deep convection. In general, one might expect river waters to influence convection mostly in areas where the polynyas are relatively close to shore and river water inputs are large. However, rubble ice (stamukhi) generated by convergence of landfast and drifting ice can form an inverted dam that traps river water on the landward side of the polynya during the winter months (Fig. 5 ). This has been well-documented in the Mackenzie River/Beaufort Sea system (Macdonald and Carmack 1991; Macdonald et al. 1995; Carmack and Macdonald 2002) . In other areas, such as the Lena River/ Laptev Sea system (Eicken et al. 2005) , the Alaskan Beaufort Sea coast (Alkire and Trefry 2006) , and the Churchill River region of the Hudson Bay (Kuzyk et al. 2008) , stamukhi dams appear to be less important in controlling river water spread over the shelf. Aside from the presence or absence of seasonal effects related to ice dams, river water residence times over different shelf regions are an important consideration with respect to convection. Where residence times are greater than 1 year, river inputs from preceding years help set the stage for whether sea-ice formation can produce penetrative convection during any given ice growth season. River water residence times in the Kara, Laptev, and East Siberian shelf regions are around 2-4 years whereas river water residence times over the Beaufort and Chukchi shelves are typically less than 1 year (Macdonald 2000) .", "cite_spans": [{"start": 1074, "end": 1102, "text": "(Macdonald and Carmack 1991;", "ref_id": "BIBREF59"}, {"start": 1103, "end": 1125, "text": "Macdonald et al. 1995;", "ref_id": "BIBREF61"}, {"start": 1126, "end": 1153, "text": "Carmack and Macdonald 2002)", "ref_id": "BIBREF9"}, {"start": 1214, "end": 1234, "text": "(Eicken et al. 2005)", "ref_id": "BIBREF28"}, {"start": 1268, "end": 1292, "text": "(Alkire and Trefry 2006)", "ref_id": "BIBREF4"}, {"start": 1344, "end": 1363, "text": "(Kuzyk et al. 2008)", "ref_id": "BIBREF53"}, {"start": 2058, "end": 2074, "text": "(Macdonald 2000)", "ref_id": "BIBREF58"}], "ref_spans": [{"start": 82, "end": 90, "text": "(Fig. 5)", "ref_id": "FIGREF2"}, {"start": 990, "end": 997, "text": "(Fig. 5", "ref_id": "FIGREF2"}]}, {"section": "Nutrient and Organic Matter Dynamics in Arctic Estuaries", "text": "The nutrient and organic matter concentrations of ocean endmembers for Arctic estuaries can be coarsely separated into a Pacific water source that mixes with freshwater inputs from North America and an Atlantic water source that mixes with freshwater inputs from Eurasia; the ocean end-members have different nutrient concentrations (Macdonald et al. 1989 ) and different ratios between the nutrients (Jones et al. 2003) . Below the mixed layer, the Pacific source is characterized by \u223c15 nitrate, \u223c2 phosphate, and \u223c30 \u03bcM silica at salinities near 33.1 (Macdonald et al. 1989; Carmack et al. 2004) , while the Atlantic source is characterized by\u223c8 nitrate, \u223c1 phosphate, and \u223c6 \u03bcM silica at a salinity of 34.9 (Cauwet and Sidorov 1996; Dittmar et al. 2001) . DOC concentrations are 50-60 \u03bcM in both sources (Dittmar et al. 2001; Emmerton et al. 2008) . Average (discharge-weighted) concentrations of nitrate and phosphate in arctic rivers are lower than these ocean end-members, and average (dischargeweighted) concentrations of silica and DOC are higher than these ocean end-members (Holmes et al. 2011, this issue) . Thus, river inputs act to dilute the Arctic Ocean with respect to nitrate and phosphate and enrich the Arctic Ocean with respect to silica and DOC. That said, it is important to keep in mind that stratification and biological uptake in surface waters can leave effective ocean end-member concentrations much lower with respect to nitrate, phosphate, and silica during summer months. While nitrate and phosphate availability have the potential to limit total primary production in the photic zone, availability of silica can limit diatom growth and thus influence the proportion of total production contributed by diatoms (Davis et al. 1978; Egge 1998; Officer and Ryther 1980) . High dissolved inorganic Si/N and Si/P ratios in Arctic rivers relative to diatom stoichiometry (Si/ N/P of \u223c17:16:1) set the stage for unrestricted competition between diatoms and other primary producers in coastal waters. However, different patterns of Si, N, and P cycling along estuarine gradients lead to temporal and spatial variability in nutrient limitation.", "cite_spans": [{"start": 333, "end": 355, "text": "(Macdonald et al. 1989", "ref_id": "BIBREF60"}, {"start": 401, "end": 420, "text": "(Jones et al. 2003)", "ref_id": "BIBREF45"}, {"start": 554, "end": 577, "text": "(Macdonald et al. 1989;", "ref_id": "BIBREF60"}, {"start": 578, "end": 598, "text": "Carmack et al. 2004)", "ref_id": "BIBREF12"}, {"start": 711, "end": 736, "text": "(Cauwet and Sidorov 1996;", "ref_id": "BIBREF14"}, {"start": 737, "end": 757, "text": "Dittmar et al. 2001)", "ref_id": "BIBREF23"}, {"start": 808, "end": 829, "text": "(Dittmar et al. 2001;", "ref_id": "BIBREF23"}, {"start": 830, "end": 851, "text": "Emmerton et al. 2008)", "ref_id": "BIBREF29"}, {"start": 1741, "end": 1760, "text": "(Davis et al. 1978;", "ref_id": "BIBREF20"}, {"start": 1761, "end": 1771, "text": "Egge 1998;", "ref_id": "BIBREF27"}, {"start": 1772, "end": 1796, "text": "Officer and Ryther 1980)", "ref_id": "BIBREF81"}], "ref_spans": []}, {"section": "Nutrient and Organic Matter Dynamics in Arctic Estuaries", "text": "During the open water season, distributions of inorganic nutrients in Arctic estuaries are not strikingly different than observed in many other estuaries (particularly those with low nutrient loads) around the world. For example, concentrations of dissolved phosphate and nitrate fall below estimated values for conservative mixing across wide salinity ranges in the Lena and Mackenzie estuaries (Cauwet and Sidorov 1996; Carmack et al. 2004; Emmerton et al. 2008) . Extra care must be taken when interpreting salinity-property plots in the Arctic because formation and thawing of sea-ice can significantly alter the salinity regime. Additional freshwater tracers such as stable oxygen isotope ratios in water (H 2 O-\u03b4 18 O) help separate runoff from sea-ice effects (\u00d6stlund and Hut 1984; Macdonald et al. 1995; Cooper et al. 2008) . In any case, variations in dissolved nitrate and phosphate concentrations relative to the Redfield ratio (N/P of 16:1) suggest that phosphorus limits total primary production at the lower end of the estuarine gradient (salinities from \u223c0 to 10) and nitrogen limits total primary production further off-shore in the Mackenzie/Beaufort system. In the Lena/Laptev system, nitrogen appears to be the limiting nutrient for total primary production throughout the estuary. Distributions of dissolved silica also reflect effects of biological uptake in the estuaries, but the silica concentrations are much higher than the nitrate and phosphate concentrations over most of the salinity range. In waters over the Canadian Shelf of the Beaufort Sea, spatial variations in nutrient ratios suggest that silica delivered from the Mackenzie River is sufficient to support optimum diatom growth over the inner shelf, but becomes a limiting factor over the middle to outer shelf (Carmack et al. 2004) .", "cite_spans": [{"start": 396, "end": 421, "text": "(Cauwet and Sidorov 1996;", "ref_id": "BIBREF14"}, {"start": 422, "end": 442, "text": "Carmack et al. 2004;", "ref_id": "BIBREF12"}, {"start": 443, "end": 464, "text": "Emmerton et al. 2008)", "ref_id": "BIBREF29"}, {"start": 767, "end": 789, "text": "(\u00d6stlund and Hut 1984;", "ref_id": "BIBREF84"}, {"start": 790, "end": 812, "text": "Macdonald et al. 1995;", "ref_id": "BIBREF61"}, {"start": 1799, "end": 1820, "text": "(Carmack et al. 2004)", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Nutrient and Organic Matter Dynamics in Arctic Estuaries", "text": "In contrast with the non-conservative behavior of inorganic nutrients discussed above, several studies have shown that DOC concentrations in Arctic estuaries fall along conservative mixing lines from high concentrations in river waters to much lower concentrations at the marine end (Cauwet and Sidorov 1996; Emmerton et al. 2008; K\u00f6hler et al. 2003) . In some cases, these results have been cited as evidence that river-borne dissolved organic matter is highly refractory and passes through the estuaries largely unaltered. Several studies have estimated significant losses of terrigenous DOC within the Arctic Ocean over longer timeframes (Opsahl et al. 1999; Hansell et al. 2004; Cooper et al. 2005) , but losses in the near-shore and shelf environments have generally been considered negligible. However, recent studies of photomineralization (Osburn et al. 2009 ) and bacterial consumption ) of river-borne DOC exported to Arctic estuaries have demonstrated substantial losses over relatively short timeframes during bottle incubation experiments. Furthermore, Granskog et al. (2009) showed that over 50% of the chromophoric dissolved organic matter delivered by rivers was photobleached within months as it was transported under ice-free conditions in the Hudson Bay coastal current. Seasonal variations may help reconcile the conservative mixing results with the results showing substantial short-term losses of dissolved organic matter. In the bottle incubation experiments Osburn et al. 2009 ), losses were much higher in water collected during spring as compared with late summer. The more reactive fraction of DOC delivered to the estuaries during the spring freshet may largely be gone by mid-to late summer, when most of the research on Arctic estuaries has been done. Dissolved organic nitrogen (DON) shows similar pattern to DOC in the Ob and Yenisey estuaries (K\u00f6hler et al. 2003) , but very different patterns than DOC in the Mackenzie (Emmerton et al. 2008) and Lena (Cauwet and Sidorov 1996) estuaries. In the Lena case, non-conservative behavior of DON suggests major losses within the lower end of the salinity range (0 to \u223c10). In the Mackenzie case, DON concentrations are positively correlated with salinity, increasing toward remarkably high DON concentrations (\u223c20 to 25 \u03bcM) over the shelf. The different patterns for DON relative to those observed for DOC serve as a reminder that the dissolved organic matter pool contains a complex mixture of molecules that range widely in their reactivity. In a study of 12 Russian arctic rivers and associated shelf waters, Dittmar et al. (2001) reported that dissolved hydrolyzable amino acids (DHAA) account for \u223c10% (ocean) to \u223c40% (river) of the total DON. The composition of the DHAA pool suggested that these amino acids were largely recalcitrant. However, as discussed with respect to DOC, more reactive fractions delivered during the spring freshet may have been missed as a consequence of sampling during mid-to late summer. Tank et al. (2011, this issue ) use a modeling approach to examine the potential of river-supplied DON to support production across the near-shore, shelf, and basin domains of the Arctic Ocean. This approach accounts for seasonally varying inputs of DON and explicitly considers the roles of photomineralization and microbial processing.", "cite_spans": [{"start": 283, "end": 308, "text": "(Cauwet and Sidorov 1996;", "ref_id": "BIBREF14"}, {"start": 309, "end": 330, "text": "Emmerton et al. 2008;", "ref_id": "BIBREF29"}, {"start": 331, "end": 350, "text": "K\u00f6hler et al. 2003)", "ref_id": "BIBREF51"}, {"start": 641, "end": 661, "text": "(Opsahl et al. 1999;", "ref_id": "BIBREF82"}, {"start": 662, "end": 682, "text": "Hansell et al. 2004;", "ref_id": "BIBREF38"}, {"start": 683, "end": 702, "text": "Cooper et al. 2005)", "ref_id": "BIBREF17"}, {"start": 847, "end": 866, "text": "(Osburn et al. 2009", "ref_id": "BIBREF83"}, {"start": 1482, "end": 1500, "text": "Osburn et al. 2009", "ref_id": "BIBREF83"}, {"start": 1876, "end": 1896, "text": "(K\u00f6hler et al. 2003)", "ref_id": "BIBREF51"}, {"start": 1953, "end": 1975, "text": "(Emmerton et al. 2008)", "ref_id": "BIBREF29"}, {"start": 1985, "end": 2010, "text": "(Cauwet and Sidorov 1996)", "ref_id": "BIBREF14"}, {"start": 2589, "end": 2610, "text": "Dittmar et al. (2001)", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Nutrient and Organic Matter Dynamics in Arctic Estuaries", "text": "Bulk particulate concentrations in Arctic estuaries decrease rapidly in the near-shore environment (referred to as the \"marginal filter\" by Lisitsyn 1995) due to net sedimentation. As observed globally, this process is facilitated by flocculation as freshwater and saltwater mix. Particulate organic matter concentrations decrease with the bulk suspended material (Macdonald and Yu 2006; Emmerton et al. 2008) , and the proportion of phytoplankton contributing to the suspended organic matter pool increases (N\u00f6thig et al. 2003; . However, there are also some notable differences among Arctic estuaries with respect to phytoplankton distributions during the open water season (as indicated by chlorophyll and/or biomass). Concentrations of phytoplankton peak strongly at the freshwater ends of the Ob, Yenisey, and Lena estuaries (Sorokin and Sorokin 1996; N\u00f6thig et al. 2003; Makarevich et al. 2003) , whereas phytoplankton concentrations remain relatively level across the river-to-estuary transition in the Mackenzie system, and there is a marked chlorophyll maximum at a depth of \u223c25 m farther off-shore (Carmack et al. 2004; Retamal et al. 2008; Emmerton et al. 2008) . This difference may be related to greater light attenuation in near-shore waters of the Mackenzie River estuary as a consequence of much higher suspended sediment inputs compared with the other estuaries.", "cite_spans": [{"start": 364, "end": 387, "text": "(Macdonald and Yu 2006;", "ref_id": "BIBREF65"}, {"start": 388, "end": 409, "text": "Emmerton et al. 2008)", "ref_id": "BIBREF29"}, {"start": 508, "end": 528, "text": "(N\u00f6thig et al. 2003;", "ref_id": "BIBREF79"}, {"start": 830, "end": 856, "text": "(Sorokin and Sorokin 1996;", "ref_id": "BIBREF97"}, {"start": 857, "end": 876, "text": "N\u00f6thig et al. 2003;", "ref_id": "BIBREF79"}, {"start": 877, "end": 900, "text": "Makarevich et al. 2003)", "ref_id": "BIBREF67"}, {"start": 1108, "end": 1129, "text": "(Carmack et al. 2004;", "ref_id": "BIBREF12"}, {"start": 1130, "end": 1150, "text": "Retamal et al. 2008;", "ref_id": "BIBREF92"}, {"start": 1151, "end": 1172, "text": "Emmerton et al. 2008)", "ref_id": "BIBREF29"}], "ref_spans": []}, {"section": "Nutrient and Organic Matter Dynamics in Arctic Estuaries", "text": "While the above discussion, and most of the research on biogeochemistry of Arctic estuaries to date, has emphasized nutrient and organic matter dynamics during mid-to late summer, the marked seasonality of Arctic estuaries is what makes them truly unique. Short daylight hours and thick ice/ snow cover strongly limit light availability in the water column during 8-9 months each year. Under these conditions, nutrients delivered to coastal waters via rivers (i.e., rivers large enough to maintain year-round flow) are not rapidly consumed and thus spread out and build-up under the ice (Cauwet and Sidorov 1996; Carmack et al. 2004; Kuzyk et al. 2008) . The distribution of river-supplied nutrients over the shelf can be tightly constrained by stamukhi dams, as in the Mackenzie case, or much less so where flaw leads are further off-shore and/or there is less ice deformation. In any case, these nutrients are a potentially important resource supporting primary production as day length increases and ice cover thins. Growth of algae within brine channels and attached to the bottom of the ice provide an important food source to consumers during the early growing season (Horner and Schrader 1982; Juul-Pedersen et al. 2008; Rozanska et al. 2009) , and this ice algae is well situated to take advantage of a winter build-up of nutrients. Nutrients supplied by rivers during winter may also help support early phytoplankton blooms in the water column at flaw lead polynyas, but again, this depends on the location of the flaw lead and the extent to which stamukhi dams constrain winter river plumes.", "cite_spans": [{"start": 587, "end": 612, "text": "(Cauwet and Sidorov 1996;", "ref_id": "BIBREF14"}, {"start": 613, "end": 633, "text": "Carmack et al. 2004;", "ref_id": "BIBREF12"}, {"start": 634, "end": 652, "text": "Kuzyk et al. 2008)", "ref_id": "BIBREF53"}, {"start": 1174, "end": 1200, "text": "(Horner and Schrader 1982;", "ref_id": "BIBREF42"}, {"start": 1201, "end": 1227, "text": "Juul-Pedersen et al. 2008;", "ref_id": "BIBREF46"}, {"start": 1228, "end": 1249, "text": "Rozanska et al. 2009)", "ref_id": "BIBREF93"}], "ref_spans": []}, {"section": "Nutrient and Organic Matter Dynamics in Arctic Estuaries", "text": "Inputs of organic matter from arctic rivers have the potential to contribute to secondary production throughout the year, and in the absence of primary production (i.e., during the winter), these inputs may provide a particularly important subsidy to estuarine communities. Stable isotopic evidence suggests that land-derived organic matter contributes to the food webs of Alaskan Beaufort Sea lagoons (Dunton et al. 2006) . Likewise, studies of heterotrophic production and food web relationships in the Mackenzie estuary have demonstrated that river-supplied organic matter is a significant resource for plankton communities near the river mouth (Parsons et al. 1988 (Parsons et al. , 1989 Garneau et al. 2006) . Furthermore, analyses of carbon quantity and quality in sediment samples from the Mackenzie River and Beaufort Shelf point to significant annualized losses of river-supplied particulate organic matter in the coastal ocean (Go\u00f1i et al. 2005 ). The Go\u00f1i et al. (2005) study did not separate losses due to burial within the delta from leaching and/or net respiration. However, larger percentage loss of modern carbon as compared with ancient carbon in this study suggests that a significant proportion of the modern carbon in the particle load delivered by the Mackenzie River is respired. The extent to which landderived organic matter specifically supports heterotrophic activity during the winter remains to be seen. One might reasonably assume that lower temperatures and organic matter inputs limit heterotrophic activity during the long arctic winter. Yet, non-conservative behavior of ammonium and nitrate within the Lena estuary during the winter suggest that significant nitrification and denitrification occur over this time period (Cauwet and Sidorov 1996) . Dunton et al. (2012, this issue) address near-shore ecosystem dynamics in the Arctic, including seasonality and potential trophic linkages with terrestrial organic matter, in greater detail.", "cite_spans": [{"start": 402, "end": 422, "text": "(Dunton et al. 2006)", "ref_id": "BIBREF24"}, {"start": 648, "end": 668, "text": "(Parsons et al. 1988", "ref_id": "BIBREF86"}, {"start": 669, "end": 691, "text": "(Parsons et al. , 1989", "ref_id": "BIBREF87"}, {"start": 692, "end": 712, "text": "Garneau et al. 2006)", "ref_id": "BIBREF31"}, {"start": 937, "end": 954, "text": "(Go\u00f1i et al. 2005", "ref_id": "BIBREF32"}, {"start": 962, "end": 980, "text": "Go\u00f1i et al. (2005)", "ref_id": "BIBREF32"}, {"start": 1754, "end": 1779, "text": "(Cauwet and Sidorov 1996)", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Nutrient and Organic Matter Dynamics in Arctic Estuaries", "text": "At the onset of the spring freshet, landfast ice is still in place around much of the pan-Arctic domain. Increased river discharge can accelerate ice melt when river water temperatures are higher than the coastal waters they flow into, and river water that flows out over the ice surface accelerates melting through effects on albedo (Dean et al. 1994) . However, most of the river water delivered during the spring freshet pushes out under the ice, mixing with and/or displacing the river water that built up slowly during the winter (Macdonald 2000) . This has interesting consequences for the estuarine nutrient regime because the river waters delivered during the spring freshet have much lower inorganic nutrient concentrations and much higher organic matter concentrations than the river waters delivered during the winter (Holmes et al. 2011, this issue) . When the ice breaks up and primary production in the water column is able to begin in earnest, nutrient concentrations may be higher off-shore than near-shore. Carmack et al. (2004) demonstrated that landfast ice in the Mackenzie River region delays the onset of phytoplankton production in the water column by \u223c1 month over the inner shelf compared with the outer shelf. While this delay is largely a function of light availability, the off-shore nutrient regime supports more primary production as well. The patterns in phytoplankton production reported in Carmack et al. (2004) are broadly corroborated by sediment trap data (O'Brien et al. 2006 ). In addition, O'Brien et al. (2006) demonstrate the importance of coastal erosion and sediment re-suspension as contributors to organic matter content in the water column after the ice retreats.", "cite_spans": [{"start": 334, "end": 352, "text": "(Dean et al. 1994)", "ref_id": "BIBREF21"}, {"start": 535, "end": 551, "text": "(Macdonald 2000)", "ref_id": "BIBREF58"}, {"start": 1024, "end": 1045, "text": "Carmack et al. (2004)", "ref_id": "BIBREF12"}, {"start": 1423, "end": 1444, "text": "Carmack et al. (2004)", "ref_id": "BIBREF12"}, {"start": 1492, "end": 1512, "text": "(O'Brien et al. 2006", "ref_id": "BIBREF80"}, {"start": 1529, "end": 1550, "text": "O'Brien et al. (2006)", "ref_id": "BIBREF80"}], "ref_spans": []}, {"section": "Nutrient and Organic Matter Dynamics in Arctic Estuaries", "text": "As winter approaches and ice once again forms over Arctic estuaries, brine rejection concentrates nutrients and organic matter in surface waters (Macdonald and Yu 2006) . This process is most evident for constituents that are already at relatively high concentrations when the ice begins to form. For example, a positive offset in mixing lines for dissolved silica between summer and winter in the Mackenzie estuary has been attributed to rejection of dissolved silica from the accumulating ice. A maximum ice thickness of approximately 2 m ultimately limits this effect over the inner shelf, while it continues with ice production throughout the winter at flaw lead polynyas.", "cite_spans": [{"start": 145, "end": 168, "text": "(Macdonald and Yu 2006)", "ref_id": "BIBREF65"}], "ref_spans": []}, {"section": "Estuarine Character of the Arctic Ocean as a Whole", "text": "In the Introduction, we identified continental runoff, inflow of Pacific waters through Bering Strait, and net precipitation on the ocean surface as the major freshwater sources to the Arctic Ocean. The salty end of this great estuary is the northern Atlantic Ocean. In general, stratification of the Arctic Ocean consists of a seasonally variable surface mixed layer occupying the upper \u223c30 to 50 m of the water column, a complex of cold, salt stratified layers that define the halocline, a saline but warmer Atlantic layer, and deepwater below 1,600 m (Carmack 2000) . The mixed layer is fresher and the halocline extends deeper in the western Arctic as compared with the eastern Arctic. The halocline in the western Arctic also exhibits more structure. These differences largely reflect the influence of Pacific water inflow to the western Arctic. The Atlantic layer is primarily derived from inflow of North Atlantic water through Fram Strait and the Barents Sea. The surface water inflows from the Pacific and North Atlantic are shown as red arrows in Fig. 6 . In all cases, the inflowing waters submerge under more buoyant surface waters as they enter the Arctic Ocean basin.", "cite_spans": [{"start": 554, "end": 568, "text": "(Carmack 2000)", "ref_id": "BIBREF7"}], "ref_spans": [{"start": 1057, "end": 1063, "text": "Fig. 6", "ref_id": "FIGREF3"}]}, {"section": "Estuarine Character of the Arctic Ocean as a Whole", "text": "Within the interior basins of the Arctic Ocean, there are two main flow fields for surface waters. Waters on the Eurasian side primarily move from the Siberian shelf toward Greenland along the Transpolar Drift, whereas waters on the North American side circulate through the Beaufort Gyre (Fig. 6) . The Arctic Ocean also supports a large-scale connected network of coastal currents that facilitate movement of continental runoff out of the Arctic (e.g., Carmack et al. 2008; McLaughlin et al. 2006 ). Depending on winds, river inflow can be constrained to the coastal currents or form lengthy plumes that efficiently transport runoff into the ocean's interior (Macdonald et al. 1999 Macdonald & Yu 2006) . Approximately 50% of the freshwater exported from the Arctic Ocean rides out over the Atlantic water through Fram Strait (Serreze et al. 2006 ). Most of the remaining freshwater export occurs via the Canadian Arctic Archipelago (\u223c36%). Roughly half of the freshwater exported through Fram Strait is in the form of ice, whereas freshwater export through the Canadian Arctic Archipelago is mostly liquid.", "cite_spans": [{"start": 455, "end": 475, "text": "Carmack et al. 2008;", "ref_id": "BIBREF13"}, {"start": 661, "end": 683, "text": "(Macdonald et al. 1999", "ref_id": "BIBREF63"}, {"start": 684, "end": 704, "text": "Macdonald & Yu 2006)", "ref_id": "BIBREF65"}, {"start": 828, "end": 848, "text": "(Serreze et al. 2006", "ref_id": "BIBREF95"}], "ref_spans": [{"start": 289, "end": 297, "text": "(Fig. 6)", "ref_id": "FIGREF3"}]}, {"section": "Estuarine Character of the Arctic Ocean as a Whole", "text": "The various routes that river waters take as they circulate through the Arctic Ocean have important implications with respect to freshwater storage within and release from the ocean basin (Fig. 7) . In general, runoff entrained into rapidly transporting coastal currents (Granskog et al. 2009 ) is exported more quickly than runoff that is shunted into the ocean's interior (Proshutinsky et al. 2002) . Furthermore, runoff that enters the Beaufort Gyre has a much longer residence time (\u223c10 years) than runoff transported via the Transpolar Drift (\u223c2 years). For the Eurasian rivers, it appears that the state of the Arctic Oscillation (AO) can impact where river waters enter the ocean interior (Johnson and Polyakov 2001) : a high AO index forces runoff eastward and into the Beaufort Gyre and a low AO index forces runoff directly into the Transpolar Drift. The (1998) bifurcations in river water transport then have effects on the interior ocean structure of the receiving basins (Steele and Boyd 1998; Schlosser et al. 2002) . Storage and release of ice is similarly affected by transport pathways through the Arctic Ocean (Fig. 7) .", "cite_spans": [{"start": 374, "end": 400, "text": "(Proshutinsky et al. 2002)", "ref_id": "BIBREF89"}, {"start": 696, "end": 723, "text": "(Johnson and Polyakov 2001)", "ref_id": "BIBREF44"}, {"start": 984, "end": 1006, "text": "(Steele and Boyd 1998;", "ref_id": "BIBREF98"}, {"start": 1007, "end": 1029, "text": "Schlosser et al. 2002)", "ref_id": "BIBREF94"}], "ref_spans": []}, {"section": "Estuarine Character of the Arctic Ocean as a Whole", "text": "While Pacific water was identified as a marine endmember in our earlier discussion of individual Arctic estuaries, it is important to recall that this nutrient-rich water serves as a freshwater end-member with respect to the Atlantic water in the Arctic Ocean estuary more generally ( Fig. 1) and is a crucial contributor to the stratification in the Canada Basin, lying as it does between the surface mixed layer and the Atlantic water (Macdonald et al. 1989) . During winter, surface waters rich in nitrate, phosphate, and silica pass through the Bering Strait and spread out over the Chukchi shelf (Codispoti et al. , 2009 ). These nutrients fuel intense phytoplankton blooms in the spring and early summer (as the sea-ice recedes) that support productive microbial and metazoan communities in the Chukchi Sea (Mathis et al. 2009; Sukhanova et al. 2009; Kirchman et al. 2009; Dyda et al. 2009; Sherr et al. 2009; Campbell et al. 2009 ). In contrast, the surface waters of the Canada Basin, which store fresh water, have far less opportunity to access the Pacific nutrients and, as a result, exhibit exceptionally low export production (Honjo et al. 2010) . Where freshwater moves, entrainment and mixing enhance production; where freshwater accumulates, entrainment and mixing are prevented and low production ensues.", "cite_spans": [{"start": 437, "end": 460, "text": "(Macdonald et al. 1989)", "ref_id": "BIBREF60"}, {"start": 601, "end": 625, "text": "(Codispoti et al. , 2009", "ref_id": "BIBREF16"}, {"start": 813, "end": 833, "text": "(Mathis et al. 2009;", "ref_id": "BIBREF69"}, {"start": 834, "end": 856, "text": "Sukhanova et al. 2009;", "ref_id": "BIBREF103"}, {"start": 857, "end": 878, "text": "Kirchman et al. 2009;", "ref_id": "BIBREF50"}, {"start": 879, "end": 896, "text": "Dyda et al. 2009;", "ref_id": "BIBREF26"}, {"start": 897, "end": 915, "text": "Sherr et al. 2009;", "ref_id": "BIBREF96"}, {"start": 916, "end": 936, "text": "Campbell et al. 2009", "ref_id": "BIBREF6"}, {"start": 1138, "end": 1157, "text": "(Honjo et al. 2010)", "ref_id": "BIBREF43"}], "ref_spans": []}, {"section": "Climate Change", "text": "Arctic estuaries, from the small scale of coastal embayments to the large-scale of the entire Arctic Ocean, are vulnerable to climate variability and change. We are already seeing significant climate-driven changes throughout the Arctic and more are predicted for the future (ACIA 2005) . Many of these changes involve storage and cycling of fresh water, including changes in the timing and magnitude of river discharge and sea-ice coverage. Annual river discharge to the Arctic Ocean increased by an average of \u223c7 km 3 each year over the 1964-2000 time period, with a large increase from Eurasia tempered by a small decrease from North America (McClelland et al. 2006) . Summertime sea-ice cover around the pan-Arctic domain decreased by \u223c8% per decade over the 1979-2005 time period, with most extensive losses in the Eurasian sector (Parkinson et al. 1999) and extreme minima observed in the 2000s (Stroeve et al. 2008) . Changes in precipitation, evaporation, and a variety of permafrost characteristics have been identified as likely contributors to the changes in annual river discharge, with the relative importance of these different drivers varying across watersheds. Changes in the seasonality of river discharge are also dependent on the above-mentioned drivers. However, snow cover characteristics (i.e., extent, water equivalent, and timing of melt) are particularly important with respect to the timing and magnitude of the spring freshet (Kane et al. 2000; Woo 1986; Yang et al. 2003) . Warming has caused snowmelt to begin earlier in northern regions during recent decades (Yang et al. 2002 Zhang et al. 2000) . Likewise, sea-ice thaw/break-up is occurring earlier. See White et al. (2007) for a comprehensive tabulation and analysis of changes in terrestrial and marine components of the arctic freshwater system.", "cite_spans": [{"start": 275, "end": 286, "text": "(ACIA 2005)", "ref_id": "BIBREF3"}, {"start": 645, "end": 669, "text": "(McClelland et al. 2006)", "ref_id": "BIBREF71"}, {"start": 836, "end": 859, "text": "(Parkinson et al. 1999)", "ref_id": "BIBREF85"}, {"start": 901, "end": 922, "text": "(Stroeve et al. 2008)", "ref_id": "BIBREF102"}, {"start": 1453, "end": 1471, "text": "(Kane et al. 2000;", "ref_id": "BIBREF47"}, {"start": 1482, "end": 1499, "text": "Yang et al. 2003)", "ref_id": "BIBREF112"}, {"start": 1589, "end": 1606, "text": "(Yang et al. 2002", "ref_id": "BIBREF111"}, {"start": 1607, "end": 1625, "text": "Zhang et al. 2000)", "ref_id": "BIBREF115"}, {"start": 1686, "end": 1705, "text": "White et al. (2007)", "ref_id": "BIBREF107"}], "ref_spans": []}, {"section": "Climate Change", "text": "As Arctic river discharge increases, changes in the physical and biogeochemical properties of coastal, shelf, and basin waters of the Arctic Ocean are anticipated. Greater freshwater inflow will support stronger stratification, but will also support stronger estuarine entrainment of deeper water. At the same time, concentrations of nutrients and organic matter in the river inputs are likely to change as consequence of warmer temperatures and thawing permafrost (Frey and McClelland, 2009) . There is general agreement that soluble reactive phosphorus and silica concentrations in arctic rivers will increase. There is less agreement about how concentrations of inorganic nitrogen and organic matter in arctic rivers will change, but it is likely that export will increase in some regions and decrease in others depending on vegetation, soil composition, microbial activity, and changes in water flow paths as permafrost thaws. Such changes in nutrient and organic matter export from rivers to the Arctic Ocean have the potential to significantly influence productivity in Arctic coastal waters, whereas river-induced changes in the productivity of outer shelf and basin waters would largely be limited to effects of freshwater inflow on circulation.", "cite_spans": [{"start": 465, "end": 492, "text": "(Frey and McClelland, 2009)", "ref_id": "BIBREF30"}], "ref_spans": []}, {"section": "Climate Change", "text": "In addition to potential changes in productivity associated with overall river inputs, changes in seasonality are Fig. 7 Schematic diagram showing switches (bifurcations) and oscillations (temporal trends) possible in the runoff and ice components of the Arctic's freshwater cycle. Runoff entering the shelf may exit the Arctic rapidly in boundary currents or the Transpolar Drift, or it may enter the basin to be stored. Likewise, ice production may generate fresh water that is stored in the interior ocean or swept rapidly out of the ocean. Upon exiting the Arctic Ocean, fresh water may enter convecting areas or bypass them on the way south likely to have (and may already be having) a significant impact on the timing, magnitude, and distribution of ecosystem production in coastal and shelf waters of the Arctic (Loeng et al. 2005; . In particular, shifts in the timing of the spring freshet and ice break-up could lead to a variety of contrasting outcomes. If the spring freshet occurs earlier relative to sea-ice break-up, more of the nutrient-rich river water from winter discharge will be displaced/diluted by nutrient-poor water from the freshet before the onset of the phytoplankton bloom. Under this scenario, peak production would occur farther from shore, and the relative importance of river-borne organic matter versus inorganic nutrient contributions to production in near-shore waters would increase. On the other hand, if the spring freshet occurs later relative to sea-ice break-up, less of the nutrientrich river water from winter discharge will be displaced/ diluted by nutrient-poor water from the freshet before the onset of the phytoplankton bloom. In this case, peak production would occur nearer to shore, and the relative importance of river-borne organic matter versus inorganic nutrient contributions to production in near-shore waters would decrease. Even if the relative timing of the spring freshet and ice break-up remain constant as they shift to earlier in the year, lower incident light levels during ice retreat would change the progression of the phytoplankton bloom, lessening its initial intensity, slowing the drawdown of nutrients, and smoothing the on-shore to off-shore gradient in production.", "cite_spans": [{"start": 819, "end": 838, "text": "(Loeng et al. 2005;", "ref_id": "BIBREF57"}], "ref_spans": []}, {"section": "Climate Change", "text": "Changes in wind-driven mixing associated with decreasing ice cover are also likely to effect productivity in coastal, shelf, and basin waters. Increased mixing will work against the stratification effect of greater freshwater inflows. At the same time, increased shoreline erosion associated with decreasing ice cover will enhance sediment, nutrient, and organic matter contributions to coastal waters (Lantuit et al. 2011, this issue) . The added nutrients and organic matter have the potential to increase biological production, but greater light attenuation as a consequence of enhanced sediment loads may limit this effect near-shore.", "cite_spans": [], "ref_spans": []}, {"section": "Climate Change", "text": "Finally, climate change is likely to affect the balance between freshwater storage within the Arctic Ocean and export of fresh water to the North Atlantic. Each of the switches and oscillations depicted in Fig. 7 is sensitive to changes in runoff, ice dynamics, and large-scale wind patterns. However, given that changes in some switches/ oscillations will enhance freshwater storage while others will facilitate export, it is difficult to predict the overall outcome of these effects. For example, greater runoff will work against brine formation during seasonal ice growth, making conditions less favorable for deep convection (which supports long-term separation of sea-ice from the salt rejected during its formation) and thus diminishing the capacity for sea-ice to serve as an exportable freshwater source. At the same time, diminished ice cover in the fall together with more open water storms may help to remove freshwater inventories from the shelves and precondition them toward a greater potential to generate dense water from ice production in the ensuing winter. In any case, changes in freshwater export from the Arctic Ocean have potential consequences for North Atlantic Deep Water formation and associated larger-scale ocean circulation and climate patterns (Manabe and Stouffer 1994; Rahmstorf 1995; Broecker 1997) . Changes in regional climate, including a relative cooling of Europe and enhanced warming in the equatorial Atlantic as consequences of reduced meridional overturning circulation triggered by greater freshwater export from the Arctic have been given particular attention. However, the severity of these consequences will depend strongly on the magnitudes of the changes in freshwater export as well as the timeframes over which they occur. An estimate of the storage capacities and residence times of freshwater in the Arctic Ocean (Fig. 8 ) Fig. 8 Schematic diagram showing the potential of various Arctic domains to store fresh water (BG Beaufort Gyre) suggests that shelves can be affected quite quickly by change in, for example, wind fields (Johnson and Polyakov 2001) , whereas the Beaufort Gyre takes longer to store and shed its freshwater inventory (decadal), but is capable of storing larger quantities, which, when released, have a greater potential to affect thermohaline circulation in the GreenlandIceland-Norwegian Seas. Effects of increasing freshwater inputs may not, therefore, be felt immediately, but later as the Beaufort Gyre begins to store and release larger quantities of freshwater at the decadal scale in response to variability in, for example, the Arctic Oscillation. The complexity of bifurcations in freshwater pathways (Fig. 7) and in the capacity to store and release freshwater (Fig. 8) are what make the Arctic Ocean Estuary one of the most important components of feedback in Arctic as well as global change.", "cite_spans": [{"start": 1275, "end": 1301, "text": "(Manabe and Stouffer 1994;", "ref_id": "BIBREF68"}, {"start": 1302, "end": 1317, "text": "Rahmstorf 1995;", "ref_id": "BIBREF90"}, {"start": 1318, "end": 1332, "text": "Broecker 1997)", "ref_id": "BIBREF5"}, {"start": 2080, "end": 2107, "text": "(Johnson and Polyakov 2001)", "ref_id": "BIBREF44"}], "ref_spans": []}, {"section": "Concluding Remarks", "text": "Estuarine science in the Arctic is young in comparison to many other regions of the world where major human population centers are situated along the coastline and scientists are able to access field sites with relative ease and regularity. Our current knowledge of Arctic estuaries is largely based on studies of a few major systems (i.e., estuaries associated with major river inputs). Furthermore, seasonal coverage of Arctic estuarine dynamics has been very limited. However, with clear signals of climate change occurring in the Arctic and greater changes anticipated in the future, there is good reason to accelerate estuarine research efforts in the region. In particular, elucidating estuarine dynamics across the near-shore to ocean-wide domains is an important pre-requisite for understanding potential climate feedbacks associated with storage and release of fresh water and carbon. Changes in freshwater export from the Arctic Ocean have the potential to alter ocean convection in the North Atlantic, while mobilization of large organic carbon stocks in arctic watersheds (most notably those trapped in permafrost) have the potential to accelerate the build-up of atmospheric CO 2 . Much of the mobilized carbon might be processed and released to the atmosphere within the continental domain, but the fate of terrigenous carbon within the ocean domain is also an important consideration with respect to the carbon budget of the Arctic.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "The role of sea ice and other fresh water in the Arctic circulation", "authors": [{"first": "K", "middle": [], "last": "Aagaard", "suffix": ""}, {"first": "E", "middle": ["C"], "last": "Carmack", "suffix": ""}], "year": 1989, "venue": "Journal of Geophysical Research", "link": "131694738"}, "BIBREF1": {"title": "The Arctic Ocean and climate: A perspective. 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Data are average monthly runoff for 1990-1999. Regional runoff climatologies were calculated using the following rivers: Barents Sea (Mezen, Norway Tana, Onega, Pechora, and Severnaya Dvina), Kara Sea (Norilka, Ob, Pur, and Yenisey), Laptev Sea (Anabar, Lena, Olenek, and Yana). East Siberina Sea (Alazeya, Indigirka, Kolyma), Beaufort Sea (Anderson, Kuparuk, Mackenzie), Hudson Bay (Churchill, Hayes, Saskatchewan, Seal, Thlewiaza, Missinaibi, Kazan, Red, Winnipeg, Notaway, Eastmain, Grande Baleine, Harricana, Broadback, Nastapoca, Kogaluc, Innuksuac, Thelon). Data from RArcticNet (http://www.r-arcticnet. sr.unh.edu/), Arctic RIMS (http:// rims/unh.edu), the US Geological Survey (http://waterdata.usgs.gov/ nwis), and Water Survey of Canada's Hydrometric Database-YDAT (www.wsc.ec.gc.ca/)", "type": "figure"}, "FIGREF1": {"text": "Fig. 4 Concentrations (left column) and yields (right column) of nitrate, dissolved organic carbon, and total suspended sediment in the six largest rivers draining the pan-Arctic watershed (red bars) as well as several other major rivers around the world (blue bars). Average annual water discharge: Amazon (6,590), Congo (1,200), Yangtze (928), Yenisey (620), Lena (530), Mississippi (529), Ob (404), Mackenzie (307), Yukon (205), and Kolyma (132 km", "type": "figure"}, "FIGREF2": {"text": "Fig. 5 Schematic diagram showing major features of frozen estuaries in the Arctic. Note that the ice dam depicted at the seaward extent of the landfast ice is a prominent feature of the Mackenzie estuary that constrains spreading of river water over the shelf. This damming effect varies among Arctic estuaries depending on the location of the flaw lead and the amount of rubble ice (stamukhi) that forms at the landfast ice edge. WRP Winter River Plume, PML Polar Mixed Layer", "type": "figure"}, "FIGREF3": {"text": "Fig. 6 Surface currents in the Arctic Ocean and surrounding seas. Boxes mark general locations where denser inflowing waters submerge under more buoyant surface waters in the Arctic Ocean. Red arrows warm currents. Black arrows cold currents. Adapted from Fig. 3.29 in AMAP (1998)", "type": "figure"}, "TABREF0": {"text": ". 2 River runoff climatologies (millimeters per month) for six regions around the pan-Arctic domain. Data are average monthly runoff for 1990-1999. Regional runoff climatologies were calculated using the following rivers: Barents Sea (Mezen,become more variable at smaller scales. For example, only about one third of the annual runoff within the upper Kuparuk River basin (140 km 2 ) is contributed by snowmelt", "type": "table"}}}
{"paper_id": "84886734", "_pdf_hash": "75d376a7068f4f5ffbca82fd7640aff62e4af230", "abstract": [{"section": "Abstract", "text": "Understanding the in\u00a3uence of parasites on the community ecology of free-living organisms is an emerging theme in ecology. The cockle Austrovenus stutchburyi is an abundant mollusc inhabiting the sheltered shores of New Zealand. This species, which lives just a few centimetres under the surface, plays a key role for many benthic invertebrate species, because in these habitats the cockle shell is the only available hard surface where invertebrates can establish. However, the behaviour of this cockle can be altered locally by a parasite, the trematode Curtuteria australis. Indeed, heavily infected cockles are unable to bury perfectly and typically lie entirely exposed at the surface of the mud. In this study, we investigated the ecological consequences of this behavioural alteration for two invertebrate species commonly associated with cockles, the anemone Anthopleura aureoradiata and the limpet Notoacmea helmsi. A \u00a2eld study \u00a2rst demonstrated that in both infected and non-infected populations of cockles, there was a negative relationship between the number of anemones and limpets found on cockles. In the laboratory, we showed that predation of limpets by anemones is possible when they share the same cockle shell. In a heavily infected population of cockles, limpets were signi\u00a2cantly more frequent and more abundant on cockles manipulated by C. australis than on cockles with a normal behaviour. A colonization test conducted in natural conditions demonstrated that the predominance of limpets on manipulated cockles results from a direct habitat preference. Conversely, anemones were signi\u00a2cantly less frequent and less abundant on manipulated cockles than on cockles manipulated by C. australis. A desiccation test revealed that, relative to limpets, they had a lower resistance to this physical stress. We discuss our results in relation to current ideas on ecosystem engineering by organisms.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION", "text": "In recent years, a great deal of attention has been devoted to understanding the relative importance of direct and indirect interactions between species in structuring natural communities (Strauss 1991; Daily et al. 1993; Bertness & Callaway 1994; Jones et al. 1994 Jones et al. , 1997 Menge 1995; Flecker 1996; Bertness & Leonard 1997; Hacker & Gaines 1997; Miller & Travis 1997 ). Yet, evidence suggests that many species have the potential to change the environment via their own physical structures (autogenic engineer (Jones et al. 1994 (Jones et al. , 1997 ), or by transforming living or non-living materials from one physical state to another (allogenic engineer; Jones et al. 1994 Jones et al. , 1997 . Knowing that these changes can markedly in\u00a3uence the diversity of ecosystems, understanding engineering processes and their consequences is one of the current goals of community ecology (Jones et al. 1997) .", "cite_spans": [{"start": 188, "end": 202, "text": "(Strauss 1991;", "ref_id": "BIBREF35"}, {"start": 203, "end": 221, "text": "Daily et al. 1993;", "ref_id": "BIBREF7"}, {"start": 222, "end": 247, "text": "Bertness & Callaway 1994;", "ref_id": "BIBREF0"}, {"start": 248, "end": 265, "text": "Jones et al. 1994", "ref_id": "BIBREF14"}, {"start": 266, "end": 285, "text": "Jones et al. , 1997", "ref_id": "BIBREF15"}, {"start": 286, "end": 297, "text": "Menge 1995;", "ref_id": "BIBREF21"}, {"start": 298, "end": 311, "text": "Flecker 1996;", "ref_id": "BIBREF10"}, {"start": 312, "end": 336, "text": "Bertness & Leonard 1997;", "ref_id": "BIBREF1"}, {"start": 337, "end": 358, "text": "Hacker & Gaines 1997;", "ref_id": "BIBREF12"}, {"start": 523, "end": 541, "text": "(Jones et al. 1994", "ref_id": "BIBREF14"}, {"start": 542, "end": 562, "text": "(Jones et al. , 1997", "ref_id": "BIBREF15"}, {"start": 672, "end": 689, "text": "Jones et al. 1994", "ref_id": "BIBREF14"}, {"start": 690, "end": 709, "text": "Jones et al. , 1997", "ref_id": "BIBREF15"}, {"start": 898, "end": 917, "text": "(Jones et al. 1997)", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "To date, most of the studies illustrating the key role of parasites in structuring animal communities rely on evidence for a di\u00a1erential susceptibility of closely related host species to infection or its consequences (Park 1948; Barbehenn 1969; Feener 1981; Freeland 1983; Holt & Pickering 1985; Price et al. 1986; Boule\u00a8treau et al. 1991; Minchella & Scott 1991; Thomas et al. 1995; Combes 1996; Bonsall & Hassel 1997) . Given the diversity of ways in which parasites a\u00a1ect host species, we may, however, expect processes other than a di\u00a1erential susceptibility of hosts to in\u00a3uence the structure of animal communities. Parasite-induced alterations in host phenotype have been frequently reported in a wide range of protozoan and metazoan parasites with complex life cycles (Combes 1991; Poulin 1998) . Because alterations in the phenotype of parasitized hosts are sometimes substantial, it is not unrealistic to consider that manipulated hosts can be equivalent to new organisms in the ecosystem, involved in new direct and/or indirect interactions with other species (e.g. La\u00a1erty 1992; Thomas et al. 1997a Thomas et al. , 1998 . When a host species constitutes an important component of habitat structure, manipulative parasites altering the characteristics of host populations could have a variety of indirect e\u00a1ects on other species. However, ecological consequences of phenotypic alterations induced by parasites remain largely unexplored.", "cite_spans": [{"start": 217, "end": 228, "text": "(Park 1948;", "ref_id": "BIBREF28"}, {"start": 229, "end": 244, "text": "Barbehenn 1969;", "ref_id": "BIBREF0"}, {"start": 245, "end": 257, "text": "Feener 1981;", "ref_id": "BIBREF9"}, {"start": 258, "end": 272, "text": "Freeland 1983;", "ref_id": "BIBREF11"}, {"start": 273, "end": 295, "text": "Holt & Pickering 1985;", "ref_id": "BIBREF13"}, {"start": 296, "end": 314, "text": "Price et al. 1986;", "ref_id": "BIBREF31"}, {"start": 315, "end": 339, "text": "Boule\u00a8treau et al. 1991;", "ref_id": "BIBREF3"}, {"start": 340, "end": 363, "text": "Minchella & Scott 1991;", "ref_id": "BIBREF25"}, {"start": 364, "end": 383, "text": "Thomas et al. 1995;", "ref_id": "BIBREF36"}, {"start": 384, "end": 396, "text": "Combes 1996;", "ref_id": "BIBREF5"}, {"start": 397, "end": 419, "text": "Bonsall & Hassel 1997)", "ref_id": "BIBREF2"}, {"start": 775, "end": 788, "text": "(Combes 1991;", "ref_id": "BIBREF4"}, {"start": 789, "end": 801, "text": "Poulin 1998)", "ref_id": "BIBREF30"}, {"start": 1090, "end": 1109, "text": "Thomas et al. 1997a", "ref_id": "BIBREF37"}, {"start": 1110, "end": 1130, "text": "Thomas et al. , 1998", "ref_id": "BIBREF39"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "The cockle Austrovenus stutchburyi is an extremely abundant bivalve in sheltered shores of New Zealand (Morton & Miller 1973; . This mollusc usually lives between 0 and 2 cm below the surface, and individuals closest to the surface play a crucial role for benthic invertebrate species (Morton & Miller 1973) . Indeed, the shell of A. stutchburyi constitutes in many shores of New Zealand the only hard surface where benthic invertebrate species can establish. Whereas some of these invertebrates live almost exclusively on cockle shells and form a distinctive community (Morton & Miller 1973) , other species can also be found on rocky habitat elsewhere (F. Thomas and R. Poulin, unpublished observations) .", "cite_spans": [{"start": 103, "end": 125, "text": "(Morton & Miller 1973;", "ref_id": "BIBREF26"}, {"start": 285, "end": 307, "text": "(Morton & Miller 1973)", "ref_id": "BIBREF26"}, {"start": 570, "end": 592, "text": "(Morton & Miller 1973)", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "Recently, demonstrated that the burrowing behaviour of A. stutchburyi is strongly altered by the trematode Curtuteria australis. Indeed, metacercariae of this parasite handicap the host by reducing the growth of its foot. Heavily infected cockles with a stunted foot typically lie entirely exposed at the surface of the mud and experience a higher risk of predation by oystercatchers, the de\u00a2nitive host of the parasite ). This parasite can be locally very common with a prevalence of 100% among cockles and with intensities of infection sometimes greater than one thousand cysts per cockle .", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "Given the important ecological di\u00a1erences (light, temperature and desiccation) between living under or above the mud surface, manipulated cockles undoubtedly constitute a new type of habitat for benthic invertebrates. The aim of this study was to analyse the consequences of this behavioural alteration for the organization of the invertebrate community living on cockles. We \u00a2rst investigated in the \u00a2eld and at the laboratory the distribution of, and the nature of, the interactions between two invertebrate species typically found on A. stutchburyi, the anemone Anthopleura aureoradiata and the small limpet Notoacmea helmsi. Then, we observed the pattern of their distributions in a population of cockles heavily infected by C. australis, and conducted several experiments to identify the processes by which C. australis indirectly structures this invertebrate community.", "cite_spans": [], "ref_spans": []}, {"section": "MATERIALS AND METHODS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "(a) Field study", "text": "To analyse the distribution of limpets and anemones on cockles and the nature of their interactions, we \u00a2rst collected at low tide three large samples of cockles (S1, n 424; S2, n 546; and S3, n 478) in three localities (Oyster Bay, 41818' S, 17487' E; Akaroa Harbour, 43845' S, 172855' E; Company Bay, 45850' S, 170840' E, respectively) on the South Island coast of New Zealand during November 1997. To avoid any bias during sampling, all cockles were collected using quadrats (50 cm \u00c2 50 cm) thrown at random on the surface of the sediment along a transect parallel to the sea. We collected all the cockles present in three quadrats. In the heavily infected population (S3), we also used the quadrat to collect along the same transect 103 cockles entirely exposed at the surface (i.e. cockles manipulated by C. australis; . Given the demonstrated relationship between parasite load and cockle behaviour , we only determined the mean parasite load of each sampling site by counting the number of C. australis metacercariae in 50 cockles chosen randomly in each sample. To describe the characteristics of the infection by C. australis and the colonization by anemones and limpets, we used the terminology (prevalence, abundance and intensity) proposed by Margolis et al. (1982) .", "cite_spans": [{"start": 1255, "end": 1277, "text": "Margolis et al. (1982)", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "(b) Predation experiment", "text": "To examine the possibility that limpets are eaten by anemones when sharing the same cockle, we \u00a2rst determined in the laboratory whether limpets were palatable prey for anemones. For this, one limpet was gently placed on the tentacle circle of 11 anemones. To check whether anemones were able to capture limpets by themselves, we placed 24 cockles with a normal behaviour and harbouring at least one anemone (26 anemones in total) in an aquarium (30 cm \u00c212 cm) containing 4 cm of natural sediment (mixture of sand and mud) and \u00a2lled with constantly aerated seawater (18 8C, 38%). Cockles burrowed rapidly under the sediment and, as in natural conditions, only anemones and sometimes a small part of the cockle shell emerged at the surface of the sediment. We then placed 25 limpets in this aquarium for 96 h, placing them on the surface of the sediment and at a distance of at least 2 cm from the closest anemone. We concluded that predation had occurred when a limpet was found digested (empty shell) close to an anemone.", "cite_spans": [], "ref_spans": []}, {"section": "(c) Resistance to desiccation", "text": "To compare the resistance to desiccation between anemones and limpets, we collected 56 cockles in the \u00a2eld (Company Bay) harbouring one anemone, and 56 cockles harbouring one limpet. We conducted the experiment in open air during a normal summer day in Dunedin (20 8C). Cockles were placed on the \u00a3oor with the side harbouring limpets or anemones directly exposed to the sun for 1h. Then, we placed all the cockles in oxygenated seawater (15 8C, 38%) and examined the activity of cockles and both limpets and anemones for 12 h; we concluded that death had occurred when no activity was observed during this time.", "cite_spans": [], "ref_spans": []}, {"section": "(d) Colonization test", "text": "We conducted a colonization test under natural conditions to investigate whether the habitat preference of limpets for manipulated or non-manipulated cockles was a direct phenomenon, or resulted from the interaction with the anemones. For this, we collected in Company Bay 102 cockles manipulated by C. australis, and 102 cockles with a normal behaviour during June 1997. The mean shell length of these two groups was not signi\u00a2cantly di\u00a1erent (t-test, t 0.2, d.f. 202, p 0.84). In the laboratory, we removed all the invertebrates present on the shells. Because cockles in the \u00a2eld may be displaced by currents, or may be di\u00a4cult to \u00a2nd again under the sediment, we attached them to iron stakes using a transparent string (20 cm) with a small piece of brown tissue (1cm \u00c2 0.5 cm) glued onto the shell with`superglue'. On each of 51 stakes, we attached two cockles manipulated by C. australis and two cockles with a normal behaviour. Although the repeatability of the behaviour for the two categories of cockles is very high in the \u00a2eld ), we darkened, for manipulated cockles only, the part of the string closest to the stake over 2 cm with a water resistant pen, allowing us to discriminate at any time the two categories of cockles on each stake. These cockles were returned to Waipuna Bay, a site located in the Otago Harbour of Dunedin opposite Company Bay. Indeed, in this area, limpets are commonly found on cockles, while anemones are scarce (F. Thomas, unpublished observations). Stakes were planted 1m apart along a transect running parallel to the low-water mark. We started this experiment in August (winter) and we stopped it three weeks later. We recorded colonization by counting limpets present on the shells of all cockles. In several cases, cockles were found unglued or predated by oystercatchers, so that the \u00a2nal comparison of colonization rates was conducted between 76 cockles manipulated by C. australis and 99 cockles with a normal behaviour. There is no reason to believe that this loss of marked cockles could change the results or their interpretation.", "cite_spans": [], "ref_spans": []}, {"section": "(d) Colonization test", "text": "All statistical tests were performed following Sokal & Rohlf (1995) and Siegel & Castellan (1988) . All tests were two-tailed. Results were considered signi\u00a2cant at the 5% level.", "cite_spans": [{"start": 72, "end": 97, "text": "Siegel & Castellan (1988)", "ref_id": "BIBREF32"}], "ref_spans": []}, {"section": "RESULTS", "text": "Dissection revealed that in both S1 and S2, C. australis had a lower prevalence and a lower intensity of infection among cockles compared with S3 (prevalence: S1 16%, S2 6%, S3 100%, Fisher's exact test, p50.0001; mean intensity AEs.e.: S1, 2.1 AE0.6, n 8; S2, 1 AE0, n 3; S3, 144.6 AE14.9, n 50; Kruskal^Wallis ANOVA, H 25.9, d.f. 2, p50.0001). Whereas in S1 and S2 there were no manipulated cockles at the surface of the mud, they could easily be found in S3, as they were several months earlier in this area .", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "Despite broad similarities between the study sites, the mean shell length of cockles was signi\u00a2cantly di\u00a1erent (mean AE s.e.: S1, 26.3 mm AE 0.3 mm; S2, 22.6 mm AE 0.2 mm; S3, 31.1mm AE 0.1mm; ANOVA, F 2,1445 390.03, p50.0001). In the three sampling areas, we observed limpets and anemones colonizing the shell of cockles. Within each quadrat, anemones and limpets were only found on cockle shells. Forboth limpets and anemones, there were signi\u00a2cant variations between sites in prevalence ( Relationships between abundances and intensities of these invertebrates and the shell lengths of cockles tended to be positive and signi\u00a2cant, but this was not a consistent pattern in all samples (table 2) .", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "Among cockles harbouring at least one anemone and/or one limpet, there was for all samples a negative and signi\u00a2cant relationship between the number of anemones and the number of limpets found on the cockle shell (Spearman rank order correlation coe\u00a4cient: S1, r s 70.30, n 169, p50.0001; S2, r s 70.74, n 103, p50.0001; S3, r s 70.39, n 323, p50.0001). This relationship was also signi\u00a2cant when observed among the two categories of cockles in S3 (non-manipulated cockles, r s 70.29, n 249, p50.0001; manipulated cockles, r s 70.51, n 74, p50.0001).", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "In the heavily infected population (S3), distributions of limpets and anemones on manipulated cockles were signi\u00a2cantly di\u00a1erent compared with those observed on nonmanipulated cockles. Indeed, among cockles harbouring at least one invertebrate species, limpets were signi\u00a2cantly more frequent (\u00a2gure 1, Fisher exact test, p50.0001) and more abundant (\u00a2gure 2, Mann^Whitney U-test, Z 75.7, p50.0001) on manipulated cockles than on cockles with a Parasites and host community ecology F. Thomas and others 1093 Proc. R. Soc. Lond. B (1998) .0001). In the laboratory, limpets gently placed on the surface of anemones were rapidly ingested in all 11cases. In no more than 6 h, all the limpets were digested, with their shells expelled outside the anemones. After 96 h, 4 out of the 25 limpets initially placed in the aquarium were missing and we found their empty shells near four di\u00a1erent anemones. The desiccation test revealed that none of the 112 cockles exposed to the sun died during the experiment. However, mortality was observed for the other two invertebrate species as 28 anemones (50%) and six limpets (10.7%) out of 56 initially exposed were dead. These rates of mortality are signi\u00a2cantly di\u00a1erent (Fisher exact test, p50.0001) and thus indicate a lower resistance of anemones compared to limpets as regards desiccation.", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "The colonization test demonstrated that even in the absence of anemones, limpets colonize the shells of manipulated cockles signi\u00a2cantly more often than those of cockles with a normal behaviour. Indeed, whereas 43 manipulated cockles out of 76 harboured at least one limpet after three weeks, only two cockles with a normal behaviour out of 99 were colonized by limpets (Fisher's exact test, p50.0001).", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "Understanding the factors that govern the organization of intertidal communities has been the topic of numerous studies (Lewis 1960; Dayton 1971; Connell 1972; Menge 1976; Peterson 1979; Menge & Lubchenco 1981; Paine 1984; Menge & Farell 1989; Wilson 1991) . Physical gradients, spatial heterogeneity, competition, predation, disturbance and refuge are traditionally recognized as major factors in\u00a3uencing the structure of these communities. Although most of the organisms living in intertidal habitats are hosts for parasites (Laukner 1987; Sousa 1991; Thomas et al. 1997b) , ecologists in general have paid little attention to the possible in\u00a3uence of parasites in structuring intertidal communities.", "cite_spans": [{"start": 120, "end": 132, "text": "(Lewis 1960;", "ref_id": "BIBREF18"}, {"start": 133, "end": 145, "text": "Dayton 1971;", "ref_id": "BIBREF8"}, {"start": 146, "end": 159, "text": "Connell 1972;", "ref_id": "BIBREF6"}, {"start": 160, "end": 171, "text": "Menge 1976;", "ref_id": "BIBREF20"}, {"start": 172, "end": 186, "text": "Peterson 1979;", "ref_id": "BIBREF29"}, {"start": 187, "end": 210, "text": "Menge & Lubchenco 1981;", "ref_id": "BIBREF23"}, {"start": 211, "end": 222, "text": "Paine 1984;", "ref_id": "BIBREF27"}, {"start": 244, "end": 256, "text": "Wilson 1991)", "ref_id": "BIBREF40"}, {"start": 542, "end": 553, "text": "Sousa 1991;", "ref_id": "BIBREF34"}, {"start": 554, "end": 574, "text": "Thomas et al. 1997b)", "ref_id": "BIBREF38"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "Our study \u00a2rst gives support to the idea that A. stutchburyi is an important component of habitat structure in sheltered shores of New Zealand. Indeed, in our study sites, the shell of A. stutchburyi was obviously the main hard surface available for limpets and anemones. In addition to these species, we also observed in other localities cockles harbouring mussels, bryozoans, chitons, spionid worms and barnacles in areas without rocky surfaces (F. Thomas, F. Renaud and T. de Meeu\u00aa s, unpublished observations) . The large density of this cockle and the fact that it burrows only 1^2 cm are likely to be important factors explaining the key role of this mollusc for benthic invertebrate communities. Because the cockle A. stutchburyi is a direct provider, through its shell, of living space for numerous species, it can be considered as an autogenic physical engineer (sensu Jones et al. 1997) .", "cite_spans": [{"start": 878, "end": 896, "text": "Jones et al. 1997)", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "In all our samples, the distribution of limpets and anemones was consistent with a negative relationship between the abundance of these two invertebrates. Several phenomena could explain this relationship, for instance, competition for living space on the cockle shell. In addition, the physical presence of anemones on the shell is likely to directly limit the grazing surface of limpets. Our results also indicated that, at least in experimental conditions, predation of limpets by anemones is possible. This is probably due to the concentration of both anemones and limpets on the part of the shell closest to, or slightly emerging from, the surface of the mud. Further information is necessary to determine precisely the contribution of these di\u00a1erent phenomena to the observed pattern.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "The most striking pattern of distribution remains, however, the di\u00a1erential colonization rate of limpets and anemones on manipulated and non-manipulated cockles. Indeed, as opposed to anemones, limpets were more frequent and more abundant on cockles manipulated by C. australis than on cockles with a normal behaviour. This distribution is not a consequence of interactions between limpets and anemones, as the colonization test showed that limpets prefer manipulated cockles even when anemones are absent. Several advantages could be obtained by limpets from the colonization of manipulated hosts rather than from hosts with a normal behaviour. First, substrate location is probably easier on manipulated cockles than on cockles partly or completely buried (limpets do not burrow in the mud to \u00a2nd a substrate). Second, when anemones are present in the ecosystem, competition for living space and predation risk by anemones are likely to be reduced because of the lower abundance of anemones on manipulated cockles. The reason why anemones are less abundant on manipulated cockles might be their higher susceptibility to desiccation at low tide compared to limpets. Colonization could be, for instance, random during the recruitment period of anemones, but a di\u00a1eren-tial mortality through time between anemones living on manipulated cockles and those living on non-manipulated cockles would lead to the observed pattern. It is also possible that direct avoidance of manipulated cockles by anemones, rather than a di\u00a1erential mortality, explains the di\u00a1erential colonization observed in nature. This would be a possible illustration of the evolutionary importance of indirect e\u00a1ects in ecosystems (Miller & Travis 1996) . However, further experiments are needed to address this last point. Another interesting aspect is that cockles are larger at sites with a higher prevalence of parasites. It could be possible that reduction in foot growth caused by parasites allows an increased allocation of resources to shell growth. Given that there are also positive relationships between shell length and invertebrate abundance and intensity, this e\u00a1ect should be explored in more detail.", "cite_spans": [{"start": 1698, "end": 1720, "text": "(Miller & Travis 1996)", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "In any event, our results suggest that parasites that alter the phenotype of their host can have several indirect e\u00a1ects on the whole community. Using the terminology of Jones et al. (1994) , the parasite C. australis would be an allogenic engineer as it turns living material (i.e. its host) from one physical state (buried) into a second physical state (surface). This act of engineering alters both the availability and the quality of habitats for other species. Although limpets apparently bene\u00a2t from the new environment created, anemones experience less favourable conditions than on non-manipulated cockles. Further research is needed in order to understand the net e\u00a1ects of C. australis on the rich invertebrate community living on A. stutchburyi.", "cite_spans": [{"start": 170, "end": 189, "text": "Jones et al. (1994)", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "We are grateful to Josephine Pastor-Kaine for technical assistance during the experiments. This work was supported by Dr Luc Ho\u00a1mann (Station biologique de la tour du Valat), the embassy of France in New Zealand, the foundation Basler Stiftung fu\u00ab r Biologische Forschung (Switzerland), and the Re\u00a8seau Biodiversite\u00eb t Ecologie des Interactions Durables (CNRS, France).", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Host^parasite relationships and species diversity in mammals: a hypothesis", "authors": [{"first": "K", "middle": ["R"], "last": "Barbehenn", "suffix": ""}, {"first": "", "middle": [], "last": "29^35", "suffix": ""}, {"first": "M", "middle": ["D"], "last": "Bertness", "suffix": ""}, {"first": "C", "middle": [], "last": "Callaway", "suffix": ""}], "year": 1969, "venue": "Trends Ecol. 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Mean abundance ( AE s.e.) of limpets and anemones (a) on cockles with a normal behaviour and (b) on cockles manipulated by C. australis.", "type": "figure"}, "TABREF0": {"text": "Fisher exact test: limpets, p50.0001; anemones, p50.0001), abundance (table 1, Kruskal^Wallis ANOVA: limpets, H 14.3, d.f. 2, p50.0008; anemones, H 382.3, d.f. 2, p50.0001), and in intensity (table 1, Kruskal^Wallis ANOVA: limpets, H 11.1, d.f. 2, p50.004; anemones, H 49.7, d.f. 2, p50.0001).", "type": "table"}, "TABREF1": {"text": "Characteristics of the colonization by limpets and anemones on cockles in the three samples", "type": "table"}}}
{"paper_id": "84887362", "_pdf_hash": "4672bbc182d5d234426333974690fd323154cbf6", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
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{"paper_id": "84889749", "_pdf_hash": "2b23a33f93f2ecee8b51ddf296e4d5eecf439c29", "abstract": [{"section": "Abstract", "text": "Oral administration of carnosine (\u03b2-alanyl-L-histidine) in mice treated with restraint stress moderately alleviated a stress-induced decrease in plasma oxygen radical absorbance capacity (ORAC) activity (P = 0.075). Carnosine treatment also increased the level of plasma glutathione (GSH) and ascorbic acid compared with those in the restraint stress mice. Carnosine and related compounds anserine, histidine and histamine exhibited ORAC activity in vitro, while \u03b2-alanine was not effective. These results suggest that carnosine exerts a protective effect against the stress-induced elevation of the oxidative level in plasma.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Carnosine (\u03b2-alanyl-L-histidine) is mainly synthesized in the brain, muscles, and other innervated tissues (Zapp et al., 1938; William et al., 1962) . In recent years, numerous studies have shown that long-lived cells such as neurons and myocytes, which do not divide, contain high levels of carnosine (Hipkiss et al., 2002) . Even though the carnosine content in the brain is high, its function has not been clarified. Early studies indicated that carnosine levels were correlated with the maximum life span of members of an animal species (Hipkiss et al., 1995) . Carnosine levels decline with age, which may account for the normal age-related decline in tissues and function (Stuerenburg, 2000) . In addition, in the brain, which consumes a large amount of oxygen and glucose, high levels of carnosine may be needed to protect membrane lipids and metals against active oxygen species (Salim- Hanna et al., 1991) . Several authors reported that the brain membranes of carnosine-treated mice had significantly lower levels of malondialdehyde (MDA). Carnosine protects against MDA-induced damage (Hipkiss et al., 1997) , and several studies indicated that carnosine suppressed proteinsugar interactions leading to advanced glycosylation endproduct (AGE) formation (Hipkiss et al., 1998) .", "cite_spans": [{"start": 107, "end": 126, "text": "(Zapp et al., 1938;", "ref_id": "BIBREF47"}, {"start": 127, "end": 148, "text": "William et al., 1962)", "ref_id": "BIBREF42"}, {"start": 302, "end": 324, "text": "(Hipkiss et al., 2002)", "ref_id": "BIBREF19"}, {"start": 541, "end": 563, "text": "(Hipkiss et al., 1995)", "ref_id": "BIBREF16"}, {"start": 678, "end": 697, "text": "(Stuerenburg, 2000)", "ref_id": "BIBREF37"}, {"start": 895, "end": 914, "text": "Hanna et al., 1991)", "ref_id": "BIBREF34"}, {"start": 1096, "end": 1118, "text": "(Hipkiss et al., 1997)", "ref_id": "BIBREF17"}, {"start": 1264, "end": 1286, "text": "(Hipkiss et al., 1998)", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Introduction", "text": "Other studies have found that stress increases lipid peroxidation (Kurihara et al., 2002) , and decreases the amount of endogenous antioxidative substances (Kurihara et al., 2004) , including GSH (Sen et al., 1994) and vitamin E (Zhang et al., 2002) . Diminished antioxidant protection and induced oxidative stress may be correlated with life-style related diseases such as cancer (Dreher et al., 1996) , diabetes (Maritim et al., 2003) , atherosclerosis (Griendling et al., 2003) , and Alzheimer's (William et al., 1999) .", "cite_spans": [{"start": 66, "end": 89, "text": "(Kurihara et al., 2002)", "ref_id": "BIBREF24"}, {"start": 156, "end": 179, "text": "(Kurihara et al., 2004)", "ref_id": "BIBREF25"}, {"start": 196, "end": 214, "text": "(Sen et al., 1994)", "ref_id": "BIBREF35"}, {"start": 381, "end": 402, "text": "(Dreher et al., 1996)", "ref_id": "BIBREF7"}, {"start": 414, "end": 436, "text": "(Maritim et al., 2003)", "ref_id": "BIBREF28"}, {"start": 455, "end": 480, "text": "(Griendling et al., 2003)", "ref_id": "BIBREF12"}, {"start": 499, "end": 521, "text": "(William et al., 1999)", "ref_id": "BIBREF43"}], "ref_spans": []}, {"section": "Introduction", "text": "Nutritionists have sought to understand the body's oxidation processes and to prevent damage caused by active oxygen molecules (Mayne, 2003) . Several studies have indicated that certain antioxidants might have additional activities, such as quenching free radicals or suppressing the generation of free radicals by interrupting oxidation chain-reactions (Kerr et al., 1996) . Antioxidants that trap free radicals and lipid peroxides may delay the onset of lipid peroxidation, which inhibits further production of free radicals and suppresses damage induced by certain enzymes that can degrade connective tissues (Halliwell et al., 1995) .", "cite_spans": [{"start": 127, "end": 140, "text": "(Mayne, 2003)", "ref_id": "BIBREF29"}, {"start": 355, "end": 374, "text": "(Kerr et al., 1996)", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Introduction", "text": "The oxygen radical absorbance capacity (ORAC) is measured as the loss of fluorescence of disodium fluorescein induced by using 2,2'-azobis (2-amidinopropane) hydrochloride (AAPH) as a peroxyl radical generator (Ou et al., 2002) . In recent years, the ORAC assay has been used as a method for the antioxidant evaluation of plasma and other tissues, antioxidative foods and supplements (Cao et al., 1995; Prior et al., 2003) .", "cite_spans": [{"start": 210, "end": 227, "text": "(Ou et al., 2002)", "ref_id": "BIBREF31"}, {"start": 403, "end": 422, "text": "Prior et al., 2003)", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "Introduction", "text": "Early studies indicated that carnosine inhibited lipid oxidation and scavenged superoxide radicals (Gariballa et al., 2000; Decker et al., 2000) . However, these findings were obtained by in vitro experiments and the effective doses were rather high. Therefore, we evaluated the anti-stress effects of carnosine by examining plasma ORAC, GSH, and ascorbic acid levels in mice exposed to restraint stress. Restraint, which has an extensive history, has been widely used in investigations of animal physiology, pathology, and pharmacology (Par\u00e9 et al., 1986) . This type of stress promotes lipid peroxidation in liver tissue and decreases natural killer cell levels, which are susceptible to reactive oxygen species and lose their activity as a result of damage incurred by such oxygen species (Kurihara et al., 2002) .", "cite_spans": [{"start": 99, "end": 123, "text": "(Gariballa et al., 2000;", "ref_id": "BIBREF11"}, {"start": 124, "end": 144, "text": "Decker et al., 2000)", "ref_id": "BIBREF5"}, {"start": 537, "end": 556, "text": "(Par\u00e9 et al., 1986)", "ref_id": "BIBREF32"}, {"start": 792, "end": 815, "text": "(Kurihara et al., 2002)", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Materials and Methods", "text": "Chemicals and preparation L-carnosine, \u03b2-alanine, L-anserine, L-histidine, and histamine were purchased from Sigma Chemical (St. Louis, MO, USA), and ascorbic acid, disodium fluorescein, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox, a water-soluble \u03b1-tocopherol analogue as a control standard), and AAPH were purchased from Wako Pure Chemical Industries, Ltd. (Osaka, Japan). Ascorbic acid and fluorescein were dissolved directly in an acetone/water mixture (50:50, v/v) and diluted with 75 mM potassium phosphate buffer (pH 7.4) for analysis. Trolox, AAPH, carnosine, \u03b2-alanine, anserine, histidine, and histamine were dissolved in potassium phosphate buffer immediately before the ORAC assay.", "cite_spans": [], "ref_spans": []}, {"section": "Materials and Methods", "text": "To examine plasma antioxidant status, carnosine was dissolved in distilled water (20 mg/mL) before use, and the solution was administered orally to animals at 0.1 mL/10 g body weight (200 mg/kg=0.88 mmol/kg) at 24 h and 30 min before exposure to restraint stress. Ten animals in each group were sacrificed for the analysis of antioxidative capacity after restraint-stress.", "cite_spans": [], "ref_spans": []}, {"section": "Materials and Methods", "text": "Animals Seven-week-old male ICR mice were purchased from Charles River Japan Inc. (Tokyo, Japan). The animals were kept in a specific pathogen-free animal room at 23 \u00b1 1\u2103 with a 12 h light-dark cycle (lights on from 6:00 to 18:00) and were fed standard laboratory chow (CE-2; Clea Japan, Inc., Japan) and tap water. The animals were kept for 1 week before the experiment. For the restraint stress experiment, each mouse was confined to an oval metal restraint cage for 20 h before the assay. As the mice were not fed during the 20 h restraint period, another control group was created, in which mice were not given any food and water for 20 h without restraint stress (starved control). The care and treatment of the animals conformed to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH publication No. 85-23, revised 1985) and the Japanese Society of Nutrition and Food Science (Law No. 105 and Notification No. 6 of the Japanese government).", "cite_spans": [], "ref_spans": []}, {"section": "Materials and Methods", "text": "Assessment of ORAC levels in vivo and in vitro Under anesthesia with diethyl ether, blood samples were drawn from the heart after 20 h of stress treatment into a tube containing 2% sodium heparin. Each tube was centrifuged at 5,000 rpm for 5 min and the plasma was treated with 3% perchloric acid (PCA) adjusted from 60% PCA. The plasma was centrifuged at 15,000 rpm for 15 min at 4\u2103. Then, the supernatant was removed as the non-protein plasma fraction and diluted in phosphate buffer (pH 7.4) for ORAC analysis.", "cite_spans": [], "ref_spans": []}, {"section": "Materials and Methods", "text": "An automated ORAC assay was carried out using a Labsystems Fluoroskan Ascent plate reader (Helsinki, Finland) with fluorescent filters (excitation wavelength: 485 nm, emission filter: 527 nm) (Decker et al., 2000) . Fluorescein was used as a target for free radicals to attack and the reaction was initiated with AAPH. Trolox was used as a control standard. Final results were calculated based on the difference in the area under the fluorescein decay curve between the blank and each sample.", "cite_spans": [{"start": 192, "end": 213, "text": "(Decker et al., 2000)", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Materials and Methods", "text": "Plasma GSH and ascorbic acid levels The concentration of GSH in the plasma was determined by high-performance liquid chromatography (HPLC; column: SC-5 ODS (Eicom Co; 4.6 \u00d7 150 mm; i.d. 5 \u00b5m); mobile phase: 99% phosphate buffer (pH 2.5)-1% methanol including 100 mg/L SOS and 5 mg/L EDTA; flow rate: 0.5 mL/min) and an electrochemical detection system (ECD-300, Eicom Co) (Haramaki et al., 2001 ) operated at room temperature. The quantification of GSH was carried out using standard calibration curves. For plasma GSH analysis, blood samples were taken and treated the same as in ORAC analysis. The sample was subsequently stored at -80\u2103 before analysis. Each sample was filtered through a 0.45 \u00b5m membrane filter and 10 \u00b5l was subjected to HPLC to determine the GSH level.", "cite_spans": [{"start": 372, "end": 394, "text": "(Haramaki et al., 2001", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "Materials and Methods", "text": "Plasma ascorbic acid analysis was carried out using an automatic serum analyzer (model 7070, Hitachi Co., Ltd., Ja-pan) using the ascorbate oxidase method (Ihara et al., 2000) .", "cite_spans": [{"start": 155, "end": 175, "text": "(Ihara et al., 2000)", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Materials and Methods", "text": "Statistical evaluation Data are expressed as mean \u00b1 S.D. and evaluated by analysis of variance (ANOVA) using SPSS software (SPSS Inc Japan, Tokyo). Differences between the group means were considered to be significant at P < 0.05 using Tukey's procedure generated by this program.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "Effect of carnosine on plasma ORAC level Two hundred mg/kg of carnosine (0.88 mmol/kg) were administered orally twice, at 24 h and 30 min before exposure to stress, and the same volume of water was given to the stressed control animals. These experimental conditions were determined in preliminary experiments. The plasma ORAC value was calculated as the ratio of the area under the fluorescence decay curve for Trolox as a standard. The plasma ORAC level was 905.7 \u00b1 158.2 \u00b5M Trolox eq./L for the starved control, while the ORAC value observed after 20 h exposure to stress was significantly decreased (727.7 \u00b1 189.3 \u00b5M Trolox eq./L, P = 0.031) compared to the starved control (Fig. 1) . The average value for the ORAC of carnosine-treated stressed mice was 886.8 \u00b1 89.2 \u00b5M Trolox eq./L, and the total antioxidative capacity of the plasma increased by 21.9% compared with the stressed control (P = 0.075). Likewise, 0.44 mmol/ kg carnosine moderately improved the plasma ORAC level, but the difference was not statistically significant.", "cite_spans": [], "ref_spans": [{"start": 678, "end": 686, "text": "(Fig. 1)", "ref_id": "FIGREF0"}]}, {"section": "Effects of carnosine on GSH and ascorbic acid plasma levels", "text": "The plasma GSH concentration in the starved control was 2.98 \u00b1 0.26 nmol/mL, while that of the stressed control was 0.77 \u00b1 0.15 nmol/mL (Fig. 2) . Stress resulted in a substantial reduction in the plasma GSH concentration. When 0.88 mmol/kg of carnosine was given, the plasma GSH level increased (1.19 \u00b1 0.13 nmol/mL) as compared to the stressed control (P = 0.15). Carnosine (0.44 mmol/kg) moderately increased GSH levels compared to the stressed control (1.01 \u00b1 0.08 nmol/mL).", "cite_spans": [], "ref_spans": [{"start": 136, "end": 144, "text": "(Fig. 2)", "ref_id": "FIGREF1"}]}, {"section": "Effects of carnosine on GSH and ascorbic acid plasma levels", "text": "Likewise, stress also lowered the plasma ascorbic acid level (70.9 \u00b1 6.8 \u00b5mol/mL) compared to the starved control (92.8 \u00b1 11.6 \u00b5mol/mL), but the decrease in plasma ascorbic acid was smaller than that for the plasma GSH concentration. Compared to the stressed control, 0.88 and 0.44 mmol/kg of carnosine significantly increased plasma ascorbic acid levels (Fig. 3) . The mean values of ascorbic acid in the carnosine treated mice were 83.3 \u00b1 9.6 and 82.2 \u00b1 4.9 \u00b5mol/mL, respectively.", "cite_spans": [], "ref_spans": [{"start": 355, "end": 363, "text": "(Fig. 3)", "ref_id": "FIGREF2"}]}, {"section": "Effects of carnosine on GSH and ascorbic acid plasma levels", "text": "Radical scavenging activity of carnosine and its related compounds in vitro ORAC was determined using 10 \u00b5M of each sample, and the data is given in Table 1 . The antioxidative capacity of carnosine was rather weak. However, it is clear that the peptides carnosine and anserine have antioxidative activity. The antioxidative capacities of anserine, histidine and histamine were slightly greater than that of carnosine, while \u03b2-alanine did not exhibit antioxidative activity.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "The effects of restraint as a physiological stressor on the ORAC activity of plasma were examined in mice. Mice subjected to restraint for 20 h showed an approximately 24% decrease in plasma ORAC levels (Fig. 1) . The GSH and ascorbic acid contents in the plasma also decreased (Fig. 2  and 3 ). These results suggest that physiological stress plays a role in increasing oxidative stress. The administration of carnosine ameliorated the stress-induced decrease in plasma ORAC activity (P = 0.075) as shown in Fig. 1 . The ORAC activity in the plasma reflects the antioxidative capacity of water soluble low molecular weight antioxidants, such as GSH and ascorbic acid, present in the blood (Kurihara et al., 2004; Jiao et al., 2000) . The current findings show that carnosine attenuates oxidative stress by changing the oxidative status of plasma in mice subjected to stress, and improves antioxidative processes.", "cite_spans": [{"start": 690, "end": 713, "text": "(Kurihara et al., 2004;", "ref_id": "BIBREF25"}, {"start": 714, "end": 732, "text": "Jiao et al., 2000)", "ref_id": "BIBREF21"}], "ref_spans": [{"start": 203, "end": 211, "text": "(Fig. 1)", "ref_id": "FIGREF0"}, {"start": 278, "end": 292, "text": "(Fig. 2  and 3", "ref_id": "FIGREF1"}, {"start": 509, "end": 515, "text": "Fig. 1", "ref_id": "FIGREF0"}]}, {"section": "Discussion", "text": "GSH is the most well-known antioxidant found in tissues (Wu et al., 2004) . Recent studies have provided clear evidence that decreased liver blood flow induced by stress may attenuate GSH synthesis from circulatory sources via the \u03b3-glutamyl cycle (Deneke et al., 1989) and cause disturbances in GSH homeostasis, such as decreasing its plasma concentration, degrading its cellular redox status, and interfering with GSH transport (Leeuwenburgh et al., 1995) . As a result, GSH levels were drastically decreased by restraint stress. The administration of carnosine slightly increased the GSH level compared to the stressed control (P = 0.15). Carnosine may have a protective effect on GSH degradation during stress.", "cite_spans": [{"start": 248, "end": 269, "text": "(Deneke et al., 1989)", "ref_id": "BIBREF6"}, {"start": 430, "end": 457, "text": "(Leeuwenburgh et al., 1995)", "ref_id": "BIBREF27"}], "ref_spans": []}, {"section": "Discussion", "text": "Likewise, restraint stress also lowered the plasma ascorbic acid level compared to the starved control, but the difference was smaller than that for the GSH concentration. As mice are capable of synthesizing ascorbic acid, mouse tissues generally have higher levels of ascorbic acid, and were only slightly influenced in the stressed control as compared to the starved control. It was suggested that stress may induce the release of ascorbic acid stores into the plasma (Toutain et al., 1997) . The ingestion of carnosine in restrained mice increased plasma ascorbic acid levels compared to the stressed control (Fig. 3) , which was thought to suppress the oxidative degradation of plasma ascorbic acid.", "cite_spans": [{"start": 470, "end": 492, "text": "(Toutain et al., 1997)", "ref_id": "BIBREF40"}], "ref_spans": [{"start": 612, "end": 620, "text": "(Fig. 3)", "ref_id": "FIGREF2"}]}, {"section": "Discussion", "text": "Carnosine exhibited only a weak potential for scavenging free radicals generated by AAPH in vitro (Table 1) . However, it was shown that carnosine strongly quenches hypochlorite radicals (ClO\u2022) in vitro (Yanai et al., 2004) . This effect may be one of the antioxidative effects of carnosine.", "cite_spans": [{"start": 203, "end": 223, "text": "(Yanai et al., 2004)", "ref_id": "BIBREF46"}], "ref_spans": []}, {"section": "Discussion", "text": "Although the protective activities of carnosine against stress-induced plasma ORAC and the reduction of GSH and ascorbic acid levels in vivo are partly due to its antioxidative activity, it is possible these effects may be due to its antistress effects (Nagai et al., 2003) . Carnosine might exert direct or indirect anti-stress effects via histaminergic neural function in the brain. Carnosine is known to exhibit good oral-absorbability and increases serum levels of L-histidine and carnosine in the carotid artery and hepatic portal vein (Tamaki et al., 1985) . L-Histidine is converted to histamine by L-histidine decarboxylase, which affects histaminergic neuronal activation (Tanida et al., 2005) . As mentioned above, L-histidine exhibits radical scavenging activity in vitro. It is suggested that the observed modulation of plasma antioxidative capacity induced by restraint stress is due to both carnosine itself and L-histidine generated from carnosine by carnosinase.", "cite_spans": [{"start": 253, "end": 273, "text": "(Nagai et al., 2003)", "ref_id": "BIBREF30"}, {"start": 541, "end": 562, "text": "(Tamaki et al., 1985)", "ref_id": "BIBREF38"}, {"start": 681, "end": 702, "text": "(Tanida et al., 2005)", "ref_id": "BIBREF39"}], "ref_spans": []}, {"section": "Discussion", "text": "Usually, the generation and scavenging of oxygen free radicals is balanced in the human body. If there is an imbalance in the mechanism that regulates antioxidant enzymes, such as superoxide dismutase or catalase, excessive amounts of active oxygen radicals may be generated. Previous studies found that stress can cause free radical reactions (Esch et al., 2002) to produce deleterious modifications in membranes, proteins, enzymes, and DNA (Cooke et al., 2003) , which may be correlated with life-style related diseases such as cancer, diabetes, and atherosclerosis. Therefore, it is important to find effective scavengers of active oxygen radicals. Although carnosine is a weak antioxidant in vitro, it was found that this compound exhibited an anti-stress effect in maintaining plasma antioxidative capacity, as indicated by the ORAC assay and GSH and ascorbic acid levels in plasma. Even though the mechanism is still unknown, our results have encouraged us to investigate the pharmacology of carnosine under physiological oxidative conditions, the h. kurihara et al. Trolox was used as a control standard. The data were calculated from a calibration curve determined using three concentrations and was conducted in triplicate. Table 1 . Radical scavenging activity of carnosine and its related compounds at 10 \u00b5M in vitro.", "cite_spans": [], "ref_spans": []}, {"section": "ORAC (\u00b5M", "text": "examination of which is worthy for its potential benefits to life-style-related diseases and general health.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF1": {"title": "Automated assay of oxygen radical absorbance capacity with the COBAS FARA II", "authors": [], "year": "", "venue": "Clin. 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The distribution of carnosine and anserine in various muscles of different species", "authors": [{"first": "J", "middle": ["A"], "last": "Zapp", "suffix": ""}, {"first": "D", "middle": ["W"], "last": "Wilson", "suffix": ""}], "year": 1938, "venue": "", "link": "85826428"}, "BIBREF50": {"title": "Side-stream cigarette smoke induces dose-response in systemic inflammatory cytokine production and oxidative stress", "authors": [], "year": "", "venue": "Exp. Biol. Med", "link": "21324898"}}, "ref_entries": {"FIGREF0": {"text": "Fig. 1. Effect of carnosine on the plasma level of ORAC. The ORAC value is calculated by dividing the area under the sample curve by the area under the Trolox curve, with both areas being corrected by subtracting the area under the blank curve. One ORAC unit is assigned as the net area of protection provided by Trolox at a final concentration of 1 \u00b5M. The area under the curve for the sample is compared to the area under the curve for Trolox, and the antioxidative value is expressed in micromoles of Trolox equivalents per liter. The data are represented as mean \u00b1 S.D. of values obtained from 10 animals in each group. The different letters indicate over 90% reliability among the groups as determined by Tukey's procedure (P < 0.1).", "type": "figure"}, "FIGREF1": {"text": "Fig. 2. Effect of carnosine on the plasma level of GSH. Total GSH concentration was determined by HPLC as described in Materials and Methods. The data are represented as mean \u00b1 S.D. of values obtained from 10 animals in each group. The different letters indicate significant differences among the groups as determined by Tukey's procedure (P < 0.05).", "type": "figure"}, "FIGREF2": {"text": "Fig. 3. Effect of carnosine on the plasma level of ascorbic acid. Plasma ascorbic acid was measured by the ascorbate oxidase method. The data are represented as mean \u00b1 S.D. of values obtained from 10 animals in each group. The different letters indicate significant differences among the groups as determined by Tukey's procedure (P < 0.05).", "type": "figure"}}}
{"paper_id": "123620784", "_pdf_hash": "c875ed628c9fe4d15d771610ce17ce3d4568189e", "abstract": [], "body_text": [{"section": "", "text": "[DOWNLOAD] Application Of The Frequency Response Method For Studying The Dynamical Properties O The edreversersecret.com is your search engine for PDF files. Platform is a high quality resource for free eBooks books.It is known to be world's largest free Books site. Best sites for books in any format enjoy it and don't forget to bookmark and share the love!Download in PDF, and you can also check out ratings and reviews from other users.This library catalog is an open online project of many sites, and allows users to contribute books. No registration or fee is required, and books are available in ePub, Kindle, HTML and simple text formats. ", "cite_spans": [], "ref_spans": []}], "bib_entries": {}, "ref_entries": {"FIGREF0": {"text": "DOWNLOAD] Application Of The Frequency Response Method For Studying The Dynamical Properties Of The Combustion Zone [Reading Free] at EDREVERSERSECRET.COM Free Books Download Application Of The Frequency Response Method For Studying The Dynamical Properties Of The Combustion Zone Free Sign Up EDREVERSERSECRET.COM Any Format, because we could get too much info online through the resources. Crucible of gold the temeraire series book 7 The forest adventure division Maria or the wrongs of woman Posthumous works of the author of a vindication of the rights of woman Valperga or the life and adventures of castruccio prince of lucca Back to Top APPLICATION OF THE FREQUENCY RESPONSE METHOD FOR STUDYING THE DYNAMICAL PROPERTIES OF THE COMBUSTION ZONE Page 1/1", "type": "figure"}}}
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{"paper_id": "123621603", "_pdf_hash": "ae55ce6c39f154945f44a46d8cbb0a39beef896d", "abstract": [{"section": "Abstract", "text": "A simple growth condition is found for the Fourier coefficients of continuous 1-periodic functions of bounded fc-entropy norm. This growth condition is equivalent to the condition given by Dabrowski. The entropy norms of certain random Fourier series are considered.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "The growth condition", "text": "Let k : [0, 1] -\u25ba [0, 1] be nondecreasing, concave, with k(0+) = 0, k(l) = 1, and k'(0) = lim^Q k(x)/x = oo . We define the entropy norm based on k as in Korenblum [7] , and let Ck be the space of continuous 1-periodic functions of finite entropy norm. Let p G PM(0, 1] be the probability measure associated with k as in Dabrowski [4] , so that k(x) = -dp(u)dt. for any interval /. Let h(x) = (cosx -I + x /2)/x for x > 0. Let \u00dfn = f(0 xx2nnh(2nnx)dp(x).", "cite_spans": [{"start": 164, "end": 167, "text": "[7]", "ref_id": "BIBREF7"}, {"start": 331, "end": 334, "text": "[4]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "The growth condition", "text": "In Dabrowski [2] (and [3] ), the theorem is given: If f G Ck then Sn^o \\an\u00dfJn\\ < \u00b0\u00b0 wnere / ~ Y^anen ls tne Fourier series of / (and en(t) = e nm for n G Z). Our goal is to simplify this result. We will estimate \u00dfn .", "cite_spans": [{"start": 13, "end": 16, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 22, "end": 25, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "The growth condition", "text": "Let \u25a0 x, 0 < x < 2n -i S(x) = \\ 4n2 and an = / 2nng(2nnx)dp(x). -.", "cite_spans": [], "ref_spans": []}, {"section": "The growth condition", "text": "x>2n Jo x > 2n x We will show that a\" = Stc", "cite_spans": [], "ref_spans": []}, {"section": "The growth condition", "text": "We will also show nk(l/n)-n\u00bf\u00a1[0 x/n]k(t)dt\\ that there are cx, c2 > 0 such that cxan < \u00df\" < c2an for all n . Thus our main result will be:", "cite_spans": [], "ref_spans": []}, {"section": "The growth condition", "text": "For certain k, we may produce a simpler result: cxnk(l/n) < \u00dfn < c2nk(l/n). For such k, if f G Ck then J2n.\u00bf0 \\ank(l/n)\\ < oo where f ~V\\ ae\".", "cite_spans": [], "ref_spans": []}, {"section": "The growth condition", "text": "We give examples before proving Theorem 1.1. The Shannon entropy function k(x) = x(l -log*) and the Lipschitz entropy function k(x) = xq with 0 < q < 1 do not go to zero slowly. So Theorem 1.3 will hold for these functions. (This agrees with calculations of Dabrowski [2] .)", "cite_spans": [{"start": 268, "end": 271, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "The growth condition", "text": "The Dini entropy is defined by k(x) = 1/(1 -logx). We find that", "cite_spans": [], "ref_spans": []}, {"section": "The growth condition", "text": "using L'H\u00f4pital's rule. So this k goes to 0 slowly. We now turn to the proof of Theorem 1.1. We need two lemmas.", "cite_spans": [], "ref_spans": []}, {"section": "The growth condition", "text": "Proof. We adapt Theorem A of Hewitt [5] which states:", "cite_spans": [{"start": 36, "end": 39, "text": "[5]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "The growth condition", "text": "where p, v e M [a, b] are positive and", "cite_spans": [], "ref_spans": []}, {"section": "The growth condition", "text": "Here we let dp", "cite_spans": [], "ref_spans": []}, {"section": "The growth condition", "text": "Note we may replace", "cite_spans": [], "ref_spans": []}, {"section": "The growth condition", "text": "There is cx, c2> 0 such that 0 < cxg(x) < h(x) < c2g(x) for all x > 0, where h and g are as defined above (see before Theorem 1.1).", "cite_spans": [], "ref_spans": []}, {"section": "The growth condition", "text": "Proof. Note h(x) = (cosx -l)/x + l/2x so for large x, h(x) is close to l/2x . Using L'H\u00f4pital's rule, it may be shown that h(x) is close to x/24 for small x.", "cite_spans": [], "ref_spans": []}, {"section": "The growth condition", "text": "We may also show that h(x) > 0 for x > 0. (This follows from sint < t upon integration from t = 0 to t = x.)", "cite_spans": [], "ref_spans": []}, {"section": "The growth condition", "text": "Now we show that h(x) < l/2x for x > 0. This follows from cosx < 1, 2 2 so cosx -1 + x /2<x \u00a12, and", "cite_spans": [], "ref_spans": []}, {"section": "The growth condition", "text": "For x > 0 we now show that h(x) < x\u00a124. This follows from Taylor's series with remainder:", "cite_spans": [], "ref_spans": []}, {"section": "The growth condition", "text": "COSX -1 + -r-< (cose)24 -24 for some 0 < c < x. So ,. , x4/24 + cosx-1 + x2/2 -JC4/24 x cosx -1 + x2/2 -x4/24", "cite_spans": [], "ref_spans": []}, {"section": "The growth condition", "text": "It is now evident that c2 = 1/24 works (note l/2x < 4^ /24x ). Since h(x) x /24 for small x and /z(x) ~ l/2x for large x, it is possible to find c > 0 and an interval [e, N] with 0 < e < N < oo such that cg(x) < h(x) for positive x not in the interval. Now h(x) > 0 over [e, A], so A is bounded away from 0 over that interval. So it is possible to find cx > 0 such that cx< c and cxg(x) < h(x) on that interval. So this c, works. (A machine plot of the graph of this function suggests that cx < l/24n should work.) D Now we may prove Theorem 1.1. By Lemma 1.5, we may compare \u00dfn to an. (We know that 0 < cxan < \u00dfn < c^a\" for all n .) Now 2 n ' an= 2nng(2nnt)dp(t) + I 2nng(2nnt)dp(t)", "cite_spans": [], "ref_spans": []}, {"section": "The growth condition", "text": "[ -dp(t).", "cite_spans": [], "ref_spans": []}, {"section": "The growth condition", "text": "We compute the following integral in two different ways:", "cite_spans": [], "ref_spans": []}, {"section": "The growth condition", "text": "\u2022l/n rl j 2 2 f ' f 1 Sn n t -dp(u)dt, Jo Jt u using integration by parts, and using Fubini's theorem. First, we integrate by parts. We wish to apply Lemma 1.4 with g(t) = t and dv(t) = \u00a1t l/udp(u)dt.", "cite_spans": [], "ref_spans": []}, {"section": "The growth condition", "text": "However, v is not a finite measure: i^([0, 1]) = oo since v([t, 1]) = \u00a1t l/udp(u) = k'(t). So we let 0 < e < l/n and compute: 2 2 fX/\" fX 1 8n n t -dp(u)dt Je Jt u", "cite_spans": [], "ref_spans": []}, {"section": "The growth condition", "text": "We then let e decrease to 0. We have \u25a0l/n rt , lim / / -dp(u)dt :-\u00bb0+/\u00a3 Jo \" lim /\u2022l/n rt , ,8 ,1 j / / -dp(u)dt-/ / -dp(u)dt lim / / / -dp(v)dudt= lim / (k(t) -k(e)) dt = / fc(r)\u00ed/\u00ed. Snn t -dp(u)dt = Sn nk(l/n)-Sn n k(t)dt. Jo Jt u Jo ow we use Fubini's theorem. We have 2 2 fx/\" fx 1 8n n t -dp(u)dt Jo Jt u = Sn2n2 f If \" tdt)-dp(u) + Sn2n2 ['\"([\" tdt)-dp(u) l\"u2l o 2 2 r i i. ,., 0 2 2 r/B tT 1 , , = \u00d67T \u00ab / -=-dp(u) + Sn n I --dp(u Ji/n 2n2u J0 2 u 2 fX 1 2 2 (X,n = 4n / -dp(u) + 4nn \\ udp(u) Jl/n u Jo This function satisfies the conclusion of Corollary 1.6 for the Shannon entropy norm (i.e., Y^=x(\\o%n)/n2 < oo ), but since it is not bounded, it cannot have bounded entropy norm.", "cite_spans": [], "ref_spans": []}, {"section": "The entropy of certain random Fourier series", "text": "We may shed more light on the growth condition by considering certain random Fourier series, whose expected entropy norm is not difficult to estimate.", "cite_spans": [], "ref_spans": []}, {"section": "The entropy of certain random Fourier series", "text": "We let f(t) = E^li(l/\"PK\" cos(2\u00e4\u00ab/) , p > 0, where {\u00a3\"}~ , is a sequence of independent identically distributed subgaussian symmetric random variables on some probability space (fl, F, P). (By subgaussian, we mean a random variable X such that Eexx < exp \\-\\rX2 J for some t > 0 and all real X. Here as usual E Y = JQY dP . Subgaussian X include Rademacher random variables, where P({X = -1}) = P({X = 1}) = j , or Gaussian random variables X of mean m and variance a , so that /-oo o\\l2n L\\ a )", "cite_spans": [], "ref_spans": []}, {"section": "The entropy of certain random Fourier series", "text": "du.", "cite_spans": [], "ref_spans": []}, {"section": "The entropy of certain random Fourier series", "text": "Then we have the following theorem: Proof. (1) and (4) follow by Kolmogorov's Three Series Theorem (see for example [1] ).", "cite_spans": [{"start": 116, "end": 119, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "The entropy of certain random Fourier series", "text": "For (2) we apply Theorem 1 of chapter 7 of Kahane [6] , which implies that / is continuous almost surely when {s\u00a1}f=x is a decreasing sequence and E^Li sj < oo, where si We estimate:", "cite_spans": [{"start": 50, "end": 53, "text": "[6]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "The entropy of certain random Fourier series", "text": "Idx) =c2-^-1/2) x2p J for a certain constant c > 0. Now J2%\\ s\u00a1 w CY,\u00b0\u00a1L\\ 2~ ' converges exactly when p > j . (That this is necessary for almost sure essential boundedness of / follows from Theorem 1 of Chapter 8 of Kahane [6] . Note that condition (4) p. 93 of [6] is needed; this condition follows since / is a random Fourier series whose coefficients are subgaussian.)", "cite_spans": [{"start": 223, "end": 226, "text": "[6]", "ref_id": "BIBREF6"}, {"start": 262, "end": 265, "text": "[6]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "The entropy of certain random Fourier series", "text": "For (3), we estimate EH/I^ where k is the Shannon entropy, using Theorem 2 of Chapter 7 of Kahane [6] . That theorem states that if s. = 0(2~\u00dfi) for some for some c > 0. This last integral converges exactly when \u00df > 0. For /, we know that s} \u00ab 2~j{p~x/2). Thus E||/||fc < oo when p > \\. (Actually, this holds for only 0 < \u00df < 1 by our calculation, or \\ < p < \\. We may show that E \\\\f\\\\k < oo for p > \\ using other parts of the same theorem used in this calculation.)", "cite_spans": [{"start": 98, "end": 101, "text": "[6]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "The entropy of certain random Fourier series", "text": "Finally, we may show (5) in a manner similar to (3). D", "cite_spans": [], "ref_spans": []}, {"section": "The entropy of certain random Fourier series", "text": "As an example, consider X^=i cos2nnt/n . We noted earlier (after Corollary 1.6 ) that this does not have bounded Shannon entropy norm. But the random series J^T=i \u00b1 cos 2ft\u00ab?/\u00ab (i.e., a Rademacher series) will have bounded entropy norm almost surely. The theorem suggests a gap between the growth condition, and typical series of bounded entropy norm. For example, compare parts (1) and (3). By (2), the condition p > | is necessary in part (3). (However, in part (5) it is unclear to the present author if l-q<p<\\-q results in / \u00a3 Ck almost surely.) The author hopes that these calculations may be generalized to random Fourier series of the form (for example) oo \u00a3<:\"\u00a3\" cos 2tt\u00ab n=l where the \u00c7n are as before and the cn are arbitrary real numbers, and also for other choices of entropy norm.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Probability theory: independence, interchangeability, martingales", "authors": [{"first": "Y", "middle": [], "last": "Chow", "suffix": ""}, {"first": "H", "middle": [], "last": "Teicher", "suffix": ""}], "year": 1978, "venue": "", "link": "120741536"}, "BIBREF1": {"title": "On Fourier coefficients of a continuous periodic function of bounded entropy norm", "authors": [{"first": "R", "middle": [], "last": "Dabrowski", "suffix": ""}], "year": 1988, "venue": "Bull. Amer. Math. Soc. (N. S.)", "link": "122731140"}, "BIBREF2": {"title": "On a natural connection between the entropy spaces and Hardy space ReH", "authors": [], "year": "", "venue": "", "link": "122908004"}, "BIBREF4": {"title": "Probability measure representation of norms associated with the notion of entropy", "authors": [{"first": "_", "middle": [], "last": "", "suffix": ""}], "year": 1984, "venue": "Proc. Amer. Math. Soc", "link": "122067618"}, "BIBREF5": {"title": "Integration by parts for Stieltjes integrals", "authors": [{"first": "E", "middle": [], "last": "Hewitt", "suffix": ""}], "year": 1960, "venue": "Amer. Math. Monthly", "link": "124895518"}, "BIBREF6": {"title": "Some random series of functions", "authors": [{"first": "J.-P", "middle": [], "last": "Kahane", "suffix": ""}], "year": 1985, "venue": "Cambridge Studies in Advanced Mathematics", "link": "117822487"}, "BIBREF7": {"title": "On a class of Banach spaces associated with the notion of entropy", "authors": [{"first": "B", "middle": [], "last": "Korenblum", "suffix": ""}], "year": "", "venue": "", "link": null}}, "ref_entries": {"FIGREF3": {"text": "Sn nk(l/n)-Sn2n k(t)dt Jo and Theorem 1.1 now follows. D License or copyright restrictions may apply to redistribution; see https://www.ams.org/journal-terms-This follows from Dabrowski's result [2] by the comparison test for con- vergence of series. G Note that this result is equivalent to Dabrowski's result in the following sense: if Y^b\" is any series, then J2nj\u00bfo \\b\"\u00dfnln\\ < oo if and only if J2\\bn\\(k(l/n)-n\u00a3/nk(t)dt (This is Theorem 1.1 and the comparison test.) Also note that the converse of Corollary 1.", "type": "figure"}, "FIGREF4": {"text": "'s growth condition for Shannon entropy almost surely. (See the corollary to Theorem 3 in [2].) (2) If p > j, then f is continuous almost surely. If p <\\, then f \u00a3 L\u00b0\u00b0a lmost surely. (3) If p > \\, then f has bounded Shannon entropy norm almost surely.", "type": "figure"}, "TABREF0": {"text": "Theorem 1.3. If k does not go to zero slowly, then there are c,, c2 > 0 such that", "type": "table"}}}
{"paper_id": "123621800", "_pdf_hash": "bd163e44ed793460b4d66dac9f970efa88e79a4e", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "ISOCAM, a camera for the Infrared Space Observatory", "authors": [{"first": "C", "middle": [], "last": "Cesarsky", "suffix": ""}, {"first": "F", "middle": [], "last": "Sibille", "suffix": ""}, {"first": "L", "middle": [], "last": "Vigroux", "suffix": ""}], "year": 1989, "venue": "SPIE New technologies for astronomy", "link": "122830269"}, "BIBREF1": {"title": "Development of an infrared detector array for ISOCAM", "authors": [{"first": "C", "middle": [], "last": "Lucas", "suffix": ""}, {"first": "P", "middle": [], "last": "Maillart", "suffix": ""}, {"first": "P", "middle": [], "last": "Mottler", "suffix": ""}, {"first": "P", "middle": [], "last": "Pantigny", "suffix": ""}, {"first": "M", "middle": [], "last": "Vilain", "suffix": ""}], "year": 1987, "venue": "SPIE", "link": null}, "BIBREF2": {"title": "The random access memory concept applied to the infrared focal plane", "authors": [{"first": "L", "middle": [], "last": "Audaire", "suffix": ""}], "year": 1987, "venue": "SPIE", "link": "109340296"}, "BIBREF3": {"title": "The ISOCAM camera long wavelength channel detector", "authors": [{"first": "P", "middle": [], "last": "Agnese", "suffix": ""}, {"first": "C", "middle": [], "last": "Lucas", "suffix": ""}, {"first": "P", "middle": [], "last": "Maillart", "suffix": ""}, {"first": "P", "middle": [], "last": "Mottler", "suffix": ""}, {"first": "Y", "middle": [], "last": "Lepennec", "suffix": ""}, {"first": "P", "middle": [], "last": "Masse", "suffix": ""}], "year": 1989, "venue": "", "link": "121768825"}}, "ref_entries": {}}
{"paper_id": "123624912", "_pdf_hash": "a8dd45a9ffb65b29fbeb05743c3e540219dcfd3f", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Primary Reference Cell Calibrations at SERI: History and Methods", "authors": [{"first": "C", "middle": ["R"], "last": "Osterwald", "suffix": ""}, {"first": "K", "middle": ["A"], "last": "Emery", "suffix": ""}, {"first": "D", "middle": ["R"], "last": "Myers", "suffix": ""}, {"first": "R", "middle": ["E"], "last": "Hart", "suffix": ""}], "year": 1990, "venue": "Proc. 2 1 st IEEE Photovoltaik Specialists Conf", "link": "122027880"}, "BIBREF1": {"title": "Primary Reference Cell Calibrations at SEN: History and Methodes", "authors": [{"first": "C", "middle": ["R"], "last": "Osterwald", "suffix": ""}, {"first": "K", "middle": ["A"], "last": "Emery", "suffix": ""}, {"first": "D", "middle": ["R"], "last": "Myers", "suffix": ""}, {"first": "R", "middle": ["E"], "last": "Hart", "suffix": ""}], "year": "", "venue": "Proc. 2 1 st IEEE Photovoltaic Specialists Conf", "link": null}, "BIBREF2": {"title": "Extending the Spectral Range of Silicon-Based Direct-Beam Solar Spectral Radiometric Measurements", "authors": [{"first": "C", "middle": ["R"], "last": "Osterwald", "suffix": ""}, {"first": "K", "middle": ["A"], "last": "Emery", "suffix": ""}, {"first": "D", "middle": ["R"], "last": "Myers", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "Riordan", "suffix": ""}], "year": "", "venue": "", "link": "119692086"}, "BIBREF3": {"title": "Proc. 20th IEEE Photovoltaic Specialists Conf., Las Vegas", "authors": [], "year": 1988, "venue": "", "link": null}, "BIBREF4": {"title": "SandialNIST Feference Cell Calibration Procedure", "authors": [{"first": "D", "middle": ["L"], "last": "King", "suffix": ""}, {"first": "B", "middle": ["R"], "last": "Hansen", "suffix": ""}, {"first": "J", "middle": ["K"], "last": "Jackson", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF5": {"title": "Spectral Irradiance Calibrations", "authors": [{"first": "J", "middle": ["H R D"], "last": "Walker", "suffix": ""}, {"first": "J", "middle": ["K"], "last": "Saunders", "suffix": ""}, {"first": "D", "middle": ["A"], "last": "Jackson", "suffix": ""}, {"first": "", "middle": [], "last": "Mcsparron", "suffix": ""}], "year": 1989, "venue": "NBS Special Publication", "link": "125328890"}, "BIBREF7": {"title": "SERI Results from the PEP 1987 Summit Round Robin and a Comparison of Photovoltaic Calibration Methods", "authors": [{"first": "K", "middle": ["A"], "last": "Emery", "suffix": ""}, {"first": "D", "middle": [], "last": "Waddington", "suffix": ""}, {"first": "S", "middle": [], "last": "Rummel", "suffix": ""}, {"first": "D", "middle": ["R"], "last": "Myers", "suffix": ""}, {"first": "T", "middle": ["L"], "last": "Stoffel", "suffix": ""}, {"first": "C", "middle": ["R"], "last": "Sterwald", "suffix": ""}], "year": 1989, "venue": "", "link": "107568612"}, "BIBREF8": {"title": "Estimates of Uncertainty for Measured Spectra in the SERI Spectral Solar Radiation Data Base", "authors": [{"first": "A", "middle": [], "last": "Schonecker", "suffix": ""}, {"first": "K", "middle": [], "last": "Schitterer", "suffix": ""}, {"first": "K", "middle": [], "last": "Bucher", "suffix": ""}, {"first": "K", "middle": [], "last": "Heidler ; This Conference", "suffix": ""}, {"first": "D", "middle": ["L"], "last": "Myers", "suffix": ""}], "year": 1989, "venue": "Solar Energy", "link": "121224175"}, "BIBREF9": {"title": "A Sensitivity Analysis of the Spectral Mismatch Correction Procedure Using WavelengthDependent Error Sources", "authors": [{"first": "B", "middle": ["R"], "last": "Hansen", "suffix": ""}], "year": 1991, "venue": "Proc. 22nd IEEE Photovoltaic Specialists Conf", "link": null}, "BIBREF10": {"title": "PTB Standard Lamp SL-43, calibration document 12.S. Nann, Final report subtask C of IEA Task 17", "authors": [], "year": "", "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "123625041", "_pdf_hash": "6a8b65adaa419e2dcfdddb2851e6b9825755613d", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "123625244", "_pdf_hash": "8ecbc15ee4b22e73ab33754bc16a0d5a8d7e2fb0", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "123625282", "_pdf_hash": "1d6920dc6293cc19ce1909b6536fff50960e40fc", "abstract": [{"section": "Abstract", "text": "Recently A. V. Goldberg and R. E. TaIjan have proposed a negative cycle method for fmding miniJIlum-cost flows by selecting negative cycles of minimum-mean length and have shown that the complexity of their method is strongly polynomial. In the present paper we examine whether Goldberg and TaIjan's approach to ordinary minimum-east flows can be applied to submodular flows. We prove two key theorems, which are significant in their own right, and show that the negative cycle methods for submodular flows of S. Fujishige and U.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Zimmermann which may not terminate in fmitely many steps can be made terminate by selecting negative cycles of minimum-mean l'mgth of certain special type.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Recently A. V. Goldberg and R. E. Tarjan [7] have proposed a negative cycle method for finding minimum-cost flows by selecting negative cycles of minimum-mean length, and have shown that the complexity of their method is strongly polynomial. Goldberg and Tarjan's method is a version of Klein's negative cycle method [ID] which restricts the choice of negative cycles to those of minimum-mean length.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Klein's negative cycle method is generalized to the independent flow problem by S.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Fujishige [2] and to the submodular flow problem by U. Zimmermann [14] . However, their algorithms may not terminate in finitely many steps. The equivalence between the independent flow problem and the submodular flow problem is shown in [3] .", "cite_spans": [{"start": 10, "end": 13, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Introduction", "text": "In the present paper we shall examine whether Goldberg and Tarjan's approach to ordinary minimum-cost flows can be applied to independent flows and submodular flows. We shall prove two key theorems in Section 3, which are significant in their own right, and show that the negative cycle methods of Fujishige and Zimmermann can be made terminate by selecting negative cycles of minimum-mean length of certain special type.", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and Preliminaries", "text": "Since the independent flow problem and the submodular flow problem are equivalent and the description of the submodular flow problem is simpler, we shall consider the submodular flow problem alone.", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and Preliminaries", "text": "Let G = (V, A) be a directed graph with a vertex set V and an arc set A. For each arc a E A, a+ a and a-a denote the initial and the terminal end-vertex of a, respectively.", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and Preliminaries", "text": "Let 0 be a set of subsets of V such that for any X, Y E 0 we have X U Y, X rl Y E O.", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and Preliminaries", "text": "We call 0 a distributive lattice on V. A function 1 from 0 to the set R of reals is called a submodular function on the distributive lattice 0 if for each X, Y E 0 we have (2.1) ", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and Preliminaries", "text": "where for each X EO x(X) = E\"EX x(e). We call B C RV the base polyhedron associated where cp : A -+ R is a flow and acp : V -+ R is the boundary of the flow cp defined by (2.5) ", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and Preliminaries", "text": "Here, for any u E V X .. is a unit vector in RV such that (2. (2.8) c (b,u,v) ", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and Preliminaries", "text": "where if b+d(X .. -Xv) E B for all d 2: 0, then we define c (b,u,v) = +00. We call c (b,u,v) the exchange capacity from u to v associated with b (see [2] ). We can easily show that c (b,u,v) =I 0 if and only if v E dep (b,u) . For bE B we define (2.9) ", "cite_spans": [{"start": 150, "end": 153, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Definitions and Preliminaries", "text": "Here, a = (a-a,a+a) is the reorientation of a and we use this notation in the following. ", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and Preliminaries", "text": "is called the auxiliary network associated with cp.", "cite_spans": [], "ref_spans": []}, {"section": "Definitions and Preliminaries", "text": "In network NII' the capacity of a cycle is the minimum of the capacities of its arcs, where a cycle is a directed closed path. The cost of a cycle Q is the sum of the costs of its arcs, denoted by \"III'(Q), relative to cost function \"Ill' and a negative cycle is a eycle of negative cost. The following theorem characterizes optimal submodular flows. The following lemma will be used in the next section. Lemma 2.1 [2] . Suppose b E B and let u., v.", "cite_spans": [{"start": 415, "end": 418, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Definitions and Preliminaries", "text": "Then, we have b* E B.", "cite_spans": [], "ref_spans": []}, {"section": "Minimum-mean Cycles in the Auxiliary Network o", "text": "Based on Theorem 2.1 and Lemma 2.1 in the preceding section, the following primal algorithm for the independent flow problem was proposed by Fujishige [2] . We rewrite it for the submodular flow problem (cf. also [14] ", "cite_spans": [{"start": 151, "end": 154, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Minimum-mean Cycles in the Auxiliary Network o", "text": "where d is the capacity of the cycle Q.", "cite_spans": [], "ref_spans": []}, {"section": "Minimum-mean Cycles in the Auxiliary Network o", "text": "Because we select negative cycles of the fewest arcs, the successively obtained flows cp are submodular flows in N and have smaller costs than the previous ones. However, this algorithm may not find an optimal submodular flow in a finite number of steps (see [2] , [14] ).", "cite_spans": [{"start": 259, "end": 262, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Minimum-mean Cycles in the Auxiliary Network o", "text": "Adopting Goldberg and Tarjan's approach [7] , we give a new cycle selection rule for submodular flows which guarantees that the primal algorithm (PA) always finds an optimal submodular flow in a finite number of steps. We need a few further definitions to describe the cycle selection rule.", "cite_spans": [], "ref_spans": []}, {"section": "Copyright \u00a9 by ORSJ. Unauthorized reproduction of this article is prohibited.", "text": "The mean cost of a cycle in a directed graph with arc costs is its cost divided by the number of arcs it contains. A minimum-mean cycle is a cycle whose mean cost is as small as possible. The minimum cycle mean is the mean cost of a minimum-mean cycle.", "cite_spans": [], "ref_spans": []}, {"section": "Copyright \u00a9 by ORSJ. Unauthorized reproduction of this article is prohibited.", "text": "A cycle q in Nv> is a feasible cycle if after changing flow cp along it by (:u) the resultant flow is also submodular flow in N.", "cite_spans": [], "ref_spans": []}, {"section": "Copyright \u00a9 by ORSJ. Unauthorized reproduction of this article is prohibited.", "text": "Suppose we are given a one-to-one mapping 11\" : V -t {I, 2, ... , IV I} and let (3. 2) qv>(1J) = min{1I\"(w) I arc (v,w) lies on a minimum-mean cycle in Nv>}.", "cite_spans": [{"start": 84, "end": 86, "text": "2)", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Copyright \u00a9 by ORSJ. Unauthorized reproduction of this article is prohibited.", "text": "If there is no minimum-mean cycle containing v in Nv>, define qv>(v) = IVI + 1. Then, our cycle selection rule can be described as follows:", "cite_spans": [], "ref_spans": []}, {"section": "Copyright \u00a9 by ORSJ. Unauthorized reproduction of this article is prohibited.", "text": "(*) Select a minimum-mean cycle Q in Nv> such that for each arc a on Q we have", "cite_spans": [], "ref_spans": []}, {"section": "qv>(a+a) =1I\"(a-a)", "text": "Such a minimum-mean cycle can be found in O(IVIIAI) time using an algorithm of Karp [9] . The primal algorithm (PA) with minimum-mean cycle selection rule (*) instead of selecting negative cycles of the fewest arcs is valid due to the following theorem. Then, the theorem immediately follows from Lemma 2.1. To prove the claim, we suppose on the contrary that there were no permutation of C+ satisfying (3.4), which will lead us to a contradiction.", "cite_spans": [], "ref_spans": []}, {"section": "qv>(a+a) =1I\"(a-a)", "text": "It is ea.<>y to see that if the claim is not true, then there exist some arcs (uilO ViJ, (uh,Vh) ", "cite_spans": [], "ref_spans": []}, {"section": "qv>(a+a) =1I\"(a-a)", "text": "for some positive integer q* < q. It follows from (3.6) and (3.7) that The cycle selection rule (*) can be regarded as a generalization of the rule of selecting augmenting paths in the maximum independent flow algorithm proposed by Fujishige [2] and later refined by P. SchOnsleben [12] and E. L. Lawler and C. V. Martel [11] . Their rule is to always select a lexicographically minimum augmenting path of the fewest arcs.", "cite_spans": [{"start": 242, "end": 245, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "qv>(a+a) =1I\"(a-a)", "text": "In the next section, we show that the primal algorithm with minimum-mean cycle selection rule (*) terminates after a finite number of steps.", "cite_spans": [], "ref_spans": []}, {"section": "qv>(a+a) =1I\"(a-a)", "text": "Copyright \u00a9 by ORSJ. Unauthorized reproduction of this article is prohibited. ", "cite_spans": [], "ref_spans": []}, {"section": "Analysis of the Primal Algorithm with Minimum-mean Cycle Selection", "text": "It is well known that a base b E B is a maximum-weight base with respect to p if and only if", "cite_spans": [], "ref_spans": []}, {"section": "Analysis of the Primal Algorithm with Minimum-mean Cycle Selection", "text": "Optimal submodular flows are characterized in the following theorem (see, e.g., [5] , [6] ).", "cite_spans": [{"start": 86, "end": 89, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Analysis of the Primal Algorithm with Minimum-mean Cycle Selection", "text": "Theorem 4.1. A submodular flow cp is optimal if and only if there exists a potential p such that", "cite_spans": [], "ref_spans": []}, {"section": "Analysis of the Primal Algorithm with Minimum-mean Cycle Selection", "text": "(ii) acp is a maximum-weight base of B with respect to p. Furthermore, if p satisfies (i) and (ii) for some optimal submodular flow cp, then p satisfies (i) and (ii) for any optimal submodular flow cp. We introduce a notion of approximate optimality, called g-optimality, obtained by relaxing the above optimality condition (4.5), which plays a crucial role in our analysis.", "cite_spans": [], "ref_spans": []}, {"section": "Analysis of the Primal Algorithm with Minimum-mean Cycle Selection", "text": "The notion of approximate optimality was first introduced by E. Tardos [131 for the ordinary minimum-cost flow problem (also see [61 for submodular flows). It was also used in the analysis of a primal algorithm for finding ordinary minimum-cost flows by Goldberg and Tarjan [7] . For any g ;::: 0 a submodular flow cp is called g-optimal if for all a E A'P (4.6)", "cite_spans": [], "ref_spans": []}, {"section": "Analysis of the Primal Algorithm with Minimum-mean Cycle Selection", "text": "As is pointed out in [7] for ordinary minimum-cost flows, we can easily show that if all arc costs are integers and g < 1/1VI, then an g-optimal submodular flow is optimal. For a submodular flow cp we denote by g(cp) the minimum g such that cp is g-optimal, and by JL(tp) the mean cost of a minimum-mean cycle in N\",. The following theorem establishes a connection between the g-optimality and the minimum cycle mean. Proof: Let c = c( tp) and p be a potential with respect to which tp is c-optimal. Before cp is changed, every arc in G\", satisfies (4.6) by the c-optimality and every arc a on Q satisfies \"Y\",p = -g by the definitions of c and Q. Consider any new arc ao created by changing flow tp along Q, i.e., ao fI. A\", and ao E A\"\". IT ao fI. Aa\"\", then arc ao is the reorientation of an arc on Q and hence \"Y\"\"p(ao) = c. IT ao E Aa\"\", then there is an arc a E Aa\", on Q such that (a+a,a-ao) , (a+ao,a-a) E Aa\", (cf. [8, p.184] ). By the definition of c-optimality,", "cite_spans": [], "ref_spans": []}, {"section": "Analysis of the Primal Algorithm with Minimum-mean Cycle Selection", "text": "which implies p(a+ao) -p(a-ao) 2:: -c. It follows that every arc in G\"\" remains to satisfy (4.6) and hence c(tp) 2:: c(tp').", "cite_spans": [], "ref_spans": []}, {"section": "0", "text": "Let tp (tp') be the sub modular flow before (after) the execution of an iteration in the primal algorithm with minimum-mean cycle selection rule (*), JL(tp) (JL(tp')) be the minimum cycle mean in G\", (G\",,) , and q\", (q\",,) (1) JL(tp) ::; JL(tp'). Proof: (1) is immediate from Theorem 4.2 and Lemma 4.1. We show (2) . Let Q be the minimum-mean cycle selected by selection rule (*) in G\", and p be a potential with respect to which tp is c(tp)-optimal. Suppose JL(tp) = JL(tp'). First we show that if there is no minimum-mean cycle containing vertex x E V in G\"\" then this is also true in G\"\". For, suppose that there exists a minimum-mean cycle Q* containing such a vertex x in G\",\" Then, Q* must contain at least one new arc (w,z) in Aa\",' but not in A\", which is created by changing tp along Q. Therefore, there exists an arc (u, v) AV'(Q) U {(u,z) , (w,v) ", "cite_spans": [{"start": 312, "end": 315, "text": "(2)", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "} U (AV',(Q*) -{(w,z)})", "text": "contains the set of arcs of a minimum-mean cycle through x in GV'. This contradicts the fact that no minimum-mean cycle contains x in GV'.", "cite_spans": [], "ref_spans": []}, {"section": "} U (AV',(Q*) -{(w,z)})", "text": "Next, we consider any minimum-mean cycle Q* containing some new arc (w, z) in GV',. Similarly as in the above argument there exists an arc (u,v) in Q such that (u,z), (w,v) E AaV' and it is easy to see that arcs (u,z) and (w,v) lie on minimum-mean cycles whose arcs belong to the arc set (4.7). The definitions of Q and qV' imply that 1r(v) < 1r(z) and hence qV'(w) ~ 1r(v) < 1r(z). Therefore, the appearance of any new arc does not make qV' decrease. We thus have qV' ~ qV\". Because at least one arc in Q is deleted, there exists at least one vertex v such that qV ' (v) < qV\" (v) . 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An optimal solution of the above problem is called an optimal submodular flow in N. For b", "type": "figure"}, "FIGREF3": {"text": "14J. A submodular flow cp is optimal if and only if there are no negative cycles in NII\" 0", "type": "figure"}, "FIGREF4": {"text": ") (PA) Begin with any submodular flow cp. Do the following (t) while there is a negative cycle in N'{>:Find a negative cycle Q of the fewest arcs in N'{> and change the flow ~') along the cycle Q by", "type": "figure"}, "FIGREF5": {"text": "The cycle Q selected by the above rule (*) in the primal algorithm is a feasible cycle. Proof: Let J.I. be the minimum cycle mean of Nv>. We denote the set of arcs in Q by Av> ( Q)(Ui, Vi) liE I}. Then, all Ui, Vi (i E I) are distinct vertices be- cause Q is a minimum-mean cycle. We claim that there exists a permutation (UilO Vii)' (Uil,Vil)\"'\" (Ui\"Vi,) (p = Ill) of arcs in C+ such that for any k, I with 1 ~ k < I ~ P (3.4)", "type": "figure"}, "FIGREF6": {"text": "\"('P\" : A'P --+ R by (4.4) Then, the above (i) and (ii) hold if and only if for all a E A (4.5)", "type": "figure"}, "FIGREF7": {"text": "For any submodular flow tp, c(tp) = max{O, -JL(tp)}. Proof: This theorem easily follows from the definition of JL( tp) and is a direct adaptation of a result in [71. 0 Now, we analyze the primal algorithm with minimum-mean cycle selection rule (*). Let tp be an arbitrary submodular flow in network N, Q be a feasible minimum-mean cycle in G\"\" and tp' be the submodular flow after changing tp along Q by (3.1). Then we have the following lemma. Lemma 4.1. c( tp) 2:: c( <p')", "type": "figure"}, "FIGREF8": {"text": "IT JL(tp) = JL(tp'), then q\", ::; q\",' and there exists a vertex v E V such that q\",(v) < q\",,(v).", "type": "figure"}, "FIGREF9": {"text": "The primal algorithm for the submodular flow problem with minimum- mean selection rule (*) terminates after a finite number of steps.", "type": "figure"}, "TABREF0": {"text": "X .. (w) = {~ The function dep: B x V --+ 2 v is called the dependence function [2J. Moreover, for any v E V we define", "type": "table"}, "TABREF1": {"text": "Ab) is called the exchangeability graph associated with b. For a submodula.r flow", "type": "table"}, "TABREF2": {"text": "AII') is called the auxiliary graph associated with submodular flow cp. For each a E AII' we define a capacity function clI' byif a E A and a E B;,", "type": "table"}, "TABREF3": {"text": "Aav>, where jq+l = jl' For any two vertices x, y on Q, denote the directed path from x to y on Q by P(x,y). For each r = 1,2, ... ,q, adding arc (Uir,vir+1) to path P( Vir + l ' u 3 J , we get a cycle, which we denote by Q( Vir+l' u,J. We show that Q( vir+l> uiJ is also a minimum-mean cycle. Let \"Iv>(Q) denote the cost of Q relative to \"Iv>. Also let i be the number of arcs of Q", "type": "table"}, "TABREF4": {"text": ",Proof: The proof of this theorem is similar to that of Theorem 3.1. If the claim in the above proof is not true, then each Q( vir+l' uir) is also a minimum-mean cycle. (The proof up to this point is the same.) Here, we have ir < i which contradicts the definition of Q. o", "type": "table"}, "TABREF5": {"text": "A function p : V --+ R is called a potential in N. A base b* E B is called a maximum- weight base with respect to p if", "type": "table"}, "TABREF6": {"text": "be the function defined by (3.2). Then,", "type": "table"}, "TABREF7": {"text": "of Q such that Copyright \u00a9 by ORSJ. Unauthorized reproduction of this article is prohibited. arcs (u,z), (w,v) E AaV'. By e(cp)-optimality and the definitions of Q and Q*, we have p( w) -p(z) = Jt(cp), p( u) -p( v) = Jt(cp) , p( u) _. p(z) ~ Jt(cp) and p( w) -p( v) ~ Jt( cp), which implies p(u) -p(z) = Jt(cp) , p(w) -p(v) = Jt(cp). It is easy to see that (4.7)", "type": "table"}}}
{"paper_id": "123627079", "_pdf_hash": "ff7ed5dde868569e2fe10fa5fda3a6bb0ea5f7b2", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
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{"paper_id": "123629197", "_pdf_hash": "7444778a579faa5bf11b177aa60bf9c2d9d0ff80", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "138410520", "_pdf_hash": "a980bc9aca3674c2dc2d569fbba66803727c3121", "abstract": [{"section": "Abstract", "text": "Five different anti-wear additives, suitable for the formulation of environmentally adapted hydraulic fluids were tested, both commercially available and newly developed. The used base fluid was a high performance saturated complex ester. The formulated fluids' performance was evaluated through the use of an assembled pin & vee block in a modified Falex wear tester according to wear and frictional behaviour. The combinations of tested materials were steel-steel and bronze-steel tribopairs. The friction, wear scar volume and visual appearance both inside and outside the wear scar were studied. Some of the tested combinations gave unwanted performance, such as high friction, large wear and etching damages, whereas others gave good performance. It was found that the new additives showed promising results for formulation of environmentally adapted lubricants based on saturated complex esters. Further investigations will look closer at the chemical composition of the formed tribofilms with the use of surface sensitive analysis technology.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "The use of environmentally adapted lubricants has become extensive in certain areas, such as mobile hydraulics 1) . In many areas, the use of environmentally adapted lubricants is driven by legalisation, e.g. the forestry industry in Sweden 2) . One problem with environmentally adapted hydraulic fluids is the relatively poor resistance against aging and degradation compared to traditional mineral based products. A majority of the environmentally adapted hydraulic fluids used today are based on unsaturated ester base fluids 3) . One way to overcome the sensibility for hydrolysis and oxidation is to use saturated base fluids, which introduces new possibilities and new challenges.", "cite_spans": [{"start": 111, "end": 113, "text": "1)", "ref_id": "BIBREF0"}, {"start": 241, "end": 243, "text": "2)", "ref_id": "BIBREF1"}, {"start": 529, "end": 531, "text": "3)", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Introduction", "text": "The low temperature properties for saturated esters are usually poorer than for unsaturated due to the lack of double bonds that prevent crystallization 4) . One way to overcome this is through the use of complex esters made of one or more ester molecules that are polymerized together with carboxylic di-acids. These structures are free of unsaturations and could give high viscosity index, (VI), excellent stability and good low temperature properties. The combination of fatty acid alcohols and the number of repeating units in the complex ester are endless, making it possible to tailor made base fluids suitable for any application.", "cite_spans": [{"start": 153, "end": 155, "text": "4)", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Introduction", "text": "Knowledge of suitable additives and formulations for a saturated ester is relatively good, though knowledge of additive response for saturated base fluids is limited 5, 6) .", "cite_spans": [{"start": 166, "end": 168, "text": "5,", "ref_id": "BIBREF4"}, {"start": 169, "end": 171, "text": "6)", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Tested fluids and materials", "text": "Typical material combinations found in hydraulic applications could be steel-steel and steel-bronze combinations. In this investigation, these materials are tested together with different fluid formulations. Cast iron and cast steels are also common in hydraulic applications, but are not normally such a big problem like the tested materials, and will therefore be left to future investigations.", "cite_spans": [], "ref_spans": []}, {"section": "Base fluid and additive properties", "text": "The used base fluid in this investigation is a saturated complex ester; see Table 1 . The selected base fluid is suitable for formulating high performance products where environmental aspects are of interest. The base fluid is readily biodegradable, according to OECD 301 A/F and some percentage of the base stock is of renewable origin.", "cite_spans": [], "ref_spans": [{"start": 76, "end": 83, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Base fluid and additive properties", "text": "The base fluid was additivated with different types of Table 2 . The additives were both commercially available and tailor made special additives for saturated esters. All the used formulations were additivated to 50 mmol/l except TPPT, which has 100 mmol/l concentrations, and PSHAP, which has 50 + 50 mmol/l of PS and HAP. Minami et al. describe the preparation of HAP additives in detail 7) .", "cite_spans": [], "ref_spans": []}, {"section": "Tested materials", "text": "The used materials in the tribotests were SUJ2 steel and JM3 bronze; see Table 3 for details.", "cite_spans": [], "ref_spans": [{"start": 73, "end": 80, "text": "Table 3", "ref_id": "TABREF1"}]}, {"section": "Tested materials", "text": "The used bronze, JM3, is a tin alloyed bronze with approximately 12% tin. The alloy is extensively used in many different applications. The investigated steel, SUJ2, is a hardened ball bearing steel that corresponds to international standards. The pin is a standard Falex corporation AISI/SAE 3135 steel pin, (HRB 87-91).", "cite_spans": [], "ref_spans": []}, {"section": "Experimental set up", "text": "To obtain data for tribological behaviour and provide tribo-chemically reacted surfaces for surface analysis tribotests have to be run. In this investigation we have chosen to study the tribology in a pure sliding contact.", "cite_spans": [], "ref_spans": []}, {"section": "Falex assembled vee block", "text": "The tribotests were run in a modified Falex pin & vee block machine. The traditional ASTM D-3233 vee blocks were replaced with assembled vee blocks; see The advantages with the modified method are the improved accessibility for analysis after the test and the simplified manufacturing of high precision test specimens 8) . Other benefits are that every test produces four wear scars with a total width of 50.8 mm with respect to sliding direction. One disadvantage is the risk that damage occurring between one of the blocks and the pin propagates and damages the other blocks at the same position. For test running conditions, see Table 4 .", "cite_spans": [{"start": 318, "end": 320, "text": "8)", "ref_id": "BIBREF7"}], "ref_spans": [{"start": 632, "end": 639, "text": "Table 4", "ref_id": "TABREF2"}]}, {"section": "Falex assembled vee block", "text": "The contact pressure was calculated according to the Hertzian model at the start of the experiment for an unworn contact. All the tests were run at room temperature, (app. 25-28\u00b0C) and a relative humidity of 60-85%. The test temperature increased slightly due to friction heating and reached a maximum of app. 50\u00b0C by the end of the tests.", "cite_spans": [], "ref_spans": []}, {"section": "Friction measurements", "text": "The friction coefficient was calculated from the measured normal force and the torque in the Falex machine. A load cell that directly registers the load applied on the blocks by the pneumatic cylinder measured the normal force. A rotational torque sensor attached between the drive unit and the pin holder measured the torque. The load and torque cell were connected to a computerized system that continuously records the values during the test.", "cite_spans": [], "ref_spans": []}, {"section": "Wear scar measurements", "text": "The wear scars obtained from the Falex test were analysed in different ways. An optical microscope with an attached digital camera was used to take detailed micrographs of the wear track. The surface profile and topography were measured with a WYKO NT-1100 optical topometer.", "cite_spans": [], "ref_spans": []}, {"section": "Wear scar measurements", "text": "The worn off volume was calculated from the wear track 3-D measurements. The presented wear scar volumes are for one block calculated as an average from all four specimens in the same test.", "cite_spans": [], "ref_spans": []}, {"section": "Results and discussion", "text": "The following results are based on a chosen experiment for each additive and material combination. All tests were repeated at least once to ensure good repeatability.", "cite_spans": [], "ref_spans": []}, {"section": "Friction", "text": "Load and torque were measured and the friction was calculated and plotted for all steel tests in Figure 2 and for all bronze in Fig. 3 .", "cite_spans": [], "ref_spans": []}, {"section": "Friction", "text": "In Fig. 2 , some of the additives (TPPT, HAP and PS) lower the friction according the pure base fluid, (BF). Two of the additives (CM and PSHAP) raise the friction coefficient, though without any big differences. From  Fig. 3 for the bronze-steel tribopairs, the friction coefficient shows a larger difference than for steel-steel. The additives PSHAP and HAP show lower friction than the base fluid. PS and CM show a friction coefficient in the same range as the base fluid. The TPPT additive shows a dramatically higher friction than the other additives.", "cite_spans": [], "ref_spans": []}, {"section": "Wear scar investigation", "text": "The optical light microscope investigation shows that some of the wears scars have visible tribofilm that show the changes on bronze lubricated with PSHAP; see Fig. 4 . The same phenomenon for bronze could also be found for HAP. In the latter case, some transferred material from the blocks on the pin was also seen.", "cite_spans": [], "ref_spans": []}, {"section": "Wear scar investigation", "text": "The sizes of the micrographs are 0.8 \u00d7 0.6 mm. Fig 4  and Fig. 5 illustrate the sliding direction from down to upwards.", "cite_spans": [], "ref_spans": [{"start": 47, "end": 64, "text": "Fig 4  and Fig. 5", "ref_id": "FIGREF3"}]}, {"section": "Wear scar investigation", "text": "Some of the visible tribofilms are not continuous in the whole wear scar, as seen in Fig. 5 , that show steel lubricated with HAP. In this figure, some effect on the unworn surface outside the wear scar is also seen. This seems to be caused by a chemical reaction between aggressive residual products from the base fluid and additive degradation in the tribocontact. The steel lubricated with the pure base fluid and PSHAP shows similar patterns in the wear scar and on the unworn surface.", "cite_spans": [], "ref_spans": [{"start": 85, "end": 91, "text": "Fig. 5", "ref_id": "FIGREF3"}]}, {"section": "Wear scar investigation", "text": "There was no visible tribofilm in the wear scar for steel lubricated with PS, but a very strong discoloration could be seen on the unaffected surface.", "cite_spans": [], "ref_spans": []}, {"section": "Wear scar investigation", "text": "With the use of a 3-D topometer the following wear scar volumes were obtained; see Table 5 . The topometer measurements also provide information about surface roughness in the wear scar. This is helpful when trying to determine the wear mechanism, i.e. distinguish between abrasive, chemical or adhesive wear. The bronze lubricated with PS shows an extremely smooth wear scar, as shown in Fig.6 From the corresponding 2-D plot, the sliding direction could be seen; it is downwards in the 3-D plot.", "cite_spans": [], "ref_spans": [{"start": 389, "end": 394, "text": "Fig.6", "ref_id": "FIGREF4"}]}, {"section": "Wear scar investigation", "text": "When discolouring outside the wear scar is caused by corrosion, an analysis could be supported by the use of 3-D topometer measurements. This is the case for steel lubricated with HAP, as shown in Fig. 7 . The corroded cavities are in the same range as the depth of the wear scar. Corrosive damages are also seen within and outside the wear scar.", "cite_spans": [], "ref_spans": []}, {"section": "Wear scar investigation", "text": "Some additives give a discoloration of the unworn surfaces that could probably be handled with AO additives. A summarization of friction behaviour and wear mechanisms for all material combinations is to be found in Table 6 .", "cite_spans": [], "ref_spans": [{"start": 215, "end": 222, "text": "Table 6", "ref_id": "TABREF3"}]}, {"section": "Wear scar investigation", "text": "Proposed analysis procedure Conclusions can be drawn differently from the results. The wears scar are analysed visually with a microscope and optical 3-D topometer. The friction can only be analysed, plotted and compared between the different additives.", "cite_spans": [], "ref_spans": []}, {"section": "Wear scar investigation", "text": "The wear process can be divided into different cases: Mild wear and smooth surface: A monolayer of chemireacted tribofilm with good tribological properties is formed. The protective film can handle the load and be rebuilt immediately after breakdown / wear-off. The wear rate and friction are low and the surfaces are smooth. High wear and smooth surfaces: A weak tribofilm is formed. The built up film cannot handle the load and is broken down, but regenerated continuously at a rapid rate. The wear is severe, but the surfaces are smooth. The friction can be both high and low, though stable depending on the properties of the tribofilm.", "cite_spans": [], "ref_spans": []}, {"section": "Wear scar investigation", "text": "High wear and rough surfaces: There is no load carrying the tribofilm. The metal-metal contact is not protected and abrasive, or adhesive wear occurs, or both. The friction coefficient is high, unstable or both.", "cite_spans": [], "ref_spans": []}, {"section": "Wear scar investigation", "text": "To classify and understand the wear, a three-step method can be used.", "cite_spans": [], "ref_spans": []}, {"section": "Wear scar investigation", "text": "\u2022 How do the wear scar and the surrounding area look optically? This is the first step to determine any discolorations.", "cite_spans": [], "ref_spans": []}, {"section": "Wear scar investigation", "text": "\u2022 How big is the surface roughness inside the wear scar and are there any etching damages outside the scar? \u2022 How big are the wear scar volumes? The next step is to perform a surface investigation to determine the chemical composition of the surface.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "The additive influence on the friction coefficients and wear in this investigation is bigger for bronze-steel tribopairs than steel-steel tribopairs.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "For bronze-steel contact, PS, HAP and TPPT give lower wear than the base fluid. The PS and CM additives give higher wear rate.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "All the additives and the base fluid show a low wear rate for steel-steel except the PS additive, which has a much higher wear.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "For bronze, the best additives are HAP and PSHAP concerning both wear and friction.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "It is interesting to note that some steel samples are affected outside the wear track by the triboreacted products. Examples are HAP and PS, which may be handled by the use of AO additives.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "The combined use of active sulphur additives (PS) in bronze contacts should be avoided.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "This investigation shows that using new types of more polar additives is a possible way to formulate saturated ester base fluids to lubricants with a high level of performance.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "To increase the understanding of tribofilm formation mechanisms, an investigation of the surface with a surface sensitive spectroscopy method is valuable. Future studies will investigate the tribofilms generated by these experiments. ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Environmentally Adapted Lubricants in Swedish Forest Industry -A Critical Review and Case Study", "authors": [{"first": "T", "middle": [], "last": "Norrby", "suffix": ""}, {"first": "M", "middle": [], "last": "Kopp", "suffix": ""}], "year": 2000, "venue": "Industrial Lubrication and Tribology", "link": "110059044"}, "BIBREF1": {"title": "Environmentally Adapted LubricantsWhere are the Opportunities", "authors": [{"first": "T", "middle": [], "last": "Norrby", "suffix": ""}], "year": 2003, "venue": "Industrial Lubrication and Tribology", "link": "109906077"}, "BIBREF2": {"title": "Lubricants and Lubrication", "authors": [{"first": "T", "middle": [], "last": "Mang", "suffix": ""}, {"first": "W", "middle": [], "last": "Dresel", "suffix": ""}], "year": 2001, "venue": "", "link": "137587177"}, "BIBREF3": {"title": "High-Performance Base Fluids for Environmentally Adapted Lubricants", "authors": [{"first": "A", "middle": [], "last": "Pettersson", "suffix": ""}], "year": 2007, "venue": "Tribology International", "link": "95065937"}, "BIBREF4": {"title": "The Tribological Behaviour of Some Triazine-Dithiocarbamate Derivatives as Additives in Vegetable Oil", "authors": [{"first": "Z", "middle": [], "last": "Weiqiang", "suffix": ""}, {"first": "S", "middle": [], "last": "Yuping", "suffix": ""}, {"first": "R", "middle": [], "last": "Tianhui", "suffix": ""}, {"first": "L", "middle": [], "last": "Weimin", "suffix": ""}], "year": 2004, "venue": "Wear", "link": "97844437"}, "BIBREF5": {"title": "Additive Influence on Wear and Friction Performance of Environmentally Adapted Lubricants", "authors": [{"first": "P", "middle": [], "last": "Waara", "suffix": ""}, {"first": "J", "middle": [], "last": "Hannu", "suffix": ""}, {"first": "T", "middle": [], "last": "Norrby", "suffix": ""}, {"first": "A", "middle": [], "last": "Byheden", "suffix": ""}], "year": 2001, "venue": "Tribology International", "link": "135724920"}, "BIBREF6": {"title": "Investigation of Anti-Wear Additives for Low Viscous Synthetic Esters: Hydroxyalkyl Phosphonates", "authors": [{"first": "I", "middle": [], "last": "Minami", "suffix": ""}, {"first": "K", "middle": [], "last": "Hirao", "suffix": ""}, {"first": "M", "middle": [], "last": "Memita", "suffix": ""}, {"first": "S", "middle": [], "last": "Mori", "suffix": ""}], "year": 2007, "venue": "Tribology International", "link": "97616649"}, "BIBREF7": {"title": "Cylinder and Assembled Four-Block Type Tribo-Test: Novel Method to Study Tribo-Chemistry of Lubricant and Material", "authors": [{"first": "I", "middle": [], "last": "Minami", "suffix": ""}, {"first": "A", "middle": [], "last": "Yamazaki", "suffix": ""}, {"first": "H", "middle": [], "last": "Nanao", "suffix": ""}, {"first": "S", "middle": [], "last": "Mori", "suffix": ""}], "year": 2007, "venue": "Tribology Online", "link": "138374019"}}, "ref_entries": {"FIGREF0": {"text": "Fig.1 Assembled vee block", "type": "figure"}, "FIGREF2": {"text": "Fig.2 Friction plots for steel", "type": "figure"}, "FIGREF3": {"text": "Fig.3 Friction plots for bronze", "type": "figure"}, "FIGREF4": {"text": "Fig.6 Polished wear scar on Bronze lubricated with PS", "type": "figure"}, "TABREF0": {"text": "Base fluid properties", "type": "table"}, "TABREF1": {"text": "", "type": "table"}, "TABREF2": {"text": "Running conditions, Falex test", "type": "table"}, "TABREF3": {"text": "Result remarksFully formulated lubricants have numerous additives, but this study is only about single or dual AW/EP additives. Therefore, additional investigations about treat rates, and effects that are synergistic, antagonistic or both should be conducted to successfully formulate commercial lubricants with this new type of additives.", "type": "table"}}}
{"paper_id": "138415939", "_pdf_hash": "ce473681dc956ef753d123e767a2fad365bef7dc", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Material Design for Application to High Performance LCDs", "authors": [{"first": "A", "middle": [], "last": "Kumano", "suffix": ""}], "year": 2001, "venue": "J. Photopolym. Sci. 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Appl. Polym. Sci", "link": "97223922"}, "BIBREF5": {"title": "Synthesis, Characterization and Thermal Degradation of Glycidyl Methacrylate-a-Methyl Styrene Copolymers", "authors": [{"first": "S", "middle": [], "last": "Ahmad", "suffix": ""}, {"first": "S", "middle": [], "last": "Zulfiqar", "suffix": ""}], "year": 2002, "venue": "Polym. Degrad. Stab", "link": "94098192"}, "BIBREF6": {"title": "Synthetic Study and Material Applications for a Positive Photo Resist of the Acrylic Series", "authors": [{"first": "T", "middle": ["S"], "last": "Cheng", "suffix": ""}, {"first": "M", "middle": ["H"], "last": "Wu", "suffix": ""}, {"first": "W", "middle": ["S"], "last": "Weng", "suffix": ""}, {"first": "H", "middle": [], "last": "Chen", "suffix": ""}], "year": 2002, "venue": "Mater. 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{"paper_id": "138416027", "_pdf_hash": "8f658489732b0e8e12d85c5758f2e2f7af5ac2f9", "abstract": [{"section": "Abstract", "text": "In the stock-raising industry, it is known that beef fat quality is related to texture and scent. However, in meat markets, there is currently no method of directly evaluating fat quality on-line. Using near-infrared imaging, we have developed new equipment for evaluating the fat quality in beef rib eye. It consists of three selected, spectral wavelength LEDs and a near-infrared camera. In order to test the accuracy of this equipment, a series of prediction tests were carried out using 33 independent samples in the meat market. According to the cross-validation, the standard margin of error for the estimated accuracy of oleic acid was 2.34%. These results showed that this equipment is a rapid and non-destructive method for visualizing and evaluating the distribution of oleic acid in stock at meat markets.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Imaging Equipment for Evaluation of Oleic Acid Contents for Beef Carcass", "text": "Using Near-infrared Camera Tomoyuki Tanaka * , Toshio Yamada * , Naonori Ono * , Masayasu Esaki * * , Shin Maruyama * * * and Hideki Tanahashi * In the stock-raising industry, it is known that beef fat quality is related to texture and scent. However, in meat markets, there is currently no method of directly evaluating fat quality on-line. Using near-infrared imaging, we have developed new equipment for evaluating the fat quality in beef rib eye. It consists of three selected, spectral wavelength LEDs and a near-infrared camera. In order to test the accuracy of this equipment, a series of prediction tests were carried out using 33 independent samples in the meat market. According to the cross-validation, the standard margin of error for the estimated accuracy of oleic acid was 2.34%. These results showed that this equipment is a rapid and non-destructive method for visualizing and evaluating the distribution of oleic acid in stock at meat markets. (1) 1", "cite_spans": [], "ref_spans": []}, {"section": "1.", "text": "(2)", "cite_spans": [], "ref_spans": []}, {"section": "1.", "text": "(2) (1) ", "cite_spans": [], "ref_spans": []}, {"section": "5.", "text": "1.93%", "cite_spans": [], "ref_spans": []}, {"section": "2.34%", "text": "(SCOPE) ICT", "cite_spans": [], "ref_spans": []}], "bib_entries": {}, "ref_entries": {"FIGREF0": {"text": "Flow of creating oleic acid contents image", "type": "figure"}, "FIGREF1": {"text": "The overview of a carcass on the market of slaughter house An imaging equipment for photographing the beef rib eye", "type": "figure"}, "FIGREF2": {"text": "Fig. 2(a) Fig. 2(b) 0 4 \u2022 C 70% 300 400 mm", "type": "figure"}, "FIGREF3": {"text": "Fig. 4 Fig. 5", "type": "figure"}, "FIGREF4": {"text": "An imaging equipment to take rib eye image of carcass on the market of slaughter house", "type": "figure"}, "FIGREF5": {"text": "Sample images obtained in the experiment (a1, b1) Visible images (a2, b2) NIR (760 nm) images (a3, b3) NIR (810 nm) images (a4, b4) NIR (940 nm) images (a5, b5) Oleic acid contents images", "type": "figure"}, "TABREF0": {"text": "", "type": "table"}}}
{"paper_id": "138417162", "_pdf_hash": "383b3e5b6252b266dc2b3f158a86e554d055ddac", "abstract": [{"section": "Abstract", "text": "In this paper the operator bias in the measurement process of arc efficiency in stationary direct current electrode negative gas tungsten arc welding is discussed. An experimental study involving 15 operators (enough to reach statistical significance) has been carried out with the purpose to estimate the arc efficiency from a specific procedure for calorimetric experiments. The measurement procedure consists of three manual operations which introduces operator bias in the measurement process. An additional relevant experiment highlights the consequences of estimating the arc voltage by measuring the potential between the terminals of the welding power source instead of measuring the potential between the electrode contact tube and the workpiece. The result of the study is a statistical evaluation of the operator bias influence on the estimate, showing that operator bias is negligible in the estimate considered here. On the contrary the consequences of neglecting welding leads voltage drop results in a significant under estimation of the arc efficiency.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "The aim of this study is to evaluate the operator bias in the estimation of arc efficiency also known as process-, thermal-and heat transfer efficiency in stationary direct current electrode negative (DCEN) gas tungsten arc welding (GTAW). GTAW is one of the most widely used arc welding methods for welding stainless steels, thus representing an industrial process with significant economic importance. The arc efficiency in welding determines the weld bead formation, the formation of residual distortion and stress and also the metallurgical transformations. The metallurgy characteristics, consecutively, determine joint properties such as mechanical resistance, toughness and the degree of susceptibility to cold cracking etc. Hence, it is important to know how much of the supplied energy that is transferred to the material being welded [1] [2] [3] . The arc efficiency is also an important input to numerical heat-transfer models used for predictions and understanding of the process [4] .", "cite_spans": [{"start": 844, "end": 847, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 848, "end": 851, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 852, "end": 855, "text": "[3]", "ref_id": "BIBREF3"}, {"start": 992, "end": 995, "text": "[4]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Introduction", "text": "A literature review by Stenbacka [5] covered the years between 1955 and 2011 shows that the arc efficiency values published for GTAW lie in a very wide range. The estimates were made from calorimetrical experiments and from calibrated simulation model results. Values between 0.36 and 0.90 are reported. A question arose about the origins of this remarkable variance [5] .", "cite_spans": [{"start": 33, "end": 36, "text": "[5]", "ref_id": "BIBREF5"}, {"start": 367, "end": 370, "text": "[5]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Introduction", "text": "The evaluation method investigated is a common method based on calorimetric experiments. Estimations involving measurement procedures are always disposed to error in measurement and uncertainties. The measurement process errors include a number of factors such as tolerance limits of instruments, operator bias, errors arising from environmental conditions, or other sources. Furthermore, each measurement error is considered to be a random variable characterized by a probability distribution [6] . As a consequence the quantity in the context of the process together with the measurement process ought to be carefully explained in order to properly quantify a measurand by good statistical practice.", "cite_spans": [{"start": 494, "end": 497, "text": "[6]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Introduction", "text": "One important observation regarding arc efficiency in GTAW is that this parameter cannot be regarded as a universal constant. It is more or less dependent on the combination of several welding parameters like the arc length, weld current, weld travel speed and shielding gas composition etc. The travel speed clearly influences the arc efficiency", "cite_spans": [], "ref_spans": []}, {"section": "Operator Bias in the Estimation of Arc Efficiency in Gas Tungsten Arc Welding", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Fredrik Sikstr\u00f6m 1", "text": "Operator Bias in the Estimation of Arc Efficiency in Gas Tungsten Arc Welding although there are contradictions in statements between different references about the direction of this influence. As an example [7] reported a decrease in arc efficiency with low weld travel speed and [8] reported an increase in arc efficiency with low weld travel speed. Another parameter that significantly influences the arc efficiency is the welding power. Many authors have experimentally shown a decreased arc efficiency with increased weld current and or increased arc length, see [9] for one example.", "cite_spans": [{"start": 208, "end": 211, "text": "[7]", "ref_id": "BIBREF7"}, {"start": 281, "end": 284, "text": "[8]", "ref_id": "BIBREF8"}, {"start": 568, "end": 571, "text": "[9]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Fredrik Sikstr\u00f6m 1", "text": "This study is limited to a stationary GTAW, DCEN process where most of the influencing parameters are kept constant in order to easier discriminate the operator bias in arc efficiency estimation.", "cite_spans": [], "ref_spans": []}, {"section": "Operator Bias and Environmental Factors Error", "text": "One of the major problems in conjunction with manual measurement is operator bias, which varies in degree according to the individual. Personal errors are due to, e.g. an inappropriate physical environment, procedural mistakes and lack of understanding of the process of measurement. Because of the possibility for human operators to acquire measurements from an individual perspective, it happens that two operators observing the same measurement will systematically produce different measured values. This operator bias has a random character due to inconsistencies in the human response. In addition to this error related to human behaviors significant measurement process errors might also result from variations in environmental conditions, such as temperature, humidity, vibration etc. In order to improve an estimate it is thus necessary to consider and evaluate these types of measurement process errors.", "cite_spans": [], "ref_spans": []}, {"section": "Arc Efficiency and Calorimetry", "text": "Arc efficiency defines the fraction of the arc energy transferred to the work piece. Commonly arc efficiency is calculated as [10] : (1) where U and I are arc voltage and weld current respectively. q electrode is the heat loss due to conduction in the weld electrode, q arc is the heat radiated and convected from the arc column, q weld is the heat transferred to the base metal. The fraction of heat transferred from the arc to the base metal is n, and m is the fraction of radiation, convection and possible evaporation losses in the base metal. Figure 1 illustrates the assumed losses explained by Equation 1.", "cite_spans": [{"start": 126, "end": 130, "text": "[10]", "ref_id": "BIBREF11"}, {"start": 133, "end": 136, "text": "(1)", "ref_id": "BIBREF0"}], "ref_spans": [{"start": 548, "end": 556, "text": "Figure 1", "ref_id": "FIGREF0"}]}, {"section": "Arc Efficiency and Calorimetry", "text": "The technique used in this study to estimate arc efficiency is water calorimetry, as principally is described by e.g. [11, 12] . The method utilizes water cooling of the weld anode by a continuous water flow to remove heat during welding. The water temperature difference between the inlet and outlet of the weld anode is recorded and the electrically induced heat input is related to the temperature rise of the cooling water. The arc efficiency is estimated by the following relation: (2) where t weld is the total welding time, Q is the volume rate of flow of the cooling water, \u00f1 and C are density 988 [kg/m 3 ] and heat capacity of water 4180 [J/(kg\u00b7K)] respectively. T in is the cooling water inlet temperature and T out is the outlet temperature. An approximation is made in Equation 2 by using the average estimate x i of each quantity indicated by an over bar, and where \u2206T = T out -T in . Figure 2 gives the principle of the calorimetry.", "cite_spans": [{"start": 118, "end": 122, "text": "[11,", "ref_id": "BIBREF12"}, {"start": 123, "end": 126, "text": "12]", "ref_id": "BIBREF13"}, {"start": 487, "end": 490, "text": "(2)", "ref_id": "BIBREF1"}], "ref_spans": [{"start": 899, "end": 907, "text": "Figure 2", "ref_id": "FIGREF1"}]}, {"section": "Experimental Procedure", "text": "A specially designed copper anode has been used as a calorimeter device together with a fixed weld torch, see Figure 3 .", "cite_spans": [], "ref_spans": [{"start": 110, "end": 118, "text": "Figure 3", "ref_id": "FIGREF2"}]}, {"section": "Experimental Procedure", "text": "The power source used was a TIG Commander 400 AC/DC from Migatronic AB, and the weld torch was a Binzel Tornado WH0 from Alexander Binzel Schweisstechnik GmbH & Co. A thoriated tungsten electrode WT20 from", "cite_spans": [], "ref_spans": []}, {"section": "Sikstr\u00f6m", "text": "Wolfram Industrie GmbH and argon as a shielding gas was used. Table 1 provides the nominal welding parameters. The calorimeter inlet and outlet was instrumented with thermocouples, type K, in order to acquire the history of this temperature difference. The thermocouples were connected to an analogue input device from National Instrument, NI-9211 with a specified tolerance limit for temperature measurements of \u00b11%. A flow meter, SF-800-3/8, from SwissflowR with a specified tolerance limit of \u00b11%, was used to acquire the water flow rate. The weld current was measured with a Hall-effect transducer with a specified tolerance limit of \u00b11% and finally, the arc voltage was measured with an analogue voltage input device NI-9205. The voltage probe was connected to the electrode contact tube through a resistive voltage divider. The tolerance limit for the arc voltage measurement in this arrangement is estimated to be \u00b11%. All measured data were recorded with a sampling rate of 2 Hz and stored in a file for post analysis. The signal processing and recording was implemented in National Instrument's LabVIEW software.", "cite_spans": [], "ref_spans": [{"start": 62, "end": 69, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Sikstr\u00f6m", "text": "An additional relevant experiment consider the consequences of estimating the arc voltage by measuring the potential between the terminals of the weld power source instead of measuring the potential between the electrode contact tube and the workpiece. The result is a neglecting of the resistive power losses in the welding leads, including the electrode and ground cable and the resistive losses in the contact surfaces between connectors in the total electrical conductor. During welding with varying arc length and current an estimate of this loss was obtained. The estimate was based on 22 measurements where the voltage at the weld power terminals and the electrode contact tube was measured by a digital multimeter with an uncertainty of 1%. The corresponding weld current was measured by a digital clampmeter, also with an uncertainty of 1%.", "cite_spans": [], "ref_spans": []}, {"section": "Instructions for operators", "text": "The instructions for the operators were to use the nominal welding parameters provided in Table 1 . In practice this involved manually adjustments of the arc length by using a set of gauge blocks, to manually adjust the shield gas flow rate reading a single flow tube rotameter, and finally to estimate the time when a steady state welding condition had been reached. When reaching the steady state welding condition the data acquisition system should then be turned on to acquire a sample of the signals consisted of at least 240 data during 120 seconds. Mean values of this sample was then used to estimate the arc efficiency according to the equation in the previous section. Fifteen individuals independently performed this estimate and reported their Operator Bias in the Estimation of Arc Efficiency in Gas Tungsten Arc Welding result. All persons are engineers or researchers and their report was given with the number of significant figures decided on their own.", "cite_spans": [], "ref_spans": [{"start": 90, "end": 97, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Results", "text": "The resulting set of reported observations is a too small sample size (N=15) to conclude about normality from a histogram, see Figure 4 . Therefore a chi-square goodness-of-fit test [13] was performed. From this test it was not possible to conclude about the set of observations if it was a normally distributed sample. However, it is reasonable to conclude from the central limit theorem that a sufficiently large number of observations, each with a well-defined mean and well-defined variance, will be approximately normally distributed. From these considerations the median value of the reported data is used as an estimate of the arc efficiency, 0.80, and the interquartile range, 0.01, is used to indicate variation. This result could be compared with the estimate and the expanded uncertainty in the measurement in itself, assuming no operator bias. It is presumed that the measurement errors are statistically independent sources. The combined uncertainty u c (\u03b7) is calculated as: (3) where X i are the physical quantities in the estimate of the arc efficiency \u03b7, x i are their estimate and are their sensitivity coefficients. The expanded uncertainty is further calculated from u c (\u03b7) using a coverage factor k with Equation 3.", "cite_spans": [{"start": 182, "end": 186, "text": "[13]", "ref_id": "BIBREF14"}, {"start": 989, "end": 992, "text": "(3)", "ref_id": "BIBREF3"}], "ref_spans": [{"start": 127, "end": 135, "text": "Figure 4", "ref_id": "FIGREF3"}]}, {"section": "Results", "text": "The resulting estimate of the arc efficiency calculated as in Equation 4 is, \u03b7(0.95) = 0.80 \u00b1 0.03.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "The reported uncertainty is an expanded uncertainty (Equation 4) calculated using a coverage factor of 2 which gives a level of confidence of approximately 95%. Table 2 gives an uncertainty budget including all sources of uncertainty in this combined measurement. ", "cite_spans": [], "ref_spans": [{"start": 161, "end": 168, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "Sikstr\u00f6m", "text": "Since all the measurement uncertainties are specified as manufacturer tolerance limits they are treated as type B uncertainties with a rectangular probability distribution. This also applies to the parameter estimates of the thermophysical properties of water. Thus, the uncertainty equation for each of them is where \u00b1a are the bounding limits.", "cite_spans": [], "ref_spans": []}, {"section": "Sikstr\u00f6m", "text": "A robust estimate of the welding leads resistivity was computed with a robust regression algorithm using iteratively reweighted least squares with a bisquare weighting function [14] [15] [16] [17] . Robust estimation was used since the measurements were acquired during unknown experimental conditions where it is assumed that the variance in individual data was dependent on the data. Figure 5 shows the voltage drop over the welding leads \u0394U as a function of the weld current. The slope of thick line is the estimate of the welding leads resistivity, R(0.95) = 0.01\u00b10.001 \u03a9. The thin lines are the robust estimate of the standard deviation.", "cite_spans": [{"start": 177, "end": 181, "text": "[14]", "ref_id": "BIBREF15"}, {"start": 182, "end": 186, "text": "[15]", "ref_id": "BIBREF17"}, {"start": 187, "end": 191, "text": "[16]", "ref_id": "BIBREF18"}, {"start": 192, "end": 196, "text": "[17]", "ref_id": "BIBREF19"}], "ref_spans": [{"start": 386, "end": 394, "text": "Figure 5", "ref_id": "FIGREF4"}]}, {"section": "Discussion and Conclusion", "text": "For the cause of understanding the measurement process is relevant to evaluate the portion of the individual standard uncertainties in the combined uncertainty. Figure 6 shows a Pareto chart of the percent contribution to the combined uncertainty u c (\u03b7). The influence of uncertainties in the thermophysical properties of water is negligible justifying the use of constants in the calculation. The most prominent uncertainty is the temperature difference indicating that this measurement could benefit from using instruments with a narrower specification in the tolerance limit.", "cite_spans": [], "ref_spans": [{"start": 161, "end": 169, "text": "Figure 6", "ref_id": "FIGREF5"}]}, {"section": "Discussion and Conclusion", "text": "In the case when the estimate is based on measurements of the arc voltage on the weld power source terminals the resulting individual standard uncertainties in the combined uncertainty is shown in Figure 7 .", "cite_spans": [], "ref_spans": [{"start": 197, "end": 205, "text": "Figure 7", "ref_id": "FIGREF6"}]}, {"section": "Discussion and Conclusion", "text": "In this case the dominating source of uncertainty is obviously the arc voltage standard uncertainty. Table 3 gives the estimates of the arc efficiency considering the instrumental measurement error in one case, the operator bias in the other case and finally the case where the power loss in the welding leads is neglected.", "cite_spans": [], "ref_spans": [{"start": 101, "end": 108, "text": "Table 3", "ref_id": "TABREF2"}]}, {"section": "Discussion and Conclusion", "text": "It is clear that the operator bias is of minor importance. The underestimation of the arc efficiency due to power losses in the welding leads can be an explanation to some of the published low values highlighted in [5] . Furthermore it is reasonable to assume that other factors than the scalar electrical power influences the arc efficiency. For instance, the arc length and weld current have a significant influence. With increasing current and arc length, both Operator Bias in the Estimation of Arc Efficiency in Gas Tungsten Arc Welding the mean temperature [18] and the radiation source strength in the arc column are rising which in turn causes higher radiation losses. The arc shape and heat source distribution is affected by variations in all of the nominal parameters given in Table 1 . And even by other parameters like features in the electrode tip geometry as well as shielding gas composition, the material being welded and the weld travel speed etc. The arc efficiency is clearly affected by the arc geometry and its heat source distribution. This means in practice that an accurate arc efficiency estimate only can be made with knowledge of all these various aspects.", "cite_spans": [{"start": 215, "end": 218, "text": "[5]", "ref_id": "BIBREF5"}, {"start": 563, "end": 567, "text": "[18]", "ref_id": "BIBREF20"}], "ref_spans": [{"start": 788, "end": 795, "text": "Table 1", "ref_id": "TABREF0"}]}], "bib_entries": {"BIBREF0": {"title": "Computational welding mechanics: thermomechanical and microstructural simulations", "authors": [{"first": "L-E", "middle": [], "last": "Lindgren", "suffix": ""}], "year": 2007, "venue": "Series in Welding and Other Joining Technologies)", "link": "138177677"}, "BIBREF1": {"title": "Heat effects of welding: temperature field, residual stress, distortion", "authors": [{"first": "D", "middle": [], "last": "Radaj", "suffix": ""}], "year": "", "venue": "", "link": "137349492"}, "BIBREF3": {"title": "Oxford: International Institute of Welding", "authors": [{"first": "J", "middle": ["F"], "last": "Lancaster", "suffix": ""}], "year": 1986, "venue": "", "link": null}, "BIBREF4": {"title": "A heat-transfer and fluid-flow-based model to obtain a specific weld geometry using various combinations of welding variables", "authors": [{"first": "S", "middle": [], "last": "Mishra", "suffix": ""}, {"first": "T", "middle": [], "last": "Debroy", "suffix": ""}], "year": 2005, "venue": "Journal of Applied Physics", "link": "85465108"}, "BIBREF5": {"title": "On arc efficiency in gas tungsten arc welding", "authors": [{"first": "N", "middle": [], "last": "Stenbacka", "suffix": ""}], "year": 2013, "venue": "Soldagem & Inspe\u00e7\u00e3o", "link": null}, "BIBREF6": {"title": "GUM: Guide to the Expression of Uncertainty in Measurement. Geneva: International Organization for Standardization", "authors": [], "year": 2008, "venue": "Bureau International des Poids et Mesures -BIPM", "link": null}, "BIBREF7": {"title": "A study of melting efficiency in plasma arc and gas tungsten arc welding", "authors": [{"first": "P", "middle": ["W"], "last": "Fuerschbach", "suffix": ""}, {"first": "G", "middle": [], "last": "Knorovsky", "suffix": ""}], "year": 1991, "venue": "Welding Journal", "link": null}, "BIBREF8": {"title": "Determination of gas tungsten arc welding efficiencies. Experimental Thermal and Fluid Science", "authors": [{"first": "P", "middle": [], "last": "Dutta", "suffix": ""}, {"first": "Y", "middle": [], "last": "Joshi", "suffix": ""}, {"first": "C", "middle": [], "last": "Franche", "suffix": ""}], "year": 1994, "venue": "", "link": null}, "BIBREF9": {"title": "Arc efficiency for Gas Tungsten Arc Welding -GTAW", "authors": [{"first": "H", "middle": [], "last": "\u00c5str\u00f6m", "suffix": ""}], "year": 2008, "venue": "JOM-17 International Conference", "link": null}, "BIBREF10": {"title": "Helsing\u00f6r: Institute for the Joining of Materials", "authors": [{"first": "Denmark", "middle": [], "last": "Helsing\u00f6r", "suffix": ""}], "year": 2013, "venue": "", "link": null}, "BIBREF11": {"title": "Thermal analysis of welds developments in heat transfer. Southampton: WIT", "authors": [{"first": "N", "middle": ["T"], "last": "Nguyen", "suffix": ""}], "year": 2004, "venue": "", "link": null}, "BIBREF12": {"title": "Power inputs in gas metal arc welding of aluminum -Part 1", "authors": [{"first": "M", "middle": ["J"], "last": "Lu", "suffix": ""}, {"first": "S", "middle": [], "last": "Kou", "suffix": ""}], "year": 1989, "venue": "Welding Journal", "link": null}, "BIBREF13": {"title": "Power inputs in gas metal arc welding of aluminum -Part 2", "authors": [{"first": "M", "middle": ["J"], "last": "Lu", "suffix": ""}, {"first": "S", "middle": [], "last": "Kou", "suffix": ""}], "year": 1989, "venue": "Welding Journal", "link": null}, "BIBREF14": {"title": "Testing for normality", "authors": [{"first": "H", "middle": ["C"], "last": "Thode", "suffix": ""}], "year": 2002, "venue": "", "link": "116907404"}, "BIBREF15": {"title": "Integrating a robust option into a multiple regression computing environment", "authors": [{"first": "W", "middle": [], "last": "Dumouchel", "suffix": ""}, {"first": "F", "middle": [], "last": "O&apos;brien", "suffix": ""}], "year": 1989, "venue": "Computer Science and Statistics: Proceedings of the 21st Symposium on the Interface", "link": "61012126"}, "BIBREF17": {"title": "A note on computing robust regression estimates via iteratively reweighted least squares", "authors": [{"first": "J", "middle": ["O"], "last": "Street", "suffix": ""}, {"first": "Rjrj", "middle": [], "last": "Carroll", "suffix": ""}, {"first": "D", "middle": [], "last": "Ruppert", "suffix": ""}], "year": 1988, "venue": "The American Statistician", "link": "120953255"}, "BIBREF18": {"title": "Robust regression using iteratively reweighted least-squares", "authors": [{"first": "P", "middle": ["W"], "last": "Holland", "suffix": ""}, {"first": "R", "middle": ["E"], "last": "Welsch", "suffix": ""}], "year": 1977, "venue": "Communications in Statistics. Theory and Methods", "link": "122208291"}, "BIBREF19": {"title": "Robust statistics", "authors": [{"first": "P", "middle": ["J"], "last": "Huber", "suffix": ""}], "year": 1981, "venue": "", "link": null}, "BIBREF20": {"title": "Temperature measurements in gas tungsten arcs", "authors": [{"first": "G", "middle": ["N"], "last": "Haddad", "suffix": ""}, {"first": "Ajd", "middle": [], "last": "Farmer", "suffix": ""}], "year": 1985, "venue": "Welding Journal", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Arc efficiency.", "type": "figure"}, "FIGREF1": {"text": "Principle of calorimetry.", "type": "figure"}, "FIGREF2": {"text": "Experimental setup with the calorimeter.", "type": "figure"}, "FIGREF3": {"text": "Reported observations of the arc efficiency. Mean value solid line and the interquartile range dotted lines.", "type": "figure"}, "FIGREF4": {"text": "Voltage drop in welding leads.", "type": "figure"}, "FIGREF5": {"text": "Relative contribution to u c (\u03b7) during nominal measurement conditions.", "type": "figure"}, "FIGREF6": {"text": "Relative contribution to u c (\u03b7) reflecting a systematic error in the arc voltage measurement.", "type": "figure"}, "TABREF0": {"text": "Nominal welding parameters.", "type": "table"}, "TABREF1": {"text": "Uncertainty budget of the measurement.", "type": "table"}, "TABREF2": {"text": "Estimates of arc efficiency.", "type": "table"}}}
{"paper_id": "138419916", "_pdf_hash": "32496bbeab8030d0556e654959558da45906ab9e", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "102800956", "_pdf_hash": "a8d9494ffa2b899efabc323144cd873eaf778da7", "abstract": [], "body_text": [{"section": "INTRODUCTION", "text": "In the last two decades, nitrogen-rich and poly-nitrogen compounds have received significant attention due to their interesting chemical properties and potentiality to serve as environmentally friendly high energy density materials (HEDMs) [1] [2] [3] . These species release a large amount of energy during the decomposition of single/ double bonded nitrogen in the condensed phase into triple-bonded gas-phase inert N 2 molecules. Nitrogenrich compounds constitute a large family of interesting compounds, which are certainly no less active than the traditional CHON energetic materials [4, 5] . It is worth noting that they have boosted the development of energetic salts [6] [7] [8] , energetic coordination polymers (CPs, also defined as energetic metal organic frameworks (MOFs) in some cases) [9] [10] [11] , and energetic co-crystals [12, 13] , and thus significantly expanded the range of energetic materials.", "cite_spans": [{"start": 800, "end": 803, "text": "[9]", "ref_id": "BIBREF0"}, {"start": 804, "end": 808, "text": "[10]", "ref_id": "BIBREF1"}, {"start": 809, "end": 813, "text": "[11]", "ref_id": "BIBREF2"}, {"start": 842, "end": 846, "text": "[12,", "ref_id": "BIBREF3"}, {"start": 847, "end": 850, "text": "13]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "In contrast, the experimental difficulties in studying poly-nitrogen compounds have delayed their contribution to the field of energetic materials. For a very long time, only the azide anion was used to produce energetic salts or simple CPs [14, 15] . In 1999, a major breakthrough in poly-nitrogen area was achieved with the preparation of the N 5 + ion and its relative stable energetic salts were subsequently synthesized [16, 17] . Unfortunately, owing to the unstable bonding interactions with other anions, further developments of N 5 + ion have been limited. The pentazole anion cyclo-N 5 -was first detected in 2002 via mass spectrometry (MS) [18, 19] and was not adopted for bulk production until recently [20] [21] [22] [23] [24] [25] [26] . However, the anhydrous pentazole sample NaN 5 [21] and CsN 5 [22] were only observed under extreme high pressure and the metal-pentazole hydrates [24] [25] [26] decomposed in the range of 100-110\u00b0C. Both high pressure preparing method and hydrates samples are the disadvantages in terms of their application. Fortunately, the cyclo-N 5 -anion shows good adaptability to take part in ionic, coordination, and hydrogen bonding interactions [24, 27] . Furthermore, there is a possibility to form either energetic CPs or co-crystals by self-assembling, which is a new technology for modifying or enhancing the properties of existing energetic substances.", "cite_spans": [{"start": 241, "end": 245, "text": "[14,", "ref_id": "BIBREF5"}, {"start": 246, "end": 249, "text": "15]", "ref_id": "BIBREF7"}, {"start": 425, "end": 429, "text": "[16,", "ref_id": "BIBREF8"}, {"start": 430, "end": 433, "text": "17]", "ref_id": "BIBREF9"}, {"start": 651, "end": 655, "text": "[18,", "ref_id": "BIBREF11"}, {"start": 656, "end": 659, "text": "19]", "ref_id": "BIBREF13"}, {"start": 715, "end": 719, "text": "[20]", "ref_id": "BIBREF15"}, {"start": 720, "end": 724, "text": "[21]", "ref_id": "BIBREF16"}, {"start": 725, "end": 729, "text": "[22]", "ref_id": "BIBREF17"}, {"start": 730, "end": 734, "text": "[23]", "ref_id": "BIBREF18"}, {"start": 735, "end": 739, "text": "[24]", "ref_id": "BIBREF19"}, {"start": 740, "end": 744, "text": "[25]", "ref_id": "BIBREF20"}, {"start": 745, "end": 749, "text": "[26]", "ref_id": "BIBREF22"}, {"start": 798, "end": 802, "text": "[21]", "ref_id": "BIBREF16"}, {"start": 813, "end": 817, "text": "[22]", "ref_id": "BIBREF17"}, {"start": 898, "end": 902, "text": "[24]", "ref_id": "BIBREF19"}, {"start": 903, "end": 907, "text": "[25]", "ref_id": "BIBREF20"}, {"start": 908, "end": 912, "text": "[26]", "ref_id": "BIBREF22"}, {"start": 1190, "end": 1194, "text": "[24,", "ref_id": "BIBREF19"}, {"start": 1195, "end": 1198, "text": "27]", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "In this work, anhydrous coordination polymers (NaN 5 ) 5 [(CH 6 N 3 )N 5 ](N 5 ) \u2212 3 (1) and (NaN 5 ) 2 (C 2 H 4 N 4 ) (2) have been synthesized with ion exchange method. The formation of these crystals is mainly assisted by coordination bonding between the metal ion Na + , inorganic cyclo-N 5 and organic components, which exceed the range of MOFs and shall be classified as CPs. Moreover, the diverse structure and thermal stabilization reveal another advantage of the crystal approach to access explosives with high performance.", "cite_spans": [], "ref_spans": []}, {"section": "EXPERIMENTAL SECTION", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Safety precautions", "text": "Caution! The energetic coordination polymers with cyclo-N 5 -are partly extremely high energetic compounds that may detonate violently; therefore they should be handled only on a very small scale while using appropriate safety precautions (safety glasses, face shield, leather coat, earthen equipment and shoes, Kevlar gloves and ear plugs).", "cite_spans": [], "ref_spans": []}, {"section": "Materials and methods", "text": "All reagents and solvents were purchased from SigmaAldrich, Aladdin, and Energy Chemical as analytical grade and were used as received. The single crystal X-ray diffraction (XRD) measurements were conducted on a Bruker Smart Apex II diffractometer using Mo-K\u03b1 radiation (\u03bb = 0.71073 \u00c5) with a graphite monochromator at 170 K. XRD data were collected with Cu K\u03b1 radiation on Bruker D8 ADVANCE scanning from 10\u00b0to 80\u00b0. Fourier transform infrared spectroscopy (FT-IR) spectra were recorded on a Thermo Nicolet IS10 instrument. Raman spectra were collected using a Horiba-Jobin Yvon Labram HR800 Raman spectrometer with a 514.532 nm Ar + laser. A 50\u00d7 objective was used to focus the laser beam. Differential scanning calorimeter (DSC) plots were acquired on a differential scanning calorimeter (Mettler Toledo DSC-1) at a scan rate of 5\u00b0C min \u22121 in perforated stainless steel containers under a nitrogen flow of 50 mL min \u22121 . Transmission electron microscope (TEM) was performed on FEI Tecnai G2 F30 S-TWIN.", "cite_spans": [], "ref_spans": []}, {"section": "Materials and methods", "text": "All computations were performed using the Gaussian 09 program [28] invoking hybrid HF-DFT calculations with the three-parameter gradient-corrected exchange potential of Becke and the gradient-corrected correlation potential of Lee, Yang, and Parr (B3LYP) [29, 30] using the 6-311G* basis set. The structures were optimized for energy minimization before spectra acquisition and frequency calculations. The wave-functions of coordination polymers generated from Gaussian were imported into the software Multiwfn [31] to calculate the reduced density gradient (RDG) which was used for revealing noncovalent interactions [32] analysis.", "cite_spans": [{"start": 62, "end": 66, "text": "[28]", "ref_id": "BIBREF24"}, {"start": 255, "end": 259, "text": "[29,", "ref_id": "BIBREF25"}, {"start": 260, "end": 263, "text": "30]", "ref_id": "BIBREF26"}, {"start": 511, "end": 515, "text": "[31]", "ref_id": "BIBREF27"}, {"start": 618, "end": 622, "text": "[32]", "ref_id": "BIBREF28"}], "ref_spans": []}, {"section": "Crystallography", "text": "Integration and scaling of intensity data was accomplished using the SAINT program [33] . The structures were solved by intrinsic using SHELXT2014 and refinement was carried out by a full-matrix least-squares technique using SHELXT2014 [34] . The hydrogen atoms were refined isotropically, and the heavy atoms were refined anisotropically. N-H and O-H hydrogens were located from different electron density maps, and C-H hydrogens were placed in calculated positions and refined with a riding model. Data were corrected for the effects of absorption using SADABS [35] .", "cite_spans": [], "ref_spans": []}, {"section": "Synthetic procedures [Na(H 2 O)(N 5 )]\u00b72H 2 O:", "text": "This compound was prepared according to our previously reported methods [21] . A solution of arylpentazole (5.000 g, 26.18 mmol) and ferrous glycinate (8.600 g, 42.16 mmol) in a mixed solution of 100 mL methyl alcohol and 100 mL acetonitrile was stirred at -47\u00b0C. After 30 min, metachloroperbenzoic acid (85%, 19.25 g, 94.82 mmol) was added in portions. The reaction mixture was maintained at -43\u00b0C for 24 h. The precipitate was removed by filtration, and the filtrate was vaporized under reduced pressure. The residue was suspended in 200 mL of water. The precipitate was filtered off and washed with 50 mL water. The filtrate was concentrated. After removing all the solvent under vacuum, the residue was purified by chromatography with ethyl alcohol/ethyl acetate (1:10-1:3 gradient elution). Crude NaN 5 hydrate was obtained as an off-white product (427 mg, 19.56%).", "cite_spans": [{"start": 72, "end": 76, "text": "[21]", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Synthetic procedures [Na(H 2 O)(N 5 )]\u00b72H 2 O:", "text": "[Na 5 (CH 6 N 3 )(N 5 ", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS AND DISCUSSION", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Crystal structure", "text": "The prepared CPs are analyzed by single-crystal XRD as shown in Table 1 . Polymer 1 crystallizs into a 3D porous metal-inorganic framework with hexagonal crystal system and belongs to the P6 3 /mmc space group. Here the polymer 1 represents a negatively charged structure, because sometimes charge-balancing cations in the cages is irregular and cannot be directly located in the crystal structure analysis. The detailed crystallographic data are provided in Supplementary Tables S1-S3. As depicted in Fig. 1 , each sodium center Na(I) is hexahedral linked to pentazole linkers (Na-N bond length 2.462-2.499\u00c5), involving a \u03b7 1 -bonding-type coordination. There are two types of pentazole rings in polymer 1. The first type is one N 5 ring attached to three Na(I) ions with coordination angle of \u223c90 and 140\u00b0(Na\u2212N 5 \u2212Na), analogous to imidazolate rings in zeolite\u2212imidazolate frameworks (ZIFs). The N atoms in these N 5 rings are not completely coplane, with N1-N2-N3-N4 and N1-N5-N4-N3 torsion angles of 0.5\u00b0and 0.7\u00b0, respectively. The second type is one N 5 ring attached to four Na(I) ions with coordination angle of \u223c150\u00b0(Na\u2212N 5 \u2212Na). These N 5 rings and Na(I) are of perfect planarity and the plane is perpendicular to c axis. Moreover, the N 5 rings in both types do not have identical N-N bond lengths with average values found to be 1.316 and 1.320 \u00c5 respectively. Through these connection modes, 8 Na(I) ions and 9 N 5 rings stitch into a cage of a \u223c7.5 \u00c5 diameter cavity with guanidine cation [C (NH 2 ) 3 ] + placed in it. The cage as a repeat unit is further extended into microporous zeolite-like 3D framework with SOD topology (Fig. 1c) . Upon removal of guest molecules, the structure of polymer 1 has a porosity of \u223c35%, as calculated with PLATON software [36] .", "cite_spans": [{"start": 1771, "end": 1775, "text": "[36]", "ref_id": "BIBREF32"}], "ref_spans": [{"start": 64, "end": 71, "text": "Table 1", "ref_id": "TABREF0"}, {"start": 502, "end": 508, "text": "Fig. 1", "ref_id": "FIGREF2"}, {"start": 1640, "end": 1649, "text": "(Fig. 1c)", "ref_id": "FIGREF2"}]}, {"section": "Crystal structure", "text": "In contrast to CP 1, both N 5 and 4-amino-1,2,4-triazole (ATz) rings act as a linker in 2 and form a different kind of 3D porous framework with trigonal crystals in the P3 2 21 space group (Tables S4, S5 ). As shown in Fig. 2 and Fig. S4 , all of the N atoms in the pentazole ring are coordinated to Na(I). The atoms N2 and N5 participate in constructing the DNA-like double helix structure. The atoms N1, N3, and N4, together with the N atoms in the ATz ring form links between the different helices, whose dihedral angle with the ab plane is~70\u00b0. The N atoms in these N 5 rings are not perfectly coplanar, with N1-N2-N3-N4 and N1-N5-N4-N3 torsion angles being 0.5\u00b0and 0.2\u00b0, respectively. As all of the N atoms in the N 5 rings are in the same chemical environment that is affected by the weak coordination with the Na(I) ion and all the Na-N bond length being~2.5 \u00c5, the N 5 ring retains almost identical N-N bond lengths; these bonds are of length 1.317 \u00c5. Six groups of double helices construct a channel of 9.5 \u00c5 diameter, similar to that in zeolites (Fig. 2c) . However, in contrast to the typical zeolites, the channel in 2 is filled with coordinated ATz rings, which implies that ", "cite_spans": [], "ref_spans": [{"start": 219, "end": 225, "text": "Fig. 2", "ref_id": "FIGREF1"}, {"start": 1056, "end": 1065, "text": "(Fig. 2c)", "ref_id": "FIGREF1"}]}, {"section": "Spectra analysis", "text": "A comparison of the spectra of CPs 1 and 2 together with that of the starting material is shown in Fig. 3 . This figure reveals that several band shifts occur when the three CPs are formed. Furthermore, it indicates the existence of weak interactions between the individual components even when they are not directly coordinated. Both the coordination bond and weak interactions cause a deformation of cyclo-N 5 -in frameworks. From the geometric parameters of the N 5 ring in 1 and 2, it can be concluded that the tri-and tetradentate cyclo-N 5 -(N 5 -1A and N 5 -1B in 1), pentadentate cyclo-N 5 -anion (N 5 -2) all represent C 2v symmetry. However, the coordination effect between Na + and cyclo-N 5 -in the CPs is weaker than that . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ", "cite_spans": [], "ref_spans": [{"start": 99, "end": 105, "text": "Fig. 3", "ref_id": "FIGREF5"}]}, {"section": "ARTICLES", "text": "January 2019 | Vol. 62 No. 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 of previously reported transition metal-N 5 -complexes. So the bond lengths in cyclo-N 5 -, especially N 5 -2, vary slightly and they are also close to D 5h symmetry, with IR spectra at 1,225 and 1,229 cm -1 observed respectively in Fig. 3a . From Raman spectra, the typical cyclo-N 5 -in C 2v symmetry with significantly different bond length in N 5 -1B compared with previous transition metal complexes represents a strong peak at 1,170-1,190 cm -1 in Fig. 3b ; the other cyclo-N 5 -in C 2v symmetry including N 5 -1A and N 5 -2 with similar bond length which is also close to D 5h symmetry shows a strong peak at 1,000-1,010 cm (Fig. S5) ; meanwhile, they also show that the cyclo-N 5 -is unstable under electron beam.", "cite_spans": [], "ref_spans": [{"start": 23, "end": 202, "text": "No. 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125", "ref_id": "FIGREF1"}, {"start": 436, "end": 443, "text": "Fig. 3a", "ref_id": "FIGREF5"}, {"start": 657, "end": 664, "text": "Fig. 3b", "ref_id": "FIGREF5"}]}, {"section": "Thermal properties", "text": "The DSC curves of the synthesized CPs are shown in Fig.  4 . No endothermic peaks can be observed below 100\u00b0C, which suggests that the polymers contain very little water. The first exothermic peak of 1 and 2 is observed at 118.4 and 126.5\u00b0C (onset temperature). This suggests a decomposition of the CPs takes place during the heating sequence and from an assessment of the amount of heat released. The products of CPs 1 and 2 heated at 118.4 and 126.5\u00b0C were tested with FeCl 3 solution and the color of solution turned into red, which indicated that both of them have decomposed from cyclo-N 5 \u2212 to N 3 \u2212 (Fig. S6) . The decomposition point, compared with that of the 1D structure [Na(H 2 O)(N 5 )]\u00b72H 2 O, is increased by 7.4 and 15.5\u00b0C in 1 and 2, respectively. These observations indicate that the coordination and hydrogen bonding interactions (Fig. S7) is beneficial for stabilizing the N 5 ring. From another point of view, the identical N-N bond lengths are indicative of better conjugation and stability.", "cite_spans": [], "ref_spans": []}, {"section": "Detonation properties", "text": "The heat of detonation is greatly affected by the standard enthalpies of formation of energetic CPs, which is calculated using their constant-volume combustion energies. . . . . . . . . . . . . . . . . . . . . . . . . SCIENCE CHINA Materials   126 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . , and detonation pressure (P) are pivotal parameters for energetic CPs. On the basis of the largest exothermic principle proposed by Kamlet-Jacobs (K-J) [37] , We employed a widely used empirical method [38, 39] proposed by Pang and coworkers [40] to investigate the detonation properties of metal-containing energetic CPs. The detonation reactions of CP 1 and 2 are described by Equation S5, 6, and the detonation properties are calculated by K-J equations (see Supporting Information). As shown in Table 2 , the nitrogen contents (>66%) and heats of formation (>800 kJ mol \u22121 ) for the two CPs are much higher than those of the traditional energetic materials (TNT, RDX, and HMX). But only the heat of detonation for CP 2 (1.65 kcal g \u22121 ) is higher than those of TNT, RDX, HMX, and CL-20 (about 1.5 kcal g \u22121 ). The D and P of CP 2 are calculated to be 7,863 m s \u22121 and 26.44 GPa, respectively, which are slightly higher than TNT. The poor detonation performance of CP 1 is attributed to their low density (<1.3 g cm \u22123 ) caused by porous structure. From another point of view, this porous structure may hold other small energetic materials and improve the energetic performance.", "cite_spans": [{"start": 533, "end": 537, "text": "[37]", "ref_id": "BIBREF33"}, {"start": 583, "end": 587, "text": "[38,", "ref_id": "BIBREF34"}, {"start": 588, "end": 591, "text": "39]", "ref_id": "BIBREF35"}, {"start": 623, "end": 627, "text": "[40]", "ref_id": "BIBREF36"}], "ref_spans": [{"start": 170, "end": 379, "text": ". . . . . . . . . . . . . . . . . . . . . . . . SCIENCE CHINA Materials   126 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .", "ref_id": "FIGREF1"}, {"start": 880, "end": 887, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "CONCLUSIONS", "text": "The target of our designs is to obtain multidimensional structure that possess the potential high energy (provided by N 5 ) and better stability compared with previously reported species (through coordination and hydrogen bonding provided by framework). With this strategy, guanidine hydrochloride and ATz standing for the cation and neutral molecule with similar size are employed to coordinate with NaN 5 . Two novel energetic CPs, (NaN 5 ) 5 -[(CH 6 N 3 )N 5 ](N 5 ) \u2212 3 and (NaN 5 ) 2 (C 2 H 4 N 4 ), were synthesized and characterized. From crystal structure analysis, the cyclo-N 5 \u2212 anion shows a unique coordination ability that some other polynitrogen species do not have. In CPs 1 and 2, it can form tri-, quadri-and pentadentate with central Na + due to the various coordination positions and represents two different structures. As a result of the coordination effect, hydrogen bonding and structural modification, cyclo-N 5 \u2212 anions in CPs 1 and 2 possess better thermal stability (118.4 and 126.5\u00b0C as onset decomposition temperature) than that in NaN 5 and its hydrate [Na(H 2 O)(N 5 )]\u00b72H 2 O. Moreover, the fully coordination of possible positions prevents H 2 O entering the crystal and generates anhydrate compounds, which is a big forward step to obtain final energetic materials. The 3D CPs 1 and 2 also show high heats of formation (>800 kJ mol \u22121 ). Considering their detonation properties, the anhydrous products of sodium-pentazole species with better thermal stability and higher heats of formation are potential to being applied in HEDMs. ). f) The heat of detonation. g) Detonation velocity. h) Detonation pressure.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "High-energy metal-organic frameworks (HE-MOFs): Synthesis, structure and energetic performance", "authors": [{"first": "S", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "Q", "middle": [], "last": "Yang", "suffix": ""}, {"first": "X", "middle": [], "last": "Liu", "suffix": ""}], "year": 2016, "venue": "Coord Chem Rev", "link": "94552867"}, "BIBREF1": {"title": "3D energetic metal-organic frameworks: synthesis and properties of high energy materials", "authors": [{"first": "S", "middle": [], "last": "Li", "suffix": ""}, {"first": "Y", "middle": [], "last": "Wang", "suffix": ""}, {"first": "C", "middle": [], "last": "Qi", "suffix": 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The colorless solution was evaporated to dryness followed by repeated recrystallization in anhydrous ethanol to remove the sodium nitrate. Single crystal of 2 was obtained by maintaining 95% alcohol solutions at ambient tempera- ture for several days. Colorless crystals; yield: 80%; T d = 118.4\u00b0C; IR (KBr): = 3,473, 3,354, 3,161, 1,653, 1,354, 1,225, 1,013, 729 cm \u22121 ; Raman (514.532 nm, 25\u00b0C): 1,172, 1,008, 118 cm \u22121 . [(NaN 5 ) 2 (C 2 H 4 N 4 )] (2): 1.0 mmol of [Na(H 2 O)-(N 5 )]\u00b72H 2 O (147 mg) and 1.0 mmol of 4-amino-1,2,4- triazole (84 mg) was added to 15 mL methanol. Colorless rod-like crystal of 2 was obtained by maintaining the solutions at ambient temperature for several days. Col- orless crystals; yield: 82%; T d = 126.5\u00b0C; IR (KBr):", "type": "figure"}, "FIGREF1": {"text": "Figure 2 Crystal structure of 2. (a) The coordination mode of Na + in CP 2. (b) A topological net of simplified unit cell. (c) Two-helical structure of simplified unit cell. (d) Unit cell stacking diagram view along a axis (4\u00d74\u00d74). (e) Unit cell stacking diagram view along c axis (4\u00d74\u00d74). Carbon, hydrogen, nitrogen, oxygen, and sodium atoms are shown in gray, white, blue, red, and purple respectively.", "type": "figure"}, "FIGREF2": {"text": "Figure 1 Crystal structure of 1. (a) The coordination mode of Na + in CP 1. (b) Perspective view of the coordination mode along c axis. (c) A topological net of simplified unit cell. (d) Unit cell stacking diagram view along b axis (4\u00d74\u00d74). (e) Unit cell stacking diagram view along c axis (4\u00d74\u00d74). Carbon, hydrogen, nitrogen, oxygen, and sodium atoms are shown in gray, white, blue, red, and purple respectively.", "type": "figure"}, "FIGREF3": {"text": "That is to say although N 5 -1A and N 5 -2 belongs to C 2v sym- metry in theoretical, but they indeed present the prop- erties of D 5h symmetry because of very close N-N bond length. Combining previous reports and the results of this paper, cyclo-N 5 -can provide up to five coordination po- sitions and all of them show C 2v symmetry. The absolute configuration of D 5h symmetry is difficult to be achieved even in the pentadentate cyclo-N 5 -(N 5 -2) in which each N atom is at almost the same chemical conditions or non- dentate cyclo-N 5 -[Mg(H 2 O) 6 (N 5 ) 2 ]\u00b74H 2 O [23]. The experimental powder XRD (PXRD) patterns for the CPs 1 and 2 are shown in Fig. S4. Comparison of the experimental XRD pattern with the calculated pattern for the simulated unit cell shows good agreement of the re- flection positions. The PXRD patterns of the CPs differed from those of the constituents, confirming the formation of a new complex phase. HRTEM pictures confirm the new formed phases of prepared samples are highly or- dered structures", "type": "figure"}, "FIGREF4": {"text": "Figure 4 Differential scanning calorimetry spectra of CPs 1 and 2. The point of decomposition temperature is onset temperature.", "type": "figure"}, "FIGREF5": {"text": "Figure 3 Geometric parameter, FT-IR and Raman spectra of CPs 1 and 2. (a) Bond length of tri-quadri-, and pentadentate-cyclo-N 5 -in CPs 1 and 2. (b) FT-IR spectra of CPs 1 and 2, Gu (guanidine hydrochloride), and ATz (4-amino-1,2,4-triazole). (c) Raman spectra of CPs 1 and 2, Gu, and ATz.", "type": "figure"}, "FIGREF6": {"text": ". . . . January 2019 | Vol. 62 No. 1 and 2 are obtained via the known \u0394 f H m \u04e9 of the com- bustion products and \u0394 C H m \u04e9 of CP 1 and 2 (see ESI). Heat of detonation (Q), detonation velocity (D)", "type": "figure"}, "FIGREF7": {"text": "March 2018; accepted 30 March 2018; published online 27 April 2018 1 Christe KO. Polynitrogen chemistry enters the ring. Science, 2017, 355: 351-351 2 Klap\u00f6tke TM. Chemistry of High-Energy Materials. Boston: De Gruyter, 2017 3 Yin P, Shreeve JM. Advances in heterocyclic chemistry. London: Elsevier, 2017, 121: 89-131 4 Zhang Q, Shreeve J'M. Energetic ionic liquids as explosives and propellant fuels: a new journey of ionic liquid chemistry. Chem Rev, 2014, 114: 10527-10574 5 Singh RP, Gao H, Meshri DT, Shreeve JM. High Energy Density Materials. Berlin: Springer, 2007, 35-83 6 Chen SL, Yang ZR, Wang BJ, et al. Molecular perovskite high- energetic materials. Sci China Mater, 2018, 61: 1123-1128 7 Gao H, Shreeve J'M. Azole-based energetic salts. Chem Rev, 2011, 111: 7377-7436 8 Fischer N, Fischer D, Klap\u00f6tke TM, et al. Pushing the limits of energetic materials-the synthesis and characterization of dihy- droxylammonium 5,5'-bistetrazole-1,1'-diolate. J Mater Chem, 2012, 22: 20418-20422", "type": "figure"}, "FIGREF9": {"text": "from low-temperature X-ray densities (\u03c1 = \u03c1 T /(1 + \u03b1 V (298 -T 0 )); \u03b1 V =1.5\u00d710. b) Nitrogen content. c) Oxygen balance. d) Calculated heat of formation. e) Thermal decomposition temperature (onset) under nitrogen gas (DSC, 5\u00b0C min \u22121", "type": "figure"}, "TABREF0": {"text": "Crystal data and structure refinement details of CPs 1 and 2", "type": "table"}, "TABREF1": {"text": "Properties of 1 and 2 and comparison with TNT, RDX, and HMX", "type": "table"}}}
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{"paper_id": "102809339", "_pdf_hash": "1e721c817a9275555099fd28d2c3ef136dbb6709", "abstract": [{"section": "Abstract", "text": "Research on corrosion protection of aluminum has intensified over the past decades due to environmental concerns regarding chromate-based conversion coatings and also the higher material performance requirements in automotive and aviation industries. Phosphonic acid-based organic and organic-inorganic coatings are increasingly investigated as potential replacements of toxic and inefficient surface treatments for aluminum. In this review, we have briefly summarized recent work (since 2000) on pretreatments or coatings based on various phosphonic acids for aluminum and its alloys. Surface characterization methods, the mechanism of bonding of phosphonic acids to aluminum surface, methods for accessing the corrosion behavior of the treated aluminum, and applications have been discussed. There is a clear trend to develop multifunctional phosphonic acids and to produce hybrid organic-inorganic coatings. In most cases, the phosphonic acids are either assembled as a monolayer on the aluminum or incorporated in a coating matrix on top of aluminum, which is either organic or organic-inorganic in nature. Increased corrosion protection has often been observed. However, much work is still needed in terms of their ecological impact and adaptation to the industrially-feasible process for possible commercial exploitation.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Aluminum (Al) and its alloys have been widely used in engineering applications because of their higher strength to weight ratio, ductility, formability, and lower costs. In many applications, such as in aircraft, automobiles, and structural parts in buildings, its corrosion resistance becomes very important. Aluminum, by itself, is relatively stable to corrosion because it readily oxidizes to form a passive protective oxide layer on its surface which is robust and does not simply flake off. However, the galvanic corrosion of aluminum is very critical and is complicated in various alloys and under acidic pH. An excellent review on corrosion protection of aluminum prior to the year 2000 can be found in the literature [1] . The need to develop chromate-free treatments for aluminum is becoming increasingly important. Many organic and inorganic protective coatings are being investigated by researchers with the potential advantages and shortcomings [1] . Organic-inorganic conversion coatings are quite attractive due to the simplicity of their application and possible favorable interaction with organic layers in hybrid materials, which offer enhanced corrosion resistance and mechanical performance [2] .", "cite_spans": [{"start": 725, "end": 728, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 957, "end": 960, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 1210, "end": 1213, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Introduction", "text": "A variety of phosphonic acids is commonly used to modify the surfaces of metals and their oxides for their corrosion protection, stabilization as nano-particles, adhesion improvement to organic layers, hydrophobization, hydrophilization, etc. They are excellent chelating agents and bind very strongly to metals resulting in different 1D to 3D metal organic frameworks (MOFs), also called metal phosphonates [3, 4] . They form hydrolytically-stable bonds with the metals and provide excellent coverage compared to many thiols, silanes, and carboxylic acids. A phosphonate corrosion inhibitor adsorbs well on the metal surface, reducing its solubility in aqueous media and, thus, decreases the area of active metal surface and increases the activation energy to hydrolysis. Such phosphonic acids can be a simple molecule where the phosphonic acid is attached to an alkyl or aromatic group. Self-assembly of such phosphonic acids on aluminum surface is well studied where the binding of these molecules to aluminum can be monodentate, bidentate, or tridentate [5] [6] [7] . More recently there is an increased impetus to develop functional phosphonic acids, which can not only bind to the metal surface but also provide linkage to an organic matrix in multicomponent systems [8, 9] . In some cases, phosphonic acid acts as a linker between aluminum and a hydrophobic polymerizable group (pyrrole) [10] or chemically-stable protective material (graphene oxide) [11] . Such molecules are applied on the surface of aluminum via dip coatings, spray from aqueous solutions, or are incorporated in a polymeric matrix (adhesives, glues, or paints) which is then coated on the metal surface. A novel ultrasonic assisted deposition (USAD) method has also been developed to coat phosphate films on aluminum [12] . This application procedure is believed to improve the interaction of the phosphonic acid to the aluminum surface.", "cite_spans": [{"start": 408, "end": 411, "text": "[3,", "ref_id": "BIBREF2"}, {"start": 412, "end": 414, "text": "4]", "ref_id": "BIBREF3"}, {"start": 1058, "end": 1061, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 1066, "end": 1069, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 1273, "end": 1276, "text": "[8,", "ref_id": "BIBREF7"}, {"start": 1277, "end": 1279, "text": "9]", "ref_id": "BIBREF8"}, {"start": 1395, "end": 1399, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 1458, "end": 1462, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Introduction", "text": "Functional phosphonic acids with hydrophobic aliphatic groups or fluorinated groups can increase the hydrophobicity of the metal surface, thereby acting as barrier to aqueous solutions and improving its corrosion protection. In some cases the functional groups of phosphonic acids react with organic layers (adhesives) and provide a stable barrier against aqueous environments.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The following sections first briefly summarize the methods for characterization of phosphonic acids on aluminum surfaces and several techniques used to evaluate the corrosion behavior, in order to understand the following chapter, which deals with the application of various types of phosphonic acids on aluminum, together with their physico-chemical behavior relevant to corrosion protection and adhesion to organic layers. Thereby, a distinction has been made between the aluminum surface treatment with phosphonic acids or phosphates as a pre-coating and surface coatings dissolved in paints that contain phosphonic acids.", "cite_spans": [], "ref_spans": []}, {"section": "Characterization of the Phosphonic Acid-Modified Aluminum Surfaces", "text": "Self-assembled monolayers (SAM) are ordered molecular assemblies and are commonly used to modify aluminum surfaces. They are spontaneously formed by the adsorption of molecules with head groups that show affinity to a specific substrate [13] . Phosphonic acids form SAMs on aluminum surfaces by condensation reactions of the acid functional group with basic surface-bound alumino-hydroxyl species. Thereby, the phosphonic acid head group shows a strong affinity to the aluminum substrate, creating an alumino-phosphonate linkage via a strong Al-O-P chemical bond:", "cite_spans": [{"start": 237, "end": 241, "text": "[13]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "R-PO(OH) 2 + Al-OH\u2192R-(OH)OP-O-Al + H 2 O [5-7].", "text": "To investigate a successful formation of the organophosphorus layers, including information about the properties of the films (surface morphology, structural ordering, density and uniformity, binding mode to the aluminum substrate, as well as stability), different analytical methods have been applied in the literature. A detailed characterization of the layers is necessary to understand their intended function (for instance corrosion protection, adhesion promotion, (non)-wettability, surface passivation). Table 1 summarizes the various analytical techniques that have been used in the last 20 years, or so, to study the organization and chemistry of organophosphorus compounds on an aluminum substrate. Various characterization techniques have been categorized by us into three groups: Surface morphology; presence, composition, and stability of layers; orientation of molecules and binding mode to aluminum, and are all briefly explained in the remainder of this section. ", "cite_spans": [], "ref_spans": [{"start": 511, "end": 518, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Characterization Technique Literature", "text": "Surface morphology Scanning electron microscopy (SEM) [9, 14, 15 ] Atomic force microscopy (AFM) [8, 15] Presence, composition and stability of layer X-ray photoelectron spectroscopy (XPS) [6] [7] [8] 11, [16] [17] [18] [19] [20] [21] Auger electron spectroscopy (AES) [22] Fourier-transform infrared spectroscopy (FTIR) [8, 11, 14, 16, 17, 23, 24 ] Time-of-flight secondary ion mass spectrometry (ToF-SIMS)", "cite_spans": [{"start": 54, "end": 57, "text": "[9,", "ref_id": "BIBREF8"}, {"start": 58, "end": 61, "text": "14,", "ref_id": "BIBREF13"}, {"start": 62, "end": 64, "text": "15", "ref_id": "BIBREF14"}, {"start": 97, "end": 100, "text": "[8,", "ref_id": "BIBREF7"}, {"start": 101, "end": 104, "text": "15]", "ref_id": "BIBREF14"}, {"start": 193, "end": 196, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 197, "end": 200, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 201, "end": 204, "text": "11,", "ref_id": "BIBREF10"}, {"start": 205, "end": 209, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 210, "end": 214, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 215, "end": 219, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 220, "end": 224, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 225, "end": 229, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 230, "end": 234, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 269, "end": 273, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 321, "end": 324, "text": "[8,", "ref_id": "BIBREF7"}, {"start": 325, "end": 328, "text": "11,", "ref_id": "BIBREF10"}, {"start": 329, "end": 332, "text": "14,", "ref_id": "BIBREF13"}, {"start": 333, "end": 336, "text": "16,", "ref_id": "BIBREF15"}, {"start": 337, "end": 340, "text": "17,", "ref_id": "BIBREF16"}, {"start": 341, "end": 344, "text": "23,", "ref_id": "BIBREF22"}, {"start": 345, "end": 347, "text": "24", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Characterization Technique Literature", "text": "[6] Water contact angle measurements (WCA) [5, 7, 10, 16, 25, 26] Orientation of molecules and binding mode to aluminum", "cite_spans": [{"start": 43, "end": 46, "text": "[5,", "ref_id": "BIBREF4"}, {"start": 47, "end": 49, "text": "7,", "ref_id": "BIBREF6"}, {"start": 50, "end": 53, "text": "10,", "ref_id": "BIBREF9"}, {"start": 54, "end": 57, "text": "16,", "ref_id": "BIBREF15"}, {"start": 58, "end": 61, "text": "25,", "ref_id": "BIBREF24"}, {"start": 62, "end": 65, "text": "26]", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "Characterization Technique Literature", "text": "Angle-resolved X-ray photoelectron spectroscopy (ARXPS) [7, 10, 27 ,28] Infrared reflection absorption spectroscopy at grazing angle (IRRAS) [5, 12, 16, [29] [30] [31] [32] [33] ] X-ray photoelectron spectroscopy (XPS) [20, 28, 34 ] Solid-state 31 P nuclear magnetic resonance (NMR) [12, [31] [32] [33] ", "cite_spans": [{"start": 56, "end": 59, "text": "[7,", "ref_id": "BIBREF6"}, {"start": 60, "end": 63, "text": "10,", "ref_id": "BIBREF9"}, {"start": 64, "end": 66, "text": "27", "ref_id": "BIBREF26"}, {"start": 141, "end": 144, "text": "[5,", "ref_id": "BIBREF4"}, {"start": 149, "end": 152, "text": "16,", "ref_id": "BIBREF15"}, {"start": 153, "end": 157, "text": "[29]", "ref_id": "BIBREF28"}, {"start": 158, "end": 162, "text": "[30]", "ref_id": "BIBREF29"}, {"start": 163, "end": 167, "text": "[31]", "ref_id": "BIBREF30"}, {"start": 168, "end": 172, "text": "[32]", "ref_id": "BIBREF31"}, {"start": 173, "end": 177, "text": "[33]", "ref_id": "BIBREF32"}, {"start": 219, "end": 223, "text": "[20,", "ref_id": "BIBREF19"}, {"start": 224, "end": 227, "text": "28,", "ref_id": "BIBREF27"}, {"start": 228, "end": 230, "text": "34", "ref_id": "BIBREF33"}, {"start": 288, "end": 292, "text": "[31]", "ref_id": "BIBREF30"}, {"start": 293, "end": 297, "text": "[32]", "ref_id": "BIBREF31"}, {"start": 298, "end": 302, "text": "[33]", "ref_id": "BIBREF32"}], "ref_spans": []}, {"section": "Surface Morphology", "text": "Microscopy measurements, i.e., optical microscopy, scanning electron microscopy (SEM) and atomic force microscopy (AFM), were used to investigate the surface morphology of the organophosphorus self-assembled monolayers onto the aluminum substrate. Physical characteristics, like uniformity and homogeneity of the surface phosphatization, were obtained by comparing the coated with the bare aluminum substrate using SEM [14] . AFM has been used to obtain information about the surface smoothness [8, 15] .", "cite_spans": [{"start": 419, "end": 423, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 495, "end": 498, "text": "[8,", "ref_id": "BIBREF7"}, {"start": 499, "end": 502, "text": "15]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Presence, Composition, and Stability of Layer", "text": "A variety of surface sensitive analytical techniques has been used to investigate the presence of the layer and its composition. X-ray photoelectron spectroscopy (XPS) and Auger electron spectroscopy (AES) are both methods which determine the elemental composition in the first couple of nanometers of a surface and, hence, were often applied to verify the presence of phosphorus, indicating a successful organophosphorus coating chemically-bound to aluminum [6, 8, 11, 16, 17, [19] [20] [21] [22] . As a general preparative step, the samples were usually rinsed/washed after the coating process to remove the residual chemicals and physically adsorbed organophosphorus compounds. In addition to the determination of the presence of the organophosphorus coating, XPS was also used to study the concentration of the organic molecules on the aluminum surface [18] . The experimental phosphorus to aluminum concentration ratio allowed the quantification of the organophosphorus molecule surface concentration and modelling of the XPS data helped to determine the thickness of the monolayer [18] . Thereby, the ratio of signals from the coating and from the underlying aluminum substrate was recorded, from which the coating thickness can be derived. Depth profiling via argon ion sputtering in combination with XPS was also used to determine the coating thickness (especially for thicker layers). The comparison between experimental and theoretical values for the carbon-to-phosphorus ratio was used as proof that chemically-uniform organophosphorus films formed on aluminum [7] . The recording of characteristic binding energies allowed to follow the individual steps in the decomposition of the phosphonates on the aluminum surface [20] . Table 2 summarizes XPS binding energies found in the literature for organophosphorus layers on metal surfaces.", "cite_spans": [{"start": 463, "end": 465, "text": "8,", "ref_id": "BIBREF7"}, {"start": 466, "end": 469, "text": "11,", "ref_id": "BIBREF10"}, {"start": 470, "end": 473, "text": "16,", "ref_id": "BIBREF15"}, {"start": 474, "end": 477, "text": "17,", "ref_id": "BIBREF16"}, {"start": 478, "end": 482, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 483, "end": 487, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 488, "end": 492, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 493, "end": 497, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 857, "end": 861, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 1087, "end": 1091, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 1572, "end": 1575, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 1731, "end": 1735, "text": "[20]", "ref_id": "BIBREF19"}], "ref_spans": [{"start": 1738, "end": 1745, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "Presence, Composition, and Stability of Layer", "text": "Another analytical technique often used to study the presence and composition of organophosphorus layers on aluminum is reflectance Fourier-transform infrared spectroscopy (FTIR), often measured at a grazing angle to increase the surface sensitivity. FTIR was applied to investigate the adsorption of the coating by detecting specific vibrational modes involving phosphorus bonds [8, 11, 14, 16, 17, 23, 24] . Table 3 contains a summary of frequencies of vibrational modes involving the phosphorus atom found in the literature for self-assembled organophosphorus monolayers on aluminum. Time-of-flight secondary ion mass spectrometry (ToF-SIMS), as a complementary technique to XPS, has also been used to demonstrate the presence of the organophosphorus layer, thereby investigating selective functionalization on aluminum and glass regions of a surface by mapping analysis [6] . In addition, surface plasmon resonance spectroscopy (SPR) was applied to examine the kinetics of the adsorption process [27] . Thereby, it was found that the adsorption process of phosphonic acids on aluminum starts very quickly and reaches a plateau after some minutes.", "cite_spans": [{"start": 380, "end": 383, "text": "[8,", "ref_id": "BIBREF7"}, {"start": 384, "end": 387, "text": "11,", "ref_id": "BIBREF10"}, {"start": 388, "end": 391, "text": "14,", "ref_id": "BIBREF13"}, {"start": 392, "end": 395, "text": "16,", "ref_id": "BIBREF15"}, {"start": 396, "end": 399, "text": "17,", "ref_id": "BIBREF16"}, {"start": 400, "end": 403, "text": "23,", "ref_id": "BIBREF22"}, {"start": 404, "end": 407, "text": "24]", "ref_id": "BIBREF23"}, {"start": 1000, "end": 1004, "text": "[27]", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "Presence, Composition, and Stability of Layer", "text": "Water contact angle (WCA) measurements were used to investigate the hydrophilicity and hydrophobicity of the surface. A change compared to a reference untreated aluminum surface indicated the successful formation of an organophosphorus layer. In addition, WCA measurements were also applied to study the orientation of the molecules (see also below) because in well-ordered monolayers, the access of the water drop to the aluminum surface is reduced [7] . From the investigation of the temporal behavior of WCA, information about surface coverage and chain ordering was obtained [5] . Finally, the stability of the adsorbed layers was determined by recording advancing and receding contact angles by repeated cycling [10, 26] .", "cite_spans": [{"start": 450, "end": 453, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 579, "end": 582, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 717, "end": 721, "text": "[10,", "ref_id": "BIBREF9"}, {"start": 722, "end": 725, "text": "26]", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "Orientation of Molecules and Binding Mode to Aluminum", "text": "In order to characterize the binding (orientation and mode) of the organophosphorus molecules to an aluminum surface, mostly three methods have been used in the literature: Infrared reflection absorption spectroscopy (IRRAS) at grazing angle (often applying polarized infrared radiation), X-ray photoelectron spectroscopy (XPS) at a fixed electron take-off angle as well as angle-resolved (ARXPS) and solid-state 31 P nuclear magnetic resonance (NMR) spectroscopy. The most expected orientation with the phosphonic acid group reacting with the surface hydroxyl groups of the aluminum substrate and the hydrocarbon tail and/or terminal functional groups on top was proven by angle-resolved XPS. The carbon (from the tail) to phosphorus (from the head group) intensity ratio was determined at low and high electron take-off angles, representing two different information depths [7, 10, 27, 28] . In addition, using infrared reflection absorption spectroscopy (IRRAS) and comparing the intensities of vibrations polarized perpendicular or parallel to the hydrocarbon backbone, information about the orientation of the organophosphorus molecule was also obtained [5] .", "cite_spans": [{"start": 876, "end": 879, "text": "[7,", "ref_id": "BIBREF6"}, {"start": 880, "end": 883, "text": "10,", "ref_id": "BIBREF9"}, {"start": 884, "end": 887, "text": "27,", "ref_id": "BIBREF26"}, {"start": 888, "end": 891, "text": "28]", "ref_id": "BIBREF27"}, {"start": 1159, "end": 1162, "text": "[5]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Orientation of Molecules and Binding Mode to Aluminum", "text": "The phosphonic group can bind to the aluminum atom via a direct P-O-Al bond in different modes, i.e., mono-, bi-, or tridentate, depending on whether one, two or all three oxygen atoms from the phosphonic group are involved, respectively. It has been found that both the deposition mode (for instance stirring, sonication), as well as the structure of the phosphonates, play a role [12] . Additionally, the evolution from tridentate to lower binding modes as film formation proceeds (the increase of coverage can change the chain ordering) was observed in the literature [5] . These behaviors might explain the variety of binding modes reported in the literature for organophosphorus layers on aluminum. Table 3 summarizes the frequencies of infrared vibrational modes found in the literature for self-assembled organophosphorus layers on aluminum. By observing which vibrational bands are present and which are not, certain binding modes have been assigned (mostly bidentate [16, 29] and tridentate [12, 32, 33] , and some monodentate [30] ). For instance, a missing P-OH stretching mode together with the presence of PO 3 2\u2212 stretching modes (deprotonation of the phosphonic acid group) in the IR spectrum indicates the formation of a bidentate binding. Mixtures of binding modes have also been found [5, 30, 31] . As a second technique to investigate the binding mode of organophosphorus molecules to aluminum, X-ray photoelectron spectroscopy (XPS) was used. Table 2 summarizes the XPS binding energies found in the literature for self-assembled organophosphorus layers on aluminum. As can be seen from Table 2 , due to overlapping bands, neither the aluminum nor the phosphorus signal allows to clearly differentiate between various binding modes of phosphorus to aluminum. It has to be noted that a trend in the experimental binding energy to increase for the structure [PO n (OR) m ] y\u2212 is observed as the ratio of n:m of \"free\" O ligands (n) to covalently bound OR ligands (m) is stepwise changed from 4:0 to 3:1 to 2:2 and to 1:3. Therefore, also the XPS phosphorus binding energy has been used to assign the binding mode (i.e., mono-, bi-, or tridentate) [34] . However, a final conclusion cannot be drawn just from the P 2p signal and further experimental evidence is needed. The O 1s signal is of particular interest regarding the assessment of the type of bond between organophosphorus and the aluminum substrate. As the binding energy for P=O and P-O-Metal is different from the one for P-OH and P-OR (see Table 2 ), the ratio of the intensities at these two binding energies was used to determine the binding mode. In agreement with other studies using IR (see above), a mixed monodentate and bidentate mode was found [34] . As a third method, the linewidth and shifts of peaks in 31 P NMR spectra have been used to study the bonds between the aluminum and the oxygen atoms of the organophosphorus molecule and to assign a specific binding mode by comparison with literature data [12, 31] .", "cite_spans": [{"start": 571, "end": 574, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 976, "end": 980, "text": "[16,", "ref_id": "BIBREF15"}, {"start": 981, "end": 984, "text": "29]", "ref_id": "BIBREF28"}, {"start": 1005, "end": 1008, "text": "32,", "ref_id": "BIBREF31"}, {"start": 1009, "end": 1012, "text": "33]", "ref_id": "BIBREF32"}, {"start": 1036, "end": 1040, "text": "[30]", "ref_id": "BIBREF29"}, {"start": 1122, "end": 1123, "text": "3", "ref_id": "BIBREF2"}, {"start": 1303, "end": 1306, "text": "[5,", "ref_id": "BIBREF4"}, {"start": 1307, "end": 1310, "text": "30,", "ref_id": "BIBREF29"}, {"start": 1311, "end": 1314, "text": "31]", "ref_id": "BIBREF30"}, {"start": 2165, "end": 2169, "text": "[34]", "ref_id": "BIBREF33"}, {"start": 2733, "end": 2737, "text": "[34]", "ref_id": "BIBREF33"}, {"start": 3000, "end": 3003, "text": "31]", "ref_id": "BIBREF30"}], "ref_spans": [{"start": 1463, "end": 1470, "text": "Table 2", "ref_id": "TABREF1"}, {"start": 1607, "end": 1614, "text": "Table 2", "ref_id": "TABREF1"}, {"start": 2520, "end": 2527, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "Corrosion Evaluation Methods", "text": "The corrosion resistance of the coated aluminum surface is evaluated mainly by four different ways: Electrochemical measurements, conventional measurements, spectral analysis and surface analysis, and are briefly summarized in Table 4 . In most cases treated aluminum substrates are coated with an epoxy layer to study its adhesion and corrosion performance. The corrosion resistance of aluminum substrates is highly related to the microstructure, chemical composition, electrochemical behavior of the coating, and to the interface between coating/metal. Therefore, the measurements mentioned in Table 4 are mostly comprehensive and are used to gather more information in order to analyze the corrosion behavior from different perspectives. [43] Spectral analysis Infrared spectroscopy (IR) [12] Wettability Contact angle measurements [10, 19] ", "cite_spans": [{"start": 741, "end": 745, "text": "[43]", "ref_id": "BIBREF42"}, {"start": 835, "end": 839, "text": "[10,", "ref_id": "BIBREF9"}, {"start": 840, "end": 843, "text": "19]", "ref_id": "BIBREF18"}], "ref_spans": [{"start": 227, "end": 234, "text": "Table 4", "ref_id": "TABREF2"}, {"start": 596, "end": 603, "text": "Table 4", "ref_id": "TABREF2"}]}, {"section": "Electrochemical Measurements", "text": "Electrochemical changes occurring during the coating failure can be detected via an electrical signal which could provide information of metal corrosion and coating property alterations. Quantitative and semi-quantitative evaluation of coatings could be achieved by electrochemical measurements, such as EIS, ENM, and hydrogen permeation current method.", "cite_spans": [], "ref_spans": []}, {"section": "Electrochemical Impedance Spectroscopy (EIS)", "text": "EIS is a non-destructive measurement, which can provide time dependent surface information in a corrosive medium. A small amplitude sinusoidal alternating signal was added in the coating/primer/metal system. Through analyzing the impedance spectrum and the admittance spectrum, an equivalent circuit model, shown in Figure 1 , was built to evaluate electrochemical information of the coating system. During the electrolyte penetration through the coating, C coat increases and R coat decreases. It is confirmed that a surface with an impedance at the low frequency below 10 7 \u2126\u00b7cm 2 is considered a poor protective barrier [44] .", "cite_spans": [{"start": 623, "end": 627, "text": "[44]", "ref_id": "BIBREF43"}], "ref_spans": [{"start": 316, "end": 324, "text": "Figure 1", "ref_id": "FIGREF2"}]}, {"section": "Electrochemical Impedance Spectroscopy (EIS)", "text": "EIS is a nondestructive method and provides fast detection and comprehensive information on coating corrosive behavior. The G106-89 standard has been developed for EIS measurement. However, EIS only provides general information on corrosion behavior of the surface, which means it cannot help understand the mechanism of the corrosion start point [45] . Contact angle measurements [10, 19] ", "cite_spans": [{"start": 347, "end": 351, "text": "[45]", "ref_id": "BIBREF44"}, {"start": 381, "end": 385, "text": "[10,", "ref_id": "BIBREF9"}, {"start": 386, "end": 389, "text": "19]", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Electrochemical Measurements", "text": "Electrochemical changes occurring during the coating failure can be detected via an electrical signal which could provide information of metal corrosion and coating property alterations. Quantitative and semi-quantitative evaluation of coatings could be achieved by electrochemical measurements, such as EIS, ENM, and hydrogen permeation current method.", "cite_spans": [], "ref_spans": []}, {"section": "Electrochemical Impedance Spectroscopy (EIS)", "text": "EIS is a non-destructive measurement, which can provide time dependent surface information in a corrosive medium. A small amplitude sinusoidal alternating signal was added in the coating/primer/metal system. Through analyzing the impedance spectrum and the admittance spectrum, an equivalent circuit model, shown in Figure 1 , was built to evaluate electrochemical information of the coating system. During the electrolyte penetration through the coating, Ccoat increases and Rcoat decreases. It is confirmed that a surface with an impedance at the low frequency below 10 7 \u03a9\u2022cm 2 is considered a poor protective barrier [44] .", "cite_spans": [{"start": 621, "end": 625, "text": "[44]", "ref_id": "BIBREF43"}], "ref_spans": [{"start": 316, "end": 324, "text": "Figure 1", "ref_id": "FIGREF2"}]}, {"section": "Electrochemical Impedance Spectroscopy (EIS)", "text": "EIS is a nondestructive method and provides fast detection and comprehensive information on coating corrosive behavior. The G106-89 standard has been developed for EIS measurement. However, EIS only provides general information on corrosion behavior of the surface, which means it cannot help understand the mechanism of the corrosion start point [45] . ", "cite_spans": [{"start": 347, "end": 351, "text": "[45]", "ref_id": "BIBREF44"}], "ref_spans": []}, {"section": "Electrochemical Noise Method (ENM)", "text": "Electrochemical noise can be described as naturally-occurring fluctuations in potential and current around a mean value in the electrochemical cell [46] . The parameters voltage noise (\u03c3v) and current noise (\u03c3i) can be derived from the fluctuations. The noise resistance Rn, which can be calculated by the Ohms Law, is used to evaluate the corrosion resistance (see Equation (1) ", "cite_spans": [{"start": 148, "end": 152, "text": "[46]", "ref_id": "BIBREF45"}], "ref_spans": []}, {"section": "Electrochemical Noise Method (ENM)", "text": "Electrochemical noise can be described as naturally-occurring fluctuations in potential and current around a mean value in the electrochemical cell [46] . The parameters voltage noise (\u03c3 v ) and current noise (\u03c3 i ) can be derived from the fluctuations. The noise resistance R n , which can be calculated by the Ohms Law, is used to evaluate the corrosion resistance (see Equation (1)):", "cite_spans": [{"start": 148, "end": 152, "text": "[46]", "ref_id": "BIBREF45"}], "ref_spans": []}, {"section": "Electrochemical Noise Method (ENM)", "text": "The higher the value of R n is, the better the corrosion resistance of the coating [22] . When the value of noise resistance R n is less than 10 6 \u2126\u00b7cm 2 , the coating shows poor corrosion resistance. When R n is more than 10 8 \u2126\u00b7cm 2 , the coating exhibits good corrosion protection. The value between 10 6 and 10 8 \u2126\u00b7cm 2 indicates an intermediate level of corrosion resistance [47] .", "cite_spans": [{"start": 83, "end": 87, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 380, "end": 384, "text": "[47]", "ref_id": "BIBREF46"}], "ref_spans": []}, {"section": "Electrochemical Noise Method (ENM)", "text": "ENM is an electrically non-intrusive sensitive method, which requires only a few minutes for a single measurement [48] . Recently, it has become the main measurement method for determining the metal corrosion rate, the localized corrosion process, and is widely used in industry for corrosion detection.", "cite_spans": [{"start": 114, "end": 118, "text": "[48]", "ref_id": "BIBREF47"}], "ref_spans": []}, {"section": "Potentiodynamic Polarization Measurements", "text": "Potentiodynamic anodic polarization can characterize the metal corrosion behavior by its current potential relationship. It can be used to determine the function and the type of inhibitor. The sample potential is scanned slowly in the positive direction, which means it forms an oxide coating during the test. The passivation tendencies and inhibitors influence can be easily studied by this method. Meanwhile, the corrosion behavior of different coatings or metals can be compared on a rational basis, and it can be used as a pretest to give a suitable corrosive condition range for further long-term measurements. The general corrosion behavior of coated substrates can be evaluated by the corrosion potential E corr . Specifically, the more positive E corr and the lower the current values, the better the corrosion resistance [22] .", "cite_spans": [{"start": 830, "end": 834, "text": "[22]", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Localized Electrochemical Techniques", "text": "For many corrosion phenomena, high resolution instead of average data about the behavior of an electrochemically-active surface is required (for instance to differentiate small local anodes and cathodes on a metal surface) [42] . A scanning Kelvin probe (SKP), as a non-contact and non-destructive method, allows measuring and mapping the local potential and current difference on the microscale. The scanning vibrating electrode technique (SVET) enables to spatially characterize corrosion activity by measuring the potential gradients in the electrolyte due the presence of anodic and cathodic areas on a metal surface. These localized techniques find applications in different corrosion investigations like effect of microstructure and finish on corrosion initiation, localized corrosion phenomena, and detection of electrochemically-active pin-hole defects in coatings.", "cite_spans": [{"start": 223, "end": 227, "text": "[42]", "ref_id": "BIBREF41"}], "ref_spans": []}, {"section": "Conventional Measurements", "text": "Conventional corrosion measurement methods are inexpensive and easy to perform. Different national and international standards have been developed which include immersion, salt spray, damp heat, gas corrosion, and filiform corrosion tests. They are commonly used in industry. However, they are not suitable for the corrosion kinetics study or the corrosion mechanism study as they provide qualitative results, usually involving long test cycles and poor repeatability.", "cite_spans": [], "ref_spans": []}, {"section": "Immersion Test", "text": "The coated substrates are directly immersed in the corrosive medium. After a certain exposure to corrosion medium, the damage or corrosion of the coating is observed to evaluate corrosion resistance. The immersion tests are widely used for different coatings in different corrosion media. The common immersion tests are water resistance test, salt water resistance test, acid resistance test, and various organic solvent resistance tests. One can find numerous national immersion tests specific to a country. Some international ASTM standards for immersion tests are B895-05, G44, and G110. ", "cite_spans": [], "ref_spans": []}, {"section": "Salt Spray Test", "text": "The salt spray test is the most classic and widely-used method to evaluate the corrosion resistance of coatings. The first international salt spray standard, ASTM B117, was recognized in 1939. The coated substrates are scratched first and then the test is carried out in a closed test chamber, where salt water (5% NaCl solution, pH 6.5-7.2) is sprayed using pressurized air at 35 \u00b1 2 \u2022 C. Later standards include ISO9227, JIS Z 2371, and ASTM G85. To modify the corrosion condition, acetic acid-salt spray (ASS), copper-accelerated acetic acid-salt spray (CASS), prohesion cycle test as well as various modified versions were established.", "cite_spans": [], "ref_spans": []}, {"section": "Spectral Analysis", "text": "The decomposition of a polymer in the coating is one of the main reason that causes coating failures and metal corrosion, which would lead to further deposition. The chemical changes of the polymer and the inorganic corrosion products can be quantitatively detected by, for example, FTIR, infrared microscopy, or laser Raman spectroscopy (LRS). They can be used to study the corrosion performance and corrosion mechanism because of the highly-precise positioning and quantification [45] . The detail about spectral analysis has been described in Sections 2.2 and 2.3.", "cite_spans": [{"start": 482, "end": 486, "text": "[45]", "ref_id": "BIBREF44"}], "ref_spans": []}, {"section": "Surface Analysis", "text": "The various properties of the coating are highly related to its microstructure, chemical composition, and its bonding condition at the interface of coating/metal. The surface changes during the corrosion process were characterized using the same analytical methods as already described in Section 2.1.", "cite_spans": [], "ref_spans": []}, {"section": "Aluminum Surface Treatments with Phosphonic Acids", "text": "The following sections describe the various types of phosphonic acids and some phosphates which have been used to modify the surface of aluminum with the main objective to improve its corrosion protection and/or adhesion promotion to organic layers. A list of phosphonic acids commonly used to improve corrosion protection of aluminum is shown in Table 5 . Some of these phosphonic acids have simple structures (PPA or MSAP), others are more functional phosphonic acids with terminal groups like vinyl (VPA), amino (APP), and pyrrol (Cn-Ph-P). The salt spray test is the most classic and widely-used method to evaluate the corrosion resistance of coatings. The first international salt spray standard, ASTM B117, was recognized in 1939. The coated substrates are scratched first and then the test is carried out in a closed test chamber, where salt water (5% NaCl solution, pH 6.5-7.2) is sprayed using pressurized air at 35 \u00b1 2 \u00b0C. Later standards include ISO9227, JIS Z 2371, and ASTM G85. To modify the corrosion condition, acetic acidsalt spray (ASS), copper-accelerated acetic acid-salt spray (CASS), prohesion cycle test as well as various modified versions were established.", "cite_spans": [], "ref_spans": [{"start": 347, "end": 354, "text": "Table 5", "ref_id": "TABREF4"}]}, {"section": "Spectral Analysis", "text": "The decomposition of a polymer in the coating is one of the main reason that causes coating failures and metal corrosion, which would lead to further deposition. The chemical changes of the polymer and the inorganic corrosion products can be quantitatively detected by, for example, FTIR, infrared microscopy, or laser Raman spectroscopy (LRS). They can be used to study the corrosion performance and corrosion mechanism because of the highly-precise positioning and quantification [45] . The detail about spectral analysis has been described in Sections 2.2 and 2.3.", "cite_spans": [{"start": 482, "end": 486, "text": "[45]", "ref_id": "BIBREF44"}], "ref_spans": []}, {"section": "Surface Analysis", "text": "The various properties of the coating are highly related to its microstructure, chemical composition, and its bonding condition at the interface of coating/metal. The surface changes during the corrosion process were characterized using the same analytical methods as already described in Section 2.1.", "cite_spans": [], "ref_spans": []}, {"section": "Aluminum Surface Treatments with Phosphonic Acids", "text": "The following sections describe the various types of phosphonic acids and some phosphates which have been used to modify the surface of aluminum with the main objective to improve its corrosion protection and/or adhesion promotion to organic layers. A list of phosphonic acids commonly used to improve corrosion protection of aluminum is shown in Table 5 . Some of these phosphonic acids have simple structures (PPA or MSAP), others are more functional phosphonic acids with terminal groups like vinyl (VPA), amino (APP), and pyrrol (Cn-Ph-P). The salt spray test is the most classic and widely-used method to evaluate the corrosion resistance of coatings. The first international salt spray standard, ASTM B117, was recognized in 1939. The coated substrates are scratched first and then the test is carried out in a closed test chamber, where salt water (5% NaCl solution, pH 6.5-7.2) is sprayed using pressurized air at 35 \u00b1 2 \u00b0C. Later standards include ISO9227, JIS Z 2371, and ASTM G85. To modify the corrosion condition, acetic acidsalt spray (ASS), copper-accelerated acetic acid-salt spray (CASS), prohesion cycle test as well as various modified versions were established.", "cite_spans": [], "ref_spans": [{"start": 347, "end": 354, "text": "Table 5", "ref_id": "TABREF4"}]}, {"section": "Spectral Analysis", "text": "The decomposition of a polymer in the coating is one of the main reason that causes coating failures and metal corrosion, which would lead to further deposition. The chemical changes of the polymer and the inorganic corrosion products can be quantitatively detected by, for example, FTIR, infrared microscopy, or laser Raman spectroscopy (LRS). They can be used to study the corrosion performance and corrosion mechanism because of the highly-precise positioning and quantification [45] . The detail about spectral analysis has been described in Sections 2.2 and 2.3.", "cite_spans": [{"start": 482, "end": 486, "text": "[45]", "ref_id": "BIBREF44"}], "ref_spans": []}, {"section": "Surface Analysis", "text": "The various properties of the coating are highly related to its microstructure, chemical composition, and its bonding condition at the interface of coating/metal. The surface changes during the corrosion process were characterized using the same analytical methods as already described in Section 2.1.", "cite_spans": [], "ref_spans": []}, {"section": "Aluminum Surface Treatments with Phosphonic Acids", "text": "The following sections describe the various types of phosphonic acids and some phosphates which have been used to modify the surface of aluminum with the main objective to improve its corrosion protection and/or adhesion promotion to organic layers. A list of phosphonic acids commonly used to improve corrosion protection of aluminum is shown in Table 5 . Some of these phosphonic acids have simple structures (PPA or MSAP), others are more functional phosphonic acids with terminal groups like vinyl (VPA), amino (APP), and pyrrol (Cn-Ph-P). The salt spray test is the most classic and widely-used method to evaluate the corrosion resistance of coatings. The first international salt spray standard, ASTM B117, was recognized in 1939. The coated substrates are scratched first and then the test is carried out in a closed test chamber, where salt water (5% NaCl solution, pH 6.5-7.2) is sprayed using pressurized air at 35 \u00b1 2 \u00b0C. Later standards include ISO9227, JIS Z 2371, and ASTM G85. To modify the corrosion condition, acetic acidsalt spray (ASS), copper-accelerated acetic acid-salt spray (CASS), prohesion cycle test as well as various modified versions were established.", "cite_spans": [], "ref_spans": [{"start": 347, "end": 354, "text": "Table 5", "ref_id": "TABREF4"}]}, {"section": "Spectral Analysis", "text": "The decomposition of a polymer in the coating is one of the main reason that causes coating failures and metal corrosion, which would lead to further deposition. The chemical changes of the polymer and the inorganic corrosion products can be quantitatively detected by, for example, FTIR, infrared microscopy, or laser Raman spectroscopy (LRS). They can be used to study the corrosion performance and corrosion mechanism because of the highly-precise positioning and quantification [45] . The detail about spectral analysis has been described in Sections 2.2 and 2.3.", "cite_spans": [{"start": 482, "end": 486, "text": "[45]", "ref_id": "BIBREF44"}], "ref_spans": []}, {"section": "Surface Analysis", "text": "The various properties of the coating are highly related to its microstructure, chemical composition, and its bonding condition at the interface of coating/metal. The surface changes during the corrosion process were characterized using the same analytical methods as already described in Section 2.1.", "cite_spans": [], "ref_spans": []}, {"section": "Aluminum Surface Treatments with Phosphonic Acids", "text": "The following sections describe the various types of phosphonic acids and some phosphates which have been used to modify the surface of aluminum with the main objective to improve its corrosion protection and/or adhesion promotion to organic layers. A list of phosphonic acids commonly used to improve corrosion protection of aluminum is shown in Table 5 . Some of these phosphonic acids have simple structures (PPA or MSAP), others are more functional phosphonic acids with terminal groups like vinyl (VPA), amino (APP), and pyrrol (Cn-Ph-P). The salt spray test is the most classic and widely-used method to evaluate the corrosion resistance of coatings. The first international salt spray standard, ASTM B117, was recognized in 1939. The coated substrates are scratched first and then the test is carried out in a closed test chamber, where salt water (5% NaCl solution, pH 6.5-7.2) is sprayed using pressurized air at 35 \u00b1 2 \u00b0C. Later standards include ISO9227, JIS Z 2371, and ASTM G85. To modify the corrosion condition, acetic acidsalt spray (ASS), copper-accelerated acetic acid-salt spray (CASS), prohesion cycle test as well as various modified versions were established.", "cite_spans": [], "ref_spans": [{"start": 347, "end": 354, "text": "Table 5", "ref_id": "TABREF4"}]}, {"section": "Spectral Analysis", "text": "The decomposition of a polymer in the coating is one of the main reason that causes coating failures and metal corrosion, which would lead to further deposition. The chemical changes of the polymer and the inorganic corrosion products can be quantitatively detected by, for example, FTIR, infrared microscopy, or laser Raman spectroscopy (LRS). They can be used to study the corrosion performance and corrosion mechanism because of the highly-precise positioning and quantification [45] . The detail about spectral analysis has been described in Sections 2.2 and 2.3.", "cite_spans": [{"start": 482, "end": 486, "text": "[45]", "ref_id": "BIBREF44"}], "ref_spans": []}, {"section": "Surface Analysis", "text": "The various properties of the coating are highly related to its microstructure, chemical composition, and its bonding condition at the interface of coating/metal. The surface changes during the corrosion process were characterized using the same analytical methods as already described in Section 2.1.", "cite_spans": [], "ref_spans": []}, {"section": "Aluminum Surface Treatments with Phosphonic Acids", "text": "The following sections describe the various types of phosphonic acids and some phosphates which have been used to modify the surface of aluminum with the main objective to improve its corrosion protection and/or adhesion promotion to organic layers. A list of phosphonic acids commonly used to improve corrosion protection of aluminum is shown in Table 5 . Some of these phosphonic acids have simple structures (PPA or MSAP), others are more functional phosphonic acids with terminal groups like vinyl (VPA), amino (APP), and pyrrol (Cn-Ph-P). Aminopropyl phosphonate APP [9, 11] \u03c9-(3-phenylpyrrol-1-ylalkyl) phosphonic acid Cn-Ph-P [10] \u03c9-(2,5-Dithienylpyrrol-1-ylalky) phosphonic acid SNS-n-P [10] 2-(Phosphonooxy) benzoic acid Fosfosal [14] Phosphonosuccinic acid PPSA [14] Cn-Ph-P [10] \u03c9-(2,5-Dithienylpyrrol-1-yl-alky) phosphonic acid Rx PO(OH)y R = CF3(CF2CF2)z(CH2CH2O) x = 1, 2 or 3, x + y = 3, z = 1 to 7 HDF-PA [19] Fluoro alkyl phosphates Zonyl UR [12] Rx PO(OH)y R = CF3(CF2CF2)z(CH2CH2O) x = 1, 2 or 3, x + y = 3, z = 1 to 7", "cite_spans": [{"start": 572, "end": 575, "text": "[9,", "ref_id": "BIBREF8"}, {"start": 576, "end": 579, "text": "11]", "ref_id": "BIBREF10"}, {"start": 633, "end": 637, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 695, "end": 699, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 739, "end": 743, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 772, "end": 776, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 785, "end": 789, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 921, "end": 925, "text": "[19]", "ref_id": "BIBREF18"}], "ref_spans": [{"start": 347, "end": 354, "text": "Table 5", "ref_id": "TABREF4"}]}, {"section": "Aluminum Surface Treatments with Phosphonic Acids", "text": "Poly (vinyl phosphonic acid) PvPA [24] ", "cite_spans": [{"start": 34, "end": 38, "text": "[24]", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Phosphonic Acids Used as Pre-Coating", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Phenylphosphonic Acid (PPA)", "text": "In an earlier work, it was found that a hydrophobic sol-gel film can provide good corrosion resistance to aluminum [50] . Subsequently, the same researchers incorporated organic phenyl phosphonic acid as an anion in a hydrophobic sol-gel film to further enhance the protection of aluminum against pitting corrosion. It was expected that such combinations of phosphonic acid and sol-gel coatings would be beneficial in corrosion protection. Various sol-gel coatings with two different anions were coated on the aluminum substrate. The formulations of such coatings used in this research are shown in Table 6 . Table 6 . Various formulations of sol-gel coatings. Aluminum rods embedded in a Teflon sheath (99.999%) and aluminum plates (5050-H24) were used as substrates and coated using various sol-gel formulations (Table 6 ) via dip-coating. The substrates were then submerged in 100 ppm NaCl solution at 25 \u00b0C for 20 min and subjected to ENM to study the initiation and propagation of corrosion at the interface of aluminum plates and coating. It is considered that the higher the value of Rn, the better the corrosion resistance of the coating. The results showed that PTMOS + PPA sol-gel coatings exhibited the best protection (Rn = 6.0 k\u03a9) compared to uncoated aluminum (Rn = 1.5 k\u03a9) and PTMOS coatings (Rn = 4.0 k\u03a9).", "cite_spans": [{"start": 115, "end": 119, "text": "[50]", "ref_id": "BIBREF49"}], "ref_spans": [{"start": 599, "end": 606, "text": "Table 6", "ref_id": "TABREF25"}, {"start": 609, "end": 616, "text": "Table 6", "ref_id": "TABREF25"}, {"start": 814, "end": 822, "text": "(Table 6", "ref_id": "TABREF25"}]}, {"section": "Sol-Gel Chemistry PTMOS PTMOS PTMOS + TMA PTMOS TEOS TEOS TEOS + TMA", "text": "In potentiodynamic polarization measurements, aluminum in the form of rods was used. These rods were exposed to 100 ppm NaCl solution for 30 min before the measurements. For these measurements, as mentioned before, the more positive Ecorr and the lower the current values, the better the corrosion resistance. PTMOS + PPA showed the highest Ecorr value and a low current. In contrast, the TEOS-based film showed a negative Ecorr value, which indicated the poor corrosion resistance. Even addition of TMA in TEOS film accelerated the corrosion process. Potentiodynamic polarization measurements of samples for electrodeposition process showed slight enhancement of corrosion inhibition. Elemental analysis was used to detected phosphorus (due to PPA) in the films. Fluoro alkyl phosphates Zonyl UR [12] Rx PO(OH)y R = CF3(CF2CF2)z(CH2CH2O) x = 1, 2 or 3, x + y = 3, z = 1 to 7", "cite_spans": [], "ref_spans": []}, {"section": "Sol-Gel Chemistry PTMOS PTMOS PTMOS + TMA PTMOS TEOS TEOS TEOS + TMA", "text": "Poly (vinyl phosphonic acid) PvPA [24] ", "cite_spans": [{"start": 34, "end": 38, "text": "[24]", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Phosphonic Acids Used as Pre-Coating", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Phenylphosphonic Acid (PPA)", "text": "In an earlier work, it was found that a hydrophobic sol-gel film can provide good corrosion resistance to aluminum [50] . Subsequently, the same researchers incorporated organic phenyl phosphonic acid as an anion in a hydrophobic sol-gel film to further enhance the protection of aluminum against pitting corrosion. It was expected that such combinations of phosphonic acid and sol-gel coatings would be beneficial in corrosion protection. Various sol-gel coatings with two different anions were coated on the aluminum substrate. The formulations of such coatings used in this research are shown in Table 6 . Table 6 . Various formulations of sol-gel coatings. Aluminum rods embedded in a Teflon sheath (99.999%) and aluminum plates (5050-H24) were used as substrates and coated using various sol-gel formulations (Table 6 ) via dip-coating. The substrates were then submerged in 100 ppm NaCl solution at 25 \u00b0C for 20 min and subjected to ENM to study the initiation and propagation of corrosion at the interface of aluminum plates and coating. It is considered that the higher the value of Rn, the better the corrosion resistance of the coating. The results showed that PTMOS + PPA sol-gel coatings exhibited the best protection (Rn = 6.0 k\u03a9) compared to uncoated aluminum (Rn = 1.5 k\u03a9) and PTMOS coatings (Rn = 4.0 k\u03a9).", "cite_spans": [{"start": 115, "end": 119, "text": "[50]", "ref_id": "BIBREF49"}], "ref_spans": [{"start": 599, "end": 606, "text": "Table 6", "ref_id": "TABREF25"}, {"start": 609, "end": 616, "text": "Table 6", "ref_id": "TABREF25"}, {"start": 814, "end": 822, "text": "(Table 6", "ref_id": "TABREF25"}]}, {"section": "Sol-Gel Chemistry PTMOS PTMOS PTMOS + TMA PTMOS TEOS TEOS TEOS + TMA", "text": "In potentiodynamic polarization measurements, aluminum in the form of rods was used. These rods were exposed to 100 ppm NaCl solution for 30 min before the measurements. For these measurements, as mentioned before, the more positive Ecorr and the lower the current values, the better the corrosion resistance. PTMOS + PPA showed the highest Ecorr value and a low current. In contrast, the TEOS-based film showed a negative Ecorr value, which indicated the poor corrosion resistance. Even addition of TMA in TEOS film accelerated the corrosion process. Potentiodynamic polarization measurements of samples for electrodeposition process showed slight enhancement of corrosion inhibition. Elemental analysis was used to detected phosphorus (due to PPA) in the films.", "cite_spans": [], "ref_spans": []}, {"section": "Sol-Gel Chemistry PTMOS PTMOS PTMOS + TMA PTMOS TEOS TEOS TEOS + TMA", "text": "PvPA [24] 4.1. Phosphonic Acids Used as Pre-Coating", "cite_spans": [{"start": 5, "end": 9, "text": "[24]", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Sol-Gel Chemistry PTMOS PTMOS PTMOS + TMA PTMOS TEOS TEOS TEOS + TMA", "text": "In an earlier work, it was found that a hydrophobic sol-gel film can provide good corrosion resistance to aluminum [50] . Subsequently, the same researchers incorporated organic phenyl phosphonic acid as an anion in a hydrophobic sol-gel film to further enhance the protection of aluminum against pitting corrosion. It was expected that such combinations of phosphonic acid and sol-gel coatings would be beneficial in corrosion protection. Various sol-gel coatings with two different anions were coated on the aluminum substrate. The formulations of such coatings used in this research are shown in Table 6 . Aluminum rods embedded in a Teflon sheath (99.999%) and aluminum plates (5050-H24) were used as substrates and coated using various sol-gel formulations (Table 6 ) via dip-coating. The substrates were then submerged in 100 ppm NaCl solution at 25 \u2022 C for 20 min and subjected to ENM to study the initiation and propagation of corrosion at the interface of aluminum plates and coating. It is considered that the higher the value of R n , the better the corrosion resistance of the coating. The results showed that PTMOS + PPA sol-gel coatings exhibited the best protection (R n = 6.0 k\u2126) compared to uncoated aluminum (R n = 1.5 k\u2126) and PTMOS coatings (R n = 4.0 k\u2126).", "cite_spans": [{"start": 115, "end": 119, "text": "[50]", "ref_id": "BIBREF49"}], "ref_spans": [{"start": 599, "end": 606, "text": "Table 6", "ref_id": "TABREF25"}, {"start": 762, "end": 770, "text": "(Table 6", "ref_id": "TABREF25"}]}, {"section": "Sol-Gel Chemistry PTMOS PTMOS PTMOS + TMA PTMOS TEOS TEOS TEOS + TMA", "text": "In potentiodynamic polarization measurements, aluminum in the form of rods was used. These rods were exposed to 100 ppm NaCl solution for 30 min before the measurements. For these measurements, as mentioned before, the more positive E corr and the lower the current values, the better the corrosion resistance. PTMOS + PPA showed the highest E corr value and a low current. In contrast, the TEOS-based film showed a negative E corr value, which indicated the poor corrosion resistance. Even addition of TMA in TEOS film accelerated the corrosion process. Potentiodynamic polarization measurements of samples for electrodeposition process showed slight enhancement of corrosion inhibition. Elemental analysis was used to detected phosphorus (due to PPA) in the films. For PTMOS based film, phosphorus was detected and it was hypothesized that the anion of PPA and phenyl group of PTMOS tends to form stable \u03c0-interactions in the sol-gel system [22] .", "cite_spans": [{"start": 943, "end": 947, "text": "[22]", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Vinylphosphonic Acid (VPA)", "text": "Cooling of an aluminum alloy plate heat exchanger by seawater needs superior corrosion resistance. Trifluoroethylene polymers were preferred to form a fluorocarbon resin coating on aluminum alloy because of high adhesion to the organic phosphonic acid primer coating and high corrosion resistance. Vinylphosphonic acid (VPA) was used as the organic phosphonic acid primer because of its handle and its superior adhesion effect. The aluminum alloy (3003) was first anodically oxidized and then immersed in VPA aqueous solution (10 g/L) at 65 \u2022 C for 10 s or 120 s, followed by fluorocarbon resin coating and dried at 50 \u2022 C for 24 h. For the corrosion test, one hundred 1 mm 2 cross-cuts were formed on the coating, and a tape was attached on it and then peeled by the method specified in JIS K 5600-5-6. For samples with coatings without an organic phosphonic acid primer, all hundred cross-cuts of the coating were peeled off (0/100) upon tape peeling. However, for the coating with VPA (10 s or 120 s), all 100 cross-cuts remained unpeeled (100/100), which indicated an excellent anti-corrosion property [49] .", "cite_spans": [{"start": 1106, "end": 1110, "text": "[49]", "ref_id": "BIBREF48"}], "ref_spans": []}, {"section": "1,12-Dodecyldiphosphonic Acid (DDP)", "text": "Self-assembled monolayers (SAMs) consisting of zirconium phosphate and their derivatives were used as the substitute to chromating on aluminum for ecological reasons [8] . Aluminum alloy (1100) was pretreated with 0.4 vol % of 3-aminopropyltriethoxysilane (APTES) in toluene by chemical vapor deposition. APTES is believed to prevent the formation of defects and provide protection against the harsh subsequent phosphonation treatment (pH \u2264 2). Subsequently, the substrate was immersed in 0.2 mol POCl 3 and \u03b3-collidine of acetonitrile solution. After ultrasonically rinsing with acetonitrile, the substrate was dipped in 5 mmol/dm 3 zirconyl chloride ZrCl 2 \u00b78H 2 O of ethyl alcohol-aqueous solution to form a zirconium phosphate (ZrP) layer. Ultimately the substrate was suspended in 2 mmol/dm 3 DDP of acetone-aqueous solution to form the three layered Zr-DDP coating as shown in Scheme 1.", "cite_spans": [{"start": 166, "end": 169, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "1,12-Dodecyldiphosphonic Acid (DDP)", "text": "Coatings 2017, 7, 133 For PTMOS based film, phosphorus was detected and it was hypothesized that the anion of PPA and phenyl group of PTMOS tends to form stable \u03c0-interactions in the sol-gel system [22] .", "cite_spans": [{"start": 15, "end": 17, "text": "7,", "ref_id": "BIBREF6"}, {"start": 198, "end": 202, "text": "[22]", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Vinylphosphonic Acid (VPA)", "text": "Cooling of an aluminum alloy plate heat exchanger by seawater needs superior corrosion resistance. Trifluoroethylene polymers were preferred to form a fluorocarbon resin coating on aluminum alloy because of high adhesion to the organic phosphonic acid primer coating and high corrosion resistance. Vinylphosphonic acid (VPA) was used as the organic phosphonic acid primer because of its handle and its superior adhesion effect. The aluminum alloy (3003) was first anodically oxidized and then immersed in VPA aqueous solution (10 g/L) at 65 \u00b0C for 10 s or 120 s, followed by fluorocarbon resin coating and dried at 50 \u00b0C for 24 h. For the corrosion test, one hundred 1 mm 2 cross-cuts were formed on the coating, and a tape was attached on it and then peeled by the method specified in JIS K 5600-5-6. For samples with coatings without an organic phosphonic acid primer, all hundred cross-cuts of the coating were peeled off (0/100) upon tape peeling. However, for the coating with VPA (10 s or 120 s), all 100 cross-cuts remained unpeeled (100/100), which indicated an excellent anti-corrosion property [49] .", "cite_spans": [{"start": 1104, "end": 1108, "text": "[49]", "ref_id": "BIBREF48"}], "ref_spans": []}, {"section": "1,12-Dodecyldiphosphonic Acid (DDP)", "text": "Self-assembled monolayers (SAMs) consisting of zirconium phosphate and their derivatives were used as the substitute to chromating on aluminum for ecological reasons [8] . Aluminum alloy (1100) was pretreated with 0.4 vol % of 3-aminopropyltriethoxysilane (APTES) in toluene by chemical vapor deposition. APTES is believed to prevent the formation of defects and provide protection against the harsh subsequent phosphonation treatment (pH \u2264 2). Subsequently, the substrate was immersed in 0.2 mol POCl3 and \u03b3-collidine of acetonitrile solution. After ultrasonically rinsing with acetonitrile, the substrate was dipped in 5 mmol/dm 3 zirconyl chloride ZrCl2\u20228H2O of ethyl alcoholaqueous solution to form a zirconium phosphate (ZrP) layer. Ultimately the substrate was suspended in 2 mmol/dm 3 DDP of acetone-aqueous solution to form the three layered Zr-DDP coating as shown in Scheme 1. The Zr-DDP multi-layers film was tested for corrosion resistance by exposure to 5 wt % NaCl solution at 308 K for 48 h in the salt-spray test. The corrosion rate of multi-layer Zr-DDP coating is 0% (indicating no corrosion at all) and showed superior anti-corrosion properties compared to APTES coating (100%), POCl 3 coating (80%), and conventional ZrP coating (100%). After a 72 h salt spray test, Zr-DDP films were corroded with a corrosion rate of 60% whereas the other treatments showed 100% corrosion rate. The authors concluded that Zr-DDP films constructed by SAMs are promising surface finishing treatments to replace the conventional phosphating or chromating treatments [8] .", "cite_spans": [{"start": 166, "end": 169, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 1568, "end": 1571, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Amino Trimethylene Phosphonic Acid (ATMP)", "text": "ATMP is known to have anti-scale performance due to its excellent chelating ability, and a low threshold inhibition and lattice distortion process. ATMP was used as an inhibitor to improve the anti-corrosion properties of aluminum alloy (AA2024-T3) [15] . The deposition bath was made by mixing ATMP in distilled water, tetraethylorthosilicate (TEOS), and ethanol in a 6:4:90 (v/v/v) ratio. In this work, the effect of three different pretreatments (acetic acid, acetic acid-NaOH, NaOH) and ATMP concentration on the corrosion protection were studied. SEM and energy-dispersive X-ray spectroscopy (EDS) analysis of the treated aluminum surface confirmed that acetic acid pretreatment of the aluminum surface was the most efficient pretreatment. The authors assumed that acetic acid pretreatment increased surface area of the alloy matrix, which led to more formation of favorable metalosiloxane and metal-phosphonic bonds to the surface.", "cite_spans": [{"start": 249, "end": 253, "text": "[15]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Amino Trimethylene Phosphonic Acid (ATMP)", "text": "Three different ATMP concentrations of deposition baths were investigated. The corrosion behavior of the treated aluminum was tested against 0.05 M NaCl solution for 48 h. EIS was used to assess the corrosion resistance, as mentioned in Section 3.1.1. High R HF (the resistance of the high frequency related to the coating layer) value and low CPE HF (the capacitance of the high frequency related to the coating layer) value indicated higher corrosion resistance. Results of the TEOS coating containing ATMP (5.00 \u00d7 10 \u22124 M) showed R HF (kOhm\u00b7cm 2 ): 81.4, CPE HF (\u00b5F\u00b7cm \u22122 \u00b7s n\u22121 ): 16.2, whereas increasing or decreasing the ATMP concentration had an adverse effect on corrosion protection. In contrast, TEOS coating without ATMP resulted in R HF (kOhm\u00b7cm 2 ): 5.06, CPE HF (\u00b5F\u00b7cm \u22122 \u00b7s n\u22121 ): 160.5, indicating no corrosion resistance at all. The authors believe that the corrosion protection was caused by the strong chemical bonding of phosphonic groups to the aluminum substrate [15] .", "cite_spans": [{"start": 986, "end": 990, "text": "[15]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Ethylenediamine Tetra Methylene Phosphonic Acid (EDTPO)", "text": "Modification of aluminum alloy (AA2024) with a well-known anticorrosive epoxy-polyamide paint in combination with vinyltrimethoxysilane (VTMS)/tetraethylorthosilicate (TEOS) nanocoating was used to improve its corrosion resistance and adhesion to organic layers. EDTPO, as a catalyst, was incorporated into VTMS/TEOS to form a sol-gel coating on the substrate surface and is believed to improve the formation of Al-O-P bonds which is beneficial for anticorrosive properties [17] . The concentration of EDTPO in the sol-gel deposition solution was 3.75 \u00d7 10 \u22125 mol\u00b7L \u22121 . EIS measurement was carried out in 3.5% NaCl aqueous solution. Substrates coated with epoxy and sol-gel film with or without EDTPO showed good corrosion resistance: The EIS results remained constant at 10 9.5 \u2126\u00b7cm \u22122 up to 300 days, which indicated an excellent corrosion resistance. Whereas the values for the epoxy coating without sol-gel film started to decrease after 160 days and 300 days later, coating resistance was only 10 7.9 \u2126\u00b7cm 2 . A cyclic accelerated corrosion test in 3.5% NaCl solution for 60 days was evaluated by ASTM D-1654. The results showed that the failure area of the coating with EDTPO was 0.8%, which indicates an excellent corrosion resistance compared to the coating without EDTPO (1.3%) or the coating without any sol-gel primer (32%). After accelerated corrosion, the pull-off test (UNE-EN-ISO 4624) showed that the adhesion reduction for the coating with EDTPO to be 0%. However, the adhesion of coating without EDTPO showed a reduction of 15%, and the adhesion of the coating without any sol-gel primer reduced to 40%. It was concluded that the EDTPO-modified silane coating (VTMS/TEOS) has excellent adhesion and anti-corrosion properties because of its barrier properties [17] .", "cite_spans": [{"start": 474, "end": 478, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 1778, "end": 1782, "text": "[17]", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Ethylenediamine Tetra Methylene Phosphonic Acid (EDTPO)", "text": "In a similar work, two different concentrations of EDTPO (3.75 \u00d7 10 \u22125 and 3.75 \u00d7 10 \u22124 mol\u00b7L \u22121 ) were incorporated in TEOS to form sol-gel deposition solutions, which are named TEOS/EDTPO 10 \u22125 and TEOS/EDTPO 10 \u22124 , respectively. Aluminum alloy (AA2024-T3) panels were immersed in these formulations to form an anti-corrosion film. As mentioned in Section 3.1.1, a high R HF value and low CPE HF value indicates a corrosion resistance. After seven days of soaking in the 0.05 mol\u00b7L \u22121 NaCl solution at 25 \u2022 C, EIS test results of TEOS/EDTPO 10 \u22124 was R HF (\u2126\u00b7cm 2 ): 248.3, CPE HF (\u00b5F\u00b7cm \u22122 \u00b7s n\u22121 ): 1.74 and for TEOS/EDTPO 10 \u22125 it was R HF (\u2126\u00b7cm 2 ): 177.4, CPE HF (\u00b5F\u00b7cm \u22122 \u00b7s n\u22121 ): 15.8. Thus, it was clear that TEOS/EDTPO 10 \u22124 could provide a better corrosion resistance. The substrate coated with TEOS/EDTPO 10 \u22124 was further investigated by soaking it in 0.05 mol\u00b7L \u22121 NaCl solution at 70 \u2022 C with various immersion times. After a 24 h exposure, the impedance modulus is lower than the measurements for 25 \u2022 C. Nevertheless, the corrosion resistance of the EDTPO containing coatings was still approximately six times higher than for TEOS-only coatings. In this work, it was also confirmed that EDTPO enhanced the corrosion resistance of the sol-gel coating even at a higher temperature [30] .", "cite_spans": [{"start": 1299, "end": 1303, "text": "[30]", "ref_id": "BIBREF29"}], "ref_spans": []}, {"section": "Ethylenediamine Tetra Methylene Phosphonic Acid (EDTPO)", "text": "In a separate work done by the same authors, the corrosion behavior of EDTPO and ATMP was compared in TEOS sol-gel coating on the aluminum alloy (AA1100) surface. Substrates were dip-coated in two different solutions: 3.75 \u00d7 10 \u22124 mol\u00b7L \u22121 EDTPO in TEOS ethanol solution and 5.00 \u00d7 10 \u22124 mol\u00b7L \u22121 ATMP in TEOS ethanol solution. EIS was used to evaluate the corrosion of coated substrates in a 0.05 mol\u00b7L \u22121 NaCl solution for seven days. The corrosion resistance of TEOS/EDTPO was R HF (\u2126\u00b7cm 2 ): 141.0, CPE HF (\u00b5F\u00b7cm \u22122 \u00b7s n\u22121 ): 2.45. For TEOS/ATMP it was R HF (\u2126\u00b7cm 2 ): 113.7, CPE HF (\u00b5F\u00b7cm \u22122 \u00b7s n\u22121 ): 1.65. It was concluded that both EDTPO and ATMP could provide considerable corrosion protection for AA1100. However, the corrosion resistance of EDTPO-containing coatings was higher than for ATMP-containing coatings [40] .", "cite_spans": [{"start": 823, "end": 827, "text": "[40]", "ref_id": "BIBREF39"}], "ref_spans": []}, {"section": "1,2-Diaminoethanetetrakis-Methylenephosphonic Acid (DETAPO)", "text": "The adhesion and corrosion performance of silane sol-gel film coating on aluminum has been reported. Especially ATMP and EDTPO, as the phosphonic catalysts in a sol-gel system, have been well studied for the protection against corrosion [15, 17, 30, 40] . Phosphonic derivative DETAPO, which has a similar structure has also been tested because of higher concentration of O=P-OH group in its structure compared to ATMP and EDTPO [23] . In this work, aluminum alloy (AA2024-T3) was coated with VTMS/TEOS sol-gel film containing DETAPO and the epoxy-polyamide resin. A cyclic accelerated corrosion test in 3.5% NaCl for 45 days was performed according to the ASTM D1654 method. The results showed that the failure area of DETAPO modified coating was around 10-11%, compared to the 35% failure area for the epoxy coating without any silane film. Pull-off tests after accelerated corrosion showed that adhesion reduction of DETAPO-modified silane coating was around 62.5-52.9%, on the other hand, the coating without any silane film reduced to 34.7% adhesion. It was clear that the DETAPO-modified coating can provide an outstanding corrosion resistance for aluminum surface [23] .", "cite_spans": [{"start": 237, "end": 241, "text": "[15,", "ref_id": "BIBREF14"}, {"start": 242, "end": 245, "text": "17,", "ref_id": "BIBREF16"}, {"start": 246, "end": 249, "text": "30,", "ref_id": "BIBREF29"}, {"start": 250, "end": 253, "text": "40]", "ref_id": "BIBREF39"}, {"start": 429, "end": 433, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 1171, "end": 1175, "text": "[23]", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "(12-Ethylamino-Dodecyl)-Phosphonic Acid", "text": "Self-assembled monolayers (SAMs) were used to form thin organic adhesion promoter layers to replace the chromating process on aluminum. (12-ethylamino-dodecyl)-phosphonic acid was chosen as a model functional organic phosphonic acid in this work because of its phosphonic acid anchor group which acts as a reactive group for the aluminum surface, its aliphatic part acting as a hydrophobic spacer, and its amino head group serving as a reactive group to organic material [27] . The aluminum alloy (AlMg) was dip-coated in the 10 \u22123 M (12-ethylamino-dodecyl)-phosphonic acid solution of ethanol/water (3:1 vol %). The surface analysis by FTIR and surface plasmon resonance spectroscopy (SPR) confirmed that organophosphonic acid could spontaneously adsorb on the aluminum surface and subsequently form oriented layers. The adhesion promotion and corrosion resistance of the aluminum surface were confirmed by the acetic acid salt spray-test (ASS-test, DIN 50021) and filiform test (DIN 50024). Coated panels were scratched and exposed in a climate chamber of NaCl solution and acetic acid. After 1200 h exposure, the infiltrations for the amino phosphonic acid coating was less than 1 mm, which indicates excellent corrosion resistance compared to 8 mm infiltration for the uncoated substrate [27] .", "cite_spans": [{"start": 471, "end": 475, "text": "[27]", "ref_id": "BIBREF26"}, {"start": 1292, "end": 1296, "text": "[27]", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "Aminopropyl Phosphonate (APP)", "text": "To replace harmful chromate conversion layers, environmentally-friendly aminopropyl phosphonate (APP), aminopropyl silane (APS), and hexamethyldisiloxane (HMDSO) were used to coat aluminum alloy (6016) [9] . As known, filiform corrosion (FFC) usually occurs at the interface of a polymer and an aluminum alloy. Hence, the corrosion resistance and adhesion promotion of these coatings were studied to find a suitable pretreatment for automotive applications. The influence of the rolling direction on filiform corrosion was also investigated. Substrates were dipped in 1 mmol APP solution with pH 7 for 1 h followed by an epoxy coating. APS was coated on substrates with the same dip-coating method and, for HMDSO, a plasma coating technique was used. Before the corrosion test, substrates were scribed perpendicularly or parallel to the rolling direction. The corrosion test was carried out by soaking scratched substrates in a vessel with concentrated HCl vapor for 20 min. FFC was evaluated based on filament initiating time and the number of filaments observed in the digital microscope. From visual observation, it could be confirmed that filaments grew predominantly along the rolling direction, which indicated that the rolling direction had an influence on the interfacial bonding. The FFC severities were as follows: APS > etching > APP > HMDSO plasma. The adhesion of the epoxy adhesive to the substrate was analyzed by a peeling test, and the results follow a trend for different coatings: HMDSO plasma > APS > APP > etching. It was concluded that the adhesion of the coating had a great influence on filament morphology and further on filament propagation, but an increase in adhesion of the coating was not a guarantee of resistance to FFC [9] .", "cite_spans": [{"start": 202, "end": 205, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 1752, "end": 1755, "text": "[9]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Aminopropyl Phosphonate (APP)", "text": "The corrosion performance of aluminum powder was enhanced by a novel functionalization with graphene oxide (GO) with phosphonic acid as a linker [11] . APP was used as the \"link\" agent to connect graphene oxide (GO) with aluminum powder. APP was added in a suspension of GO and deionized water. After stirring, refluxing, dialyzing, and drying, GO-APP was added in the aluminum powder suspension to form the oxide modified aluminum powder (GO-Al). Corrosion performance was tested in dilute hydrochloric acid. Since corrosion of aluminum generated hydrogen, corrosion behavior could be evaluated by detecting the amount and the yield time of hydrogen gas. The results showed that for the Al/HCl system, the hydrogen was detected after 100 min. However, in the GO-Al/HCl system, hydrogen was detected only after 140 min, which confirms enhanced the anti-corrosive performance of GO-Al. Through XPS, FTIR, field emission scanning electron microscopy (FE-SEM), and EDS, it could be confirmed that the flaky aluminum particle was successfully covalently bonded and covered by GO. In conclusion, GO as a barrier coating was well connected with epoxy through APP [11] .", "cite_spans": [{"start": 145, "end": 149, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 1157, "end": 1161, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Aminopropyl Phosphonate (APP)", "text": "4.1.9. \u03c9-(3-Phenylpyrrol-1-ylalkyl) Phosphonic Acid (Cn-Ph-P) Cn-Ph-P was used to build SAMs on the aluminum surface (Al/Al 2 O 3 chemical vapor deposition on polished, p-doped Si wafers) because its phosphonic acid group could anchor to the aluminum surface and its pyrrole group could be used to achieve an in situ surface polymerization with further monomers [10] . The substrates were immersed in a Cn-Ph-P solution for different time intervals (5 min, 1 h, and 24 h) to form SAMs on the surface. After that, the pyrrole monomer was polymerized with the free terminal pyrrole group of the SAM by oxidants, like sodium or ammonium peroxidisulphate, followed by the growth of polypyrrole (PPY) on the surface. The contact angle was used to evaluate the adsorption behavior. It was inferred that a more hydrophobic surface (higher contact angles) was caused by phosphonic acid group reacting with surface and the terminal polymerizable group present on top of it. The surface contact angle rose up after adsorption of CnPhP, which indicated that CnPhP was oriented on the surface. The contact angles of C12PhP were slightly higher than C10PhP because of the stronger van der Waals interaction between the alkyl chains. C12PhP showed excellent stability after eight repeated cycling using the Wilhelmy method [10] . 4.1.10. \u03c9-(2,5-Dithienylpyrrol-1-yl-alkyl) Phosphonic Acid (SNS-n-P) SNS-n-P as a model functional phosphonic acid was used to study the influence of varying alkyl chain length (SNS10P, SNS4P) to the adsorption on the aluminum surface (Al/Al 2 O 3 chemical vapor deposition on polished, p-doped Si wafers). The contact angle of SNS10P coated surface did not change after ten repeated cycles by the Wilhelmy method, which indicated that SNS10P had a very stable bond to the surface. However, the contact angle of SNS4P coating decreased significantly with the increasing number of repeated cycles. Thus, this comparison of analogue structures SNS10P and SNS4P showed that the alkyl chain length of the structures influences the bonding at the surface [10] . 4.1.11. (1H,1H, 2H ,2H-Heptadecafluorodec-1-yl) Phosphonic Acid (HDF-PA) Trichlorosilane or metal-ligand coordination has mostly been used to engineer surface wetting properties on metals. However, they were highly moisture sensitive due to hydrolysis and self-condensation of silanes [51] [52] [53] . Therefore, HDF-PA was employed to coat different self-assembled monolayers (SAMs) on metal oxide surfaces because phosphonic acid-functionalized molecules were stable in water, and built a stable metal-ligand coordination and hetero-condensation between phosphonate and substrate surfaces. Substrates with a 30 nm thick Al 2 O 3 film were dip-coated in 2 mM HDF-PA isopropyl alcohol for 1 h. After the water flow test, changes in surface contact angle were analyzed to evaluate the reliability of the chemical bond between SAMs and substrate surface. PvPA was coated as a thin polymeric interfacial layer on aluminum alloy (AA 1050) surface by dip-coating and compared to the poly (acrylic acid) (PAA), poly (ethylene-alt-maleic anhydride) (PEMah) coated aluminum surface. After that, an epoxy (Resolution Epikote 1001) adhesive was coated on the modified substrate. The PvPA-based system showed poor adhesion performance in the pull-off test compared to PEMah, because PvPA forms a weakly-cured epoxy/polymer interphase [24] .", "cite_spans": [{"start": 362, "end": 366, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 1309, "end": 1313, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 2066, "end": 2070, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 2358, "end": 2362, "text": "[51]", "ref_id": "BIBREF50"}, {"start": 2363, "end": 2367, "text": "[52]", "ref_id": "BIBREF51"}, {"start": 2368, "end": 2372, "text": "[53]", "ref_id": "BIBREF52"}, {"start": 3396, "end": 3400, "text": "[24]", "ref_id": "BIBREF23"}], "ref_spans": [{"start": 2081, "end": 2091, "text": "(1H,1H, 2H", "ref_id": "FIGREF2"}]}, {"section": "Phosphates Used as Pre-Coating", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Monostearyl Acid Phosphate (MSAP)", "text": "A novel ultrasonic assisted deposition (USAD) method was used to coat phosphate films on aluminum and compared with films formed by mild mechanical stirring [12] . MSAP was used in this study and its impact on the adsorption behavior of these films was evaluated. Simultaneously, the corrosion resistance and adhesion properties of the coatings were studied as well. Infrared spectroscopy (IR) and NMR were used to analyze the stability of the MSAP film, after soaking the substrates for 5 h at 100 \u2022 C in a reflux distillation column containing water and steam. It was observed in NMR spectra that the USAD substrates had resolved peaks at \u22127 and \u221214 ppm, whereas the chemical shift of the stirring coated substrates occurred at 0 ppm. Based on the previous NMR studies for alkylphosphate films on metal oxide surfaces [54] [55] [56] [57] [58] , it was confirmed that the peaks at \u22127 and \u221214 ppm meant bidentate and tridentate interactions between the aluminum oxide surface and the phosphate. It was concluded that the USAD treatment favored tridentate interaction between MSAP and aluminum oxide [12] .", "cite_spans": [{"start": 820, "end": 824, "text": "[54]", "ref_id": "BIBREF53"}, {"start": 825, "end": 829, "text": "[55]", "ref_id": "BIBREF54"}, {"start": 830, "end": 834, "text": "[56]", "ref_id": "BIBREF55"}, {"start": 835, "end": 839, "text": "[57]", "ref_id": "BIBREF56"}, {"start": 840, "end": 844, "text": "[58]", "ref_id": "BIBREF57"}], "ref_spans": []}, {"section": "Phosphoric Acid Mono-(12-Hydroxy-Dodecyl) Ester", "text": "From earlier studies, it was clear that cooperated pretreatments of phosphoric acid anodic oxidation (PAA) and an adhesion promoter (AP) (phosphoric acid mono alkyl ester) could enhance the adhesion and durability of the aluminum/epoxy bonding and thus could be considered as an alternative to the chromium-based pretreatment for aluminum [59] . In a more recent work, aluminum substrates were first anodized in a phosphoric acid solution to create PAA. Then the PPA substrates were dip-coated in 10 \u22123 M aqueous solution of phosphoric acid mono-(12-hydroxy-dodecyl) ester for 5 min at room temperature [41] . EIS and the floating roller peel test were used to study the corrosion performance of PAA and PAA/AP systems. After 48 h soaking in 3% NaCl solution at 80 \u2022 C, the EIS results showed that the PAA and PAA/AP pretreated surfaces had a strong influence on the crosslinking of the epoxy at the interphase. For the floating roller peel test, one rigid and one flexible coated substrate was first bonded with Delo-Duopox 1891 adhesive. The joints were then corroded according to accelerated method VDA 621-415. The peel test was performed based on DIN EN 1464. The results indicated that after aging, PAA/AP treated substrates showed higher peel strength (around 3.3 N/mm) than PAA treated substrates (around 2.8 N/mm). It was confirmed that AP could enhance the cross-linking of the epoxy coat. The authors suggested that the AP layer was well-ordered on the surface and the strong bonding of the phosphoric acid anchor group to PAA led to the good adhesion and corrosion resistance [41] .", "cite_spans": [{"start": 339, "end": 343, "text": "[59]", "ref_id": "BIBREF58"}, {"start": 603, "end": 607, "text": "[41]", "ref_id": "BIBREF40"}, {"start": 1588, "end": 1592, "text": "[41]", "ref_id": "BIBREF40"}], "ref_spans": []}, {"section": "Fluoro Alkyl Phosphates (Zonyl UR)", "text": "Zonyl UR was deposited on aluminum plate and aluminum oxide powder as a corrosion inhibitor and adhesion promoter. Two different deposition methods were compared: The ultrasonic assisted deposition (USAD) or magnetic stirring. Environmental stability of the coating was observed in a reflux distillation column (100 \u2022 C). For aluminum plate, the change in IR spectra was used to evaluate the stability of the coatings, which showed that after 5 h refluxing, barely any changes occurred to the USAD-coated surface. In contrast, clear evidence of corrosion was observed for stirring deposition. For aluminum powder, IR spectra of stirring deposition exhibited broad features, which did not exist in USAD. Solid state nuclear magnetic resonance (NMR) was used to study the interactions between the phosphate group and the aluminum oxide powder. The results confirmed that USAD could provide a more homogeneous film with mostly tridentate interaction and low coverage of mono-and bidentate interaction [12] .", "cite_spans": [], "ref_spans": []}, {"section": "Coatings Dissolved in Paints that Contain Phosphonic Acids or Phosphates", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Phenylphosphonic Acid (PPA)", "text": "PPA has been used as a self-phosphating agent and an acid catalyst in the formulation of a polyester-melamine coating for aluminum surface [14] . In this work, a chrome-free single-step in situ phosphatizing coating (ISPC) was used on aluminum alloy (3003 or 3105). This work is based on a patent published earlier, where for an ISPC, an optimum amount of an in situ phosphatizing reagent (ISPR) or a mixture of ISPRs is predisposed in the paint system to form a stable and compatible coating formulation [60] . It is believed that when a chrome-free single-step coating of the in situ self-phosphating paint is applied to a bare metal substrate, the phosphatizing reagent chemically and/or physically reacts in situ with the metal surface to produce a metal phosphate layer and simultaneously forms covalent P-O-C (phosphorus-oxygen-carbon) linkages with the polymer resin. Such linkages enhance the adhesion of the coating and suppress substrate corrosion. It was assumed that PPA could also provide phosphate formation on the metal surface in the in-situ phosphatizing treatment [14] . The aluminum panels were spray coated with polyester-melamine paint containing 1 wt % PPA and other formulations containing commercially available acid sources (phosphonosuccinic acid, para toluene sulphonic acid). Coated substrates were analyzed for corrosion behavior using EIS measurements, saltwater immersion, and pencil hardness tests. The paint on cured panels was removed by a razor and analyzed for the glass transition temperature (T g ) using differential scanning calorimetry (DSC). A higher T g correlates with a coating with a higher cross-linking density in the polymer. T g of 1 wt % PPA paint formulation was 22 \u2022 C. After the paint was exposed to 300 \u2022 C, T g increased to 65 \u2022 C indicating an increase in the crosslinking density of the polymer. For formulations containing para toluene sulphonic acid (commercial solution), the crosslinking density dropped as the T g dropped after severe heating. This resulted from the possible cleavage of polyester-melamine cross-links in favor of the melamine self-condensation in the paint films [61] .", "cite_spans": [{"start": 139, "end": 143, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 505, "end": 509, "text": "[60]", "ref_id": "BIBREF59"}, {"start": 1082, "end": 1086, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 2144, "end": 2148, "text": "[61]", "ref_id": "BIBREF60"}], "ref_spans": []}, {"section": "Phenylphosphonic Acid (PPA)", "text": "After immersion of the coated substrate in 3% NaCl for three days, EIS was used to study the corrosion behavior. It is known from previous work that a surface with an impedance at the low frequency below 10 7 \u2126\u00b7cm 2 is considered a poor protective barrier [44] . The paint with 1 wt % PPA resulted in the impedance value of 10 10 \u2126\u00b7cm 2 at low frequency. This result indicates the superior corrosion protection of PPA-sol-gel coatings. For saltwater immersion test, test panels were scribed with an \"X\" and then were soaked in a 3% NaCl solution for 66 days. After that, a tape was firmly pressed against the scribed area and pulled to remove. The saltwater corrosion test was evaluated using the ASTM D3359A method, which showed that there was no discoloration of the paint and no paint was removed with the tape. Only very few tiny blisters (\u00d8 < 1 mm) around the scribe were observed, which may result from paint defects. The pencil hardness of the paint (ASTM D3363) was F. The paint was without any discoloration. The authors concluded the paint with 1 wt % of PPA provided excellent corrosion resistance [14] .", "cite_spans": [{"start": 256, "end": 260, "text": "[44]", "ref_id": "BIBREF43"}, {"start": 1109, "end": 1113, "text": "[14]", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "2-(Phosphonooxy) Benzoic Acid (Fosfosal)", "text": "Fosfosal was used as an acid additive in the polyester-melamine paint and was used in the in situ phosphatizing treatment on aluminum alloy (3003) [14] . Substrates were spray-coated with polyester-melamine paint containing different concentrations (0.5%, 0.75%, and 1%) of Fosfosal. DSC was used to evaluate the cross-linking density of polymer by analyzing the glass transition temperature (T g ). The DSC program involved annealing at 80 \u2022 C, then scanning from \u221250 \u2022 C to 300 \u2022 C with a heating rate of 10 \u2022 C /min. Higher T g means higher cross-linking density. EIS was used to study the corrosion performance of coated substrates after three days in 3% NaCl immersion. As mentioned earlier, EIS results of lower than 10 7 \u2126\u00b7cm 2 at low frequency meant poor anti-corrosion properties. Corrosion resistance was further studied after saltwater immersion. Coated substrates were scribed with an \"X\" and immersed in 3% NaCl solution for 66 days. After drying, a tape was firmly pressed against the \"X\" area and pulled to remove. The corrosion resistance was evaluated by ASTM method D3359 A The pencil hardness of the painted Al panels was measured using ASTM method D3363. The results of the corrosion test are summarized in Table 7 . The corrosion resistance (saltwater immersion) for 1% Fosfosal coatings could not be estimated with the ASTM method. For 0.5% Fosfosal, saltwater immersion results were not reproducible; one panel had no paint removal and was evaluated as 5A in the ASTM D3359 A test. One panel had a clump of blisters of size~\u00d8 2 mm and the rest had no blistering. DSC results for coatings with 0.5% Fosfosal showed that cross-linking density increased and EIS results showed 0.5% Fosfosal provided sufficient corrosion protection. In case of pencil hardness test, coatings containing 1% and 0.75% Fosfosal (4H) were harder than for 0.5% Fosfosal (HB). However, EIS results for coatings containing 1% Fosfosal were not reproducible and saltwater immersion results of 0.75% Fosfosal were worse than for 0.5% Fosfosal. Therefore, the authors suggested that 0.5% Fosfosal should be used in the in situ phosphatizing treatment [14] .", "cite_spans": [{"start": 147, "end": 151, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 2144, "end": 2148, "text": "[14]", "ref_id": "BIBREF13"}], "ref_spans": [{"start": 1227, "end": 1234, "text": "Table 7", "ref_id": "TABREF26"}]}, {"section": "Phosphonosuccinic Acid (PPSA)", "text": "PPSA, as an acid additive, was added to the polyester-melamine paint coated on the aluminum alloy (3003) surface. The EIS accelerated corrosion test was used to study the corrosion performance of these coatings. Polyester-melamine paint with 5% PPSA could not be fully cured. Thus, paint with 1 wt % PPSA was coated on the substrate and cured, but these coatings exhibited poor coating properties. EIS results showed that the impedance at low frequency was in the order of 10 6 \u2126\u00b7cm 2 . After one week immersion in 3% salt solution, many blisters were observed on the paint surface. PPSA performed badly as a catalyst in the polyester-melamine paint system [14] .", "cite_spans": [{"start": 657, "end": 661, "text": "[14]", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Conclusions", "text": "Environmental issues with existing pretreatments for aluminum, together with the need to develop new materials with higher mechanical and chemical performance, is driving the research and industrial communities to develop new pretreatments based on phosphonic acids. The new treatments are shown to have higher mechanical performance and corrosion protection; however, much work in adaptation to industrial processes and their real environmental impact need to be evaluated to demonstrate the commercial feasibility of these treatments. In many cases, the phosphonic acids are incorporated in sol-gel coatings, which look simple in batch-scale application in laboratory research. However, it is not clear if such treatments can be adapted to continuous handling in industrial production. The use of hybrid systems, such as phosphonic acid-modified graphene oxide, is quite promising. However, the economics of such treatments will determine its potential commercial exploitation. We believe that the combination of various organic and inorganic conversion technologies for aluminum is needed to obtain industrially-feasible solutions. The development of novel phosphonic acid chemistry with a focus on self-healing, superior galvanic protection, and higher mechanical performance will have a strong focus in the future. 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R oxide is the resistance of oxide aluminum layer, C oxide is the capacitance of oxide aluminum layer, R coat is the resistance of the coating, and C coat is the capacitance of the coating. (Reproduced from [41] with permission; Copyright 2004 Elsevier).", "type": "figure"}, "FIGREF7": {"text": "PTMOS), tetraethyl orthosilicate (TEOS), N-trimethoxysilylpropyl-N,N,N- trimethyl ammonium chloride (TMA), tert-butylphosphonic acid (TBPA).", "type": "figure"}, "FIGREF9": {"text": "PTMOS), tetraethyl orthosilicate (TEOS), N-trimethoxysilylpropyl-N,N,N- trimethyl ammonium chloride (TMA), tert-butylphosphonic acid (TBPA).", "type": "figure"}, "FIGREF10": {"text": "Scheme 1. Multilayer zirconium phosphate treatment consisting of DDP. (Reproduced from [8] with permission; Copyright 2003 Elsevier).", "type": "figure"}, "FIGREF11": {"text": "Scheme 1. Multilayer zirconium phosphate treatment consisting of DDP. (Reproduced from [8] with permission; Copyright 2003 Elsevier).", "type": "figure"}, "FIGREF12": {"text": "tetrahydrodecyl) trichlorosilane (HDF-S) was also studied as a comparison. The bare Al 2 O 3 films showed contact angle values of 70.0 \u2022 \u00b1 1.5 \u2022 , the contact angles of HDF-PA and HDF-S-coated Al 2 O 3 films were enhanced to 99.9 \u2022 \u00b1 1.0 \u2022 and 102.7 \u2022 \u00b1 2.4 \u2022 . After exposing the surface to 5 L of water droplets, contact angles of HDF-S coating remained around 102.7 \u2022 , whereas the contact angles of HDF-PA coating reduced from 99.9 \u2022 to 69.3 \u2022 . The results showed that HDF-S formed a more stable bond than HDF-PA, which may be due to the cross-linked siloxane network on the surface. A low-temperature (<150 \u2022 C) thermal annealing process was used to improve the HDF-PA bond formation. The results showed that after the water flow test, contact angles for 100 \u2022 C and 150 \u2022 C annealed substrates were stable at around 101 \u2022 C. Therefore, the durability of HDF-PA coatings could be improved by an additional thermal annealing process at 100-150 \u2022 C [19]. 4.1.12. Poly (Vinyl Phosphonic Acid) (PvPA)", "type": "figure"}, "TABREF0": {"text": "Commonly-employed surface characterization techniques.", "type": "table"}, "TABREF1": {"text": "XPS binding energies relevant to phosphonic acids modified aluminum surface.Table 3. Infrared vibrational modes involving the phosphorus atom for the self-assembled organophosphorus layer on aluminum.", "type": "table"}, "TABREF2": {"text": "Common methods for corrosion measurements.", "type": "table"}, "TABREF3": {"text": "Common methods for corrosion measurements.", "type": "table"}, "TABREF4": {"text": "Chemical name, structure, and abbreviation of organophosphonic acids.", "type": "table"}, "TABREF5": {"text": "Chemical name, structure, and abbreviation of organophosphonic acids.", "type": "table"}, "TABREF6": {"text": "Chemical name, structure, and abbreviation of organophosphonic acids.", "type": "table"}, "TABREF7": {"text": "Chemical name, structure, and abbreviation of organophosphonic acids.", "type": "table"}, "TABREF8": {"text": "Chemical name, structure, and abbreviation of organophosphonic acids.", "type": "table"}, "TABREF9": {"text": "Cont.", "type": "table"}, "TABREF10": {"text": "Cont.", "type": "table"}, "TABREF11": {"text": "Cont.", "type": "table"}, "TABREF12": {"text": "Cont.", "type": "table"}, "TABREF13": {"text": "Cont.", "type": "table"}, "TABREF14": {"text": "Cont.", "type": "table"}, "TABREF15": {"text": "Cont.", "type": "table"}, "TABREF16": {"text": "Cont.", "type": "table"}, "TABREF18": {"text": "Cont.", "type": "table"}, "TABREF19": {"text": "Cont.", "type": "table"}, "TABREF20": {"text": "Cont.", "type": "table"}, "TABREF21": {"text": "Cont.", "type": "table"}, "TABREF22": {"text": "Cont.", "type": "table"}, "TABREF23": {"text": "Cont.", "type": "table"}, "TABREF24": {"text": "Cont.", "type": "table"}, "TABREF25": {"text": "Various formulations of sol-gel coatings.", "type": "table"}, "TABREF26": {"text": "Measurement results of different Fosfosal concentrations.", "type": "table"}}}
{"paper_id": "102809658", "_pdf_hash": "ed4d29c820532828df541bd1ae496a5ab82e85ab", "abstract": [{"section": "Abstract", "text": "Multiprotein complexes are key regulators of most biomolecular mechanisms. Numerous multiprotein expression technologies (ACEMBL, MultiBac, etc) [1] developed in our lab have played an important role in recent breakthroughs in studying these complexes. This multiprotein expression toolbox has always been under continuous improvisation. Various recent advances made in these systems will be discussed here. Recently a Polyprotein strategy was developed to improve the stoichiometry of different subunits within a protein complex. A SynBac [2] system is being developed to further stabilize the baculovirus genome in order to improvise the expression of much bigger protein complexes. Multiprotein complex expression was successfully expanded to mammalian cells with MultiMam and MultiBacMam. Various tools for expression of modified protein complexes have also been developed in our lab. A new system, MultiBacTAG [3] made it possible to do multiprotein complex engineering for various structural and functional studies. Protein (complexes) were successfully expressed with specific post-translational modification by introducing various enzymes into the MultiBac system, for example glycosylases (SweetBac), deglycosylases, kinases and acetylases.", "cite_spans": [], "ref_spans": []}], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "149771237", "_pdf_hash": "78b30a9df223b5fdb36b758983d966e54ccb6127", "abstract": [{"section": "Abstract", "text": "during pre-transplantation work-up is crucial from a quality-adjusted life expectancy perspective. The cumulative time on HD can be considered a more important driver of the differences in QALYs between the 4 strategies than the higher rate of metastatic progression associated with AS. Future decision-analytic research should mainly focus on the investigation of the 2 favored strategies B & D and also incorporate a cost perspective.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "INTRODUCTION AND OBJECTIVES: Robot-assisted surgery of the inferior vena cava (IVC) has been increasingly utilized as a minimally invasive alternative to a traditionally open approach. This surgical technique has been primarily described for renal masses with tumor thrombus, however similar principles can be applied to other less commonly performed procedures such as removal of IVC filters (IVCF) and left renal vein transposition (RVT) for nut cracker syndrome. We aim to describe our operative experience with robot assisted surgery of the IVC with regard to feasibility, safety, and preservation of caval diameter.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "METHODS: A retrospective review was performed on surgeries completed within the last decade at Mayo Clinic Arizona. All patients had complete mobilization of the IVC with division of lumbar veins when required, allowing for proximal and distal control prior to cavotomy. Patient characteristics, operative reports, and follow up visits were analyzed. Preoperative and postoperative imaging was independently reviewed by a single radiologist. Complications were analyzed using the Clavien-Dindo grading system. RESULTS: Twenty-seven patients were identified to have undergone robot-assisted surgery of the IVC from January 2008-May 2018. 21 patients underwent surgery for urologic malignancy, 4 for IVCF removal, and 3 for RVT. Median age was 62 years. Median operative time and estimated blood loss was 323 minutes and 400mL, respectively. Median length of stay was 3 nights. All cavotomies were closed primarily except one, which required ligation due to chronic thrombus. 22 (82%) patients received some form of anticoagulation/antiplatelet therapy on discharge, at a median duration of 14 days. There were five complications, ranging from Clavien-Dindo grade II-IIIa. No patients required return to the operating room and there were no perioperative mortalities. Two patients experienced thromboembolic complications. Postoperative abdominal imaging was completed in 12 (44%) patients. In all imaging studies, the vena cava was patent, and no patients had symptoms of venous congestion. The median (interquartile range) percent reduction in IVC diameter was 41% (29-62%) on axial diameter, and 63% (50-72%) on sagittal diameter.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "CONCLUSIONS: Robot assisted surgery offers the advantage of minimally invasive surgery with the additional ability to apply open surgical principles. Patients experienced minimal perioperative complications with preservation of the IVC diameter.", "cite_spans": [], "ref_spans": []}, {"section": "Source of Funding: none", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "PD54-06 TREATMENT OF RENAL ARTERY IN-STENT RESTENOSIS: A BAYESIAN NETWORK META-ANALYSIS", "text": "Jeffrey Sack*, Sarasota, FL; Jayme Sack, Saddle River, NJ; Hari Tunuguntla, Piscataway, NJ INTRODUCTION AND OBJECTIVES: The optimal treatment for renal artery in-stent restenosis (RAISR) is unknown. To determine the optimal treatment for RAISR, we conducted a Bayesian network metaanalysis comparing percutaneous balloon angioplasty (PTA), bare metal stent (BMS), drug eluding stent (DES), and cutting balloon angioplasty (CB METHODS: We searched MEDLINE, Cochrane and EMBASE libraries for all studies using pre-specified criteria of endovascular treatments for RAISR without restriction on language between January 1980 to April 2018. We excluded patients who had renal transplant renal artery stenosis. A Bayesian network meta-analysis was performed using WinBUGS (v1.4.3) comparing PTA vs BMS vs DES vs CB using both a fixed and random effect model using non-informative priors. PTA was considered the reference treatment and odds ratios (OR) for 12-month restenosis were calculated for all comparisons along with 95% confidence intervals (CI). There was insufficient data to include covered stents, drug coated balloons and brachytherapy. We calculated the surface under the cumulative ranking (SUCRA) a simple numerical summary of the probabilities. SUCRA is 100% when a treatment is certain to be the best and 0% when the treatment is certain to be the worst. Bias was assessed using heterogeneity plots and the Cochrane tool. RESULTS: We included 13 studies involving a total of 943 patients. (mean age 65.1 years, 60% male). DES was the most effective treatment for RAISR with an OR[0.26 [95% CI, (0.02-3.04)], compared with PTA and a SUCRA of 81% followed by CB [OR 0.28, (0.06-1.00), SUCRA[70%] and BMS [OR 0.62, SUCRA[37%] . PTA scored the lowest SUCRA of 12%, consistent with the least effect treatment of those compared.", "cite_spans": [], "ref_spans": []}, {"section": "PD54-06 TREATMENT OF RENAL ARTERY IN-STENT RESTENOSIS: A BAYESIAN NETWORK META-ANALYSIS", "text": "CONCLUSIONS: Based on these data, treatment of RAISR with DES appears to be most favored, followed by CB, BMS and then PTA. The lack of randomized controlled trials and the small data sets of the included studies limits our findings.", "cite_spans": [], "ref_spans": []}], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "149771967", "_pdf_hash": "893df0b807406ef2e9e487e470f7c7b767ed2346", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "149772757", "_pdf_hash": "8e95052877ae29de52f91b37333c17a4a7a3b5b1", "abstract": [{"section": "Abstract", "text": "Applying a Bourdieusian feminist practice theory approach to the study of norm implementation, this article introduces a fourth level of analysis, the embodied subject who is expected to be governed by peacekeeping norms. It does so by examining the training experiences of Rwandan tactical-level female military peacekeepers deployed in mix-gender contingents to UNAMID. It is argued that the pre-deployment training space is a field of norm contestation and negotiation, wherein gendered peacekeeper subject positions and gendered peacekeeping labouring practices are constructed and performed. The research findings suggest that by partially complying with the UN's gender mainstreaming norms, the Rwanda Defence Force strengthens the military's gender protection norms and establishes the sexual division of labour of the mission area. Trained to perform a scripted Rwandan female subject position, some women find they are not adequately prepared for the more challenging situations they find themselves in when working in multi-dimensional peacekeeping operations and devise alternative, informal training practices to better equip themselves prior to deployment. The case study draws on 65 depth-interviews with Rwandan military personnel, trainers and external consultants and non-participatory observations of field exercises.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "How do we conceptualise norm implementation in peacekeeping? How do we account for the ways in which the implementation of institutionalised peacekeeping norms 1 can lead to variation of practice on the ground? These are the overarching research questions posed by scholars that seek to problematise processes that have largely been overlooked in the norm diffusion/circulation literature. 2 Norm implementation scholars start from the premise that implementation is a 'distinct process' running in parallel to international norm institutionalisation processes. 3 Betts and Orchard describe norm implementation as the steps required 'to introduce' an 'international norm's precepts into formal legal and policy mechanisms within the state or organisation in order to routinise compliance', wherein compliance is conceptualised as an 'act' 4 The conceptual distinction facilitates the study of variance in norm implementation and its effects, even when the act of norm compliance has occurred at the domestic level within the state and its security institutions that engage in peacekeeping. This article contributes to recent theorising of norm implementation by introducing a fourth level of analysis, the embodied subject who is expected to be governed by peacekeeping norms. It does so by examining how UN gender mainstreaming norms are translated into practice in pre-deployment training programmes for tactical-level peacekeepers in Rwanda.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Examining norm implementation processes necessitates a different set of research questions to those posed by norm circulation theorists. The focus shifts away from 'how norms spread' to 'who operationalises norms and under what conditions?' Constructivists define norms as the 'collective expectations for the proper behaviour of actors with a given identity in global politics' 5 that 'serve the purpose of guiding behaviour by providing motivations for action '. 6 Constructivist scholars often distinguish between the level of the international, regional and the domestic (the state) to structure their norm diffusion/circulation models, and have recognised the influence epistemic communities inside the state have in determining how norms are internalised at the domestic level. 7 They have advanced understandings of how international norms are translated, negotiated and contested to challenge the early norm cascade models, which allocated primacy of power and agency to western actors. 8 However, these theorists have been criticised for failing to locate actors as central to diffusion and implementation, instead ascribing agency to the norm itself. 9 They have also been criticised for introducing an 'ideational bias' into theorising norm dynamics which positions material interests as secondary in determining what motivates actors to perform, or to change their behaviour. 10 In contrast, norm implementation theorists acknowledge that ideational, material and institutional factors determine how norms are implemented. 11 They infer that 'acting persons' 12 are agentive and embodied subjects who shape norm implementation processes. How agentive subjects engage in translating institutionalised norms into routinised practices therefore demands greater attention. It requires a conceptual framework that bridges the ideational-material divide, and calls for a rethinking of what is meant by 'internalisation' and 'socialisation' -two metaphors 13 commonly used by norm diffusion/circulation scholars to denote the moment when a norm is accepted by a state or state institutions.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Peacekeeping training is recognised as a site wherein the UN institutionalised norms that are intended to govern and discipline peacekeeper subjects are diffused and implemented.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "14 Pre-deployment training is conceptualised frequently in the literature as a mechanism or channel through which (liberal peace) norms, values and beliefs, as well as technical skills are transferred to peacekeepers, rather than a field of social practice wherein norms are translated and/or negotiated, consciously or unconsciously, by embodied subjects engaged in the training process. Suspending the regional and local socio-political and economic contexts which shape peacekeeping training and peacekeeping training spaces, this narrow conceptualisation reinforces the assumption that training trainers, standardising training materials and sharing good practice (with the intention of strengthening the flow of knowledge from the core to the periphery) will by default enhance the capabilities of peacekeepers, establish norm compliance and improve operational effectiveness. Two underlying concepts in the peacekeeping training literature -norm diffusion and peacekeeper socialisation -support the constructivist emphasis on the ability of norms to 'change the behaviour' of peacekeeper subjects, and in doing so reconfirm the primacy of the norm's agency. As a result, the agency of the peacekeeper subjects who are participants in the training process is eclipsed. The article is divided into four parts. The first part outlines how norms, norm dynamics and agency are conceptualised in the peacekeeping training literature. In the second, the article makes the case that the pre-deployment training space as a field of norm negotiation and contestation wherein gendered peacekeeper subject positions are constructed and performed through embodied practices. The article then examines how UN gender mainstreaming norms embedded in DPKO/DFS policies and training guidance construct women's peacekeeping labouring practices, and illustrates how these norms are operationalised during pre-deployment training. After analysing how a diversity of female military personnel engage in norm implementation during pre-deployment training, the article concludes by reflecting on the explanatory power that a Bourdieusian feminist praxiography contributes to the study of norm 21 Statistics provided by RDF Gender Desk, 9 July 2015. 22 Holmes, 2014. implementation processes. In conducting this analysis, I offer a significant contribution towards understanding how peacekeeping is gendered, and a conceptual framework to help link agency to norm implementation. The case study draws on 65 depth-interviews with Rwandan military personnel, trainers and external consultants, and non-participatory observations of field exercises.", "cite_spans": [{"start": 2234, "end": 2247, "text": "Holmes, 2014.", "ref_id": "BIBREF43"}], "ref_spans": []}, {"section": "A Feminist praxiography", "text": "The research strategy employed is based on the methodological approaches located in Sixty-five semi-structured interviews were conducted with male and female Rwandan 32 Karlsrud, 2016, 7. 33 Bueger and Gadinger, 2014, 83 34 Pouliot, 2013, 48; Bueger and Gadinger, 2014, 83. 35 Bueger and Gadinger, 2014, 83 36 Halperin and Heath, 2012, 258. 37 Bueger and Gadinger, 2014, 85. military personnel, trainers and external consultants (see The analysis presented in this article are based on practices observed (identified) and recorded by the author during participant observations, formal and informal research encounters in the pre-deployment training field, and training materials provided by the RDF. provided what were perceived by the author to be socially acceptable answers for an outsider researcher. 39 Others diverged from formal narratives and spoke at a more personal and critical level. This discrepancy helped identify the embodied practices female military personnel were expected to perform during training vis-\u00e0-vis the practices the women chose to perform, and facilitated reconstruction of the 'scripted' Rwandan female peacekeeper subject position.", "cite_spans": [{"start": 191, "end": 201, "text": "Bueger and", "ref_id": "BIBREF19"}, {"start": 277, "end": 287, "text": "Bueger and", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "A Feminist praxiography", "text": "38 Holmes, 2013, 36-40 . 39 Halperin and Heath, 2012, 259. Triangulation identified a range of practices and the repetition and routinisation of practices 40 , as did conducting interviews over four field research trips, each lasting 2-3 weeks. To differentiate between types of background knowledge and practices acquired during training, and afterwards during deployment, a comparative analysis of interview transcripts with female peacekeepers that had not deployed and those that had was conducted.", "cite_spans": [], "ref_spans": []}, {"section": "A Feminist praxiography", "text": "Interviews were translated into English and transcribed by three assistants in Rwanda and the UK, although small variations in translation occurred. Research participants consented to the interviews and are referred to by a number, rank and role to ensure anonymity. ]constitute' peacekeeper subjects. 44 They are institutionalised at the international level, before 40 Pouliot, 2013. 41 United Nations, 2016a. 42 Curran, 2016 , 119. 43 Betts Featherston, 1998 Duffy, 2000 . 44 Bj\u00f6rkdahl, 2002 cascading to the domestic level once the tipping point is reached, as described in Finnemore See Whitworth, 2004; Mackay, 2005; Lyytik\u00e4inen 2007; Laplonge, 2015; Carson, 2016. 60 See Higate and Henry, 2009; Whitworth, 2004; Duncanson, 2009; Bevan and MacKenzie, 2012 . 61 Laplonge, 2015; . 62 Carreiras, 2006 Holmes, 2017; Karim and Beardsley, 2017 . 63 Heineken, 2015, 241. UN gender mainstreaming norms and reinforce domestic gender protection norms. 64 Crawford and Macdonald suggest that gender mainstreaming is a UN-led demand-driven response to 'past mission failures', rather than a supply-driven response of TCCs.", "cite_spans": [{"start": 461, "end": 472, "text": "Duffy, 2000", "ref_id": "BIBREF35"}, {"start": 608, "end": 621, "text": "Mackay, 2005;", "ref_id": "BIBREF56"}, {"start": 640, "end": 655, "text": "Laplonge, 2015;", "ref_id": "BIBREF54"}, {"start": 677, "end": 700, "text": "Higate and Henry, 2009;", "ref_id": "BIBREF41"}, {"start": 701, "end": 717, "text": "Whitworth, 2004;", "ref_id": "BIBREF69"}, {"start": 718, "end": 734, "text": "Duncanson, 2009;", "ref_id": "BIBREF36"}, {"start": 735, "end": 760, "text": "Bevan and MacKenzie, 2012", "ref_id": "BIBREF17"}, {"start": 766, "end": 781, "text": "Laplonge, 2015;", "ref_id": "BIBREF54"}, {"start": 803, "end": 816, "text": "Holmes, 2017;", "ref_id": "BIBREF44"}], "ref_spans": []}, {"section": "Norms and agency in peacekeeping training", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "77", "text": "The appropriation of Bourdieu's theory of social practice to explain how domestic norms are supplanted and gendered peacekeeper subjects transformed overlooks how gendered peacekeeping labouring practices are constructed during the training encounter.", "cite_spans": [], "ref_spans": []}, {"section": "77", "text": "Peacekeepers are not just commodities, they are also capital accumulating subjects 78 who bring their own ideational and material interests to peacekeeping missions 79 , as well as to peacekeeping training. Therefore, the act of norm compliance, non-compliance or partial 72 Flasp\u00f6ler, 2015; Jowell, 2017; Wil\u00e9n, 2018 . 73 MacKay, 2005 Sion, 2008; Laplonge, 2016; Carson, 2016. 74 See Bridges and Horsfall, 2008; Jennings, 2011; Kronsell, 2012; Simic, 2014; Gizelis and Olsson, 2015; Beardsley, 2017. 75 See Sion, 2008; Heathcote and Otto, 2014; Simic, 2014; Beardsley and Karim, 2013; Pruitt, 2016; Beardsley, 2017. 76 Pruitt, 2016, 78. 77 Crawford and Macdonald, 2013. 78 Lovell, 2000, 20. 79 Higate and Henry, 2008. compliance, which occurs during the norm implementation process, carries transactional value both for the TCC and the individual peacekeeper.", "cite_spans": [{"start": 292, "end": 305, "text": "Jowell, 2017;", "ref_id": "BIBREF48"}, {"start": 306, "end": 317, "text": "Wil\u00e9n, 2018", "ref_id": "BIBREF71"}, {"start": 336, "end": 347, "text": "Sion, 2008;", "ref_id": "BIBREF64"}, {"start": 413, "end": 428, "text": "Jennings, 2011;", "ref_id": "BIBREF46"}, {"start": 445, "end": 457, "text": "Simic, 2014;", "ref_id": "BIBREF65"}, {"start": 520, "end": 545, "text": "Heathcote and Otto, 2014;", "ref_id": "BIBREF39"}, {"start": 546, "end": 558, "text": "Simic, 2014;", "ref_id": "BIBREF65"}, {"start": 559, "end": 585, "text": "Beardsley and Karim, 2013;", "ref_id": "BIBREF13"}, {"start": 586, "end": 599, "text": "Pruitt, 2016;", "ref_id": "BIBREF60"}, {"start": 641, "end": 653, "text": "Crawford and", "ref_id": "BIBREF29"}], "ref_spans": []}, {"section": "77", "text": "Taken together, the ideational bias in the existing peacekeeping training literature foregrounds structure over socially embedded agency and relations of power 80 in the material training space, and hinders analysis of how a diversity of raced, classed, sexed and gendered peacekeeper subjects engage in norm implementation.", "cite_spans": [], "ref_spans": []}, {"section": "Conceptualising pre-deployment training", "text": "The pre-deployment training space is a field of practice and a site of norm contestation, negotiation and implementation. Actors (subjects) that engage in predeployment training are located within a field and both shape and are shaped by the field's ", "cite_spans": [], "ref_spans": []}, {"section": "Constructing gendered peacekeeper subject positions", "text": "The pre-deployment training space is a militarised field of power, as well as an educational field of practice wherein subject positions are constructed and negotiated during transfers of knowledge between educators and learners. Through military education and training, male and female personnel are assigned (pre-)constructed subject positions, which they must learn to perform in accordance with the logic of appropriateness within the fields in which they will operate. 85 Informed by historical, gendered military practices and patterns of action, the training curriculum 'establishes hierarchical relations between different forms of knowledge'", "cite_spans": [], "ref_spans": []}, {"section": "Constructing gendered peacekeeper subject positions", "text": "and 'generates a network of subject positions in relation to these hierarchies'. Bourdieu's theory of practice and his suggestion that the habitus of the pre-deployment training field changes according to the actors operating within it reminds us of the temporality of norm implementation processes. Norms-in-practice, then, are continually negotiated by the subjects engaged in norm implementation. Yet, the repetition and routinisation of embodied practices stabilises implemented norms, albeit precariously.", "cite_spans": [], "ref_spans": []}, {"section": "DPKO/DFS embedded gender mainstreaming norms", "text": "The use-value of tactical-level female military peacekeepers is described in DPKO/DFS's 'Gender Policy for UN Peacekeeping' (2010) The proceeding case study illustrates how DPKO/DFS embedded gender mainstreaming norms become implemented in the Rwandan pre-deployment training programme for mixed-gender battalions. Overall, the RDF accepts DPKO/DFS integrationist gender mainstreaming norms and rejects transformative gender mainstreaming norms.", "cite_spans": [], "ref_spans": []}, {"section": "Norm contestation and negotiation", "text": "The RDF trained three battalions concurrently at Gako Military Academy. Battalions productive, the limited content selection facilitated partial compliance of UN gender mainstreaming norms.", "cite_spans": [], "ref_spans": []}, {"section": "Norm contestation and negotiation", "text": "The RDF only incorporated a gender dimension when teaching modules on preventing SEA, peacekeeper discipline and performance; cultural diversity and PoC. All modules, including the gender module, were taught by RDF officers, rather than in-house gender experts.", "cite_spans": [], "ref_spans": []}, {"section": "Norm contestation and negotiation", "text": "In interviews, these officers indicated that the UN's more transformative gender agenda was irrelevant for preparing peacekeepers for deployment. Modules were taught didactically as 30-45 minute-long lectures by trainers using powerpoint slides to all 800 military personnel in the battalion mess. As an RDF Gender Desk staff member explained, emphasis was placed on ensuring discipline among male troops. 100 Training objectives specified that the Rwandan male peacekeeper should understand that gender as socially constructed, know the concepts SEA and 'GBV' and understand the different ways conflict affects men, women and children. Heinecken and Sion's analyses, women were excluded from performing certain security practices and were confined to 'safe spaces' and 'safe tasks' 103 . They did not join male Rwandan military peacekeepers on short-duration day patrols unless it was known in advance that female military peacekeepers were required, 104 and they were not allowed to participate in night patrols or long-duration patrols. None of the female peacekeepers interviewed engaged in DDR/SSR programmes, which were not UNAMID priorities. Four women engaged in intelligence gathering, but most who worked with local populations outside the base camp supported empowerment and education projects and discussed human rights, HIV/AIDs awareness and reproductive health with Sudanese women.", "cite_spans": [], "ref_spans": []}, {"section": "Norm contestation and negotiation", "text": "In the 40km\u00b2 training compound, a simulated mission area incorporating three base camps was constructed. The gender order of the UNAMID-Rwandan base camp was reproduced in the simulated mission area: first, in the ordering of the peacekeeping training space itself, which was designed by the RDF, and second in the ordering of training practices in accordance with mission objectives. According to a former Director of Gako Military", "cite_spans": [], "ref_spans": []}, {"section": "Norm contestation and negotiation", "text": "Training Academy, the simulated base camps were organised identically to Rwanda's base camps in the conflict zone to ensure RDF military personnel experienced the closest they could to mission life. 105 RDF policy and practice dictated that the all-female unit's tent and bathroom facilities were located next to the officers' accommodation. 106 These embodied practices reveal the subtle ways in which a network of gendered and classed subject positions is created.", "cite_spans": [], "ref_spans": []}, {"section": "Norm contestation and negotiation", "text": "Although sexual abuse and harassment should be prevented, the spatial zoning of the simulated base camp positioned all Rwandan women as potential victims requiring protection, but also agents who needed to be vigilant of personal security threats; educated middle-class Rwandan male senior officers were positioned as their protectors, while lower-ranking, (predominantly)", "cite_spans": [], "ref_spans": []}, {"section": "Norm contestation and negotiation", "text": "working class Rwandan male soldiers were potential aggressors and thus subordinate to male senior officers.", "cite_spans": [], "ref_spans": []}, {"section": "Constructing the Rwandan female peacekeeper subject position", "text": "As in most militaries, male and female personnel train together to form a cohesive team.", "cite_spans": [], "ref_spans": []}, {"section": "Constructing the Rwandan female peacekeeper subject position", "text": "Though the Rwandan male peacekeeper subject was foregrounded in the classroom, women were expected to perform gendered labouring practices during field exercises. Taskorientated 107 field exercises, designed to test peacekeepers on knowledge learnt in the classroom 108 and rehearse peacekeeping labouring practices, addressed gender in narrow terms.", "cite_spans": [], "ref_spans": []}, {"section": "Constructing the Rwandan female peacekeeper subject position", "text": "During a half-day participant observation, the battalion was presented with two scenarios. In the first, warring factions had set up roadblocks, were conducting ambushes and hindering peacekeepers from reaching IDP camps and isolated, dehydrated Sudanese women. In the second, the battalion encountered IDP demonstrations near the Rwandan base camp. Nine out of the 10 women in the battalion executed basic military tasks within the base camp and one woman, a captain, was an intelligence analyst. In the first scenario, female military personnel performed as the scripted Rwandan female peacekeeper and tasks were assigned according to their gender. Process-orientated role-plays included teaching local women and girls about gender equality; searching a poor woman's house, rebuilding houses and giving IDPs water. In Rwanda, homosexuality is not illegal, though a strategic silence around LGBT rights in the military and broader society exists. The scripted Rwandan female peacekeeper subject position RDF women rehearsed was implicitly heterosexual, while role-plays focused on responding to women and girl survivors of rape, rather than men and boys. Due to their low rank, the women did not make decisions about managing convoys and ambushes. Peacekeepers were not required to negotiate with female combatants during the patrol exercise because, according to senior RDF staff, it was 'rare to find women in ambushes in Darfur'.", "cite_spans": [], "ref_spans": []}, {"section": "109", "text": "All the women interviewed self-identified as gender-neutral peacekeepers. Yet, two- ", "cite_spans": [], "ref_spans": []}, {"section": "How female peacekeepers engage in norm implementation", "text": "Female military personnel are not just commodities, but capital accumulating subjects that bring their own ideational and material interests to peacekeeping training. All the women interviewed regarded pre-deployment training as a strategic investment. Yet, when asked whether they felt the pre-deployment training equipped them to perform peacekeeping labouring practices competently, the women responded in diverse ways, depending on their position within the military; how much capital they had access to, and the background knowledge they brought to the training.", "cite_spans": [], "ref_spans": []}, {"section": "How female peacekeepers engage in norm implementation", "text": "Many women -notably lower-ranking and younger privates -felt confident they were equipped with the skills required to deploy to UNAMID, although they often spoke about Several returned peacekeepers wanted to out-perform the scripted Rwandan female peacekeeper subject position, believing as one lieutenant explained, 'if women perform their tasks well they will give us more challenging and good tasks, like the ones of men'. 127 Like the junior women who had not deployed, these women saw implementing RDF-accepted integrationist gender mainstreaming norms as a strategic investment.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "Applying a Bourdieusian feminist praxiography, this article has introduced a fourth level of analysis to norm implementation, the embodied subject who is expected to be governed by peacekeeping norms. A feminist reading of Bourdieu's theory of social practice, with its insistence that subordinated men and women are capital-bearing objects and capital accumulating subjects, enhances the study of norm implementation by demonstrating how these subjects are both compelled and choose to engage in norm implementation. In doing so, the conceptual framework helps to bridge the ideational-material divide found in the norm diffusion/circulation literature. Indeed, Bourdieu regarded rationalist and constructivist paradigms as 'incomplete pictures' and sought a synthesis that would not 'reduce the logic of practice to either instrumental rationality or structural determinism', nor 'reify abstract concepts' such as norms.", "cite_spans": [], "ref_spans": []}, {"section": "128", "text": "Bourdieu's inference of the field and habitus' mutability depending on the actors operating within them, reminds us of the temporality of norm implementation processes.", "cite_spans": [], "ref_spans": []}, {"section": "128", "text": "Norms are continually negotiated by the embodied subjects engaged in norm implementation.", "cite_spans": [], "ref_spans": []}, {"section": "128", "text": "Yet, as Betts and Orchard observe, there has to be some kind of settling process in order for norms to exist. 129 In Rwanda, settling occurred via the routinisation and repetition of embodied in one recorded instance, their unit. 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Research participants would not discuss whether ethnicity affected their training experiences and this variable is excluded from the study. Research participants were selected by RDF staff in MINEDEF's Peace Support Operations division and by the Office of the Director of Gako Military Training Academy from a pool of peacekeepers who may have been screened and briefed in advance to ensure regularity of performance during research encounters. Several research participants appeared to perform to an RDF institutional (public) transcript or", "type": "figure"}, "FIGREF1": {"text": "DPKO/DFS outline three training phrases for peacekeepers: pre-deployment training; early deployment (induction) training and ongoing training during deployment. 41 Under General Assembly resolution A/RES/49/37 (1995), TCCS are responsible for training uniformed personnel and since 2009 are expected to use core pre-deployment training materials (CPTMs) produced by DPKO/DFS and the Integrated Training Service (ITS). Theorising how UN institutionalised peacekeeping norms are implemented in peacekeeping training is an emergent area of research. In the existing literature, critical peacekeeping scholars borrow constructivist definitions of norms and norm dynamics to explain how the politics of global governance play out in peacekeeping training. First generation scholars writing in the 1990s contended that peacekeepers deployed to multi-dimensional peacekeeping operations require softer conflict resolution skills than the conventional combatant soldier. Transforming the traditional warrior peacekeeper into the 'cosmopolitan peacekeeper' 42 was the focus, as was improving peacekeeper interactions with host communities to deliver protection of civilian (POC) tasks and support mission-specific peacebuilding efforts. 43 Peacekeeping training is conceptualised as a mechanism or channel through which to transfer UN institutionalised human rights and protection norms in order to 're-socialise' military personnel as UN peacekeepers; or to transfer technical skills to the peacekeeper. Reflecting constructionist definitions, norms change behaviour and '[re-", "type": "figure"}, "FIGREF2": {"text": "the TCC military, pre-deployment training does not necessarily aim to transform the mindset (consciousness) of subordinate peacekeepers if raising awareness of the military habitus has the potential to disrupt the military's existing power relations. Instead, the aim is to ensure that deployed peacekeeper subjects perform peacekeeping practices to the standardised level of competence required -either by the UN or by the TCC. Accepted norms, then, do not need to be internalised by the peacekeeper subject, but they do need to be implemented and 'incorporated' into the routinised, embodied practices that peacekeeper subjects perform. Subject positions are constructed according to institutionally and socially recognised (often dialectical) categorisations and sub-categorisations, such as 'man'/'woman', 'masculine'/'feminine', 'heterosexual'/'homosexual', 'black'/'white'. They are performed repetitively overtime according to the military institution's accepted norms, practices and discourses, 87 leading to the creation of what I call 'scripted' peacekeeper subject positions.", "type": "figure"}, "FIGREF3": {"text": "comprised 800 personnel, with one all-female unit of 10-20 personnel. 97 During the three- month pre-deployment training programme, battalions spent two weeks in the classroom and six engaged in field exercises. There was ongoing, ad hoc input from external consultants, primarily the US-funded agency ACOTA and the United States Institute of Peace (USIP) who provided technical advice on setting up practical exercises or occasional training for officers on communication, negotiation and conflict resolution. At the time of the field research, ACOTA consultants (who were US ex-military men) did not design or deliver battalion classroom-based training, but did not regard integrating gender into practical exercises a priority 98 , suggesting there was no conflict of interest between ACOTA consultants and the RDF. Since RDF trainers delivered classroom-based modules, DPKO/DFS embedded gender mainstreaming norms were operationalised by internal norm brokers rather than external norm brokers (consultants). RDF trainers did not use the CPTM curriculum, nor mainstream gender issues across the training programme, as recommended by DPKO/DFS. They selected elements of the older SGMTs 99 , which presented a narrower, integrationist reading of gender mainstreaming. These older training materials were used in conjunction with modules developed by the African Union and the RDF itself. Thus, the training materials informed a hybridised curriculum, where RDF values and ethics were promoted in the context of teaching military personnel UN/AU modes of operation, as well as the RDF's own modes of operation practiced within Rwandan base camps. According to the male trainers, the hybridised curriculum and relatable domestic examples helped trainees understand theoretical concepts such as 'gender based violence' (GBV). While this hybridised approach can be seen as 97 Senior officer 1, interview with the author, 28 May 2014. 98 Brigadier General, interview with the author, 10 June 2014. 99 I thank Anne Flasp\u00f6ler for this observation.", "type": "figure"}, "FIGREF4": {"text": "of the UN's transformative gender mainstreaming norms also took effect through norm subsidiarity and in the subtle operationalisation of the RDF's formal (codified and visible) and informal (invisible) gender rules that established the gendered logic of practice of Rwandan base camps within UNAMID and the pre-deployment training space. In Sudan, the RDF's gender protection norms policing the sexual division of labour reproduced stereotypes that 'portrayed women as incapable of providing protection'. 102 Tactical-level female military peacekeepers who only received TCC-led pre-deployment training worked solely within the Rwandan military base camp unless they were told to visit IDP camps. As in", "type": "figure"}, "FIGREF5": {"text": "gendered peacekeeping labouring practices performed by peacekeeper trainees across successive training programmes. The article also enhances understanding of how through variance in norm implementation, TCCs contribute to sustaining or transforming the gender regimes of peacekeeping operations. As has been observed in other peacekeeping contexts 130 , the RDF partially complied with UN gender mainstreaming norms by foregrounding an integrationist approach, rather than a combined integrationist/transformative approach. This partial compliance allowed male military elites to strengthen the RDF's institutional gender protection norms. Explaining how the gendered labouring practices female peacekeepers are expected to perform in the mission are constructed prior to their deployment, the present study fills an important gap in the existing literature. The study demonstrates how militarized gender protection norms are reproduced and stabilised, and how women become relegated to perceived safe spaces and safe tasks in peacekeeping operations. Female peacekeepers, like male peacekeepers, require more training and support in handling difficult situations involving traumatised populations. Senior military women with more educational and social capital devised alternative (informal) training practices to better equip themselves for deployment and,", "type": "figure"}, "TABREF0": {"text": "I use practices as my core unit of analysis 18 to demonstrate how peacekeepers are trained to perform gendered peacekeeping labouring practices prior to deployment. Bourdieu's theory of social practice and his concepts field, habitus and capitals help identify relations of power between international, regional and domestic actors and structures at play in norm contestation. Though Bourdieu has been criticised for overemphasising structure and oversimplifying relations between the dominated and the dominating in his theorising of power 19 , feminist readings of Bourdieu located in political studies and sociology open his theory up to the possibility of observing the agency of subordinated actors, who may work with or against the structures, discourses and practices that govern them. Specifically, feminist theorising of women as both commodities and 'capital-accumulating subjects' 20 within fields of power, helps us to examine how individual peacekeepers engage in norm contestation during the implementation process. Focusing on the training experiences of Rwandan tactical-level female military peacekeepers deployed in mix-gender contingents to UNAMID, the article sets out to answer three interrelated questions: 1) How are DPKO/DFS-embedded gender mainstreaming norms translated into routinised practices during pre-deployment training? 2) What kinds of subject positions are female military personnel trained to enact? 3) How do female peacekeeper trainees engage in norm implementation during the pre-deployment training process? It is argued that the pre-deployment training space is a field of norm contestation and negotiation, wherein gendered peacekeeper subject positions are constructed and reproduced through the embodied performances of institutional practices. The research findings suggest that a 'scripted' Rwandan female peacekeeper subject position is constructed which is based on how RDF senior officers perceive women's use-value within a given mission. Trained to perform this scripted subject position, some Rwandan female military peacekeepers find they are not adequately prepared for challenging working environments and devise alternative, informal training practices to better equip themselves prior to deployment. Rwanda is an important case study for examining how UN gender mainstreaming norms are operationalised in pre-deployment training programmes. The small African state is among the ten largest contributors of peacekeepers globally and is deploying female military peacekeepers to complex peacekeeping missions including the UN/African Union Mission in Darfur (UNAMID) and the UN Mission in the Republic of South Sudan (UNMISS). Rwanda has deployed troops since 2006 and over the past five years has contributed some 6,000 troops", "type": "table"}, "TABREF2": {"text": "table) in Kinyarwanda, English and French by the author, two female research assistants and two translators.", "type": "table"}, "TABREF3": {"text": "adapters as well as norm-takers and/or norm-resisters. Flasp\u00f6ler questions whether African peacekeepers can be socialised as 'international peacekeepers', as Betts Featherston presumes, and suggests that TCCs deploy 'hybridised' peacekeeper subjects. 53 The literature aligns with Acharya's norm circulation model, who evidences the agency and power of domestic (local) actors by demonstrating how these actors 'build congruence' 54 between institutionalised and domestic norms during implementation.In parallel to this research, gender scholars are examining how UN institutionalised gender mainstreaming norms are implemented in peacekeeping training since UN Security Council Resolution 1325 (Women, Peace and Security) was adopted in 2000. For these scholars, UN gender mainstreaming norms are adaptive and adaptable 55 'constitutive norms' that 'create new actors, interests or categories of action' and 'give meaning to action'. 56 UN gender mainstreaming norms can be broadened or narrowed once operationalised. When broadened, the norms set policy formation agendas and transform existing organisational structures and practices. When narrowed, they may be 'submitted to other goals than that ofThese scholars acknowledge that training curricular are already gendered before gendered perspectives are integrated. Most empirical studies examine how male uniformed personnel are re-socialised as peacekeepers and focus on preventing male peacekeepers from committing Sexual Exploitation and Abuse (SEA) by enforcing norm compliance through behavioural change. 59 The studies draw on constructivist norm cascade models to show 1) why UN institutionalised gender mainstreaming norms should be implemented through peacekeeping training; 2) the implications for peacekeeping cultures if TCC military institutions resist norm change. As in Betts Featherstone's analysis, men are products of their domestic military institution's habitus; are taught to behave as hypermasculine warriors and should be resocialised as 'gender sensitive', morally virtuous, 'good' peacekeepers.Effective gender training 'enlightens' men to the failings of their domestic military habitus.How female peacekeepers are trained to work in mixed-gender contingents is underexplored, in part due to the prevailing assumption that women naturally possess the softer skills required of the cosmopolitan peacekeeper. 62 Heineken argues that 'the embodiment of hegemonic masculinities' and 'the hyper-masculine peacekeeping environment' undermine South African women's ability to 'function as equals in peacekeeping'. 63 Pre-deployment training provides an opportunity for military elites to resist", "type": "table"}, "TABREF4": {"text": "Women are the vulnerable sex to be protected by men against other(ed) predatory men, and are a 'gendered security risk' 65 that weakens a deployed battalion's capacity. Women receive the same training as men, but are considered an anomaly in peacekeeping because they cannot embody the peacekeeper masculinity expected of military personnel, a conclusion shared by Sion in her analysis of Dutch pre-deployment training. 66 These structural limitations prevent women from enhancing operational effectiveness. Several shared understandings about norm implementation processes may be deduced from this literature review. First, norm implementation constitutes a different process to norm institutionalisation, although implementation and diffusion are used interchangeably. Norms are primarily complied with or rejected, but seldom negotiated. Second, agency and power is assigned to military institutions/military elites (the norm-takers, norm-resisters, and norm- adaptors), but not to subordinate peacekeeper subjects. In Betts Featherston's analysis, as in the gendered analyses, tactical-level peacekeepers who are expected to be governed by UN institutionalised norms, or who are understood to be governed by the TCC military institutional norms and practices, are passive receivers and conveyors of norms, whose mindsets can be manipulated and changed. Linguistically, the metaphors 'internalisation', 'socialisation', and 'assimulation' 67 suggest that norms have agency 68 , can penetrate the peacekeeper subject or persuade him/her to behave or think differently. If norms are correctly implemented by the TCC military, 'automatic norm adoption' and acceptance 69 (internalisation) will occur and change the subordinate peacekeeper's subjectivity. This neglects the underlying, everyday", "type": "table"}, "TABREF5": {"text": "UN Women, DPKO/DFS) engage in curriculum design and delivery and contribute to operationalising UN norms. Norms are contested, adapted, rejected or accepted by the TCC military during 'frictional encounters' with external agents, as they negotiate training content", "type": "table"}, "TABREF6": {"text": "How gendered scripted peacekeeper subject positions are constructed is determined by a peacekeeper's perceived use-value. Here, I borrow from the Marxist idea that labouring bodiesare considered to improve operational effectiveness. Peacekeepers are resources (assets) and commodities which TCCs rent out to the UN in exchange for material and symbolic capital (such as international prestige and military experience). If scripted peacekeeper subject positions are performed competently, the TCC may accrue more symbolic and material capital.norm, since how practices are performed is dependent on the subject, who may perform them competently or incompetently. Whether embodied practices are perceived to be competently performed will vary according to the different perspectives of the actors within the field. An external consultant may judge that a peacekeeper trainer or trainees' performance is incompetent, while a senior military staff member may presume otherwise, or vice-versa.", "type": "table"}, "TABREF7": {"text": "gender, and women are expected to perform as 'female peacekeepers' to deliver specific mission objectives. Yet, DPKO/DFS also support the conscious separation of biological sex and gender to facilitate fair and equal treatment of all staff.", "type": "table"}, "TABREF9": {"text": "tactical-level military tasks, rather than the soft skills required for PoC tasks. It was assumed that the background knowledge women acquired growing up in post-conflict Rwanda would enable them to engage effectively with traumatised people in the mission, and many spoke passionately about assisting Sudanese women. A 2nd lieutenant explained, The RDF, we have experience. For example, the genocide in our country -we saw many things. This made us able to help other countries overcome their war problems'.Women preparing to deploy also presumed they could communicate easily with Sudanese women, despite their different cultures, religions (all research participants self-identified as Christian), education, age, ability or personal circumstance: 117 Female peacekeeper 41, interview with the author, 18 November 2015. Private: For example, she has been raped. She can't talk to a man but she feels free to talk to me. Interviewer: Have you been specifically trained on how to talk to a woman that has experienced conflict-related sexual violence? Private: I have not received that training, but as a person I can imagine what it must be like to speak to her\u2026What is happening in Darfur is almost the same as what happened in Rwanda because they kill each other and [the women and children] are left as widows and orphans. So I really pity them because I know what they are going through and I feel I should counsel them.For these women, implementing RDF-accepted integrationist gender mainstreaming norms may have carried enough transactional value and they did not request changes to existing training practices. Many performed the scripted Rwanda female peacekeeper subject position in interviews, although it was difficult to ascertain whether performing the scripted subject position was deemed safer than speaking off-script, given their subordinate positions in the military. Senior, degree-educated officers in their late twenties and thirties who had not deployed demonstrated greater awareness of transformative approaches to gender mainstreaming - perhaps background knowledge acquired through their military/political elite networks. These middle-class women, some of whom spoke passionately about the importance of gender equality, felt the training on gender issues was too short, lacked depth about how conflict affected men and women 119 and focused on good behaviour (norm compliance), rather than on equal opportunity peacekeeping. One female captain requested training on how to 'better implement a gender perspective into the conduct of operations', in intelligence analysis, and wanted to learn how 'gender could be integrated into decision-making'. She believed more complicated scenarios taught in smaller classes would teach peacekeepers how to 'handle problems and execute decisions well'.These women used their educational and social capital to develop alternative (informal) training practices to source knowledge about the mission and peacekeeping labouring practices they would be required to perform. Practices included talking to previously deployed colleagues; reading training manuals; undertaking self-directed learning and conductinginternet searches. The captain and leader of the all-female unit from the battalion trained in 2014 who had a BA degree in international politics, in discussion with her subordinates, organised nightly tutorials which took place in their tent, providing the women space to reflect on the day's learning. This initiative added to the captain's burden of labour suggesting that some female peacekeepers' 'second-shift', or additional, voluntary work 121 , commenced prior to deployment. Despite these educational investment strategies, which evidence the military women's creative agency, the capacity of female peacekeepers to implement transformative DPKO/DFS embedded gender mainstreaming norms within the mission area was 'constrained by the capital value' 122 they represented for the RDF. This can be seen in the responses of women who had returned from UNAMID and their perspectives differed depending on their deployment. Low-ranking women who worked only in their professional military trades within the base camp or mission headquarters considered the pre-deployment training adequate. Women who worked outside the Rwandan base camp in multicultural teams observed gender inequalities within the peacekeeping workforce and talked more about the need for transformative gender mainstreaming initiatives. However, among these women, pre-deployment training was a site where only integrationist gender mainstreaming norms should be implemented, and women focused on discussing how training could better prepare them for mission-specific tasks. Women who worked directly with the local population in challenging contexts considered the training inadequate. These women, who engaged in complex protection duties or worked in isolated teams outside the Rwandan base camp, rejected the idea that soft skills such as communication, negotiation and empathy were feminine traits. Dealing with local people who were traumatised was the primary issue discussed. A degree educated major who had deployed to UNAMID as a liaison officer, felt that training peacekeepers to follow a short protocol for assisting rape survivors did not prepare them for prolonged engagements with survivors over several hours. Referring to the pre-deployment training schedule, she remarked: All these things were helpful. But when I encountered gender based violence it was not easy\u2026When I was on the ground and reached the [IDP] camp, you find this person who was raped for two or three hours and the people [around her] don't want tocommunicate, they don't care about what happened. So you take care of her. You don't go alone, you go with military observers and there must be a female there, the police - they must be female. So you get this person, you put her in touch with the NGOs, you take her to hospital, but you need to spend three or four hours with her.One private required techniques on having 'conversations with local people in order to find out where the problem is and how they really live'. 124 The Liaison Officer wanted information on the 'psychological impact' CRSV has on survivors. 125 In parallel with requests for deeper context on gender issues and soft skills, several women wanted more mission- specific scenarios and interactive role-plays for PoC activities. A 2nd lieutenant was critical of the limitations of translating classroom-taught gender theories (which she believed the women did not always understand) during field exercises: We study [gender issues] theoretically, but in the mission area, when we start putting [theory] into practice there are challenges. In trainings, my mate acts as a refugee and I act as I'm going to help her. But that is like theatre -you can't grasp [the reality] well.", "type": "table"}}}
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{"paper_id": "149775544", "_pdf_hash": "0aa33b1214ce0fb3345a2b70fa6f7e2d8b1b8977", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "149777142", "_pdf_hash": "c06f9415f9a9325de17d0cdc67cdc60db657f8d0", "abstract": [], "body_text": [{"section": "Introduction", "text": "Statistics and data science have developed a wide number of measures to tackle the notion of centrality. The mean and the median of descriptive statistics are part of the high-school curriculum. Statistics 101 introduces additional measures such as range, percentile, mode, standard deviation, and z-scores to explore given distributions. In graph theory, still other forms of centrality are used to determine which nodes (= actors) are \"central\" to a network. Here basic measures are e.g. Degree, Betweenness, Closeness and Eigenvector Centrality.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "1 Each measure captures different aspects of centrality, and different measures will often identify different sets of nodes as most \"central.\" The following is a first attempt to apply centrality measures to a historical social network of Chinese Buddhism.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "2 One aim is to identify quantitatively who was important in the history of Chinese Buddhism and, more fundamentally, what kind of importance such measures reveal. Another aim is exploratory: can we discover actors whose importance/centrality have hitherto gone unnoticed? Methodologically, we want to explore which measures are most suitable for the analysis of our particular dataset that spans several centuries.", "cite_spans": [], "ref_spans": []}, {"section": "The Dataset", "text": "The bulk of the data was collected between 2007 and 2012 at Dharma Drum as part of a larger project to markup biographies of eminent monks.", "cite_spans": [], "ref_spans": []}, {"section": "The Dataset", "text": "3 Most actors in the network are Chinese Buddhists -monks, nuns and lay-peoplewho appear in the biographical literature on eminent monks or nuns, 4 but the network also includes antagonistic figures who are mentioned for their role in persecutions.", "cite_spans": [], "ref_spans": []}, {"section": "The Dataset", "text": "5 Gaoseng zhuan collections form the single most important source for the study of Chinese Buddhism in the first millennium. 6 In the markup, which identifies dates, person and place names with the help of authority databases, we have created \"nexus points,\" i.e. computable statements expressed in TEI/XML, that express where and when people interacted. As of March 2017, the total number of nexus points is ca. 17,800.", "cite_spans": [], "ref_spans": []}, {"section": "The Dataset", "text": "7 Many of these connect only one single person to a place or a point in time, which is relevant for GIS or timeline-based analysis. For SNA we can only apply the ca. 7,800 nexus points which involve two or more actors. The nexus point construct does not contain semantic information about what the actors did, but simply that they are mentioned in a source as interacting with each other or being in the same place at the same time. Due to the nature of the sources this means that they knew each other, met, or were otherwise in contact (e.g. through correspondence).", "cite_spans": [], "ref_spans": []}, {"section": "The Dataset", "text": "The data we have for this network is thus undirected, but there is the general, generational directedness of the historical network. It is therefore, in principle, possible to model the information flow through the network, since in diachronic, historical networks information (and influence) is transmitted along a timeline from earlier to later generations.", "cite_spans": [], "ref_spans": []}, {"section": "8", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Network Size", "text": "The network dataset (\"GSZ-HSNA_version_2018-01.gexf \") that is used here has 6,470 nodes (actors), and 13,257 edges. Filtering out 277 small unconnected components, the largest connected component with 5,505 nodes and 12,414 edges remains. The network diameter (longest path) of the giant component is 33, its average path length is ca. 10.61. Below, \"network\" refers to the giant component of this version of the dataset.", "cite_spans": [], "ref_spans": []}, {"section": "Layout", "text": "This historical network represents interactions that took place between ca.150 CE and ca.1650 CE. Any network that extends across several generations has natural limits regarding to which actors could have interacted. A visualization should take this into account and the result should resemble the Milky Way rather than a furball. Below the elongated \"Milky Way\" network is rotated such that it approximates a timeline, with the first clusters to the left corresponding roughly to the second to fourth centuries and the right-most nodes representing actors that lived in the seventeenth century.", "cite_spans": [], "ref_spans": []}, {"section": "Limitations", "text": "Temporal coverage: The dataset in principle covers the period between ca. 100 to ca. 1650 CE.", "cite_spans": [], "ref_spans": []}, {"section": "Limitations", "text": "9 However, there is a strong bias toward the first millennium.", "cite_spans": [], "ref_spans": []}, {"section": "10", "text": "For the largest component we know the death year for ca. 3280 actors (ca. 60 percent of all nodes). The death year of ca. 2700 (ca. 84 percent) of these falls on a date before 1000 CE. Assuming actors with unknown death year are distributed evenly over the network, this means that ca. 85 percent of the interactions recorded in the current dataset took place before 1000 CE. This only to be expected as the sources from which the data is derived are mainly concerned with that time. Edge weights: As the information in the sources overlaps-a fact stated in one source (e.g. the CSZJJ) might be repeated in a later one (e.g. the GSZ)-", "cite_spans": [], "ref_spans": []}, {"section": "[Figure 1]", "text": "Network layout: Main Component of GSZ-HSNA_version_2018-01.gexf (produced in Gephi (0.9.2) using ForceAtlas2) different links might simply be duplicates of the same event. Thus, edges might have a stronger weight not because more interactions took place, but because these interactions have been recorded multiple times. Ideally, if A and B met twice, the edge between them should have a corresponding value. However, in case their first meeting was reported four times in different sources (or several times within the same source), the weight of the edge would be five rather than two. Thus, edge weight in our data is not a reliable indicator, neither of the number nor of the variety of encounters, they simply reflect how often interactions between two actors are mentioned in the sources. For this reason, we will (for now) work with simple Degree Centrality instead of Weighted Degree Centrality.", "cite_spans": [], "ref_spans": []}, {"section": "Degree, Betweenness and other Centrality Measures in the Network of Chinese Buddhism", "text": "In the following I suggest that SNA centrality measures are a useful heuristic means to discover influential actors in the historical network of Chinese Buddhism. I do not want to suggest that we can expect centrality measures to return all influential players. Based on his research about support networks for persecuted Jews during the Holocaust, D\u00fcring (2016, 100) finds that \"centrality measures are useful to narrow down the list of potentially influential actors in a network, but will always fail to detect those ca. 20-30 percent of actors whose influence does not correspond with above average connectedness.\" Thus, the below is a first step towards discerning a macro-historic outline view of Chinese Buddhism, rather than a statement about the exact importance of individual actors.", "cite_spans": [], "ref_spans": []}, {"section": "Degree Centrality", "text": "Degree Centrality is the most basic centrality measure in that it simply looks at the number of links of an actor. Degree Centrality is a \"local\" measure in the sense that it is mainly indicative about the importance of a node in its immediate environment, which in our case means also in its own time. For a historical network this reflects the phenomenon that there are figures who were important in their generation, but not beyond.", "cite_spans": [], "ref_spans": []}, {"section": "Betweenness Centrality", "text": "The importance of Betweenness Centrality rests on the assumption that goods and information tend to move through a network on the shortest path. Nodes that are situated on many shortest paths have a high Betweenness Centrality. This is important for historical networks because Betweenness Centrality might turn out to be an indicator for the information flow between generations. In our case a shortest path between any two figures of different periods does not necessarily imply actual transmission, but this network can and should be seen as communication network, in which information about Buddhism unfolds in China. In that sense the sum of shortest paths between actors over different generations is relevant.", "cite_spans": [], "ref_spans": []}, {"section": "11", "text": "Betweenness Centrality is often used to identify bridge actors -nodes that, though they are neither strongly connected themselves (Degree Centrality) or to important players (Eigenvector Centrality) , are on a large number of shortest path between different parts of the network. We found that whereas Degree Centrality, as a local measure, is fairly robust, Betweenness Centrality is sensitive to false positives. One single wrong connection can increase the Betweenness Centrality for a node disproportionately, if it causes the node to link two otherwise distant sections of the network.", "cite_spans": [], "ref_spans": []}, {"section": "11", "text": "12 This is in line with research in the robustness of centrality measures, which found that global measures (e.g. Betweenness Centrality) are \"more sensitive to measurement errors than local measures\" (such as Degree Centrality).", "cite_spans": [], "ref_spans": []}, {"section": "13", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Closeness and Eigenvector Centrality", "text": "The usefulness of Closeness and Eigenvector centrality for larger networks has been questioned. Closeness Centrality is based on a node being close, i.e. having short paths, to all other nodes. This can be useful when deciding in which city to build a warehouse, or in measuring the maximum speed with which information passes through a large computer network. In a historical social network, however, actors can only socially interact with contemporary actors and applied to the network as a whole Closeness Centrality is therefore not really helpful to indicate anything. If applied, Closeness Centrality strongly favors actors in the middle of the period covered by the network. In contrast to a non-historical network here centrality is not indicative of influence, but simply incidental to the actors' position in time. Indeed, when sorting by Closeness Centrality all 20 most central individuals were born between 509 and 709 CE, a relatively narrow band compared, compared with a spread of birth years between 314/738CE for Degree, and 418/1263CE for Betweenness Centrality.", "cite_spans": [], "ref_spans": []}, {"section": "Closeness and Eigenvector Centrality", "text": "Eigenvector Centrality differs from Degree Centrality in that it does not only measure a person's connectedness, but also takes into account whether he or she is connected with other highly connected people. It attempts to capture an actor's influence within a network based on the idea that important nodes need connections to other highly connected nodes in order to exert influence. Someone might wield great influence by being connected to only a few highly connected individuals and thus an actor's Eigenvector Centrality can be larger than its Degree Centrality suggests. But the same restrictions as with Closeness Centrality apply, and for the network as a whole Eigenvector Centrality is not very useful. Eigenvector Centrality has an even narrower band of birth years (611 to 688) mainly, it seems, due to the overwhelming weight of the cliques described in data for the early Tang. Nevertheless, it should be noted that it does successfully identify the industrious Seungjang \u52dd\u838a (fl. 651-714), a Silla monk, who has no biography of his own, but was extremely well connected, having worked in several translation teams and known many influential patrons. That Eigenvector Centrality highlights Seungjang as the \"most well-connected monk\" in our dataset, shows how historical SNA can bring interesting and important actors into view that traditional Chinese historiography has so far failed to identify as \"central.\"", "cite_spans": [], "ref_spans": []}, {"section": "Visualizing Three Types of Centrality", "text": "One way to visualize how different forms of centrality order the network is to compare how the network looks when the nodes are arranged in an ordered circular layout. The node with the highest value for Degree/Betweenness/ Eigenvector Centrality is placed at 12:00 o' clock, the nodes are ordered according to the respective measure clockwise along the circumference of a circle. [Figure 2.1.] The hatching effect that appears in a circular layout ordered by Degree Centrality, is a \"naturally\" occurring pattern that depends on this order. Pretty and meaningless beyond the fact that it is dependent on the ordering of nodes with many connections (=lines) in the same segment of the circle, it merely reflects how patterns can arise on the basis of sorting rules. In contrast, the \"chaotic\" effect that appears in the circular layout sorted by Betweenness Centrality is due to the fact that the number of connections for each node is not directly related to the sequence of the nodes on the circle. The \"busy\" nodes at 7:30 and 10:00 o' clock indicate actors which have relatively many connections with actors who have a higher Betweenness Centrality (and are thus situated between 12:00 and ca. 4:00). Such anomalies are good starting points for exploration. Another study might reveal who these actors are and whether this pattern is historically interesting. [Figure 2.2.] The characteristic opening or hole that appears below 12:00 o' clock when the circular layout is sorted by Eigenvector Centrality [Figure 2.3.] exists because those actors who are well-connected to other well-connected actors are not, in general, also connected to the least connected. In other words, if someone in the least well-connected segment (at 11:55-11:59) would be connected to a player in the most well-connected segment (at, say, 12:01-12 :05), they would not be among the \"least connected.\"", "cite_spans": [], "ref_spans": []}, {"section": "Visualizing Three Types of Centrality", "text": "Visualizations such as these help to understand the particular character of centrality measures as pertaining to this dataset. The patterning can also help to identify individuals or groups which deserve further research.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "Below are two tables that list the top twenty actors (out of ca. 5,500) according to Degree and Betweenness Centrality. These lists correspond roughly to the nodes on the first second (12:00-12:00:01) in the circular layouts in Figure 2 .1 and 2.2 above. The ID numbers in the first column refer to the Dharma Drum Buddhist Person Name Authority Database.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "[ The dataset used here reflects the information about Chinese Buddhists that is preserved in Gaoseng zhuan literature. Due to overlaps between the Liang and the Tang Gaoseng zhuan, as well as between the Tang and the Song Gaoseng zhuan most information concerns relationships that have formed between the sixth and the ninth centuries.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "For the sake of our study, it is significant that Degree Centrality highlights translator monks (7), famous patrons (4 emperors, 1 prince, 1 chancellor), authors of commentaries (4), and Vinaya masters (2) . No Chan figure is on the list and among the Pure Land masters only Huiyuan (A001204) appears prominently. The other Huiyuan (A0020000) too wrote commentaries on Pure Land texts, but significant Pure Land figures such as Tanluan \u66c7\u9e1e (ranked 1572/5500 by Degree Centrality), Daochuo \u9053\u7dbd (ranked 909), or Shandao \u5584\u5c0e (ranked 2843) are not on the top-20 list, although they were active in the period for which our dataset contains most information.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "14 All three of these \"patriarchs\" play an important role in the Pure Land narrative in many modern histories of Chinese Buddhism.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "15 The relative lack of information about their social networks, however, well reflects the fact that the Pure Land patriarchate was created retrospectively by Tiantai Buddhist historians during the Southern Song.", "cite_spans": [], "ref_spans": []}, {"section": "16", "text": "[ The immediate finding here is that analyzing the same data for Betweenness Centrality returns a quite different set of actors who were \"central\" to the historical network of Chinese Buddhism. Viewing the network from this angle it is a group of Chan monks, some famous, some not, who tie together the two millennia of Chinese Buddhism. Although much in our data for the first millennium is about patron and translator networks, the longitudinal aspect of information flow through the network into the second millennium rests on the transmission lines of the Chan School. This accords well with the fact that since the Song Dynasty most larger monastic institutions had to identify as belonging to a Chan lineage, and the abbotship could as a rule only be filled by a monk who had received official transmission in an established lineage. The success of Chan to become the preeminent institutional form of Buddhism after the Song Dynasty stands in contrast to other doctrinal formations such as the Huayan and Faxiang (Yogac\u0101ra) schools, which were not able to build enduring institutions.", "cite_spans": [], "ref_spans": []}, {"section": "16", "text": "Also remarkable in the result of applying Betweenness Centrality is the role of Vinaya masters some of whom are included in the \"Top 20\" of Table 2 . Obviously, though often overlooked, Vinaya masters would have assumed a central function in the long-term transmission flow of the Buddhist community, because they organized ordinations and maintained the discourse on monastic law, which was an crucial factor in the maintenance of institutional Buddhist identity.", "cite_spans": [], "ref_spans": [{"start": 140, "end": 147, "text": "Table 2", "ref_id": "TABREF2"}]}, {"section": "16", "text": "Finally, one wonders how other Buddhist formations that are known to have survived the end of the Tang, such as Tiantai, esoteric Buddhism, and Pure Land practices, are represented in the network. The actors that transmitted these might not be among the (somewhat arbitrary) set of the \"Top 20,\" but their transmission lines too must show up in the network and could be studied with its help.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "This study is a first attempt at applying centrality measures to a SNA dataset based on Gaoseng zhuan literature and to assess their usefulness for historians. Comparing the top actors measured by Degree and Betweenness Centrality, respectively, two distinct categories appear: Degree Centrality favors translators and patrons, while Betweenness Centrality returns Chan and Vinaya masters.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "The difference illustrates the slow and truly fundamental change that occurred when Chinese Buddhism started to organize its institutions and perceive its own history as a lineage system modeled on family genealogies. The change in historiography, but also in organizational structures, becomes apparent when different measures of centrality are applied to a model -our dataset -of Chinese Buddhist history. Two objections might be raised here, one regarding the role of Buddhist historiography, the other regarding the quality of the current data.", "cite_spans": [], "ref_spans": []}, {"section": "History or Historiography?", "text": "First, does the difference between the two sets of key players that is revealed by Degree and Betweenness Centrality reflect a change in history or historiography? Are the different views on centrality merely a optical illusion that is caused by different ways of writing history, or do they indeed reflect a difference in the social, institutional reality? In English the word \"central\" can be joined by a number of different prepositions. A player can be central to a game, in a game or for a game. Using quantitative centrality measures we have, conservatively speaking, shown merely what nodes are central in the graph-a social network visualization of Chinese Buddhist history. This type of \"central in\" is derived arithmetically and changes with the data. When the data is expanded or corrected, we might find a different permutation of names at the top. But does \"central in the graph\" translate into \"central for the history of Chinese Buddhism\"? The Chan school, after all, is known for defining itself as a network of lineages. Lineages as graphs are tree structures, and in tree structures nodes closer to the root will naturally be on many shortest paths and therefore have high Betweenness Centrality. This is all true, but the appearance of major Chan figures as key-actors is nevertheless remarkable, because our data is reliant on a relatively small number of historiographers that wrote and/or collected biographies on eminent monks and nuns in a genre that formed before the lineage narrative firmly took hold in Buddhism. The data used here is by no means based on the vast historiography of the Chan School, which is encoded in \"Lamp Transmission Records\" (zhuandenglu \u50b3\u71c8\u9304) and \"Recorded Sayings\" (yulu \u8a9e\u9304), genres which are quite different from the Gaoseng zhuan format. Significantly therefore, the turn towards Chan lineage in the social structure of Chinese Buddhist history is indicated by sources that are in no way partial to Chan.", "cite_spans": [], "ref_spans": []}, {"section": "17", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Data Quality and Scope", "text": "A second objection one might make is regarding the quality of the data, which, as mentioned above, is rather weak for the second millennium. This leads to a constellation where the more recent parts of the network are relatively thin compared to the bulk of the data that covers the fourth to the tenth century. One could assume that the Chan figures in Table 2 merely join the otherwise weakly connected pre-Song and post-Song regions of the network and only because of this are therefore identified as important when applying Betweenness Centrality. However, there are reasons to think that this is not the case.", "cite_spans": [], "ref_spans": [{"start": 354, "end": 361, "text": "Table 2", "ref_id": "TABREF2"}]}, {"section": "Data Quality and Scope", "text": "Firstly, as the table shows, Betweenness Centrality does highlight important Chan masters, but does not do so exclusively. The official Ruan Tao, the poet monk Jiaoran and some Vinaya masters belong to the pre-Chan period. Other actors with high Degree Centrality, such as Sui Yangdi, Xiao Yan, or Xuanzang, appear further down the list (but still in the Top 30) when calculating Betweenness Centrality.", "cite_spans": [], "ref_spans": []}, {"section": "Data Quality and Scope", "text": "Secondly, based on our current understanding of Chinese Buddhist history, between the late Tang and the Southern Song there indeed occurred fundamental changes in institutional practice, in doctrinal discourse, in the production of new texts genres, canonical collections, as well as in historiography. That some of these changes appear in an analysis of social networks based on information purely drawn from the particular genre of Gaoseng zhuan literature, merely confirms the pervasiveness of these trends and their embeddedness in the social fabric of Chinese Buddhism.", "cite_spans": [], "ref_spans": []}, {"section": "Data Quality and Scope", "text": "Thirdly, I have one more reason to believe that the different views on history that centrality measures reveal are indeed factual and not merely an artifact of data bias. A currently ongoing research project dedicated to expanding second millennium data, although still in its early stages, already shows Chan lineages have even greater weight in the second millennium and that the centrality (dare we say \"importance\"?) of figures like Mazu Daoyi, can indeed be confirmed by a larger and more temporally balanced dataset.", "cite_spans": [], "ref_spans": []}, {"section": "Data Quality and Scope", "text": "18 This proves that centrality measures do correctly reflect the historical information that we use to build our model.", "cite_spans": [], "ref_spans": []}, {"section": "Data Quality and Scope", "text": "Other sources that could provide denser information about who knew whom in Buddhist history are the corpus of Buddhist temple gazetteers (Bingenheimer 2015) , and the zhuandeng and yulu literature of the Chan school. As for more recent material the humongous para-canonical Xinxu gaosengzhuan \u65b0\u7e8c\u9ad8\u50e7\u50b3 (1923) in 65 fascicles, provides rich, zhuan style biographies for monks of the Song, Yuan, Ming and Qing periods, but is rarely used by researchers of late imperial Buddhism. Furthermore information from secular histories, as well as archaeological, epigraphic, and art historical data would be helpful, but so far no efforts have been made to digitize these sources as structured data.", "cite_spans": [{"start": 137, "end": 156, "text": "(Bingenheimer 2015)", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Data Quality and Scope", "text": "Nevertheless, as more and more computable data becomes available, this first exploration of centrality measures in the study of Chinese Buddhism is but a beginning. Next steps might include determining group centrality (identifying influential cliques), edge betweenness (identifying especially important connections), experimenting with multi-modal networks that relate multiple sets of social network(s), 19 such as citation networks, and (next on my list) the integration of the wider network of Chinese history available from the Chinese Bibliographic Database (CBDB).", "cite_spans": [], "ref_spans": []}, {"section": "Notes", "text": "1 There are numerous other measures. An outline is Wassermann and Faust (1994, 169-219) .", "cite_spans": [], "ref_spans": []}, {"section": "Notes", "text": "2 For an example of the successful use of historical SNA which touches on centrality measures see the by now classical study by Padgett & Ansell (1993) on the rise of the Medici. Recent years have seen research on Byzantine Egypt (Ruffini 2008) , ancient Greek (Collar 2011) , medieval Sicily (Engl 2014 ) to name only a few. For a critical appraisal of the use of centrality measures in historical social network analysis see D\u00fcring (2016) . 3 Where not otherwise stated the visualizations and lists in this paper are derived from \"GSZ-HSNA_version_2018-01.gexf.\" The markup design for the corpus and how the data can be derived from it has been explained in detail elsewhere (Bingenheimer et al. 2011 The earliest death year of an actor is 65 CE, the latest 1684 CE. 10 Currently, a project is underway to address that imbalance. After including biographic data on Ming-Qing dynasty monks compiled by Hasebe Y\u016bkei and others, the second millennium will be better represented in future SNA datasets. 11 From the point of view of information too Betweenness Centrality is an important measure because a signal will suffer from less distortion the fewer nodes it traverses, thus, again very generally, the shortest paths across generations is the one which promises the least lossy transfer of information. 12 Analyzing for Betweenness Centrality, I had to correct several mistakes in earlier versions of the data, which are corrected in the outputs available on my website. Thus, the use of certain centrality measures can help with error detection. 13 See Zemlji\u010d and Hlebec (2005, 73) . Already Wassermann and Faust (1994, 215) have remarked that Betweenness Centrality values show the strongest variance. 14 The wide difference in their rank is not significant. Beyond the first ca. 500 positions the number of degree connections is less than 12 and ranking by degree ceases to effectively differentiate actors. 15 See e.g. Lai (2010, Vol.7, 383-400) . 16 Getz (1999, 477) . 17 Zanning (919-1001), the first Gaoseng zhuan author aware of Chan, was, according to Albert Welter, \"disturbed over assertions of Chan's institutional autonomy. According to Zanning, there was no basis for distinguishing independent Chan monasteries from regular vinaya monasteries.\" (Welter 2008 , 37) None of the major Gaoseng zhuan collections does display a particular bias in favor of the Chan narrative. 18 We are currently digitizing data about monastic lineage networks of the Ming and Qing gathered by Hasebe Y\u016bkei (2008) . This includes information on more than 4,700 monks and nuns, who lived from 1368 CE until 1911 CE. Compared to the data from the Gaoseng zhuan corpus, the data from Hasebe's tables is relatively \"flat,\" in that it is mainly arranged along the lineage framework and does not record events and encounters. It will go a long way, however, to address the imbalance between the first and the second millennium. The new data is made available provisionally at http://mbingenheimer.net/ tools/socnet. Once the project is concluded the data will be archived at Zenodo. 19 For such extensions of centrality measures see Everett and Borgatti (2005 ", "cite_spans": [{"start": 128, "end": 151, "text": "Padgett & Ansell (1993)", "ref_id": "BIBREF17"}, {"start": 230, "end": 244, "text": "(Ruffini 2008)", "ref_id": "BIBREF18"}, {"start": 261, "end": 274, "text": "(Collar 2011)", "ref_id": "BIBREF7"}, {"start": 293, "end": 303, "text": "(Engl 2014", "ref_id": "BIBREF9"}, {"start": 427, "end": 440, "text": "D\u00fcring (2016)", "ref_id": "BIBREF8"}, {"start": 677, "end": 702, "text": "(Bingenheimer et al. 2011", "ref_id": "BIBREF1"}, {"start": 3124, "end": 3150, "text": "Everett and Borgatti (2005", "ref_id": "BIBREF11"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Gesellschaftliche Umbr\u00fcche und religi\u00f6se Netzwerke -Analysen von der Antike bis zur Gegenwart", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF1": {"title": "Social Network Visualization from TEI Data", "authors": [{"first": "Marcus", "middle": [], "last": "Bingenheimer", "suffix": ""}, {"first": "Jen-Jou", "middle": [], "last": "Hung", "suffix": ""}, {"first": "Simon", "middle": [], "last": "Wiles", "suffix": ""}], "year": 2011, "venue": "Literary and Linguistic Computing", "link": "46243120"}, "BIBREF2": {"title": "The Digital Archive of Buddhist Temple Gazetteers and Named Entity Recognition (NER) in Classical Chinese", "authors": [{"first": "Marcus", "middle": [], "last": "Bingenheimer", "suffix": ""}], "year": 2015, "venue": "Lingua Sinica", "link": "45752252"}, "BIBREF4": {"title": "A graph theoretic perspective on centrality", "authors": [], "year": "", "venue": "Social Networks", "link": "300735"}, "BIBREF6": {"title": "The Many Lives of Fazang", "authors": [{"first": "", "middle": [], "last": "Philospher", "suffix": ""}, {"first": "Politician", "middle": [], "last": "Practioner", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF7": {"title": "Military Networks and the Cult of Jupiter Dolichenus", "authors": [{"first": "Anna", "middle": [], "last": "Collar", "suffix": ""}], "year": 2011, "venue": "Von Kummuh Nach Telouch. Historische Und Arch\u00e4ologische Untersuchungen in Kommagene", "link": null}, "BIBREF8": {"title": "How Reliable are Centrality Measures for Data Collected from Fragmentary and Heterogenous Historical Sources? A Case Study", "authors": [{"first": "Marten", "middle": [], "last": "D\u00fcring", "suffix": ""}], "year": 2016, "venue": "The Connected Past -Challenges to Network Studies in Archaeology and History", "link": "64940358"}, "BIBREF9": {"title": "Das Ende muslimischen Lebens im mittelalterlichen S\u00fcditalien. 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Tokyo: \u014cbaku bunka kenky\u016bsho \u9ec4\u6a97\u6587\u5316\u7814\u7a76\u6240", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF16": {"title": "Zhongguo fojiao tongshi \u4e2d\u570b\u4f5b\u6559\u901a\u53f2. 15 vols", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF17": {"title": "Robust Action and the Rise of the Medici, 1400-1434", "authors": [{"first": "John", "middle": ["F"], "last": "Padgett", "suffix": ""}, {"first": "Christopher", "middle": ["K"], "last": "Ansell", "suffix": ""}], "year": 1993, "venue": "American Journal of Sociology", "link": "56166159"}, "BIBREF18": {"title": "Social Networks in Byzantine Egypt", "authors": [{"first": "Giovanni", "middle": [], "last": "Ruffini", "suffix": ""}], "year": 2008, "venue": "", "link": "129420803"}, "BIBREF19": {"title": "Two Sources of Chinese Buddhist Biographies", "authors": [{"first": "K\u014dichi", "middle": [], "last": "Shinohara", "suffix": ""}], "year": 1988, "venue": "Monks and Magicians -Religious Biographies in Asia", "link": null}, "BIBREF20": {"title": "Central\" in the History of Chinese Buddhism? 67", "authors": [{"first": "", "middle": [], "last": "Bingenheimer \u2022 Who", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF22": {"title": "The Linji-lu and the Creation of Chan Orthodoxy", "authors": [], "year": "", "venue": "", "link": "190913613"}, "BIBREF23": {"title": "Reliability of measures of centrality and prominence", "authors": [{"first": "Barbara", "middle": [], "last": "Zemljic", "suffix": ""}, {"first": "Valentina", "middle": [], "last": "Hlebec", "suffix": ""}], "year": 2005, "venue": "Social Networks", "link": "40336733"}}, "ref_entries": {"FIGREF0": {"text": "Figure 2.1.] Nodes of the Main Component sorted clockwise by Degree Centrality [Figure 2.2.] Nodes of the Main Component sorted clockwise by Betweenness Centrality [Figure 2.3.] Nodes of the Main Component sorted clockwise by Eigenvector Centrality", "type": "figure"}, "TABREF0": {"text": "Most nexus points come from the Tang and the Song Collection of Biographies of Eminent Monks authored in the seventh and tenth century respectively. The available information about the second millennium in the dataset used here is limited to the nexus points recorded in the Ming Collection of Biographies of Eminent Monks (dated 1600) and the Supplementary Collection of Biographies of Eminent Monks (dated 1647).", "type": "table"}, "TABREF1": {"text": "Top 20 actors Degree Centrality", "type": "table"}, "TABREF2": {"text": "Top 20 actors Betweenness Centrality", "type": "table"}, "TABREF3": {"text": "). The marked-up Gaoseng zhuan texts with the nexus points are available at and https://gitlab.com/dila/biographies and http://buddhistinformatics.dila.edu.tw/ biographies/gis/. The Dharma Drum person authority that provides dates and additional information on the actors is available at http://authority.dila.edu.tw/docs/open_content/ download.php. The analysis below is based on these two sources. I make merged versions of the data for immediate use in GEPHI available at http://mbingenheimer.net/tools/ socnet/. 4 Chu sanzang jiji (Part 5: Biographies) \u51fa\u4e09\u85cf\u8a18\u96c6 (\u5217\u50b3\u90e8) by Sengyou \u50e7\u7950, completed 510-518 (=CSZJJ); Biqiuni zhuan \u6bd4\u4e18\u5c3c\u50b3 by Baochang \u5bf6\u5531, dated 516 (=BNZ); Liang gaoseng zhuan \u6881\u9ad8\u50e7\u50b3 by Huijiao \u6167\u768e, dated 519 (=GSZ); Tang gaoseng zhuan \u5510\u9ad8\u50e7\u50b3 by Daoxuan \u9053\u5ba3, dated 665 (=TGSZ); Song gaoseng zhuan \u5b8b\u9ad8\u50e7\u50b3 by Zanning \u8d0a\u5be7, dated 988 (=SGSZ); Mingseng zhuan chao \u540d\u50e7\u50b3\u6284 (X.1523), by S\u014dsh\u014d \u5b97\u6027, 13th cent. (=MSZC); Ming gaoseng zhuan \u660e\u9ad8\u50e7\u50b3 by Ruxing \u5982\u60fa, dated 1600 (=MGSZ); Buxu gaoseng zhuan \u88dc\u7e8c\u9ad8\u50e7\u50b3 by Minghe \u660e\u6cb3, dated 1647 (=BXGSZ). 5 For instance the official Du, who, as her biography tells us, grievely injured the nun Zhixian (T 2063, 935a). 6 This, of course, is not to say that they are always reliable witnesses. Detailed research, often drawing on surviving epigraphy and other sources, has repeatedly revealed contradictions, mistakes and misinterpretations in the biographic record. K\u014dichi Shinohara and Jinhua Chen especially have demonstrated how the Gaoseng zhuan accounts can and must be corrected in light of other sources (e.g. Shinohara 1988; Chen 2007, 36-39). 7 Nexus points per source: CSZJJ: 474, BNZ: 375, GSZ: 1790, TGSZ: 5410, SGSZ: 4994, MSZC: 188, MGSZ: 591, BXGSZ: 3976. 8 Based on life dates we can visualize the network dynamically. For first attempts see a sample at http://mbingenheimer.net/tools/socnet/. One problem is that the life dates for many actors are not available and must be extrapolated from existing connections to actors with known dates. The construction of dynamic networks with this data is a rich field for experimentation which, however, exceeds the scope of this paper. 9", "type": "table"}, "TABREF4": {"text": "). 20 I am grateful for the support of the Chung-hwa Institute of Buddhist Studies, esp. Director Venerable Guojing, for funding the data collection and sharing the data under an open access license. Much of the information in the current dataset has been painstakingly collected and encoded by Mr. Boyong Zhang without whose collaboration this project would not have been possible.Taish\u014d Shinsh\u016b Daiz\u014dky\u014d \u5927\u6b63\u65b0\u4fee\u5927\u85cf\u7d93 [Revised Buddhist canon compiled during the Taish\u014d reign period], eds. Takakusu Junjir\u014d \u9ad8\u6960\u9806\u6b21\u90de and Watanabe Kaikyoku \u6e21\u908a\u6d77\u65ed et. al., 100 vols., Tokyo: Daiz\u014dky\u014dkai, 1924-1935.", "type": "table"}}}
{"paper_id": "149778073", "_pdf_hash": "6b332bfadfd8d6f0cafe4827e2b80f1654e53efd", "abstract": [], "body_text": [], "bib_entries": {"BIBREF1": {"title": "Dyes Pigments", "authors": [{"first": "B", "middle": ["H"], "last": "Lee", "suffix": ""}, {"first": "J", "middle": ["Y"], "last": "Jaung", "suffix": ""}], "year": 2003, "venue": "", "link": null}, "BIBREF12": {"title": "The Properties of Gases and Liquids", "authors": [{"first": "R", "middle": ["C"], "last": "Reid", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Prausnitz", "suffix": ""}, {"first": "T", "middle": ["K"], "last": "Sherwood", "suffix": ""}, {"first": "", "middle": [], "last": "Eds", "suffix": ""}], "year": 1977, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "149778239", "_pdf_hash": "1dfbfa25b404cab5c5ff1f57822b4f4cab9b8136", "abstract": [], "body_text": [{"section": "Introduction", "text": "Physical inactivity is considered the greatest public health problem of the current century [1] . Adequate PA is defined as achieving 150-300 minutes of moderate intensity activity (e.g. gentle cycling or swimming) or 75-150 minutes of vigorous intensity activity (e.g. race cycling or spin class) weekly, as well as muscle strengthening for all major muscle groups twice weekly [2] . However, adults are not achieving sufficient levels of physical activity (PA) to support good health. Self-report data suggests 31.1% of adults worldwide are not meeting PA guidelines [3] . In 2014-2015, 44.5% of Australian adults did not achieve the minimum recommended PA levels [4] .", "cite_spans": [{"start": 92, "end": 95, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 379, "end": 382, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 569, "end": 572, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Introduction", "text": "Physiotherapists are healthcare practitioners who treat patients with musculoskeletal conditions and who also have a responsibility to promote PA [5] . Physiotherapists treat patients with a wide range of musculoskeletal conditions that can contribute to disability and form a large comp onent of a physiotherapist\"s work. The global prevalence of musculoskeletal conditions, such as low back pain (9.2%) and other musculoskeletal disorders (8.1%), indicates these conditions are some of the most prevalent diseases in the world [6] . In 2014-2015, 30 .0% of Australians reported having a musculoskeletal condition, with 23.0% also having another chronic comorbid condition, such as cardiovascular disease [7] . The presence of a musculoskeletal condition, and its associated symptoms (e.g. pain) and signs (e.g. poor physical condition), can act as a barrier to being physically active [8] and can increase the risk of developing comorbid conditions. Therefore, it is important that physiotherapists pay particular attention to supporting patients with musculoskeletal conditions to participate in PA. The type of PA that is specific to improving or maintaining general health, as opposed to being used to treat a musculoskeletal condition, is called non-treatment physical activity (NTPA) [9] . It is imperative that physiotherapists promote NTPA to improve the PA levels of Australian adults.", "cite_spans": [{"start": 146, "end": 149, "text": "[5]", "ref_id": "BIBREF3"}, {"start": 529, "end": 532, "text": "[6]", "ref_id": "BIBREF4"}, {"start": 549, "end": 551, "text": "30", "ref_id": "BIBREF28"}, {"start": 706, "end": 709, "text": "[7]", "ref_id": "BIBREF5"}, {"start": 887, "end": 890, "text": "[8]", "ref_id": "BIBREF6"}, {"start": 1291, "end": 1294, "text": "[9]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Introduction", "text": "A recent systematic review reported that physiotherapists can successfully increase patient PA levels, but the PA improvements were small and not maintained [10] . It is important to be aware of how practicing physiotherapists experience NTPA promotion to understand how this might influence the success of their promotion efforts. Understanding these experiences is important to be able to more effectively engage physiotherapists as active agents in improving the PA levels of Australians.", "cite_spans": [{"start": 157, "end": 161, "text": "[10]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Introduction", "text": "This qualitative study investigated the experiences of Australian physiotherapists promoting NTPA to patients with musculoskeletal conditions.", "cite_spans": [], "ref_spans": []}, {"section": "Materials and methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Design", "text": "This was a cross-sectional qualitative study that used interpretative phenomenological analysis (IPA) as the methodological framework because IPA facilitates the exploration of interviewee experiences of a specific topic (e.g. NTPA promotion) [11] . Interpretative phenomenological analysis facilitates the exploration of the perceptions and experiences of people by using an in-depth qualitative analysis and a homogenous sample to examine how people perceive and understand what is happening to them [12] .", "cite_spans": [{"start": 243, "end": 247, "text": "[11]", "ref_id": "BIBREF9"}, {"start": 502, "end": 506, "text": "[12]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Interviewees", "text": "Australian physiotherapists who treated patients with musculoskeletal conditions in private practice and/or outpatient settings were eligible to participate and were recruited using social media (Facebook, Twitter) and snowballing. All potential interviewees were provided with a plain language information statement and informed consent form outlining the study and were asked to return the signed consent form prior to participation. Thirteen interviewees were asked to participate in the study. Ten participated and received one $AU20 gift card as an incentive.", "cite_spans": [], "ref_spans": []}, {"section": "Ethics", "text": "The Federation University Australia Human Research Ethics Committee approved this study (project number B16-131).", "cite_spans": [], "ref_spans": []}, {"section": "Data collection", "text": "The interview guide (Supplementary file 1) was designed based on the results of two systematic reviews [10, 13] and previous relevant literature [14] [15] [16] specific to NTPA promotion in physiotherapy. The guide was piloted with one physiotherapist and reviewed by all co-authors prior to use. Yardley\"s criteria [17] was used to guide the design and completion of this study (Supplementary file 2) .", "cite_spans": [{"start": 103, "end": 107, "text": "[10,", "ref_id": "BIBREF8"}, {"start": 108, "end": 111, "text": "13]", "ref_id": "BIBREF11"}, {"start": 145, "end": 149, "text": "[14]", "ref_id": "BIBREF12"}, {"start": 150, "end": 154, "text": "[15]", "ref_id": "BIBREF13"}, {"start": 155, "end": 159, "text": "[16]", "ref_id": "BIBREF14"}, {"start": 316, "end": 320, "text": "[17]", "ref_id": "BIBREF15"}], "ref_spans": [{"start": 379, "end": 401, "text": "(Supplementary file 2)", "ref_id": "TABREF1"}]}, {"section": "Data collection", "text": "Semi-structured interviews were conducted by the lead author face-to-face (n = 6), by telephone (n = 2) and online using a video service (n = 2). The reduced emphasis on structure in semi-structured interviews allows for flexible exploration of physiotherapists\" experiences, making them the favoured data collection method for IPA-based qualitative studies [11, 18] .", "cite_spans": [{"start": 358, "end": 362, "text": "[11,", "ref_id": "BIBREF9"}, {"start": 363, "end": 366, "text": "18]", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Data collection", "text": "Each interview was approximately 60-minutes in duration and was recorded. After rapport was established and the definition of NTPA was understood, all interviews commenced with the opening question \"Can you please tell me about your experiences promoting non-treatment physical activity?\" The following topics were used to facilitate further discussion if the physiotherapist needed help choosing topics to discuss:", "cite_spans": [], "ref_spans": []}, {"section": "Data collection", "text": "\u2022 The perceived barriers and facilitators to NTPA;", "cite_spans": [], "ref_spans": []}, {"section": "Data collection", "text": "\u2022 Compatibility of NTPA promotion and physiotherapy;", "cite_spans": [], "ref_spans": []}, {"section": "Data collection", "text": "\u2022 The support available to promote NTPA;", "cite_spans": [], "ref_spans": []}, {"section": "Data collection", "text": "\u2022 The tools used to promote NTPA;", "cite_spans": [], "ref_spans": []}, {"section": "Data collection", "text": "\u2022 Planning involved to promote NTPA;", "cite_spans": [], "ref_spans": []}, {"section": "Data collection", "text": "\u2022 How patient presentation and expectations influence plans to promote NTPA; and \u2022 The skills and training needed to promote NTPA and change patient behaviour.", "cite_spans": [], "ref_spans": []}, {"section": "Data analysis", "text": "Interviews were transcribed verbatim, read several times and summaries of each transcript were produced to foster familiarisation with the interviewees\" responses prior to entering data into NVivo 11 qualitative software (QSR International Pty Ltd, Melbourne, Australia). Codes were used to identify emergent and superordinate themes after repetitive interpretation and summarising [11] . Pseudonyms were used to identify quotes and de-identify interviewees. The Behaviour Change Technique Taxonomy was used to code the behaviour change techniques (BCTs) used to promote NTPA [19] . The written analysis and reasoning leading to the identification of emergent themes was reviewed by all interviewees prior to finalising superordinate themes. Consensus was reached with all interviewees, confirming accuracy of transcript interpretation, before additional evaluation by the authorship team. Emergent and superordinate themes were evaluated by two authors and, in the case of any discrepancies, final superordinate themes were decided by consensus with the research team.", "cite_spans": [{"start": 382, "end": 386, "text": "[11]", "ref_id": "BIBREF9"}, {"start": 576, "end": 580, "text": "[19]", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Interviewee characteristics", "text": "Ten interviewees were individually interviewed. The majority of interviewees worked in metropolitan private practices, saw more than 15 patients each week and had been practicing physiotherapy for longer than 5 years (Table 1 ). More than half of the interviewees were aged between 25-34 years, female and physically active. Most interviewees reported promoting NTPA.", "cite_spans": [], "ref_spans": [{"start": 217, "end": 225, "text": "(Table 1", "ref_id": "TABREF0"}]}, {"section": "Key themes", "text": "The themes identified from the interview transcripts were categorised into five emergent themes and four superordinate themes ( Table 2) . ^D efined as meeting the minimum recommended physical activity level. # Meeting recommended levels of cardiovascular OR strength activity.", "cite_spans": [], "ref_spans": [{"start": 128, "end": 136, "text": "Table 2)", "ref_id": "TABREF1"}]}, {"section": "Key themes", "text": "* Having education in these areas was defined as having additional qualifications (e.g. diploma) or attending at least 10 hours of educational classes (e.g. professional development workshops). \"Unsure\" results are not reported. Most interviewees believed that they were well-placed to promote NTPA. Many interviewees thought each consultation should involve a discussion about healthy behaviours to ensure holistic care, with PA being considered a healthy behaviour that can also prevent subsequent injury.", "cite_spans": [], "ref_spans": []}, {"section": "\"If they got a little bit fitter then probably their back pain would probably disappear or their knee pain would disappear or, actually, just their whole general mood would improve and, thus, most of their things would disappear\" IB.", "text": "All interviewees perceived their role to include both treating musculoskeletal conditions and also promoting NTPA, despite them reporting that some patients and doctors think their primary role was to provide hands-on treatment.", "cite_spans": [], "ref_spans": []}, {"section": "\"If they got a little bit fitter then probably their back pain would probably disappear or their knee pain would disappear or, actually, just their whole general mood would improve and, thus, most of their things would disappear\" IB.", "text": "\"\u2026physio is very much seen as hands-on here. And it\"s expected by the doctors, it\"s expected by the patients\" FB.", "cite_spans": [], "ref_spans": []}, {"section": "Patient expectations", "text": "Patients were perceived by most interviewees as expecting hands-on treatment, not NTPA promotion. The patient was considered a customer who has paid for a service they have pre-determined. This saw interviewees prioritise providing hands-on treatment or rehabilitation exercises to treat the condition before NTPA promotion.", "cite_spans": [], "ref_spans": []}, {"section": "Patient expectations", "text": "\"\u2026they\"re paying for an appointment and they want you to not talk to them, they want you to put your hands on them\" VR.", "cite_spans": [], "ref_spans": []}, {"section": "Patient expectations", "text": "Many interviewees reported that patients were surprised when they introduced the topic of NTPA, particularly when the patient could not see how increasing PA levels was related to their presenting complaint. Some interviewees felt this surprise could damage their rapport with the patient. Several interviewees delayed promoting NTPA until they established good rapport (e.g. in later consultations where PA can be discussed in the context of injury prevention) or did not promote it at all to avoid damaging rapport. This problem was particularly evident in recent graduate physiotherapists (within 5 years of graduating physiotherapy) who felt patients trusted them less as they were less experienced.", "cite_spans": [], "ref_spans": []}, {"section": "Patient expectations", "text": "\"\u2026if it comes from me, and they\"ve come to me with a shoulder problem, and they kind of go \"well how is this even relevant?\" and often they get quite defensive and that\"s, quite, (they\"re) sort of almost confrontational about the whole thing, which is challenging\" IB.", "cite_spans": [], "ref_spans": []}, {"section": "Workplace factors", "text": "Several interviewees reported that having a multidisciplinary clinic with an open-plan layout facilitated NTPA promotion by allowing access to other professionals who can help to facilitate PA participation (e.g. exercise physiologists running exercise classes) and for patients to see others exercising. Some interviewees found the open-plan design prompted patients to ask the physiotherapist why others were exercising and if they should do it too, providing an opportunity to discuss NTPA.", "cite_spans": [], "ref_spans": []}, {"section": "Workplace factors", "text": "Some interviewees reported that including PA messages in newsletters and on social media, as well as having staff actively commuting to work, was one way the clinic itself promoted NTPA to current and potential patients. Having management staff who promoted NTPA to their patients, valued health promotion and encouraged staff to learn how to promote NTPA made some interviewees feel NTPA promotion was their job.", "cite_spans": [], "ref_spans": []}, {"section": "\"The partner who is driving this wellness and health promotion (program) is fantastic, he works tirelessly, we have new styles of classes being added, a high-intensity post-natal exercise class, that\"s in the last 12 months\" FB.", "text": "Most interviewees thought short consultation times (especially when patients present with multiple concerns), tight appointment schedules, uncertainty regarding insurance funding for NTPA promotion, and the expectation to only deliver services that patients expect contributed to less NTPA promotion.", "cite_spans": [], "ref_spans": []}, {"section": "\"The partner who is driving this wellness and health promotion (program) is fantastic, he works tirelessly, we have new styles of classes being added, a high-intensity post-natal exercise class, that\"s in the last 12 months\" FB.", "text": "Some workplaces had policies encouraging physiotherapists to refer patients to exercise physiologists for NTPA promotion. This made some interviewees feel their role was being restricted to treatment only, however others liked being able to refer the patient to another skilled professional.", "cite_spans": [], "ref_spans": []}, {"section": "\"The partner who is driving this wellness and health promotion (program) is fantastic, he works tirelessly, we have new styles of classes being added, a high-intensity post-natal exercise class, that\"s in the last 12 months\" FB.", "text": "\"Our exercise physiolog(ists) get all our general physical activity ones, specifically physical activity. I\"ll often get people who will be sent to me because they might have a large falls risk and they can\"t do activity because they\"re such a big falls risk or because they\"ve got knee pain and they can\"t do their other things\" IB.", "cite_spans": [], "ref_spans": []}, {"section": "Approach taken by the physiotherapist towards NTPA promotion", "text": "Interviewees reported that patients responded better to NTPA advice if it considered their preferences (e.g. NTPA advice included active commuting if the patient enjoyed bike riding) and their symptoms. Tailoring PA advice often involved adding additional support (e.g. providing a referral to an exercise physiologist) or not prescribing the levels of PA outlined in the guidelines (e.g. 150-300 minutes of walking). Some interviewees felt prescribing enough walking to meet the guidelines was too much for someone who was currently inactive, potentially deterring the patient from doing any activity.", "cite_spans": [], "ref_spans": []}, {"section": "Approach taken by the physiotherapist towards NTPA promotion", "text": "\"For someone who\"s done nothing, for you to tell them that they need to do 30 to 60 minutes of physical activity most days, at least 5 days a week, that\"s going to be a bit overwhelming\" BK.", "cite_spans": [], "ref_spans": []}, {"section": "Use of BCTs", "text": "Interviewees reported using goal setting (behaviour), action planning, graded tasks, problem solving, self-monitoring of behaviour and social support (unspecified) to promote NTPA.", "cite_spans": [], "ref_spans": []}, {"section": "Use of BCTs", "text": "Self-monitoring devices (e.g. pedometers) were used by some interviewees to help patients monitor their activity levels. Interviewees reported that electronic devices and apps were more trustworthy and easier to use compared to conventional methods (e.g. paper-based exercise diary).", "cite_spans": [], "ref_spans": []}, {"section": "Use of BCTs", "text": "\"She could actually see what she was achieving and she could see fluctuations and then she could correlate the number of steps with how well she was sleeping and how she was feeling\" DB.", "cite_spans": [], "ref_spans": []}, {"section": "Use of BCTs", "text": "Some interviewees avoided using incentive and reward BCTs. Techniques to incentivise or reward a patient for being active were considered short-lasting and not conducive to long-term change.", "cite_spans": [], "ref_spans": []}, {"section": "Use of BCTs", "text": "\"", "cite_spans": [], "ref_spans": []}, {"section": "\u2026have you actually kind of addressed why it was a problem or have you just kinda given them some sort of carrot, which in the short term is OK, but in the long term is that going to be very sustainable?\" IB.", "text": "Social comparison was used by some interviewees who felt comparing inactive patients to active patients could motivate them to improve. In contrast, those who did not use it felt this BCT had the potential to demotivate patients if they felt they could not achieve the same amount of PA.", "cite_spans": [], "ref_spans": []}, {"section": "\"I guess that can go either way, so like sometimes the patient is like \"oh everyone is so much better than me, I\"m never going to be that good\" and sometimes they\"re like \"oh yeah, that looks really interesting, that kind of looks fine\"\" KM.", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Referral to other professionals", "text": "Most interviewees reported referring patients to trusted professionals for guidance to increase PA levels once the patient\"s symptoms had improved. Interviewees considered experience, education and open communication as determinants of trust.", "cite_spans": [], "ref_spans": []}, {"section": "Referral to other professionals", "text": "Most interviewees were unlikely to refer patients to professionals who lacked experience with injured patients. Having high-level skills and education in exercise prescription and injury prevention was considered necessary to avoid symptom aggravation and subsequent injury. High-level skills were considered those learnt during a university degree, meaning interviewees often referred patients to exercise physiologists before personal trainers.", "cite_spans": [], "ref_spans": []}, {"section": "\"You have to have done your time (study), um because yeah, because I do get a lot of clients out of it (personal training) and because they go into it too hard too quick with patients and they get injured\" BK.", "text": "Exercise physiologists were considered specialists in NTPA promotion for certain conditions (e.g. chronic disease) by many interviewees. Several interviewees would begin the discussion about increasing PA levels with patients and then refer them to an exercise physiologist for ongoing guidance.", "cite_spans": [], "ref_spans": []}, {"section": "\"I think I have a base level of skill and I think they (exercise physiologists) do it better as an ongoing thing. I think they have more skill in it, yeah I think we get a very baseline level at uni, I", "text": "think you pick up skills as you go depending on who you work with\" IB.", "cite_spans": [], "ref_spans": []}, {"section": "Challenges experienced when promoting NTPA", "text": "Patients who were hesitant to increase their PA levels or had little motivation to become physically active made NTPA promotion difficult for most interviewees. Several interviewees felt the patient needed to be \"ready to change\" (KM) before they could help them.", "cite_spans": [], "ref_spans": []}, {"section": "Challenges experienced when promoting NTPA", "text": "\" Some interviewees reported that they were not confident promoting NTPA, making them less likely to do it themselves and instead they would refer the patient to an exercise physiologist. One interviewee recited feeling uncomfortable when presented with a patient who only wanted NTPA promotion. This interviewee was not used to only promoting health within consultations.", "cite_spans": [], "ref_spans": []}, {"section": "\"Yeah it made me quite on edge\u2026trying to ask them and lead them to me maybe having a look at their neck to see if there\"s any stiffness there, you know, treat them for something!\" VR.", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Skills and training", "text": "Many interviewees felt that any confidence they had to promote NTPA came from having health promotion skills and clinical experience. Several interviewees reported the NTPA promotion and behaviour change skills they possess came from clinical and personal experience (e.g. using techniques that have worked for themselves, or were suggested by patients or peers).", "cite_spans": [], "ref_spans": []}, {"section": "\"I haven\"t learnt anything about behaviour change techniques or motivational interviewing. If you asked me to give you the definition of motivational interviewing I wouldn\"t have a clue\" SB.", "text": "Most interviewees wanted more training in NTPA promotion and behaviour change. Specifically, they wanted to learn techniques to help unmotivated patients to increase their PA levels.", "cite_spans": [], "ref_spans": []}, {"section": "\"Motivation\"s really hard. Um, that\"s probably the thing I struggle with most because if they don\"t want to do it then they won\"t do it\" KM.", "text": "Graduate and experienced (graduated from physiotherapy more than 5 years ago) interviewees felt learning about NTPA promotion needed to occur in the professional development setting, as opposed to university, as an appreciation for health promotion was considered to increase with experience. Face-to-face (e.g. lectures, conferences) and online (e.g. online courses, journals and social media) methods were used by interviewees for professional development on various topics, with online methods considered better if no task practice was required. Several interviewees suggested a professional development workshop run by their workplace or professional association and facilitated by a behaviour change expert would help them to learn how to promote NTPA. However, the cost and travel necessary to attend a workshop for rural and regional physiotherapists made their attendance unlikely.", "cite_spans": [], "ref_spans": []}, {"section": "\"Motivation\"s really hard. Um, that\"s probably the thing I struggle with most because if they don\"t want to do it then they won\"t do it\" KM.", "text": "\"\u2026by the time you get flights\u2026there\"s half my PD budget gone\u2026getting to Sydney or Melbourne is probably 400 bucks at a minimum\" FB, split quote.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Physiotherapists believed that NTPA promotion is part of their role. However, it can be difficult to do. Physiotherapists reported tailoring their promotion approaches to the patient and using BCTs that they have learnt clinically, rather than at university. Workplaces that had staff who promoted NTPA and had an open-plan and multidisciplinary environment made NTPA promotion easier for physiotherapists. Physiotherapists often faced resistance from patients who attended physiotherapy sessions not expecting NTPA promotion but instead only expecting treatments for their presenting condition (e.g. hands-on therapy and exercises). Barriers like these, as well as low patient motivation and physiotherapist confidence in changing behaviours, resulted in many physiotherapists feeling frustrated and promoting NTPA less, or referring the patient to exercise physiologists. Most physiotherapists wanted additional training in changing behaviours of unmotivated patients and saw behaviour change experts as integral to this.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Physiotherapists in this study felt it was part of their role to promote NTPA, despite some patients and doctors seeing their role mainly in treatment. This finding is supported by a recent Australian survey that reported 98.8% of physiotherapists agreed it was their role to promote PA [20] . Results from a small Australian study of physiotherapy patients suggest that patients feel it is the role of the physiotherapist to promote NTPA. The Health Promoting Pilot Program run in Victoria, Australia over 2014-2015 surveyed 59 physiotherapy patients and found that 94.5% believed it is the role of the physiotherapist to promote NTPA [21] . Patients accepted that they would receive NTPA promotion from their physiotherapist because it was their role to do this [21] . Therefore, physiotherapists\" perceptions that patients expect hands-on therapy more than NTPA promotion might not be accurate in all cases.", "cite_spans": [{"start": 287, "end": 291, "text": "[20]", "ref_id": "BIBREF18"}, {"start": 636, "end": 640, "text": "[21]", "ref_id": "BIBREF19"}, {"start": 764, "end": 768, "text": "[21]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "Discussion", "text": "Physiotherapists found their workplace could influence how easy NTPA promotion was by valuing health and PA promotion, providing an exercise-promoting environment and using advertising that includes PA messages. These findings are similar to those in a recent qualitative study that reported organisations facilitate PA promotion when they have values in-line with PA promotion, leaders committed to delivering promotion programs and appropriate facilities to support exercise [22] . Therefore, there are likely to be several factors external to the physiotherapist that influence NTPA promotion.", "cite_spans": [{"start": 477, "end": 481, "text": "[22]", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Discussion", "text": "The clinic environment and the advertising used by the clinic can frame patients\" expectations of the service they will receive at that clinic [23] . Patient expectations are not met when advertising is not consistent with the services delivered; this can lead to patient dissatisfaction [23] . For example, having an image of someone getting a massage on the clinic window advertises a hands-on service, thus patient expectations might not be met when the physiotherapist promotes NTPA instead of providing massage. Not meeting the expectations of patients acted as a barrier to many interviewees promoting NTPA in this study. This finding is supported by a recent study that reported patients expecting passive therapy was a barrier for chiropractors prescribing exercise for low back pain management [24] . Additionally, not being able to promote NTPA, albeit clinically indicated, due to the need to meet patient expectations (e.g. for massage) was expressed with frustration by several physiotherapists in this study, suggesting difficulty promoting NTPA might induce job-specific frustration. This type of conflict-induced frustration can contribute towards employee dissatisfaction [23] . Changes to the services advertised by a clinic (e.g. using people who are exercising in advertising) might make NTPA promotion easier for physiotherapists.", "cite_spans": [{"start": 143, "end": 147, "text": "[23]", "ref_id": "BIBREF21"}, {"start": 288, "end": 292, "text": "[23]", "ref_id": "BIBREF21"}, {"start": 803, "end": 807, "text": "[24]", "ref_id": "BIBREF22"}, {"start": 1189, "end": 1193, "text": "[23]", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Discussion", "text": "Musculoskeletal physiotherapists might not feel confident using psychology-based behaviour change interventions [25] . Physiotherapists in this study who were not confident promoting NTPA thought it was because they lacked the behaviour change skills necessary to do it. Australian podiatrists (another profession that has a role in PA promotion) have also reported that they lack behaviour change skills, limiting PA promotion [26] . Lack of PA counselling skills has been reported to reduce the odds (OR = 0.165, 95%CI 0.038 to 0.710) a physiotherapist will promote PA [20] . This might suggest additional training is needed, as training might improve confidence in delivering behaviour change interventions [27] . However, receiving training in how to deliver behaviour change interventions does not always mean that such interventions are delivered more often [28, 29] . Thus, training in NTPA promotion alone is unlikely to lead to NTPA being promoted more often.", "cite_spans": [{"start": 112, "end": 116, "text": "[25]", "ref_id": "BIBREF23"}, {"start": 428, "end": 432, "text": "[26]", "ref_id": "BIBREF24"}, {"start": 571, "end": 575, "text": "[20]", "ref_id": "BIBREF18"}, {"start": 710, "end": 714, "text": "[27]", "ref_id": "BIBREF25"}, {"start": 864, "end": 868, "text": "[28,", "ref_id": "BIBREF26"}, {"start": 869, "end": 872, "text": "29]", "ref_id": "BIBREF27"}], "ref_spans": []}, {"section": "Discussion", "text": "Physiotherapists stated that the behaviour change skills necessary for NTPA promotion came from clinical and life experience, as opposed to more formal (university or professional development) learning environments. A recent phenomenological study also found that life, learning and clinical experiences all influenced physiotherapists\" practice [30] . Therefore, training and support for NTPA promotion might be best delivered within the clinical environment as opposed to a formal learning environment. Having PA champions has been suggested by health care professionals as useful to support them to promote exercise to patients with breast cancer [31] and are considered facilitators to health and PA promotion by primary care professionals [32] and stakeholders [16] . Having current staff who are PA champions who can provide formal (e.g. internal workshop) and informal (e.g. lunchroom discussion) support for NTPA promotion can provide the information physiotherapists seek while also avoiding any travel related barriers associated with formal education.", "cite_spans": [{"start": 346, "end": 350, "text": "[30]", "ref_id": "BIBREF28"}, {"start": 650, "end": 654, "text": "[31]", "ref_id": "BIBREF29"}, {"start": 744, "end": 748, "text": "[32]", "ref_id": "BIBREF30"}, {"start": 766, "end": 770, "text": "[16]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Discussion", "text": "There are some potential limitations to this study. Social desirability bias might have been present between the interviewees and interviewer who were all physiotherapists. This might have seen interviewees change their responses to questions to please the interviewer or avoid ridicule. The use of telephone interviews in place of face-to-face interviews could be considered an inferior method of data collection due to the lack of non-verbal communication and increased reliance on verbal acknowledgements [33] . However, telephone interviews have been used successfully before for qualitative data collection and are considered a valuable alternative for when interviewees cannot attend in person [34] . Using telephone interviews allowed for more physiotherapists to participate in this study, particularly those who lived in rural and regional areas or did not have access to internet. Finally, following Yardley\"s criteria when designing and conducting this study provided the framework necessary for a high-quality study and ensured transparency when reporting findings.", "cite_spans": [{"start": 508, "end": 512, "text": "[33]", "ref_id": "BIBREF31"}, {"start": 700, "end": 704, "text": "[34]", "ref_id": "BIBREF32"}], "ref_spans": []}, {"section": "Conclusion", "text": "Physiotherapists felt they were well placed to promote NTPA but faced several challenges. The apparent need to meet patient expectations and the modest perceived ability to change the behaviour of unmotivated patients made NTPA promotion difficult for physiotherapists. Nevertheless, physiotherapists often tailored their PA advice to the patient, used BCTs to support PA adoption and referred patients to exercise physiologists for additional guidance. Physiotherapists felt NTPA promotion was facilitated by several workplace specific factors, notably having an open-plan environment and senior staff who valued NTPA promotion. Creating exercise-promoting clinical environments, which allow the physical features of the clinic to promote NTPA, could make NTPA promotion easier and less frustrating for physiotherapists.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Physical inactivity: The biggest public health problem of the 21st century", "authors": [{"first": "S", "middle": ["N"], "last": "Blair", "suffix": ""}], "year": 2009, "venue": "Br J Sports Med", "link": "29083349"}, "BIBREF1": {"title": "Australia\"s physical activity & sedentary behaviour guidelines for adults (18-64 years)", "authors": [{"first": "Australia", "middle": [], "last": "Commonwealth Of", "suffix": ""}], "year": 2014, "venue": "", "link": null}, "BIBREF2": {"title": "Global physical activity levels: Surveillance progress, pitfalls, and prospects", "authors": [{"first": "P", "middle": [], "last": "Hallal", "suffix": ""}, {"first": "L", "middle": [], "last": "Andersen", "suffix": ""}, {"first": "F", "middle": 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physiotherapists who participated in an interview on their experiences promoting non-treatment physical activity.", "type": "table"}, "TABREF1": {"text": "The superordinate and emergent themes that arose from interviews with 10 physiotherapists about their experiences promoting non-treatment physical activity.", "type": "table"}, "TABREF2": {"text": "I\"ll say, you know, \"if you, if you change your mind, if you\"re interested, I\"m here, you can book an appointment any time and just come in and we\"ll just start talking through your goals, but I can see that you\"re not ready yet\". So, I mean, you know, you need to be ready and you need to want to do it. I can\"t, I can\"t force you there basically\" FB. Some interviewees felt frustrated when patients resisted their advice to become physically active, making them feel powerless, which impacted their job satisfaction.up hill, you know, but, you gotta, you gotta enjoy your wins, as few and far between as they are\" (The wins were interpreted as when a patient improves their PA levels in some way).", "type": "table"}}}
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{"paper_id": "191687002", "_pdf_hash": "7fc0cb9757ffc18c4b207f47ffcc3e94a36230a0", "abstract": [{"section": "Abstract", "text": "A research gap was found in evaluating the role of Innovative Work Behavior in the food and Beverage sector, which is important for organizations to gain a competitive advantage. Therefore, this research aims to test the impact of the Perceived Organization Support and on the Employees Innovative Work Behavior in the Food and Beverage Sector in Egypt. It also aims to test the mediation role of Learning Organizations and Work Engagement between each of Perceived Organization Support and Employees Innovative Work Behavior. Thus, a semi-structured interview will be constructed with managers of Food and Beverage SMEs to explore the dimensions affecting Innovative Work Behavior. Also, a questionnaire will be constructed with the employees of the same SMEs to test the relationships under study. Regression analysis and structural equation modeling will be used to respond to the research hypotheses.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Innovative Work Behavior had been proved to be important for the purpose of organizations success. An evidence was introduced that employees innovative work behavior (IWB) has a highly important role which helps organizations to gain competitive advantage. A focus on the factors that improve IWB was done; on the other hand, few studies have investigated the negative aspects of it and Open Access Library Journal how to buffer such conflict [1] . Nowadays, knowledge-driven economy, maximizing the innovative potentials of employees has become a top priority in every organization. Employees offer organizations a competitive advantage through differentiation and enhancement of products or services by generating new ideas and initiatives. Employees were encouraged to be engaged in innovative behavior through effective interventions provided by researchers and practitioners in human resource development (HRD), with the growing significance of intellectual capital across all business sectors [2] .", "cite_spans": [{"start": 443, "end": 446, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 999, "end": 1002, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Introduction", "text": "Furthermore, it was expected that HRD plays a more critical role in facilitating a culture that supports innovation than ever before, considering that innovation requires a cultural change with collaboration. Given the existing emphasis on innovation in HRD, however, research on determinants that motivate employees' innovative behavior is still incomplete [2] . The intentional introduction of new and useful ideas, in addition to a set of behaviors needed to develop, launch and implement ideas with an aim to improve personal and/or business performance is referred to by IWB. Employee's attempt to find ultimate meaning and purpose in his/her work and strengthen his/her interconnectedness is referred to by workplace spirituality. It was suggested that workplace spirituality, when nurtured with perceptions of organizational support, fosters employee's creativity [3] .", "cite_spans": [{"start": 358, "end": 361, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 871, "end": 874, "text": "[3]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Literature Review", "text": "This section will introduce the definition of Innovative work behavior according to previous contributions and studies, and the relations between Innovative work behavior with learning organization and perceived organizational support moderated by work engagement.", "cite_spans": [], "ref_spans": []}, {"section": "Innovative Work Behavior Concept and Meaning", "text": "Innovative work behavior was defined as \"intentional creation, introduction and application of new ideas within a work role, group or organization, in order to benefit role performance, the group, or the organization\". Then this definition is limited to the creation, promotion, and implementation of new ideas that benefit organizations. This innovative work behavior can be in the form of the implementation of new methods, new procedures, or new approaches in an organization that are valuable to the organization. For example, in at an international media company one of the mangers created a new method to encourage innovation by establishing \"rebel camps\" for training other managers to be innovators, which give benefit to the company. So, according to this definition employees are encouraged to extra tasks more than team, group, or organization routines [1] .", "cite_spans": [{"start": 864, "end": 867, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Innovative Work Behavior Concept and Meaning", "text": "The respond to rapid change might be not applicable through the routines implemented by teams or organizations. Then, employees need to develop, endorse, and implement new methods, approaches or procedures. The definition Open Access Library Journal also includes taking risks. The effects of new ideas knowledge are not well known to innovative employees. In other words, this innovation may put employee's status and rewards in the organization at risk. At the end, a truly new idea or combination of existing ideas may create innovation. Creation, promotion and implementation of ideas are the three steps of the complex process called IWB. The problem that needs a solution is then the initiative of innovation process which motivates employee creation of new ideas. After creation an individual have to market the idea to gain support for their implementation as real products, services, methods, or techniques. The organization can benefit from supporting these new ideas at the end. Also, innovative employees might gain more job satisfaction, get better performance in the workplace, develop better relationships with other colleagues, experience relatively low stress, enjoy higher personal growth and produce positive conflicts [1] .", "cite_spans": [{"start": 1238, "end": 1241, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Innovative Work Behavior Concept and Meaning", "text": "Individual innovative behavior was also defined as an individual intentional behavior introduce and/or apply new ideas, products, processes and procedures to his or her work role, unit or organization. Based on this definition, new ideas, products, processes and procedures are considered both in their introduction and implementation, as they pertain to innovative behavior. Moreover, the word 'New' the previous statement does not necessarily refer to new idea to the field but it may refer to relatively new to the unit or initiating new technology which has not been used in the organization before. In addition, innovative behavior includes both technical and administrative innovation. Introducing and/or applying of new technologies, products and services is referred to as technical innovation, while introducing and/or applying of new procedures and policies is considered administrative innovations [4] .", "cite_spans": [{"start": 909, "end": 912, "text": "[4]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Innovative Work Behavior Concept and Meaning", "text": "Employee innovation behavior EIB is an expression referring to of the inner creativity of employees; it is a method to innovate creative products and processes through employees which generate and implement new ideas to improve performance or solve work-related problems. Introducing all individual behaviors which guide to the generation, introduction and application of beneficial novelty at various levels is included in EIB. It is highly related to employee creativity, which must result in final outputs and produce actual benefits to the organization. Creativity reflects the initial stage in a multiple stage process called [5] .", "cite_spans": [{"start": 631, "end": 634, "text": "[5]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Innovative Work Behavior Concept and Meaning", "text": "New ideas are generated by the employee after recognizing the problem, then mobilizing support from others for applying the new idea. Later on, the idea is now ready for implementation and come to reality by producing a new prototype or model. Various behaviors formulate a single stage of the process in which altogether may get new process, product, market or organizational structure. Employees' intentional introduction of new products/services or new ways of doing things through the process of idea generation and implementation refer to EIB. In services, EIB may be influenced by various job characteristics and it is also considered as workplace behaviors; thus, they unavoidably relate to job characteristics, which have been found to affect the behaviors of employees di-Open Access Library Journal rectly or indirectly through psychological states [5] .", "cite_spans": [{"start": 859, "end": 862, "text": "[5]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "The Relationship between Social Support and Innovative Work Behavior", "text": "Tangible and intangible outcomes from employee experiences develop perceptions of organizational support through the daily exchange process with the organization. When positive outcomes come from these exchanges employee's extra-role activities are also triggered. It was also proposed that inclination toward initiating creative ideas, exploring possible opportunities, solving current and future problems and translating their creative inputs into actions and innovative output increase when employees recognize that the organization shows concern, offers nonjudgmental, honest feedback about their work and supports their actions. IWB is not one-time discrete activity and it seems to be continuous process as employees generate new ideas and, in parallel way they are busy in implementing these ideas by building organizational support and others' ideas by being a part of the overall team that has to implement the ideas [3] .", "cite_spans": [{"start": 926, "end": 929, "text": "[3]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Social support types including Perceived Organizational Support (POS), Perceived Supervisor Support (PSS), and Perceived Coworker Support (PCS). Social", "text": "support is part of the job resources; it refers to the extent to which organizations and supervisors' value the contribution and well-being of their employees [6] .", "cite_spans": [{"start": 159, "end": 162, "text": "[6]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Social support types including Perceived Organizational Support (POS), Perceived Supervisor Support (PSS), and Perceived Coworker Support (PCS). Social", "text": "and coworkers' willingness to help each other complete work-related tasks [7] .", "cite_spans": [{"start": 74, "end": 77, "text": "[7]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Social support types including Perceived Organizational Support (POS), Perceived Supervisor Support (PSS), and Perceived Coworker Support (PCS). Social", "text": "Employees need strong perceptions of management and supervisor support to ", "cite_spans": [], "ref_spans": []}, {"section": "Mediating Role of Learning Organization between Social Support and Innovative Work Behavior", "text": "Nowadays, maximizing the innovative potentials of employees has become a top priority in every organization. Employees generate new ideas and initiatives offering the organizations a competitive advantage through differentiation and enhancement of products or services. Employees are encouraged to engage in innovative behavior, with the growing significance of intellectual capital across all business sectors, researchers and practitioners in human resource development (HRD) can thus be expected to develop and provide effective interventions. Furthermore, it is now expected that that HRD plays a more critical role in Open Access Library Journal facilitating a culture that supports innovation than ever before, considering that innovation requires a cultural change with collaboration. However, research on determinants that stimulate employees' innovative behavior is still incomplete, given the current emphasis on innovation in HRD [2] . Motivating organizational culture that values continuous learning, knowledge sharing, employee empowerment, and social interactions among its members altogether enhance employees' innovative behaviors seems important. An important component of innovation is employee intrinsic motivation and positive emotions that elicit a deeper engagement with the innovation process. The role of intrinsic motivation was emphasized in the innovation process by identifying three dimensions of creativity: motivation, knowledge, and skills. It was also stated that intrinsic motivation helps employees become flexible, persistent, and goal-oriented. It was also highlighted that motivation is linked to innovation and that people who are highly motivated are most likely to deal with obstacles they face and take a proactive attitude to their work. Individuals' work engagement promoted by intrinsic motivation is significantly related to innovation in terms of improving personal initiatives. In addition, employees devoted their time and energy to their work facilitating their creativity when they have confidence in their personal ability to achieve goals. It was also stated that individual work engagement improves personal initiative, and accordingly influences innovation [2] .", "cite_spans": [{"start": 941, "end": 944, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 2213, "end": 2216, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Mediating Role of Learning Organization between Social Support and Innovative Work Behavior", "text": "Organizational innovation is also boosted by energy that engaged employees bring into their work by enabling them to be more proactive and responsible. People feel positive when they are engaged to their work which leads to creative and explorative thinking and idea implementation, which in turn increase personal resources. At the end, it is concluded that engagement seems to play a mediating role in the relationship between the learning organization and innovative behavior. There is a link between innovative behaviors and engaged employees. A framework that aligns engagement with the organization's leadership, learning, and support system is necessary when employees' innovative behaviors are Open Access Library Journal to be systematically motivated and developed within an organization [2] .", "cite_spans": [{"start": 798, "end": 801, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Mediating Role of Work Engagement between Social Support and Innovative Work Behavior", "text": "Work engagement is a persistent, positive, affective-motivational state of fulfilment in employees that is characterized by energy, dedication and absorption [8] . Given its importance, an increasing number of studies examined factors that affect work engagement (e.g. [9] ). Among these factors were social support types including Perceived Organizational Support (POS), Perceived Supervisor", "cite_spans": [{"start": 158, "end": 161, "text": "[8]", "ref_id": "BIBREF10"}, {"start": 269, "end": 272, "text": "[9]", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "Support (PSS), and Perceived Coworker Support (PCS).", "text": "Moreover, studies that have examined the effect of the three types of social support on work engagement specifically, also recorded some non-uniformity in results. For example, in one of the studies, all the three types had significant effect, with POS having the greatest effect.", "cite_spans": [], "ref_spans": []}, {"section": "Support (PSS), and Perceived Coworker Support (PCS).", "text": "Nevertheless, a review of the literature on studies focusing on one or two types of social support confirms the positive impact of POS on work engagement (e.g.", "cite_spans": [], "ref_spans": []}, {"section": "Support (PSS), and Perceived Coworker Support (PCS).", "text": "[10]. However, inconsistency of results was witnessed among PSS and PCS.", "cite_spans": [], "ref_spans": []}, {"section": "Support (PSS), and Perceived Coworker Support (PCS).", "text": "Some studies have failed to prove the significant effect of PSS and/or PCS on work engagement (e.g. [11] [12]), whereas others are debatable regarding the relative importance of PSS and PCS to work engagement. Those who believe that PSS is more important consider it as a more stable resource to employees [9] , while PCS advocates believe that colleagues are the heart of social support [7] , and help combat health impairment symptoms [13] . From the review above, it can be concluded that the few studies including the three social support types together, as well as those that concentrated on one or two types show that POS has a relatively higher consistency in its results compared to PSS and PCS. Accordingly, this research attempts to distinguish between the effects of each type of social support through including them in one study and examining their effect on work engagement.", "cite_spans": [{"start": 100, "end": 104, "text": "[11]", "ref_id": "BIBREF15"}, {"start": 306, "end": 309, "text": "[9]", "ref_id": "BIBREF11"}, {"start": 388, "end": 391, "text": "[7]", "ref_id": "BIBREF9"}, {"start": 437, "end": 441, "text": "[13]", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "Support (PSS), and Perceived Coworker Support (PCS).", "text": "Besides social support, other personal resources such as psychological empowerment in spite of its importance in raising employees' work engagement have been rarely investigated [14] . Psychological empowerment (including meaning, competence, self-determination, and impact) refers to a set of psychological states that are necessary for individuals to feel a sense of control in relation to their work [15] . Unlike job resources, psychological empowerment leads to intrinsic motivation through employees' perception of empowerment. Hence, it is considered a personal belief rather than a job characteristic [16] .", "cite_spans": [{"start": 178, "end": 182, "text": "[14]", "ref_id": "BIBREF19"}, {"start": 403, "end": 407, "text": "[15]", "ref_id": "BIBREF21"}, {"start": 609, "end": 613, "text": "[16]", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Support (PSS), and Perceived Coworker Support (PCS).", "text": "Additionally, empowerment theorists view psychological empowerment as an explanatory mechanism through which contextual factors affect individuals' attitudes. This can be attributed to the fact that psychological empowerment is a cognitive model that reflects people's perception toward themselves in relation to work environment based on individual differences. Consequently, it can be argued that adding psychological empowerment as a mediator could help ex- [15] .", "cite_spans": [{"start": 461, "end": 465, "text": "[15]", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Support (PSS), and Perceived Coworker Support (PCS).", "text": "Another point that has been raised in the work engagement literature is that the research is predominantly Western-based [17] . Explaining work engagement in different cultural contexts will add value to the established literature by comparing its results to other relatively new contexts, which will eventually help generalize the findings and broaden understanding of the engagement process. To fill this research gap, this study examines work engagement in Egypt.", "cite_spans": [{"start": 121, "end": 125, "text": "[17]", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "Support (PSS), and Perceived Coworker Support (PCS).", "text": "Studying work engagement in Egypt is important because Egypt tends to have high propensity of disengaged employees; it alone accounted for 32 percent of disengaged employees in the Middle East region [18] . The disengagement problem in Egypt has been a crucial but under-resolved challenge. Factors such as autocratic management styles denoted by a high-power distance culture have contributed to the disengagement status for many years. In addition, with the recent economic and political unrest.", "cite_spans": [{"start": 200, "end": 204, "text": "[18]", "ref_id": "BIBREF27"}], "ref_spans": []}, {"section": "Support (PSS), and Perceived Coworker Support (PCS).", "text": "following the 2011 revolution, employees' attitudes toward their work have changed [19] , their demands increased and the disengagement problem intensified, as reflected in 1969 strikes in 2012 compared to 530 in 2010 [20] . Therefore, this study focuses on examining the effect of both social support and psychological empowerment in raising Egyptians' engagement under the current tough conditions.", "cite_spans": [{"start": 83, "end": 87, "text": "[19]", "ref_id": "BIBREF28"}, {"start": 218, "end": 222, "text": "[20]", "ref_id": "BIBREF30"}], "ref_spans": []}, {"section": "Research Framework", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Variables and Measurement", "text": "The variables used in this study can be categorized into three main types which are; the dependent, independent variables and mediator variables.", "cite_spans": [], "ref_spans": []}, {"section": "Dependent Variable", "text": "The dependent variable for this study is Innovative Work Behavior.", "cite_spans": [], "ref_spans": []}, {"section": "Independent Variable", "text": "There are three independent variables that will be measured. These are state POS, PSS, IWB", "cite_spans": [], "ref_spans": []}, {"section": "Mediator Variables", "text": "There are three variables representing the mediator Learning Organization Work Engagement (Vigor, Dedication, and Absorption). The relationship between dependent variable, mediator variables and independent variables is explained in Figure 1 .", "cite_spans": [], "ref_spans": [{"start": 233, "end": 241, "text": "Figure 1", "ref_id": "FIGREF1"}]}, {"section": "Mediator Variables", "text": "In the questionnaire assigned, the questions were adopted to measure the dimensions under study by implementing a 5-point Likert -scale used for all responses with (1 = Strongly Disagree, 2 = Disagree, 3 = Neutral, 4 = Agree, 5 = Strongly Agree). Thus, the literature had been reviewed and the following hypotheses were assumed: Open Access Library Journal ", "cite_spans": [], "ref_spans": []}, {"section": "Results and Findings", "text": "To test the hypotheses mentioned above, the current research used regression analysis and structural equation modeling (SEM). This requires testing the validity and reliability of the research variables as well as presenting a descriptive analysis of the research variables under study. After that, the hypotheses testing will be presented through the model constructed. As a preliminary step, the frequency tables are computed for the research variables.", "cite_spans": [], "ref_spans": []}, {"section": "Descriptive Analysis", "text": "The descriptive statistics is a tool in which it explains and gives a distinct under- Frequency statistics sum how many times each variable is repeated; for instance, the number of employed and unemployed among the sample. In the following section, means, standard deviations and frequency statistics will be conducted on both; demographic data and the research variables. ", "cite_spans": [], "ref_spans": []}, {"section": "Data Testing", "text": "To test the validity of the research variables, confirmatory factor analysis was used to calculate the Average Variance Extracted (AVE) and Factor Loading (FL) of each construct. Therefore, confirmatory factor analysis using the principal component method was used to examine the convergent validity of the research dimensions. Reliability test is an assessment of the degree of consistency between multiple measurements of a variable. Cronbach's alpha is the most widely used measurement tool with a generally agreed lower limit of 0.7. Table 2 provides an overview of the reliability scores. As can be seen from this ", "cite_spans": [], "ref_spans": [{"start": 538, "end": 545, "text": "Table 2", "ref_id": "TABREF6"}]}, {"section": "Hypotheses Testing", "text": "In this section, the researcher will present the findings of the model significance through presenting the correlation and regression analysis results. This will provide a decision whether to accept or reject the hypotheses under study.", "cite_spans": [], "ref_spans": []}, {"section": "Testing the First Hypothesis: The impact of Perceived Organizational Support on Innovative Work Behavior", "text": "This hypothesis is designed to test the impact of Perceived Organizational Support on Innovative Work Behavior. Table 3 shows the output of applying multiple regression analysis, where it was found that the Perceived Organizational Support under study explain 32.4% of the variation in Innovative Work Behavior, as R-square = 0.324. The importance of Perceived Organizational Support according to the standardized coefficient beta is determined as follows: (\u03b2 = 0.552, P-value = 0.00) which indicates that the variable \"Perceived Organizational Support\" was found to be Significant as its P-values was less than 0.05. Table 4 shows the output of applying multiple regression analysis, where it was found that the Perceived Supervision Support under study explain 32.6% of the variation in Innovative Work Behavior, as R-square = 0.326. The importance of Perceived Supervision Support according to the standardized coefficient beta is determined as follows: (\u03b2 = 0.588, P-value = 0.00) which indicates that the variable 'Perceived Supervision Support' was found to be Significant as its P-values was less than 0.05. observed that there is a significant effect of Perceived Organization Support, and Perceived Supervisor Support, with estimates of 0.373, and 0.545 respectively and P-values of 0.00. Also, the R Square is 0.498, which means that Social Support; Perceived Organization Support, and Perceived Supervisor Supportexplain 49.8% of the variation in Innovative Work Behavior.", "cite_spans": [], "ref_spans": [{"start": 618, "end": 625, "text": "Table 4", "ref_id": "TABREF7"}]}, {"section": "Testing the Second Hypothesis: The impact of Perceived Supervision Support on Innovative Work Behavior", "text": "The model fit indices shown in Table 6 ", "cite_spans": [], "ref_spans": []}, {"section": "Discussion and Conclusion", "text": "The statistical tests of multiple regression analysis and Structural Equation Modeling (SEM) presented above enabled the researcher to identify the social support that had the most significant positive impact on Innovative Work Behavior.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion and Conclusion", "text": "The multiple regression applied showed that the constructs that had the most significant positive impact on Innovative Work Behavior could be classified as Perceived Organizational Support and Perceived Supervision.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Is Innovative Behavior Really Good for the Firm? Innovative Work Behavior, Conflict with Coworkers and Turnover Intention: Moderating Roles of Perceived Distributive Fairness", "authors": [{"first": "H", "middle": ["A"], "last": "Shih", "suffix": ""}, {"first": "E", "middle": [], "last": "Susanto", "suffix": ""}], "year": 2011, "venue": "International Journal of Conflict Management", "link": null}, "BIBREF1": {"title": "Learning Organization and Innovative Behavior: The Mediating Effect of Work Engagement", "authors": [{"first": "Y", "middle": ["K"], "last": "Park", "suffix": ""}, {"first": "J", "middle": ["H"], "last": "Song", "suffix": ""}, {"first": "S", "middle": ["W"], "last": "Yoon", "suffix": ""}, {"first": "J", "middle": [], "last": "Kim", "suffix": ""}], "year": 2014, "venue": "European Journal of Training and Development", "link": "142710250"}, "BIBREF3": {"title": "Workplace Spirituality, Perceived Organizational Support and Innovative Work Behavior: The Mediating Effects of Person-Organization Fit", "authors": [{"first": "B", "middle": [], "last": "Afsar", "suffix": ""}, {"first": "Y", "middle": [], "last": "Badir", "suffix": ""}], "year": 2017, "venue": "Journal of Workplace Learning", "link": null}, "BIBREF5": {"title": "Importance of Commitment in Encouraging Employees' Innovative Behaviour", "authors": [{"first": "F", "middle": [], "last": "Hakimian", "suffix": ""}, {"first": "H", "middle": [], "last": "Farid", "suffix": ""}, {"first": "M", "middle": ["N"], "last": "Ismail", "suffix": ""}, {"first": "P", "middle": ["K"], "last": "Nair", "suffix": ""}], "year": 2016, "venue": "Asia-Pacific Journal of Business Administration", "link": "147432122"}, "BIBREF6": {"title": "A Review of Employee Innovative Behavior in Services", "authors": [{"first": "M", "middle": [], "last": "Li", "suffix": ""}, {"first": "C", "middle": ["C H"], "last": "Hsu", "suffix": ""}], "year": 2016, "venue": "International Journal of Contemporary Hospitality Management", "link": "157263346"}, "BIBREF7": {"title": "Perceived Organizational Support: A Review of the Literature", "authors": [{"first": "L", "middle": [], "last": "Rhoades", "suffix": ""}, {"first": "R", "middle": [], "last": "Eisenberger", "suffix": ""}], "year": 2002, "venue": "Journal of Applied Psychology", "link": "10928728"}, "BIBREF9": {"title": "The Role of Exchange Ideology in Coworker Social Support and Work Engagement", "authors": [{"first": "S", "middle": ["S"], "last": "Cureton", "suffix": ""}], "year": 2014, "venue": "", "link": "141226810"}, "BIBREF10": {"title": "Job Demands, Job Resources, and Their Relationship with Burnout and Engagement: A Multi-Sample Study", "authors": [{"first": "W", "middle": ["B"], "last": "Schaufeli", "suffix": ""}, {"first": "A", "middle": ["B"], "last": "Bakker", "suffix": ""}], "year": 2004, "venue": "Journal of Organizational Behavior: Journal of Organizational Behavior", "link": "51988794"}, "BIBREF11": {"title": "The Impact of Work Engagement and Workaholism on Well-Being: The Role of Work-Related Social Support", "authors": [{"first": "G", "middle": [], "last": "Caesens", "suffix": ""}, {"first": "F", "middle": [], "last": "Stinglhamber", "suffix": ""}, {"first": "G", "middle": [], "last": "Luypaert", "suffix": ""}], "year": 2014, "venue": "Career Development International", "link": "142505966"}, "BIBREF13": {"title": "Antecedents and Consequences of Employee Engagement", "authors": [{"first": "A", "middle": ["M"], "last": "Saks", "suffix": ""}], "year": 2006, "venue": "Journal of Managerial Psychology", "link": "143964302"}, "BIBREF15": {"title": "The Effects of Job and Personal Resources on Hotel Employees' Work Engagement", "authors": [{"first": "O", "middle": ["M"], "last": "Karatepe", "suffix": ""}, {"first": "O", "middle": ["A"], "last": "Olugbade", "suffix": ""}], "year": 2009, "venue": "International Journal of Hospitality Management", "link": "154277260"}, "BIBREF16": {"title": "Job Demands, Job Resources, and Work Engagement of Japanese Employees: A Prospective Cohort Study. 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It is then expected that perceived organizational support POS encompasses cer- tain psychological characteristics which may motivate IWB of employees. In- crease behaviors that support organizational goals, and IWB is one of such posi- tive behaviors, is a result of feelings of obligation which come from the percep- tions of the social exchange framework that underlies POS. Thus, this obligation feeling result that POS would drive extra-role behavior such as IWB. It was fi- nally concluded that employees perceived organizational support POS positively influences innovative work behavior IWB [3].", "type": "figure"}, "FIGREF1": {"text": "Figure 1. Research framework for the current study.", "type": "figure"}, "FIGREF2": {"text": "standing of the features of certain data set, by giving short summaries about samples and how to measure the data. The three major types of descriptive anal- ysis are frequency, measures the central tendency such as averages, and measure of variability such as standard deviation. Measures of variability describes the level of how different the scores are from the mean. Measures of central tenden- cy suggest unique value that generally represents the entire scores set.", "type": "figure"}, "FIGREF4": {"text": "Figure 2. SEM model for the effect of social support on innovative work behavior.", "type": "figure"}, "FIGREF5": {"text": "are described as minimum discrepan- cy (CMIN), goodness of fit index (GFI), comparative fit index (CFI), incremen- tal fit index (IFI), Tucker-Lewis index (TLI), and root mean square of approxi- mation (RMSEA). It was found that CMIN/df = 1.500, GFI = 0.948, CFI = 0.Openboth the first hypothesis that there is positive impact of Perceived Or- ganizational Support on Innovative Work Behavior and the second hypothesis that there is positive impact of Perceived Supervision Support on Innovative Work Behavior are fully supported.", "type": "figure"}, "TABREF0": {"text": "Problem-solving skills or motivation and organizational factors including leadership and work group relations influence innovative behavior. It is consi- dered an important factor when organizational culture motivates innovation because innovation goes beyond individual-level idea generation. An attempt was found to examine the effect of organizational climate on innovative beha- vior. It was found that innovative behavior is motivated by organizational justice through the psychological mechanism of perceived organizational support. It was also stated that individual innovative behavior is affected by role expecta- tions and leader-member exchange. Moreover, innovative behavior is predicted by transformational leadership and this relationship is mediated by psychologi- cal empowerment. Employees' innovative behaviors sources was explored and stated as organizational learning capabilities and knowledge sharing (another innovative effort), because knowledge dissemination serves as initial idea gener- ation [2].", "type": "table"}, "TABREF2": {"text": "", "type": "table"}, "TABREF3": {"text": "Frequency table for research variables.", "type": "table"}, "TABREF5": {"text": "shows the SEM model for the effect of Perceived Organization Support, and Perceived Supervisor Support on Innovative Work Behavior. It was Open Access Library Journal", "type": "table"}, "TABREF6": {"text": "KMO, average variance extracted and factor loadings of items.Table 3. Regression analysis of perceived organizational support on innovative work be- havior.", "type": "table"}, "TABREF7": {"text": "Regression analysis of perceived supervisor support on innovative work beha- vior.Dependent variable: Innovative work behavior. Open Access Library Journal", "type": "table"}, "TABREF8": {"text": "SEM model for the effect of social support on innovative work behavior.Table 6. Model fit for the effect of social support on innovative work behavior.", "type": "table"}}}
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{"paper_id": "128191795", "_pdf_hash": "a7330a309d9ab70ed49acdf259a2a801f4698614", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "128192696", "_pdf_hash": "bf0591ca4125f894f678dee538ace58b3bfcb9b8", "abstract": [{"section": "Abstract", "text": "Abstract. This paper presents a stochastic coordinate descent algorithm for solving bound constrained global optimization problems. The algorithm borrows ideas from some stochastic optimization methods available for the minimization of expected and empirical risks that arise in large-scale machine learning. Initially, the algorithm generates a population of points although only a small subpopulation of points is randomly selected and moved at each iteration towards the global optimal solution. Each point of the subpopulation is moved along one component only of the negative gradient direction. Preliminary experiments show that the algorithm is effective in reaching the required solution.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION", "text": "In this paper, we consider the problem of finding a global solution of a bound constrained nonlinear optimization problem in the following form: minimize f (x) subject to x \u2208 \u2126,", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "where f : R n \u2192 R is a nonlinear function and \u2126 = {x \u2208 R n : \u2212\u221e < l i \u2264 x i \u2264 u i < \u221e, i = 1, . . . , n} is a bounded feasible region. We assume that the objective function f is differentiable, is nonconvex and may possess many local minima in the set \u2126. We assume that the optimal set X * of the problem (1) is nonempty and bounded, x * is a global minimizer and f * represents the global optimal value. To solve the global optimization (GO) problem shown in (1), a stochastic or a deterministic method may be selected. A stochastic method is able to provide a solution that may not be globally optimal. On the other hand, a deterministic method provides an interval that contains the global optimal solution, but requires in general a much larger computational effort [1] . Techniques to find a global optimal solution rely on two search procedures. The exploration procedure aims to diversify the search so that a global optimal solution is located; the exploitation procedure is devoted to intensify the search in a vicinity of a promising region so that a good approximation is computed. Approximate methods or heuristics are designed to generate good solutions with less computational effort and time than the more classical algorithms. Stochastic heuristics use random procedures to generate candidate solutions and perform a series of operations on those solutions in order to find different and hopefully better solutions.", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "Recent and promising optimization methods for large-scale machine learning make use of classical gradientbased methods, like the full gradient, accelerated gradient, conjugate gradient and quasi-Newton, classified as batch approaches. On the other hand, stochastic gradient approaches have relied on intuitive schemes to employ data information more efficiently than the batch methods. It has been recognized that working with small data samples can avoid redundancy and be quite appealing [2, 3, 4] . The coordinate descent method (CDM) is one of the oldest methods in optimization. It is very popular for its simplicity and it has been applied in a variety of practical situations. Cyclic coordinate search, block coordinate descent and random coordinate search are known variants of the CDM and differ mainly on the choice of the component(s) of the gradient for the update of the variables. Convergence issues for convex objective f are clear and well defined for some variants of the CDM [5] .", "cite_spans": [{"start": 490, "end": 493, "text": "[2,", "ref_id": "BIBREF1"}, {"start": 497, "end": 499, "text": "4]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "This paper is devoted to the use of a variant of the CDM in the context of a stochastic population-based method for solving bound constrained GO problems that may have a large number of variables. The new stochastic CDM has started to be tested and the numerical results seem promising.", "cite_spans": [], "ref_spans": []}, {"section": "STOCHASTIC COORDINATE DESCENT FRAMEWORK", "text": "This section presents the motivation for the use of the stochastic coordinate descent method in the context of a population-based method for solving the problem (1).", "cite_spans": [], "ref_spans": []}, {"section": "STOCHASTIC COORDINATE DESCENT FRAMEWORK", "text": "Coordinate Descent Method The CDM operates by taking steps along the coordinate directions [2, 5] . Hence, the search direction for minimizing f from the iterate x (k) , at iteration k, is defined as", "cite_spans": [{"start": 91, "end": 94, "text": "[2,", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "STOCHASTIC COORDINATE DESCENT FRAMEWORK", "text": "where e i k represents the i k th coordinate vector for some index i k , usually chosen by cycling through {1, 2, . . . , n}, and x i k is the i k th component of the vector x \u2208 R n . For a positive step size, \u03b1 (k) , the new approximation, x (k+1) , is computed as shown below and differ from x (k) only in the i k th component:", "cite_spans": [], "ref_spans": []}, {"section": "STOCHASTIC COORDINATE DESCENT FRAMEWORK", "text": "Stochastic Coordinate Descent Method Stochastic gradient methods and stochastic CDM (S-CDM) have been attracting the attention of the scientific community because of their usefulness in data analysis and machine learning.", "cite_spans": [], "ref_spans": []}, {"section": "STOCHASTIC COORDINATE DESCENT FRAMEWORK", "text": "Applications to practical problems of the CDM are varied being the support vector machine problem the most known application of S-CDM, see [6] and references therein. In the S-CDM, the index i k to define the search direction and the component of x (k) to be adjusted (see (2) and (3)) is chosen randomly by uniform distribution on {1, 2, . . . , n} with replacement in each iteration. If the random choice is made without replacement, a set of n consecutive iterations defines an \"epoch\" and at the start of each epoch, the set {1, 2, . . . , n} is shuffled [6] . As shown above the approximation x (k) is moved along the direction corresponding to the component of the gradient with index i k . We note here that the direction shown in (2) might not be a negative directional derivative for f from x (k) .", "cite_spans": [{"start": 273, "end": 276, "text": "(2)", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Population-Based Stochastic Coordinate Descent Method", "text": "At each iteration of a population-based algorithm, a set of candidate solutions/points is generated aiming to explore the feasible region for a global optimum. Let |P| denote the number of points in the population, where x i \u2208 R n represents the ith point (i \u2208 P = {1, 2, . . . , |P|}). The likelihood is that the greater the |P| the better is the exploration feature of the algorithm. However, to handle and evaluate the objective f for a large number of points is time consuming. We now describe an S-CDM adapted to a populationbased framework, herein coined by P-S-CDM. To prevent the computational burden of moving and evaluating the full population, without spoiling the exploration capability of the algorithm, a subpopulation of points is randomly selected to be potentially moved in direction to the global optimum. In practical terms, the indices of the subpopulation are randomly selected by a uniform distribution on {1, 2, . . . , |P|} without replacement. Let P 1 , P 2 , . . . , P k , . . . be the sets of indices of the subpopulation randomly chosen from P. After movement, the best point of each subpopulation will be maintained for the next iteration. We note that, for k = 1, P 1 includes the index of the best point, while for the subsequent iterations, P k does not include the index of the best point of the previous subpopulation. Hence, for k = 1 the size of the population is |P 1 |, and for k > 1, the size is |P k | + 1. The rules to generate the subsets of indices, from the set P, for the subpopulations are the following:", "cite_spans": [], "ref_spans": []}, {"section": "Population-Based Stochastic Coordinate Descent Method", "text": "r1:", "cite_spans": [], "ref_spans": []}, {"section": "Population-Based Stochastic Coordinate Descent Method", "text": "|P 1 | |P|; r3:", "cite_spans": [], "ref_spans": []}, {"section": "Population-Based Stochastic Coordinate Descent Method", "text": "where j k\u22121 is the index of the best point of the subpopulation of iteration k \u2212 1. We usex, the central point, to represent the region defined by the points of a subpopulation, which in the context of our algorithm is defined as follows:", "cite_spans": [], "ref_spans": []}, {"section": "Population-Based Stochastic Coordinate Descent Method", "text": "We define P + 1 = P 1 and P", "cite_spans": [], "ref_spans": []}, {"section": "Population-Based Stochastic Coordinate Descent Method", "text": "is a descent direction for f from x j , where \u03b1 k j is a positive step size computed by a backtracking strategy; otherwise, the point x j is not moved. Whenever the new position of the point falls outside the bounds, a projection onto \u2126 is carried out. For each j \u2208 P + k , the search direction is along a component of the gradient at the central point, with the index i k randomly selected by uniform distribution on {1, 2, . . . , n} one at a time for each j with replacement:", "cite_spans": [], "ref_spans": []}, {"section": "Population-Based Stochastic Coordinate Descent Method", "text": "Input: \u03b5, N.F. max , \u00b5 Output:", "cite_spans": [], "ref_spans": []}, {"section": "Population-Based Stochastic Coordinate Descent Method", "text": "Randomly generate a set of |P| points in \u2126, {x 1 , x 2 , . . . , x |P| } while stopping condition is not satisfied and N.F. \u2264 N.F. max do Randomly select a subset of indices P k from P following rules r1, r2 and r3 ", "cite_spans": [], "ref_spans": []}, {"section": "Population-Based Stochastic Coordinate Descent Method", "text": "Algorithm 1: Population-based stochastic coordinate descent algorithm Although using only one component of the gradient to adjust each point x j of the population seems a weakness in contrast with using the full gradient, it is in fact a strength since in a population-based environment (with a variety of candidate solutions at each iteration) the likelihood is that all components of the gradient end up to be used to move the points. The smaller the number of variables the greater is the probability that all components are selected. We also note that, even if the direction with the full gradient is not a descent direction for f from x j , the selected coordinate direction could be and some progress is achieved along this direction. Algorithm 1 shows the main steps of the algorithm. The stopping condition to guarantee a solution in the vicinity of f * is", "cite_spans": [], "ref_spans": []}, {"section": "Population-Based Stochastic Coordinate Descent Method", "text": "where x j k is the best point of the subpopulation, j k = arg min{ f (x j ), j \u2208 P + k }. However, if (6) is not satisfied for a given tolerance, \u03b5 > 0, the algorithm stops after a specified number of function evaluations, N.F. max .", "cite_spans": [], "ref_spans": []}, {"section": "PRELIMINARY EXPERIMENTS AND CONCLUSION", "text": "For a preliminary practical validation of the proposed P-S-CDM five well-known benchmark problems are used: GP (Goldstein and Price), MHB (Modified Himmelblau), RA-2, RA-5, RA-10 (Rastrigin n = 2, n = 5, n = 10 respectively), described in Table 1 of [7] . The algorithm is implemented in the Matlab TM (Matlab is a registered trademark of the MathWorks, Inc.) programming language. The selected parameter values for the algorithm are |P| = 500,", "cite_spans": [{"start": 250, "end": 253, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": [{"start": 239, "end": 246, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "PRELIMINARY EXPERIMENTS AND CONCLUSION", "text": "We compare our results with other population-based methods from the literature using the same stopping condition, mEM (modified electromagnetism-like mechanism based on memory force vector), mAFS-P (priority-based modified artificial fish swarm), mDE (modified differential evolution with mixing mutation), mGA (modified genetic algorithm with diversity preserving mechanism) and the results are taken from [7] . Table 1 shows the average of the obtained minimum f values, f avg , after 30 runs, and the average number of function evaluations, N.F. avg . The preliminary experiments show that the proposed P-S-CDM is effective in reaching the required solution. In the comparisons with other stochastic population-based methods, our algorithm has 100% of successful runs (according to (6) ) in four of five tested problems. It wins in efficiency over mAFS-P on GP, over mAFS-P and mGA on MHB, over mEM, mAFS-P and mGA on RA-2 and over mEM and mGA on RA-5. When solving RA-10, our algorithm reaches a solution with the required accuracy (according to (6) ) on 77% of the runs (mEM reports 100%, mAFS-P reports 38%, mDE 100% and mGA 0%). We also note that both mEM and mAFS-P implement a local search starting from the best solution at each iteration aiming to enhance the quality of the obtained solutions.", "cite_spans": [{"start": 407, "end": 410, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": [{"start": 413, "end": 420, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "PRELIMINARY EXPERIMENTS AND CONCLUSION", "text": "Future developments will focus on improving the convergence of our proposal by using a self-adaptive strategy to define the size of each subpopulation and a new strategy to sample a block of components of the gradient to move points of the subpopulation. Classes of randomly generated test problems [8] will be used for a comparison between deterministic descent methods, our improved algorithm and other stochastic metaheuristics via operational zones [9, 10] . The convergence for nonconvex objective functions will be also analyzed.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF1": {"title": "Optimization methods for large-scale machine learning", "authors": [{"first": "L", "middle": [], "last": "Bottou", "suffix": ""}, {"first": "F", "middle": ["E"], "last": "Curtis", "suffix": ""}, {"first": "J", "middle": [], "last": "", "suffix": ""}], "year": 2018, "venue": "", "link": null}, "BIBREF3": {"title": "Random permutations fix a worst case for cyclic coordinate descent", "authors": [{"first": "C.-P", "middle": [], "last": "Lee", "suffix": ""}, {"first": "S", "middle": ["J"], "last": "Wright", "suffix": ""}], "year": 2018, "venue": "", "link": "16586424"}, "BIBREF6": {"title": "On challenging techniques for constrained global optimization", "authors": [{"first": "I", "middle": ["A C P"], "last": "Santo", "suffix": ""}, {"first": "L", "middle": [], "last": "Costa", "suffix": ""}, {"first": "A", "middle": ["M A C"], "last": "Rocha", "suffix": ""}, {"first": "M", "middle": ["A K"], "last": "Azad", "suffix": ""}, {"first": "E", "middle": ["M G P"], "last": "Fernandes", "suffix": ""}], "year": 2013, "venue": "ISRL", "link": "32137955"}}, "ref_entries": {"FIGREF0": {"text": "for f from x j has not been computed before then Compute f (x j ); Set N.F. = N.F. + 1 Set m = 0 and N.F. = N.F. + 1; Compute f", "type": "figure"}, "TABREF0": {"text": "Comparative results.", "type": "table"}}}
{"paper_id": "128195319", "_pdf_hash": "c0cd8c5c4cf646c94b680777043abe17455cea05", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "128196128", "_pdf_hash": "7ccdc62b7ff545a0ba9348dd6b16969ef338edc8", "abstract": [{"section": "Abstract", "text": "In this paper the reflection and refraction of the electromagnetic waves from the planar interface of an anisotropic medium are investigated. The considered anisotropic medium is a uniaxial material whose optical axis lies in the incident plane and makes an arbitrary angle with the normal to the interface. It is shown that the directions of the wave and Poynting vectors of the transmitted wave depend on the incident angle and the orientation of the optical axis of the uniaxial material. Also, the situation that the negative refraction can happen for such media is obtained. In addition, the dependence of the Brewster angle to the orientation of the optical axis of the uniaxial material is considered. More interestingly, it is shown that there is a situation for which the wave and Poynting vectors of the transmitted transverse magnetic wave are parallel.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "An electromagnetic (EM) wave passed through the interface of two media experiences some reflection and transmission. The reflection and transmission coefficients at the interface described by the Fresnel equations depend on the polarization, the incident angle of the incoming wave, and the optical properties of two media, including their permittivity and permeability. The reflection and refraction of EM waves at the interface of isotropic materials are widely used for controlling the polarization, intensity, phase of EM waves in the wide range of applications [1, 2] .", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "During the last decades, the response of anisotropic materials to the electromagnetic waves has increasingly attracted a great deal of attention because of the phenomena that different from those in isotropic materials. The reflection and transmission applications at the interface of anisotropic materials encourage the researchers to more study the Fresnel equations in such media. There are some approaches to determine the reflection and refraction of the EM waves in the uniaxial crystals [3, 4] . Generally, an EM wave falling on the interface of the anisotropic media is refracted into two waves with different directions of propagation. At the interface of usual materials the incident and refracted waves are in opposite side of the interface normal. However, the incident and refracted waves may be in the same side of the interface normal (negative refraction) in the case of light refraction in the interface of isotropic and anisotropic media [5] [6] [7] [8] [9] [10] . The phenomenon of negative refraction which is shown in the negative uniaxial anisotropic materials has imaging applications in superlenses beyond the diffraction limit [11] . A detailed analysis of the reflection, refraction characteristics, and the features of the Brewster angle for both TM and TE waves have been investigated at the planar interface associated with the uniaxial media [3, 10, [12] [13] [14] [15] . As one knows, the Poynting and wave vectors in anisotropic materials are not necessarily collinear. The directions of the Poynting and wave vectors which show the propagation of the energy flow and the phase velocity, respectively, strongly depend on the optical properties of the materials and the isofrequency surfaces of the incoming wave. To the best of our knowledge, the relation between directions of the Poynting and wave vectors have not been studied in uniaxial materials, analytically.", "cite_spans": [{"start": 494, "end": 497, "text": "[3,", "ref_id": "BIBREF1"}, {"start": 498, "end": 500, "text": "4]", "ref_id": "BIBREF2"}, {"start": 956, "end": 959, "text": "[5]", "ref_id": "BIBREF3"}, {"start": 960, "end": 963, "text": "[6]", "ref_id": "BIBREF4"}, {"start": 964, "end": 967, "text": "[7]", "ref_id": "BIBREF5"}, {"start": 968, "end": 971, "text": "[8]", "ref_id": "BIBREF6"}, {"start": 972, "end": 975, "text": "[9]", "ref_id": "BIBREF7"}, {"start": 976, "end": 980, "text": "[10]", "ref_id": "BIBREF8"}, {"start": 1152, "end": 1156, "text": "[11]", "ref_id": "BIBREF9"}, {"start": 1372, "end": 1375, "text": "[3,", "ref_id": "BIBREF1"}, {"start": 1376, "end": 1379, "text": "10,", "ref_id": "BIBREF8"}, {"start": 1385, "end": 1389, "text": "[13]", "ref_id": "BIBREF11"}, {"start": 1390, "end": 1394, "text": "[14]", "ref_id": "BIBREF12"}, {"start": 1395, "end": 1399, "text": "[15]", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Introduction", "text": "In the present paper, using boundary conditions for the electric and magnetic fields at the interface of two lossless isotropic and uniaxial materials, the Fresnel reflection and transmission coefficients of the TE and TM modes are derived. The dependence of the wave and Poynting vectors direction for the reflected and transmitted waves on the incident angle and the orientation of the optical axis of the material is studied, and illustrated using isofrequency curves. The results are realized by numerical calculations for calcite and liquid crystal 5CB as the typical negative and positive uniaxial materials.", "cite_spans": [], "ref_spans": []}, {"section": "Calculation and theoretical model", "text": "Consider the isotropic medium 1 and the anisotropic medium 2 as depicted in figure 1. We define the coordinates as the reflecting surface being the xy plane and the plane of incidence being the xz plane with the z axis normal to the interface of the two media. Suppose a TM plane wave is incident with the angle \u03b8 1 from the isotropic medium 1 with the real relative permittivity \u03b5 1 onto the medium 2 which its permittivity is described by the real permittivity tensor \u00ea 2 : where, \u03b5 0 is the permittivity of the vacuum and \u03b5 zx \uf0a0=\uf0a0\u03b5 xz . We treat the media 1 and 2 as nonmagnetic materials with m m m = = 1 2 0 , where \u03bc 0 is the permeability of the free space. For the TM mode, the magnetic and electric fields of the waves in the media 1 and 2 are given as:", "cite_spans": [], "ref_spans": []}, {"section": "Calculation and theoretical model", "text": "e e w = - ", "cite_spans": [], "ref_spans": []}, {"section": "Calculation and theoretical model", "text": "are the z components of the wave vectors in the media 1 and 2. We can easily obtain the Fresnel reflection and transmission coefficients by applying the continuity conditions of the tangential magnetic and electric fields at the interface of the two media as:", "cite_spans": [], "ref_spans": []}, {"section": "Calculation and theoretical model", "text": "e e e e e e e e e e e e = = -", "cite_spans": [], "ref_spans": []}, {"section": "Calculation and theoretical model", "text": "e e e e e e e e e = = -", "cite_spans": [], "ref_spans": []}, {"section": "Calculation and theoretical model", "text": "The reflection R TM and transmission T TM are defined by: Like as the TM mode, the Fresnel equations of the TE mode can be obtained as: 1 . In addition, the Poynting vector of the TE mode in the medium 2 is given by: ", "cite_spans": [], "ref_spans": []}, {"section": "Results and numerical calculations", "text": "In this section, we study the behavior of the TM and TE modes, by numerical calculations, at the interface of the medium 1 assumed to be free space with the relative permittivity \u03b5 1 \uf0a0=\uf0a01 and the uniaxial medium 2. Here, the medium 2 is considered to be the uniaxial material which its optical axis lies in the xz plane and makes the angle j with the normal to the interface of two media. For such medium, the elements of the permittivity tensor \u00ea 2 are given by [5, 6, 16] : Here, e \uf050 and \u03b5 \u22a5 are the parallel and perpendicular components of the relative permittivity of the uniaxial material with respect to its optical axis, respectively. It is well known to define the birefringence e e D = -\uf050 n , which can be positive or negative for the positive or negative uniaxial materials, respectively. We want to investigate the transmission and reflection at the interface of the uniaxial materials.", "cite_spans": [{"start": 463, "end": 466, "text": "[5,", "ref_id": "BIBREF3"}, {"start": 467, "end": 469, "text": "6,", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Results and numerical calculations", "text": "We assume that the uniaxial material to be CaCO 3 which is a transparent negative uniaxial crystal at \u03bb\uf0a0=\uf0a0589 nm with e e = = . It is useful to define the parameter \u03b4 which shows the polarization of the reflected wave as fallows:", "cite_spans": [], "ref_spans": []}, {"section": "Results and numerical calculations", "text": "where, \u03b4\uf0a0=\uf0a01 and \u22121 indicate that the polarization of the reflected wave is TM or TE, respectively. In figure 3 the parameter \u03b4 is depicted as a function of the incident angle. From equations (21), (29) it is clear that the Brewster angle \u03b8 B strongly depends on the orientation of the optical axis of the uniaxial medium 2. To show this, we plotted \u03b8 B versus j in figure 4 . Now, we use equations (16), (17) For the incident angles \u03b8 1 \uf0a0<\uf0a0\u03b8 c the negative refraction can happen, in which the refracted Poynting vector and the incident wave are in the same side of the normal to the interface. Since, the TM wave is the extraordinary mode, so the Poynting vector of the TM wave in the considered uniaxial medium is not necessarily in the direction of its wave vector. This can be understood from the dispersion equation of the TM mode in the uniaxial material. By using Maxwell equations the isofrequency curves in the medium 2 can be obtained: As mentioned earlier, the direction of the Poynting vector which is perpendicular to the isofrequency curves depends on the value and the sign of the permittivity of medium. In figure 5(a) the isofrequency curves (ellipsoids), the directions of the Poynting vector (dashed arrows) and wave vector (dotted arrows) of the TM mode depicted schematically, for different incident angels. On the other hand, the isofrequency curves for such media for the TE mode are given by:", "cite_spans": [], "ref_spans": [{"start": 103, "end": 111, "text": "figure 3", "ref_id": "FIGREF12"}, {"start": 366, "end": 374, "text": "figure 4", "ref_id": "FIGREF13"}]}, {"section": "Results and numerical calculations", "text": "which is obviously a circle, so the wave and Poynting vectors are in the same direction. This situation illustrated in figure 5 (b). More interestingly, figure 5(a) reveals that", "cite_spans": [], "ref_spans": [{"start": 119, "end": 127, "text": "figure 5", "ref_id": "FIGREF14"}]}, {"section": "Results and numerical calculations", "text": "TM at the incident angle \u03b8 1 \uf0a0=\uf0a034.54\u00b0. In other words, the Poynting and the wave vectors of the transmitted TM mode will be parallel at the incident angle \u03b8 1 \uf0a0=\uf0a034.54\u00b0. The incident angle for which the Poynting and the wave vectors of the transmitted TM mode are parallel depends on j as shown in figure 6 . The TM wave is the extraordinary wave, so the Poynting and wave vectors have the walk-off. We define the TE , and the walk-off angle between the wave vectors of the TM and TE waves as", "cite_spans": [], "ref_spans": [{"start": 299, "end": 307, "text": "figure 6", "ref_id": "FIGREF15"}]}, {"section": "Results and numerical calculations", "text": "TE . The walk-off angles are shown in figure 7 . In continue, we consider a positive uniaxial material as the medium 2 with \u03b5 xz \uf0a0\uf0a00. The liquid crystal 5CB with e e = = \uf050 2.91, 2.36 at \u03bb\uf0a0=\uf0a0589 nm can be an example of such media [16, 18] . In order to investigate the effect of positive \u03b5 xz on q k TE are positive for the considered uniaxial medium 2. As a result, the negative refraction will not happen in this case. In figure 8 the isofrequency curves, the direction of the Poynting and wave vectors for the TM mode ( figure 8(a) ) and TE mode ( figure 8(b) ) depicted schematically, for different incident angels. However, as in the case of the anisotropic medium 2 with \u03b5 xz \uf0a0<\uf0a00, there exists an incident angle \u03b8 1 for which q q = k s 2 TM 2", "cite_spans": [{"start": 234, "end": 237, "text": "18]", "ref_id": "BIBREF16"}], "ref_spans": [{"start": 38, "end": 46, "text": "figure 7", "ref_id": "FIGREF16"}]}, {"section": "Results and numerical calculations", "text": "TM . The dependence of this incident angle on the optical axis orientation of the uniaxial medium 2 is shown in figure 9 .", "cite_spans": [], "ref_spans": [{"start": 112, "end": 120, "text": "figure 9", "ref_id": "FIGREF19"}]}, {"section": "Conclusion", "text": "In summary, the reflection and refraction of the electromagnetic wave from the planar interface of anisotropic uniaxial medium are investigated. It is shown that the angle that the wave vector of the transmitted wave makes with the normal to the interface always is positive for both TE and TM modes. However, the angle that the Poynting vector of the transmitted TM wave makes with the normal to the interface may be negative or positive. The results reveal that the negative refraction can happen in negative uniaxial material whose optical axis is not parallel or perpendicular to the interface. Moreover, it is shown that there is an incident angle for which the wave and Poynting vectors of the transmitted TM wave are parallel.", "cite_spans": [], "ref_spans": []}, {"section": "ORCID iDs", "text": "M Karimi Habil https:/ /orcid.org/0000-0002-3216-5868 ", "cite_spans": [], "ref_spans": []}, {"section": "References", "text": "", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF1": {"title": "Brewster angles in reflection by uniaxial crystals", "authors": [{"first": "J", "middle": [], "last": "Lekner", "suffix": ""}], "year": 1993, "venue": "J. Opt. Soc. Am. A", "link": "123149303"}, "BIBREF2": {"title": "Reflection and refraction by interfaces of uniaxial crystals Opt. 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Commun", "link": "120931354"}, "BIBREF16": {"title": "High temperature-gradient refractive index liquid crystals", "authors": [{"first": "J", "middle": [], "last": "Li", "suffix": ""}, {"first": "S", "middle": [], "last": "Gauzia", "suffix": ""}, {"first": "S T", "middle": [], "last": "Wu", "suffix": ""}], "year": 2004, "venue": "Opt. Express", "link": "10760730"}}, "ref_entries": {"FIGREF2": {"text": "the unit vector normal to the interface (i.e. the z direction), a =the Poynting vectors of the incident, reflected and transmitted waves which are given as:", "type": "figure"}, "FIGREF4": {"text": "We define q k 2 TM as the angle between the z axis and the wave vector of the TM wave, and q s 2 TM as the angle between the z axis and the Poynting vector of the TM wave. So", "type": "figure"}, "FIGREF5": {"text": "Figure 1. Schematic diagram for the incident, reflected and transmitted waves at the interface of the isotropic medium 1 and the anisotropic medium 2 for the TM mode. Here, E , H and D show the electric field, magnetic field and electric displacement, respectively. The direction of the wave vector k and Poynting vector S is shown in both media.", "type": "figure"}, "FIGREF8": {"text": "749 [17]. For this choice of the para- meters using equation (29) we have \u03b5 xx \uf0a0=\uf0a02.685,and \u03b5 xz \uf0a0=\uf0a0\u22120.173 at j\uf0a0=\uf0a020\u00b0. In figure 2 the reflection and transmission of both TE and TM modes are plotted as a function of incident angle \u03b8 1 . As it is seen from the figure the reflection of the TM mode is zero at the Brewster angle q", "type": "figure"}, "FIGREF9": {"text": "and equations (25), (26) to investigate the dependence of q.e. the energy flows normal to the interface) at the incidence angle \u03b8 c given by:", "type": "figure"}, "FIGREF11": {"text": "Figure 2. The reflection and transmission of both TE and TM modes as a function of incident angle \u03b8 1 when the uniaxial medium 2 is considered to be CaCO 3 with e e = = \uf050 2.208, 2.749 at \u03bb\uf0a0=\uf0a0589 nm with j = \uf0b0 20 [17]. Here, the dotted and dotted-dashed lines indicate the reflection and transmission for the TE mode, and the dashed and solid lines indicate the reflection and transmission for the TM mode, respectively.", "type": "figure"}, "FIGREF12": {"text": "Figure 3. The parameter \u03b4 as a function of incident angle. Here, the parameters are same as figure 2.", "type": "figure"}, "FIGREF13": {"text": "Figure 4. The dependence of the Brewster angle \u03b8 B to j. Here, the parameters are the same as figure 2.", "type": "figure"}, "FIGREF14": {"text": "Figure 5. (a) The dependence of q k 2 TM (solid line) and q s 2 TM (dashed line) for TM mode, and (b) the dependence of q k 2 TE (solid line) and q s 2 TE (dashed line) for TE mode to the incident angle \u03b8 1 . The isofrequency curves (ellipsoid for TM and circle for TE modes) and the direction of the wave vector (dotted arrows) and Poynting vector (dashed arrows) for some incident angles are depicted schematically. Here, the parameters are the same as figure 2.", "type": "figure"}, "FIGREF15": {"text": "Figure 6. The incident angle \u03b8 1 for which the Poynting and wave vectors of the transmitted TM mode are parallel versus j. Here, the parameters are the same as figure 2.", "type": "figure"}, "FIGREF16": {"text": "Figure 7. The walk-off angles of the Poynting vector \u03b4\u03b8 s and wave vector \u03b4\u03b8 k as a function of incident angle \u03b8 1 . Here, the parameters are same as figure 2.", "type": "figure"}, "FIGREF17": {"text": "we plotted these angles versus \u03b8 1 in figure 8.\uf0a0As it is seen from figure 8, all angles q k 2 TM , q q ,", "type": "figure"}, "FIGREF18": {"text": "Figure 8. The dependence of q q , k s 2 TM 2 TM , q k 2 TE and q s 2 TE to the incident angle \u03b8 1 . Here, e = \uf050 2.91, \u03b5 \u22a5 \uf0a0=\uf0a02.36 at \u03bb\uf0a0=\uf0a0589 nm with j\uf0a0=\uf0a020\u00b0[ 16, 18]. Here, the captions are the same as figure 5.", "type": "figure"}, "FIGREF19": {"text": "Figure 9. The incident angle \u03b8 1 for which the Poynting and the wave vectors of the transmitted TM mode are parallel versus j. Here, the parameters are same as figure 8.", "type": "figure"}, "TABREF0": {"text": "which c is the speed of light in free space. Here", "type": "table"}, "TABREF2": {"text": ")From equation (18) one can find the Brewster angle \u03b8 B for which the reflected energy from the interface of the aniso- tropic medium 2 is zero. It is easy to show that the Brewster angle \u03b8 B satisfies the following equation:", "type": "table"}}}
{"paper_id": "128196401", "_pdf_hash": "795b60d99ed3ec33e22780c41f1030afa5a52af2", "abstract": [], "body_text": [{"section": "INTRODUCTION", "text": "In April 1955, at the request of the Department of Defense, the U.S. Geological Survey began an investigation of ground-water conditions in the vicinity of Lake Mead Base, Las Vegas Valley, Nev. The chemical quality of the water from two of four wells supplying the base had deteriorated to the point where it was wholly unsatisfactory for use. The study was made to determine the cause of the deterioration and to provide data that might be helpful in maintaining a satisfactory supply for the base.", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "As part of the study, all known pertinent geologic and hydrologic data for the area were assembled and studied. During the investigation, considerable additional data were collected and studied. These data were obtained from pumping tests in the area, current-meter and conductivity surveys, and chemical analyses of water samples from wells.", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "The results of the investigation were made available to the Department of Defense upon completion of the study. On the basis of the 1955 study, a well was drilled in the summer of 1961 to augment the water supply of Lake Mead Base (R. J. Houghton, oral communication, 1962 ). The well is 2,000 feet west of well 4 and is pumped Ql at the rate of 130 gpm (gallons per minute). The chemical quality of the water is more suitable for use on the base than the chemical quality of the water from any of the other wells. No significant change in chemical quality or yield of the water from wells 2,3, and 4 has been noted.", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "Data on file at Lake Mead Base were used extensively in the present study of the wells and water supply. Useful data also were obtained from a study by Maxey and Jameson (1948) and from a guidebook to the geology of Utah (Intermountain Association of Petroleum Geologists, 1952) . In this report wells are given the same numbers used by the defense agencies for designating wells on their respective bases.", "cite_spans": [{"start": 152, "end": 176, "text": "Maxey and Jameson (1948)", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "GEOGRAPHY LOCATION", "text": "The area described in this report is in the eastern part of Las Vegas Valley (see fig. 1 ). The area studied most intensively is near the eastern edge of the valley between Nellis Air Force Base and Lake Mead Base, about 10 miles northeast of Las Vegas, where the well field for Lake Mead Base is located.", "cite_spans": [], "ref_spans": [{"start": 82, "end": 88, "text": "fig. 1", "ref_id": "FIGREF0"}]}, {"section": "TOPOGRAPHIC FEATURES", "text": "Las Vegas Valley trends northwestward about 50 miles and is as much as 20 miles wide. The Spring Mountains, which have a maximum altitude of 11,910 feet, border the west side of the valley. The southern parts of the Pintwater, Desert, Sheep, and Las Vegas Ranges form the northeastern boundary. Frenchman and Sunrise Mountains and a group of unnamed low hills border the east side of the valley. The River Mountains and the McCullough Range form the southeastern boundary.", "cite_spans": [], "ref_spans": []}, {"section": "TOPOGRAPHIC FEATURES", "text": "The relief of the mountains ranges from a few thousand feet to about 10,000 feet. The mountains are rugged and commonly rise abruptly above the alluvial apron that separates them from the basin lowlands. Large alluvial fans extend far out from the Spring Mountains. The alluvial fans on the east side of the valley are small. The fans merge into the basin lowlands, which are nearly flat and slope southeastward.", "cite_spans": [], "ref_spans": []}, {"section": "TOPOGRAPHIC FEATURES", "text": "Drainage is southeastward to the Colorado River (east of the area shown in fig. 1 ) through Las Vegas Wash. There are no perennial streams in the area. Runoff ordinarily infiltrates into the ground high on the alluvial fans. After intense summer storms, however, the runoff may be sufficient for short periods of time to flow onto the floor of the valley. Occasionally the runoff causes extensive damage to railroads, roads, and urban areas. ", "cite_spans": [], "ref_spans": [{"start": 75, "end": 81, "text": "fig. 1", "ref_id": "FIGREF0"}]}, {"section": "CLIMATE", "text": "The climate is arid. Relative humidity is low, the percentage of sunshine is high, and the daily and seasonal range in temperature is large. Strong winds are common throughout the year.", "cite_spans": [], "ref_spans": []}, {"section": "GEOLOGY", "text": "The mountains generally are composed of consolidated sedimentary and igneous rocks of Precambrian, Paleozoic, Mesozoic, and early Tertiary age. Rocks of Precambrian age are exposed only at the base of Frenchman Mountain. The structure of the consolidated rocks is exceedingly complex because of numerous thrust, lateral, and normal faults. The alluvial apron and the valley fill are composed mostly of unconsolidated deposits of Miocene(?), Pliocene, Pleistocene, and Recent age.", "cite_spans": [], "ref_spans": []}, {"section": "GEOLOGY", "text": "Except for the Sultan and the Monte Cristo Limestones of middle Paleozoic age, the older rocks of the mountains generally are barriers to the movement of ground water. The Sultan and the Monte Cristo Limestones locally transmit large quantities of water through solution channels formed mainly along faults and joints. These rocks are exposed in Frenchman Mountain, and they probably are in contact with saturated alluvium east of Nellis Air Force Base.", "cite_spans": [], "ref_spans": []}, {"section": "GEOLOGY", "text": "The alluvial apron is composed largely of poorly sorted gravel, sand, silt, and clay. However, some of the alluvial fans that extend far out from the mountains contain clean gravel strata on their higher slopes. Most of these fans emerge from canyons in the Spring Mountains and are the principal areas of recharge to the ground-water reservoir of Las Vegas Valley.", "cite_spans": [], "ref_spans": []}, {"section": "GEOLOGY", "text": "The valley fill consists, to an unknown depth, of deposits of gravel, sand, silt, and clay. Most of the water developed to date has been from strata less than 700 feet deep. At greater depths the deposits tend to be finer grained and may be consolidated.", "cite_spans": [], "ref_spans": []}, {"section": "GROUND WATER", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "RECHARGE", "text": "The source of recharge to the ground-water reservoir of Las Vegas Valley is within the drainage basin. Precipitation in the Spring Mountains is the major source of the recharge, although some recharge results from the infiltration of precipitation and resulting runoff on the lower ranges.", "cite_spans": [], "ref_spans": []}, {"section": "RECHARGE", "text": "The aquifers in the Nellis Air Force Base area are recharged principally from precipitation on the alluvial fans at the south end of the Las Vegas Range, although part of the recharge may be derived from precipitation in the Spring Mountains.", "cite_spans": [], "ref_spans": []}, {"section": "RECHARGE", "text": "Probably the only significant source of recharge to the aquifers in the Lake Mead Base area is precipitation on the southern part of the Las Vegas Range. Thus, most of the ground-water recharge to the respective well fields is from a common source, precipitation on the southern part of the Las Vegas Range and the alluvial fans that border it.", "cite_spans": [], "ref_spans": []}, {"section": "MOVEMENT AND DISCHABGE", "text": "Ground water in Las Vegas Valley moves from the Spring Mountains and other recharge areas toward pumped and flowing wells and toward springs and areas of evapotranspiration, principally near and east of Las Vegas.", "cite_spans": [], "ref_spans": []}, {"section": "MOVEMENT AND DISCHABGE", "text": "In the vicinity of Las Vegas, artesian water moves generally eastward toward Frenchman Mountain and then southward along the east side of the valley toward Las Vegas Wash.", "cite_spans": [], "ref_spans": []}, {"section": "MOVEMENT AND DISCHABGE", "text": "Data for the area near Lake Mead Base and Nellis Air Force Base are insufficient for accurate mapping of the direction of ground-water movement, but it is inferred to be southeastward beneath the military bases toward Frenchman Mountain. (See fig. 2.) Whether some or all of the ground water in the Lake Mead Base area moves southeastward into Frenchman Mountain is not known. The possibility of movement into the mountain is recognized because the contours on the piezometric surface, although insufficiently controlled, infer such movement, and the nature and structure of the rocks do not preclude movement of water through them. As was pointed out in the discussion on the geology of the valley, the Sultan and Monte Cristo Limestones, both exceptions to the general rule that the rocks of the mountains are barriers to the movement of ground water, are probably in the zone of saturation in the Lake Mead Base area. Furthermore, the rocks into which the water may be moving have been extensively faulted, a condition that might allow the transmission of water in otherwise nearly impermeable rocks. The fact that no large springs or large areas of evapotranspiration are known to result from the southeastward movement of water through Frenchman Mountain does not preclude such movement, because the amount of water involved (see p. Q10) probably is very small.", "cite_spans": [], "ref_spans": []}, {"section": "CHEMICAL QUALITY OF THE WATEB", "text": "Much of Las Vegas Valley yields water suitable for most domestic uses and for irrigation. In general, ground water in the northern and central parts of the valley has a low dissolved-solids content. For example, near Las Vegas the dissolved-solids content generally is about 300 ppm (parts per million). In the southern part of Las Vegas Valley, however, much of the ground water is so highly mineralized that it is unsatisfactory for domestic and irrigation use. For example, in the vicinity of Whitney and Pittman the concentration of dissolved solids commonly is several thousand parts per million.", "cite_spans": [], "ref_spans": []}, {"section": "690-209 63 2", "text": "A notable exception to the rule that water in the central part of the valley commonly has a low dissolved-solids content is the water in wells 1 and 2 at Lake Mead Base. The dissolved-solids content of the water of well 1, on Mar. 2, 1955, after the well had not been used for months, was 1,810 ppm. The dissolved-solids content of the water of well 2, on the same date, was 1,170 ppm. These values are in marked contrast to those of the water of the other two wells on the base (about 500 ppm) and to those of the water of the wells supplying Nellis Air Force Base (250 to 500 ppm). The water from wells 1 and 2 was used during 1953 and 1954 to supply the needs of Lake Mead Base. It is reported that the water was unsatisfactory in many respects, especially for evaporative coolers and for the hot-water system. In 1955, wells 3 and 4 supplied water for the base, and wells 1 and 2 were virtually unused.", "cite_spans": [], "ref_spans": []}, {"section": "INVESTIGATIONAL PROCEDURES AND CONCLUSIONS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "PIEZOMETBIC SURFACE", "text": "In an effort to determine the direction of ground-water movement in the vicinity of Lake Mead Base, contour lines of the piezometric surface in that area were drawn ( fig. 2 ). (Meinzer (1923) defined the piezometric surface as an imaginary surface that everywhere coincides with the static level of the water in the aquifer.) In this study, the nonpumping levels of water in the wells in the spring of 1955 were considered to be points on the piezometric surface. The position and shape of the surface at other points were inferred from these few known points, and contour lines were drawn to show the position and shape of the piezometric surface as of that time.", "cite_spans": [{"start": 177, "end": 192, "text": "(Meinzer (1923)", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "PIEZOMETBIC SURFACE", "text": "The position of the contour lines on figure 2 is considered tentative because of inadequate and conflicting water-level data. If some of the data collected previous to the investigation had been used, the contour lines in the vicinity of the well field of Lake Mead Base would have been almost at right angles to those shown in figure 2. The altitude of the water level in well 1 in March 1952 reportedly was 1,768 feet. At the time of the investigation, April 1955, the altitude of the water level was 1,754 feet. The altitude of the water level in well 2 in March 1952, according to the same source, was 1,765 feet. During the present study, the altitude was 1,762 feet. The altitude of the water level in the Young and Smith well, which is about half a mile northeast of well 2, was 1,794 feet in January 1953, if the depth to water as given in the driller's log is correct. In April 1955, the altitude of the water level was 1,762 feet.", "cite_spans": [], "ref_spans": []}, {"section": "PIEZOMETBIC SURFACE", "text": "In contrast to these declines, the available data indicate a substantial rise in water levels in wells 3 and 4 since the date of their completion in late 1953. Beportedly, the altitude of the water level in well 3 in December 1953 was 1,734 feet. During the present study, the altitude of the water level was 1,758 feet. The same source indicates that the altitude of the water level in well 4 in December 1953 was 1,739 feet. During the present study the altitude of the water level was 1,761 feet.", "cite_spans": [], "ref_spans": []}, {"section": "PIEZOMETBIC SURFACE", "text": "Because the methods used to collect data prior to the present study and the circumstances under which those data were collected are not fully known, the following statements are based largely on data obtained and verified during the present study in which depths to water were measured with a steel tape.", "cite_spans": [], "ref_spans": []}, {"section": "PIEZOMETBIC SURFACE", "text": "The contour lines ( fig. 2 ) suggest that the main source of the ground water beneath the Lake Mead Base well field is the precipitation and runoff that infiltrates into the alluvial fans at the southern end of the Las Vegas Range ( fig. 1) . A negligible amount also may be derived from precipitation on the hills and mountains north and east of the base. Because of the gypsiferous nature of some of the rocks comprising these hills and mountains, such water may be highly mineralized. Whether the water passing beneath the well field moves southeastward into Frenchman Mountain or is deflected southward along the base of the mountain is not known. In any event, the source of the water of low dissolved-solids content appears to be northwest of the well field.", "cite_spans": [], "ref_spans": [{"start": 233, "end": 240, "text": "fig. 1)", "ref_id": "FIGREF0"}]}, {"section": "ATTITUDE OF PBINCIPAL AQUIFERS", "text": "Electric logs are available for wells 1 to 4. The logs indicate that the principal aquifers dip eastward 500 feet per mile and more. At well 3, the principal aquifers are about 150 feet lower than at well 4; at well 2 they are more than 500 feet lower; at well 1 they are about 300 feet lower. Because the alluvium slopes southwestward in the vicinity of the well field, the depth to the principal aquifers increases rapidly eastward. The main aquifers, which to date have been tapped by the Lake Mead Base wells, therefore, probably lie at shallower depths westward from wells 3 and 4.", "cite_spans": [], "ref_spans": []}, {"section": "PUMPING TESTS", "text": "To obtain estimates of the coefficients 'of transmissibility and storage, wells 2 and 4 were pumped at constant rates at different times, and the effects of such pumping on the water levels in the pumped wells and the other wells in the well field were noted.", "cite_spans": [], "ref_spans": []}, {"section": "PUMPING TESTS", "text": "Beginning at 9:23 a.m. on April 18, 1955, well 4 was pumped at a nearly constant rate of 130 gpm for 30 hours. Although none of the wells had been pumped for 24 hours before the test,, the wells were recovering from the effects of earlier pumping. The rate of recovery in well 4 was considerably less than 0.1 foot per hour at the time the pumping test began. Based on the drawdown and subsequent recovery data, the coefficient of transmissibility was computed to be somewhat less than 1,500 gpd (gallons per day) per ft. Periodic measurements were made in wells 1, 2, and 3 to the nearest hundreth of a foot, and the Young and Smith well was equipped with a recording gage. Effects of the pumping could be identified only in well 3, and these effects, a marked change in the previously established pattern of recovery of water levels in well 3, were noted about 7 hours after beginning of pumping of well 4. By extrapolating the recovery curve for well 3, it is estimated that pumping well 4 for 30 hours retarded the normal rate of recovery of well 3 by more than Ifoot.", "cite_spans": [], "ref_spans": []}, {"section": "PUMPING TESTS", "text": "That interference effects were noted in well 3 indicates that some of the strata common to both wells contain confined (artesian) water, because under unconfined (water-table) conditions the effects of the pumping would have been too small to be measurable. The coefficient of storage, 3.6 X10-5, computed on the basis of interference effects in well 3, also indicates artesian conditions. However, the value obtained may be considerably in error, because the coefficient of transmissibility for aquifers tapped by well 3, computed from the intereference data, is about 20,000 gpd per ft, or about 20 times larger than a much more reliable determination of the coefficient of transmissibility made from data obtained when well 3 itself was pumped. (See p. Q10.) The coefficient of transmissibility computed from interference data will exceed the true value if either well taps aquifers that are not common to both or if, because of the duration of this particular pumping test and the distance between wells, either well taps strata containing unconfined water. One of these conditions, perhaps both, probably exists, hence, the value of the coefficient of transmissibility as determined by interference effects very likely is too high.", "cite_spans": [], "ref_spans": []}, {"section": "PUMPING TESTS", "text": "The lack of measurable interference effects in wells 1 and 2 and in the Young and Smith well indicates that these wells have little, if any, artesian hydraulic connection with well 4. The test does not eliminate the possibility that the wells are connected hydraulically with well 4 by a water-table aquifer. Under water-table conditions, pumping at 100 gpm might be continued for 30 days or more before interference effects of 0.01 foot or more between wells 2,000 feet apart would occur.", "cite_spans": [], "ref_spans": []}, {"section": "PUMPING TESTS", "text": "Well 2 was pumped at a constant rate of about 140 gpm for 20 hours, beginning at 12:08 p.m. on April 20, 1955. The computed coefficient of transmissibility was about 800 gpd per ft. Because no interference with other wells could be detected as a result of the pumping, a value for the coefficient of storage could not be obtained.", "cite_spans": [], "ref_spans": []}, {"section": "PUMPING TESTS", "text": "The hydraulic continuity under artesian conditions, if any, is evidently poorer between wells 1 and 2 than it is between wells 3 and 4. However, as noted earlier, all the wells still may be hydraulically connected under unconfined conditions. The foregoing tests show that interference effects between wells spaced 2,000 feet apart are negligible for the rates of pumping and the pumping schedules that have been used on the base in the past.", "cite_spans": [], "ref_spans": []}, {"section": "PUMPING TESTS", "text": "Well 3 was pumped for 1 hour at 195 gpm, beginning at 10:06 a.m. on April 21, 1955. The coefficient of transmissibility was computed to be about 1,000 gpd per ft.", "cite_spans": [], "ref_spans": []}, {"section": "PUMPING TESTS", "text": "The low coefficients of transmissibility of the aquifers tapped by the Lake Mead Base wells indicate that it is not possible to obtain yields of more than a few gallons per minute per foot of drawdown from these wells.", "cite_spans": [], "ref_spans": []}, {"section": "PUMPING TESTS", "text": "To estimate the amount of water moving through the area under natural conditions, pumping tests also were made on all the Nellis Air Force Base wells for which the required data could be obtained. In the Lake Mead Base well field, the coefficient of transmissibility was estimated to be 1,000 gpd per ft. In the vicinity of Nellis Air Force Base, the coefficient of transmissibility was estimated to be 5,000 gpd per ft. The general hydraulic gradient toward Lake Mead Base is about 30 feet per mile, and that toward Nellis Air Force Base is about 40 feet per mile. Thus, in the vicinity of the Lake Mead Base well field, only about 30,000 gpd moves across each mile-wide section normal to the direction of ground-water movement, and in the Nellis Air Force Base area the quantity is about 200,000 gpd. Although these estimates show only the general order of magnitude of the quantity of water that is moving through the saturated deposits beneath the two bases, they indicate that the quantity is small and that the demand for water can easily equal or exceed the amount of water naturally passing through a given area.", "cite_spans": [], "ref_spans": []}, {"section": "PUMPING TESTS", "text": "The peak demand at Lake Mead Base in 1961 exceeded 100,000 gpd. The yearly demand averaged about 85,000 gpd, and a substantial increase in demand is anticipated. The natural movement of water through that part of the well field from which ground-water withdrawals were being made, a strip about half a mile wide, was only about 10,000 gpd. To continue to meet the demands of the base indefinitely, water will have to be diverted to the well field. This diversion can be accomplished by continuing withdrawals to meet the demands of the base, provided the demands do not greatly exceed several hundred thousand gallons per day. Under this practice, water will be taken from ground water in storage and water levels will continue to decline. As the practice is continued, however, more of the water that is diverted to the well field from storage will be derived from an ever increasing volume of sedimentary deposits, probably principally from deposits of Las Vegas Valley lying west of the well field, and consequently water levels will decline at a slower rate for a given withdrawal. Although the total decline, including the general decline of water levels anticipated for Las Vegas Valley, may be substantial, it will hardly in the forseeable future reach the several hundred feet that would be required to deplete the supply to the well field to the point where the field would be incapable of meeting demands of the base.", "cite_spans": [], "ref_spans": []}, {"section": "CHEMICAL ANALYSES", "text": "The records to date indicate that, except for wells 1 and 2, the water from wells in the Lake Mead Base and Nellis Air Force Base well fields is only moderately mineralized.", "cite_spans": [], "ref_spans": []}, {"section": "CHEMICAL ANALYSES", "text": "The hardness (as CaCO3 ) of the water from well 3 is about 300 ppm, about 100 ppm higher than the hardness of the water from well 4 and from the wells supplying Nellis Air Force Base. The dissolved-solids content of water from wells 3 and 4 is about 500 ppm, or several hundreds parts per million higher than that of most of the water used at Nellis Air Force Base. The higher dissolvedsolids content in the ground water of the Lake Mead Base well field probably is due partly to the slower movement of water in the vicinity of Lake Mead Base and partly to the mineralogy of the sedimentary strata. The valley fill in the vicinity of the Lake Mead Base well field probably contains a large amount of gypsum because the hills and mountains north and east of the well field from which at least part of the fill was derived contain gypsum. Ground water moving through the valley fill dissolves some of the gypsum and becomes highly mineralized.", "cite_spans": [], "ref_spans": []}, {"section": "CHEMICAL ANALYSES", "text": "There is no evidence that withdrawals have caused a significant deterioration of the quality of the water yielded by most of the wells of Lake Mead Base and Nellis Air Force Base. Water from Nellis Air Force Base well 1 in the SE^SE^NE^ sec. 4, T. 20 S., R. 62 E., probably has been analyzed over the longest period of time. On May 5, 1941, the hardness was 220 ppm, and the dissolved-solids content was 255 ppm. On November 28, 1954, the hardness was 105 ppm, and the dissolved-solids content was 263 ppm. Other analyses between these dates likewise indicate no significant change.", "cite_spans": [], "ref_spans": []}, {"section": "CHEMICAL ANALYSES", "text": "Water from well 1 of Lake Mead Base, however, not only is highly mineralized, but the degree of mineralization changes with the amount of water pumped from the well. For example, the dissolved-solids content reportedly decreased from 1,310 to 861 ppm in a 1-week period in March 1952. A later analysis on November 30,1953, after the well had been pumped for almost 6 months, showed that the dissolvedsolids content had decreased only slightly, from 861 to 851 ppm, but that the hardness of the water had increased from 357 to 422 ppm.", "cite_spans": [], "ref_spans": []}, {"section": "CHEMICAL ANALYSES", "text": "On March 2, 1955, after well 1 had been idle for several months, a sample of water collected from it at the end of a 1-hour period of pumping at about 225 gpm had a hardness of 1,210 ppm and dissolvedsolids content of almost 1,900 ppm. Even higher concentrations were noted at the beginning of the pumping period. A sample, collected 6 minutes after pumping began, had a hardness of 1,590 ppm, and; the specific conductance indicated a dissolved-solids content of more than 2,300 ppm. Measurements of the conductivity of samples collected during the period of pumping indicated that the conductivity, and hence the dissolved-solids content, decreased only slightly during the last 30 minutes of pumping. How much more the mineralization might have been reduced by continued pumping is not known, but it seems unlikely that the dissolved-solids content could have been lowered to the point where it approached that of the water from wells 3 and 4. The constituents principally responsible for increase in the dissolved-solids content are calcium, magnesium, and sulfate.", "cite_spans": [], "ref_spans": []}, {"section": "CHEMICAL ANALYSES", "text": "The results of chemical analyses of typical samples of water obtained during this investigation are shown in the following table.", "cite_spans": [], "ref_spans": []}, {"section": "Chemical analyses of water samples from Lake Mead Base wells, Las Vegas", "text": "Valley, Clark County, Nev. In addition to the 1-hour pumping test on March 2, 1955, during which changes in temperature and chemical constituents of water from well 1 were observed, two other tests were made to obtain additional information as to the quality and quantity of the water yielded by different strata.", "cite_spans": [], "ref_spans": []}, {"section": "Chemical analyses of water samples from Lake Mead Base wells, Las Vegas", "text": "On June 30,1955, after the well had been idle for months, the conductivity of the water in the well versus depth was determined by a conductivity apparatus lowered into the well. The survey showed an increase in the conductivity of the water to a depth of about 300 feet below the top of the casing, after which little change in conductivity was noted. (See fig. 3.) A survey by means of a deep-well current meter indicated that, if there was movement from strata below a depth of 680 feet to higher strata, such movement was too slow to be detected by the current meter. The meter probably would have detected movements as small as a gallon or two per minute, because a gasket of rubber belting attached to the meter tube presumably forced virtually all the water in the casing to pass through the 3-inch-diameter tube in which the meter was housed. The sensitivity of the meter to vertical movement was lessened considerably at depths above 600 feet, because the casing diameter changed from 10 to 14 inches at 600 feet. Nevertheless, any substantial movement in the 14-inch casing probably would have been detected.", "cite_spans": [], "ref_spans": []}, {"section": "Chemical analyses of water samples from Lake Mead Base wells, Las Vegas", "text": "On July 1, 1955, from 7:30 a.m. to 9:20 a.m., water from wells 3 and 4 was introduced into well 1 at a rate of about 210 gpm. At 9:10 a.m., a conductivity survey showed a rather uniform low conductivity at all depths above 1,040 feet, and indicated that all the water in the well above that point had been displaced by the mixture of water from wells 3 and 4. At 9:22 a.m., a survey was started from the bottom of the well to the top of the water. Four other surveys were made shortly thereafter. The results of all the surveys are shown in figure 3 . From the surveys one can infer that water in strata at depths of 300, 350, 850, and 910 feet probably has a higher head than water in other strata, because the strata having higher heads more likely would be the first to redischarge the highly mineralized water into the wells after recharge operations were stopped. The additional downward movement shown from strata in the region of 350 feet to strata at least 450 feet deep indicates that aquifers containing water under less head are at or below that depth. One might also infer that strata below a depth of 920 feet contain water whose head is lower than the head immediately above a depth of 920 feet.", "cite_spans": [], "ref_spans": []}, {"section": "Chemical analyses of water samples from Lake Mead Base wells, Las Vegas", "text": "On September 9,1955, well 1, which had been idle since the surveys in July, was started and a conductivity survey was made while the well was being pumped. The bottom of the suction pipe was 220 feet below the top of the casing, or about 90 feet below the nonpumping level. The well was pumped at about 80 gpm from 9:57 a.m. to 12:45 p.m., then at about 150 gpm to 12:53 p.m., at which time the water level had lowered to the bottom of the suction pipe, and then at about 110 gpm until the completion of the survey at 5 p.m. At 10:15 a.m., the conductivity of the water being pumped was 3,200 micromhos at 25\u00b0 C., the temperature of the water was 72\u00b0 F. At 10:42 a.m., these characteristics were 3,080 and 73\u00b0, respectively; at 12:40 p.m., they were 2,990 and 77\u00b0; at 2 p.m., 2,970 and 77.5\u00b0; and at 3:17 p.m., 2,850 and 78\u00b0. The readings of the milliammeter at various depths below the top of the casing are shown in figure 3 . The data obtained on September 9,1955, indicate that the dissolvedsolids content above 200 feet was only about half the dissolved-solids content below that depth. The data indicate also that strata at about 920 feet are contributing water that is more highly mineralized than that from the lower strata. The concentration of dissolved solids does not appear to decrease significantly at any point between the depths of 500 and 920 feet, the region in which the highest concentrations occur; hence, it seems unlikely that water of satisfactory chemical quality can be obtained at reasonable rates from this section.", "cite_spans": [], "ref_spans": []}, {"section": "Chemical analyses of water samples from Lake Mead Base wells, Las Vegas", "text": "Although the water in the casing below 920 feet is of somewhat better chemical quality, the dissolved-solids content is not sufficiently less to offer any encouragement for obtaining a satisfactory supply from that section of the well either.", "cite_spans": [], "ref_spans": []}, {"section": "Chemical analyses of water samples from Lake Mead Base wells, Las Vegas", "text": "On the basis of milliampere readings, the dissolved-solids content of the best quality of water in the well is about half that of the water pumped from depths in excess of 250 feet. However, the fact that a sample of the water that was being used on the base at the time of the survey showed a reading of only about 4 milliamperes, or slightly more than half the reading obtained from the best quality of water in well 1, indicates that even this lower concentration may still be high.", "cite_spans": [], "ref_spans": []}, {"section": "Chemical analyses of water samples from Lake Mead Base wells, Las Vegas", "text": "The relative volumes of water from aquifers above 220 feet (the depth of the bottom of the suction pipe) and from aquifers below this depth, based on a milliampere reading of 7 for the water above 220 feet, 14 for the water below 220 feet, and 11 for the water discharged by the pump, are two-sevenths for the water above 220 feet and five-sevenths for the water below 220 feet.", "cite_spans": [], "ref_spans": []}, {"section": "Chemical analyses of water samples from Lake Mead Base wells, Las Vegas", "text": "As a result of the exploratory work done on well 1, it cannot be stated positively that water of satisfactory chemical quality cannot be developed at the site, though it almost certainly would be impractical to do so.", "cite_spans": [], "ref_spans": []}, {"section": "Chemical analyses of water samples from Lake Mead Base wells, Las Vegas", "text": "Because the chemical quality of the water deteriorates with nonuse of the well, it is inferred that one or more strata contain highly mineralized water at heads higher than the heads in strata containing water having a lower dissolved-solids content. When the well is not used, the highly mineralized water flows into the well and out again into the strata containing the water of lower mineralization under lesser head and thus contaminates these strata. When the well is pumped, the strata that received the highly mineralized water will, of course, yield the highly mineralized water back to the well before yielding the water of lower mineralization.", "cite_spans": [], "ref_spans": []}, {"section": "Chemical analyses of water samples from Lake Mead Base wells, Las Vegas", "text": "The length of pumping time and rate of pumping that will be necessary to cause aquifers to yield the true quality of the water they contain are dependent on the preceding length of nonpumping time and the rate of leakage under nonpumping conditions. The opportune time to determine the true chemical quality of the water in the various strata in a well in which leakage from one strata to another is taking place is immediately upon its completion.", "cite_spans": [], "ref_spans": []}, {"section": "Chemical analyses of water samples from Lake Mead Base wells, Las Vegas", "text": "In well 1, months of continuous pumping to waste at a rate of 100 gpm or so may be required to flush the aquifers that have been contaminated as a result of nonuse of the well. Whether this would be a justifiable procedure is questionable, because of a lack of evidence that strata penetrated by the well contain a sufficient quantity of water of satisfactory chemical quality or that they contain any satisfactory water at all.", "cite_spans": [], "ref_spans": []}, {"section": "SUMMARY", "text": "The findings of the study may be summarized as follows: 1. The principal source of the water in the Lake Mead Base well field is precipitation in the Las Vegas Valley drainage basin northwest of the well field. 2. The ground water is moving southeastward. 3. The amount of water passing through the area under natural conditions is small. 4. The principal aquifers in the well field probably dip eastward 500 feet per mile or more. 5. There is no conclusive evidence that withdrawals to date have caused a marked lowering of water levels. 6. By lowering the water levels, sufficient additional water can be diverted to the area from the main supply of Las Vegas Valley or obtained from storage to take care of the foreseeable needs of the base.", "cite_spans": [], "ref_spans": []}, {"section": "SUMMARY", "text": "7. Wells having specific capacities in excess of a few gallons per minute per foot of drawdown are not likely to be developed in the immediate area of the base. 8. Interference effects between existing wells are too small to be measured or are insignificant under the present pumping schedules. 9. There is a good probability that all the wells are hydraulically connected; therefore, continued pumping from wells 3 and 4 at sufficiently high rates eventually may cause the more highly mineralized water in wells 1 and 2 to enter wells 3 and 4. 10. As yet, there has been no significant deterioration in the chemical quality of the water from wells 3 and 4. 11. The mineralization of the water from wells 1 and 2 increases during periods of nonuse. 12. Calcium, magnesium, and sulfate are the principal constituents of the highly mineralized water. 13. It does not appear practical to attempt to obtain a satisfactory supply of water from well 1. 14. Additional data relative to pumpage, water levels, and changes in chemical quality of the water are needed for more accurate future evaluation of the geologic and hydrologic factors that control the occurrence, movement, and chemical quality of the ground water.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Intel-mountain Association of Petroleum Geologists, 1952, Guidebook to the geology of Utah", "authors": [], "year": 1952, "venue": "3d Ann. Field Conf", "link": null}, "BIBREF1": {"title": "Geology and water resources of Las Vegas", "authors": [{"first": "G", "middle": ["B"], "last": "Maxey", "suffix": ""}, {"first": "Jameson", "middle": [], "last": "", "suffix": ""}, {"first": "C", "middle": ["H"], "last": "", "suffix": ""}], "year": 1948, "venue": "Nevada Water Resources Bull", "link": null}, "BIBREF2": {"title": "Outline of ground-water hydrology, with definitions: U.S. Geol. Survey Water-Supply Paper 494", "authors": [{"first": "O", "middle": ["E"], "last": "Meinzer", "suffix": ""}], "year": 1923, "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Sketch map of Las Vegas Valley, dark County, Ner.", "type": "figure"}, "FIGREF1": {"text": "Analyses by U.S. Geol. Survey. Chemical constituents in parts per million] Well No-.... ............................................... Pumping period ___________ __________ hours.- Silica(SiOj)..... ......_ .__ .__._________________.___._.__. Iron (Fe) [total]....... . . ..................... ........... Calcium (Ca). . ________________________________________ _ Magnesium (Mg). ___ ______________ ...... .. . Potassium (K)...... ....... __ .............. _ ......... ...... Bicarbonate (HCOs) __ . ____ . .. .. ___ . _ . _ Carbonate (COs). _____ -__ . ___ . _____ ..... .... Sulfate (SO4) -__ ... Chloride (Cl).._ ............. ........... _ ............. . Fluoride(F). ........................................ .......... Nitrate (NOs)-.~ . . . - Dissolved solids: Total ___________________ ___ ____ ppm._ Residue on evaporation at 180\u00b0 C ___ . ________ do...- Hardness: AsCaCOs ................. ___ __-__ _ do.... Specific conductance. ________ __ micrombos at 25\u00b0 C pH................. .......... ............... ..................", "type": "figure"}}}
{"paper_id": "128197997", "_pdf_hash": "d4b852625a27cc035fd11e4b89ea2d328a7feafc", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Monitoring rock bursts by outworking of rock deposits with block structure// Geodynamics and stress state of the", "authors": [{"first": "P", "middle": ["V"], "last": "Yegorov", "suffix": ""}, {"first": "A", "middle": ["V"], "last": "Redkin", "suffix": ""}], "year": 2001, "venue": "", "link": null}, "BIBREF2": {"title": "Geophysical monitoring of state of the rock massive with use of the idea of physical mesomechanics // Physika Zemli", "authors": [{"first": "O", "middle": ["A"], "last": "Hachay", "suffix": ""}], "year": 2007, "venue": "", "link": null}, "BIBREF3": {"title": "Sinergetics of condensed medium", "authors": [{"first": "A", "middle": ["I"], "last": "Olemskoy", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "Kaznelson", "suffix": ""}], "year": 2003, "venue": "", "link": null}, "BIBREF4": {"title": "Approach to a physics of open systems", "authors": [{"first": "Klimontovitch", "middle": ["L"], "last": "Yu", "suffix": ""}], "year": 2002, "venue": "", "link": null}, "BIBREF5": {"title": "Modern problems of nonlinear geomechanics.// Geodynamics and stress state of the Earth Novosibirsk SD RAS", "authors": [{"first": "M", "middle": ["V"], "last": "Kurlenja", "suffix": ""}, {"first": "V", "middle": ["N"], "last": "Oparin", "suffix": ""}], "year": 1999, "venue": "", "link": null}, "BIBREF6": {"title": "New method of revealing disintegration zones in the massif of different matter content // Mining information analytic bulletin", "authors": [{"first": "O", "middle": ["A"], "last": "Hachay", "suffix": ""}, {"first": "E", "middle": ["N"], "last": "Novgorodova", "suffix": ""}, {"first": "O", "middle": [], "last": "Khachay", "suffix": ""}, {"first": "", "middle": [], "last": "Yu", "suffix": ""}], "year": 2003, "venue": "", "link": null}, "BIBREF7": {"title": "To the problem of structure an state research of geological heterogenic medium in the frame of discrete and hierarchic model //Geomechanics in mining", "authors": [{"first": "O", "middle": ["A"], "last": "Hachay", "suffix": ""}], "year": 2003, "venue": "", "link": null}, "BIBREF8": {"title": "Three-dimensional electromagnetic monitoring of rock massive state. // Phyzika Zemli", "authors": [{"first": "O", "middle": ["A"], "last": "Hachay", "suffix": ""}], "year": 2001, "venue": "", "link": null}, "BIBREF9": {"title": "A. the phenomenon of self organization in the rock massive by man-made influence. // Physical mesomechanics 7, special issue", "authors": [{"first": "O", "middle": [], "last": "Hachay", "suffix": ""}], "year": 2004, "venue": "", "link": null}, "BIBREF10": {"title": "The problem of the transient process of redistribution of stress and phase rock states between powerful man-caused influences. // Mining information analytic bulletin", "authors": [{"first": "O", "middle": ["A"], "last": "Hachay", "suffix": ""}], "year": 2006, "venue": "", "link": null}, "BIBREF11": {"title": "Research of non stability of the rock massive with use of the aktive electromagnetic monitoring. // Physika Zemli", "authors": [{"first": "O", "middle": ["A"], "last": "Hachay", "suffix": ""}], "year": 2007, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "128198862", "_pdf_hash": "3e417ff9eb19bdfb70f577c3306e6017a7059d92", "abstract": [], "body_text": [], "bib_entries": {"BIBREF2": {"title": "Manila: Economics and Development Resource Center", "authors": [{"first": "Asian", "middle": [], "last": "Development Bank", "suffix": ""}], "year": 1996, "venue": "", "link": null}, "BIBREF3": {"title": "China and International financial crisis", "authors": [{"first": "P", "middle": [], "last": "Bottelier", "suffix": ""}], "year": 2009, "venue": "Economic meltdown and geopolitical stability", "link": null}, "BIBREF4": {"title": "World on fire: how exporting free market democracy breeds ethnic hatred and global instability", "authors": [{"first": "Cankao", "middle": [], "last": "Xiaoxi", "suffix": ""}], "year": 1996, "venue": "", "link": "49380522"}, "BIBREF5": {"title": "A history of China", "authors": [{"first": "Y", "middle": [], "last": "Dai", "suffix": ""}], "year": 2000, "venue": "", "link": null}, "BIBREF6": {"title": "Some issues relating to the greater China economic cooperation [da zhonguo jingji xiezuo de jige wenti", "authors": [{"first": "S", "middle": [], "last": "Dong", "suffix": ""}, {"first": "C", "middle": [], "last": "Xu", "suffix": ""}], "year": 1992, "venue": "The CrossTaiwan strait: sustainable development of the issues of resources and environment", "link": null}, "BIBREF7": {"title": "Economic analysis of China economic area", "authors": [{"first": "W", "middle": [], "last": "Fei", "suffix": ""}], "year": 1993, "venue": "", "link": null}, "BIBREF9": {"title": "The trends of Asian-Pacific regional cooperation and the formation and development of the Chinese economic circle. 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{"paper_id": "119420086", "_pdf_hash": "3129711ca06c15536efd6941e1c3d4749253caa8", "abstract": [{"section": "Abstract", "text": "We have studied the circular photogalvanic effect (CPGE) in Cu/Bi bilayers. When a circularly polarized light in the visible range is irradiated to the bilayer from an oblique incidence, we find a photocurrent that depends on the helicity of light. Such photocurrent appears in a direction perpendicular to the light plane of incidence but is absent in the parallel configuration. The helicity dependent photocurrent is significantly reduced for a Bi single layer film and the effect is nearly absent for a Cu single layer film. Conventional interpretation of the CPGE suggests the existence of spin-momentum locked band(s) of a Rashba type in the Cu/Bi bilayer. In contrast to previous reports on the CPGE studied in other systems, however, the light energy used here to excite the carriers is much larger than the band gap of Bi. Moreover, the CPGE of the Cu/Bi bilayer is larger when the energy of the light is larger: the helicity dependent photocurrent excited with a blue light is nearly two times larger than that of a red light. We therefore consider the CPGE of the Cu/Bi bilayer may have a different origin compared to conventional systems.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Spin-momentum locked bands are one of the key signatures of the emergence of topologically protected states in topological insulators and Weyl semimetals [1] . Such bands also appear in heterostructures with broken structure inversion symmetry and/or large spin orbit coupling (SOC) [2] [3] [4] . The spin texture of the spin-momentum locked bands in the reciprocal space depends on the symmetry of the system. For example, the electron's spin and momentum directions are orthogonal to each other for systems that can be described by a Rashba Hamiltonian [5, 6] .", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "The presence of spin-momentum locked bands within the bulk or at surfaces/interfaces allows generation of non-equilibrium spin accumulation when current is passed to the system [7, 8] . Significant effort has been placed to generate spin accumulation in semiconductor heterostructures [9, 10] . Recent studies have extended such effort into metallic heterostructures [2, 6, 11, 12] , where the SOC can be larger than that of typical semiconductor heterostructure constituents. Current-induced spin accumulation at interfaces has been reported in metallic heterostructures which manifests itself in magnetization switching and domain wall motion [13, 14] . It is thus of high importance to identify the presence of spinmomentum locked bands in thin film heterostructures.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Angle resolved photoemission spectroscopy (ARPES) is a powerful tool to study band structures and has been used to reveal the surface electronic states of, for example, topological insulators and Weyl semimetals [1] . However, its use is typically limited to clean surfaces and involves difficulty in studying interface states of films which are not particularly clean (e.g. films deposited by sputtering). To study spin-momentum locking of such interface states, it has been shown recently that combination of spin pumping and the inverse Rashba-Edelstein effect (IREE) allows its direct probing [2] [3] [4] . Spin current generated from a ferromagnetic layer via spin pumping diffuses into an interface with strong spin orbit coupling where IREE converts spin current into electric current.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "The Rashba parameter of interface states has been estimated using this approach and is expanding its use to different systems.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Another approach to studying the electronic structure is the circular photogalvanic effect (CPGE) [15, 16] . When a circularly polarized light is irradiated to a sample from an oblique incidence, carriers with fixed spin orientation are excited due to the selection rule (under the presence of spin orbit coupling) and conservation of spin angular momentum. The excited carriers diffuse along a direction perpendicular to the spin orientation when a spin-momentum locked band of Rashba type is involved in the excitation process. Under such circumstance, a spin polarized photocurrent flows orthogonal to the light plane of incidence. Studies of such helicity dependent anisotropic photocurrent allows direct probing of the spin-momentum locked bands within the sample. The CPGE has been observed in semiconductor heterostructures [17] [18] [19] and more recently in topological insulators [20] [21] [22] [23] Weyl semimetals [24] and the two dimensional calchogenides [25, 26] . In contrast to the spin voltaic effect that has been observed in semiconductor heterostructures due to optically induced spin accumulation [27] [28] [29] [30] , the CPGE does not require any magnetic field or ferromagnetic layer. In addition, the photovoltage generated from the spin voltaic effect appears along the film (interface) normal whereas the photocurrent associated with the CPGE is often observed along the film plane.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Here we use the CPGE to study the presence of spinmomentum locked bands in (semi-)metallic heterostructures. In Cu/Bi bilayers, we measure the photocurrent when a polarized light in the visible range (405 nm and 635 nm) is irradiated to the sample from an oblique angle. Light helicity dependent photocurrent is found along the direction orthogonal to the light plane of incidence but is negligibly small in the direction parallel to it. The helicity dependent anisotropic photocurrent is significantly reduced in a Bi single layer film and is nearly zero for", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "We have studied the circular photogalvanic effect (CPGE) in Cu/Bi bilayers. When a circularly polarized light in the visible range is irradiated to the bilayer from an oblique incidence, we find a photocurrent that depends on the helicity of light. Such photocurrent appears in a direction perpendicular to the light plane of incidence but is absent in the parallel configuration. The helicity dependent photocurrent is significantly reduced for a Bi single layer film and the effect is nearly absent for a Cu single layer film. Conventional interpretation of the CPGE suggests the existence of spin-momentum locked band(s) of a Rashba type in the Cu/Bi bilayer. In contrast to previous reports on the CPGE studied in other systems, however, the light energy used here to excite the carriers is much larger than the band gap of Bi. Moreover, the CPGE of the Cu/Bi bilayer is larger when the energy of the light is larger: the helicity dependent photocurrent excited with a blue light is nearly two times larger than that of a red light. We therefore consider the CPGE of the Cu/Bi bilayer may have a different origin compared to conventional systems.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Spin-momentum locked bands are one of the key signatures of the emergence of topologically protected states in topological insulators and Weyl semimetals [1] . Such bands also appear in heterostructures with broken structure inversion symmetry and/or large spin orbit coupling (SOC) [2] [3] [4] . The spin texture of the spin-momentum locked bands in the reciprocal space depends on the symmetry of the system. For example, the electron's spin and momentum directions are orthogonal to each other for systems that can be described by a Rashba Hamiltonian [5, 6] .", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "The presence of spin-momentum locked bands within the bulk or at surfaces/interfaces allows generation of non-equilibrium spin accumulation when current is passed to the system [7, 8] . Significant effort has been placed to generate spin accumulation in semiconductor heterostructures [9, 10] . Recent studies have extended such effort into metallic heterostructures [2, 6, 11, 12] , where the SOC can be larger than that of typical semiconductor heterostructure constituents. Current-induced spin accumulation at interfaces has been reported in metallic heterostructures which manifests itself in magnetization switching and domain wall motion [13, 14] . It is thus of high importance to identify the presence of spinmomentum locked bands in thin film heterostructures.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Angle resolved photoemission spectroscopy (ARPES) is a powerful tool to study band structures and has been used to reveal the surface electronic states of, for example, topological insulators and Weyl semimetals [1] . However, its use is typically limited to clean surfaces and involves difficulty in studying interface states of films which are not particularly clean (e.g. films deposited by sputtering). To study spin-momentum locking of such interface states, it has been shown recently that combination of spin pumping and the inverse Rashba-Edelstein effect (IREE) allows its direct probing [2] [3] [4] . Spin current generated from a ferromagnetic layer via spin pumping diffuses into an interface with strong spin orbit coupling where IREE converts spin current into electric current.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "The Rashba parameter of interface states has been estimated using this approach and is expanding its use to different systems.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Another approach to studying the electronic structure is the circular photogalvanic effect (CPGE) [15, 16] . When a circularly polarized light is irradiated to a sample from an oblique incidence, carriers with fixed spin orientation are excited due to the selection rule (under the presence of spin orbit coupling) and conservation of spin angular momentum. The excited carriers diffuse along a direction perpendicular to the spin orientation when a spin-momentum locked band of Rashba type is involved in the excitation process. Under such circumstance, a spin polarized photocurrent flows orthogonal to the light plane of incidence. Studies of such helicity dependent anisotropic photocurrent allows direct probing of the spin-momentum locked bands within the sample. The CPGE has been observed in semiconductor heterostructures [17] [18] [19] and more recently in topological insulators [20] [21] [22] [23] , Weyl semimetals [24] and the two dimensional calchogenides [25, 26] . In contrast to the spin voltaic effect that has been observed in semiconductor heterostructures due to optically induced spin accumulation [27] [28] [29] [30] , the CPGE does not require any magnetic field or ferromagnetic layer. In addition, the photovoltage generated from the spin voltaic effect appears along the film (interface) normal whereas the photocurrent associated with the CPGE is often observed along the film plane.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Here we use the CPGE to study the presence of spinmomentum locked bands in (semi-)metallic heterostructures. In Cu/Bi bilayers, we measure the photocurrent when a polarized light in the visible range (405 nm and 635 nm) is irradiated to the sample from an oblique angle. Light helicity dependent photocurrent is found along the direction orthogonal to the light plane of incidence but is negligibly small in the direction parallel to it. The helicity dependent anisotropic photocurrent is significantly reduced in a Bi single layer film and is nearly zero for The yellow caterpillar-like structure illustrates the area where the film is deposited through a shadow mask: the surrounding grey area represents the substrate. Light is irradiated from an oblique angle \u03b8 with respect to the film plane. \u03c6 is defined as the angle between the light plane of incidence and the long axis of the wire.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "a Cu single layer film. Although the CPGE may originate from spin-momentum locked bands formed at local Cu/Bi interfaces, we infer it may include contributions from the bulk of the bilayer as the light energy is much larger than the band gap of Bi.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Films are deposited via RF magnetron sputtering on Si substrates coated with 600 nm thick thermal oxide (SiO 2 ). We show representative results from three film structures, A: sub./0.5 Ta/2 Cu/10 Bi/2 MgO/1 Ta, B: sub./0.5 Ta/2 Cu/2 MgO/1 Ta and C: sub./10 Bi/2 MgO/1 Ta (thickness in nm). The 2 MgO/1 Ta is used as a capping layer to prevent oxidation and possible subsequent degradation of the top layer. The half a nanometer thick Ta layer underneath the 2 nm Cu layer (samples A and B) is used as a seed layer to promote uniform growth of the Cu layer. The resistivities of the Bi and Cu layers are measured using four-point probe technique and are found to be \u223c 820 \u00b5\u2126\u00b7cm and \u223c 110 \u00b5\u2126\u00b7cm, respectively. Films are deposited through a metallic shadow mask to create patterned structures. A schematic illustration of the patterned structure is shown in Fig. 1 . An elongated wire with contact pads attached to the sides and ends is used to study the spatial profile of the photocurrent/photovoltage. The width of the wire is \u223c 0.4 mm. The side contact pads are located \u223c 1 mm apart and are labeled with numbers (0 to 7) as depicted in Fig. 1 .", "cite_spans": [], "ref_spans": [{"start": 855, "end": 861, "text": "Fig. 1", "ref_id": "FIGREF0"}, {"start": 1137, "end": 1143, "text": "Fig. 1", "ref_id": "FIGREF0"}]}, {"section": "", "text": "A continuous wave (CW) semiconductor laser (wavelength: 405 nm (635 nm), power: 4.0 mW (4.5 mW)) is used to generate light. The laser light is chopped at a frequency f \u223c 311 Hz: the frequency is chosen to avoid noise from the power line. The laser spot at the sample is a circle with a diameter of \u223c 0.5 mm. The light is irradiated at the center of the sample, between side contacts 3 and 4, from an oblique angle \u03b8 (see Fig. 1 for the definition of angles \u03b8 and \u03c6). We use \u03b8 \u223c 45", "cite_spans": [], "ref_spans": [{"start": 421, "end": 427, "text": "Fig. 1", "ref_id": "FIGREF0"}]}, {"section": "", "text": "\u2022 which gives a relatively large CPGE [18, 22, 26] . The azimuthal angle \u03c6 is set to either 0", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "\u2022 or 90", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "\u2022 to study the relationship between the light plane of incidence and the direction of the photocurrent/photovoltage. The light plane of incidence is defined as the plane that contains both the film normal and the light propagation vector.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "We use an open circuit condition to measure the photovoltage V and estimate the corresponding photocurrent by dividing V with the resistance of wire between contacts 3 and 4. The resistance is determined using the four-point probe technique. The photovoltage V between side contacts i (i = 0...7) and 0 (contact 0 is always set as the reference) is measured using a lock-in amplifier with its frequency locked to the laser light chopping frequency f . The reflected light from the sample is measured using a photodetector and its signal is measured together with the photovoltage to determine the phase of V with respect to the light irradiation.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "A quarter wave plate is used to control the light helicity. We rotate the quarter wave plate within the plane normal to the light propagation. The angle of the rotation is defined as \u03b1 (see Fig. 1 ). Here the light is linearly (s-) polarized when \u03b1 = 0", "cite_spans": [], "ref_spans": [{"start": 190, "end": 196, "text": "Fig. 1", "ref_id": "FIGREF0"}]}, {"section": "", "text": "\u2022 , 90", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "\u2022 , 180", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "\u2022 , 270", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "\u2022 . The light is circularly polarized when \u03b1 = 45", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "\u2022 , 225", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "\u2022 (left handed) and 135", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "\u2022 , 315", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "\u2022 (right handed). At a given \u03b8 and \u03c6 (\u03b8 is always fixed to 45", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "\u2022 ), the quarter wave plate is rotated to measure the \u03b1 dependence of V . All measurements are performed at room temperature under ambient condition.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "The open circles in Fig. 2 show the light helicity dependence of photovoltage V , normalized by the laser power P , between side contacts 7 and 0 of the Cu/Bi bilayer (sample A). The light plane of incidence is orthogonal (\u03c6 \u223c 90", "cite_spans": [], "ref_spans": [{"start": 20, "end": 26, "text": "Fig. 2", "ref_id": "FIGREF1"}]}, {"section": "", "text": "\u2022 ) and parallel (\u03c6 \u223c 0 \u2022 ) to the wire's long axis in Figs. 2(a) and 2(b) , respectively. For \u03c6 \u223c 90", "cite_spans": [], "ref_spans": [{"start": 55, "end": 74, "text": "Figs. 2(a) and 2(b)", "ref_id": "FIGREF1"}]}, {"section": "", "text": "\u2022 , we find a large difference in V /P when left and right handed circularly polarized light is irradiated. In contrast, V /P for \u03c6 \u223c 0", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "\u2022 shows little dependence on the light helicity and instead a difference in V /P is observed when circularly polarized light and linearly polarized light are irradiated.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "To characterize the normalized photovoltage, we fit the experimental results with the following phenomenological form:", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "where C represents the difference in the photovoltage when left and right handed polarized light are irradiated, L 1 and L 2 are the change in the photovoltage between irradiation of circularly polarized light and linearly polarized light (with a phase difference of 22.5", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "\u2022 between the two). In theory, C represents the strength of the CPGE and L 1 and L 2 correspond to the linear photogalvanic and the photon-drag effects, respectively [22, 25, 31] . D is a constant independent of \u03b1. \u03b1 0 is an offset angle associated with the quarter wave plate and the experimental setup: here \u03b1 0 \u223c \u22127", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "\u2022 and \u223c 3 Fig. 2(a) ): C is \u223c 49 \u00b5V/W which corresponds to a photocurrent of \u223c 80 nA/W. This is in similar magnitude with what has been observed in other systems [22, 26] . In contrast, C is nearly zero when \u03c6 \u223c 0", "cite_spans": [], "ref_spans": [{"start": 10, "end": 19, "text": "Fig. 2(a)", "ref_id": "FIGREF1"}]}, {"section": "", "text": "\u2022 and we find the L 2 term dominates the signal with L 2 \u223c 9 \u00b5V/W.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "The spatial profile of each component of the normalized photovoltage is shown in Fig. 3 . The position of one of the voltage probes is varied from side contacts 0 to 7: the reference voltage probe is fixed to contact 0. Results from light wavelength of 405 nm (blue circles) and 635 nm (red squares) are shown together. We find nearly zero C for \u03c6 \u223c 0", "cite_spans": [], "ref_spans": [{"start": 81, "end": 87, "text": "Fig. 3", "ref_id": "FIGREF2"}]}, {"section": "", "text": "\u2022 , consistent with the results of Fig. 2 ", "cite_spans": [], "ref_spans": [{"start": 35, "end": 41, "text": "Fig. 2", "ref_id": "FIGREF1"}]}, {"section": "(b) . For \u03c6 \u223c 90", "text": "\u2022 , C abruptly changes across the laser light spot, i.e. between contacts 3 and 4. C is constant on both sides of the light spot. These results suggest that the CPGE occurs within the area of side contacts 3 and 4 (it is likely that the effect takes place within the laser spot). As the excited carriers due to the CPGE flow within this area, we divide the measured photovoltage V by the resistance of the wire between contacts 3 and 4 to estimate the corresponding photocurrent I from V (note that V is constant across the laser spot). I will thus provide the lower limit of the actual photocurrent generated via the CPGE.", "cite_spans": [], "ref_spans": []}, {"section": "(b) . For \u03c6 \u223c 90", "text": "We find C is larger for the blue light (wavelength: 405 nm) than that for the red light (wavelength: 635 nm). Note that energy of the blue and red light is much larger than the band gap of Bi [32, 33] : it is thus not obvious whether the number of excitation that contributes to the generation of the CPGE scales with the light energy in the visible range. We find also a step like features across the laser spot in L 1 with \u03c6 \u223c 90", "cite_spans": [], "ref_spans": []}, {"section": "(b) . For \u03c6 \u223c 90", "text": "\u2022 and L 2 with \u03c6 \u223c 0", "cite_spans": [], "ref_spans": []}, {"section": "(b) . For \u03c6 \u223c 90", "text": "\u2022 . In addition, L 1 and L 2 show a broad background signal with an extremum near the laser spot. The tail of the background signal extends to the edge of the wire, and the profile looks similar for both configurations \u03c6 \u223c 90", "cite_spans": [], "ref_spans": []}, {"section": "(b) . For \u03c6 \u223c 90", "text": "\u2022 and 0", "cite_spans": [], "ref_spans": []}, {"section": "(b) . For \u03c6 \u223c 90", "text": "\u2022 . Such large length scale (millimeter long diffusion length) is consistent with laser-induced heating and thermal diffusion.", "cite_spans": [], "ref_spans": []}, {"section": "(b) . For \u03c6 \u223c 90", "text": "To identify the origin of the CPGE in Cu/Bi bilayer, we have studied the photovoltage of the Cu (sample B) and Bi (sample C) single layers. The \u03b1 dependence of V /P for the two samples is shown in Fig. 4 . Side contacts 7 and 0 are used to probe the photovoltage. Blue light (wavelength: 405 nm) is irradiated and the angle \u03c6 is set to 90", "cite_spans": [], "ref_spans": [{"start": 197, "end": 203, "text": "Fig. 4", "ref_id": "FIGREF4"}]}, {"section": "(b) . For \u03c6 \u223c 90", "text": "\u2022 . The experimental results in Fig. 4 are fitted using Eq. (1): the fitting results are displayed using the dashed and solid lines. A summary of the fitting parameters for all samples are shown in Table I . For the Cu single layer (Fig. 4(a) ), we find V /P that is dominated by the L 2 term: L 1 and C are nearly zero. Table I shows that the L 2 term is similar in magnitude for all samples. This is consistent with the observation that the L 2 term originates from an effect that occurs within the bulk of the film [25] . (Note that the degree of absorption is different when the irradiated light is linearly polarized and circularly polarized. Such difference likely contributes to the generation of L 2 .) The CPGE of the Bi single layer film is non-negligible: we find C \u223c 7\u00b5V/W (the corresponding photocurrent is \u223c 5 nA/W). Although Bi itself is known to possess spinmomentum locked bands in its surface state [34, 35] , the observed C is nearly an order of magnitude smaller than that found in the Cu/Bi bilayer. These results support the conventional interpretation that the CPGE of the Cu/Bi bilayer (sample A) originates, if not entirely, from spin-momentum locked bands of Rashba type at the Cu/Bi interface.", "cite_spans": [], "ref_spans": [{"start": 32, "end": 38, "text": "Fig. 4", "ref_id": "FIGREF4"}, {"start": 232, "end": 242, "text": "(Fig. 4(a)", "ref_id": "FIGREF4"}]}, {"section": "(b) . For \u03c6 \u223c 90", "text": "Atomic force microscopy (AFM) imaging and X-ray diffraction (XRD) are used to characterize the film structure (see supplementary material). The AFM images show the Cu/Bi bilayer (sample A) and the Bi single layer film (sample C) grow in three dimensional form [36] with typical grain size of \u223c 100 nm and \u223c50 nm, respectively. From the XRD spectrum, we find the grains of the bilayer are textured but oriented in random directions. As we find diffraction peaks from the plane perpendicular to the c-axis of the hexagonal phase of Bi, which is known to give relatively large Rashba coupling at surfaces or interfaces between Bi(001) and various materials [2, 34, 37] , the CPGE of the bilayer may originate from local Cu/Bi interfaces with spin-momentum locked bands of Rashba type. (It is not clear how the other planes that exist in the bilayer contribute to the CPGE.)", "cite_spans": [], "ref_spans": []}, {"section": "(b) . For \u03c6 \u223c 90", "text": "Previous studies on the CPGE show that the helicity dependent photocurrent is the largest when the light energy is close to the bandgap of the system [16] . In contrast, here we find the CPGE can be induced by light with its energy being much larger than the band gap of Bi. Moreover, the helicity dependent photocurrent is larger for larger light energy. It is therefore possible that the origin of the helicity dependent anisotropic photocurrent is different from that of conventional systems, e.g. semiconductor heterostructures. We infer the CPGE in Cu/Bi bilayer may originate from spin dependent scattering of the photo-excited carriers via the strong spin orbit coupling of Bi. The existence of Cu atoms in Bi, which may occur by thermal diffusion, may enhance the spin dependent scattering as Bi doped Cu induces giant spin Hall effect [38] .", "cite_spans": [], "ref_spans": []}, {"section": "(b) . For \u03c6 \u223c 90", "text": "In summary, we have studied the circular photogalvanic effect (CPGE) in Cu/Bi bilayers excited by visible light. We find helicity dependent photocurrent that appears only along the direction perpendicular to the light plane of incidence. These results indicate that the spin selective photo-excited carriers in the Cu/Bi bilayer undergo processes that break the symmetry within the film plane and generate the anisotropic photocurrent. The anisotropy of the helicity dependent photocurrent agrees with the existence of spin-momentum locked bands of Rashba type. Reference films consisting of single layer of Cu or Bi show reduced signal of the CPGE, suggesting that the spin-momentum locked bands of Rashba type emerge at the Cu/Bi interface. In contrast to previous studies, however, the CPGE is observed with light excitation energy that is orders of magnitude larger than the characteristic energy of the system, i.e. here the bandgap of Bi. Furthermore, the helicity dependent anisotropic photocurrent is larger for excitation light with larger energy. Although the CPGE of the bilayer may as well originate from spin-momentum locked bands formed at local Cu/Bi interfaces, we infer that it includes contribution from other effects. To reveal the exact mechanism of the excitation and relaxation processes, further experiments, including studies on the effect of layer thickness, film stacking and magnetic field on the CPGE, are required. The image and the line profile show that grains with lateral diameter of the order \u223c 100 nm are formed for the bilayer whereas smaller grains (diameter of \u223c50 nm) are found for the Bi single layer film. As Bi is known to grow in three dimensional form [36] , we consider the grains consist of Bi. The X-ray diffraction (XRD) spectrum of the bilayer and the Bi single layer are shown in Figs. 5(e) and 5(f), respectively. The diffraction peaks are indexed using the hexagonal phase of Bi. The peaks found in the bilayer [Figs. 5(e)] correspond to those often found in powder samples, suggesting that the grains are textured but oriented in random directions. Note that the (003) and (006) peaks correspond to diffraction from the plane perpendicular to the c-axis. This plane is known to give relatively large Rashba coupling at surfaces or interfaces between Bi(001) and various materials [34, 37] . The XRD spectrum of the Bi single layer film [Figs. 5(f)] shows peaks from the c-plane, i.e. the (003) and (006) peaks, and the (012) plane. The other peaks found in the bilayer are nearly absent.", "cite_spans": [], "ref_spans": []}, {"section": "(b) . For \u03c6 \u223c 90", "text": "It is thus possible that local Cu/Bi(001) interfaces forming spin-momentum locked bands of Rashba type give rise to the helicity dependent anisotropic photocurrent. With regard to the structural difference of the bilayer and the Bi single layer films, the diffraction peak from the (012) plane is significantly larger for the former. In addition, diffraction from (104), (015) and (107) planes are only present for the bilayer. The Bi surface states associated with these planes may possibly contribute to the CPGE of the bilayer.", "cite_spans": [], "ref_spans": []}], "bib_entries": {}, "ref_entries": {"FIGREF0": {"text": "Figure 1. Schematic illustration of the experimental setup. The yellow caterpillar-like structure illustrates the area where the film is deposited through a shadow mask: the surrounding grey area represents the substrate. Light is irradiated from an oblique angle \u03b8 with respect to the film plane. \u03c6 is defined as the angle between the light plane of incidence and the long axis of the wire.", "type": "figure"}, "FIGREF1": {"text": "Figure 2. Normalized photovoltage (V /P ) of Cu/Bi bilayer (sample A). Voltage between side contacts 7 and 0 are measured. The light (wavelength: 405 nm) is incident from \u03c6 = 90 \u2022 (a) and \u03c6 = 0 \u2022 (b). The open circles represent experimental data, the green dashed line shows fit to the data with Eq.(1). The red, dark blue and light blue solid lines show contributions from the C, L1, and L2 terms, respectively. The constant D term is subtracted from the results.", "type": "figure"}, "FIGREF2": {"text": "Figure 3. Spatial profile of C (top panels), L1 (middle panels) and L2 (bottom panels) for the Cu/Bi bilayer (sample A). The light is incident from \u03c6 = 90 \u2022 (a) and \u03c6 = 0 \u2022 (b). The blue circles and the red squares show the corresponding parameters (C, L1 and L2) obtained from measurements of the photovoltage using laser light with wavelength of 405 nm and 635 nm, respectively. The yellow shaded area represents the location of the laser spot.", "type": "figure"}, "FIGREF3": {"text": "\u2022 for the setup with laser wavelength of 405 nm and 635 nm, respectively. The green dashed lines in Figs. 2(a) and 2(b) show the results of fitting with Eq. (1): the solid lines show con- tributions from each component (C, L 1 , L 2 ). As evident, the CPGE term is dominant (solid red line) for \u03c6 \u223c 90 \u2022 (", "type": "figure"}, "FIGREF4": {"text": "Figure 4. (a,b) Normalized photovoltage (V /P ) of the Cu single layer film, sample B (a) and the Bi single layer film, sample C (b). Voltage between side contacts 7 and 0 are measured. The light (wavelength: 405 nm) is incident from \u03c6 = 90 \u2022 . The open circles represent experimental data, the green dashed line shows fit to the data with Eq.(1). The red, dark blue and light blue solid lines show contributions from the C, L1, and L2 terms, respectively. The constant D term is subtracted from the results.", "type": "figure"}, "FIGREF6": {"text": "force microscopy (AFM) images of the Cu/Bi bilayer (sample A) and the Bi single layer film (sample C) are shown in Figs. 5(a) and 5(b), respectively. Representative line profiles of the corresponding image are shown in Figs. 5(c) and 5(d).", "type": "figure"}, "FIGREF7": {"text": "Figure 5. (a-f) Atomic force microscopy (AFM) image (a,b), the line profile of the corresponding AFM image along the red line (c,d) and the X-ray diffraction (XRD) spectrum (e,f) of the Cu/Bi bilayer, sample A, (a,c,e) and the Bi single layer, sample C (b,d,f). The indices in (e,f) represent peaks associated with the hexagonal unit cell of Bi. The peak marked with * is due to diffraction from the substrate, i.e. from the Si (002) planes.", "type": "figure"}, "TABREF0": {"text": "", "type": "table"}}}
{"paper_id": "119420250", "_pdf_hash": "9eb22962c0d60dff159718df3468c0fc04734f07", "abstract": [{"section": "Abstract", "text": "Abstract. Recently increasing attention has been addressed to the fluctuations observed in percolation defined in single and multiplex networks. These fluctuations are extremely important to characterize the robustness of real finite networks but cannot be captured by the traditionally adopted mean-field theory of percolation. Here we propose a theoretical framework and a message passing algorithm that is able to fully capture the large deviation of percolation in interdependent multiplex networks with a locally tree-like structure. This framework is here applied to study the robustness of single instance multiplex networks and compared to the results obtained using extensive simulations of the initial damage. For simplicity the method is here developed for interdependent multiplex networks without link overlap, however it can be generalized to treat multiplex networks with link overlap.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Percolation is a fundamental critical phenomena [1, 2] defined in complex networks as it sheads light on the robustness of networks when a fraction f = 1 \u2212 p of nodes is randomly removed. In the last ten years important new insights on percolation theory have been gained by considering percolation processes defined on multiplex networks [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] . Multiplex networks [6, [17] [18] [19] [20] describe generalized network structures formed by several interacting networks (layers). Examples of multiplex networks include global infrastructures, interacting financial networks and biological networks in the cell or in the brain.", "cite_spans": [{"start": 351, "end": 354, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 423, "end": 426, "text": "[6,", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Introduction", "text": "Multiplex networks are often characterized by interdependencies [3] existing between nodes of different layers implying that the failure of one node in one layer necessarily causes the failure of the interdependent nodes in the other layers independently of the rest of the network. Interestingly interdependent multiplex networks are much more fragile than single networks [3] [4] [5] [6] . In particular the percolation threshold p = p c of multiplex networks is larger than the percolation threshold of their single layers taken in isolation. Moreover if the layers are not formed by identical networks, the percolation transition is discontinuous and hybrid and characterized by large avalanches of failures going back and forth among different layers. These large avalanches of failure events are the most notable effect of interdependencies and they are a strong signal of the increased fragility of multiplex networks.", "cite_spans": [{"start": 386, "end": 389, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Introduction", "text": "The order parameter of the percolation defined on interdependent multiplex networks is given by the Mutually Connected Giant Component (MCGC) [3, 5] which generalizes the giant component and is formed by the set of nodes such that each pair of nodes is connected by a path in at least one layer. In infinite interdependent multiplex networks the percolation transition can be studied using a suitable mean-field approach to percolation [3] [4] [5] [6] . In fact in multiplex network as well as in single networks, percolation theory is self-averaging and in the infinite network limit the mean-field approach gives exact results. In finite interdependent multiplex networks when the initial damage configuration is known, the percolation transition on interdependent multiplex networks can be described by a message passing algorithm [4, 6, 21, 22] that is able to predict which nodes are in the MCGC after the initial damage provided the multiplex network is locally tree-like. Interestingly this message passing algorithm has a definition that depends whether the multiplex network displays or not link overlap, i.e. it depends wheather there are pairs of nodes connected in more than one layer [10] [11] [12] [13] 22] . When the specific nature of the initial damage configuration is not known the message passing algorithm can be averaged over the distribution of the initial damage. This mean-field approach provides the probability that each node is in the MCGC when the initial damage configuration is drawn from the known distribution (for instance when each node is damaged with probability f = 1 \u2212 p). However this approach is not able to capture the fluctuations that can be observed in the size of the MCGC for different realizations of the initial damage.", "cite_spans": [{"start": 448, "end": 451, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 838, "end": 840, "text": "6,", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Introduction", "text": "Recently, there has been a surge of interest in characterizing the risk of dramatic failure of events as a consequence of a random damage [23] [24] [25] [26] [27] [28] [29] . In fact real networks are typically finite and often sufficiently far from the thermodynamic limit. Therefore the outcome of a initial damage configuration drawn from a given distribution can have large fluctuations not predicted by the mean-field approach to percolation. Characterizing these fluctuations is of fundamental importance for applications as the average response to perturbation captured by the mean-field theory of percolation can be dramatically misleading [28, 29] . Moreover characterizing the node sets that are responsible for safeguarding the cohesiveness of a network [28] or for more efficiently disrupting a network (optimal percolation) [30] [31] [32] [33] have a number of applications. These range from the design principles for robust infrastructures to the control of epidemic processes on networks. From the theoretical perspective characterizing these fluctuations is very interesting as well as it sheds new light on the nature of the percolation transition [23] [24] [25] [26] [27] .", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "These phenomena are naturally addressed using the theory of large deviations [34, 35] . On single networks the characterization of the large deviation properties of random graphs has been first tackled using the properties of the Ising model [36] and the Potts model [37, 38] . While the study of the Potts model sheads light on the large deviations of the number of components [37, 38] the properties of the Ising model can characterize the large deviations of the giant component in random Erd\u00f6s and R\u00e9nyi graphs [36] with constant average degree. However the analytical method developed in Ref. [36] is not able to predict the distribution of the giant component in a real networks or in a network model different from a Erd\u00f6s and R\u00e9nyi graph. In order to address this problem a sofisticated numerical technique based on a Markov Chain Monte Carlo method has been shown [39] to be able to uncover the full distribution of the giant component down to rare events with probabilities 10 \u2212100 . This method has subsequently been also used for numerically evaluating the distribution of the diameter [40] and of the largest biconnected component of networks [41] .", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Recently [24] a large deviation theory of percolation has been proposed to capture the fluctuations observed in percolation of single finite networks. This approach is based on message-passing algorithm and specifically on Belief Propagation [42] and can be applied to single instances of networks provided that they are locally tree-like. This work reveals that when one considers aggravating initial damage configurations, the percolation transition can become discontinuous also in percolation defined on single networks.", "cite_spans": [{"start": 242, "end": 246, "text": "[42]", "ref_id": "BIBREF41"}], "ref_spans": []}, {"section": "Introduction", "text": "Here we generalize the large deviation theory of percolation to multiplex networks. For simplicity we consider only multiplex networks without link overlap. However it is possible to generalize the method to multiplex networks with link overlap. We show that the percolation transition remains discontinuous for both aggravating and buffering configuration of the initial damage. Interestingly we can measure the fluctuations in the size of the MCGC and we observe that these fluctuations can remain very significant up to the percolation transition in the typical scenario. Finally we use the large deviation theory to theoretically predict the convex envelop of the rate function I(R) of the distribution \u03c0(R) the size R of the MCGC finding very good agreement with extensive numerical simulations.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The paper is structured as follows. In Sec. 2 we present the mean-field theory of percolation of interdependent duplex networks without link overlap. In Sec. 3 we present the large deviation theory of percolation. In Sec. 4 we show how the Belief Propagation approach can be used to fully characterize the large deviation theory of percolation. In Sec. 5 we compare the numerical results obtained with the Belief Propagation approach with extensive numerical simulations. Finally in Sec. 6 we give the conclusions.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "2. The mean-field theory of percolation in interdependent multiplex networks", "cite_spans": [], "ref_spans": []}, {"section": "Multiplex networks and mutually connected giant component", "text": "We consider an interdependent duplex network G = (G [1] , G [2] ) formed by two networks", "cite_spans": [], "ref_spans": []}, {"section": "Multiplex networks and mutually connected giant component", "text": ") (with \u03b1 = 1, 2) among the same set of N nodes V = {i|i \u2208 {1, 2, . . . , N }} [6, 20] . Each network \u03b1 is defined by the adjacency matrix a [\u03b1] . For each node i we consider two replica nodes (i, 1) and (i, 2) indicating the identity of node i in layer 1 and in layer 2 respectively. Each pair of replica nodes is connected by an interlink that has a different valence with respect to the links present in each layer. In fact in interdependent multiplex networks interlinks indicate interdependencies whose role in determining the robustness properties of the duplex network is explained in the following. Duplex networks can be classified depending on the presence or the absence of link overlap. The total overlap between the two layers of a duplex network is given by the number of pairs of nodes that are connected in both layers, i.e.", "cite_spans": [{"start": 79, "end": 82, "text": "[6,", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Multiplex networks and mutually connected giant component", "text": "We therefore call duplex networks without link overlap the duplex networks in which the total overlap vanishes and we call duplex networks with link overlap the duplex networks in which the total overlap is greater than zero. We monitor the robustness of the considered duplex networks by studying the size of the Mutually Connected Giant Component (MCGC) [3] after an initial damage of a fraction f = 1 \u2212 p of the nodes. Due to the presence of interdependencies, replica nodes cannot be in the MCGC if their corresponding replica node is not included in it. Therefore the MCGC can be evaluated by propagating the initial failure back and forth among the different layers of the duplex network [3, 6] . Specifically the algorithm that define the MCGC prescribes to first evaluate the giant component in each individual layer and subsequently to damage each replica node whose corresponding interdependent replica node is not in the giant component. This algorithm is then iterated until the damage does not propagate any more among different layers. Alternatively the MCGC can be defined as the giant component formed by pairs of nodes connected to each other at least by a path in each layer [5] .", "cite_spans": [{"start": 698, "end": 700, "text": "6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Message passing algorithm on single network and single realization of damage", "text": "On a locally tree-like interdependent duplex network without link overlap percolation can be described by the following message passing equations. We assume that initially each node of the duplex network is damaged randomly with probability f = 1 \u2212 p, and we associated a variable x i = 1 to a node i that is not initially damaged and a variable x i = 0 to a node i that is initially damaged. Additionally we assign to each node i a variable \u03c1 i indicating if the node belongs to the MCGC (\u03c1 i = 1) or not (\u03c1 i = 0). The indicator function \u03c1 i depends on the configuration of the initial damage x = {x i |i \u2208 {1, 2, . . . , N }} and the messages \u03c3 \u03b1 i\u2192j that each node i send to a neighbour node j in layer \u03b1. In particular a node i belongs to the MCGC if it is not initially damaged and receives at least one positive message in each layer,i.e.", "cite_spans": [], "ref_spans": []}, {"section": "Message passing algorithm on single network and single realization of damage", "text": "The messages \u03c3 \u03b1 i\u2192j \u2208 {0, 1} take the value \u03c3 \u03b1 i\u2192j = 1 if the node i is not initially damaged and if in each layer node i receives at least a positive message from a neighbour nodes different from node j, i.e.", "cite_spans": [], "ref_spans": []}, {"section": "Message passing algorithm on single network and single realization of damage", "text": "where here and in the following \u03b2 indicates the layer \u03b2 \u2208 {1, 2} with \u03b2 = \u03b1. The size R of the MCGC is given by the number of nodes that belong to it, i.e.", "cite_spans": [], "ref_spans": []}, {"section": "Message passing algorithm on single network and single realization of damage", "text": "We note that different initial damages can yield MCGC of different sizes. The goal of this paper is to uncover the fluctuations that can be observed in the sizes of the MCGC resulting from comparable configurations of the initial damage.", "cite_spans": [], "ref_spans": []}, {"section": "Message passing algorithm on single network and single realization of damage", "text": "We stress here that Eqs. (2), (3) are only valid in absence of link overlap. In fact when the multiplex network display link overlap these equations only define the Directed Mutually Connected Component (DMCGC) which can be considered as the outcome of an epidemic spreading dynamics in which each node can become infected only if is in contact with at least an infected individual in each layer [10, 11] . In presence of link overalp the MCGC is instead captured by a message passing algorithm in which the messages are not scalars like \u03c3 \u03b1 i\u2192j but they are instead M -dimensional vectors n i\u2192j of elements n \u03b1 i\u2192j \u2208 {0, 1}. Here n \u03b1 i\u2192j indicates wherether (n \u03b1 i\u2192j = 1) or not (n \u03b1 i\u2192j = 0) node i connects node j to the MCGC through layer \u03b1 as long as node j is assumed to be in the MCGC [11, 12] . These message elements are set of one (n \u03b1 i\u2192j = 1) if the following two conditions are met: (i) node i is in the MCGC;", "cite_spans": [], "ref_spans": []}, {"section": "Message passing algorithm on single network and single realization of damage", "text": "(ii) node i is connected in layer \u03b1 to at least one node of the MCGC different from node j.", "cite_spans": [], "ref_spans": []}, {"section": "Message passing algorithm on single network and single realization of damage", "text": "Additionally node i is in the MCGC if for any layer of the multiplex network node i is either connected to node j or connected to the MCGC through nodes different from j. Therefore the message passing equations for n \u03b1 i\u2192j read", "cite_spans": [], "ref_spans": []}, {"section": "Message passing algorithm on single network and single realization of damage", "text": "where \u03b4(c, d) indicates the Kronecker delta and v i\u2192j is defined as", "cite_spans": [], "ref_spans": []}, {"section": "Message passing algorithm on single network and single realization of damage", "text": "Therefore the message elements n \u03b1 i\u2192j are correlated and this property of these message passing equations considerably complicates the algorithm. Finally in presence of link overlap the indicator function \u03c3 i determining if a node is in the MCGC satisfies", "cite_spans": [], "ref_spans": []}, {"section": "Message passing algorithm on single network and single realization of damage", "text": "Naturally a close inspection to the message passing equations in presence of link overlap show that these equations reduce to the Eqs. (2) and (3) in absence of link overlap. Moreover we note that in absence of link overlap the equations for the MCGC and for the DMCGC coincide. We note that the message passing Eqs. (5), (6) and (7) can be also written in terms of the indicator functions \u03c3 n i\u2192j \u2208 {0, 1} that indicates if node i sends to node j the message n (\u03c3 n i\u2192j = 1) or not (\u03c3 n i\u2192j = 0). For a detailed account of the message passing theory for percolation of interdependent multiplex networks see Ref. [6, 11] .", "cite_spans": [{"start": 613, "end": 616, "text": "[6,", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Message passing algorithm on single network and single realization of damage", "text": "Here and in the following we will consider exclusively multiplex network without link overlap. In the following we will indicate with \u03c3 the set of all the messages and with \u03c3 i the set of all the messages starting or ending at node i, i.e.", "cite_spans": [], "ref_spans": []}, {"section": "Message passing algorithm on single network and single realization of damage", "text": "Additionally we will indicate with x the configuration of the initial damage, i.e.", "cite_spans": [], "ref_spans": []}, {"section": "Random realization of the damage and typical behaviour", "text": "Let us consider initial damage configurations x obtained by damaging each node with probability 1 \u2212 p, i.e. each configuration x is drawn from a distributio\u00f1", "cite_spans": [], "ref_spans": []}, {"section": "Random realization of the damage and typical behaviour", "text": "In the mean-field theory of percolation the expected sizeR of the MCGC given b\u0177", "cite_spans": [], "ref_spans": []}, {"section": "Random realization of the damage and typical behaviour", "text": "is obtained by averaging the original message passing algorithm over the distributio\u00f1 P (x). On a locally tree-like multiplex network without link overlap this procedure reduces to considering a message passing algorithm", "cite_spans": [], "ref_spans": []}, {"section": "Random realization of the damage and typical behaviour", "text": "where the messages\u03c3 \u03b1 i\u2192j correspond to the average of the messages \u03c3 \u03b1 i\u2192j over the distributionP (x), i.e.", "cite_spans": [], "ref_spans": []}, {"section": "Random realization of the damage and typical behaviour", "text": "Similarly the probability\u03c1 i that node i is in the MCGC can be obtained starting from the messages\u03c3 \u03b1 i\u2192j a\u015d", "cite_spans": [], "ref_spans": []}, {"section": "Random realization of the damage and typical behaviour", "text": "and corresponds to the average of the indicator function \u03c1 i over the distributionP (x), i.e.\u03c1", "cite_spans": [], "ref_spans": []}, {"section": "Random realization of the damage and typical behaviour", "text": "Finally the expected size of the MCGCR can be calculated directly a\u015d", "cite_spans": [], "ref_spans": []}, {"section": "Random realization of the damage and typical behaviour", "text": "Therefore by monitoringR versus p it is possible to characterize the typical response of the duplex network to random damage of the nodes", "cite_spans": [], "ref_spans": []}, {"section": "Random network ensemble and random realization of the initial damage", "text": "In the previous paragraph we have considered the message passing algorithm that allows to study percolation the mean-field theory of percolation on single instances of duplex networks when the initial damage configuration is unknown but drawn from the distributionP (x) given by Eq. (10). Here we consider the case in which also the duplex network is unknown but drawn from ensemble of duplex networks formed by two layers each one formed by an uncorrelated network with degree distribution P (k). In this case we cannot any more consider a message passing algorithm, rather we should consider the mean-field equation [3] [4] [5] [6] for percolation of interdependent duplex networks without link overlap obtained by averaging Eqs. (12) and (14) over the considered duplex network ensemble. We indicate with R the probability that a node is in the MCGC. This quantity is given by the average of\u03c1 i over the considered ensemble of duplex networks. Similarly we indicate with S the probability that by following a link in one layer we reach a node in the MCGC. This quantity is given by the average of\u03c3 i\u2192j over the duplex network ensemble. Using this notation the mean field equations for percolation of independent networks without link overlap [3, 4, 6] read", "cite_spans": [{"start": 630, "end": 633, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 1252, "end": 1254, "text": "6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Random network ensemble and random realization of the initial damage", "text": "where G 0 (x) and G 1 (x) are the generating functions", "cite_spans": [], "ref_spans": []}, {"section": "Random network ensemble and random realization of the initial damage", "text": "These equations yield a discontinuous phase transition at the percolation threshold p = p c determined [3] [4] [5] [6] by the equations (17) together with the equation", "cite_spans": [{"start": 115, "end": 118, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Random network ensemble and random realization of the initial damage", "text": "3. Large deviation theory of percolation", "cite_spans": [], "ref_spans": []}, {"section": "The large deviation approach to percolation", "text": "While in infinite networks the percolation process is self-averaging, i.e. the typical behaviour characterizes a set of measure one of random instances of the initial damage, in finite networks deviations from the typical behaviour can be observed. It is therefore necessary to establish the large deviation theory of percolation. Here our aim is to generalize the framework proposed in Ref. [24] for characterizing the large deviation in single networks in order to treat the large deviation of percolation in interdependent multiplex networks. The large deviation theory of percolation of multiplex networks aims at characterizing the probability distribution \u03c0(R) of size R of the MCGC when the initial damage configuration x is chosen with probabilityP (x), i.e.", "cite_spans": [], "ref_spans": []}, {"section": "The large deviation approach to percolation", "text": "where with \u03b4(c, d) we indicate the Kronecker delta. For large network sizes N 1 and given value of p the probability \u03c0(R) has a scaling with the network size N determined by the rate function I(R) \u2265 0. In particular we observe the scaling [34] \u03c0(R) \u223c e \u2212N I(R) .", "cite_spans": [], "ref_spans": []}, {"section": "The large deviation approach to percolation", "text": "This expression implies that for N \u2192 \u221e the percolation is self-averaging and \u03c0(R) is non-zero only for s R =R for which I(R) takes its minimum value I(R).Therefore in the infinite network limit all realizations of the initial damage yield almost surely the same size of the MCGC. However the rate function I(R) captures the fluctuations in the size of the MCGC that can be observed in finite multiplex networks. In order to find I(R) we adopt a canonical approach and we introduce the partition function Z = Z(\u03c9) given by", "cite_spans": [], "ref_spans": []}, {"section": "The large deviation approach to percolation", "text": "Using the definition of \u03c0(R) given by Eq. (20) it can be easily shown that Z is the generating function of \u03c0(R) as Z can be written as", "cite_spans": [], "ref_spans": []}, {"section": "The large deviation approach to percolation", "text": "The corresponding free-energy F and the free energy density f can be calculated as", "cite_spans": [], "ref_spans": []}, {"section": "The large deviation approach to percolation", "text": "The Legendre-Fenchel transform of the rate function I(R) [34] can be expressed in terms of the free energy density as \u03c9f (\u03c9) and we have", "cite_spans": [], "ref_spans": []}, {"section": "The large deviation approach to percolation", "text": "Additionally as long \u03c9f (\u03c9) is differentiable, the Legendre-Fenchel transform\u00ce(R) of \u03c9f (\u03c9) given b\u0177", "cite_spans": [], "ref_spans": []}, {"section": "The large deviation approach to percolation", "text": "fully determines the rate function I(R), i.e. I(R) =\u00ce(R). However when I(R) is non-convex \u03c9f (\u03c9) is not differentiable and the LegendreFenchel transform of \u03c9f (\u03c9) given by\u00ce(R) only provides the convex envelop of the rate function I(R) [34] .", "cite_spans": [], "ref_spans": []}, {"section": "The large deviation approach to percolation", "text": "Alternatevely it is possible to proceed as proposed in Ref. [39] [40] [41] and directly extract the distribution \u03c0(R) from the biased distribution\u03c0(R) given b\u1ef9", "cite_spans": [], "ref_spans": []}, {"section": "The large deviation approach to percolation", "text": "getting", "cite_spans": [], "ref_spans": []}, {"section": "The large deviation approach to percolation", "text": "Therefore the knowledge of the biased distribution\u03c0(R) which can be sampled with the Markov Chain Monte Carlo method is in principle sufficient to reconstruct the full distribution \u03c0(R). However this approach is entirely numerical. In the following we will consider the first approach and we will evaluate the partition function Z using the Belief Propagation algorithm.", "cite_spans": [], "ref_spans": []}, {"section": "The Gibbs measure over messages", "text": "In order to calculate the partition function Z we follow the approach proposed in Ref. [24] and we consider a Gibbs measure P (\u03c3) over the set \u03c3 of all messages. The probability distribution P (\u03c3) weights the configuration of the messages \u03c3 according to the probability of the corresponding initial damage configurations. Moreover we introduce a Lagrangian multiplier \u03c9 conjugated to the size of the MCGC R that is able to tune the relative weight of the configurations of the messages corresponding to different sizes of the MCGC. Therefore the Gibbs measure P (\u03c3) is given by", "cite_spans": [], "ref_spans": []}, {"section": "The Gibbs measure over messages", "text": "where the function \u03c7(\u03c3, x) enforces the message passing Eqs. (3) , i.e.", "cite_spans": [], "ref_spans": []}, {"section": "The Gibbs measure over messages", "text": "The partition function Z in Eq. (29) clearly reduces to Z defined in Eq. (23) . In fact we have", "cite_spans": [], "ref_spans": []}, {"section": "The Gibbs measure over messages", "text": "Therefore characterizing the partition function Z and the free energy F (given by Eq. (24)) corresponding to the Gibbs measure defined in Eq. (29) allows us to directly calculate the Legendre-Fenchel transform of the rate function I(R).", "cite_spans": [], "ref_spans": []}, {"section": "The Gibbs measure over messages", "text": "We note that the Gibbs measure P (\u03c3) can be interpreted as a canonical ensemble, where \u03c9 plays the role of the inverse temperature and R plays the role of the energy. Since R is the sum of the node variable \u03c1 i and \u03c1 i can only take two values (\u03c1 i = 0-the node does not belong to the MCGC or \u03c1 i = 1 the node does belong to the MCGC) the Gibbs measure can be interpreted as a a statistical mechanics problem of a two level system. It follows that in this case we can investigate the properties of the Gibbs measure for values of \u03c9 that can be also negative.", "cite_spans": [], "ref_spans": []}, {"section": "The Gibbs measure over messages", "text": "For \u03c9 < 0, the Gibbs measure weights more the buffering configurations of the initial damage resulting in a MCGC larger than the typical one. On the contrary for \u03c9 > 0 the Gibbs measure weights more the aggravating configurations of the initial damage resulting in a MCGC smaller than the typical one. For \u03c9 = 0 we recover the typical scenario.", "cite_spans": [], "ref_spans": []}, {"section": "The Gibbs measure over messages", "text": "The Gibbs measure P (\u03c3) given by Eq. (29) can also be expressed as", "cite_spans": [], "ref_spans": []}, {"section": "The Gibbs measure over messages", "text": "where the set of constraints \u03c8 i (\u03c3 i , \u03c9) for i = 1, 2, . . . , N defined over all the messages \u03c3 i starting or ending to node i read", "cite_spans": [], "ref_spans": []}, {"section": "The Gibbs measure over messages", "text": "Here \u03b4(m, n) indicates the Kronecker delta and\u03c1 i is given b\u1ef9", "cite_spans": [], "ref_spans": []}, {"section": "The Gibbs measure over messages", "text": "Finally, using Eq. (31) it can be easily shown that the partition function Z can be also written as", "cite_spans": [], "ref_spans": []}, {"section": "The Gibbs measure over messages", "text": "In the following sections we will characterize the large deviation properties of percolation on multiplex networks by calculating the Gibbs measure using Belief Propagation (BP).", "cite_spans": [], "ref_spans": []}, {"section": "Belief Propagation approach", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "The Belief Propagation equations", "text": "On a locally tree-like duplex network without link overlap the Gibbs distribution P (\u03c3) can be expressed explicitly using the Belief Propagation (BP) algorithm [42] by finding the messagesP \u03b1 i\u2192j (\u03c3 \u03b1 i\u2192j , \u03c3 \u03b1 j\u2192i ) that each node i sends to the generic neighbour node j in layer \u03b1. These messages satisfy the following recursive BP equations (see Appendix A for their explicit expression)", "cite_spans": [{"start": 160, "end": 164, "text": "[42]", "ref_id": "BIBREF41"}], "ref_spans": []}, {"section": "The Belief Propagation equations", "text": "where \u03b1 = \u03b2 and where D [\u03b1] i\u2192j are normalization constants enforcing the normalization condition", "cite_spans": [], "ref_spans": []}, {"section": "The Belief Propagation equations", "text": "In the Bethe approximation, valid on locally tree-like networks the probability distribution P (\u03c3) is given by [42] ", "cite_spans": [{"start": 111, "end": 115, "text": "[42]", "ref_id": "BIBREF41"}], "ref_spans": []}, {"section": "The Belief Propagation equations", "text": "where P i (\u03c3 i ) and P ", "cite_spans": [], "ref_spans": []}, {"section": "The Belief Propagation equations", "text": "with C i and C", "cite_spans": [], "ref_spans": []}, {"section": "[\u03b1]", "text": "ij indicating normalization constants (see Appendix B for their explicit expression).", "cite_spans": [], "ref_spans": []}, {"section": "Free energy", "text": "The free energy F given by Eq. (24) can be found by minimizing the Gibbs free energy F Gibbs given by", "cite_spans": [], "ref_spans": []}, {"section": "Free energy", "text": "where \u03c8(\u03c3) indicates the set of constraints", "cite_spans": [], "ref_spans": []}, {"section": "Free energy", "text": "In fact it can be easily shown that the Gibbs free energy F Gibbs is minimal when calculated over the probability distribution P (\u03c3) given by Eq. (31) and that its minimum value is", "cite_spans": [], "ref_spans": []}, {"section": "Free energy", "text": "On a locally tree-like duplex network the Gibbs measure P (\u03c3) reduces to Eq. (35), and it can be easily see that the free energy can be expressed as", "cite_spans": [], "ref_spans": []}, {"section": "Free energy", "text": "Given the explicit expression of C", "cite_spans": [], "ref_spans": []}, {"section": "Free energy", "text": "[\u03b1]", "cite_spans": [], "ref_spans": []}, {"section": "Free energy", "text": "ij and of C i in terms of the messages (see Appendix B), the free energy F can be calculated easily when the BP equations have been solved.", "cite_spans": [], "ref_spans": []}, {"section": "Energy and Specific Heat", "text": "The energy and the specific heat corresponding to the Gibbs measure P (\u03c3) have also a very important interpretation in terms of the underlying percolation process. The energy is given by the the average size of the MCGC R. In fact we have", "cite_spans": [], "ref_spans": []}, {"section": "Energy and Specific Heat", "text": "The mean-field percolation transition correspond to the phase transition from a nonpercolating phase with R = 0 to a percolating phase R > 0 at p = p c and \u03c9 = 0. However the present approach allows to consider the full line of critical points (p , \u03c9 ) at which the transition is observed when the large deviations are considered. Following a statistical mechanics definition, we can also define the specific heat C as", "cite_spans": [], "ref_spans": []}, {"section": "Energy and Specific Heat", "text": "The specific heat has the immediate interpretation in terms of the variance in the size of the MCGC, i.e.", "cite_spans": [], "ref_spans": []}, {"section": "Energy and Specific Heat", "text": "Both R and C/\u03c9 2 can be derived from the message passing algorithm. Indeed we have", "cite_spans": [], "ref_spans": []}, {"section": "Energy and Specific Heat", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "Energy and Specific Heat", "text": "indicating the probability that node i is in the giant component is given by", "cite_spans": [], "ref_spans": []}, {"section": "Energy and Specific Heat", "text": "where the explicit expression of z i and C i is given in Appendix B. The quantity C/\u03c9 2 can be also interpreted as the expected fraction of nodes that given two random realizations of the initial damage are found in the MCGC in one realization but not in the other. This quantity generalizes the measure proposed in Ref. [23] to characterize the fluctuations in percolation in single networks.", "cite_spans": [], "ref_spans": []}, {"section": "The typical scenario", "text": "It is instructive to see that the proposed large deviation theory of percolation reduces to the mean-field theory of percolation in the typical scenario obtained by putting \u03c9 = 0. In this case we obtain that the BP equations have solution wit\u0125", "cite_spans": [], "ref_spans": []}, {"section": "The typical scenario", "text": "and the BP equations for \u03c9 = 0 reduces to Eqs. (12) when we put", "cite_spans": [], "ref_spans": []}, {"section": "The typical scenario", "text": "Similarly it is easy to show that r i reduces to\u03c1 i given by Eq. (14).", "cite_spans": [], "ref_spans": []}, {"section": "Numerical results", "text": "Here we consider the results obtained by running the BP algorithm over a Poisson duplex network with average degree z = 6 and network size N = 100 (see Figure 1) . The typical scenario observed for \u03c9 = 0 gives a discontinuous transition of the average size R of the MCGC at p = p c = 0.409235 . . . with R = R c = 0.209405 . . . for the considered duplex network as predicted by the mean-field theory of percolation. The fluctuations of the size of the MCGC measured by C/\u03c9 2 for \u03c9 \u2192 0 have also a jump at p = p c . Therefore as we approach the critical percolation threshold from above (i.e. for p \u2192 p + c ) we observe significant fluctuations in the size of the MCGC. However these fluctuations are maximal only for larger values of p.", "cite_spans": [], "ref_spans": []}, {"section": "Numerical results", "text": "Interestingly the BP results allow us to investigate also how the average size of the MCGC R and its fluctuations C/\u03c9 2 change if we deviate from the typical scenario, i.e. for \u03c9 = 0. For \u03c9 < 0 when we consider buffering configuration of the initial damage we observe a transition for lower values of p, for \u03c9 > 0 we observe a transition for larger value of p. In both cases the transition remains discontinuous in the investigated range of values of \u03c9. Additionally we note that for buffering configurations, as \u03c9 decreases the discontinuous jump in the size of the MCGC R appears to reach a constant value. This suggests that the discontinuity might be preserved even beyond the observed range of values of \u03c9. The fluctuations in the size of the MCGC C/\u03c9 2 observed at the transition point increase for aggravating configuration of the damage. Moreover for aggravating configuration of the damage these fluctuations can achieve their maximum at the transition point itself.", "cite_spans": [], "ref_spans": []}, {"section": "Numerical results", "text": "In Figure 2 we compare the results obtained for the duplex networks to the results that can be obtained by studying the large deviations of percolation on single networks as discussed in Ref. [24] . In the duplex network we observe a discontinuous jump of C/\u03c9 2 also in the typical scenario \u03c9 = 0 while in single networks C/\u03c9 2 is continuous at the transition point. Therefore the observed discontinuity of C/\u03c9 2 at p = p c and \u03c9 = 0 is a purely multiplex network phenomenon not observed in percolation of single networks. In fact the presence of significant fluctuations of the percolation order parameter at the percolation transition can be only observed if the order parameter has a discontinuous jump and in this case only for p \u2192 p + c when R \u2192 R c > 0. Finally we note that in the multiplex case the discontinuity of C/\u03c9 2 extend also for negative value of \u03c9 corresponding to buffering configurations of the initial damage while in single networks we observe a continuous behaviour of C/\u03c9 2 . In order to test the validity of the BP algorithm, we have compared the rate function I(R) measured starting from 10 6 initial damage configurations performed on the same duplex network instance on which the BP algorithm is run, with\u00ce(R) provided by the BP algorithm finding very good results (see Figure 3) . We notice that while for large values of p the rate function I(R) is convex and therefore I(R) =\u00ce(R), as we approach the percolation transition the rate function I(R) becomes non-convex and\u00ce(R) only provides the convex envelop of I(R).", "cite_spans": [], "ref_spans": [{"start": 1298, "end": 1307, "text": "Figure 3)", "ref_id": "FIGREF2"}]}, {"section": "Conclusions", "text": "In this paper we have characterized the large deviation of percolation of interdependent multiplex networks without link overlap using a Belief Propagation algorithm. In the typical scenario, well captured by the mean-field theory of percolation we observe a discontinuous percolation transition. Our analysis reveals that when we depart from the typical scenario the percolation transition can occur for values of p significantly distant from the percolation threshold in the typical scenario while remaining discontinuous both for buffering configurations of the random damage and aggravating ones. Interestingly our study show a significant difference of interdependent percolation with respect to percolation in single layers. In fact when we consider percolation of isolated networks the fluctuations in the size of the giant component go to zero at the critical point. However in interdependent percolation we can observe significant fluctuations of the size of the MCGC when we approach the critical point from above, i.e. for p \u2192 p + c . Finally we have compared the rate function I(R) of observing a MCGC of size R with the predicted\u00ce(R) obtained using the proposed canonical BP algorithm. As observed in the single layer scenario the rate function I(R) becomes bimodal for small values of p, and therefore the proposed canonical BP algorithm can only capture its convex envelop, i.e. we have\u00ce(R) = I(R). The proposed method can be extended in different ways by considering percolation and directed percolation in multiplex network with link overlap and by developing a microcanonical approach in which instead of introducing the Lagrangian multiplier \u03c9 fixing the size of the MCGC in average, we consider the corresponding hard constraint. ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF5": {"title": "Multilayer Networks: Structure and Function", "authors": [{"first": "G", "middle": [], "last": "Bianconi", "suffix": ""}], "year": 2018, "venue": "", "link": "201139206"}, "BIBREF41": {"title": "physics, and computation", "authors": [{"first": "M", "middle": [], "last": "Mezard", "suffix": ""}, {"first": "A", "middle": [], "last": "Montanari", "suffix": ""}], "year": 2009, "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "indicate the marginal distribution of nodes and links and are given by [42]", "type": "figure"}, "FIGREF1": {"text": "Figure 1. The average fraction of nodes of the MCGC R/N and the normalized fluctuations C/(N \u03c9 2 ) of the size of the MCGC are plotted as a function of p for different values of \u03c9. The considered multiplex network is a duplex Poisson network with average degree z = 6 and total number of nodes N = 100.", "type": "figure"}, "FIGREF2": {"text": "Figure 3. The rate function I(R) measured starting from 10 6 random realizations of the initial damage (symbols) and compared to its convex envelop obtained using the BP algorithm (solid lines). The different color and symbols correspond to different values of p: p = 0.9 (blue circles), p = 0.8 (yellow squares), p = 0.7 (green diamonds), p = 0.6 (purple triangles), p = 0.5 (red triangles pointing left), p = 0.4 (purple stars). The considered multiplex network is a duplex Poisson network with average degree z = 6 and total number of nodes N = 100.", "type": "figure"}, "FIGREF3": {"text": ", C i and z i In this appendix we give the explict expression of C \u03b1 ij , C i and z i in terms of the messages that solve the BP equations. In particular by normalizing the marginals in Eqs.", "type": "figure"}}}
{"paper_id": "119420453", "_pdf_hash": "d784510b5162a8bf37f5975cb1792efc581634c2", "abstract": [{"section": "Abstract", "text": "Superconducting pairing of electrons in nanoscale metallic particles with discrete energy levels and a fixed number of electrons is described by the reduced Bardeen, Cooper, and Schrieffer model Hamiltonian. We show that this model is integrable by the algebraic Bethe ansatz. The eigenstates, spectrum, conserved operators, integrals of motion, and norms of wave functions are obtained. Furthermore, the quantum inverse problem is solved, meaning that form factors and correlation functions can be explicitly evaluated. Closed form expressions are given for the form factors and correlation functions that describe superconducting pairing. DOI: 10.1103/PhysRevB.65.060502 PACS number\u0351s\u0352: 74.20.\u03eaz, 75.10.Jm, 75.10.Lp Due to recent advances in nanotechnology it has become possible to fabricate and characterize individual metallic grains with dimensions as small as a few nanometers.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "1 They are sufficiently small that the spacing, d, of the discrete energy levels can be determined. A particularly interesting question concerns whether superconductivity can occur in a grain with d comparable to \u232c, the energy gap in a bulk system. If d\u04f6\u232c, the superconducting correlations are well described by a mean-field solution to the reduced pairing Hamiltonian \u0353Eq. \u03511\u0352 below\u0354 due to Bardeen, Cooper, and Schrieffer \u0351BCS\u0352 in the grand canonical ensemble with a variable number of electrons. However, if d\u03f3\u232c recent numerical calculations have shown that when the number of electrons is fixed \u0351as in the canonical ensemble\u0352 the superconducting fluctuations become large and approximate treatments become unreliable.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "1,2 Thus, exact calculations of physical quantities are highly desirable. It has only recently been appreciated that the exact eigenstates and spectrum of the BCS model were found in the 1960s by Richardson, in the context of nuclear physics.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "1,3 The model has subsequently been found to have a rich mathematical structure: it is integrable \u0351i.e., has a complete set of conserved operators\u0352, 4 has a connection to conformal field theory, 5 and is related to Gaudin's inhomogeneous spin-1/2 models. [6] [7] [8] [9] In this Communication we show how the BCS model can be solved using the algebraic Bethe ansatz \u0351ABA\u0352 method. This result can be deduced from the observation that the conserved operators obtained in Ref. 4 were also obtained in Ref. 9 via the ABA, but in another context. This observation has been made in Ref. 8. However, the approach we adopt here is slightly different from Ref. 9, which facilitates the solution of the quantum inverse problem 10-13 to explicitly evaluate form factors \u0351i.e., one point functions\u0352 and correlation functions. This completes the agenda recently set out by Amico et al. 8 We also readily obtain known results for eigenstates, the spectrum, and conserved operators. Our treatment is also applicable to superconductivity in fermionic atom traps 14, 15 and can also be extended to a solvable model for condensate fragmentation in boson systems. 16, 17 The Hamiltonian for the reduced BCS model consists of a kinetic energy term and an interaction term which describes the attraction between electrons in time reversed states,", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "where j\u03ed1, . . . ,\u2340 labels a shell of doubly degenerate single particle energy levels with energies \u2440 j and c j the annihilation operators; \u03ed\u03e9,\u03ea labels the degenerate time reversed states; g denotes the BCS pairing coupling constant. Using the pseudospin realization of electron pairs:", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "and S j \u03ea \u03edc j\u03ea c j\u03e9 , the BCS Hamiltonian \u03511\u0352 becomes \u0351up to a constant term\u0352", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "The R matrix. An essential ingredient of the ABA, which follows from the quantum inverse scattering method \u0351QISM\u0352, is the construction of the R matrix solving the quantum Yang-Baxter equation,", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "where the u j are spectral parameters. Here R jk denotes the matrix on V V V \u0351where V is the two-dimensional Hilbert space on which the pseudospin operators act\u0352 acting on the jth and kth spaces and as an identity on the remaining space. The R matrix may be viewed as the structural constants for the Yang-Baxter algebra generated by the monodromy matrix T(u),", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "There are two kinds of realizations of the Yang-Baxter algebra which are relevant to our construction. One is operator valued given by the R matrix R 0 j (u) and the other is a c-number representation G which does not depend on the spectral parameter u. In the latter case, we have \u0353R(u),G G\u0354\u03ed0. The comultiplication behind the Yang-Baxter algebra allows us to construct a representation of the monodromy matrix through", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "Due to recent advances in nanotechnology it has become possible to fabricate and characterize individual metallic grains with dimensions as small as a few nanometers. 1 They are sufficiently small that the spacing, d, of the discrete energy levels can be determined. A particularly interesting question concerns whether superconductivity can occur in a grain with d comparable to \u232c, the energy gap in a bulk system. If d\u04f6\u232c, the superconducting correlations are well described by a mean-field solution to the reduced pairing Hamiltonian \u0353Eq. \u03511\u0352 below\u0354 due to Bardeen, Cooper, and Schrieffer \u0351BCS\u0352 in the grand canonical ensemble with a variable number of electrons. However, if d\u03f3\u232c recent numerical calculations have shown that when the number of electrons is fixed \u0351as in the canonical ensemble\u0352 the superconducting fluctuations become large and approximate treatments become unreliable. 1, 2 Thus, exact calculations of physical quantities are highly desirable. It has only recently been appreciated that the exact eigenstates and spectrum of the BCS model were found in the 1960s by Richardson, in the context of nuclear physics. 1, 3 The model has subsequently been found to have a rich mathematical structure: it is integrable \u0351i.e., has a complete set of conserved operators\u0352, 4 has a connection to conformal field theory, 5 and is related to Gaudin's inhomogeneous spin-1/2 models. [6] [7] [8] [9] In this Communication we show how the BCS model can be solved using the algebraic Bethe ansatz \u0351ABA\u0352 method. This result can be deduced from the observation that the conserved operators obtained in Ref. 4 were also obtained in Ref. 9 via the ABA, but in another context. This observation has been made in Ref. 8 . However, the approach we adopt here is slightly different from Ref. 9 , which facilitates the solution of the quantum inverse problem [10] [11] [12] [13] to explicitly evaluate form factors \u0351i.e., one point functions\u0352 and correlation functions. This completes the agenda recently set out by Amico et al. 8 We also readily obtain known results for eigenstates, the spectrum, and conserved operators. Our treatment is also applicable to superconductivity in fermionic atom traps 14, 15 and can also be extended to a solvable model for condensate fragmentation in boson systems. 16, 17 The Hamiltonian for the reduced BCS model consists of a kinetic energy term and an interaction term which describes the attraction between electrons in time reversed states,", "cite_spans": [{"start": 1853, "end": 1857, "text": "[10]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "", "text": "where j\u03ed1, . . . ,\u2340 labels a shell of doubly degenerate single particle energy levels with energies \u2440 j and c j the annihilation operators; \u03ed\u03e9,\u03ea labels the degenerate time reversed states; g denotes the BCS pairing coupling constant. Using the pseudospin realization of electron pairs:", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "and S j \u03ea \u03edc j\u03ea c j\u03e9 , the BCS Hamiltonian \u03511\u0352 becomes \u0351up to a constant term\u0352", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "The R matrix. An essential ingredient of the ABA, which follows from the quantum inverse scattering method \u0351QISM\u0352, is the construction of the R matrix solving the quantum Yang-Baxter equation,", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "where the u j are spectral parameters. Here R jk denotes the matrix on V V V \u0351where V is the two-dimensional Hilbert space on which the pseudospin operators act\u0352 acting on the jth and kth spaces and as an identity on the remaining space. The R matrix may be viewed as the structural constants for the Yang-Baxter algebra generated by the monodromy matrix T(u),", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "There are two kinds of realizations of the Yang-Baxter algebra which are relevant to our construction. One is operator valued given by the R matrix R 0 j (u) and the other is a c-number representation G which does not depend on the spectral parameter u. In the latter case, we have \u0353R(u),G G\u0354\u03ed0. The comultiplication behind the Yang-Baxter algebra allows us to construct a representation of the monodromy matrix through Defining the transfer matrix via t(u)\u03f5tr 0 T 0 (u) it follows that \u0353t(u),t(v)\u0354\u03ed0 for all values of the parameters u, v. If the R matrix possesses the regularity property R jk (0)\u03ed P jk with P being the permutation operator, then it is easily verified that", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Let us now assume that the R matrix is quasiclassical, i.e., it admits a series expansion R(u)\u03edI\u03e9r(u)\u03e9\u2022\u2022\u2022, for an appropriate parameter . If we can also choose G such that G\u03ed1\u03e9\u232b\u03e9\u2022\u2022\u2022, then the expansion of t(\u2440 j ) in terms of takes the form,", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "An immediate consequence from the commutativity of the transfer matrices is \u0353 j , k \u0354\u03ed0. Therefore an integrable model is obtained by taking the set \u0355 i \u0356 as the conserved operators and a Hamiltonian given as a function of the j . We apply the procedure described above to the su(2) invariant R matrix R(u)\u03edb(u)I\u03e9c(u) P, with entries that are rational functions: b(u)\u03edu/(u\u03e9) and c(u)\u03ed/(u \u03e9). Note that the regularity property R(0)\u03ed P is present. For this case, we can choose G as any element of the su(2) algebra. We claim that the BCS model corresponds to the special choice", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "This can be viewed as a generalized inhomogeneous sixvertex model. Expanding this and the R matrix to first order in and substituting in Eq. \u03514\u0352 we find from Eq. \u03514\u0352 that", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "where we have discarded a constant term. These operators are the isotropic Gaudin Hamiltonians in a nonuniform magnetic field. 9 Their relevance to the spin realization of the BCS model \u03512\u0352 is that the latter is expressible \u0351up to a constant\u0352 as", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Although the above expressions for the conserved operators only apply to the case when all \u2440 j 's are distinct, our construction can be adapted to accommodate the cases when some of \u2440 j 's are the same. Algebraic Bethe ansatz. In the ABA, the integrals of motion are obtained by finding the eigenfunctions of the transfer matrix which is given by the trace of the monodromy matrix. The monodromy matrix is written in the form", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "which is the quantum equivalent of the scattering coefficients of the classical inverse scattering problem. Then from the Yang-Baxter algebra \u03513\u0352, we may derive the fundamental commutation relations \u0351FCR\u0352 between the entries of the monodromy matrix. Choosing the state \u03490\u0358\u03ed j\u03ed1 \u2340 \u0349\u2191\u0358 j as the pseudovacuum, then we have the pseudovacuum eigenvalues a(u) and", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Following the standard procedure, 10, 18 we choose the Bethe state", "cite_spans": [{"start": 34, "end": 37, "text": "10,", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "", "text": "Then we may derive the off-shell Bethe ansatz equations using the FCR, 18, 19 which, in the quasiclassical limit, take the form", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Imposing f \u2423 \u03ed0, one immediately sees that becomes the eigenvector of the conserved operator j with j as the eigenvalue. The constraint f \u2423 \u03ed0 is then equivalent to Richardson's equations,", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Here \u2340\u03eaN may be interpreted as the number of timereversed pairs of electrons. The energy eigenvalue of the Hamiltonian \u03512\u0352 is", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Scalar products and norms. Directly evaluating the norms of Bethe wave functions can be tedious, if not impossible. However, using the QISM they can be represented as determinants. 10, 20 Since this representation only depends on the R matrix, the derivation presented previously for different models can be readily applied to our \u0351generalized\u0352 inhomogeneous six-vertex model. In the QISM construction, the determinant representation for scalar products", "cite_spans": [{"start": 181, "end": 184, "text": "10,", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "", "text": "RAPID COMMUNICATIONS play a crucial role; especially, when one of the sets of parameters, for example \u0355v a \u0356, is a solution of the Bethe equations. 10, 11, 21 In the quasiclassical limit, the leading term of the scalar product for the inhomogeneous six-vertex model gives rise to the scalar product", "cite_spans": [{"start": 148, "end": 151, "text": "10,", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "", "text": "where the matrix elements of J are given by", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Here \u0355v \u2423 \u0356 are a solution to Richardson's equations \u03518\u0352, whereas \u0355w \u2424 \u0356 are arbitrary parameters. Richardson's expression 22 for the square of the norm of the Bethe state follows from Eqs. \u035110\u0352 and \u035111\u0352 by taking the limit w \u2423 \u2192v \u2423 .", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Solution of the quantum inverse problem. In order to calculate the form factors and correlation functions, we need to solve this problem for the generalized inhomogeneous sixvertex model. This then allows the reconstruction of local quantum spin operators in terms of the quantum monodromy matrix. A general procedure for doing this has recently been presented 11, 12 for the so-called fundamental models. A model is said to be fundamental whenever the local Lax operator in the transfer matrix is the same as the R matrix. In our case, where the model is not fundamental, due to the inclusion of the operators G i , we find", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "with K\u03f5\u035f j\u03ed1 \u2340 G j \u03edexp(\u03ea2\u035a j\u03ed1 \u2340 S j z /g\u2340). The above construction is one of our main results. The appearance of the powers of K arises from the c-number matrix realization of the Yang-Baxter algebra G which is peculiar to our construction. Following Ref. 11, one can obtain the representation of the correlation functions in terms of pseudovacuum eigenvalues a(u) and d(u).", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Form factors. For the BCS model the pair correlator", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "is of particular interest. ", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "can be calculated for the generalized inhomogeneous sixvertex model. In the quasiclassical limit, they reduce to the form factors of the BCS model,", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "with the matrix elements of T given by", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Above, T is the N\u03ebN matrix obtained from T by deleting the last row and column and replacing N\u03e91 by N in the matrix elements. Here we assume that both \u0355v \u2423 \u0356 and \u0355w b \u0356 ", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "In Eq. \u035114\u0352 m n is assumed, with the convention that it is zero when m\u03edn. Such a determinant representation of the correlation function will be computationally more accessible than a previous proposal 7 relying on the generating function associated with the Gaudin algebra. The above results constitute the building blocks of the Penrose-Onsager-Yang offdiagonal long-range order \u0351ODLRO\u0352 parameter \u232c OD , 24 \u232c OD \u03f5 1", "cite_spans": [], "ref_spans": []}, {"section": "\u035115\u0352", "text": "The small grain behavior of this parameter and its connection with the pair correlator \u035112\u0352 was recently discussed in Ref.", "cite_spans": [], "ref_spans": []}, {"section": "25.", "text": "Further applications. Our work is also relevant to proposals to observe BCS superconductivity in gases of fermionic atoms such as spin-polarized 6 Li.", "cite_spans": [], "ref_spans": []}, {"section": "25.", "text": "14 Quantum degeneracy of 6 Li at temperatures of about 240 nK has recently been observed in an atom trap with frequencies, \u03f31 kHz, 15 corresponding to an energy level spacing of the order of 10 \u03ea12 eV. The estimated BCS transition temperature is of the order of 20 nK, 14 corresponding to an energy gap of the order of 4\u03eb10 \u03ea12 eV. Hence, these systems are in a regime where the physics considered here will be important.", "cite_spans": [], "ref_spans": []}, {"section": "25.", "text": "Dukelsky and Schuck 16 recently introduced a solvable model for condensate fragmentation in finite boson systems. The model they solved follows from the construction used above when the Yang-Baxter algebra is realized in terms of the generators of the Lie algebra su (1, 1) . The model also provides a new mechanism for the enhancement of sd dominance in interacting boson models in the context of nuclear physics. 26 This work was supported by the Australian Research Council. *Email address: hqz@maths.uq.edu.au", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF12": {"title": "Quantum Inverse Scattering Method and Correlation Functions \u0351Cambridge University Press", "authors": [{"first": "V", "middle": ["E"], "last": "Korepin", "suffix": ""}], "year": 1993, "venue": "", "link": "115468375"}}, "ref_entries": {"TABREF0": {"text": ", . . . v N \u0349\u0349v 1 , . . . ,v N \u0358/\u0357v 1 , . . . v N \u0349v 1 , . . . ,v N \u0358 for any operator ). C m 2 can be interpreted as the probability enhancement of finding a pair of electrons in level m, instead of two uncorrelated electrons. \u0351It is zero for g\u03ed0).", "type": "table"}, "TABREF1": {"text": "Gaudin model, with the parameters v j satis- fying Richardson's Bethe ansatz equations \u03518\u0352 instead of Gaudin's ones. Here we present explicitly the two-point cor- relation function", "type": "table"}, "TABREF2": {"text": ". . . ,v \u2423 , . . . ,v \u2424 , . . . ,v N \u0358.Here the hat denotes that the corresponding parameter is not present in the set. Since \u0355w a \u0356 is a solution of the Bethe equations, \u0357w 1 , . . . ,w N \u0349S m \u03ea \u0349v 1 , . . . ,v \u2423 , . . . ,v N \u0358 is the form factor given before, while", "type": "table"}}}
{"paper_id": "119420956", "_pdf_hash": "8fe333af6994a03e18adbede8c9d6aa067b95cef", "abstract": [{"section": "Abstract", "text": "We study the Kondo effect in a single-electron transistor device realized in a single-wall carbon nanotube \u0351NT\u0352. The K-K\u0408 double orbital degeneracy of a NT, which originates from the peculiar two-dimensional band structure of graphene, plays the role of a pseudospin. Screening of this pseudospin, together with the real spin, can result in an SU\u03514\u0352 Kondo effect at low temperatures. In order to have such an exotic Kondo effect it is crucial that this orbital quantum number be conserved during tunneling. Experimentally, this conservation is not obvious and some mixing in the orbital channel may occur. Here we investigate in detail the role of mixing and asymmetry in the tunneling coupling and analyze how different Kondo effects, from an SU\u03514\u0352 symmetry to a two-level SU\u03512\u0352 Kondo effect, emerge depending on the mixing and/or asymmetry. We use four different theoretical approaches to address both the linear and nonlinear conductance for different values of external magnetic field. Our results point out clearly the experimental conditions to observe exclusively SU\u03514\u0352 Kondo physics. Although we focus on NT quantum dots \u0351QDs\u0352 our results also apply to vertical quantum dots. We also mention that a finite amount of orbital mixing corresponds, in pseudospin language, to having noncollinear leads with respect to the orbital \"magnetization\" axis which defines the two pseudospin orientations in the carbon nanotube QD. In this sense, some of our results are also relevant to the problem of a Kondo QD coupled to noncollinear ferromagnetic leads.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "I. INTRODUCTION", "text": "The first observations of Kondo effect in semiconductor quantum dots \u0351QDs\u0352 1-3 spurred a great deal of experimental and theoretical activity over the last few years. Since these experimental breakthroughs, remarkable achievements have been reported, including the observation of the unitary limit, 4 the singlet-triplet Kondo effect, 5 Kondo effect in molecular conductors, 6 and the Kondo effect in QDs connected to ferromagnetic 7 and superconducting reservoirs, 8 just to mention a few.", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "Recently, Jarillo-Herrero et al. reported perhaps the most sophisticated example, namely, the observation of an orbital Kondo effect in a carbon nanotube \u0351CNT\u0352 quantum dot \u0351QD\u0352. 9 In these experiments it was shown that the delocalized electrons of the reservoirs can screen both the orbital pseudospin degree of freedom in the CNT QD \u0351the K-K\u0408 double orbital degeneracy of the two-dimensional band structure of graphene,\u0352 and the usual spin degree of freedom resulting in an SU\u03514\u0352 Kondo effect at low temperatures. In a recent paper, 10 we showed that quantum fluctuations between the orbital and spin degrees of freedom may indeed dominate transport at low temperatures and lead to this highly symmetric SU\u03514\u0352 Kondo effect. More recently, Sakano and Kawakami 11 have studied using the Bethe ansatz method at zero temperature and the noncrossing approximation \u0351NCA\u0352 at finite temperatures the more general case where the quantum numbers of N degenerate orbital levels are conserved, and found new interesting features of SU\u03512N\u0352-symmetric Kondo effect. Importantly, an SU\u03514\u0352 Kondo effect is possible provided that both the orbital and spin indexes are conserved during tunneling. This poses an interesting question about the nature of the nanotube-lead contact because, in principle, there is no special reason why the orbital degree of freedom in the CNT should be conserved during tunneling.", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "As we mentioned, this orbital pseudospin originates from the peculiar electronic structure of the nanotube. 9, 12, 13 The electronic states of a NT form one-dimensional electron and hole subbands as a result of the quantization of the electron wavenumber perpendicular to the nanotube axis k \u040c , which arises when graphene is wrapped into a cylinder to create a NT. By symmetry, for a given subband at k \u040c = k 0 there is a second degenerate subband at k \u040c =\u2212k 0 . Semiclassically, this orbital degeneracy corresponds to the clockwise \u0351 \u0352 or coun-terclockwise \u0351 \u0352 symmetry of the wrapping modes. A plausible explanation of why this degree of freedom is preserved during tunneling could be that the QD is likely coupled to NT electrodes \u0351the metal electrodes are deposited on top of the NT so maybe the electrons tunneling out of the QD enter the NT section underneath the contacts\u0352 but this issue clearly deserves a thorough microscopic analysis about the nature of the contacts. The conservation of the orbital quantum number seems more likely in the vertical quantum dots \u0351VQD\u0352, 14 where the orbital quanutm number is the magnetic quantum number of the angular momentum.", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "Here, we take a different route and, assuming some degree of mixing in the orbital channel, ask ourselves about the robustness of the SU\u03514\u0352 Kondo effect against asymmetry in the couplings and/or mixing. The rest of the paper is organized as follows. In Sec. II we introduce the relevant model Hamiltonian and classify different schemes of lead-dot couplings. These different coupling schemes result in different symmetries and hence affect significantly the underlying Kondo physics. These effects are analyzed in the subsequent sections. We start our analysis with two renomalization group approaches in Sec. III. In Sec. IV two slave-boson approaches complement the previous results. Section V concludes the paper.", "cite_spans": [], "ref_spans": []}, {"section": "II. MODEL A. Nearly degenerate localized orbitals", "text": "We consider a QD with two \u0351nearly\u0352 degenerate localized orbitals which is coupled to reservoirs. As we mentioned before, we have in mind the experimental setup of Ref. 9 where a highly symmetric Kondo effect was demonstrated in a CNT QD. However, our description could well apply to vertical quantum dot \u0351VQD\u0352, 14 where the orbitals correspond to two degenerate Fock-Darwin states with different values of the angular momentum quantum number. Hereafter we will denote this orbital quantum number by m =1,2. The dot is then described by the Hamiltonian", "cite_spans": [], "ref_spans": []}, {"section": "II. MODEL A. Nearly degenerate localized orbitals", "text": "where \u2440 m is the single-particle energy level of the localized state with orbital m and spin , d m \u2020 \u0351d m \u0352 the fermion creation \u0351annihilation\u0352 operator of the state, n m = d m \u2020 d m the occupation, U mm \u0351m =1,2\u0352 the intraorbital Coulomb interaction, and U 12 the interorbital Coulomb interaction. The effect of the external magnetic field parallel to the symmetry axis of the system is to lifting the orbital and spin degeneracy of the single-particle energy levels. We will denote them by \u232c orb and \u232c Z , respectively, so that the single-particle energy levels \u2440 m have the form", "cite_spans": [], "ref_spans": []}, {"section": "II. MODEL A. Nearly degenerate localized orbitals", "text": "The precise values of the Coulomb interactions U mm \u0408 depend on the details of the system, but should be of the order of the charging energy E C = e 2 /2C with C being the total capacitance of the dot. In this work we focus on the regime where the system of the localized levels is occupied by a single electron \u0351\u035a m \u0357n m \u0358\u03f71, quarter filling 15 \u0352 and the Coulomb interaction energy \u0351U mm \u0408 \u03f3 E C \u0352 is much bigger than other energy scales. In this regime the Hamiltonian in Eq. \u03511a\u0352 suffices to describe all relevant physics of our concern.", "cite_spans": [], "ref_spans": []}, {"section": "B. Coupling schemes", "text": "Kondo physics arises as a result of the interplay between the strong correlation in the dot and the coupling of the localized electrons with the itinerant electrons in conduction bands. Naturally, different Kondo effects are observed depending on the way the dot is coupled to the electrodes and whether the orbital quantum number m is conserved or not. Nevertheless, it turns out highly nontrivial experimentally to distinguish those different Kondo effects. In subsequent sections we will consider different coupling shemes between the dot and the electrodes, show how different physics emerges, and propose how to distinguish them umambiguously in experiments.", "cite_spans": [], "ref_spans": []}, {"section": "B. Coupling schemes", "text": "The two leads \u2423 = L and R are treated as noninteracting gases of fermions", "cite_spans": [], "ref_spans": []}, {"section": "B. Coupling schemes", "text": "where denotes the channels in the leads. Without loss of generality, we assume that there are two distinguished \u0351groups of\u0352 channels = 1 and 2 in each lead. When the leads bears the same symmetry as the dot, this channel quantum number in the leads is identical to the orbital quantum number m in the dot and will be preserved over the tunneling of electrons from the dot to leads and vice versa; see Fig.  1\u0351a\u0352 . Otherwise, the orbital channels become mixed; see Fig.  1\u0351a\u0352 . The most general situation is described by the tunneling Hamiltonian", "cite_spans": [], "ref_spans": []}, {"section": "B. Coupling schemes", "text": "The total Hamiltonian is then given by", "cite_spans": [], "ref_spans": []}, {"section": "B. Coupling schemes", "text": "For the sake of simplicity, we will assume identical electrodes \u0351\u2440 Lk = \u2440 Rk \u0352, symmetric tunneling juctions \u0351V Lkm = V Rkm \u0352. For simplicity, we ignore their k-and -dependence of the tunneling amplitudes. Therefore, we consider a simplified model with V \u2423km = V ,m / \u0371 2 which defines the widths", "cite_spans": [], "ref_spans": []}, {"section": "B. Coupling schemes", "text": "where 0 is the density of states in the reservoirs. Then in equilibrium the Hamiltonian H in Eq. \u03511\u0352 is equivalent to", "cite_spans": [], "ref_spans": []}, {"section": "B. Coupling schemes", "text": "and discarded the decoupled term \u2440 k b k \u2020 b k . In the following sections we investigate the physics described by the Hamiltonian in Eq. \u03513\u0352 and, in particular, clarify the role of index conservation in the symmetry of the underlying Kondo regime at low temperatures. In order to do this analysis we use four different approaches, the scaling theory \u0351perturbative renormalization group approach\u0352, the renormalization group method \u0351NRG\u0352, the slave-boson mean-field \u0351SBMF\u0352 theory, and the noncrossing approximation \u0351NCA\u0352.", "cite_spans": [], "ref_spans": []}, {"section": "III. RENORMALIZATION GROUP APPROACHES", "text": "The renormalization group theory provides a convenient and powerful method to study low-energy properties of strongly correlated electron systems. Here we will take two RG approaches, the scaling theory [16] [17] [18] and the NRG method. [19] [20] [21] [22] While the scaling theory is useful for a qualitative understanding of the model, a more precise quantitative analysis requires the use of more sophisticated methods like the NRG method. This method is known to be one of the most accurate and powerful theoretical tools to study quantum impurity problems \u0351see Appendix A\u0352.", "cite_spans": [{"start": 208, "end": 212, "text": "[17]", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "A. SU(4) Kondo effect", "text": "We now turn to the case where tunneling processes conserve the orbital quantum number; see Fig. 2 . In this case, the Hamiltonian reads", "cite_spans": [], "ref_spans": []}, {"section": "A. SU(4) Kondo effect", "text": "or \u0353see Eqs. \u03513a\u0352 and \u03513b\u0352\u0354", "cite_spans": [], "ref_spans": []}, {"section": "A. SU(4) Kondo effect", "text": "From the RG point of view, starting initially with nearly degenerate levels, all the localized levels are relevant for the spin and orbital fluctuations, and, as we will see below, contribute to the Kondo effect. To investigate the low-energy properties of the orbital and spin fluctuations of the model, we perform a Schrieffer-Wolf transformation and obtain an effective Kondo-type Hamiltonian", "cite_spans": [], "ref_spans": []}, {"section": "A. SU(4) Kondo effect", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "A. SU(4) Kondo effect", "text": "The exchange coupling constants J m \u0351m =1,2\u0352 are given by", "cite_spans": [], "ref_spans": []}, {"section": "\u03519\u0352", "text": "We ", "cite_spans": [], "ref_spans": []}, {"section": "\u03519\u0352", "text": "The level splitting \u232c orb and \u232c Z remain constant under the RG transformation", "cite_spans": [], "ref_spans": []}, {"section": "\u03519\u0352", "text": "The exchange coupling constants J i \u0351i =1, ... ,5\u0352 are initially given by Eq. \u03519\u0352 and by", "cite_spans": [], "ref_spans": []}, {"section": "\u035112\u0352", "text": "Under the RG transformations, they scale as", "cite_spans": [], "ref_spans": []}, {"section": "\u035112\u0352", "text": "for D \u04f7\u232c orb \u0d1c\u232c Z . For D \u04f6\u232c orb , it is clear from Eq. \u035110\u0352 that the orbital fluctuations are frozen and only J 1 is relevant, which scales as", "cite_spans": [], "ref_spans": []}, {"section": "\u035112\u0352", "text": "It implies that we recover the single-level Anderson model for D \u04f6\u232c orb . Therefore in the remainder of this section, we will focus on the case D \u04f7\u232c orb .", "cite_spans": [], "ref_spans": []}, {"section": "\u035112\u0352", "text": "It is convenient to define the reduced variables j i \u03f5 J i / J 1 \u0351i =2, ... ,5\u0352 and rewrite the RG equations \u035113\u0352 as", "cite_spans": [], "ref_spans": []}, {"section": "\u035112\u0352", "text": "with x =ln\u0351 0 J 1 \u0352. J 1 obeys the scaling equation", "cite_spans": [], "ref_spans": []}, {"section": "\u035112\u0352", "text": "The RG equations \u035115\u0352 have two fixed points: one describing the SU\u03514\u0352 Kondo physics", "cite_spans": [], "ref_spans": []}, {"section": "\u035112\u0352", "text": "and the other describing the usual SU\u03512\u0352 Kondo physics", "cite_spans": [], "ref_spans": []}, {"section": "\u035112\u0352", "text": "both with J 1 = \u03f1 as indicated in Fig. 3 . Linearizing the RG equations \u035115\u0352 around the fixed points, one can easily show that both the SU\u03512\u0352 and SU\u03514\u0352 Kondo fixed points are stable fixed points \u0353there is one marginal parameter at the SU\u03514\u0352 fixed point\u0354. However, as indicated as a dashed semicircle in Fig. 3\u0351b\u0352 the radius of convergence is finite while the fixed point itself is located at infinity. This implies that in principle, the SU\u03514\u0352 Kondo fixed point cannot be reached for arbitrarily small values of 1 \u2212 \u232b 2 / \u232b 1 . However, as illustrated in Fig. 3\u0351a\u0352 , in the region of physical interest for sufficiently small values of 1 \u2212 \u232b 2 / \u232b 1 , the scaling behavior is essentially governed by the SU\u03514\u0352 Kondo fixed point \u0351see also Fig. 5\u0352 . More importantly, for sufficiently small values of 1 \u2212 \u232b 2 / \u232b 1 , the SU\u03512\u0352 fixed point governs the physics only at extremely low energies. This suggests that the SU\u03514\u0352 Kondo signature can be observed exclusively at relatively higher energy scales \u0351of order of the Kondo temperature\u0352, as in the recently reported experiment. 9 At B \u0288 = 0 and \u232b 1 = \u232b 2 \u03f5 \u232b 0 , the RG equations \u035113\u0352 reduce to a single equation", "cite_spans": [], "ref_spans": [{"start": 34, "end": 40, "text": "Fig. 3", "ref_id": "FIGREF0"}, {"start": 303, "end": 312, "text": "Fig. 3\u0351b\u0352", "ref_id": "FIGREF0"}, {"start": 555, "end": 564, "text": "Fig. 3\u0351a\u0352", "ref_id": "FIGREF0"}]}, {"section": "\u035112\u0352", "text": "Comparing this with the corresponding equation Eq. \u035114\u0352 for the usual single-level Anderson model, we note that the Kondo temperature is enhanced exponentially:", "cite_spans": [], "ref_spans": []}, {"section": "\u035112\u0352", "text": "with respect to the SU\u03512\u0352 Kondo temperature", "cite_spans": [], "ref_spans": []}, {"section": "\u035112\u0352", "text": "The perturbative RG analysis discussed above, whose validity is guaranteed only for 0 J i \u04f6 1, turns out to be qualitatively correct in a wide region of the parameter space and provides a clear interpretation of the model. To confirm the perturbative RG analysis and make quantitative analysis we used the NRG method \u0351see the Appendix\u0352. Our NRG results are summarized in Figs. 4 and 5 where the total spectral density", "cite_spans": [], "ref_spans": []}, {"section": "\u035112\u0352", "text": "which gives a direct information of the linear conductance, 23 is plotted. The spectral density shows a peak near the Fermi energy, corresponding to the formation of the SU\u03514\u0352 Kondo state; see Fig. 4 . The peak width, which is much broader than that for the SU\u03512\u0352 Kondo model \u0351dotted line\u0352, demonstrates the exponential enhancement of the Kondo temperature mentioned above. Another remarkable effect is that the SU\u03514\u0352 Kondo peak shifts away from = E F = 0 and is pinned at \u03f7 T K SU\u03514\u0352 . This can be understood from the Friedel sum rule 24 which, in this case, gives \u2426 = / 4 for the scattering phase shift at E F .", "cite_spans": [], "ref_spans": [{"start": 193, "end": 199, "text": "Fig. 4", "ref_id": "FIGREF1"}]}, {"section": "\u035112\u0352", "text": "Accordingly, the linear conductance at zero temperature is given by G 0 =4\u0351e 2 / h\u0352sin", "cite_spans": [], "ref_spans": []}, {"section": "\u035112\u0352", "text": "It is interesting to recall that the Friedel sum rule gives the same linear conductance also for the two-level SU\u03512\u0352 Kondo model. Thus, neither the enhancement of the Kondo temperature nor the linear conductance, can distinguish between the SU\u03514\u0352 and the twolevel SU\u03512\u0352 Kondo effects. This can only be achieved by studying the influence of a parallel magnetic field in the nonlinear conductance, as shown in Ref. 9", "cite_spans": [], "ref_spans": []}, {"section": "B. Effects of mixing of orbital quantum numbers", "text": "To examine the stability of the SU\u03514\u0352 Kondo phenomena against orbital mixing, we consider the model \u0351see Fig. 6\u0352 : where the indexes in the Hamiltonian imply 1 = 2 and 2 =1 and V 0 \u03f5 V 1,1 = V 2,2 and V X \u03f5 V 1,2 = V 2,1 . If we rewrite the Hamiltonian as", "cite_spans": [], "ref_spans": []}, {"section": "B. Effects of mixing of orbital quantum numbers", "text": "it now becomes clear that, in a pseudospin language, a finite amount of orbital mixing corresponds to having noncollinear leads with respect to the orbital \"magnetization\" axis which defines the pseudospin orientations m = 1 and m = 2 in the dot. In other words, each confined electron \u0351with defined pseudospin\u0352 couples to a linear combination of pseudospin and, as a result, becomes rotated in pseudospin space by an angle defined by tan = V X / V 0 . Note that for the maximal mixing V X = V 0 , the tunneling electrons loose completely information about their pseudospin orientation. In this limit, one recovers the spin Kondo physics \u0353SU\u03512\u0352 symmetry\u0354 of a two-level Anderson model \u0353see next subsection, Eq. \u035136\u0352\u0354. For zero mixing V X = 0, the model reduces to the SU\u03514\u0352-symmetric model of Eq. \u03516\u0352 \u0351with tunnel amplitudes that do not depend on the orbital index\u0352.", "cite_spans": [], "ref_spans": []}, {"section": "B. Effects of mixing of orbital quantum numbers", "text": "After the RG transformation of the Anderson-type model in Eq. \u035123\u0352 until the single-particle energy levels are comparable with the conduction band width \u0351when the charge fluctuations are suppressed\u0352, the SW transformation gives", "cite_spans": [], "ref_spans": []}, {"section": "B. Effects of mixing of orbital quantum numbers", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "B. Effects of mixing of orbital quantum numbers", "text": "is the SU\u03514\u0352 Kondo model and", "cite_spans": [], "ref_spans": []}, {"section": "B. Effects of mixing of orbital quantum numbers", "text": "is the SU\u03512\u0352 Kondo model. The exchange coupling constants J 0 and J X , respectively, are given by", "cite_spans": [], "ref_spans": []}, {"section": "B. Effects of mixing of orbital quantum numbers", "text": "One can already grasp an idea about the effects of the mixing J X \u0351i.e., \u232b X \u0352 of the orbital quantum numbers by considering the two limiting cases, J X =0 \u0351no mixing\u0352 and J X = J 0 \u0351maxi-mal mixing\u0352, of the effective Hamiltonian \u035125\u0352. In the case of no mixing \u0351J X =0\u0352, the effective Hamiltonian \u035125\u0352 is reduced to the SU\u03514\u0352-symmetric Kondo model Eq. \u035126\u0352, which was already discussed in the previous section. The Kondo temperature is T K \u03f3 D exp\u0351\u22121/4J 0 \u0352. When the mixing is maximal \u0351J X = J 0 \u0352, on the other hand, the effective Hamiltonian becomes H eff SU\u03512\u0352 in Eq. \u035127\u0352. Under the RG procedures, the effective Hamiltonian \u035125\u0352 transforms in the general form", "cite_spans": [], "ref_spans": []}, {"section": "B. Effects of mixing of orbital quantum numbers", "text": "The exchange coupling constants are initially given by", "cite_spans": [], "ref_spans": []}, {"section": "\u035130\u0352", "text": "With the RG transformations, they scale as", "cite_spans": [], "ref_spans": []}, {"section": "\u035130\u0352", "text": "and", "cite_spans": [], "ref_spans": []}, {"section": "\u035130\u0352", "text": "As before \u0353see Eq. \u035115\u0352\u0354, it is convenient to work with the reduced coupling constants j i \u03f5 J i / J 1 . In terms of the reduced exchange coupling constants, the RG equations read together with", "cite_spans": [], "ref_spans": []}, {"section": "\u035130\u0352", "text": "The RG equations \u035133\u0352 again have two fixed points, one associated with the SU\u03512\u0352 Kondo effects and the other with the SU\u03514\u0352 Kondo effects; see Fig. 7 . The RG flow diagram in Fig. 7 is reminiscent of that in Fig. 3 . Both fixed points are stable. However, since the radius of convergence of the SU\u03514\u0352 Kondo fixed point is finite, the SU\u03514\u0352 Kondo fixed point cannot be reachable even for arbitrarily small mixing V X ; Fig. 7\u0351b\u0352 . However, in the region of physical interest, the physics is essentially governed by the SU\u03514\u0352 Kondo fixed point for sufficiently small V X ; Fig. 7\u0351a\u0352 . Therefore, the SU\u03514\u0352 Kondo physics is in principle unstable against both the orbital quantum number anisotropy 1 \u2212 \u232b 2 / \u232b 1 and the orbital mixing \u232b X . For sufficiently small values of those, however, the SU\u03514\u0352 Kondo physics still determines the transport properties except at extremely low energy scales. As we mentioned earlier, this suggests that to observe the indications of the SU\u03514\u0352 Kondo physics exclusively one has to investigate the properties at relatively higher energies \u0351order of Kondo temperature\u0352. This is confirmed and demonstrated in the NRG results summarized in Fig. 8 . We will also see below that there is no way to distinguish the two-level SU\u03512\u0352 Kondo physics and the SU\u03514\u0352 Kondo physics experimentally by means of linear conductance.", "cite_spans": [], "ref_spans": [{"start": 143, "end": 149, "text": "Fig. 7", "ref_id": "FIGREF2"}, {"start": 175, "end": 181, "text": "Fig. 7", "ref_id": "FIGREF2"}, {"start": 208, "end": 214, "text": "Fig. 3", "ref_id": "FIGREF0"}, {"start": 418, "end": 427, "text": "Fig. 7\u0351b\u0352", "ref_id": "FIGREF2"}, {"start": 571, "end": 580, "text": "Fig. 7\u0351a\u0352", "ref_id": "FIGREF2"}]}, {"section": "C. Two-level SU(2) Kondo effect", "text": "As we have mentioned in the previous subsection, at maximum mixing V 0 = V X the physics becomes that of a twolevel SU\u03512\u0352 Anderson model \u0351see Fig. 9\u0352 . In this case, the only degree of freedom that is conserved during tunneling is spin and the total Hamiltonian reads", "cite_spans": [], "ref_spans": [{"start": 142, "end": 149, "text": "Fig. 9\u0352", "ref_id": "FIGREF3"}]}, {"section": "C. Two-level SU(2) Kondo effect", "text": "or, equivalently \u0353see Eq. \u03514\u0352\u0354, ", "cite_spans": [], "ref_spans": []}, {"section": "C. Two-level SU(2) Kondo effect", "text": "As the scaling theory of the Kondo-type Hamiltonian obtained from the two-level Anderson model has been developed in detail in Refs. 25 and 26, here we will focus on the first stage, which highlights the difference between the twolevel SU\u03512\u0352-symmetric Anderson model and the SU\u03514\u0352-symmetric Anderson model. Finally, the physical arguments based on the perturbative RG theory will be examined quantitatively by means of the NRG method.", "cite_spans": [], "ref_spans": []}, {"section": "C. Two-level SU(2) Kondo effect", "text": "As we integrate out the electronic states in the ranges \u0353\u2212D ,\u2212\u0351D \u2212 \u2426D\u0352\u0354 and \u0353D \u2212 \u2426D , D\u0354 of the conduction band, the dot Hamiltonian \u03511a\u0352 evolves as", "cite_spans": [], "ref_spans": []}, {"section": "C. Two-level SU(2) Kondo effect", "text": "with other terms in the total Hamiltonian \u035136\u0352 kept unchanged. Notice here the appearance of the new term in t, i.e., a direct transition between the two orbitals m = 1 and 2. The scaling of the parameters \u2440 m and t are governed by the RG equations", "cite_spans": [], "ref_spans": []}, {"section": "C. Two-level SU(2) Kondo effect", "text": "respectively. The RG equation \u035138\u0352 for the single-particle energy levels \u2440 m is the same as in the usual single-level Anderson model 17, 18 \u0351the corresponding RG flow diagram is shown in Fig. 10\u0352 . However, due to the direct transition t emerging from the RG equation \u035139\u0352, \u2440 m are not relevant to the Kondo effect \u0353they are not the eigenvalues of H D in Eq. \u035137\u0352\u0354. To find the relevant energy level\u0351s\u0352 that is \u0351are\u0352 directly involved in the Kondo effect, one can diagonalize H D in Eq. \u035137\u0352 by means of the canonical tranformation", "cite_spans": [{"start": 133, "end": 136, "text": "17,", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "C. Two-level SU(2) Kondo effect", "text": "where the angle is defined by the relation", "cite_spans": [], "ref_spans": []}, {"section": "C. Two-level SU(2) Kondo effect", "text": "The dot Hamiltonian in Eq. \u035137\u0352 is then rewritten as", "cite_spans": [], "ref_spans": []}, {"section": "C. Two-level SU(2) Kondo effect", "text": "At the same time, the canonical transformation in Eq. \u035140\u0352 also changes the coupling term in the total Hamiltonian \u035136\u0352 to", "cite_spans": [], "ref_spans": []}, {"section": "C. Two-level SU(2) Kondo effect", "text": "with V \u00b1 defined by", "cite_spans": [], "ref_spans": []}, {"section": "C. Two-level SU(2) Kondo effect", "text": "Accordingly, the tunneling rates \u232b \u00b1 \u03f5 0 \u0349V \u00b1 \u0349 2 of the effective orbital levels \u2440 \u00b1, are given by Figure 11 shows the scaling of \u2440 \u00b1 \u0351the arrowed lines\u0352 and \u232b \u00b1 \u0351the widths of the shadowed regions around \u2440 \u00b1 \u0352 governed by Eqs. \u035138\u0352, \u035139\u0352, \u035143\u0352, and \u035146\u0352. Note that the effective single-particle energy levels \u2440 \u00b1 always repel each other, 27 and the hybridization \u232b + \u0351\u232b \u2212 \u0352 of the lower \u0351upper\u0352 level \u2440 + \u0351\u2440 \u2212 \u0352 always increases \u0351decreases\u0352. Essential in this scaling property of the two-level Anderson model is the direct transition t between the orbitals m = 1 and 2 mediated by the conduction band. The scaling of \u2440 \u00b1 and \u232b \u00b1 stops when the lower level \u2440 + becomes comparable with D \u0351\u2440 + \u04cd D\u0352; see Fig. 11 . Then the charge fluctuations are highly suppressed and the occupation of the lower level is close to unity \u0351\u0357n + \u0358\u03f71\u0352. Therefore, only the lower level \u2440 + gets involved in the Kondo physics, and hence the resulting Kondo effect is identical to the usual SU\u03512\u0352 Kondo effect. To be more specific, let us consider the two limiting cases, \u0349\u2440 1 \u2212 \u2440 2 \u0349 \u04f7\u232b 0 and \u0349\u2440 1 \u2212 \u2440 2 \u0349 \u04f6\u232b 0 , assuming", "cite_spans": [], "ref_spans": [{"start": 100, "end": 109, "text": "Figure 11", "ref_id": "FIGREF4"}, {"start": 703, "end": 710, "text": "Fig. 11", "ref_id": "FIGREF4"}]}, {"section": "C. Two-level SU(2) Kondo effect", "text": "Since t \u03f3 \u232b 0 , one has", "cite_spans": [], "ref_spans": []}, {"section": "C. Two-level SU(2) Kondo effect", "text": "or, equivalently,", "cite_spans": [], "ref_spans": []}, {"section": "\u036e \u035149\u0352", "text": "This implies that when the two orbital levels are nearly degenerate \u0351\u0349\u2440 1 \u2212 \u2440 2 \u0349 \u04f6\u232b 0 \u0352 the Kondo temperature 17,18 is enhanced exponentially,", "cite_spans": [], "ref_spans": []}, {"section": "\u035150\u0352", "text": "\u0353with \u2440 0 \u03f5\u0351\u2440 1 + \u2440 2 \u0352 /2\u0354 compared with the single-level case \u0351i.e., \u0349\u2440 1 \u2212 \u2440 2 \u0349 \u04f7\u232b 0 \u0352 with", "cite_spans": [], "ref_spans": []}, {"section": "\u035151\u0352", "text": "In the limit of nearly degenerate levels \u0351\u0349\u2440 1 \u2212 \u2440 2 \u0349 \u04f6\u232b 0 \u0352, the upper level \u2440 \u2212 is located at distance smaller than \u232b + from the lower level \u2440 + \u0353\u0351\u2440 \u2212 \u2212 \u2440 + \u0352 \u0547\u232b + \u0351see Fig. 11\u0352\u0354 and the transition from \u2440 + to \u2440 \u2212 is allowed in general. Indeed, this effect can be taken into account by a proper SW transformation including both levels and the scaling of the resulting Kondo-like Hamiltonian, 25, 26 and gives rise to a bump structure at = \u232c eff above the Fermi energy E F of the leads, with \u232c eff given by 27 \u0351with \u2440 1 = \u2440 2 initially\u0352", "cite_spans": [], "ref_spans": [{"start": 172, "end": 181, "text": "Fig. 11\u0352\u0354", "ref_id": "FIGREF4"}]}, {"section": "\u035151\u0352", "text": "in the single-particle excitation spectrum A d \u0351\u0352 in Fig. 12 ; see below. Again, all the interpretations made above based on the perturbative RG are confirmed with the NRG method. Figure  12 shows the total spectral density A d \u0351E\u0352. One can see that as \u232c orb increases with \u232c Z = 0, the Kondo peak gets sharper, i.e., the enhancement of the Kondo temperature T K in Eq. \u035150\u0352 diminishes for \u232c orb \u0d1c\u232b 0 ; see Fig. 12\u0351a\u0352 . Notice that the bump above the Fermi energy originates from the excitation via the transition from the lower level \u2440 + to the higher level \u2440 \u2212 , and thus is located at E = \u232c eff ; see Eq. \u035152\u0352. When we allows \u232c Z finite as well, then the Kondo peak now splits into two because of the Zeeman splitting. 28, 29 ", "cite_spans": [], "ref_spans": []}, {"section": "IV. SLAVE-BOSON TREATMENT", "text": "In order to confirm our previous results and obtain analytical expressions for intermediate mixing, we also use slave boson techniques. In particular, the SBMF approach, which is a good approximation in the strong coupling limit T \u04f6 T K , allows us to obtain analytical expressions for the Kondo tem- perature and the Kondo peak position for arbitrary mixing. Our SBMFT results are complemented with a NCA, which takes into account both thermal and charge fluctuations in a self-consistent manner.", "cite_spans": [], "ref_spans": []}, {"section": "IV. SLAVE-BOSON TREATMENT", "text": "At equilibrium it is convenient to change to a representation in terms of the symmetric \u0351even\u0352 and antisymmetric \u0351odd\u0352 combinations of the localized and delocalized orbital channels. 30 Thus, the even-odd transformation consists of", "cite_spans": [], "ref_spans": []}, {"section": "IV. SLAVE-BOSON TREATMENT", "text": "Hamiltonian \u0353Eq. \u03513\u0352\u0354 in this basis reads", "cite_spans": [], "ref_spans": []}, {"section": "IV. SLAVE-BOSON TREATMENT", "text": "where, again, we have considered \u2020 f , where f , is the pseudofermion that annihilates one \"occupied state\" in the th localized orbital and b \u2020 is a boson operator that creates an \"empty state.\" Quite generally the intra\u0351inter\u0352 Coulomb interaction is very large and we can safely take the limit of U \u2192 \u03f1. This fact enforces the con-", "cite_spans": [], "ref_spans": []}, {"section": "IV. SLAVE-BOSON TREATMENT", "text": ", that prevents the accomodation of two electrons at the same time in either the same orbital or different orbitals. This constraint is treated with a Lagrange multiplier:", "cite_spans": [], "ref_spans": []}, {"section": "\u035154\u0352", "text": "Notice that we have rescaled the tunneling amplitudes V e\u0351o\u0352 \u2192 V e\u0351o\u0352 \u0371 N according to the spirit of a 1 / N expansion \u0351N is the total degeneracy of the localized orbital\u0352. Our next task is to solve this Hamiltonian, which is rather complicated due to the presence of the three operators in the tunneling part and the constraint. In order to do this we employ two approaches that describe two different physical regimes. The first one is the SBMFT approach, which describes properly the low-temperature strong coupling regime. This SBMFT is a good approximation in the deep Kondo limit, namely only spin fluctuations are taken into account. The NCA, on the other hand, takes into account both thermal and charge fluctuations in a self-consistent manner. It is well known that the NCA fails in describing the low-energy strong coupling regime. Nevertheless, the NCA has proven to give reliable results for temperatures down to a fraction of T K .", "cite_spans": [], "ref_spans": []}, {"section": "A. Slave-boson mean-field theory", "text": "We start discussing the mean-field approximation of Eq. \u035154\u0352. The merit of this approach is its simplicity while capturing the main physics of the pure Kondo regime. It has been successfully applied to investigate the out-ofequilibrium Kondo effect [31] [32] [33] [34] and double quantum dots, 35-39 just to mention a few. This approach corresponds to the lowest order in the 1 / N expansion, O\u03511\u0352 where the boson operator b\u0351t\u0352 is replaced by its classical \u0351nonfluctuating\u0352 average, namely, b\u0351t\u0352 / \u0371 N \u2192 \u0357b\u0358 / \u0371 N \u03f5 b, thereby neglecting charge fluctuations. In the limit N \u2192 \u03f1 this approximation is exact. Then the mean-field Hamiltonian is given by", "cite_spans": [], "ref_spans": []}, {"section": "\u035155\u0352", "text": "where \u1e7c = V b = V \u0357b\u0358 and 0, = 0, + are the renormalized tunneling amplitude and renormalized orbital level. The two mean field parameters b and have to be determined through the mean-field equations. These equations are the constraint", "cite_spans": [], "ref_spans": []}, {"section": "\u035155\u0352", "text": "and the equation of motion \u0351EOM\u0352 of the boson field", "cite_spans": [], "ref_spans": []}, {"section": "\u035155\u0352", "text": "Now we write these two equations in terms of nonequilibrium Green functions. The Green function for the localized orbital \u0351 e , o\u0352 G , \u03fd \u0351t \u2212 t\u0408\u0352 =\u2212i\u0357f , \u2020 \u0351t\u0408\u0352f , \u0351t\u0352\u0358, and the corresponding lesser lead-orbital Green function is G ,,k ,", "cite_spans": [], "ref_spans": []}, {"section": "\u035155\u0352", "text": "Expressing the mean-field equations in terms of these nonequilibrium Green functions, \u035156\u0352 and \u035157\u0352 become", "cite_spans": [], "ref_spans": []}, {"section": "\u035155\u0352", "text": "In order to solve the set of mean field equations, we proceed as follows. First, we employ the analytic continuation rules to the EOM of the time-ordered Green's functions", "cite_spans": [], "ref_spans": []}, {"section": "\u035155\u0352", "text": "\u2020 \u0351t\u0408\u0352f , \u0351t\u0352\u0356\u0358 \u0351where T C is the time-ordering operator along a complex time contour\u0352. 40 Second, we use the EOM technique to relate the lead-orbital Green function with the orbital Green function. And finally we rewrite the meanfield equations in the frequency domain \u0351we take 0, = 0 \u0352", "cite_spans": [{"start": 88, "end": 90, "text": "40", "ref_id": "BIBREF40"}], "ref_spans": []}, {"section": "\u035155\u0352", "text": "The integrals appearing in Eq. \u035159\u0352 can be performed analytically by using a Lorentzian cutoff \u0351\u2440\u0352 = D / \u0351\u2440 2 + D 2 \u0352 for the DOS in the leads and the lesser orbital Green function", "cite_spans": [], "ref_spans": []}, {"section": "\u035155\u0352", "text": "where \u232b e\u0351o\u0352 = \u232b e\u0351o\u0352 \u0349b\u0349 2 . In the deep Kondo limit, namely, where \u232b e\u0351o\u0352 = \u232b e\u0351o\u0352 / N are the original rates. Using the parametrization V e = V\u0351cos + sin \u0352 and V o = V\u0351cos \u2212 sin \u0352, the tunneling rates read \u232b e = V 2 \u03511 + sin 2\u0352 = \u232b\u03511 + sin 2\u0352 and \u232b o = = V 2 \u03511 \u2212 sin 2\u0352 = \u232b\u03511 \u2212 sin 2\u0352. Taking sin 2 = \u2424, with \u2424 \u03530,1\u0354 \u0351notice that 0 \u0d1b sin 2 \u0d1b 1 for \u03530, /4\u0354\u0352 we parametrize the even and odd rates as \u232b e = \u03511+\u2424\u0352\u232b, and \u232b o = \u03511\u2212\u2424\u0352\u232b, respectively. Thus, \u2424 0 accounts for processes where the even and odd channels are not coupled equally to the lead electrons or, equivalently, to processes where the orbital index is not conserved. Using the new notation, the mean field equations can be written in a compact way", "cite_spans": [], "ref_spans": []}, {"section": "\u035155\u0352", "text": "or, equivalently,", "cite_spans": [], "ref_spans": []}, {"section": "\u035163\u0352", "text": "Its real and imaginary parts are", "cite_spans": [], "ref_spans": []}, {"section": "\u035163\u0352", "text": "Equation \u035164a\u0352 has solution when 0 = \u00b1 \u0371 \u232b e \u232b o . Notice that only the positive root satisfies Eq. \u035164b\u0352. By sustituting this result in Eq. \u035164b\u0352 we arrive after some algebra at 0 /4\u232b to zero, in agreement with the Friedel sum rule. From the above results, we conclude that the odd orbital becomes decoupled at maximum mixing where we are left with SU\u03512\u0352 Kondo physics arising from spin fluctuations in the even orbital channel. This SU\u03514\u0352 \u2192 SU\u03512\u0352 transition as mixing increases is illustrated in Fig. 2 where we plot the SBMFT parameters as a function of \u2424 \u0351see Fig. 13\u0352 . Now we are in position to calculate transport properties. For this purpose it is now more convenient to write SBMFT equations in matrix form as \u0351here we are back to the original basis\u0352", "cite_spans": [], "ref_spans": [{"start": 564, "end": 572, "text": "Fig. 13\u0352", "ref_id": "FIGREF0"}]}, {"section": "\u035163\u0352", "text": "The trace includes also the sum over spin indices. Here, \u011c \u03fd is the lesser matrix orbital Green function which is related to the advanced \u011c a and retarded \u011c r matrix Green functions through the expression", "cite_spans": [], "ref_spans": []}, {"section": "\u035163\u0352", "text": "where \u233a \u03fd is the lesser matrix self-energy. The explicit expressions for these matrices are", "cite_spans": [], "ref_spans": []}, {"section": "\u035163\u0352", "text": "\u0351\u011c r is obtained by direct complex conjugation of \u011c a .\u0352 The lesser matrix self-energy reads", "cite_spans": [], "ref_spans": []}, {"section": "\u035163\u0352", "text": "In the same way the retarded matrix self-energy is", "cite_spans": [], "ref_spans": []}, {"section": "\u035172\u0352", "text": "Inserting Eqs. \u035170\u0352 and \u035171\u0352 in Eq. \u035169\u0352 we obtain for the lesser orbital Green function", "cite_spans": [], "ref_spans": []}, {"section": "\u035172\u0352", "text": "Using the explict expressions of the self-energies and the nonequilibrium Green functions we simplify Eq. \u035168b\u0352 as follows:", "cite_spans": [], "ref_spans": []}, {"section": "\u035172\u0352", "text": "By solving in a self-consistent way Eqs. \u035168a\u0352 and \u035174\u0352 for each dc bias V dc , one gets the behavior of the two renormalized parameters at nonequilibrium conditions. 36 The electrical current has in appearence the same form as the conventional Landauer-B\u00fcttiker current expression for noninteracting electrons", "cite_spans": [], "ref_spans": []}, {"section": "\u035172\u0352", "text": "Caution is needed in order to make a correct interpretation of Eq. \u035175\u0352, since it contains \"many-body\" effects via the renormalized parameters that have to be determined for each V dc in a self-consistent way. As a result, T\u0351\u2440 , V dc \u0352 has a nontrivial behavior with voltage in contrast with the noninteracting case. The nonlinear conductance is calculated by direct derivation of Eq. \u035175\u0352 with respect to the bias voltage: G \u03f5 dI / dV dc . In the limit of V dc \u2192 0 \u0351at equilibrium\u0352 the linear conductance G 0 is given by the well-known expression", "cite_spans": [], "ref_spans": []}, {"section": "\u035172\u0352", "text": "where the transmission is", "cite_spans": [], "ref_spans": []}, {"section": "\u035172\u0352", "text": "Finally, inserting Eqs. \u035170\u0352 and \u035172\u0352 in Eq. \u035177\u0352 one arrives at the explicit formula for the transmission FIG. 13 . Transition from SU\u03514\u0352 to SU\u03512\u0352 Kondo physics as obtainded from SBMFT: As the orbital mixing increases, the SU\u03514\u0352 Kondo effect reduces to an SU\u03512\u0352 spin Kondo effect. This is reflected in both the position of the Kondo resonance \u0353Fig. 2\u0351a\u0352\u0354 as well as the reduction of the odd Kondo temperature down to zero \u0353Fig. 2\u0351b\u0352\u0354, see main text.", "cite_spans": [], "ref_spans": []}, {"section": "\u035178\u0352", "text": "which is the main result of this part. Remarkably, the linear conductance G 0 does not depend on \u2424. In particular, for the SU\u03514\u0352 Kondo model \u0351\u2424 =0\u0352, the transmission takes the simple form", "cite_spans": [], "ref_spans": []}, {"section": "\u035178\u0352", "text": "In this case the resonance is pinned at \u2440 = 0 = T K with a width given by T K ; this leads to T\u03510\u0352 = 1 and in consequence G 0 =2e 2 / h. For \u2424 =1 \u0353two-level SU\u03512\u0352 Kondo model\u0354 Eq. \u035178\u0352 reduces to", "cite_spans": [], "ref_spans": []}, {"section": "\u035178\u0352", "text": "In this case the resonance occurs at \u2440 = 0 = 0 and again T\u03510\u0352 =1\u21d2 G 0 =2e 2 / h. As we pointed out, this fact makes both Kondo effects indistinguishable through linear conductance measurements.", "cite_spans": [], "ref_spans": []}, {"section": "\u035178\u0352", "text": "All these features are clearly seen in Fig. 14 where the transmission for different amount of mixing, i.e., different \u2424, is plotted. Thus, for \u2424 = 0 the transmission peak is located at T K as expected whereas for \u2424 = 1 this moves towards \u2440 =0. During the transition from the SU\u03514\u0352 to the two-level SU\u03512\u0352 Kondo model, the transmission gets narrower and develops a \"cusp\" signaling the competition between even and odd channels. This is clearly seen if we rewrite the transmission as follows:", "cite_spans": [], "ref_spans": [{"start": 39, "end": 46, "text": "Fig. 14", "ref_id": "FIGREF1"}]}, {"section": "\u035181\u0352", "text": "Note that both channels are resonant at the same energy 0 but have different widths \u0351\u232b e and \u232b o \u0352, which explains the \"cusp\" behavior. Here, we speculate that a finite splitting \u2426 originated from charge fluctuations 42 \u0351not included at the SB-MFT level\u0352 would give rise to two split resonances for \u2424 0, namely, 0 \u2192 0 \u00b1 = \u2426 \u00b1 \u0371 \u232b e \u232b o . This is confirmed in the next section where we present results obtained from a full NCA calculation including fluctuations. Eventually, for \u2424 = 1 the competition cannot occur and the transmission does not show the cusp.", "cite_spans": [], "ref_spans": []}, {"section": "B. Noncrossing approximation method", "text": "The SBMFT suffers from two drawbacks: \u03511\u0352 it leads always to local Fermi liquid behavior and \u03512\u0352 The SBMFT has a phase transition \u0351originating from the breakdown of the local gauge symmetry of the problem\u0352 that separates the low temperature state from the high temperature local moment regime. This later problem may be corrected by including 1/N corrections around the mean-field solution. The noncrossing approximation \u0351NCA\u0352 [43] [44] [45] is the lowest order selfconsistent, fully conserving and \u233d derivable theory in the Baym sense 46 which includes such corrections. Without entering into much detail of the theory, we just mention that the boson fields in Eq. \u035154\u0352, which were treated as averages in the previous subsection \u0353b\u0351t\u0352 / \u0371 N \u2192 \u0357b\u0358 / \u0371 N \u03f5 b\u0354, are treated now as fluctuating quantum objects. In particular, one has to derive self-consistent equations-of-motion for the time- A rigorous and well established way to derive these equations-of-motion was first introduced by Kadanoff and Baym, 47 and has been related to other nonequilibrium methods \u0351like the Keldysh method\u0352 by Langreth, see Ref. 40 for a review. Here, we just show numerical results of the NCA equations for our problem and refer the interested reader to Refs. 38 and 43-45 for details.", "cite_spans": [{"start": 1006, "end": 1008, "text": "47", "ref_id": "BIBREF47"}, {"start": 1110, "end": 1112, "text": "40", "ref_id": "BIBREF40"}], "ref_spans": []}, {"section": "B. Noncrossing approximation method", "text": "In particular, the density of states is given by", "cite_spans": [], "ref_spans": []}, {"section": "B. Noncrossing approximation method", "text": "where A r \u0351\u0352 is the Fourier transform of the retarded Green function", "cite_spans": [], "ref_spans": []}, {"section": "B. Noncrossing approximation method", "text": "The density of states for different values of \u2424, and different temperatures, is plotted in Fig. 15 . Interestingly, the cusp behavior of Fig. 14 in the previous subsection now becomes a splitting for the even and odd channels. This is illustrated in the inset where the curve corresponding to \u2424 = 0.5 is plotted together with the individual even and odd channel contributions. As we anticipated, the presence of charge fluctuations yields the splitting of 0 s due to the different renormalization arising from different couplings for the even and odd channels \u0351\u232b e\u0351o\u0352 \u0352 \u0353see Eqs. \u035138\u0352 and \u035139\u0352\u0354.", "cite_spans": [], "ref_spans": [{"start": 137, "end": 144, "text": "Fig. 14", "ref_id": "FIGREF1"}]}, {"section": "V. CONCLUSION", "text": "We have considered the single-electron transistor \u0351SET\u0352 device with the CNT QD or VQD as the central island in the Kondo regime. We studied the case where the CNT QD or VQD has a high symmetry so that the orbital quantum numbers are conserved through the system. We investigated in detail how different Kondo physics, the SU\u03514\u0352 Kondo effect or the two-level SU\u03512\u0352 Kondo effect, emerges depending on the extent to which the symmetry is broken in realistic situations. We used four different theoretical approaches, the scaling theory, the NRG method, the SBMFT, and the NCA method to address both the linear and nonlinear conductance for different values of external magnetic field. Our results show that there is no way to distinguish experimentally by means of the linear conductance \u0351low-energy property\u0352 alone. The SU\u03514\u0352 Kondo physics, which arises with higher symmetry, can be observed exclusively only by the nonlinear conductance \u0351higher-energy property\u0352 in the presence of finite mangetic field, as in the recent experiment. 9, 48 The symmetry breaking \u0351either the orbital anisotropy 1 \u2212 \u232b 2 / \u232b 1 or the orbital mixing \u232b X \u0352 drives the system from the SU\u03514\u0352 Kondo fixed point to the SU\u03512\u0352 Kondo fixed point. At finite yet sufficiently small symmetry breaking, the SU\u03514\u0352 Kondo phyiscs governs the transport in the system at relatively high energies \u0351order of the Kondo temperature\u0352 while the twolevel SU\u03512\u0352 Kondo effect takes it over at extremely low energies. This gives another reason why the indications of the SU\u03514\u0352 Kondo physics should be investigated by means of the nonlinear conductance in the presence of external magnetic field.", "cite_spans": [], "ref_spans": []}, {"section": "V. CONCLUSION", "text": "for numerical accuracy. The original Hamiltonian is recovered by", "cite_spans": [], "ref_spans": []}, {"section": "V. CONCLUSION", "text": "with S N \u03f5 \u2333 \u0351N\u22121\u0352/2 . At each iteration of the NRG procedures, we calculate the local spectral density, 50 which determines the transport properties through the dot", "cite_spans": [], "ref_spans": []}, {"section": "V. CONCLUSION", "text": "with A mm \u0408 ;", "cite_spans": [], "ref_spans": []}, {"section": "V. CONCLUSION", "text": "A mm \u0408 ;", "cite_spans": [], "ref_spans": []}, {"section": "V. CONCLUSION", "text": "where \u03490\u0358 \u0351\u0349\u2423\u0358\u0352 is the many-body ground \u0351excited\u0352 state of the system and E 0 \u0351E \u2423 \u0352 the corresponding energy.", "cite_spans": [], "ref_spans": []}, {"section": "V. CONCLUSION", "text": "*Electronic address: choims@korea.ac.kr", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF15": {"title": "For half filling, an interesting quantum phase transition involving SU\u03514\u0352 symmetry has been discussed in", "authors": [], "year": "", "venue": "Here, we focus on quarter filling", "link": null}, "BIBREF17": {"title": "\u03511978\u0352, see also Ref", "authors": [{"first": "F", "middle": ["D M"], "last": "Haldane", "suffix": ""}], "year": "", "venue": "Phys. Rev. Lett", "link": null}, "BIBREF40": {"title": "Linear and Nonlinear Electron Transport in Solids", "authors": [{"first": "D", "middle": ["C"], "last": "Langreth", "suffix": ""}], "year": 1976, "venue": "", "link": null}, "BIBREF41": {"title": "The Kondo Problem to Heavy Fermions \u0351Cam-bridge University Press", "authors": [{"first": "A", "middle": ["C"], "last": "Hewson", "suffix": ""}], "year": 1993, "venue": "", "link": null}, "BIBREF47": {"title": "Quantum Statistical Mechanics \u0351Benjamin", "authors": [{"first": "L", "middle": ["P"], "last": "Kadanoff", "suffix": ""}, {"first": "G", "middle": [], "last": "Baym", "suffix": ""}], "year": 1962, "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "FIG. 3. \u0351Color online\u0352 RG flows for different values of \u232b 2 / \u232b 1 with \u232b 1 fixed.", "type": "figure"}, "FIGREF1": {"text": "FIG. 4. \u0351Color online\u0352 Comparison of the SU\u03512\u0352 and SU\u03514\u0352 Kondo model.", "type": "figure"}, "FIGREF2": {"text": "FIG. 7. \u0351Color online\u0352 The RG flow in the case where there is a finite mixing of the orbital quantum numbers m.", "type": "figure"}, "FIGREF3": {"text": "FIG. 9. \u0351Color online\u0352 Schematic of the two-level SU\u03512\u0352-symmetric Anderson model.", "type": "figure"}, "FIGREF4": {"text": "FIG. 11. \u0351Color online\u0352 Scaling of the two-level SU\u03512\u0352-symmetric Anderson model. The arrowed lines indicate the RG flow of the effective single-particle energy levels \u2440 \u00b1 \u0353see Eq. \u035143\u0352\u0354 and the widths of the shadowed regions around \u2440 \u00b1 the RG flow of \u232b \u00b1 \u0353see Eq. \u035146\u0352\u0354. We have defined \u232b 0 \u03f5\u0351\u232b 1 + \u232b 2 \u0352 /2.", "type": "figure"}, "FIGREF5": {"text": "and , = 0, . The occupation per channel and spin is given by n = d \u2020 d and the total occupation per channel is n = \u035a n . In Eq. \u035153\u0352 the tunneling amplitudes for each channel are: V e \u03f5 V 0 + V X and V o \u03f5 V 0 \u2212 V X . In order to normalize the total tunneling rate we take for the diagonal and off-diagonal tunneling amplitude V 0 = V cos and V X = V sin , namely, V e = V\u0351cos + sin \u0352 and V o = V\u0351cos \u2212 sin \u0352. Notice that \u03530, /4\u0354 in order to always have V o positively defined. There are two very different situations, namely, \u0351i\u0352 when = 0, where there are only tunneling pro- cesses that conserve the orbital index and \u0351ii\u0352 when = /4 where the mixing and no mixing tunneling amplitudes are the same. Now we write the physical fermionic operator as a com- bination of a pseudofermion and a boson operator as follows: d = b", "type": "figure"}, "FIGREF7": {"text": "ordered double-time Green's function \u0351subindexes are omit- ted here\u0352 iG\u0351t,t\u0408\u0352 \u03f5 \u0357T c f\u0351t\u0352f \u2020 \u0351t\u0408\u0352\u0358, iB\u0351t,t\u0408\u0352 \u03f5 \u0357T c b\u0351t\u0352b \u2020 \u0351t\u0408\u0352\u0358 \u035182\u0352 or in terms of their analytic pieces iG\u0351t,t\u0408\u0352 = G \u03fe \u0351t,t\u0408\u0352\u0351t \u2212 t\u0408\u0352 \u2212 G \u03fd \u0351t,t\u0408\u0352\u0351t\u0408 \u2212 t\u0352, iB\u0351t,t\u0408\u0352 = B \u03fe \u0351t,t\u0408\u0352\u0351t \u2212 t\u0408\u0352 + B \u03fd \u0351t,t\u0408\u0352\u0351t\u0408 \u2212 t\u0352. \u035183\u0352", "type": "figure"}, "FIGREF8": {"text": "FIG. 14. \u0351Color online\u0352 Equilibrium SBMFT result: Transmission, T\u0351\u2440\u0352 as a function of the frequency for several values of \u2424. Left inset corresponds to the Kondo temperature vs \u2424.", "type": "figure"}, "TABREF0": {"text": "FIG. 1. \u0351Color online\u0352 Schematic of a representative mesoscopic system in question. In \u0351a\u0352 each of the two leads L and R has two conduction bands \u0351or \"modes\"\u0352 1 and 2. The model with two leads in \u0351a\u0352 is equivalent in equilibrium to the model in \u0351b\u0352 with only one lead. The operators c k \u0351 =1,2 and = \u2191 , \u2193\u0352 are related to a Lk and a Rk by the canonical tranformation in Eq. \u03514\u0352. The wiggly lines indicate the interorbital Coulomb interaction U 12 \u0353the intraor- bital itneraction U mm \u0351m =1,2\u0352 is not shown\u0354.", "type": "table"}}}
{"paper_id": "119422971", "_pdf_hash": "bea23c82a7ff04dd40618f6de1ae6670ab2d39e0", "abstract": [{"section": "Abstract", "text": "The pseudo-magnetic field generated by mechanical strain in graphene can have dramatic consequences on the behavior of electrons and holes. Here we show that pseudo-magnetic field fluctuations present in crumpled graphene can induce significant intravalley scattering of charge carriers. We detect this by measuring the confocal Raman spectra of crumpled areas, where we observe an increase of the D\u2032/D peak intensity ratio by up to a factor of 300. We reproduce our observations by numerical calculation of the double resonant Raman spectra and interpret the results as experimental evidence of the phase shift suffered by Dirac charge carriers in the presence of a pseudo-magnetic field. This lifts the restriction on complete intravalley backscattering of Dirac fermions. npj 2D Materials and Applications (2019) 3:11 ; https://doi", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION", "text": "With the discovery of the half integer quantum Hall effect in graphene 1, 2 and of topological materials, 3, 4 Berry phase effects have taken center stage in condensed matter research. In graphene and other crystals with a honeycomb structure, charge carriers have a sublattice and valley degree of freedom, described in a continuum Dirac model by a pseudospin. 5, 6 As a consequence of this spin-like property, electrons or holes belonging to the two inequivalent valleys (K and K\u2032, see Fig. 1 ) acquire a Berry phase of \u03c0 and \u2212\u03c0, respectively during a cyclotron orbit. The importance of pseudospin and the Berry phase are most striking when perturbations are smooth on the atomic scale, i.e., sublattice symmetry still holds. In this case, scattering between the two valleys is suppressed and the pseudospin is conserved, 5 leading to some important effects that are the hallmark of graphene, such as weak antilocalization, 7 the half integer quantum Hall effect 1,2 and Klein tunneling. 5, 8 Importantly, complete backscattering from a state |\u2212q\u232a to |q\u232a (see Fig. 1 ) is forbidden, due to pseudospin conservation 5 (q is the crystal momentum measured from the K point in the Brillouin zone). This was first shown and explained for metallic carbon nanotubes 9, 10 and is crucial for the exceptional mobility of graphene. 5, 11 Here we show that scattering on strain fluctuations in graphene can lift the restriction on complete backscattering. This is demonstrated by confocal Raman spectroscopy measurements of crumpled graphene, where we measure a giant increase in the D\u2032 peak intensity. This Raman peak originates from a resonant Raman process which involves intravalley backscattering of charge carriers. The intravalley to intervalley scattering peak intensity ratio is found to be as high as I D\u2032 /I D = 30, in contrast to the usual value of \u22480.1.", "cite_spans": [{"start": 71, "end": 73, "text": "1,", "ref_id": "BIBREF0"}, {"start": 74, "end": 75, "text": "2", "ref_id": "BIBREF1"}, {"start": 106, "end": 108, "text": "3,", "ref_id": "BIBREF2"}, {"start": 109, "end": 110, "text": "4", "ref_id": "BIBREF3"}, {"start": 362, "end": 364, "text": "5,", "ref_id": "BIBREF4"}, {"start": 365, "end": 366, "text": "6", "ref_id": "BIBREF5"}, {"start": 824, "end": 825, "text": "5", "ref_id": "BIBREF4"}, {"start": 926, "end": 927, "text": "7", "ref_id": "BIBREF6"}, {"start": 990, "end": 992, "text": "5,", "ref_id": "BIBREF4"}, {"start": 993, "end": 994, "text": "8", "ref_id": "BIBREF7"}, {"start": 1116, "end": 1117, "text": "5", "ref_id": "BIBREF4"}, {"start": 1260, "end": 1262, "text": "9,", "ref_id": "BIBREF8"}, {"start": 1263, "end": 1265, "text": "10", "ref_id": "BIBREF9"}, {"start": 1323, "end": 1325, "text": "5,", "ref_id": "BIBREF4"}, {"start": 1326, "end": 1328, "text": "11", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "12", "text": "Since the strain induced pseudo-magnetic field (B ps ) couples to the pseudospin, 13, 14 the enhancement of the D\u2032 peak at 1620 cm \u22121 is due to the extra phase acquired by charge carriers undergoing Raman scattering on strain fluctuations. Thus, in contrast to a scalar potential, backscattering of Dirac particles is no longer forbidden. We reproduce our measurement results, using numerical calculation of the double resonant Raman processes.", "cite_spans": [{"start": 82, "end": 85, "text": "13,", "ref_id": "BIBREF12"}, {"start": 86, "end": 88, "text": "14", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "RESULTS AND DISCUSSION", "text": "Mechanical deformations in 2D materials with a honeycomb atomic structure naturally give rise to a two component pseudogauge field, which is directly proportional to the strain tensor components. [15] [16] [17] [18] [19] These strain induced fields have a scalar (V(r)) and a vector (A(r)) component, 18 being analogous to an electrostatic potential and a magnetic vector potential. The latter having opposite sign in the two valleys and giving rise to a pseudo-magnetic field (B ps ). 18 For graphene supported on hexagonal BN, B ps is especially strong near bubbles (hundreds of Tesla) and has a major influence on transport properties. 20 Furthermore, in the highest mobility heterostructure devices it is very likely that random strain fluctuations are the main factors limiting mobility through intravalley scattering. 21 This type of scattering is characterized by small changes in the charge carrier momentum and dominates if the scattering potentials are smooth on the atomic scale, such as charged impurities, [22] [23] [24] or strain fluctuations. 21 Such scattering processes are mostly explored in charge transport experiments through weak (anti)localization measurements. 7, 10, 25 In supported graphene, B ps appears due to random strain fluctuations, stemming from non perfect stacking and interaction with the substrate. For SiO 2 supported graphene, B ps due to corrugation has values of the order of 1 T. The extra phase aquired by the wave function of the scattered carrier, much like a real magnetic field, suppresses the weak anti-localization effect. 25 Confocal Raman spectroscopy is another powerful tool to investigate strain fluctuations in graphene. Mechanical deformation induced softening or hardening of the phonon mode energy is detectable through the shift, splitting and broadening of the G and 2D peaks. 21, 26, 27 However, until now direct detection of the scattering on strain fluctuations has been lacking. Both small (intravalley) and large momentum (intervalley) scattering is measurable separately via the double resonant D\u2032 and D peaks at \u22481620 and \u22481350 cm . Lattice defects produce both intravalley as well as intervalley scattering, giving contribution to both D\u2032 and D peaks, smooth defects which are less efficient at producing large momentum change, mostly contribute to the D\u2032 peak. Numerical calculations by Venezuela et al. 28 show that for closely packed alkali metals on graphene, acting as smooth Coulomb scattering centers, the D\u2032 peak should be more intense than the D peak. However, the peak itself should be undetectably small. Furthermore, for lattice defects, able to induce both types of scattering, the measured ratio of intensities is I D\u2032 /I D = 0.1. 12 This is much smaller than the expected value of~0.5 from analytical theory of the double resonant processes, suggesting that pseudospin effects could play an important role, particularly in intravalley processes. 29 The double resonant D\u2032 process is sketched in Fig. 1b . After the creation of the electron/hole pair the largest contribution to the D\u2032 intensity is given by processes involving scattering by both an electron and a hole. 28, 30 Backscattering of the electron and/or hole involve an elastic defect scattering with small momentum change and a scattering involving an LO phonon along the \u0393M direction. 28, 31 It has been shown previously that the process involves a small portion of phonon phase space, as well as relatively small regions of the Dirac cone. 28, 30 Since the biggest contribution to the intensity involves backscattering within a single valley along \u0393M, this process necessarily involves a flip in pseudospin. Indeed it is suspected by Rodriguez-Nieva et al. 29 that the pseudospin related phases of the excited electron and hole play a dominant role in suppressing the backscattering necessary for the D\u2032 peak. Since Coulomb scatterers do not change the phase of the charge carrier wave functions, the resulting suppression of backscattering straightforwardly explains the immeasurably small calculated intensity of the D\u2032 peak. 28 The situation changes drastically if the scattering potential has a vector component, i.e., there is a sizable pseudo-magnetic field involved in the defect scattering. If the charge carriers stay within the same valley, this changes the phase of the electron or hole, similarly to a real magnetic field, enabling backscattering.", "cite_spans": [{"start": 196, "end": 200, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 201, "end": 205, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 206, "end": 210, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 211, "end": 215, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 216, "end": 220, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 301, "end": 303, "text": "18", "ref_id": "BIBREF17"}, {"start": 486, "end": 488, "text": "18", "ref_id": "BIBREF17"}, {"start": 639, "end": 641, "text": "20", "ref_id": "BIBREF19"}, {"start": 824, "end": 826, "text": "21", "ref_id": "BIBREF20"}, {"start": 1019, "end": 1023, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 1024, "end": 1028, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 1029, "end": 1033, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 1058, "end": 1060, "text": "21", "ref_id": "BIBREF20"}, {"start": 1185, "end": 1187, "text": "7,", "ref_id": "BIBREF6"}, {"start": 1188, "end": 1191, "text": "10,", "ref_id": "BIBREF9"}, {"start": 1192, "end": 1194, "text": "25", "ref_id": "BIBREF24"}, {"start": 1573, "end": 1575, "text": "25", "ref_id": "BIBREF24"}, {"start": 1838, "end": 1841, "text": "21,", "ref_id": "BIBREF20"}, {"start": 1842, "end": 1845, "text": "26,", "ref_id": "BIBREF25"}, {"start": 1846, "end": 1848, "text": "27", "ref_id": "BIBREF26"}, {"start": 2374, "end": 2376, "text": "28", "ref_id": "BIBREF27"}, {"start": 2714, "end": 2716, "text": "12", "ref_id": "BIBREF11"}, {"start": 2930, "end": 2932, "text": "29", "ref_id": "BIBREF28"}, {"start": 3154, "end": 3157, "text": "28,", "ref_id": "BIBREF27"}, {"start": 3158, "end": 3160, "text": "30", "ref_id": "BIBREF29"}, {"start": 3332, "end": 3335, "text": "28,", "ref_id": "BIBREF27"}, {"start": 3336, "end": 3338, "text": "31", "ref_id": "BIBREF30"}, {"start": 3488, "end": 3491, "text": "28,", "ref_id": "BIBREF27"}, {"start": 3492, "end": 3494, "text": "30", "ref_id": "BIBREF29"}, {"start": 3705, "end": 3707, "text": "29", "ref_id": "BIBREF28"}, {"start": 4076, "end": 4078, "text": "28", "ref_id": "BIBREF27"}], "ref_spans": []}, {"section": "RESULTS AND DISCUSSION", "text": "To detect Raman scattering from strain fluctuations with a sizable B ps , we have measured confocal Raman maps on crumpled graphene flakes exfoliated onto a SiO 2 surface. We have used to our advantage that during the exfoliation some flakes tend to crumple (see Fig. 2a ). Crumpling enhances B ps caused by the strain fluctuations by at least a factor of 100 compared to the~1 T 25 resulting from surface roughness of SiO 2 . Additionally, we found the same results on samples that were crumpled using mild annealing and crumpling by a tungsten tip (see Methods). We have measured a total of ten crumpled graphene samples, among which six show an anomalously high and dispersive D\u2032 peak (see Supplementary information S1). Here, we illustrate the effect through the example of a characteristic sample (Fig. 2) , while data for other samples can be found in the Supplementary information.", "cite_spans": [{"start": 380, "end": 382, "text": "25", "ref_id": "BIBREF24"}], "ref_spans": [{"start": 263, "end": 270, "text": "Fig. 2a", "ref_id": "FIGREF1"}, {"start": 802, "end": 810, "text": "(Fig. 2)", "ref_id": "FIGREF1"}]}, {"section": "RESULTS AND DISCUSSION", "text": "AFM measurements show that the graphene layer consists of a network of folds on it's surface. Measuring the Raman spectra with a spatial resolution of~500 nm and excitation wavelength of 532 nm, we map the intensity of the D\u2032 peak ( Fig. 2c) within the crumpled area marked in Fig. 2a . The most striking feature of the map is that the crumpled regions show increased D\u2032 intensity, the region with the strongest enhancement marked by a green circle. To shed more light on the Raman scattering, we plot the complete Raman spectrum of this region in Fig. 2d . The most surprising feature of the spectrum is the extremely high D\u2032 peak, having 20% the intensity of the G peak. This is unprecedented because the D\u2032 peak is only observed when the sample contains strong lattice defects, such as vacancies, sp 3 type defects of grain boundaries, 12, 28, 32 and it is always accompanied by the D peak, with its intensity being mostly~10% of the D intensity (I D\u2032 /I D = 0.1). 12, 33 This result has to be considered in the light that in the area where the spectrum was measured there are no graphene edges. As expected for defect free graphene, the D peak intensity is just barely larger than the background (see inset in Fig.  2d ). Furthermore, the graphene flake shows the pristine Raman spectrum of graphene in the uncrumpled areas. Ratios I D\u2032 /I D = 10 have been also found in samples, where the laser spot contains both crumpled areas and edges (see Supplementary information S1). The I D\u2032 /I D maps of two additional samples can be seen in Fig. 3 .", "cite_spans": [{"start": 839, "end": 842, "text": "12,", "ref_id": "BIBREF11"}, {"start": 843, "end": 846, "text": "28,", "ref_id": "BIBREF27"}, {"start": 847, "end": 849, "text": "32", "ref_id": "BIBREF31"}, {"start": 968, "end": 971, "text": "12,", "ref_id": "BIBREF11"}, {"start": 972, "end": 974, "text": "33", "ref_id": "BIBREF32"}], "ref_spans": [{"start": 233, "end": 241, "text": "Fig. 2c)", "ref_id": "FIGREF1"}, {"start": 277, "end": 284, "text": "Fig. 2a", "ref_id": "FIGREF1"}, {"start": 548, "end": 555, "text": "Fig. 2d", "ref_id": "FIGREF1"}, {"start": 1214, "end": 1222, "text": "Fig.  2d", "ref_id": "FIGREF1"}, {"start": 1540, "end": 1546, "text": "Fig. 3", "ref_id": "FIGREF2"}]}, {"section": "RESULTS AND DISCUSSION", "text": "It is known that overlapping graphene layers can produce a non dispersive peak ranging from 1540 up to 1630 cm \u22121 . [34] [35] [36] The non dispersive nature of this peak is due to the fact that the LO phonon from around the \u0393 point taking part in the process is selected by the mismatch angle of the two graphene layers and not by the laser energy. 35 Therefore, if the mismatch angle between the overlapping graphene layers is in the 4\u00b0to 6\u00b0range, Fig. 1 Pseudospin and intravalley scattering in graphene. a Pseudospin texture around a K point in the first Brillouin zone of graphene. If the perturbation doesn't distinguish between the two sublattices, it is unable to flip the pseudospin (\u03c3). Therefore, complete backscattering involving small changes in momentum from |\u2212q\u232a to |q\u232a is forbidden by pseudospin conservation. b Intravalley process responsible for the D\u2032 Raman band of graphene P. Kun et al. this so called R\u2032 peak could be mistaken for the D\u2032 peak. To make sure that the peak around 1620 cm \u22121 is indeed the D\u2032 peak, we measured the change in the peak position with changing excitation wavelength. The data for the presented sample can be seen in Fig. 2e , with the graph color corresponding to the excitation laser color. The measured dispersion is 7.8 cm \u22121 /eV and is similar to the values measured on other samples (see Supplementary information S2). It is slightly lower than the value of~10 cm \u22121 /eV expected for the D\u2032 peak, 32 ,33 see also our calculation of the strain induced D\u2032 peak dispersion in the same plot (see Fig. 2f ). The reason for the lower dispersion value might be the fact that the D\u2032 peak is mixed with the non dispersive R\u2032 peak in certain areas. An example where this effect is strong is shown in Fig. S5 of the Supplementary information. To reduce the possible interference from the R\u2032 peak in our measurements, we have prepared an additional set of samples. These graphene samples had their top and bottom covered in a 5 nm thick polyvinyl alcohol (PVA) film. Crumpling was achieved by using a sharp tungsten needle and a micro-manipulator stage. We found similar D\u2032 peak intensities in the crumpled areas as in the case of other samples (see Supplementary Figs. S6 and S7) . These experiments rule out any major effect from the R\u2032 peak, since the PVA layer on the graphene prevents any atomically clean interface to form between the overlapping graphene.", "cite_spans": [{"start": 116, "end": 120, "text": "[34]", "ref_id": "BIBREF33"}, {"start": 121, "end": 125, "text": "[35]", "ref_id": "BIBREF34"}, {"start": 126, "end": 130, "text": "[36]", "ref_id": "BIBREF35"}, {"start": 349, "end": 351, "text": "35", "ref_id": "BIBREF34"}, {"start": 1449, "end": 1451, "text": "32", "ref_id": "BIBREF31"}], "ref_spans": [{"start": 1163, "end": 1170, "text": "Fig. 2e", "ref_id": "FIGREF1"}, {"start": 1544, "end": 1551, "text": "Fig. 2f", "ref_id": "FIGREF1"}, {"start": 1742, "end": 1749, "text": "Fig. S5", "ref_id": "FIGREF4"}]}, {"section": "RESULTS AND DISCUSSION", "text": "Within the literature there have been some observations of a barely measurable D\u2032 peak on graphene supported on nanosized pillars 37 and nanoparticles, 38 exhibiting wrinkling. However, it is unclear what the D to D\u2032 intensity ratio is in these experiments. In experiments of graphene wrinkling on a polymer, the D\u2032 peak is obscured by the presence of the polymer substrate. 39 Next, we reproduce our measured D\u2032 peak intensities by numerical calculations of the double resonant processes. 28, 40 To explore the pseudo-magnetic field within crumpled graphene and to construct a theoretical model for the Raman scattering potential, we study the wrinkling of graphene, using the LAMMPS molecular dynamics code 41 (for details see Supplementary information S4). We consider two model geometries that make up a crumpled graphene sheet. 42 One involves a single fold (Fig.  4b) , seen all over the crumpled sample (Fig. 2b) , the other involves a double fold (Fig. 4c) , constructed by creating a second fold in a singly folded graphene. The double fold shows a complex strain pattern, containing both compression and tension and an increase in the strain by a factor of 10 compared to the single fold, as evidenced by the color scale on the atoms in Fig. 4b , c. Having determined the geometry of the crumpled graphene, it becomes possible to calculate the the pseudo-magnetic field B ps , from the atomic positions. It can be understood, as a result of the local modification of inter-atomic hopping, either through changes in bond length or bond angles. 18 Additionally, B ps can be interpreted as the consequence of Dirac quasiparticles existing in a curved space-time. 18, [43] [44] [45] [46] Here, we calculate B ps from the modulation of the hopping parameter, as described by Guinea et al. 47 This model reproduces the magnitude of B ps measured via scanning tunneling microscopy. 13, 48, 49 Computing B ps , directly from the modulation of the atomic positions 50 we find a maximum B ps of 20 T in the single fold, and as expected from the difference in strain, the double fold shows a B ps in the 200 T range (Fig. 4e, f) . This B ps originates from the modulation of the nearest neighbor hopping energy due to strain. 15, 16, 47 However, in cases where the curvature of the graphene sheet is large, there is another sizable component to the pseudomagnetic field, due to the hybridization of the \u03c3 and \u03c0 bonds. 17 The total vector potential is the sum of the hopping induced A(r) and the curvature induced A \u03c3\u03c0 (r). The experimentally relevant part of the vector potential, 13 the pseudo-magnetic field, is then formed by the rotor of the sum of these two contributions: B ps \u00bc \u2207 \u00f0A \u00fe A \u03c3\u03c0 \u00de. Using the formula for A \u03c3\u03c0 from Rainis et al., 51 we calculate the B ps for our fold. For a radius of curvature R of a fold parallel to the zigzag direction, we have A \u03c3\u03c0 x \u00f0r\u00de \u00bc 3\u03b5 \u03c0\u03c0 a 2 =8R\u00f0r\u00de 2 and A \u03c3\u03c0 y \u00f0r\u00de \u00bc 0, where \u03b5 \u03c0\u03c0 % 3eV 17, 51 and a = 1.42 \u00c5. In our calculations R is around 3 \u00c5, corresponding to the 2-3 \u00c5 measured by Annett et al., 52 while Rainis et al. 51 calculate 7 \u00c5. As an example, in the case when R = 4 \u00c5 the maximum curvature induced B ps is around 200 T, an order of magnitude larger than the hopping induced one (see Fig. 4d , e), in accordance with the finding of Rainis et al. 51 Both contributions to B ps are also dependent on the orientation of the fold within the graphene lattice, with the maximum B ps present in folds parallel to the zigzag direction and zero B ps for armchair. 51, 53 For the double fold, the hopping induced B ps is in itself in the 200 T range, due to the larger strains (Fig. 4f) . A large collection of double or multiple folds may be necessary to create the large B ps values needed to observe the enhanced D\u2032 peak, such as in the region shown by a green circle in Fig. 2b, c . Using the field theoretical approach in curved space [43] [44] [45] [46] to calculate B ps , we find values of similar magnitude. However, in our experiment we lack the spatial resolution to be able to distinguish between the two possible interpretations of B ps . 54 For further discussion see Section S6 of the Supplementary information.", "cite_spans": [{"start": 130, "end": 132, "text": "37", "ref_id": "BIBREF36"}, {"start": 152, "end": 154, "text": "38", "ref_id": "BIBREF37"}, {"start": 375, "end": 377, "text": "39", "ref_id": "BIBREF38"}, {"start": 490, "end": 493, "text": "28,", "ref_id": "BIBREF27"}, {"start": 494, "end": 496, "text": "40", "ref_id": "BIBREF39"}, {"start": 709, "end": 711, "text": "41", "ref_id": "BIBREF40"}, {"start": 833, "end": 835, "text": "42", "ref_id": "BIBREF41"}, {"start": 1553, "end": 1555, "text": "18", "ref_id": "BIBREF17"}, {"start": 1670, "end": 1673, "text": "18,", "ref_id": "BIBREF17"}, {"start": 1674, "end": 1678, "text": "[43]", "ref_id": "BIBREF42"}, {"start": 1679, "end": 1683, "text": "[44]", "ref_id": "BIBREF43"}, {"start": 1684, "end": 1688, "text": "[45]", "ref_id": "BIBREF44"}, {"start": 1689, "end": 1693, "text": "[46]", "ref_id": "BIBREF45"}, {"start": 1794, "end": 1796, "text": "47", "ref_id": "BIBREF46"}, {"start": 1885, "end": 1888, "text": "13,", "ref_id": "BIBREF12"}, {"start": 1889, "end": 1892, "text": "48,", "ref_id": "BIBREF47"}, {"start": 1893, "end": 1895, "text": "49", "ref_id": "BIBREF48"}, {"start": 1966, "end": 1968, "text": "50", "ref_id": "BIBREF49"}, {"start": 2225, "end": 2228, "text": "15,", "ref_id": "BIBREF14"}, {"start": 2229, "end": 2232, "text": "16,", "ref_id": "BIBREF15"}, {"start": 2233, "end": 2235, "text": "47", "ref_id": "BIBREF46"}, {"start": 2417, "end": 2419, "text": "17", "ref_id": "BIBREF16"}, {"start": 2580, "end": 2582, "text": "13", "ref_id": "BIBREF12"}, {"start": 2746, "end": 2748, "text": "51", "ref_id": "BIBREF50"}, {"start": 2934, "end": 2937, "text": "17,", "ref_id": "BIBREF16"}, {"start": 2938, "end": 2940, "text": "51", "ref_id": "BIBREF50"}, {"start": 3048, "end": 3050, "text": "52", "ref_id": "BIBREF51"}, {"start": 3071, "end": 3073, "text": "51", "ref_id": "BIBREF50"}, {"start": 3306, "end": 3308, "text": "51", "ref_id": "BIBREF50"}, {"start": 3515, "end": 3518, "text": "51,", "ref_id": "BIBREF50"}, {"start": 3519, "end": 3521, "text": "53", "ref_id": "BIBREF52"}, {"start": 3890, "end": 3894, "text": "[43]", "ref_id": "BIBREF42"}, {"start": 3895, "end": 3899, "text": "[44]", "ref_id": "BIBREF43"}, {"start": 3900, "end": 3904, "text": "[45]", "ref_id": "BIBREF44"}, {"start": 3905, "end": 3909, "text": "[46]", "ref_id": "BIBREF45"}, {"start": 4102, "end": 4104, "text": "54", "ref_id": "BIBREF53"}], "ref_spans": [{"start": 910, "end": 919, "text": "(Fig. 2b)", "ref_id": "FIGREF1"}, {"start": 3824, "end": 3834, "text": "Fig. 2b, c", "ref_id": "FIGREF1"}]}, {"section": "RESULTS AND DISCUSSION", "text": "We mention that here we assume B ps is not homogeneous on the scale of the magnetic length, thus Landau quantization 48 due to strain is not expected. As an example, the magnetic length at 200 T is l B = 1.7 nm. This length scale is more than a factor of 3 larger than the size of areas with high magnetic field, see Fig. 4f , making the formation of Landau levels impossible. Even though Landau levels are not expected to form, it has been shown that folded graphene areas with rapidly changing B ps can host bound states of Dirac fermions, as shown experimentally 55 and theoretically. 56, 57 Having quantified the B ps magnitude in folded, crumpled graphene, we turn our attention to numerically calculating the double resonant Raman processes in the presence of strain. Calculations are performed similarly to Venezuela et al. 28 and K\u00fcrti et al. 40 For this we need to find the electron/hole-defect Hamiltonian: H def . We model the B ps seen in crumpled graphene by a simple model, using a Gaussian deformation of the form:", "cite_spans": [{"start": 117, "end": 119, "text": "48", "ref_id": "BIBREF47"}, {"start": 566, "end": 568, "text": "55", "ref_id": "BIBREF54"}, {"start": 588, "end": 591, "text": "56,", "ref_id": "BIBREF55"}, {"start": 592, "end": 594, "text": "57", "ref_id": "BIBREF56"}, {"start": 831, "end": 833, "text": "28", "ref_id": "BIBREF27"}, {"start": 851, "end": 853, "text": "40", "ref_id": "BIBREF39"}], "ref_spans": []}, {"section": "RESULTS AND DISCUSSION", "text": ", where h is the height and b is the width of the Gaussian. For a Gaussian, the analytical form of the vector Additional data regarding the samples and further samples can be found in the Supplementary information S1. Black scalebars: 10 \u03bcm potential jAj / h 2 =b 2 is well known. 58 By choosing the height h and width b of the bump to be 5 and 20 \u00c5 respectively, the B ps within the bump area reaches a maximum of 200 T, switching sign on the nanometer scale (see Fig. 5a ). Both the magnitude and the length scale is similar to the values found within the LAMMPS calculations. In atomic units, the Hamiltonian describing the defect is H def \u00bc A\u00f0r\u00de \u00c1 \u2207 \u00fe V\u00f0r\u00de, where A is the vector potential and we also include V, the scalar potential generated by the mechanical deformation. 18 In order to calculate the scattering matrix element hkjH def jk \u00b1 qi between two states with wave vectors k and k \u00b1 q we need to calculate A( \u00b1 q) and V( \u00b1 q):", "cite_spans": [{"start": 281, "end": 283, "text": "58", "ref_id": "BIBREF57"}, {"start": 779, "end": 781, "text": "18", "ref_id": "BIBREF17"}], "ref_spans": [{"start": 465, "end": 472, "text": "Fig. 5a", "ref_id": "FIGREF4"}]}, {"section": "RESULTS AND DISCUSSION", "text": "Figure 5b shows |A(k)| 2 in the first Brillouin zone of graphene for varying sizes of the deformation. While varying the width, the height to width ratio (h/b) was kept constant at 0.25, in order to keep the maximum value of |A(k)| constant. 58 The calculated D, D\u2032, and 2D peaks for a Gaussian with h = 5 \u00c5 and b = 20 \u00c5 is shown in Fig. 5c . We reproduce I D\u2032 /I D = 32 in accordance with the experimental spectrum of Fig. 2d . As a crosscheck to our calculations we also compute the D and D\u2032 intensity for a \"hopping\" defect, as implemented by Venezuela et al., 28 modeling a lattice defect in graphene. For the hopping defect, the D\u2032 peak intensity is 11% of the D intensity, as expected for lattice defects, such as vacancies. 12 Comparing the relative intensity with respect to the 2D peak, it is clear that the D\u2032 peak is showing a measurable intensity, as opposed to the D\u2032 peak generated by Coulomb scatterers. 28 The D\u2032 intensity is generated almost completely by the vector potential A, with the scalar potential giving only a slight (less then 10 \u22124 ) contribution (see Supplementary information S5). This can be easily explained if we consider the scattering matrix element between states jhkjH def jk \u00b1 qij 2 \u00bc jH def \u00f0q\u00dej 2 cos 2 \u00f0\u03b8 k;k \u00b1 q =2\u00de, where \u03b8 k,k \u00b1 q is the angle between the the initial and the scattered state. 9 For backscattering (\u03b8 k,k \u00b1 q = \u03c0), if H def is of purely scalar character, the matrix element is zero. However, if H def has a vector potential component it can be nonzero. This is because A acts on the pseudospin of graphene, as evidenced by the pseudo-Zeeman effect. 13 Thus, it is able to change the phase of the charge carriers. The vector potential A has a slight contribution to the D peak as well, as can be seen in Fig. 5c . This is due to the non zero scattering potential at large k values, around the K points. Due to the Fourier transformation in Eq. (1), the contribution at large k increases as we make the Gaussian narrower. By decreasing b, but keeping the aspect ratio the same, we can see a marked increase in the scattering potential |A(k)| 2 at the K points, increasing the D peak intensity. This can be observed in Fig. 5d , where we plot the I D\u2032 /I D ratio on a log scale, as a function of b and excitation energy. Although it is clear that the parameter b is a tuning knob for the I D \u2032 /I D ratio, it is not possible to attribute a certain b value to the measured ratio, because the crumpling patterns can have a more complex B ps pattern than what is assumed in the Gaussian model. Additionally, the calculated model does not include lattice defects, which could be present in the experiment, such as edges. For the map seen in Fig. 2b , the D peak intensity is too low to prepare a meaningful I D\u2032 /I D map. For other samples, the map of this ratio can be found in the Supplementary information.", "cite_spans": [{"start": 242, "end": 244, "text": "58", "ref_id": "BIBREF57"}, {"start": 564, "end": 566, "text": "28", "ref_id": "BIBREF27"}, {"start": 731, "end": 733, "text": "12", "ref_id": "BIBREF11"}, {"start": 919, "end": 921, "text": "28", "ref_id": "BIBREF27"}, {"start": 1338, "end": 1339, "text": "9", "ref_id": "BIBREF8"}, {"start": 1610, "end": 1612, "text": "13", "ref_id": "BIBREF12"}], "ref_spans": [{"start": 333, "end": 340, "text": "Fig. 5c", "ref_id": "FIGREF4"}, {"start": 419, "end": 426, "text": "Fig. 2d", "ref_id": "FIGREF1"}, {"start": 1764, "end": 1771, "text": "Fig. 5c", "ref_id": "FIGREF4"}, {"start": 2177, "end": 2184, "text": "Fig. 5d", "ref_id": "FIGREF4"}, {"start": 2695, "end": 2702, "text": "Fig. 2b", "ref_id": "FIGREF1"}]}, {"section": "RESULTS AND DISCUSSION", "text": "Our experiments show a first example of resonant Raman scattering on potentials that are smooth on the atomic scale. In the lack of intervalley scattering, the pseudo-magnetic field created by the strain induced vector potential shifts the phase of the electron or hole wave function, in addition to the Berry phase. This lifts the restriction on backscattering, enabling an enhancement in the intravalley backscattering rate by orders of magnitude, evidenced by the enhancement of the D\u2032 peak in the Raman spectrum. The drastic increase in intravalley scattering, as a consequence of strain fluctuations, may be an important factor in lowering the mobility of certain CVD grown graphene samples, especially if wrinkles and folds are introduced during the transfer Fig. 4 Strain within graphene folds, deformations. a 10 \u00d7 10 nm graphene piece used in the molecular dynamics calculations. 41 b Single graphene fold along the zigzag direction. c Doubly folded graphene. Color scale on atoms shows the local strain, calculated by taking the average of the relative nearest neighbor distance changes. Positive values (yellow) correspond to tensile strain. d-f Pseudo-magnetic field magnitude in the structures shown in b, c. d Pseudo-magnetic field generated by the \u03c3-\u03c0 overlap 17 within the fold seen in b. e B ps magnitude due to the hopping modulation within the fold seen in (b). f B ps magnitude due to hopping modulation within the double fold seen in c process. Furthermore, it is well known that defects such as grain boundaries, vacancies, etc. can have a specific I D\u2032 /I D fingerprint.", "cite_spans": [{"start": 889, "end": 891, "text": "41", "ref_id": "BIBREF40"}, {"start": 1275, "end": 1277, "text": "17", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "12", "text": "Such defects also distort the graphene lattice around them 59 and this local strain field can be specific to the type of defect. Our results show that if we want to understand the origin of this Raman fingerprint, scattering on the defect induced local strain fields has to be taken into account. If experimentally, a more controlled folding of graphene can be achieved, the B ps present in these folds could be used to steer and guide 55 valley polarized 60, 61 Dirac fermions.", "cite_spans": [{"start": 59, "end": 61, "text": "59", "ref_id": "BIBREF58"}, {"start": 436, "end": 438, "text": "55", "ref_id": "BIBREF54"}, {"start": 456, "end": 459, "text": "60,", "ref_id": "BIBREF59"}, {"start": 460, "end": 462, "text": "61", "ref_id": "BIBREF60"}], "ref_spans": []}, {"section": "METHODS", "text": "Graphene samples were prepared by micromechanical exfoliation from natural graphite, purchased from NGS Trading & Consulting GmbH. Raman measurements were carried out using a Witec 300rsa+ confocal Raman system, using 488, 532, and 633 nm excitation lasers. Laser power was kept at 0.5 mW for all lasers.", "cite_spans": [], "ref_spans": []}, {"section": "METHODS", "text": "Crumpling of the graphene layers has been induced either in the exfoliation stage, as with the sample in the main text and the sample shown in Fig. S4 of the Supplementary information. However, this method has a low yield. It is known that annealing can induce folding of graphene. 52 Therefore, to increase the yield of the crumpled graphene within our samples, we have used annealing to induce wrinkling and crumpling. Samples 1-4 have been prepared by placing them onto a hotplate, preheated to 160\u00b0C for 15 min, after which the samples are removed and placed onto a metal surface to allow quick cooling. Additionally, the crumpling can be also induced by the tip of a tungsten needle.", "cite_spans": [{"start": 282, "end": 284, "text": "52", "ref_id": "BIBREF51"}], "ref_spans": []}, {"section": "DATA AVAILABILITY", "text": "The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. ", "cite_spans": [], "ref_spans": []}, {"section": "ADDITIONAL INFORMATION", "text": "Supplementary Information accompanies the paper on the npj 2D Materials and Applications website (https://doi.org/10.1038/s41699-019-0094-6).", "cite_spans": [], "ref_spans": []}, {"section": "ADDITIONAL INFORMATION", "text": "Competing interests: The authors declare no competing interests.", "cite_spans": [], "ref_spans": []}, {"section": "ADDITIONAL INFORMATION", "text": "Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. 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If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder", "authors": [], "year": "", "venue": "", "link": null}}, "ref_entries": {"FIGREF1": {"text": "Fig. 2 Intravalley scattering in crumpled graphene. a Optical microscope image of an exfoliated graphene layer on SiO 2 . b AFM image of crumpled area. Position within flake shown by red rectangle in a. c Raman spectroscopy map of the D\u2032 peak intensity in a crumpled graphene area in the position shown by the red rectangle. Scalebars in b, c 1 \u03bcm. d Raman spectrum showing a large D\u2032 peak measured at the crumpled area shown in b, c by green circle, Insets: larger magnification AFM image of the crumpled area and zoom of the D peak region of the spectrum. Scalebar: 500 nm. e D\u2032 peak of the area shown in d, measured with three different excitation wavelengths. Colors correspond to the respective laser color (red: 633 nm, green: 532 nm, blue: 488 nm). Black spectrum is measured using 532 nm excitation on the uncrumpled part of the flake, shown by the black circle in c. f Change in the peak position (\u0394\u03c9) of the 2D, G, and D\u2032 peaks, as a function excitation energy (E L ), for the area marked by the green circle in b-d. Measured dispersions (\u0394\u03c9 D\u2032 /\u0394E L ) of the experimental peaks are shown. Calculated D\u2032 peak position as a function of laser energy is shown by orange triangles", "type": "figure"}, "FIGREF2": {"text": "Fig. 3 I D\u2032 /I D intensity maps of crumpled graphene. a, b Optical microscope images of two different crumpled graphene layers on SiO 2 . c Map of the I D\u2032 /I D ratio of the sample shown in a. d Map of the I D\u2032 /I D ratio of the sample shown in b. Maps are measured using 532 nm excitation. Additional data regarding the samples and further samples can be found in the Supplementary information S1. Black scalebars: 10 \u03bcm", "type": "figure"}, "FIGREF3": {"text": "Figure data can be acessed on Figshare, https://doi.org/10.6084/m9.figshare.7700924.v1. AUTHOR CONTRIBUTIONS P.K. carried out the experiments together with PN-I, the Raman calculations were carried out by G.K. under supervision from J.K. D.G. prepared crumpled graphene samples. P.N.-I. carried out the molecular dynamics calculations. P.N.-I. conceived and coordinated the project, together with L.T. and L.P.B. P.N.-I. wrote the manuscript, with contributions from all authors.", "type": "figure"}, "FIGREF4": {"text": "Fig. 5 Calculated resonant Raman spectra. a Model used in Raman calculations. Gaussian of shape: h \u00c1 exp \u00c0 x 2 \u00fe y 2", "type": "figure"}}}
{"paper_id": "119423474", "_pdf_hash": "cc8c139e5f5b784669663b1359c13c7fa3f65b92", "abstract": [{"section": "Abstract", "text": "By using variational wave functions and quantum Monte Carlo techniques, we investigate the interplay between electron-electron and electron-phonon interactions in the two-dimensional HubbardHolstein model. Here, the ground-state phase diagram is triggered by several energy scales, i.e., the electron hopping t, the on-site electron-electron interaction U , the phonon energy \u03c90, and the electron-phonon coupling g. At half filling, the ground state is an antiferromagnetic insulator for U 2g 2 /\u03c90, while it is a charge-density-wave (or bi-polaronic) insulator for U 2g 2 /\u03c90. In addition to these phases, we find a superconducting phase that intrudes between them. For \u03c90/t = 1, superconductivity emerges when both U/t and 2g 2 /t\u03c90 are small; then, by increasing the value of the phonon energy \u03c90, it extends along the transition line between antiferromagnetic and charge-density-wave insulators. Away from half filling, phase separation occurs when doping the charge-density-wave insulator, while a uniform (superconducting) ground state is found when doping the superconducting phase. In the analysis of finite-size effects, it is extremely important to average over twisted boundary conditions, especially in the weak-coupling limit and in the doped case.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "I. INTRODUCTION", "text": "The challenge of understanding the interplay between electron-electron and electron-phonon interactions has stimulated an intense work in the condensed-matter community, since the early developments of many-body approaches to describe metals, insulators, and superconductors [1] . Indeed, the low-temperature properties of several materials are controlled by the competition, or sometimes the cooperation, between these interaction terms. For example, in high-temperature superconductors, where the presence of a strong electron-electron correlation is irrefutable, the role of phonons could be not entirely negligible, as suggested by the kinks in the electron dispersion [2] or by the signatures of the isotope effect [3, 4] . In alkali-metal-doped fullerides, a superconducting phase appears close to a Mott transition [5, 6] , even though they are often considered as phononic superconductors. This particular feature suggests that both the Coulomb repulsion and the electron-phonon coupling are strong and cooperate to establish a stronglycorrelated superconductor. Similarly, in pnictide superconductors [7] , such as LaOFeAs, and in aromatic superconductors, such as potassium-intercalated picene [8] , there are evidences that, apart from a moderately strong electron correlation, there is also a non-negligible coupling between electrons and lattice degrees of freedom.", "cite_spans": [{"start": 275, "end": 278, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "In a nutshell, the interplay between electron-electron repulsion and electron-phonon coupling is due to the fact that the former one generates spin fluctuations, which in turn mediate a non-local pairing among electrons that may give rise to d-wave superconductivity, while the latter one directly mediates a local attraction among electrons, leading to an s-wave superconductor. In addition, a strong electron correlation may also lead to spin-density waves and a magnetically ordered state, which competes with superconductivity; instead, a local attraction may also generate charge localization, i.e., charge-densitywave (CDW) or dimerized (Peierls) states. Therefore, it is a highly nontrivial task to obtain the properties of a system in which both interactions are relatively strong. In this respect, the Hubbard-Holstein model represents a prototypical example that includes these features. This model incorporates both an on-site Coulomb repulsion U (the Hubbard term) [9] and a coupling g between electrons and dispersionless Einstein phonons with energy \u03c9 0 (the Holstein terms) [10] , as well as a kinetic term for electrons:", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "sumed to be local. In addition, the latter term is modeled by coupling the lattice displacement x i \u221d (b \u2020 i +b i ) to the electron density n i . A different way to introduce the electron-phonon coupling has been considered within the Su-Schrieffer-Heeger model [11] , where lattice displacements are coupled to the hopping term rather than to the density. While the latter case is more suited to describe materials with delocalized phonons, the Holstein model can be used as a good approximation for molecular solids in which there are local phonon modes (like, for example, fullerene doped with alkali-metal atoms).", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "Although the properties of the Hubbard-Holstein model depend upon \u03c9 0 /t and g/t independently, it is useful to define the quantity \u03bb = 2g 2 /\u03c9 0 , which is often considered to measure the strength of the electron-phonon coupling. This dimensionless coupling emerges naturally in the antiadiabatic limit where the phonons have a large energy (i.e., \u03c9 0 /t \u2192 \u221e). In this case, the retarded interaction mediated by phonons becomes instantaneous. In fact, for \u03c9 0 t there is an exact mapping from the Holstein model to the negative-U Hubbard model with U att = \u2212\u03bb. Therefore, the Hubbard-Holstein model reduces to the Hubbard model with a renormalized on-site interaction, i.e., U eff = U \u2212 \u03bb. In the general case with a finite phonon energy, the multidimensional parameter space of the Hubbard-Holstein model (i.e., U/t, g/t, \u03c9 0 /t, as well as the electron density n) leads to an extremely rich physics and various approaches have been used to understand its ground-state properties.", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "In one spatial dimension, early works, based upon perturbation theory and Monte Carlo calculations, suggested that the ground state of the Holstein model displays CDW order for any non-zero electron-phonon coupling and \u03c9 0 /t < \u221e [12, 13] . Instead, subsequent studies, using density-matrix renormalization group (DMRG) and Monte Carlo techniques, have highlighted the existence of a gapless phase (with dominant superconducting pair correlations) for small values of the electron-phonon coupling and finite phonon energies, which persists also for finite values of U/t [14] [15] [16] [17] [18] [19] . In the opposite limit of infinite dimensions, dynamical mean-field theory (DMFT) has been employed to assess various aspects of the phase diagram, including the competition between superconductivity and CDW order [20] [21] [22] [23] , the role of phonons in the vicinity of the Mott transition [24, 25] , the verification of the Migdal-Eliashberg theory [26] , the polaron formation, and the existence of the isotope effect [27] [28] [29] . The two-dimensional case has been relatively little investigated in the past. Indeed, quantum Monte Carlo techniques suffer from the sign problem and stable simulations can be accomplished only in few cases [30] [31] [32] . Therefore, the Hubbard-Holstein model has been mainly considered within mean-field approaches [33] [34] [35] [36] or by using perturbative methods [37, 38] . Variational Monte Carlo (VMC) has been also employed to assess the interplay between electron-electron and electron-phonon interactions in the Su-Schrieffer-Heeger model [39] . More recently, Ohgoe and Imada used the VMC approach to assess the ground-state phase diagram of the HubbardHolstein model at half filling and in its vicinity [40] . The same variational wave functions have been implemented to study the electron-phonon coupling in multiband models [41] .", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "One important aspect in the phase diagram of the Hubbard-Holstein model is the nature of the transition between CDW (bi-polaronic) and Mott insulators at half filling and the possibility that a metallic/superconducting phase may intrude in between [42, 43] . In the antiadiabatic limit \u03c9 0 /t \u2192 \u221e, given the mapping from the Holstein model to the negative-U Hubbard model, one should expect a direct transition between an antiferromagnetic (Mott) insulator, that is stable for U > \u03bb, and a CDW insulator, that is stable for U < \u03bb. However, in this limit, the CDW state is degenerate with an s-wave superconductor, because of the SU(2) pseudospin symmetry of the negative-U Hubbard model (this fact leads to peculiar ground-state properties, with both broken translational symmetries, i.e., CDW order, and gapless excitations). By contrast, for any finite values of the phonon energy \u03c9 0 , there is no reason for having a direct transition between the two insulating states and an intermediate phase may emerge. In one dimension, the existence of a metallic phase, with strong superconducting correlations, has been reported by DMRG studies [16] [17] [18] , with a clear evidence that the intermediate region broadens with increasing the phonon energy (up to \u03c9 0 /t \u2248 5). Instead, DMFT calculations showed contradictory results, with either a direct transition between CDW and Mott insulators [22] or the presence of a small intermediate phase [23] . Also in two dimensions the situation is not conclusive, since only few calculations have been afforded [31, 32] , where some evidence for the emergence of an intermediate metallic phase has been suggested at finite temperatures. In addition, away from half filling, the sign problem is so strong that it prevents one from performing any stable simulation. Therefore, alternative approaches are highly desirable. One possibility is to define suitable wave functions that can be treated within the VMC technique. In this spirit, Ohgoe and Imada have recently extended the \"many-variable\" VMC method to include phonon degrees of freedom [40, 44] , showing evidence in favor of a metallic (with weak superconducting correlations) phase between the CDW and Mott insulators at half filling. In addition, they highlighted the presence of phase separation when doping the CDW insulator. Instead, the ground state is uniform when doping the metallic phase.", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "In this paper, we present further VMC calculations that are based upon different wave functions and smart average over twisted boundary conditions (denoted by TABC) in order to reduce size effects. Indeed, when imposing periodic or antiperiodic boundary conditions, there are very large size effects, especially for small values of \u03c9 0 /t and in the doped case, preventing us from reaching definitive conclusions in the thermodynamic limit. Thanks to TABC, we give a clear evidence that a super-conducting phase is present between the CDW and the antiferromagnetic insulators and that its stability region broadens when increasing the phonon energy. Finally, phase separation is found when doping the CDW state, while a uniform (superconducting) phase is observed by doping the uniform ground state.", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "The paper is organized as follows: in Sec. II, we show the variational wave function and briefly discuss the Monte Carlo methods that have been used; in Sec. III, we present the numerical results; finally, in Sec. IV, we draw our conclusions.", "cite_spans": [], "ref_spans": []}, {"section": "II. WAVE FUNCTIONS AND METHODS", "text": "In this section, we first describe the variational wave function that has been used in the numerical calculations. Then, we briefly discuss the updating scheme that has been implemented within the VMC method for the phononic degrees of freedom (for the electrons, we use standard updating schemes [45] ). Finally, we show the TABC procedure to reduce size effects and we highlight advantages and disadvantages of the VMC method.", "cite_spans": [{"start": 297, "end": 301, "text": "[45]", "ref_id": "BIBREF45"}], "ref_spans": []}, {"section": "II. WAVE FUNCTIONS AND METHODS", "text": "The wave function is given by the so-called JastrowSlater state that is defined by:", "cite_spans": [], "ref_spans": []}, {"section": "II. WAVE FUNCTIONS AND METHODS", "text": "Here, |\u03a6 e is the ground state of an auxiliary (quadratic) Hamiltonian that contains electron hopping and (singlet) pairing:", "cite_spans": [], "ref_spans": []}, {"section": "II. WAVE FUNCTIONS AND METHODS", "text": "where \u00b5, \u2206 CDW , \u2206 AF , and \u2206 SC are parameters that are optimized in order to minimize the variational energy [46] , . Moreover, states with coexisting orders are also possible. This Hamiltonian can be easily diagonalized to define the uncorrelated electronic state |\u03a6 e , which has the following form:", "cite_spans": [], "ref_spans": []}, {"section": "II. WAVE FUNCTIONS AND METHODS", "text": "where the pairing function f i,j depends upon the variational parameters of the auxiliary Hamiltonian. The total number of electrons is fixed to N e by the projector P Ne . The uncorrelated phononic part is then given by:", "cite_spans": [], "ref_spans": []}, {"section": "II. WAVE FUNCTIONS AND METHODS", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "II. WAVE FUNCTIONS AND METHODS", "text": "i creates a phonon in the k = 0 momentum state (N is the number of sites). Here, N b denotes the total number of phonons. Since the number of phonons is not conserved by the Hubbard-Holstein Hamiltonian of Eq. (1), |\u03a6 p has components on subspaces with any value of N b ; then, \u03b6 is a variational parameter that plays the role of a fugacity. Denoting by |m 1 , . . . , m N the (normalized) configuration with m i phonons on the site i, the uncorrelated phononic wave function can be written as:", "cite_spans": [], "ref_spans": []}, {"section": "II. WAVE FUNCTIONS AND METHODS", "text": "Finally, J ee , J pp , and J ep are density-density Jastrow factors for the electron-electron, phonon-phonon, and electron-phonon correlations, respectively:", "cite_spans": [], "ref_spans": []}, {"section": "II. WAVE FUNCTIONS AND METHODS", "text": "where v ee i,j , v pp i,j , and v ep i,j are pseudo-potentials, including the on site terms, that are taken to be translationally invariant, i.e., they depend only upon the Euclidean distance |R i \u2212 R j |. They can be optimized (each one independently) to reach the optimal variational Ansatz [46] . Here, all the pseudo-potentials are taken to be symmetric in the exchange i \u2194 j. By a full optimization of the Jastrow factors, we find that the phonon-phonon correlations only give a marginal improvement in the energy and, therefore, they are not employed. By contrast, the electron-phonon term is fundamental to obtain an accurate description when g/t and \u03c9 0 are finite. As for the Hubbard model, the electron-electron Jastrow factor is crucial to reproduce the correct low-energy behavior of the ground state [47, 48] .", "cite_spans": [], "ref_spans": []}, {"section": "II. WAVE FUNCTIONS AND METHODS", "text": "The configuration space that is sampled along the Markov chain is defined by specifying both electron and phonon occupations on each site (i.e., we work in a basis in which the number of phonons m i is specified on each lattice site, as well as the number of up-and downspin electrons n i,\u03c3 ). In our case, where the uncorrelated phononic part is given by Eq. (6) ", "cite_spans": [], "ref_spans": []}, {"section": "II. WAVE FUNCTIONS AND METHODS", "text": "Size scaling of the energy per site at quarter filling (with \u03c90/t = 1, \u03bb/t = 2, and U = 0) for periodic-periodic (red squares) and twisted average (blue diamonds) boundary conditions. Errorbars are smaller than the size of the symbols.", "cite_spans": [], "ref_spans": []}, {"section": "II. WAVE FUNCTIONS AND METHODS", "text": "variational parameter \u03b6, we do not need to include any cutoff in the number of phonons. By contrast, Ohgoe and Imada [40, 44] used a more involved parametrization of the phonon wave function, with several parameters (i.e., one for each boson number); therefore, they considered a cutoff in the maximum number of phonons. Moreover, along the Markov chain, they sampled the displacement x i , using a different electron-phonon Jastrow factor, which couples the electron density n j to x i (rather than to the phonon number m i ). Finally, also the electronic part used in Refs. [40, 44] is slightly different from the one that is employed here: they do not obtain |\u03a6 e from the auxiliary Hamiltonian (3), but perform a full optimization of the pairing function f i,j of Eq. (4). In our opinion, this procedure may be problematic, especially for large sizes, since one must deal with several variational parameters (i.e., O(N ) for a translationally invariant case) and the optimization of the long-range tail of the pairing function can be difficult within a stochastic approach. An advantage of our parametrization is that the nature of the wave function is transparent from the optimized values of the parameters, e.g., obtaining a finite \u2206 CDW immediately implies that the state displays CDW order. We also mention that the present approach allows us to easily detect metastable phases, with given physical properties: for example, by fixing \u2206 AF = 0, we are able to obtain the best paramagnetic state, even in a region where the ground state is antiferromagnetically ordered.", "cite_spans": [], "ref_spans": []}, {"section": "II. WAVE FUNCTIONS AND METHODS", "text": "When using the wave function of Eq. (2), the Metropolis algorithm can be easily implemented to propose a change in the phononic configuration. Indeed, let us consider the case in which one phonon is created/destroyed at site l, i.e., m i \u2192 m i \u00b1 \u03b4 il . Then, in order to compute the Metropolis acceptance probability, it is necessary to evaluate the following ratio:", "cite_spans": [], "ref_spans": []}, {"section": "II. WAVE FUNCTIONS AND METHODS", "text": "which can be explicitly given by the expressions of the uncorrelated phononic state (6) and the Jastrow factors (8) and (9):", "cite_spans": [], "ref_spans": []}, {"section": "II. WAVE FUNCTIONS AND METHODS", "text": "Finally, let us discuss the TABC method to reduce the size effects. Our calculations are performed on square clusters with N = L \u00d7 L sites. In most cases, periodic (or anti-periodic) boundary conditions are employed on both the Hamiltonian and the variational wave function (i.e., the auxiliary Hamiltonian defined above). However, strong size effects may be present, due to a large correlation length. It has been proposed that a selected twist in the boundary condition, or an average over different boundary conditions, may improve the convergence to the thermodynamic limit [49, 50] . On the lattice, by explicitly indicating the coordinates of the site in the creation operators (i.e., c \u2020 i,\u03c3 \u2192 c \u2020 Ri,\u03c3 , where R i = (X i , Y i ) denotes the coordinates of the site i in the lattice), twisted boundary conditions correspond to impose:", "cite_spans": [], "ref_spans": []}, {"section": "II. WAVE FUNCTIONS AND METHODS", "text": "where L x = (L, 0) and L y = (0, L) are the vectors that define the periodicity of the cluster; \u03b8 term. Then, for each choice of \u03b8 \u2261 (\u03b8", "cite_spans": [], "ref_spans": []}, {"section": "II. WAVE FUNCTIONS AND METHODS", "text": ", we define the many-body wave function |\u03a8 \u03b8 , which is obtained from the auxiliary Hamiltonian (3) with twisted boundary conditions (notice that the Jastrow factors are not affected by the twist, since they contain density-density correlations). In TABC, an average over a large number N \u03b8 of phases (typically N \u03b8 = 576 points in the Brillouin zone) is considered in order to evaluate the expectation value of the Hamiltonian or any other operator O \u03b8 , which in general depends upon the twist through Eq. (13) and (14):", "cite_spans": [], "ref_spans": []}, {"section": "II. WAVE FUNCTIONS AND METHODS", "text": "By imposing that all the twists share the same variational parameters, we can reach much faster the thermodynamic limit. For example, by considering uncorrelated (i.e., mean-field) wave functions, we verified that this procedure allows us to get the thermodynamic results even when using a small cluster. Moreover, within a Monte Carlo optimization, the average of Eq. (15) is very conveniently implemented, since the statistical error decreases with 1/ \u221a N \u03b8 and, therefore, several boundary conditions can be considered without any extra computational cost. In Fig. 1 , we show the size scaling of the energy per site when applying the TABC procedure at half filling (for U = 0, \u03bb/t = 0.98, and \u03c9 0 /t = 1), in comparison with the standard cases with periodicperiodic and periodic-antiperiodic boundary conditions. In all three cases, the optimized variational wave functions have \u2206 SC = 0 (and \u2206 CDW = \u2206 AF = 0) and the extrapolated values are all consistent (within few errorbars), giving E/t = \u22122.1725(1). Away from half filling, size effects become even more pronounced and TABC are crucial to extract an accurate value in the thermodynamic limit. In Fig. 2 , we report the case at quarter filling (with U = 0, \u03bb/t = 2, and \u03c9 0 /t = 1). Here, periodicperiodic boundary conditions give scattered results, while averaging over twisted boundary conditions gives rise to a rather smooth extrapolation to E/t = \u22121.652 (1) . The important message is that, while the cases with fixed boundary conditions possess huge size effects and require large clusters to reach accurate results in the thermodynamic limit, a remarkable flat size scaling is obtained by using TABC, thus allowing us to consider relatively small clusters in our numerical simulation, with small finite-size errors.", "cite_spans": [{"start": 1419, "end": 1422, "text": "(1)", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "II. WAVE FUNCTIONS AND METHODS", "text": "We would also like to briefly discuss the advantages and disadvantages of computing ground-state properties by means of a Monte Carlo sampling over variational wave functions. The main advantage is that stronglycorrelated states may be treated beyond perturbative approaches. For example, the physical properties (e.g., energy and correlations functions) of the simple Gutzwiller wave function can be assessed without considering the Gutzwiller approximation [51, 52] . In order to compute expectation values over variational states, a Monte Carlo sampling is necessary, thus leading to statistical errors, which, however, can be safely kept under control (i.e., they scale to zero by increasing the length of the simulation). The energy computed with variational Monte Carlo gives an upper bound to the exact value, thus providing a criterion to judge the quality of the variational states. Moreover, it is possible to assess quite large clusters, with all relevant spatial symmetries (translations, rotations, and reflections) preserved. The main disadvantage is that it is difficult to quantify the systematic errors, which are introduced by the choice of the trial state.", "cite_spans": [], "ref_spans": []}, {"section": "III. RESULTS", "text": "In this section, we start by showing our numerical results for the half-filled case n = N e /N = 1 and then move to the doped region with n < 1.", "cite_spans": [], "ref_spans": []}, {"section": "A. Half-filled case", "text": "In Fig. 3 , we show the ground-state phase diagram for three values of \u03c9 0 /t, i.e., \u03c9 0 /t = 1, 5, and 15, at half filling. Here, we identify three different phases. For large electron-electron interaction, the lowest-energy state has long-range antiferromagnetic order (namely the uncorrelated part of the electronic wave function has \u2206 AF = 0). The stability region of this phase is approximately bounded (from below) by the line U = \u03bb, for all the values of the phonon energies. This is a remarkable feature, which has been already obtained by different approaches, especially in one dimension by DMRG [16] [17] [18] and in two dimensions by VMC [40] . In fact, this is expected in the antiadiabatic limit where \u03c9 0 /t \u2192 \u221e, but there are no simple reasons that it should also hold for finite (and relatively small) values of \u03c9 0 . For large electronphonon coupling, the ground state is a CDW insulator, where doubly-occupied sites (doublons) and empty sites (holons) form a checkerboard pattern; this charge modulation is accompanied by a considerable phonon \"dressing\", namely a large number of phonons are present on top of doublons, while no phonons are present on empty sites. This phonon cloud gives a drastic reduction of the kinetic energy of electrons, which hardly hop around in the lattice. Finally, there is an intermediate supercon- ducting phase (with pairing correlations that increase by increasing \u03c9 0 /t) that intrudes between the previous insulators. For small values of the phonon energy, it is limited to a narrow region for small couplings, while for intermediate values of \u03c9 0 /t, it expands inside the region where U < \u03bb. By further increasing \u03c9 0 /t, the superconducting correlations get stronger and stronger, eventually pervading the whole CDW region. It should be mentioned that, when \u03c9 0 /t \u2192 \u221e, the CDW state returns into the game, being degenerate with the superconducting one (due to the emerging SU(2) pseudo-spin symmetry that connects the superconducting and the CDW states). In practice, we cannot recover an exact degeneracy between these two states, since the density-density Jastrow factor favors the superconducting one for very large phonon energies. For \u03c9 0 /t = 1 and large \u03bb/t, the transition between the CDW and the antiferromagnetic insulators is first order, since both wave functions can be stabilized also when the competitor gives the lowest variational energy. For example, the variational parameters \u2206 AF and \u2206 CDW across the transition for \u03bb/t = 4.5 are reported in Fig. 4 . By decreasing \u03bb/t, the local minima disappear and the transition appears to be continuous. For \u03bb/t = 2, which approximately corresponds to the tip of the superconducting region, CDW and antiferromagnetic parameters vanish for U/t \u2248 1.2, see Fig. 4 . For smaller values of \u03bb/t, a superconducting phase can be stabilized for small enough electron-electron repulsions, with a small but clearly finite pairing term \u2206 SC . We would like to remark that for U = 0, within our variational approach (implemented with TABC), we obtain a finite value of the electronphonon coupling \u03bb/t \u2248 1, separating superconducting and CDW phases. In the non-interacting limit, at the density where the Van Hove singularity occurs (i.e., at half filling, when only the nearest-neighbor hopping t is present), both the particle-hole and the particle-particle susceptibilities diverge as ln 2 (t/\u039b) [53] , where \u039b is an infrared cutoff. The former one has a larger prefactor with respect to the superconducting one, thus implying that, within the mean-field approach, an infinitesimal interaction will lead to CDW. However, bare susceptibilities may lead to an incorrect prediction and it is important to go beyond this approximation. Our variational calculations should capture the correct qualitative picture, i.e., the presence of an extended superconducting region below a given \u03bb/t, even though we cannot exclude subtle finite-size effects that could be particularly difficult to control even by using TABC. In this respect, our results contrast with recent calculations obtained by using a finite-temperature quantum Monte Carlo method [54] .", "cite_spans": [], "ref_spans": [{"start": 3, "end": 9, "text": "Fig. 3", "ref_id": "FIGREF1"}, {"start": 2522, "end": 2528, "text": "Fig. 4", "ref_id": "FIGREF2"}, {"start": 2772, "end": 2778, "text": "Fig. 4", "ref_id": "FIGREF2"}]}, {"section": "A. Half-filled case", "text": "When increasing the phonon energy, the region of stability for the superconducting phase broadens, intruding between the two insulators also when \u03bb/t is large. In Figs. 5 and 6, we report the behavior of the variational parameters \u2206 AF , \u2206 CDW , and \u2206 SC for \u03c9 0 /t = 5 and 15. In the intermediate region, both \u2206 AF and \u2206 CDW are vanishing, while \u2206 SC is finite. Notice that \u2206 SC is also finite inside the insulating CDW region. This fact does not lead to a super-solid ground state (i.e., a superconducting state with CDW order), since the presence of a finite \u2206 CDW is associated with a gap in the excitation spectrum (we determine whether the system is metallic or insulating by looking at the density-density correlations, see for instance Ref. 55) . By contrast, this result may be ascribed to the fact that superconducting and CDW solutions become degenerate for \u03c9 0 /t \u2192 \u221e, and, therefore, at the variational level, some energy gain can be obtained by mixing superconductivity and CDW order, even when the phonon energy is large but finite. Finally, we remark that the transition between the antiferromagnetic insulator and the superconductor appears to be continuous, i.e., both \u2206 AF and \u2206 SC vanish (approximately) at the same point. This is a particularly remarkable and unexpected feature, since s-wave superconductivity and local moments are not compatible.", "cite_spans": [], "ref_spans": []}, {"section": "B. Doped case", "text": "Let us now move to the doped case, for which we want to assess the stability toward phase separation. When doping an antiferromagnet, phase separation could appear for small hole concentrations, as found in the repulsive-U Hubbard model, whenever the loss in the magnetic contribution to the total energy is larger than the gain due to the kinetic part. The presence of phase separation in the repulsive-U Hubbard model has been confirmed by different methods, even if its extension as a function of U is still controversial [56] [57] [58] [59] [60] [61] [62] . In order to highlight the possible presence of phase separation in the Hubbard-Holstein model, it is very useful to consider the so-called energy per hole [63] :", "cite_spans": [], "ref_spans": []}, {"section": "B. Doped case", "text": "where E(\u03b4) is the energy per site at hole doping \u03b4 = 1\u2212n. For a uniform phase, (\u03b4) has a monotonically increasing behavior with increasing \u03b4 from 0 to 1; by contrast, phase separation is marked by the presence of a minimum of (\u03b4) on any finite-size clusters and a flat behavior (up to \u03b4 c ) in the thermodynamic limit. These facts can be easily understood by considering that (\u03b4) represents the slope of the line joining (0, E(0)) to (\u03b4, E(\u03b4)) and that, in a stable uniform phase E(\u03b4) is a convex function, while phase separation implies (after Maxwell construction) a linear behavior of E(\u03b4) up to \u03b4 c . The results of the energy per hole are shown in Fig. 7 . First of all, we discuss the case with U = 0, \u03c9 0 /t = 1, and finite \u03bb (lower panel). Here, the system does not phase separate for small values of the electron-phonon coupling, i.e., when doping the superconducting phase at half filling. Most importantly, the ground state remains superconducting also when the electron density is n < 1. This fact is most evident when \u03c9 0 /t is large enough, since the superconducting signal is rather small in the adiabatic limit and increases with \u03c9 0 /t. In order to show this feature, we present the results for \u03c9 0 /t = 15 in Fig. 8 . As for the half-filled case, in order to get smooth results when the electron density is varied, it is fundamental to consider TABC, since fixed boundary conditions (here, periodic-antiperiodic ones) give rise to a strongly scattered behavior. By contrast, when entering into the CDW phase for large values of \u03bb/t, a small hole doping leads to a charge instability, with the region where phase separation is obtained increasing with \u03bb. We remark that, within TABC, the results show a smooth behavior that is not obtained by using fixed boundary conditions. As for the case of an antiferromagnetic phase, also in the presence of CDW order the injection of few mobile holes that damage the charge periodicity is not compensated by a kinetic energy gain. Thus, phase separation appears for sufficiently small hole doping. In Fig. 7 , we also show the results for \u03bb/t = 2 and various values of U/t (upper panel). Here, the electron-electron repulsion opposes to the electron-phonon coupling, leading to a reduction of phase separation until it eventually disappears above a critical value of U/t (by further increasing the electronelectron repulsion, antiferromagnetism settles down at half filling, thus leading again to phase separation, as discussed in the positive-U Hubbard model).", "cite_spans": [], "ref_spans": []}, {"section": "B. Doped case", "text": "In Fig. 9 , we further show that, at finite values of the phonon energy, the extent of phase separation depends upon the actual values of both U and \u03bb. Indeed, we observe that, for \u03c9 0 /t = 1, phase separation is more pronounced for U/t = 1.38 and \u03bb/t = 3.38 than for U = 0 and \u03bb/t = 2, even if both cases would give the same effective interaction U eff = U \u2212 \u03bb. This fact can be explained by the presence, at half filling, of a larger CDW parameter in the former case with respect to the latter one.", "cite_spans": [], "ref_spans": [{"start": 3, "end": 9, "text": "Fig. 9", "ref_id": "FIGREF6"}]}, {"section": "B. Doped case", "text": "Finally, we compare the energy per hole for U = 0 and \u03bb/t = 2 for different values of \u03c9 0 /t, see Fig. 10 . In all these cases, the ground state at half filling has CDW order (see Fig. 3 ) and, therefore, phase separation is expected to appear away from half filling. However, in the antiadiabatic limit \u03c9 0 /t \u2192 \u221e, there is no phase separation, since the Holstein model maps to the negative-U Hubbard model, which has a uniform ground state away from half filling. In fact, we find that phase separation reduces when increasing \u03c9 0 /t, i.e., the position of the minimum in the energy per hole shifts toward \u03b4 = 0, indicating that our variational approach correctly reproduces the expected physical behavior.", "cite_spans": [], "ref_spans": [{"start": 98, "end": 105, "text": "Fig. 10", "ref_id": "FIGREF7"}, {"start": 180, "end": 186, "text": "Fig. 3", "ref_id": "FIGREF1"}]}, {"section": "IV. CONCLUSIONS", "text": "In conclusion, we have performed accurate VMC calculations to extract thermodynamic properties of the Hubbard-Holstein model, where finite-size effects have been strongly reduced by implementing an average over twisted boundary conditions. At half filling, our results confirm the existence of a gapless phase between the CDW and the antiferromagnetic insulators, as recently obtained by different VMC calculations [40] . Moreover, within our approach, which is based upon a transparent parametrization of the variational wave functions, we are able to observe the presence of superconducting correlations in the intermediate phase. When the phonon energy becomes large, pairing correlations strengthen and the superconducting region broadens to the detriment of CDW order. The emergence of superconductivity in the half-filled Hubbard-Holstein model is an example on how two competing tendencies (i.e., antiferromagnetism, favored by electron-electron interaction, and CDW order, favored by electron-phonon coupling) may lead to a third stable phase. In addition, we studied the effect of hole doping for both regimes where the half-filled ground state has either CDW or superconducting order. In the former case, a substantial phase separation is present at small dopings, resembling the case of a doped repulsive-U Hubbard [56] [57] [58] [59] [60] [61] [62] . In the latter case, instead, the ground state remains uniform with superconducting order. However, superconductivity is found to monotonically decrease upon doping. We remark that, away from half filling, TABCs are fundamental to reduce finite-size effects. From general grounds, within the Hubbard-Holstein model, superconductivity is rather fragile against electron-electron repulsion and also against electron doping. Indeed, since phonons are coupled to the local electronic density in the Hubbard-Holstein model, there is a direct competition between the formation of superconducting pairs and the local Coulomb repulsion U . In addition, superconducting pairing is maximum at half filling and strongly reduces in the presence of hole doping. In this respect, a different scenario is expected within the Su-Schrieffer-Heeger model [11] , where lattice displacements are coupled to the hopping term: here, no superconductivity is expected at half filling, since a Peierls insulator should take place for any electron-phonon coupling at U = 0 (similarly to what happens in one dimension [64] [65] [66] ). On the contrary, superconductivity is expected to emerge upon doping, being also more robust against Coulomb repulsion than in the Hubbard-Holstein model. Therefore, the Su-Schrieffer-Heeger model would provide a different mechanism for electron pairing, more pertinent for cuprate and iron-pnictide superconductors.", "cite_spans": [], "ref_spans": []}, {"section": "IV. CONCLUSIONS", "text": "Further variational investigations in this direction could benefit from the use of backflow terms, as introduced to improve the quality of the wave functions in the Hubbard model [55, 67] .", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Methods of Quantum Field Theory in Statistical Physics", "authors": [{"first": "A", "middle": ["A"], "last": "Abrikosov", "suffix": ""}, {"first": "L", "middle": ["P"], "last": "Gorkov", "suffix": ""}, {"first": "I", "middle": ["E"], "last": "Dzialoshinskii", "suffix": ""}], "year": 1975, "venue": "", "link": null}, "BIBREF45": {"title": "Quantum Monte Carlo Approaches for Correlated Systems", "authors": [{"first": "F", "middle": [], "last": "Becca", "suffix": ""}, {"first": "S", "middle": [], "last": "Sorella", "suffix": ""}], "year": 2017, "venue": "", "link": "126062904"}}, "ref_entries": {"FIGREF0": {"text": "indicates the coordinates of the site i in the square lattice, and\u03c3 = +1 (\u22121) for up (down) electrons. The auxiliary Hamiltonian of Eq. (3) is rather flexible to describe states with (i) CDW order (when \u2206 CDW = 0 and \u2206 AF = \u2206 SC = 0), (ii) antiferromagnetic N\u00e9el order (when \u2206 AF = 0 and \u2206 CDW = \u2206 SC = 0), and (iii) superconducting order (when \u2206 SC = 0 and \u2206 CDW = \u2206 AF = 0)", "type": "figure"}, "FIGREF1": {"text": "FIG. 3: Ground-state phase diagram in the (\u03bb/t, U/t) plane for the Hubbard-Holstein model at \u03c90/t = 1 (upper panel), \u03c90/t = 5 (middle panel), and \u03c90/t = 15 (lower panel). Antiferromagnetic (AF), charge-density-wave (CDW), and superconducting (SC) phases are present, the latter one being marked in blue. The calculations have been performed on the 12 \u00d7 12 cluster with TABC. The dotted line U = \u03bb is also marked for reference.", "type": "figure"}, "FIGREF2": {"text": "FIG. 4: Antiferromagnetic (red circles) and charge-densitywave (blue squares) parameters for the case with \u03c90/t = 1. The cases with \u03bb/t = 4.5 (upper panel), where a first-order phase transition between these two insulators is present, and with \u03bb/t = 2 (lower panel), where a continuous phase transition takes place, are reported. The calculations have been performed on the 12 \u00d7 12 cluster with TABC and error bars are smaller than the size of the symbols.", "type": "figure"}, "FIGREF3": {"text": "FIG. 5: Antiferromagnetic (red circles), charge-density-wave (blue squares), and superconducting (black diamonds) parameters for the case with \u03c90/t = 5. The cases with \u03bb/t = 4.5 (upper panel) and \u03bb/t = 2 (lower panel) are reported. In both cases, there is a small region where the ground state is superconducting with no charge-density-wave order. The calculations have been performed on the 12 \u00d7 12 cluster with TABC and error bars are smaller than the size of the symbols.", "type": "figure"}, "FIGREF4": {"text": "FIG. 6: Antiferromagnetic (red circles), charge-density-wave (blue squares), and superconducting (black diamonds) parameters for the case with \u03c90/t = 15. The cases with \u03bb/t = 4.5 (upper panel) and \u03bb/t = 2 (lower panel) are reported. In this cases, there is a substantial region where the ground state is superconducting with no charge-density-wave order. The calculations have been performed on the 12 \u00d7 12 cluster with TABC and error bars are smaller than the size of the symbols.", "type": "figure"}, "FIGREF5": {"text": "FIG. 7: Energy per hole of Eq. (16) for \u03bb/t = 2 and various values of U/t (upper panel) and for U = 0 and various values of \u03bb/t (lower panel). In both cases \u03c90/t = 1 and calculations are performed on the 12 \u00d7 12 cluster with TABC. Errorbars are smaller than the size of the symbols.", "type": "figure"}, "FIGREF6": {"text": "FIG. 9: Energy per hole of Eq. (16) for U = 0 and \u03bb/t = 2 (red squares), compared with U/t = 1.38 and \u03bb/t = 3.38 (black circles), that corresponds to the same value of the effective interaction U eff = U \u2212 \u03bb. In both cases \u03c90/t = 1 and calculations are performed on the 12 \u00d7 12 cluster with TABC. Errorbars are smaller than the size of the symbols.", "type": "figure"}, "FIGREF7": {"text": "FIG. 10: Energy per hole of Eq. (16) for U = 0 and \u03bb/t = 2 for \u03c90/t = 1 (red squares), 5 (black circles), and 15 (blue diamonds). Calculations are performed on the 12 \u00d7 12 cluster with TABC. Errorbars are smaller than the size of the symbols.", "type": "figure"}, "TABREF0": {"text": "and contains a single", "type": "table"}}}
{"paper_id": "119424563", "_pdf_hash": "664b4472f008605c0776996b09eb1dd5243ea76d", "abstract": [{"section": "Abstract", "text": "We study the scrambling of local quantum information in chaotic many-body systems in the presence of a locally conserved quantity like charge or energy that moves diffusively. The interplay between conservation laws and scrambling sheds light on the mechanism by which unitary quantum dynamics, which is reversible, gives rise to diffusive hydrodynamics, which is a dissipative process. We obtain our results in a random quantum circuit model that is constrained to have a conservation law. We find that a generic spreading operator consists of two parts: (i) a conserved part which comprises the weight of the spreading operator on the local conserved densities, whose dynamics is described by diffusive charge spreading. This conserved part also acts as a source that steadily emits a flux of (ii) non-conserved operators. This emission leads to dissipation in the operator hydrodynamics, with the dissipative process being the conversion of operator weight from local conserved operators to nonconserved, at a rate set by the local diffusion current. The emitted nonconserved parts then spread ballistically at a butterfly speed, thus becoming highly nonlocal and hence essentially non-observable, thereby acting as the \"reservoir\" that facilitates the dissipation. In addition, we find that the nonconserved component develops a power law tail behind its leading ballistic front due to the slow dynamics of the conserved components. This implies that the outof-time-order commutator (OTOC) between two initially separated operators grows sharply upon the arrival of the ballistic front but, in contrast to systems with no conservation laws, it develops a diffusive tail and approaches its asymptotic late-time value only as a power of time instead of exponentially. We also derive these results within an effective hydrodynamic description which contains multiple coupled diffusion equations.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "I. INTRODUCTION", "text": "The nature of quantum dynamics and thermalization in isolated many-body systems is a topic of fundamental interest. Over the last few years, a remarkable confluence of theoretical progress and experimental advances in engineering and controlling isolated many-body quantum systems, especially in cold-atomic gases, has led us to re-examine our understanding of the very foundations of quantum statistical mechanics [1] [2] [3] . On the theory side, research in the field of many-body localization (MBL) [4] [5] [6] [7] [8] [9] has revealed the existence of classes of generically interacting systems that do not obey quantum statistical mechanics, and understanding the nature of different MBL phases 10, 11 and the transition(s) between MBL and thermalizing phases 6, [12] [13] [14] [15] [16] [17] [18] is an active area of research. Complementarily, the development of tools like the AdS/CFT duality 19, 20 has led to new perspectives on the dynamics of thermalizing strongly-interacting systems. This duality has been used to relate the physics of information scrambling in black-holes to the process of thermalization in condensed-matter systems of interacting spins and/or particles [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] .", "cite_spans": [{"start": 415, "end": 418, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 419, "end": 422, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 423, "end": 426, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 503, "end": 506, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 507, "end": 510, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 511, "end": 514, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 515, "end": 518, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 519, "end": 522, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 523, "end": 526, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 701, "end": 704, "text": "10,", "ref_id": "BIBREF9"}, {"start": 705, "end": 707, "text": "11", "ref_id": "BIBREF10"}, {"start": 766, "end": 768, "text": "6,", "ref_id": "BIBREF5"}, {"start": 769, "end": 773, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 774, "end": 778, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 779, "end": 783, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 784, "end": 788, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 789, "end": 793, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 794, "end": 798, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 799, "end": 803, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 902, "end": 905, "text": "19,", "ref_id": "BIBREF18"}, {"start": 906, "end": 908, "text": "20", "ref_id": "BIBREF19"}, {"start": 1188, "end": 1192, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 1193, "end": 1197, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 1198, "end": 1202, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 1203, "end": 1207, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 1208, "end": 1212, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 1213, "end": 1217, "text": "[26]", "ref_id": "BIBREF25"}, {"start": 1218, "end": 1222, "text": "[27]", "ref_id": "BIBREF26"}, {"start": 1223, "end": 1227, "text": "[28]", "ref_id": "BIBREF27"}, {"start": 1228, "end": 1232, "text": "[29]", "ref_id": "BIBREF28"}, {"start": 1233, "end": 1237, "text": "[30]", "ref_id": "BIBREF29"}], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "One lens on the dynamics of isolated many-body quantum systems is provided by studying the spreading of initially-local operators under the system's unitary timeevolution. In the Heisenberg picture, an initially local operator O 0 evolves into O 0 (t) = U \u2020 (t)O 0 U (t) with support on a spatial region that grows with time. This spreading of O 0 (t) is reflected in the growth of the commutator between O 0 (t) and a typical local operator W x with support near position x. If x is well away from the origin, then W x initially commutes with O 0 . We define the \"OTOC\" as the norm of the \"out-of-time-order\" commutator", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "where the expectation value is taken in an appropriate equilibrium ensemble. The OTOC is related to the commutator norm that appears in Lieb-Robinson bounds 32 , and has received a great deal of attention recently as a diagnostic of information \"scrambling\" in quantum chaotic systems [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [33] [34] [35] . For a spin-1/2 chain of length L, a complete orthonormal basis for all operators is given by the 4 L \"Pauli strings\" S, which are products of Pauli matrices on distinct sites. We can then express our spreading operator in this basis of Pauli strings:", "cite_spans": [{"start": 157, "end": 159, "text": "32", "ref_id": "BIBREF31"}, {"start": 285, "end": 289, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 290, "end": 294, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 295, "end": 299, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 300, "end": 304, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 305, "end": 309, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 310, "end": 314, "text": "[26]", "ref_id": "BIBREF25"}, {"start": 315, "end": 319, "text": "[27]", "ref_id": "BIBREF26"}, {"start": 320, "end": 324, "text": "[28]", "ref_id": "BIBREF27"}, {"start": 325, "end": 329, "text": "[29]", "ref_id": "BIBREF28"}, {"start": 330, "end": 334, "text": "[30]", "ref_id": "BIBREF29"}, {"start": 335, "end": 339, "text": "[33]", "ref_id": "BIBREF32"}, {"start": 340, "end": 344, "text": "[34]", "ref_id": "BIBREF33"}, {"start": 345, "end": 349, "text": "[35]", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "The initially local operator O 0 consists only of strings S that are the local identity at all sites except one or a few sites near the origin. But, with time, the strings that dominate this sum grow in spatial extent, containing non-identity local operators at sites out to a \"front\" at a distance from the origin that grows with time. The OTOC remains near zero as long as the strings that dominate in O 0 (t) contain only local identities near position x, but it becomes nonzero once the operator front reaches this position.", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "In this paper, we are interested in understanding operator spreading and scrambling in the physically ubiquitous setting of thermalizing systems with one or a few local conservation laws that result in diffusive transport. This includes, for example, certain Hamiltonian models, since they do conserve energy, and in many cases energy transport is diffusive. It also includes certain Floquet systems which don't conserve energy but do conserve a charge or spin. We first investigate this question in a random tensor network spin chain model where the tensors are constrained to obey a single local U (1) spin conservation law. We can derive a number of exact results in this setting, which we conjecture (and numerically verify) should also universally apply to Hamiltonian and Floquet spin chains with diffusing conserved quantities.", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "A set of recent papers has studied entanglement and operator dynamics in random tensor network models with no conservation laws 33, [36] [37] [38] . A subset of these 37, 38 showed that, despite the absence of traditional hydrodynamic conservation laws, unitarity alone amounts to a type of conservation law since the operator norm,", "cite_spans": [{"start": 128, "end": 131, "text": "33,", "ref_id": "BIBREF32"}, {"start": 132, "end": 136, "text": "[36]", "ref_id": "BIBREF35"}, {"start": 137, "end": 141, "text": "[37]", "ref_id": "BIBREF36"}, {"start": 142, "end": 146, "text": "[38]", "ref_id": "BIBREF37"}, {"start": 167, "end": 170, "text": "37,", "ref_id": "BIBREF36"}, {"start": 171, "end": 173, "text": "38", "ref_id": "BIBREF37"}], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": ", is conserved which means that the total weight of the operator on all Pauli strings, S |a S | 2 , is conserved. This leads to an emergent \"hydrodynamical\" picture for describing operator spreading wherein, in one dimension, the dynamics of the operator front can be described by a distribution of biased random walkers (where the bias reflects the fact that it is more likely for an operator string to grow rather than to shrink) 37, 38 , while in higher dimensions the front is modeled by a random growth model 36, 37 . This leads to a picture in which the operator front propagates ballistically with \"butterfly\" speed v B , while in low dimensions the width of the front grows as a sublinear power of time (\u223c \u221a t in 1D) 37, 38 . This means that the bulk of the total weight of O 0 (t) is contained in the spatial region lying within the \"light cone\" defined by the front whose spatial linear size grows linearly with time. Further, O 0 (t) is scrambled within the spatial region defined by the light cone and, with respect to some (but not all) measures, resembles an unconstrained random operator in this region 39 .", "cite_spans": [{"start": 432, "end": 435, "text": "37,", "ref_id": "BIBREF36"}, {"start": 436, "end": 438, "text": "38", "ref_id": "BIBREF37"}, {"start": 514, "end": 517, "text": "36,", "ref_id": "BIBREF35"}, {"start": 518, "end": 520, "text": "37", "ref_id": "BIBREF36"}, {"start": 725, "end": 728, "text": "37,", "ref_id": "BIBREF36"}, {"start": 729, "end": 731, "text": "38", "ref_id": "BIBREF37"}, {"start": 1118, "end": 1120, "text": "39", "ref_id": "BIBREF38"}], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "In this work, we build on the picture above and study the interplay between the \"actual\" hydrodynamics governing the dissipative diffusion of conserved charges and the \"emergent\" hydrodynamics of unitary operator spreading in systems with conservation laws. Starting from a local operator that contains the conserved charge, we find that there is again a ballistically propagating front describing the operator spreading. However, unlike the fully nonconserved case, O 0 (t) has a significant (decreasing as a power law in time) amount of weight on operator strings whose fronts lag far behind the main operator front. This can be understood as follows: Since conserved charges spread diffusively, the parts of O 0 (t) that overlap with the conserved charges are \"left behind\" in a region of linear size \u223c \u221a t near the origin, even while the main operator front has reached distance v B t. But the total weight of O 0 (t) on these conserved operators decreases as a power-law in time \u223c t \u2212d/2 in d dimensions as the conserved density spreads diffusively. This loss of operator weight makes this diffusion effectively nonunitary and thus dissipative. But the full dynamics of the system is unitary so the full operator weight is not lost. Instead the dissipation due to the diffusive currents of the conserved density steadily converts operator weight from conserved to non-conserved operators, thus emitting a \"flux\" of non-conserved operators that then spread ballistically. This emitted flux is proportional to the square of the diffusive current, as expected for \"Ohmic\" dissipation. One point of view is that once the non-conserved operators start spreading ballistically, they rapidly become so highly nonlocal that they stop being observables. Then they can be viewed as effectively random, functioning as the bath whose entropy increases due to the dissipative diffusion.", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "Moreover, in the models we study here, we can also study the unitary \"inner workings\" of this effective bath, following the spreading of the non-conserved parts of the operator. The bulk of these non-conserved operators are emitted almost immediately, near time t = 0, and these grow to form the leading operator front at distance v B t at time t. However, as a result of the conservation law, there is still significant weight left on the conserved parts even after the initial emission, and these continue to emit non-conserved operators at a slow rate that decreases only as a power law in time. Thus, those non-conserved parts of the operator that are emitted at a later time t e have a front that lags behind the main operator front by distance v B t e . This leads to a power-law tail in the operator profile behind the front. By contrast, the unconstrained random circuit model does not show such a power-law tail, since in that case there are no slow dissipative modes so no significant part of the operator has a front that lags substantially behind the main operator front. Fig. 2 shows a sketch of the operator profile depicting all three regimes: (i) the diffusive conserved charges remaining near the origin, (ii) the ballistically moving front, and (iii) the power law tail behind the front.", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "The picture that emerges from our study is of multiple coupled hydrodynamic equations: The first is the dissipative diffusion of the conserved quantity. This dissipation serves as the source of the ballistically spreading nonconserved operators. The dynamics of the fronts of these nonconserved operators is biased diffusion in 1D and a random growth model in higher dimensions 36, 37 . Moreover, we find that the local operator content in the interior of the spreading operator is also governed by two coupled noisy diffusion equations, with the leading front of the operator serving as a moving boundary condition on these equations. And finally, there is at least one more \"layer\" of this hydrodynamics that governs the entanglement dynamics of the spreading operator 40 .", "cite_spans": [{"start": 378, "end": 381, "text": "36,", "ref_id": "BIBREF35"}, {"start": 382, "end": 384, "text": "37", "ref_id": "BIBREF36"}], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "The spatial profile of the spreading operator described above is also reflected in the behavior of the OTOC C(x, t) defined in Eq (1). We show that C(x, t) increases sharply when the ballistic operator front reaches x but, as a result of the power-law tails behind the main operator front, it only approaches its asymptotic late-time value as a power-law in time. This is contrast to systems without conservation laws where there are no such power-law diffusive tails 37, 38 . Our results help explain the numerical observations in Ref. 41 where this late-time power-law in the OTOC was observed in systems with conservation laws.", "cite_spans": [{"start": 468, "end": 471, "text": "37,", "ref_id": "BIBREF36"}, {"start": 472, "end": 474, "text": "38", "ref_id": "BIBREF37"}, {"start": 537, "end": 539, "text": "41", "ref_id": "BIBREF40"}], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "We note that much recent work has focused on computing the OTOC at low temperatures in systems with energy conservation, and bounds on the growth of the OTOC have been derived in this setting 42 . On the other hand, random circuit models do not conserve energy and thus the \"infinite temperature\" Gibbs ensemble is the only meaningful one for such models. Nevertheless, for circuit models endowed with extra conservation laws like total spin/charge, the dynamics can be resolved into different spin sectors with the \"chemical potential\" \u00b5 now playing a role somewhat analogous to the inverse temperature \u03b2. We mostly focus on \u00b5 = 0 in this work, while briefly addressing the \u00b5 = 0 case.", "cite_spans": [{"start": 192, "end": 194, "text": "42", "ref_id": "BIBREF41"}], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "We note that several papers have recently noted that quantum information can spread ballistically in systems with diffusively relaxing conserved charges [43] [44] [45] [46] [47] [48] . This, by itself, is not that surprising since even MBL systems with no charge transport can show logarithmic spreading of entanglement 8, 49 . Of these papers, Refs. 46-48 study a weakly interacting diffusive metal and, using a perturbative semiclassical scattering calculation, relate the butterfly speed v B to the diffusion constant of the metal via a \"Lyapunov exponent\" which characterizes the exponential growth of \"chaos\" in this semiclassical setting as measured by the growth of the OTOC before the front arrives: C(x, t) \u223c e \u2212\u03bb L (x\u2212v B t) . On the other hand, Refs. 43-45 numerically study fully quantum spin-chains which cannot be treated semiclassically, and for which no prolonged period of exponential growth in the OTOC has been observed to date (the existence of a fully quantum Lyapunov exponent in spatially extended systems with small local Hilbert spaces and only short-range interactions, while perhaps expected, is a presently unresolved question). In this fully quantum setting where semiclassical analytical methods don't apply, the aforementioned numerical papers [43] [44] [45] generally treat the diffusive charge relaxation and the ballistic information spreading as two independent numerical observations that do not interface with one another.", "cite_spans": [{"start": 153, "end": 157, "text": "[43]", "ref_id": "BIBREF42"}, {"start": 158, "end": 162, "text": "[44]", "ref_id": "BIBREF43"}, {"start": 163, "end": 167, "text": "[45]", "ref_id": "BIBREF44"}, {"start": 168, "end": 172, "text": "[46]", "ref_id": "BIBREF45"}, {"start": 173, "end": 177, "text": "[47]", "ref_id": "BIBREF46"}, {"start": 178, "end": 182, "text": "[48]", "ref_id": "BIBREF47"}, {"start": 320, "end": 322, "text": "8,", "ref_id": "BIBREF7"}, {"start": 323, "end": 325, "text": "49", "ref_id": "BIBREF48"}, {"start": 1275, "end": 1279, "text": "[43]", "ref_id": "BIBREF42"}, {"start": 1280, "end": 1284, "text": "[44]", "ref_id": "BIBREF43"}, {"start": 1285, "end": 1289, "text": "[45]", "ref_id": "BIBREF44"}], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "One of our main contributions in this work is to connect the diffusive charge dynamics with the ballistic front spreading in strongly quantum systems with local conservation laws into a composite picture for the operator profile, showing how the different regimes connect at different time and length scales. En route, we elucidate how reversible unitary dynamics can still display dissipative hydrodynamic modes, wherein the dissipative process is the conversion of operator weight from locally observable conserved parts to non-local and essentially unobservable non-conserved parts at a slow rate set by the local diffusion current of the conserved densities. Thus while the von Neumann entropy of the full system is conserved under the unitary dynamics, we show how the local \"observable\" entropy can still increase at a slow hydrodynamic rate, very concretely illustrating a resolution of the fundamental tension between unitarity and dissipation in closed quantum systems.", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "The balance of this paper is structured as follows. We begin in Section II with a description of our constrained random unitary circuit model which has a local U (1) conservation law total for total spin. This is followed by a detailed discussion of the spatial profile of spreading operators in Section III. We show that the conserved charges evolve diffusively under the action of the circuit. The coupling between the charge conservation and unitarity produces a steady flux of operator weight from the diffusively spreading conserved components to ballistically spreading nonconserved components, leading to a power law tail in the spatial profile of the operator weight. We present the coupled hydrodynamics describing this process. Next, in Section IV, we expose another layer of structure in the spreading operator by studying the local operator content of the highly nonlocal operator strings within the light cone defined by the leading ballistic front. We find that the distribution of different local operators is itself governed by a set of coupled noisy diffusion equations that \"turn on\" once the front passes a given position. In Section V, we turn to a discussion of OTOC's in this model, and find that the diffusive processes governing the shape and internal structure of the spreading operators lead to a late time diffusive tail in OTOC's involving the conserved charges. We numerically verify that the universal aspects of our results also apply to more \"physical\" spin chains with energy/charge conservation in Section VI, and conclude in Section VII. Some additional details are discussed in the Appendices.", "cite_spans": [], "ref_spans": []}, {"section": "II. RANDOM UNITARY CIRCUIT MODEL", "text": "As an explicit example where we can obtain analytical results, we consider a one-dimensional chain of length L sites where the degree of freedom on each site is the direct product of a spin-1/2 (or qubit) and a qudit with Hilbert space dimension q. For definiteness we take a finite L, but we will be interested in the behavior in the limit of infinite L. The time-evolution is constrained to conserve the total z component of the spin-1/2's, which we call S tot z , while the qudits are not subject to any conservation laws. We note that we include the qudit at each site because some results can only be obtained analytically in the large-q limit, although some of our results do apply for all q, including the case q = 1 that has no qudits.", "cite_spans": [], "ref_spans": []}, {"section": "II. RANDOM UNITARY CIRCUIT MODEL", "text": "Generalizing from Refs. 33, 36-38, the time-evolution is governed by a random quantum circuit comprising staggered layers of two-site unitary gates acting on even and odd spatial bonds at even and odd times respectively (see Fig. 1 ). The time evolution operator is given by U (t) = t t =1 U (t , t \u2212 1), where", "cite_spans": [], "ref_spans": []}, {"section": "II. RANDOM UNITARY CIRCUIT MODEL", "text": "As a result of the conservation law, each two-site unitary gate U i,i+1 is a (4q 2 \u00d7 4q 2 )-dimensional block-diagonal matrix. Labeling the spin state on each site i as (\u2191 a) i or (\u2193 b) i , where the first label is the spin state in the Pauli z basis and the second label is the qudit state, the structure of U i,i+1 looks like:", "cite_spans": [], "ref_spans": []}, {"section": "II. RANDOM UNITARY CIRCUIT MODEL", "text": "subspace. Each of these blocks is a Haar-random unitary, and each block in each two-site gate is chosen independently of all others.", "cite_spans": [], "ref_spans": []}, {"section": "II. RANDOM UNITARY CIRCUIT MODEL", "text": "To characterize the time-evolution of local operators, it is useful to define a complete orthonormal basis of operators on each site. For the spin, we can use the Pauli matrices on each site to define an onsite basis as", "cite_spans": [], "ref_spans": []}, {"section": "II. RANDOM UNITARY CIRCUIT MODEL", "text": "Using this basis, the time evolved operator O(t) can be expanded as: ", "cite_spans": [], "ref_spans": []}, {"section": "II. RANDOM UNITARY CIRCUIT MODEL", "text": "L which, by the unitarity of the dynamics, implies that the total weight of O(t) on all strings S is also normalized to 1:", "cite_spans": [], "ref_spans": []}, {"section": "II. RANDOM UNITARY CIRCUIT MODEL", "text": "This sum rule is the effective conservation law due to unitarity 37, 38 . There are a few classes of operators on site i that evolve differently under the action of this conserving unitary circuit. First, (zI) i measures the local conserved charge, and (II) i is the identity operator. The conservation law implies that S tot z is conserved so that", "cite_spans": [{"start": 65, "end": 68, "text": "37,", "ref_id": "BIBREF36"}, {"start": 69, "end": 71, "text": "38", "ref_id": "BIBREF37"}], "ref_spans": []}, {"section": "II. RANDOM UNITARY CIRCUIT MODEL", "text": "and the operators ( It will be subsequently useful to separate the spreading operator into conserved and non-conserved pieces. To intuitively understand this separation, consider an initial density matrix", "cite_spans": [], "ref_spans": []}, {"section": "II. RANDOM UNITARY CIRCUIT MODEL", "text": "where I all is the background equilibrium state which is the identity on the full system; AO 0 is a traceless local onsite perturbation at the origin to this equilibrium state,", "cite_spans": [], "ref_spans": []}, {"section": "II. RANDOM UNITARY CIRCUIT MODEL", "text": "and A is the amplitude of this perturbation, which must be small enough so \u03c1 remains non-negative. The system conserves S tot z (6) so that", "cite_spans": [], "ref_spans": []}, {"section": "II. RANDOM UNITARY CIRCUIT MODEL", "text": "where (t) denotes expectation values in the state \u03c1(t).", "cite_spans": [], "ref_spans": []}, {"section": "II. RANDOM UNITARY CIRCUIT MODEL", "text": "If the perturbation injects some local charge at the origin then, on general grounds, we expect this \"extra\" charge to spread diffusively so that (zI", "cite_spans": [], "ref_spans": []}, {"section": "II. RANDOM UNITARY CIRCUIT MODEL", "text": "will see how this diffusion arises in operator language and explore its consequences for operator dynamics in this system. To separate the part of O 0 (t) that has overlap with the conserved charges, we define a c i (t) as the amplitude of the conserved charge (zI) i in the operator expansion of O 0 (t):", "cite_spans": [], "ref_spans": []}, {"section": "II. RANDOM UNITARY CIRCUIT MODEL", "text": "The conserved charges which act as (zI) i on site i and as the identity everywhere else are a subset of the full basis of operator strings, and the \"conserved part\" of O 0 (t) is defined as the part of O 0 (t) with weight on these basis strings:", "cite_spans": [], "ref_spans": []}, {"section": "II. RANDOM UNITARY CIRCUIT MODEL", "text": "with the \"non-conserved part\" being the rest,", "cite_spans": [], "ref_spans": []}, {"section": "II. RANDOM UNITARY CIRCUIT MODEL", "text": "The dynamics of operator spreading in this model is governed by the interplay between (i) this explicit charge conservation (11) which is a sum rule on the amplitudes of the conserved operators, and (ii) the conservation of the operator weight (which follows from unitarity) which is a sum rule on the squares of the amplitudes of all basis strings (5).", "cite_spans": [{"start": 124, "end": 128, "text": "(11)", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "III. \"SHAPE\" OF SPREADING OPERATORS", "text": "A complete characterization of the spreading and scrambling of an initially local operator O 0 requires knowledge of the exponentially-many coefficients a S (t) in the expansion of O 0 (t) as in Eq. (4). Instead of doing this, we first consider a more coarse-grained approach and define the \"right-weight\" \u03c1 R (i, t) as the total weight in O(t) of basis strings that end at site i, which means that they act as the identity on all sites to the right of site i, but act as a non-identity on site i. This is the weight on all strings of the form", "cite_spans": [], "ref_spans": []}, {"section": "III. \"SHAPE\" OF SPREADING OPERATORS", "text": "The conservation law on \u03c1 R (i, t) which follows from unitarity (5) gives \u03c1 R (i, t) the interpretation of an emergent local conserved \"density\", and Refs. 37, 38 showed that the (hydro)dynamics for \u03c1 R (i, t) is governed by a biased diffusion equation. Of course, one can analogously define the left-weight \u03c1 L (i, t) and, together, these can be used to characterize some illuminating aspects of the spatial structure of the spreading operator (we will consider other measures probing the local operator content inside the spreading operator in the next section).", "cite_spans": [{"start": 156, "end": 159, "text": "37,", "ref_id": "BIBREF36"}, {"start": 160, "end": 162, "text": "38", "ref_id": "BIBREF37"}], "ref_spans": []}, {"section": "III. \"SHAPE\" OF SPREADING OPERATORS", "text": "It is instructive to first understand the dynamics of \u03c1 R (i, t) in an unconstrained random circuit model in 1D with local Hilbert space dimension q. It was shown in Refs. 37, 38 that the weighted distribution of the endpoints of the basis strings in the operator time-evolve as biased random walkers, where the bias reflects the fact that it more likely for the strings to grow rather than to shrink. If we define the \"right-front\" of a string as the location of the rightmost unitary gate that sees a nonidentity, one can obtain the probabilities for the front to move forwards or backwards by noting that under the action of the front gate, all the (q 4 \u2212 1) non-identity operators at the gate are produced with equal weights, on average. If the front gate is U i,i+1 , only q 2 \u2212 1 of the operators that can be produced by this gate act as the identity on the right site of the gate (i + 1), and each of these outcomes results in the front moving a step backwards, an event with probability p = 1 (q 2 +1) . Then, from the theory of random walks, the mean location of the front after time t is x = (1 \u2212 2p)t \u2261 v B t, which defines the butterfly speed v B , and the width of the front grows as \u223c D \u03c1 t, where", "cite_spans": [{"start": 172, "end": 175, "text": "37,", "ref_id": "BIBREF36"}, {"start": 176, "end": 178, "text": "38", "ref_id": "BIBREF37"}], "ref_spans": []}, {"section": "III. \"SHAPE\" OF SPREADING OPERATORS", "text": "/2 is the diffusivity of the resulting biased random walk. Evidently, the front location can be described by the emergent random walk hydrodynamics 37, 38 ", "cite_spans": [{"start": 148, "end": 151, "text": "37,", "ref_id": "BIBREF36"}, {"start": 152, "end": 154, "text": "38", "ref_id": "BIBREF37"}], "ref_spans": []}, {"section": "III. \"SHAPE\" OF SPREADING OPERATORS", "text": ", and the fact that the right side of this equation is a total spatial derivative reflects the conservation of the emergent density \u03c1 R (12) .  Fig 2(c) shows a sketch of the Haar-averaged front for this random circuit evolution which, in the scaling limit t, x \u2192 \u221e for x \u2248 v B t takes the form", "cite_spans": [], "ref_spans": []}, {"section": "III. \"SHAPE\" OF SPREADING OPERATORS", "text": "In the limit q \u2192 \u221e, the front becomes sharp and v B \u223c 1 \u2212 2 q 2 \u2192 1 so that the front deterministically moves forwards for all basis strings at each time step in this limit (Fig 2(d) ). Note that the geometry of the circuit limits the operator growth to at most one site on the left and right ends per time step. This imposes a strict upper bound on v B set by the \"causal limit speed\" v CL = 1, and v B goes to this limit as q \u2192 \u221e.", "cite_spans": [], "ref_spans": []}, {"section": "III. \"SHAPE\" OF SPREADING OPERATORS", "text": "Let us now turn to how this picture changes in the presence of an explicit U (1) conservation law with diffusively spreading charges.", "cite_spans": [], "ref_spans": []}, {"section": "A. Spreading of the local conserved charge", "text": "Let us begin with the case when the initial operator is a conserved U (1) charge located at the origin, O 0 = (zI) 0 . In this case, the spatial structure of the operator shows ,", "cite_spans": [], "ref_spans": []}, {"section": "A. Spreading of the local conserved charge", "text": "which is an exact result true for all q including q = 1. If we coarse-grain, in the scaling limit x, t \u2192 \u221e we get", "cite_spans": [], "ref_spans": []}, {"section": "A. Spreading of the local conserved charge", "text": "showing diffusion of the conserved charge with diffusion constant D c = 1/2. If we consider similar random circuits acting on a system in higher dimensions d > 1, a similar diffusive behavior will be present, just with diffusion along all directions. It is noteworthy that as a consequence of the conservation law, the Haar-averaged amplitudes a c i (t) are non-zero (16) . In an unconstrained random circuit, only the squared weights |a S | 2 survive Haar averaging while all amplitudes average to zero. Likewise, in our model with S tot z conservation, certain off-diagonal products of amplitudes a S a S can also survive Haar averaging (Appendix C), while all such averages are zero in the unconstrained model.", "cite_spans": [{"start": 367, "end": 371, "text": "(16)", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "Ballistic front and power law tails", "text": "We now turn to the effect of the diffusive dynamics on the shape of the spreading operator as measured by \u03c1 R (i, t). It is important to note that \u03c1 R (i) measures the weights, |a S | 2 , of all operator strings ending on i, while the preceding discussion was about the diffusive dynamics of the amplitudes, a c i , of only the conserved charges in the expansion of O 0 (t); these conserved operators are strings of length one site. Of course, the weight of O 0 (t) on a conserved charge at site i contributes to \u03c1 R (i, t) and it is convenient to separate out this contribution:", "cite_spans": [], "ref_spans": []}, {"section": "Ballistic front and power law tails", "text": "where \u03c1 nc R denotes the right-weight from all \"nonconserved\" operator strings that are not one of the conserved charges (zI", "cite_spans": [], "ref_spans": []}, {"section": "Ballistic front and power law tails", "text": "We will show that the total weight of O 0 (t) on the conserved charges, \u03c1 c tot , decreases as a power law in time; these then act a source, continuously emitting a flux of non-conserved operators that spread ballistically and contribute to \u03c1 nc tot .", "cite_spans": [], "ref_spans": []}, {"section": "50", "text": "Let us see how this comes about. First, we show in Appendix C that the circuit-to-circuit variance in the conserved amplitudes is suppressed both in the large q and the late time t limit:", "cite_spans": [], "ref_spans": []}, {"section": "50", "text": "while the leading term |a c i (t)| 2 scales as \u223c 1/t (17). In this limit, \u2206 a i (t) \u2248 0 and |a c i (t)| 2 \u2248 |a c i (t)| 2 . Then, the power law decrease in \u03c1 c tot is obtained as", "cite_spans": [], "ref_spans": []}, {"section": "50", "text": "where we coarse-grain at long times to obtain the penultimate equality, using (17) . Likewise, in higher dimensions, this power law decrease will scale as \u03c1 c tot (t) \u223c t \u2212d/2 as can be easily seen by considering the higher dimensional generalization of (17) . Because of the conservation of total density (19) , this decrease in \u03c1 c tot has to be compensated by a corresponding increase in \u03c1 nc tot . Indeed, from the previous discussion, we see that the local decrease in \u03c1 c tot", "cite_spans": [{"start": 78, "end": 82, "text": "(17)", "ref_id": "BIBREF16"}, {"start": 254, "end": 258, "text": "(17)", "ref_id": "BIBREF16"}, {"start": 306, "end": 310, "text": "(19)", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "50", "text": "This is the increase in \u03c1 nc tot that is locally generated at this gate, and this quantity is proportional to the square of the conserved quantity's local current. These", "cite_spans": [], "ref_spans": []}, {"section": "50", "text": "Eq. (13) \u2212400 \u2212200 0 200 400", "cite_spans": [], "ref_spans": []}, {"section": "50", "text": "Eq. (24) \u2212400 \u2212200 0 200 400", "cite_spans": [], "ref_spans": []}, {"section": "50", "text": "showing the spreading of an initially local conserved charge (zI)0(t) in a random circuit model with S tot z conservation in a system of size L = 1000 at different times t. These profiles depict three regimes: (i) a \"lump\" in the region |x| \u221a Dct reflecting the weight of the operator on diffusively spreading conserved charges (shaded purple). This lump emits ballistically spreading nonconserved operators at a slow power-law rate. This emission creates (ii) the leading ballistic \"fronts\" near |x| \u223c vBt within which the majority of the operator right-and left-weight is contained (shaded red for the latest time). These leading fronts are from nonconserved operators emitted at early times and they are perfectly sharp at q = \u221e where vB = 1 (b), and have a width D\u03c1t for finite q (a); Finally, the slow emission also leads to (iii) diffusive tails \u223c (vBt \u2212 |x|) \u22123/2 behind the leading fronts which reflect the operator weight in \"lagging\" fronts of nonconserved operator strings that were emitted at later times (shaded blue for the latest time). The curves in (a) are obtained via a simulation at q = 3 which takes into account the different processes (diffusion of charges, emission of nonconserved operators and the biased diffusion of the nonconserved right-and left-weights) to order 1/q 2 . The red dashed curve is the exact infinite q answer for the \"tail\" (24) . (c,d): For comparision, \u03c1 R/L (x, t) in an unconstrained random circuit model 37, 38 where z0(t) isn't \"special\". Regimes (i) and (iii) do not exist in an unconstrained circuit, and the ballistically spreading operator fronts describe the entire right-and left-weight profiles. The fronts are again infinitely sharp at q = \u221e (d) and have a finite width \u223c D\u03c1t for q < \u221e (c).", "cite_spans": [{"start": 1369, "end": 1373, "text": "(24)", "ref_id": "BIBREF23"}, {"start": 1454, "end": 1457, "text": "37,", "ref_id": "BIBREF36"}, {"start": 1458, "end": 1460, "text": "38", "ref_id": "BIBREF37"}], "ref_spans": []}, {"section": "50", "text": "newly-produced non-conserved operators then evolve under the unitary dynamics and get converted to other nonconserved operators with increasing size. As in the case of the evolution of \u03c1 R (x, t) for an unconstrained random circuit, the front of non-conserved operators (once generated) spreads ballistically, with v B = 1 for q = \u221e since the likelihood of the front moving backwards is again suppressed by \u223c 1/q 2 (Appendix B). Further, in the q = \u221e limit, there is no \"backflow\" of density from non-conserved operators to conserved charges; this backflow only appears at order 1/q 4 . Thus, at q = \u221e and in the scaling limit, these considerations imply that:", "cite_spans": [], "ref_spans": []}, {"section": "50", "text": "This expression tells a very natural story. The total nonconserved right-weight at position x at time t is the integrated weight of all \"fronts\" emitted at locations y at times t y = t \u2212 (x \u2212 y)/v B such that the front travelling with velocity v B makes it to position x at time t. Moreover, since the conserved charges are primarily spread within a distance \u223c \u221a D c t near the origin, the emission of non-conserved flux is only significant at locations within this diffusively spreading \"lump of charge\". Then, at late time t, we see the three pieces in the shape of \u03c1 R (x, t) mentioned earlier:", "cite_spans": [], "ref_spans": []}, {"section": "50", "text": "1. The diffusive \"lump\": In the spatial region |x| \u221a D c t near the origin, the right-weight comes almost entirely from the diffusively spreading conserved part of the operator, \u03c1 R (x, t) |a c (x, t)| 2 . As a result, the spreading operator has significant weight that is \"left behind\" near the starting position of the operator, and this weight decreases only as a power-law in time \u223c t \u2212d/2 in d dimensions (21) . By contrast, a spreading operator in the unconstrained circuit model has negligible right-weight (exponentially decreasing with t) near its initial location at late times.", "cite_spans": [{"start": 410, "end": 414, "text": "(21)", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "50", "text": "2. The ballistic front: The leading ballistic operator front (at the right end) is at x = v B t, and the weight at the leading front is from non-conserved operators that were emitted at early times. At q = \u221e, the leading front is sharp, the right-weight is strictly zero for x > v B t with v B = 1, and the sharp front is due to those non-conserved operators that were emitted by gates acting at the precise edge of the causal light cone. At finite q, as in the unconstrained circuit model 37, 38 , the front distributions execute biased diffusion instead of strictly moving forwards at each time step. This leads to an order 1/q 2 correction in v B : v B 1 \u2212 8/(9q 2 ) (Appendix B) and gives the main operator front a nonzero width \u223c D \u03c1 t \u223c t/q 2 . Thus, at finite q, the leading front is mostly due to nonconserved operators that were emitted at early times t e D \u03c1 t/v B . For systems in d > 1, the broadening of the front at finite q is given by a random growth model and grows (if at all) with a smaller power of time 36, 37 .", "cite_spans": [{"start": 490, "end": 493, "text": "37,", "ref_id": "BIBREF36"}, {"start": 494, "end": 496, "text": "38", "ref_id": "BIBREF37"}, {"start": 1024, "end": 1027, "text": "36,", "ref_id": "BIBREF35"}, {"start": 1028, "end": 1030, "text": "37", "ref_id": "BIBREF36"}], "ref_spans": []}, {"section": "50", "text": "3. The diffusive tail: Finally, the fronts of nonconserved operator strings that were emitted at later times t e D \u03c1 t/v B lag behind the leading front by v B t e , leading to the development of powerlaw tails in the right-weight behind the main operator front. Consider positions x well separated from both the leading ballistic front and the diffusively spreading charge \"lump\" such that \u221a D c t x and v B t \u2212 x max{D \u03c1 t, 1}. In this regime, at infinite q,", "cite_spans": [], "ref_spans": []}, {"section": "50", "text": "which has a power-law tail in both space and time. Indeed, for x far separated from the lump, the diffusive charge lump emitting non-conserved flux can be approximately treated as a point source with the same integrated weight, so that \u03c1 nc R (x, t) is given by the rate of change of the total conserved density in the lump \u2202\u03c1 c tot /\u2202t \u223c t \u22123/2 at time t e = (t \u2212 x/v B ), which explains the 3/2 power (21). The leading functional dependence of this tail is the same at both infinite and finite q. For d > 1 the exponent in this power law is 1 + (d/2). By contrast, there is no such tail in the spatial profile of operators evolving under unconstrained circuits, since such circuits have no mechanism for generating fronts that significantly lag behind the main operator front. At q = \u221e for the unconstrained circuit, \u03c1 rand R = \u03b4(x \u2212 v B t) so there is strictly no tail; at finite q, the right-weight behind the leading front for the unconstrained circuit falls off exponentially in time at locations x behind the front scaling with any fixed 0 \u2264 x/t < v B .", "cite_spans": [], "ref_spans": []}, {"section": "50", "text": "The left-weight shows the same three regimes, by reflection symmetry. Fig. 2 shows \u03c1 R/L (x, t) for both the unconstrained and charge-conserving random circuit models at infinite and finite q.", "cite_spans": [], "ref_spans": []}, {"section": "Hydrodynamic description", "text": "We now turn to a long-time hydrodynamic description of the coupled processes involving diffusion of the conserved \"charge\" and the propagation of the fronts of the nonconserved operators emitted from this diffusing conserved charge.", "cite_spans": [], "ref_spans": []}, {"section": "Hydrodynamic description", "text": "For specificity, we restrict our attention to systems that are statistically translationally invariant and inversion symmetric. In such systems the amplitudes of the conserved part of the operator obey an unbiased diffusion equation. In more than one dimension, the diffusivity may not be isotropic; if that is the case, we rescale distances along the eigendirections of the diffusivity to make it isotropic:", "cite_spans": [], "ref_spans": []}, {"section": "Hydrodynamic description", "text": "where D c = 1/2 in our d = 1 random circuit model (17) . This diffusion is also subject to noise which will lead to fluctuations in a c across different realizations of the random circuit but, as we discussed above (20) , for initial operators that do contain the conserved quantity the noise is a parametrically subleading correction to the amplitudes a c in the late time limit that is relevant to the hydrodynamics.", "cite_spans": [{"start": 50, "end": 54, "text": "(17)", "ref_id": "BIBREF16"}, {"start": 215, "end": 219, "text": "(20)", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "Hydrodynamic description", "text": "Diffusion is a dissipative process, and this is reflected here in the decrease with time of the total operator weight of the conserved part of the operator, \u03c1 c tot (t) = dx|a c (x, t)| 2 . Since the full system is undergoing unitary dynamics, this loss of conserved operator weight means that weight is being converted to nonconserved operator weight. The density of local rate of this emission of nonconserved operators is 2D c |\u2207a c | 2 (22) , where we show that this coefficient is 2D c below. Note that this dissipation is proportional to the conserved quantity's local current squared, as in Ohm's law. These \"emitted\" nonconserved operators then spread rapidly, becoming highly nonlocal. This is an example of a presumably much more general picture of how dissipative processes happen within closed systems undergoing unitary dynamics: Correlations captured by low-order observables are moved by the unitary dynamics to highly nonlocal, and thus effectively non-observable operators. Dissipation in such closed systems is thus the \"hiding\" of correlations in highly nonlocal operators so that the correlations that remain detectable to low-order observables are reduced and thus the \"observable\" entropy increases, even though the von Neumann entropy of the full system remains unchanged.", "cite_spans": [{"start": 440, "end": 444, "text": "(22)", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Hydrodynamic description", "text": "The dynamics of the spreading of the front of the emitted nonconserved operators is given by a random and nonlinear growth model for d > 1, which we will not discuss further here 36, 37 . For d = 1 the weighted distributions of the fronts of the spreading strings move by biased diffusion 37, 38 . We will focus on the right-moving front, but the left-moving front is doing the same thing, just spatially reflected so it moves in the opposite direction.", "cite_spans": [{"start": 179, "end": 182, "text": "36,", "ref_id": "BIBREF35"}, {"start": 183, "end": 185, "text": "37", "ref_id": "BIBREF36"}, {"start": 289, "end": 292, "text": "37,", "ref_id": "BIBREF36"}, {"start": 293, "end": 295, "text": "38", "ref_id": "BIBREF37"}], "ref_spans": []}, {"section": "Hydrodynamic description", "text": "Thus the leading order continuum hydrodynamics in d = 1 of the right-density \u03c1 nc R (x, t) is described by a diffusion equation with drift and a source term representing the emission of non-conserved operators from local gradients in a c (x, t):", "cite_spans": [], "ref_spans": []}, {"section": "Hydrodynamic description", "text": "where we show in Appendix B that the drift and diffusion constants are v B 1 \u2212 37,38 that the circuit-to-circuit fluctuations in \u03c1 R (x, t) (and hence \u03c1 nc R (x, t)) scale with a parametrically smaller power of t, so we can ignore the noise in \u03c1 nc R in the leading order hydrodynamics. Thus, the coupled diffusion equations (25) and (26) describe the leading order hydrodynamics for those aspects of the shape of the operator that are described by \u03c1 R (x, t).", "cite_spans": [], "ref_spans": []}, {"section": "Hydrodynamic description", "text": "It is instructive to also directly consider the hydrodynamics for the total right-weight,", "cite_spans": [], "ref_spans": []}, {"section": "Hydrodynamic description", "text": "2 , an exercise that explicitly reveals the form of the source term for \u03c1", "cite_spans": [], "ref_spans": []}, {"section": "Hydrodynamic description", "text": "where we've left the functional form of the source term S nc for \u03c1 nc R undetermined, and we've used (25) in evaluating the time-derivative for the squared amplitudes of the conserved charges. Note however that since dx\u03c1 R (x, t) is conserved, the continuity equation requires that \u2202 t \u03c1 R (x, t) is the total spatial gradient of a current J (x, t). Thus, the two terms in (27) that are not spatial derivatives must cancel each other (up to a total derivative), giving", "cite_spans": [{"start": 101, "end": 105, "text": "(25)", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Hydrodynamic description", "text": "which gives the hydrodynamics for \u03c1 nc R (26) . With this relation,", "cite_spans": [{"start": 41, "end": 45, "text": "(26)", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "Hydrodynamic description", "text": "which nicely shows that the non-conserved part of \u03c1 R exhibits diffusive dynamics with a drift, while the conserved part simply diffuses with no net drift.", "cite_spans": [], "ref_spans": []}, {"section": "B. Spreading of local non-conserved operators", "text": "We now briefly describe the spreading of initial operators O 0 that are orthogonal to S = 0 (such as r 1 l 2 ). The first category of operators only have weight on basis strings with the same \u2206S z = 0 for all times, and thus remain orthogonal to each conserved charge (zI) i so that a i (t) = 0 \u2200 i, t. Thus, in this case, \u03c1 R (x, t) = \u03c1 nc R (x, t) and these operators do not have any left-or right-weight that is \"left behind\" near the initial location due to slow diffusive dynamics. This means that their right-weight profile does not have diffusive tails and looks essentially the same as \u03c1 R for an operator spreading under the action of an unconstrained random circuit (13), albeit with different drift and diffusion coefficients. This can also be seen from the hydrodynamic equation (26) since the source term will be zero for this case. However, we will show in the next section that the local operator content within the spreading operator, i.e. internal to the light-cone, still shows power-law correlations due to the conservation law.", "cite_spans": [], "ref_spans": []}, {"section": "B. Spreading of local non-conserved operators", "text": "Let us now turn to the second category of initial operators with \u2206S which still contain the local conserved charges but with amplitudes that sum to zero. In this case, one can show that the coarse-grained Haar-averaged conserved amplitudes a c (x, t) look like the spatial derivative of the amplitudes obtained for the case starting with a monopole source (17):", "cite_spans": [], "ref_spans": []}, {"section": "B. Spreading of local non-conserved operators", "text": "Indeed, this is also easily obtained from the hydrodynamic diffusion equation (25) with a dipole initial condition. Then, the total conserved weight again decreases as a power law in time, but with a faster decay as compared to the monopole case: \u03c1 c tot (t) \u223c t \u22123/2 in 1d. The conserved densities again act a source of non-conserved operators leading to a power law tail in \u03c1 R (x, t), but with scaling 1/(x \u2212 v B t) 5/2 in 1d as is seen by considering the rate of change of \u03c1 c tot (t). For q < \u221e, charge-neutral operators like r 1 l 2 create a dipole with nonzero probability at early times which then spreads as just described, again giving such a power-law tail in the asymptotic operator shape.", "cite_spans": [], "ref_spans": []}, {"section": "B. Spreading of local non-conserved operators", "text": "This brings us to a technical aside about the large q limit which is relevant for the spreading of non-conserved operators. An initial operator (rI) 1 (lI) 2 becomes a superposition of order q 4 operators, each with \u2206S z = 0, under the action of the first gate. Only operators that act as the identity on the qudit spins (and as z on the spin 1/2) have a chance of making a charge dipole and thereby contributing to the conserved weight \u03c1 c tot -but these are suppressed in probability by 1/q 4 . This illustrates one aspect of the dynamics that is suppressed by the infinite q limit, namely the likelihood for certain operators to make dipoles and thus to pick up power law tails in \u03c1 R (x, t). As a related point, if one starts directly with the dipole operator O dip 01 as before, then the q = \u221e limit is sensitive to whether the dipole is acted upon by a single gate U 01 at the first time step, or whether it is acted upon by the two gates U \u221210 and U 12 . The latter case proceeds exactly as described above since each initial gate sees a conserved (zI), while in the former case the single gate immediately converts the dipole to order q 4 non-conserved operators leading to a 1/q 4 suppression in the power-law tail. This strong sensitivity to microscopic initial details in the spreading of this class of operators is a peculiarity of the large q limit.", "cite_spans": [], "ref_spans": []}, {"section": "C. Spreading of multi-local conserved operators", "text": "We now briefly address the spreading of initial Pauli strings that are a product of N conserved charges,", "cite_spans": [], "ref_spans": []}, {"section": "C. Spreading of multi-local conserved operators", "text": "with the sites ordered so that i 1 < i 2 < \u00b7 \u00b7 \u00b7 < i N . The operator dynamics of such strings is also directly constrained by the conversation law since the conservation of S tot z implies the conservation of (S", "cite_spans": [], "ref_spans": []}, {"section": "C. Spreading of multi-local conserved operators", "text": "and thus \"multi-localized\" strings of charges act as the \"conserved densities\" of this higher order conservation law. Then, as in (14), the sum of all amplitudes a c j1j2\u00b7\u00b7\u00b7j N of the strings of z that appear in the expansion of (S N involves basis strings with less than N charges (in fact the relevant conserved operator is the appropriate weighted sum of (S We can now ask about the time evolution of amplitudes of the form a j1j2\u00b7\u00b7\u00b7j N with j 1 < j 2 < \u00b7 \u00b7 \u00b7 < j N . Note that if all the j s lie on different gates at a given time t, then we have independent diffusion of charges on each of the gates and action of the circuit simply averages all the inter-gate correlations and makes them equal. Indeed, if one starts in an infinitely large system with the charges in the initial string well-spaced such that the \"diffusive cones\" of the individual charges never intersect,", "cite_spans": [], "ref_spans": []}, {"section": "C. Spreading of multi-local conserved operators", "text": "and these amplitudes decay with time parametrically faster than those for a single conserved charge. On the other hand, if we start with a finite density of charges such that the independently diffusing charges encounter each other on a gate, then we have to account for the \"hard-core\" interaction between these charges which is encoded in the invariance of (zI) i (zI) i+1 under the action of a gate. As a result of this, the diffusing charges can never pass each other and the coarse-grained problem is that of \"single-file diffusion\" of N particles with a hard-core contact interaction. This problem has been solved in the literature 51 , and predicts that", "cite_spans": [{"start": 638, "end": 640, "text": "51", "ref_id": "BIBREF50"}], "ref_spans": []}, {"section": "C. Spreading of multi-local conserved operators", "text": "where the sum is over all N ! permutations \u03c3 for the particle labels at time t, the initial locations of the charges are i 1 \u00b7 \u00b7 \u00b7 i N , and we require j 1 < j 2 \u00b7 \u00b7 \u00b7 < j N .", "cite_spans": [], "ref_spans": []}, {"section": "C. Spreading of multi-local conserved operators", "text": "Finally, note that initial strings that are products of conserved operators on some sites and non-conserved operators on other sites do not have any overlap with any of the conserved charges or their higher moments. All Haaraveraged amplitudes for all basis strings will be zero in this case (although two-point correlations of the amplitudes can still survive averaging). Further, even if there is initially a diffusive \"cone\" of locally conserved charges in the vicinity of a conserved operator in the initial string, these quickly lose their coherence upon encountering the ballistic cones emanating from the initial locations of the non-conserved operators.", "cite_spans": [], "ref_spans": []}, {"section": "IV. INTERNAL STRUCTURE OF SPREADING OPERATORS", "text": "So far we have discussed the shape of the spreading operator in terms of the right-weight \u03c1 R (x, t); we've used this to describe the ballistic \"light cone\" within which the operator has spread, and the power law tails in the distributions of right-and left-weights within the light cone. We now turn to another layer of structure in the \"shape\" of the spreading operator that is relevant, for example, for the resulting OTOC's. This is the weighted local distributions of the different qubit operators (I, r, l, z) within the strings S that make up the operator. For an unconstrained random circuit, the distribution of these local operators is uniform between the four operator types after the leading operator front has passed a given location, but the distribution is highly biased towards identities before the front reaches. On the other hand, different operators are inequivalent in the conserving random circuit, leading to imbalances in these local densities that persist after the front passes. Indeed, the evolution of these local densities and their correlations are constrained by two further conservation laws that encode the fact that the unitary circuit conserves the action of the initial operator under the U (1) symmetry. These are the conservation of the total \"spin\" s if one starts in a state with definite S tot z , and the conservation of the net \"raising charge\" R \u2261 \u2206S tot z of an operator. Further, we will see that these conservation laws are coupled to each other through suitably-defined two-point correlations of charge/spin within the operator.", "cite_spans": [], "ref_spans": []}, {"section": "A. Conservation of raising charge", "text": "The action of the conserving circuit preserves the net \"raising charge\" R \u2261 \u2206S tot z of an initial operator that starts with a definite \u2206S tot z action. Concretely, for a given basis string S, the local R i = +1 if the qubit operator in S at site i is a raising operator r, while a lowering operator l has R i = \u22121, and z and I have R i = 0. Note that R i is neither sensitive to the qudit operator content, nor the operator content on all other sites. The unitary circuit conserves R tot = i R i for operators that start with a definite R tot , and the operator's local \"raising charge\" R i moves diffusively. Nevertheless, the circuit still converts a given basis string into a superposition of many strings each with different local patterns of R i (but with the same R tot ) and this choice of strings means that the diffusion of \"raising charge\" is subject to noise. For example, if a unitary gate U 12 acts on a two-site operator with R tot = +1 such as (rI) 1 (zI) 2 , the action of the gate produces a superposition of (4q 4 ) two-site strings of the form {(ra) 1 ", "cite_spans": [{"start": 1070, "end": 1071, "text": "1", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "A. Conservation of raising charge", "text": "where a and and b are arbitrary operators on the qudit and, within this ensemble of strings, the raising charge r is equally likely to be on either of the two sites acted upon by the gate (Appendix A). Of course, there is also noise from circuit-to-circuit fluctuations. If we average over the weighted ensemble of all strings within an operator that is evolved by a particular circuit and across circuits, then", "cite_spans": [], "ref_spans": []}, {"section": "A. Conservation of raising charge", "text": "where denotes the joint average, and the notation S i = (ra) means that the basis string acts as r on the spin-1/2 on site i and acts arbitrarily on the qudit. The last equality defines \u03c1 r/l (i, t) as the weight on all basis strings in the operator expansion of O(t) that locally act as r/l on the spin-1/2 on site i (one can analogously define \u03c1 I/z (i, t)). As discussed above, the action of a gate U 12 makes R i equal on the two sites and produces a \"raising charge\" current \u223c \u2202 x R(x, t):", "cite_spans": [], "ref_spans": []}, {"section": "A. Conservation of raising charge", "text": "which is identical to the structure we had previously obtained for the dynamics of a c i (t) (15) . Thus, any initially local spatial distribution of R i , for example if O 0 = (rI) 0 , spreads diffusively with diffusion constant D r = D c .", "cite_spans": [{"start": 93, "end": 97, "text": "(15)", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "B. Conservation of spin", "text": "Likewise, there is a noisy diffusion process governing the conservation of total spin s which measures the projections onto definite S tot z states. If we rotate the local spin-1/2 operator basis to the projection \"up\", u = (I + z)/ \u221a 2 and \"down\" d = (I \u2212 z)/ \u221a 2 operators, then these are charged under s as s = \u00b11 respectively, while r, l have s = 0. In this basis, the opera-", "cite_spans": [], "ref_spans": []}, {"section": "B. Conservation of spin", "text": "are special and left invariant by the action of all two-site gates U i,i+1 , while the others mix between themselves in a manner that locally conserves s tot = i s i on each gate. Thus, as before, the circuit conserves total s tot while generating noise, so that after averaging over circuits and strings", "cite_spans": [], "ref_spans": []}, {"section": "B. Conservation of spin", "text": "The action of a gate makes the average spin equal on the two sites:", "cite_spans": [], "ref_spans": []}, {"section": "B. Conservation of spin", "text": "This again means that an initial spin polarization spreads diffusively with D s = D c . Note that this equality between diffusivities and the one for raising charge above (33) are not completely trivial statements, since D c is for the amplitudes of the conserved operators that are a nonidentity only at one site, while D s /D r are for the local operator weights (amplitudes squared) of u/d's and r/l's within all strings, both conserved and non-conserved.", "cite_spans": [{"start": 171, "end": 175, "text": "(33)", "ref_id": "BIBREF32"}], "ref_spans": []}, {"section": "C. Coupling between spin and raising charge", "text": "If the initially local operator contains a nonzero net value of either of these two \"charges\", then that charge will only spread diffusively. Thus, if we look near the ballistically-moving operator front at long times, none of this initial charge can be there yet. Moreover, the action of the circuit is symmetric with respect to interchanging r \u2194 l and u \u2194 d (Appendix A), so that no new imbalances of the average charges is created due to the action of the circuit. Thus, both these average charges are zero far from the initial location at late times so that \u03c1 r (x, t) = \u03c1 l (x, t) and \u03c1 u (x, t) = \u03c1 d (x, t) for |x| \u221a D c t. However, for all ballistically spreading operators, there is a next layer of structure in the two-point correlations of these charge densities that evolves diffusively near the front and influences some of the OTOC's. This structure stems from the initial condition in which the local operators are the identity on all sites except those near the origin, and these identities only contribute to \u03c1 u/d and not to \u03c1 l/r . That is, before the front comes through, the operator is locally the identity which is an equalamplitude linear combination of all strings that contain only u's and d's. On the other hand, in the final \"local equilibrium\" state of the operator, all local strings are equally likely a long time after the front has passed through (up to corrections that decay as a power law in L). This equilibrium state is reached via a noisy diffusion process that turns on at each position when the front passes through that position. The two point correlations before the front passes through are R i R j = 0 and s i s j = \u03b4 ij , and these serve as the initial conditions on the diffusion process. This diffusion relaxes the initial imbalances between the relative density of local operators charged under spin and raising charge, in particular the imbalance in (\u03c1 u (x, t) + \u03c1 d (x, t)) \u2212 (\u03c1 r (x, t) + \u03c1 l (x, t)). We now see how this comes about.", "cite_spans": [], "ref_spans": []}, {"section": "C. Coupling between spin and raising charge", "text": "To start, we look at the dynamics of inter -gate correlations. Consider two different gates acting at the same time t on sites i, i + 1 and j, j + 1. These two gates simply set all inter-gate correlations of each type equal, just as they do for the average densities:", "cite_spans": [], "ref_spans": []}, {"section": "C. Coupling between spin and raising charge", "text": "and 7 other similar equations for the other inter-gate correlations of s and R of the form R i R j+1 (t + 1) etc. For concreteness, s i s j = +1 for strings that locally look like u i u j /d i d j on sites i, j and s i s j = \u22121 for strings that look like u i d j /d i u j , and is zero otherwise (analogous expressions for R i R j ), and the equation above can be derived by looking at the action of the circuit gates on the different types of operators (Appendix A). The zero inter-gate correlations before the front comes through are indeed invariant under this dynamics. The coarse-grained diffusion equation for this two-point correlation for x = y is thus", "cite_spans": [], "ref_spans": []}, {"section": "C. Coupling between spin and raising charge", "text": "with R(x)R(y) (t) obeying the same equation. This is for d = 1, but the generalization of this and the results below to higher d seems straightforward. Thus far we have two separate diffusion processes governing the diffusion of \"raising charge\" R and \"spin\" s correlations. In fact, these two processes are coupled once we consider the action within one gate on \"dipoles\". The \"dipoles\" of R are net raising-neutral operators like {(ra) i (lb) i+1 , (la) i (rb) i+1 }, while the dipoles of spin s are operators of the form {(ua) i (db) i+1 , (da) i (ub) i+1 }. The coupling between spin and raising charge stems from the fact that while the total density of all such dipoles within one gate is locally conserved, the different dipole species mix among each other under the action of the gate. And it is this process that allows an initial operator that contains no r's or l's to relax to the final equilibrium where all local strings are equally likely. The precise \"boundary conditions\" that couple the above diffusion equations within one gate i.e. at x = y are q-dependent and involve other correlations that can initially be well out of equilibrium just after the front passes.", "cite_spans": [], "ref_spans": []}, {"section": "C. Coupling between spin and raising charge", "text": "The coupling between the charges can be simplified by looking at particular linear combinations of the R i R j 0 100 200 300 400 500", "cite_spans": [], "ref_spans": []}, {"section": "C. Coupling between spin and raising charge", "text": "(vBt \u2212 |x|)", "cite_spans": [], "ref_spans": []}, {"section": "C. Coupling between spin and raising charge", "text": "Densities of local operators charged under \"spin\" and \"raising action\" behind the ballistic front of a spreading operator at q = \u221e and late times (41) . \u03c1 u/d (x, t) measures the local operator weight on site x on u/d operators that are charged under spin, while \u03c1 r/l (x, t) measures the local weight on r/l operators that have raising charge. Outside the ballistic operator front (at |x| > vBt), the spreading operator locally is purely identities which contribute equally to \u03c1 u/d = 1/2, but do not contribute to \u03c1 r/l = 0. The arrival of the front at a given site turns on a noisy coupled diffusion process between the spin and raising charges which relaxes the initially imbalanced densities of these charges to the final \"equilibrium\" value where all local operators are equally likely. Note that \u03c1u = \u03c1 d and \u03c1r = \u03c1 l in this regime since any initial imbalances in raising/spin charges spread only diffusively and are not present near the ballistic front at late times. Dashed lines plot the \"coarse-grained\" densities in the scaling limit (42) . and s i s j correlations. If we consider R i R j + s i s j , this has the initial condition R i R j + s i s j = \u03b4 ij . This initial condition is identical to the equilibrium final state where all strings are equally likely. And if we consider the action both within one gate and between two different gates, it does not change this quantity, which is therefore time-independent. Thus, although we do have two coupled diffusion equations, it reduces to just one diffusion equation for", "cite_spans": [{"start": 146, "end": 150, "text": "(41)", "ref_id": "BIBREF40"}, {"start": 1047, "end": 1051, "text": "(42)", "ref_id": "BIBREF41"}], "ref_spans": []}, {"section": "C. Coupling between spin and raising charge", "text": "for this initial state, which also has G ij (0) = \u03b4 ij as its initial condition. The local effective diffusivity due to the processes within one gate is, in general, q-dependent and different from that when i and j are in different gates, but at long time this affects a \"region\" of G ij that is a fraction \u223c 1/t of the distance (i \u2212 j) over which it has spread. Thus the leading coarse-grained long-time behavior of G ij is", "cite_spans": [], "ref_spans": []}, {"section": "C. Coupling between spin and raising charge", "text": "where the time t here is measured from the time when the front passes, say, the point (x + y)/2. Note that the effective diffusivity here is 2D c = 1, since we have independent diffusion at the locations x and y. In fact, at q = \u221e, the evolution of G ij (t) within one gate is identical in structure to the intra-gate evolution and we can solve for G ij exactly in this limit (Appendix D), and the coarse-grained answer agrees with (39) . Finally, note that this form for G(x, y, t) when evaluated at x = y shows how the initial imbalances in the populations of u, d vs. r, l decay diffusively away from the location of the front:", "cite_spans": [{"start": 432, "end": 436, "text": "(39)", "ref_id": "BIBREF38"}], "ref_spans": []}, {"section": "C. Coupling between spin and raising charge", "text": "For q = \u221e, where v B = 1, these imbalances can be evaluated exactly and they take the form \u2206 Rs (x, t) = 1 3", "cite_spans": [], "ref_spans": []}, {"section": "C. Coupling between spin and raising charge", "text": "where we've taken the late-time coarse-grained limit in the last line to evaluate the sum via a saddle-point approximation (Appendix D), and restored units. At finite q, we expect the leading functional dependence to still be the same, just with a reduced v B . This equation, coupled with the fact that \u03c1 l \u2248 \u03c1 r and \u03c1 u \u2248 \u03c1 d away from the diffusive lump allows us to solve for the local densities of the different operators, and this is sketched in Fig. 3 , showing how all local densities diffusively approach the equilibrium value of 1/4 after the front passes through. This diffusive relaxation of the imbalance leads to a power-law diffusive tail in certain OTOC's, as we will see in the next section.", "cite_spans": [], "ref_spans": []}, {"section": "V. OUT-OF-TIME-ORDER COMMUTATORS", "text": "We now turn to measuring the out-of-time-order commutator between different classes of operators (1) . We find that, in several cases, this quantity is sensitive to both the \"shape\" and the internal structure of spreading operators. If we consider the OTOC between two generic (initially) local operators, then this quantity is close to zero until the arrival of the ballistically spreading operator front and shows a sharp increase upon the arrival of the front. However, the OTOC for systems with local conservation laws also generically develops a \"diffusive tail\" and approaches its late time asymptotic value only as a power-law in time. Let us now see how this arises.", "cite_spans": [{"start": 97, "end": 100, "text": "(1)", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "V. OUT-OF-TIME-ORDER COMMUTATORS", "text": "Define", "cite_spans": [], "ref_spans": []}, {"section": "V. OUT-OF-TIME-ORDER COMMUTATORS", "text": "where \u03c3 {\u03b1=1,2,3} x = {r x , l x , z x } as before, we suppress the identity operators acting on the qudit spins on sites 0, x for notational simplicity, and", "cite_spans": [], "ref_spans": []}, {"section": "V. OUT-OF-TIME-ORDER COMMUTATORS", "text": "is the equilibrium \"grand-canonical\" ensemble at a particular chemical potential \u00b5. Note that while the infinitetemperature average is the only equilibrium for a random circuit model with no energy conservation, for a circuit model with an extra conservation law (like ours), we may also consider a non-zero chemical potential which weights the different spin sectors as above. We will focus on the equal-weight ensemble with \u00b5 = 0 for the majority of this section, briefly commenting on \u00b5 = 0 towards the end. We now study the OTOC for several different choices of \u03b1, \u03b2.", "cite_spans": [], "ref_spans": []}, {"section": "V. OUT-OF-TIME-ORDER COMMUTATORS", "text": "A. OTOC between z0(t) and rx Let us start with \u00b5 = 0, \u03b1 = 3 = z and \u03b2 = 1 = r. Then", "cite_spans": [], "ref_spans": []}, {"section": "V. OUT-OF-TIME-ORDER COMMUTATORS", "text": "and it is clear that only basis strings in the operator expansion of z 0 (t) that act as (la) or (za) on site x contribute to C 0 zr (x, t). Then, using the commutation relations [z x , r x ] = 2r x and [l x , r x ] = \u22122z x , and the orthonormality of basis strings, we get", "cite_spans": [], "ref_spans": []}, {"section": "V. OUT-OF-TIME-ORDER COMMUTATORS", "text": "where the notation a z S (t) denotes the amplitude of basis string S in the expansion of z 0 (t). A bit of algebra shows", "cite_spans": [], "ref_spans": []}, {"section": "V. OUT-OF-TIME-ORDER COMMUTATORS", "text": "which is a useful way of writing this for x > 0; an analogous expression involving the left-weight \u03c1 L can be written for x < 0. Note that the first two terms in (46) are sensitive to the overall operator shape, namely the right-weight profile of the spreading operator, while the latter two terms are sensitive to the local \"internal\" operator content after the front has passed site x. In random circuits with no conservation laws, all operator types are equally likely after the front has passed through and thus only the first two terms contribute substantially to the OTOC 37, 38 . Notice that for this particular pair of operators, the second line measures the local raising charge R x (32) and the difference between the local densities of z's and I's at site x after the front has passed x. As discussed in the previous section, there is no average raising charge away from the diffusing \"lump\" near the origin, and the difference in local densities of z's vs. I's is also zero except near the origin and right at the front. So, to leading order the second line in (46) vanishes in the region between the diffusive lump and the front. Further, since we start with zero raising charge, the only contribution to the second line comes from the imbalance between \u03c1 z (x) and \u03c1 I (x). Indeed, all conserved operators (zI) i with i \u2265 x contribute to \u03c1 I (x), while only (zI) x contributes to \u03c1 z (x). These conserved operators are the leading source of the imbalance between \u03c1 I (x) and \u03c1 z (x) near the origin. Nonconserved strings do not substantially contribute to the imbalance between \u03c1 z (x) and \u03c1 I (x) away from the front. Then, putting it all together,", "cite_spans": [{"start": 162, "end": 166, "text": "(46)", "ref_id": "BIBREF45"}, {"start": 578, "end": 581, "text": "37,", "ref_id": "BIBREF36"}, {"start": 582, "end": 584, "text": "38", "ref_id": "BIBREF37"}, {"start": 1073, "end": 1077, "text": "(46)", "ref_id": "BIBREF45"}], "ref_spans": []}, {"section": "V. OUT-OF-TIME-ORDER COMMUTATORS", "text": "where we've separated the contributions from conserved and non-conserved operators (18) and used also the leftweight \u03c1 nc L to produce an expression that is valid at late time for all x. Since \u03c1", "cite_spans": [{"start": 83, "end": 87, "text": "(18)", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "V. OUT-OF-TIME-ORDER COMMUTATORS", "text": "c (x, t) \u223c t \u22121 at late times, the contribution of \u03c1 c (x, t) is also subdominant at late times and will be neglected below, although it is visible as a weak \"dimple\" in the diffusive regime near the origin in Fig. 4 . Thus, away from the fronts and the diffusive regime near the origin, the OTOC for this pair of operators receives its primary contribution from the total right-or left-weights alone, just as in the unconstrained circuit 37, 38 . We saw above that the right-and left-weight profiles for z(t) show diffusive power-law tails, and these translate into diffusive tails for this OTOC as well.", "cite_spans": [{"start": 439, "end": 442, "text": "37,", "ref_id": "BIBREF36"}, {"start": 443, "end": 445, "text": "38", "ref_id": "BIBREF37"}], "ref_spans": [{"start": 210, "end": 216, "text": "Fig. 4", "ref_id": "FIGREF6"}]}, {"section": "V. OUT-OF-TIME-ORDER COMMUTATORS", "text": "Let us now examine this OTOC in different regimes at late times such that the leading ballistic front is well separated from the diffusive \"lump\" near the origin:", "cite_spans": [], "ref_spans": []}, {"section": "V. OUT-OF-TIME-ORDER COMMUTATORS", "text": "1. Outside the \"light cone\" |x| > t: Due to the locality of the circuit, a spreading operator O 0 (t) acts as the identity outside the light cone defined by |x| \u2264 t. Thus, the commutator C(x, t) = 0 in this regime.", "cite_spans": [], "ref_spans": []}, {"section": "V. OUT-OF-TIME-ORDER COMMUTATORS", "text": "2. Beyond the leading operator fronts so |x| v B t + D \u03c1 t, but within the causal light cone so |x| < t: Before the main operator front gets to x, any operator weight that is not locally the identity is exponentially small in t and thus the OTOC is also exponentially small in t (for fixed x/t in this regime). This regime does not exist for q = \u221e. Ref. 38 showed that the OTOC shows a nearexponential increase with time in this regime for the unconstrained circuit model, but with a positiondependent analog of the \"Lyapunov exponent\". ", "cite_spans": [{"start": 354, "end": 356, "text": "38", "ref_id": "BIBREF37"}], "ref_spans": []}, {"section": "FIG. 4.", "text": "One minus the out-of-time-order commutator (OTOC) between z0(t) and rx at zero chemical potential, C 0 zr , plotted against x for a system of length L = 1000 at different times t showing the different regimes discussed in the text. For |x| > t (outside the dashed vertical lines), the OTOC is strictly zero due to the locality of the circuit. In the region vBt < |x| < t, which is inside the causal light cone but before the leading front arrives, the OTOC is exponentially small (green shaded area for the latest time). The arrival of the ballistic operator front (|x| \u223c vBt) leads to a strong increase in the OTOC from a value exponentially small to an O(1) value (shaded red area for the latest time). However, diffusive tails in the operator shape or internal structure lead to diffusive power-law tails in space and time \u223c (x \u2212 vBt)", "cite_spans": [], "ref_spans": []}, {"section": "FIG. 4.", "text": "in the late-time approach of the OTOC to its final value of 1 (shaded blue area for the latest time). By contrast, for an unconstrained random circuit (not shown), the OTOC at a given site approaches one exponentially quickly after the leading front passes 37, 38 . The diffusive region near the origin |x| \u221a Dct (shaded purple) receives a subleading 1/t contribution from the conserved charges which shows up as a \"dimple\" in the curves at early times which becomes weaker at late times. All curves are obtained via a simulation using q = 3 and taking into account all processes to order 1/q 2 . The dashed red curve is the q = \u221e prediction for the functional form of the tail (48).", "cite_spans": [{"start": 257, "end": 260, "text": "37,", "ref_id": "BIBREF36"}, {"start": 261, "end": 263, "text": "38", "ref_id": "BIBREF37"}], "ref_spans": []}, {"section": "FIG. 4.", "text": "We expect the same qualitative behavior in this regime for our model, since this operator \"edge\" just comes from non-conserved operators emitted at early times whose right-and left-weights then show biased diffusion, just as in the unconstrained circuit.", "cite_spans": [], "ref_spans": []}, {"section": "FIG. 4.", "text": "3. Within the leading operator fronts, |x| \u2212 v B t \u223c D \u03c1 t: This regime describes the growth of the OTOC from an exponentially small value in t to an order one number due to the arrival of the ballistic front. Here the operator right-or left-weight is again from non-conserved operators emitted at early times and, to leading order at long time for finite q, is a Gaussian of width \u223c D \u03c1 t, so the leading behavior of the OTOC in this regime is given by the corresponding error function that is the integral of this Gaussian profile, just as in the unconstrained circuit 37, 38 .", "cite_spans": [{"start": 571, "end": 574, "text": "37,", "ref_id": "BIBREF36"}, {"start": 575, "end": 577, "text": "38", "ref_id": "BIBREF37"}], "ref_spans": []}, {"section": "FIG. 4.", "text": "4. In the \"tails\", |x|", "cite_spans": [], "ref_spans": []}, {"section": "FIG. 4.", "text": "This regime describes the late-time approach of the OTOC to its final asymptotic value long after the main front has passed site x. In this regime, the deviation of the OTOC from its final value of one is given by the total weight (conserved and non-conserved) of operator strings that have not yet reached site x at time t. This is obtained by considering the total conserved weight at time t = (t \u2212 |x|/v B ), since any non-conserved fronts emitted after after time t do not reach site x by time t. Then, from (47) and (21),", "cite_spans": [{"start": 512, "end": 516, "text": "(47)", "ref_id": "BIBREF46"}], "ref_spans": []}, {"section": "FIG. 4.", "text": "Thus, the tails in the right-and left-weights of z 0 (t) lead to tails in the OTOC and, long after the front has passed site x, the OTOC still has a power law (in x and t) deficit from its asymptotic value. By contrast, in an unconstrained random circuit, the OTOC approaches 1 exponentially in time after the front passes. This slow power-law approach characterizes the \"diffusive tail\" in the late time behavior of the OTOC. In the diffusive regime near the origin, |x| \u223c \u221a D c t, there are further corrections to this of order \u223c 1/t from \u03c1 c (x) that smoothly connect the OTOC's x-dependence between x < 0 and x > 0. ", "cite_spans": [], "ref_spans": []}, {"section": "B. OTOC between r0(t) and zx", "text": "Let us now consider the OTOC between r 0 (t) and z x so that \u00b5 = 0, \u03b1 = 1 = r and \u03b2 = 3 = z. Then", "cite_spans": [], "ref_spans": []}, {"section": "B. OTOC between r0(t) and zx", "text": "In this case, the first line is again sensitive to the overall operator shape, while the second line cares about the relative density difference within strings between local operators that are charged vs. uncharged under R, i.e. the difference in the local densities of r/l's compared to I/z's -note that this is a different combination of local densities as compared to the one in (46) . Next, note that the averge OTOC between r 0 (t) and z x should equal the average OTOC between z 0 (t) and r x since the two are related by time-reversal: C 0 rz (x, t) = C 0 zr (x, \u2212t), and the average properties of our circuit are invariant under time-reversal. In the previous subsection, we saw that the diffusive tail in the OTOC C 0 zr (48) came from the tail in the right-weight profile of z 0 (t). However, recall from Section III B that the spreading r 0 (t) shows no tails in its \u03c1 R , since this operator starts out orthogonal to the conserved charges so that \u03c1 R (x, t) \u223c e \u2212(x\u2212v B t) 2 /4D\u03c1t / 4\u03c0D \u03c1 t, and \u03c1 R (x, t) is exponentially small for x v B t. Thus, the tail in C 0 rz behind the ballistic front must come from the imbalance between the density of raising charges r/l and spin charges u/d (which are superpositions of I/z) . Indeed, we saw in Section IV that the coupling of spin and raising charge combined with the initial condition at the left and right fronts leads to a diffusive decay of the imbalance \u2206 Rs between the local \u03c1 r /\u03c1 l and \u03c1 u /\u03c1 d densities away from the locations of the fronts (42) (Fig. 3) . Using (42), we find that the OTOC C 0 rz in the regime", "cite_spans": [{"start": 382, "end": 386, "text": "(46)", "ref_id": "BIBREF45"}, {"start": 730, "end": 734, "text": "(48)", "ref_id": "BIBREF47"}, {"start": 1512, "end": 1516, "text": "(42)", "ref_id": "BIBREF41"}], "ref_spans": []}, {"section": "B. OTOC between r0(t) and zx", "text": ", which agrees with (48) , as it must.", "cite_spans": [{"start": 20, "end": 24, "text": "(48)", "ref_id": "BIBREF47"}], "ref_spans": []}, {"section": "B. OTOC between r0(t) and zx", "text": "This case provides a nice example of how the OTOC can probe the internal operator content inside the light cone and show diffusive tails, even when there are no tails in the overall operator shape of the spreading operator as measured by \u03c1 R/L .", "cite_spans": [], "ref_spans": []}, {"section": "C. OTOC between z0(t) and zx", "text": "Turning next to the \"diagonal\" case \u00b5 = 0, \u03b1 = \u03b2 = 3 = z, we find that C 0 zz has the same structure as in (49) , but \u03c1 R now refers to the right-weight profile of z 0 (t). Thus, this commutator receives contributions both from the tails in the right-weight and from the tails in the imbalance between the spin and raising charges, so", "cite_spans": [{"start": 107, "end": 111, "text": "(49)", "ref_id": "BIBREF48"}], "ref_spans": []}, {"section": "C. OTOC between z0(t) and zx", "text": "for |x| v B t. Thus, a commutator between two conserved charges couples more strongly to the diffusive processes in the system, doubling the amplitude of the diffusive power-law tail in the OTOC, relative to the two other cases discussed above.", "cite_spans": [], "ref_spans": []}, {"section": "D. OTOC between r0(t) and rx", "text": "Finally, consider the commutator between r 0 (t) and r x so that \u03b1 = \u03b2 = 1. Note that C 0 rr has the same structure as in (46) (with \u03c1 R referring to the right-weight of r 0 (t)). This commutator again shows a sharp increase when the ballistic front reaches site x, but now both the contributions from the right-weight and the \"internal\" operator content are exponentially suppressed away from the front so this OTOC does not show power law tails in the regime \u221a D c t x v B t and approaches its asymptotic value exponentially after the front passes through. Instead, if we probe the commutator at short distances x \u223c \u221a D c t, then the OTOC displays a weak effect within the \"diffusive cone\" from the diffusion of the initial raising charge i.e. the diffusion of the imbalance between \u03c1 r and \u03c1 l . The same is true for OTOC's between r(t) and l x .", "cite_spans": [], "ref_spans": []}, {"section": "D. OTOC between r0(t) and rx", "text": "This result emphasizes that the diffusive tails in the OTOC at long distances and late times are tied to the operator dynamics of the conserved charges in the system. OTOC's between operators that are both orthogonal to the conserved charges do not display diffusive tails behind their fronts. Of course, if one simply measures the OTOC between two generic local operators, then these will have some overlap with the conserved charges and show diffusive tails.", "cite_spans": [], "ref_spans": []}, {"section": "D. OTOC between r0(t) and rx", "text": "We now consider OTOC's evaluated in an equilibrium ensemble with a chemical potential \u00b5 > 0 that weights different S tot z sectors , and we will be interested in understanding the degree to which this compares with the finite temperature OTOC's that have been evaluated for Hamiltonian models. A difference between the energy conserving and S tot z conserving cases is that, on the Hamiltonian side, both the Gibbs factor e \u2212\u03b2H and the time-evolution are governed by the same Hamiltonian. On the other hand, for the U (1) problem, the \"Gibbs factor\" e \u00b5N commutes with the time evolution operator U (t) but is otherwise unrelated to it. This distinction between the two becomes important when considering non-zero \u00b5.", "cite_spans": [], "ref_spans": []}, {"section": "D. OTOC between r0(t) and rx", "text": "To start, consider again the equilibrium Gibbs ensemble for a given chemical potential:", "cite_spans": [], "ref_spans": []}, {"section": "D. OTOC between r0(t) and rx", "text": "where we've switched to the (normalized) u/d basis which projects onto up and down conserved spins in the last line. In the limit \u00b5 \u2192 \u221e,", "cite_spans": [], "ref_spans": []}, {"section": "D. OTOC between r0(t) and rx", "text": "In this limit, \u03c1 eq \u221e projects the conserved spins to the \"all up\" state so that the conserved part of the dynamics is completely \"frozen out\", reducing the system to just the unconstrained qudit spins. The unconstrained qudit system is chaotic and displays ballistic growth of operators with a non-zero q-dependent butterfly velocity, just as in the unconstrained random circuit model 37, 38 . This illustrates how the independence of U (t) and \u03c1 eq can lead to chaotic dynamics even in the \u00b5 \u2192 \u221e limit, while the analogous T \u2192 0 limit for Hamiltonian systems arrests chaos. On the other hand, if one considers \u00b5 \u2192 \u221e with q = 1, then the butterfly speed does go to zero since since spin flips in this fully polarized background can move at most diffusively. Thus, the q = 1 problem as \u00b5 \u2192 \u221e is closer to the zero temperature dynamics of Hamiltonian systems. In the rest of this section, we will work at q = 1 in the \u00b5 \u2192 \u221e limit.", "cite_spans": [{"start": 386, "end": 389, "text": "37,", "ref_id": "BIBREF36"}, {"start": 390, "end": 392, "text": "38", "ref_id": "BIBREF37"}], "ref_spans": []}, {"section": "D. OTOC between r0(t) and rx", "text": "We start with \u00b5 = \u221e where \u03c1 eq \u221e reduces to the projector on the |0 \u2261 | \u2191\u2191 \u00b7 \u00b7 \u00b7 \u2191 state. Then,", "cite_spans": [], "ref_spans": []}, {"section": "D. OTOC between r0(t) and rx", "text": "First consider OTOC's involving z and r. Since |0 is an eigenstate of both r and z (with eigenvalues 0 and 1 respectively), any commutator involving only r's or z's must be strictly zero. Thus, the only non-trivial OTOCs are those involving [l 0 (t), z x ] and [l 0 (t), r x ] (the commutators between [z 0 (t), l x ] and [r 0 (t), l x ] will be related to these by time-reversal). Let us start with C \u221e lz . Expanding the commutator, we find:", "cite_spans": [], "ref_spans": []}, {"section": "D. OTOC between r0(t) and rx", "text": "where we've made use of the fact that |0 is an eigenstate of U (t), z and r 0 l 0 in the last line, with eigenvalues 1,1, and 2 respectively. Now, every basis string that appears in the operator expansion of l 0 (t) has net raising charge R tot = \u22121. Since |0 is annihilated by any r i , all strings in the expansion of l 0 (t) that contain r's cannot contribute to the OTOC, and thus only strings containing exactly one l i on some site (with arbitrary I's and z's on the others) can contribute. These create single spin flips in the polarized background. Of these, only the strings which contain l x fail to commute with z x . However, due to the diffusion of \"raising charge\" R i discussed in Section IV, the weight of the operator on such \"single l\" strings decays only diffusively away from the origin, showing that this OTOC displays only diffusive (as opposed to ballistic) behavior corresponding to a zero butterfly speed. Likewise, consider the infinite \u00b5 OTOC involving [l 0 (t), r x ]:", "cite_spans": [], "ref_spans": []}, {"section": "D. OTOC between r0(t) and rx", "text": "where we've made use of the fact that r x |0 = 0|l x = 0, and (lr) = (1 \u2212 z). Thus, this OTOC has an identical structure to (53) and also displays purely diffusive behavior. Perturbing \u03c1 \u221e \u00b5 away from \u00b5 = \u221e to leading order in large but not infinite \u00b5 gives (50)", "cite_spans": [{"start": 124, "end": 128, "text": "(53)", "ref_id": "BIBREF52"}], "ref_spans": []}, {"section": "D. OTOC between r0(t) and rx", "text": "Understanding the modifications to the diffusive \u00b5 = \u221e behavior of the OTOCs at large but finite \u00b5 is an interesting question that has been explored in detail in Ref. 52 .", "cite_spans": [{"start": 167, "end": 169, "text": "52", "ref_id": "BIBREF51"}], "ref_spans": []}, {"section": "VI. PHYSICAL SYSTEMS", "text": "Let us now turn to more generic examples of thermalizing spin chains with conservation laws, and examine to what extent the universal aspects of our results continue to hold in this setting. We will first look at a periodically driven \"Floquet\" spin chain where energy is not conserved, but S tot z is, just like in our random circuit model. We then turn to a interacting quantum chaotic spin chain with energy conservation.", "cite_spans": [], "ref_spans": []}, {"section": "VI. PHYSICAL SYSTEMS", "text": "A. S tot z", "cite_spans": [], "ref_spans": []}, {"section": "Conserving Floquet chain", "text": "We consider a one-dimensional chain of spin-1/2 qubits that is periodically driven in time with period \u03c4 between two separate Hamiltonians H z and H xy , each of which act for half the period. The time evolution operator for this system is", "cite_spans": [], "ref_spans": []}, {"section": "Conserving Floquet chain", "text": "with", "cite_spans": [], "ref_spans": []}, {"section": "Conserving Floquet chain", "text": "The parameters we choose for this model are action which is respected by the time evolution. We will measure time discretely in multiples of \u03c4 , and the time evolution of operators in the Heisenberg picture is given by O(n\u03c4 ) = U \u2020 F (n\u03c4 )O(0)U F (n\u03c4 ). Finally, there is no randomness in this problem, and the time evolution respects locality.", "cite_spans": [], "ref_spans": []}, {"section": "Conserving Floquet chain", "text": "Of course, the fact that charges in this thermalizing model will display diffusive dynamics is well understood. We wish to probe the interaction between the diffusive charge dynamics and the ballistic operator growth, say as probed through the right-weight profiles \u03c1 R (x, t) of r 0 (t) and z 0 (t). While \u03c1 R for z(t) does show a tail for this model, it is difficult to tease apart the different regimes for small finite-sized systems (it only takes time t \u223c L 2 for the diffusive charges to reach the end of the chain). To aid with this, we consider a related quantity, theweight W (x, t) which measures the weight on all Pauli strings with maximum end-to-end separation between non-identity elements equal to x: ", "cite_spans": [], "ref_spans": []}, {"section": "Conserving Floquet chain", "text": "-weight profile W (x, t) (58) of spreading operators z0(t) and r0(t) in a Floquet model that conserves S tot z (57), plotted for a system of length L = 12. The expected diffusive \"lump\" in the right-weight profile of the spreading conserved charge is manifested in the enhanced weight of W (x, t) at x = 0 for z0(t), even at late times (b). No such enhancement is observed for r0(t) which evolves orthogonal to the conserved charges (a). Notice also that the late-time decay of W (x, t) away from x = L is much slower for z0(t) as compared to r0(t), consistent with the presence of power law diffusive tails in the right-weight profile of the former but not the latter.", "cite_spans": [], "ref_spans": []}, {"section": "Conserving Floquet chain", "text": "where, as before, the LHS and RHS of S define the locations of the rightmost and leftmost non-identity operators in S. This has the advantage that all conserved charges have the form z i and these are all mapped to x = 0. On the other hand, strings that are part of the ballistic front and stretched between \u2212v B t, v B t contribute to x = 2v B t. Thus, the non-conserved contributions to this quantity still show ballistic dynamics. In a system with no conservation laws, W (x, t) for x < v B t decays exponentially with t and quickly approaches its asymptotic value which is itself exponentially small in L. On the other hand, in a system with conservation laws, this quantity decays as a power law and approaches its asymptotic value which is instead only power law small in L if one starts with an initial operator which has overlap with the conserved densities (at late times, each conserved amplitude \u223c 1/L so that the total weight on all conserved charges is \u223c L/L 2 = 1/L). This helps us tease apart the dynamics of the conserved charge at these small sizes. Fig. 5 shows the -weight profiles W (x, t) for both r 0 (t) and z 0 (t) for a 12 site chain, with both operators starting starts out orthogonal to the conserved charges and its latetime -weight profile does not show a \"lump\" at x = 0, 1. While the late time decay of W (x, t) away from x = L is again faster for \u03c3 y 0 (t) as compared to \u03c3 x 0 (t), the difference is not as pronounced as the difference between z0(t) and r0(t) in the U (1) Floquet case. This is because \u03c3 y 0 (t) can develop overlap with the slow conserved charges, unlike r0(t) which is constrained to remain strictly orthogonal to the charges during its entire evoluton.", "cite_spans": [], "ref_spans": []}, {"section": "Conserving Floquet chain", "text": "at the end of the chain to maximize the available distance for spreading. We clearly see the tail and \"lump\" with enhanced -weight at x = 0 for z 0 (t). On the other hand, the late time profile for r 0 (t) shows a simple decay of the -weight, with the most weight on strings stretched across the entire system i.e. those with x = L. This data shows that the central aspects of our results on operator shape seem to be born out for this more \"physical\" spin chain, although for such a short chain this can only be qualitatively tested.", "cite_spans": [], "ref_spans": []}, {"section": "B. Hamiltonian spin chain", "text": "We now turn to a thermalizing Hamiltonian spinchain with energy conservation, but no other continuous symmetries 43 : . The conservation of total energy implies that Tr (O 0 (t)H) = const, and thus if we start with an operator with a non-zero overlap with a local energy density, then the sum of the amplitudes of the spreading operator on all the local energy density strings is conserved. A difference between this Hamiltonian model and the U (1) conserving model is that energy is not quantized and there are no special operators (like r) with definite algebras under H. Even if we start with a local operator that is orthogonal to all the conserved energy densities (like \u03c3 y i ), its operator expansion will, in time, develop some overlaps with the conserved charges. Fig. 6 shows the -weight profile for the spreading of \u03c3 x 0 (t) and \u03c3 y 0 (t) in a system of length L = 14 and, once again, we see the \"lump\" at x = 0, 1 only in the former. Notice, however, that the difference between \u03c3 x 0 and \u03c3 y 0 in the decay of W (x, t) away from x = L at late times is not as pronounced as it is in the Floquet problem (Fig. 5) . We attribute this to the fact that the time-evolving \u03c3 y 0 (t) develops non-trivial overlap with the diffusing conserved charges (even though the sum of the amplitudes on all conserved charges is constrained to be zero), slowing down its dynamics relative to r 0 (t) in the Floquet model which always evolves strictly orthogonal to the conserved charges. This is one example of a difference between U (1) conservation with quantized charges and energy conservation where the charges are continuous.", "cite_spans": [{"start": 113, "end": 115, "text": "43", "ref_id": "BIBREF42"}], "ref_spans": [{"start": 773, "end": 779, "text": "Fig. 6", "ref_id": "FIGREF9"}]}, {"section": "B. Hamiltonian spin chain", "text": "As discussed in the previous section, these power law tails in operator shape translate into power law tails in the long distance and late time OTOC, and these have been observed numerically in Hamiltonian systems with conservation laws 41 .", "cite_spans": [{"start": 237, "end": 239, "text": "41", "ref_id": "BIBREF40"}], "ref_spans": []}, {"section": "VII. CONCLUSIONS", "text": "In conclusion, we presented an extensive study of the \"scrambling\" dynamics of local operators in chaotic quantum systems with a conserved, diffusing charge (or energy) density. A generic local operator in this setting has some weight on the conserved charges, and the late time spreading dynamics of such an operator is described by multiple coupled hydrodynamic processes. The first is the \"physical\" hydrodynamics associated with the diffusive dynamics of the conserved charges. We show that the total operator weight on these conserved charges decreases as power law in time which, by unitarity, necessitates a steady \"emission\" process that transfers operator weight from local conserved densities to nonconserved operators. This emission happens at a slow hydrodynamic rate set by the local diffusive currents of the conserved density but, once emitted, the fronts of the nonconserved operators spread ballistically and rapidly become nonlocal. The propagation of the nonconserved fronts is described via an \"emergent hydrodynamics\" that is biased diffusion for the one-dimensional case 37, 38 , and this coupled diffusion-emission-propagation process reveals a composite picture for the operator profile, showing how the ballistic and diffusive processes in the system connect at different time and length scales. In particular, the presence of slow diffusive modes leads to the development of a power-law tail in the operator profile that reflects the weight of nonconserved operator strings emitted at later times that \"lag\" behind the leading ballistic front.", "cite_spans": [{"start": 1093, "end": 1096, "text": "37,", "ref_id": "BIBREF36"}, {"start": 1097, "end": 1099, "text": "38", "ref_id": "BIBREF37"}], "ref_spans": []}, {"section": "VII. CONCLUSIONS", "text": "Our picture illustrates how reversible unitary dynamics in closed quantum systems can display dissipative diffusive hydrodynamic modes. The dissipation arises from the conversion of operator weight from locally observable conserved parts to nonlocal nonconserved parts at a slow hydrodynamic rate, a process which increases the \"observable\" entropy of the system. By contrast, in systems without conservation laws, any local operator is rapidly converted to non-local, so the dissipation does not appear in the late-time hydrodynamics of operator or entanglement spreading.", "cite_spans": [], "ref_spans": []}, {"section": "VII. CONCLUSIONS", "text": "In addition to the diffusive tails in the distribution of operator weight, we found an additional layer of structure describing the local operator content behind the ballistic front, within the spreading operator. Outside the ballistic operator front, the spreading operator locally consists only of local identities. The arrival of the front at a given site turns on a noisy coupled diffusion process between different species of local operators, which relaxes the initially imbalanced local operator content to the final equilibrium value where all local operators are equally likely.", "cite_spans": [], "ref_spans": []}, {"section": "VII. CONCLUSIONS", "text": "Once again, this relaxation happens at a power-law slow rate and contributes to the operator hydrodynamics, in contrast to the unconstrained random circuit case where the action of a single gate at the front erases the initial bias towards the identities. These power law tails in the distributions of operator weight and local operator content also lead to diffusive tails in the late-time approach of certain out-of-time-order commutators (OTOC's) to their asymptotic values.", "cite_spans": [], "ref_spans": []}, {"section": "VII. CONCLUSIONS", "text": "In all, our work reveals several rich layers of physics in the scrambling dynamics of systems with conservation laws. We expect this approach (which builds on work by Refs 36-38) of probing the dynamics of such systems via an analytically tractable constrained random unitary circuits will have broader applicability in understanding the many open questions about the fundamentals of thermalization and quantum statistical mechanics in chaotic quantum systems with conservation laws. It would also be interesting to ask which of our results can also be calculated (or extended) in a holographic setting, where they might connect with the dynamics of black holes with charges.", "cite_spans": [], "ref_spans": []}, {"section": "VII. CONCLUSIONS", "text": "Related Work: Shortly before completing this manuscript, we became aware of related work by Rakovszky et. al. which should appear in the same arXiv posting 52 . 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Appendix A summarizes the action of U i,i+1 on all possible two-site operators.", "type": "figure"}, "FIGREF3": {"text": "tot z ) N is conserved in time. Further, if O(t = 0) has N conserved charges, then only amplitudes a S on basis strings with exactly N con- served charges survive Haar averaging, even though the expansion (S tot z )", "type": "figure"}, "FIGREF4": {"text": "N \u22122 , etc., such that it only contains these basis strings of exactly N charges).", "type": "figure"}, "FIGREF6": {"text": "Fig. 4 shows a sketch of C 0 zr (x, t) at different times, depicting the different regimes above.", "type": "figure"}, "FIGREF7": {"text": "16, J x = J y = (5 + 5 \u221a 5)/16, and \u03c4 = 1, where we have found that this system is well thermal- izing, even though the individual Hamiltonians in the drive are integrable 53 . The time-evolution conserves to- tal S tot z : [U (\u03c4 ), S tot z ] = 0 and, just as in the random circuit problem, operators like r/l have a definite \u2206S tot z", "type": "figure"}, "FIGREF9": {"text": "FIG. 6. -weight profile W (x, t) (58) of spreading operators \u03c3 x 0 (t) and \u03c3 y 0 (t) in a thermalizing Hamiltonian model that conserves energy (59), plotted for a system of length L = 14. \u03c3 x 0 has non-trivial overlap with the local conserved energy density operators, which is visible in the enhanced weight of W (x, t) for x = 0, 1 even at late times (a). By contrast, \u03c3 y 0", "type": "figure"}}}
{"paper_id": "119424662", "_pdf_hash": "c33628c82cf2a2a8ab041525fc5a9c5210ed5a04", "abstract": [{"section": "Abstract", "text": "Relativistic atomic structure calculations are carried out in alkaline-earth-metal ions using a semiempirical-core-potential approach. The systems are partitioned into frozen-core electrons and an active valence electron. The core orbitals are defined by a Dirac-Hartree-Fock calculation using the grasp2k package. The valence electron is described by a Dirac-like Hamiltonian involving a core-polarization potential to simulate the core-valence electron correlation. The associated equation is solved with the Lagrange-mesh method, which is an approximate variational approach having the form of a mesh calculation because of the use of a Gauss quadrature to calculate matrix elements. Properties involving the low-lying metastable 2 D 3/2,5/2 states of Ca + , Sr + , and Ba + are studied, such as polarizabilities, one-and two-photon decay rates, and lifetimes. Good agreement is found with other theory and observation, which is promising for further applications in alkali-like systems.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "I. INTRODUCTION", "text": "Atomic polarizabilities and forbidden transitions are of much interest due to their various applications, e.g. in optical atomic clocks, which are based on transitions involving long-lived metastable states [1, 2] . Experiments in this field have reached such a high accuracy that relativistic effects are visible and must be precisely accounted for in the calculations [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] . Today's most advanced atomic clocks report relative systematic frequency uncertainties below 10 \u221217 [15, 16] . Reaching higher accuracy is limited by small energy shifts resulting from blackbody radiation and quadratic Stark effect [5, 10, 12] , highly dependent on the accuracy of static and dynamic polarizabilities [1] .", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "Singly ionized calcium (Ca + ), strontium (Sr + ), and barium (Ba + ) have been proposed as candidates for optical frequency standards due to the long lifetime of their 2 D 3/2,5/2 states [2] . Numerous experiments have been performed in these alkaline-earth-metal ions [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] . Additionally, several theoretical studies have been carried out using many-body approaches [4, [9] [10] [11] [34] [35] [36] [37] . The estimation of these lifetimes involves the study of the competition between the one-photon electric quadrupole (E2) and magnetic dipole (M 1) channels and the twophoton electric dipole (2E1) transitions. While the E2 and M 1 decay rates are widely studied, to our knowledge only one prior calculation [38] of 2E1 decay rates of the 2 D 3/2,5/2 states has been carried out in these ions. * Livio.Filippin@ulb.ac.be \u2020 Sacha.Schiffmann@ulb.ac.be \u2021 dohet@pi.infn.it \u00a7 dbaye@ulb.ac.be \u00b6 mrgodef@ulb.ac.be", "cite_spans": [{"start": 330, "end": 334, "text": "[29]", "ref_id": "BIBREF28"}, {"start": 335, "end": 339, "text": "[30]", "ref_id": "BIBREF29"}], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "Ab initio methods include electron correlation through explicit electron excitations. The codes based on these approaches enable the calculation of various spectroscopic properties [39] [40] [41] . However, the computational task is important, requiring the diagonalization of large matrices. By contrast, methods introducing a semiempirical core potential simulate the core-valence correlations for an atom with few valence electrons by means of a core-polarization (CP) potential, offering reduced computational times [1, 42, 43] . The CP potential is tuned to ensure that the energies of the valence electrons reproduce the observed binding energies. Relativistic semiempirical-core-potential calculations of lifetimes and polarizabilities have been performed in Ca + [4] and Sr + [9] , but no such work exists in Ba + .", "cite_spans": [{"start": 181, "end": 185, "text": "[39]", "ref_id": "BIBREF38"}], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "The present work combines a semiempirical-corepotential Dirac-Hartree-Fock approach (DHFCP) and the Lagrange-mesh method (LMM) [44, 45] to study relativistic polarizabilities, one-and two-photon decay rates, and associated lifetimes in Ca + , Sr + , and Ba + ions. The LMM is an approximate variational approach involving a basis of Lagrange functions related to a set of mesh points associated with a Gauss quadrature [44] [45] [46] . Lagrange functions are continuous functions that vanish at all points of the corresponding mesh but one. The principal simplification appearing in the LMM is that matrix elements are calculated with the Gauss quadrature. The one-body potential matrices are then diagonal and only involve values of the potential at mesh points.", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "Recently, we have shown that numerically exact solutions of the Dirac-Coulomb equation are obtained with the LMM [45, 47] . The method is accurate for most central potentials, such as Yukawa potentials [47] . It also allows the accurate calculation of polarizabilities and of one-and two-photon decay rates in various types of potentials with small computing times [48, 49] . In this work, the core orbitals obtained from a closed-shell DHF calculation with the grasp2k package [50, 51] are projected on Lagrange bases, contrary to Refs. [4, 9] where a DHF program has been developed using B splines or S-spinors. The DHFCP-LMM method is used for singlevalence-electron calculations.", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "In Sec. II, the formulation of the DHFCP method is recalled, and relativistic expressions of polarizabilities and of one-and two-photon decay rates are presented in the case of a single valence electron in a DHFCP potential. In Sec. III, the principle of the LMM is summarized and the studied properties are approximated with Gauss quadratures. Section IV reports numerical results for low-lying states in Ca + , Sr + , and Ba + , and analyzes the accuracy of the semiempirical-core-potential approach by comparison with ab initio calculations and experimental data. Section V contains conclusions.", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "We use for the fine-structure constant and the atomic unit (a.u.) of time the 2014 CODATA recommended values 1/\u03b1 = 137.035 999 139 and /E h = 2.418 884 326 509 \u00d7 10 \u221217 s [52] .", "cite_spans": [], "ref_spans": []}, {"section": "II. RELATIVISTIC FORMULATION", "text": "A. Closed-shell DHF equations and core orbitals", "cite_spans": [], "ref_spans": []}, {"section": "II. RELATIVISTIC FORMULATION", "text": "The starting point of the present approach is a DHF calculation for the closed-shell core state of the atoms. In a.u., the Dirac-Coulomb Hamiltonian for N el electrons in a central field for a point nucleus of charge Z is given by [39] ", "cite_spans": [{"start": 231, "end": 235, "text": "[39]", "ref_id": "BIBREF38"}], "ref_spans": []}, {"section": "II. RELATIVISTIC FORMULATION", "text": "where c is the speed of light and \u03b1 and \u03b2 are the (4 \u00d7 4) Dirac matrices. Since, in the present work, the DHF method is applied to the ground state of closed-shell ions, the total symmetry J \u03a0 is equal to 0 + , with J denoting the total electronic angular momentum and \u03a0 the parity. For such systems, the total wave function corresponds to a single Configuration State Function (CSF), constructed using anti-symmetrized products of Dirac spinors", "cite_spans": [], "ref_spans": []}, {"section": "II. RELATIVISTIC FORMULATION", "text": "involving the large and small radial components, P n\u03ba (r) and Q n\u03ba (r), respectively. The spinor spherical harmonics \u03c7 \u03bam (r) are common eigenstates of L 2 , S 2 , J 2 , and J z with respective eigenvalues l(l + 1), 3/4, j(j + 1), and m where j = |\u03ba| \u2212 1 2 and l = j + 1 2 sgn \u03ba. The quantum number n labels the different states with the same \u03ba-symmetry.", "cite_spans": [], "ref_spans": []}, {"section": "II. RELATIVISTIC FORMULATION", "text": "The energy of the closed-shell ion is expressed through one-electron integrals I and two-electron Slater integrals R k as [39, 54] ", "cite_spans": [{"start": 122, "end": 126, "text": "[39,", "ref_id": "BIBREF38"}], "ref_spans": []}, {"section": "II. RELATIVISTIC FORMULATION", "text": "where the notation [j] means (2j + 1), and contributions to the sums over k are not null when l a + l b + k is even. Indices a and b refer to one-electron orbitals n a \u03ba a and n b \u03ba b , respectively, and q a is the occupation number of orbital a.", "cite_spans": [], "ref_spans": []}, {"section": "II. RELATIVISTIC FORMULATION", "text": "The one-and two-electron integrals appearing in Eq. (3) are respectively given by", "cite_spans": [], "ref_spans": []}, {"section": "II. RELATIVISTIC FORMULATION", "text": "and", "cite_spans": [], "ref_spans": []}, {"section": "II. RELATIVISTIC FORMULATION", "text": "where r < (r > ) denotes the minimum (maximum) of r 1 and r 2 . The one-electron radial orbitals used to construct the single CSF are determined variationally so as to leave E core , and additional terms for preserving their orthonormality, stationary with respect to their variations. The resulting coupled radial equations are solved iteratively within the self-consistent field procedure, by means of finite difference techniques on an exponential grid [41] . The DHF program used in this work is implemented in the grasp2k package [50, 51] .", "cite_spans": [], "ref_spans": []}, {"section": "B. DHFCP Hamiltonian and valence orbitals", "text": "Within the frozen core approximation [39, 53] , where the relaxation of the core is neglected, the radial DHFCP equation for a single valence electron, denoted by the subscript v \u2261 n v \u03ba v in the following, is given by", "cite_spans": [{"start": 37, "end": 41, "text": "[39,", "ref_id": "BIBREF38"}, {"start": 42, "end": 45, "text": "53]", "ref_id": "BIBREF52"}], "ref_spans": []}, {"section": "B. DHFCP Hamiltonian and valence orbitals", "text": "where \u03b5 DHFCP v is the energy of the valence electron. The Hamiltonian H DHFCP reads", "cite_spans": [], "ref_spans": []}, {"section": "B. DHFCP Hamiltonian and valence orbitals", "text": "and acts on a 2-component radial wave function", "cite_spans": [], "ref_spans": []}, {"section": "B. DHFCP Hamiltonian and valence orbitals", "text": "T , where the superscript T means transposition. The semiempirical core potential, V core (r), appearing in Eq. (7) is defined as the single-electron operator", "cite_spans": [], "ref_spans": []}, {"section": "B. DHFCP Hamiltonian and valence orbitals", "text": "where, in the case of the interaction with a closed-shell core (core electrons are denoted by the subscript c \u2261 n c \u03ba c in the following), the direct and exchange potentials V dir (r) and V exc (r) are defined by their matrix elements [9, 39, 55] ,", "cite_spans": [{"start": 239, "end": 242, "text": "39,", "ref_id": "BIBREF38"}], "ref_spans": []}, {"section": "B. DHFCP Hamiltonian and valence orbitals", "text": "The core-polarization potential, V CP (r), has been introduced to simulate the core-valence correlation neglected in the DHF approximation [56] [57] [58] [59] . The electric field of the valence electron polarizes the core, which acquires an induced dipole moment proportional to the core static dipole polarizability, \u03b1 1 (core), interacting with the valence electron [56] [57] [58] [59] . Potential V CP (r) is written as", "cite_spans": [], "ref_spans": []}, {"section": "B. DHFCP Hamiltonian and valence orbitals", "text": "where \u03c1 \u03ba is a cutoff parameter that is tuned to reproduce the experimental binding energy of the lowest state of each \u03ba-symmetry, and 1 \u2212 exp \u2212r 6 /\u03c1 6 \u03ba is a cutoff function regularizing V CP (r) at the origin [4] . Expression (11) can be extended by taking higher-order corrections into account [9] .", "cite_spans": [], "ref_spans": []}, {"section": "B. DHFCP Hamiltonian and valence orbitals", "text": "The present semiempirical approach implies corrections to operators. In particular, when computing matrix elements of 2 \u03bb -pole transitions between states n a \u03ba a and n b \u03ba b , the radial transition operator needs to be modified as [4, 9, 56, 60] ", "cite_spans": [], "ref_spans": []}, {"section": "B. DHFCP Hamiltonian and valence orbitals", "text": "where \u03b1 \u03bb (core) is the static multipole polarizability of the core and\u03c1 is the average value\u03c1 = (\u03c1 \u03baa + \u03c1 \u03ba b )/2.", "cite_spans": [], "ref_spans": []}, {"section": "C. Polarizabilities", "text": "The static polarizability of an atomic system can be separated into two terms: a dominant first term from the intermediate valence-excited states, \u03b1(v), and a smaller second term from the intermediate core-excited states, \u03b1(core) [12] . The latter is smaller than the former by several orders of magnitude [1] . For an atomic system described with Eq. (6), the dipole polarizability \u03b1 1 (n v \u03ba v m v ) of a state n v \u03ba v m v with angular momentum j v > 1/2 depends on the magnetic projection m v [1] . It is given by", "cite_spans": [], "ref_spans": []}, {"section": "C. Polarizabilities", "text": ".", "cite_spans": [], "ref_spans": []}, {"section": "C. Polarizabilities", "text": "The quantity \u03b1 S 1 (v) is the scalar polarizability while \u03b1 T 1 (v) is the tensor polarizability in j representation. The 2 \u03bb -pole scalar polarizability reads [1, 9, 48] ", "cite_spans": [], "ref_spans": []}, {"section": "C. Polarizabilities", "text": "with the subscript", "cite_spans": [], "ref_spans": []}, {"section": "C. Polarizabilities", "text": "The radial functions P v (r), Q v (r) and P v \u2032 (r), Q v \u2032 (r) are solutions of Eq. (6) with respective energies \u03b5 v and \u03b5 v \u2032 . The sum over n \u2032 v represents a sum over the discrete states and an integral over the continuum that also involves negative energies. The dipole tensor polarizability is defined as [1, 9] ", "cite_spans": [], "ref_spans": []}, {"section": "D. Decay rates and lifetimes", "text": "The lifetime (in s) of an atomic state is given by the inverse of the sum of all possible decay rates (in s \u22121 ), \u03c4 = 1/ i W i . The dominant one-photon E2 and M 1 and two-photon 2E1 contributions are studied in this work.", "cite_spans": [], "ref_spans": []}, {"section": "D. Decay rates and lifetimes", "text": "For an atomic system described with Eq. (6), the average partial decay rates describing the 2E1 two-photon transitions reads in a.u. [49, 61, 63] ", "cite_spans": [], "ref_spans": []}, {"section": "D. Decay rates and lifetimes", "text": "where the angular coupling factor d", "cite_spans": [], "ref_spans": []}, {"section": "D. Decay rates and lifetimes", "text": "is given in Ref. [49] , and S j\u03bd 2E1 (2, 1) reads", "cite_spans": [], "ref_spans": []}, {"section": "D. Decay rates and lifetimes", "text": "4", "cite_spans": [], "ref_spans": []}, {"section": "D. Decay rates and lifetimes", "text": "The angular factor \u2206 j\u03bd 2E1 (2, 1) is given in Ref. [49] . S j\u03bd 2E1 (1, 2) is analogously obtained by permuting indices 1 and 2. Kets |i \u2261 |n i \u03ba i and |f \u2261 |n f \u03ba f correspond to solutions of Eq. (6) for the initial and final states with respective energies \u03b5 i and \u03b5 f , and \u03c9 j is the frequency of the jth photon. Energy conservation imposes \u03b5 i \u2212 \u03b5 f = \u03c9 1 + \u03c9 2 , where the recoil of the nucleus is neglected. As for polarizabilities, the transition proceeds through an infinite set of intermediate states |\u03bd \u2261 |n \u03bd \u03ba \u03bd at energy \u03b5 \u03bd .", "cite_spans": [], "ref_spans": []}, {"section": "D. Decay rates and lifetimes", "text": "The electric radial matrix elements M EL in Eq. (17) contain an arbitrary gauge parameter G from which the results should be independent [61, 62] . The G = 0 value defines the Coulomb (or velocity) gauge, which leads to the electric multipole velocity form in the non-relativistic limit. The value G = (L + 1)/L defines the Babushkin (or length) gauge, which leads to the non-relativistic electric multipole length form of the transition operator, and hence allows to account for correction (12) . In the long-wavelength (LW) approximation [39, 62] , the radial matrix element M ", "cite_spans": [{"start": 540, "end": 544, "text": "[39,", "ref_id": "BIBREF38"}], "ref_spans": []}, {"section": "D. Decay rates and lifetimes", "text": "The spontaneous 2E1 decay rate, W 2E1 , is obtained by integrating dW 2E1 /d\u03c9 1 over \u03c9 1 from 0 to \u03b5 i \u2212 \u03b5 f . The value of W 2E1 is multiplied by 1/2 to avoid counting twice each pair, because both photons have the same characteristics [63] .", "cite_spans": [], "ref_spans": []}, {"section": "D. Decay rates and lifetimes", "text": "The spontaneous emission rate for a one-photon tran-", "cite_spans": [], "ref_spans": []}, {"section": "D. Decay rates and lifetimes", "text": "No correction similar to Eq. (12) is applied to the magnetic transition operator. The excellent comparison between the present M 1 decay rates and the reference values [64] (see Table VII ) infers that such corrections would be small.", "cite_spans": [], "ref_spans": [{"start": 178, "end": 187, "text": "Table VII", "ref_id": "TABREF0"}]}, {"section": "D. Decay rates and lifetimes", "text": "The use of the LW approximation is justified by the small variation (only on the sixth digit) found in the obtained results when considering (\u03c9r/c) L /(2L + 1)!! operators instead of spherical Bessel functions j L (\u03c9r/c) that occur in the relativistic transition operators [62] .", "cite_spans": [], "ref_spans": []}, {"section": "D. Decay rates and lifetimes", "text": "The multipole matrix elements involved in the calculation of polarizabilities, one-and two-photon decay rates are dominated by the form of the wave function at long distances from the nucleus. By tuning energies to experimental values, semiempirical-core-potential methods enable to obtain wave functions having the correct asymptotic decrease [9] .", "cite_spans": [], "ref_spans": []}, {"section": "III. LAGRANGE-MESH METHOD A. Expansions on a Lagrange basis", "text": "The principles of the LMM are described in Refs. [44] [45] [46] and its application to the Dirac equation is presented in Refs. [45, 47] . The mesh points x j are defined by [44] ", "cite_spans": [], "ref_spans": []}, {"section": "III. LAGRANGE-MESH METHOD A. Expansions on a Lagrange basis", "text": "where j = 1 to N , and L \u03b1 N is a generalized Laguerre polynomial [65] . This mesh is associated with a GaussLaguerre quadrature", "cite_spans": [{"start": 66, "end": 70, "text": "[65]", "ref_id": "BIBREF64"}], "ref_spans": []}, {"section": "III. LAGRANGE-MESH METHOD A. Expansions on a Lagrange basis", "text": "with the weights \u03bb j . Note that the dependence of x j and \u03bb j on parameter \u03b1 is implicit. The Gauss quadrature is exact for the Laguerre weight function x \u03b1 e \u2212x multiplied by any polynomial of degree at most 2N \u2212 1 [66] . The regularized Lagrange functions are defined by [45, 67, 68] ", "cite_spans": [{"start": 217, "end": 221, "text": "[66]", "ref_id": "BIBREF65"}], "ref_spans": []}, {"section": "III. LAGRANGE-MESH METHOD A. Expansions on a Lagrange basis", "text": "The functionsf", "cite_spans": [], "ref_spans": []}, {"section": "III. LAGRANGE-MESH METHOD A. Expansions on a Lagrange basis", "text": "j (x) are polynomials of degree N \u2212 1 multiplied by x and by the square root of the Laguerre weight x \u03b1 e \u2212x . The Lagrange functions satisfy the Lagrange conditionsf", "cite_spans": [], "ref_spans": []}, {"section": "III. LAGRANGE-MESH METHOD A. Expansions on a Lagrange basis", "text": "They are not orthonormal, but become orthonormal at the Gauss-quadrature approximation. Condition (25) drastically simplifies the expressions of the one-body matrix elements calculated with the Gauss quadrature. Radial functions P v (r) and Q v (r) are expanded in regularized Lagrange functions (24) as", "cite_spans": [], "ref_spans": []}, {"section": "III. LAGRANGE-MESH METHOD A. Expansions on a Lagrange basis", "text": "where h v is a scaling parameter aimed at adapting the scaled mesh", "cite_spans": [], "ref_spans": []}, {"section": "III. LAGRANGE-MESH METHOD A. Expansions on a Lagrange basis", "text": "to the physical extension of the problem. The parameter \u03b1 v = 2(\u03b3 v \u2212 1), where \u03b3 v = \u03ba 2 v \u2212 (\u03b1Z) 2 , can be selected so that the Lagrange functions behave as r \u03b3v near the origin [47] . Here, another choice \u03b1 v = 2(\u03b3 v \u2212 |\u03ba v |) is preferable [48, 49] . The basis functions then behave as r \u03b3v \u2212|\u03bav|+1 , and the physical r \u03b3v behavior can be simulated by linear combinations. Let us introduce expansions (26) and (27) in Eq. (6). Projecting on the Lagrange functions and using the associated Gauss quadrature leads to the 2N v \u00d7 2N v Hamiltonian matrix", "cite_spans": [], "ref_spans": []}, {"section": "III. LAGRANGE-MESH METHOD A. Expansions on a Lagrange basis", "text": "Hamiltonian at the Gaussquadrature approximation, and reads", "cite_spans": [], "ref_spans": []}, {"section": "III. LAGRANGE-MESH METHOD A. Expansions on a Lagrange basis", "text": "with a 2 \u00d7 2 block structure, where the matrix elements", "cite_spans": [], "ref_spans": []}, {"section": "III. LAGRANGE-MESH METHOD A. Expansions on a Lagrange basis", "text": "are calculated at the Gaussquadrature approximation as", "cite_spans": [], "ref_spans": []}, {"section": "III. LAGRANGE-MESH METHOD A. Expansions on a Lagrange basis", "text": "The diagonalization of Hamiltonian matrix (28) provides a set of", "cite_spans": [], "ref_spans": []}, {"section": "III. LAGRANGE-MESH METHOD A. Expansions on a Lagrange basis", "text": "T for each valence orbital \u03c6 v of a given \u03ba v -symmetry, and ", "cite_spans": [], "ref_spans": []}, {"section": "B. Evaluation of two-electron Slater integrals", "text": "Let us illustrate the calculation of the two-electron Slater integrals R k by considering e.g. the exchange potential matrix in Eq. (28) ", "cite_spans": [], "ref_spans": []}, {"section": "B. Evaluation of two-electron Slater integrals", "text": "Two integration methods are devised in order to accurately compute R k pq (ic, cj) with Gauss-Laguerre quadratures. The first one, denoted as \"M I\", corresponds to the strategy suggested by Hartree [41, 69] , who first introduced the functions Y k (bd; r). In the present case (31) ,", "cite_spans": [{"start": 203, "end": 206, "text": "69]", "ref_id": "BIBREF68"}], "ref_spans": []}, {"section": "B. Evaluation of two-electron Slater integrals", "text": "with r \u2261 r 1 and s \u2261 r 2 , and is solution of the secondorder differential equation", "cite_spans": [], "ref_spans": []}, {"section": "B. Evaluation of two-electron Slater integrals", "text": "with the boundary conditions Y k q (jc; 0) = 0 and dY (33) is solved on Lagrange meshes, as presented in the Appendix. Once Y k q (jc; r) is known, the two-electron Slater integral (31) is expressed as", "cite_spans": [], "ref_spans": []}, {"section": "B. Evaluation of two-electron Slater integrals", "text": "and can be computed with the appropriate GaussLaguerre quadrature (see the Appendix).", "cite_spans": [], "ref_spans": []}, {"section": "B. Evaluation of two-electron Slater integrals", "text": "The second method, denoted as \"M II\", separates R k pq (ic, cj) in two terms as", "cite_spans": [], "ref_spans": []}, {"section": "B. Evaluation of two-electron Slater integrals", "text": "The first term is denoted as R k pq (ic, cj), and the order of integration is permuted in the second term. The integration bounds", "cite_spans": [], "ref_spans": []}, {"section": "B. Evaluation of two-electron Slater integrals", "text": "By using the change of variable r 1 = r + r 2 , R k pq (ic, cj) is integrated over variables r 2 and r, and reads", "cite_spans": [], "ref_spans": []}, {"section": "B. Evaluation of two-electron Slater integrals", "text": "This double integral is evaluated with two different Gauss-Laguerre quadratures, one for each integration variable (see the Appendix). Gauss quadratures of R k pp (ic, cj) and R k qq (ic, cj) are analogously obtained using M I and M II, as well as the Slater integral R", "cite_spans": [], "ref_spans": []}, {"section": "C. Projection of core orbitals on Lagrange bases", "text": "Each grasp2k core orbital is expanded over a basis of Lagrange functions depending on parameter \u03b1 c = 2(\u03b3 c \u2212 |\u03ba c |). A different value of h c is assigned to each orbital, and is chosen such that the largest grasp2k grid point of orbital c, R c , is at the center of [h c x Nc\u22121 , h c x Nc ], where x Nc\u22121 and x Nc denote the last two Lagrange mesh points, i.e., h c = 2R c /(x Nc\u22121 + x Nc ). To compute the unknown {p cj } Nc j=1 and {q cj } Nc j=1 coefficients for each core orbital, the radial wave functions P c (r) and Q c (r) are evaluated at each point h c x i of the scaled Lagrange mesh. Because the grasp2k grid points do not correspond to Lagrange mesh points, the wave functions are first interpolated with cubic splines, which are piecewise polynomials, allowing to evaluate the functions at any r. Applying Lagrange condition (25) respectively yields the expansion coefficients", "cite_spans": [], "ref_spans": []}, {"section": "D. Polarizabilities and decay rates on Lagrange meshes", "text": "Polarizabilities and two-photon decay rates proceed through an infinite set of intermediate states with some value of \u03ba \u2032 v . Finite-basis techniques such as the LMM allow a discretization of the continuum, leading to a truncated sum over 2N \u2032 v intermediate states. Some of these states may correspond to approximate eigenstates of Eq. (6), while the other ones, discretizing the continuum, have no physical meaning and are called pseudostates.", "cite_spans": [], "ref_spans": []}, {"section": "D. Polarizabilities and decay rates on Lagrange meshes", "text": "Let (14), (15) and (17) (14) as ", "cite_spans": [], "ref_spans": []}, {"section": "D. Polarizabilities and decay rates on Lagrange meshes", "text": "where the notations n \u03bd , j \u03bd and \u03ba \u03bd related to the intermediate states \u03bd are replaced by n \u2032 , j \u2032 and \u03ba", "cite_spans": [], "ref_spans": []}, {"section": "D. Polarizabilities and decay rates on Lagrange meshes", "text": "(1, 2) are analogously approximated. The integral common to Eqs. (38) and (39) is calculated with the Gauss quadrature as", "cite_spans": [], "ref_spans": []}, {"section": "D. Polarizabilities and decay rates on Lagrange meshes", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "D. Polarizabilities and decay rates on Lagrange meshes", "text": "and the non-polynomial factorr", "cite_spans": [], "ref_spans": []}, {"section": "D. Polarizabilities and decay rates on Lagrange meshes", "text": "Ifr k was replaced by r k , the Gauss quadrature (23) would be exact with N G \u2265 (N +N \u2032 +k+1)/2 mesh points. This suggests to use N G > (N + N \u2032 + k + 1)/2 in the present case. The integrals appearing in the one-photon E2 and M 1 decay rates (20) and (21) are analogously calculated with a Gauss-Laguerre quadrature.", "cite_spans": [], "ref_spans": []}, {"section": "D. Polarizabilities and decay rates on Lagrange meshes", "text": "In the two-photon case, the integral over \u03c9 1 is evaluated with a Gauss-Legendre quadrature using N \u03c91 mesh points.", "cite_spans": [], "ref_spans": []}, {"section": "IV. NUMERICAL RESULTS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "A. Calculations of core orbitals", "text": "The core orbitals of each ion are calculated with grasp2k and are projected on Lagrange bases. Comparing the original orbitals, the one-and two-electron integrals and the core energies with those computed with the LMM allows to assess the accuracy of the core description within the present approach.", "cite_spans": [], "ref_spans": []}, {"section": "A. Calculations of core orbitals", "text": "Let (40) and (41) Let us now compute with the LMM the core energies (3), E core , and compare them with the grasp2k results. Projecting P c (r) and Q c (r) on N c Lagrange functions and using the Gauss quadrature yields I(c, c) = p ", "cite_spans": [], "ref_spans": []}, {"section": "A. Calculations of core orbitals", "text": "The total two-electron energy of the core, R tot , is expressed as E core \u2212 I tot , i.e., as the sum of the last two terms on the r.h.s. of Eq. (3). Table I displays the Ca 2+ , Sr 2+ , and Ba 2+ core energies using a basis of N c = 50 Lagrange functions. The relative error on I tot with respect to grasp2k ranges from 5.7 \u00d7 10 \u22127 to 7.4 \u00d7 10 \u22127 . Hence, the accuracy on oneelectron integrals is of the same order of magnitude as the one on the wave functions themselves. The relative error on R tot is 2 \u00d7 10 \u22126 , and both M I and M II provide the same order of accuracy. Summing the one-and twoelectron contributions, the accuracy on E core is 3 \u00d7 10 (8), are compared with results from grasp2k at the frozen-core approximation. The relative error on \u03b5 DHF v with respect to grasp2k is similar for M I and M II, and slightly increases with Z, ranging from 1.4 \u00d7 10 \u22125 to 3.3 \u00d7 10 \u22125 in Ca + , from 3.3 \u00d7 10 \u22125 to 5.9 \u00d7 10 \u22125 in Sr + , and from 6.3 \u00d7 10 \u22125 to 9.9 \u00d7 10 \u22125 in Ba + . Besides, the fine-structure splittings are well reproduced for the nd j and (n + 1)p j states. The accuracy of the present valence calculations is sufficient to obtain reliable results for polarizabilities, one-and two-photon decay rates and associated lifetimes when adding the contribution of V CP (r), as shown in Secs. IV C and IV D. Increasing the number of Lagrange functions beyond N v = 50 does not improve the accuracy of the results.", "cite_spans": [], "ref_spans": [{"start": 149, "end": 156, "text": "Table I", "ref_id": "TABREF0"}]}, {"section": "A. Calculations of core orbitals", "text": "The values of the core static dipole polarizabilities used in the DHFCP-LMM calculations are computed at the relativistic random-phase approximation (RRPA) and are taken from Ref. [71] Tables IV and V. A more stringent estimate of the precision achieved by the DHFCP-LMM approach is given by studying the effect of variations in the values of the core dipole and quadrupole polarizabilities on the final results. A second set of core dipole values is provided by Ref. [ Using the second set of core polarizabilities in Eqs. (11) and (12) enables to estimate theoretical uncertainties on the values displayed in Tables IV and V. Note that using another set of core dipole values implies to determine other \u03c1 \u03bav -values in Eq. (11) , to ensure relative errors on \u03b5 DHFCP v below 10 \u22127 with respect to NIST data. In order to study the accuracy of the DHFCP-LMM approach, the present results are compared with other semiempirical-core-potential approaches (RCICPrelativistic configuration interaction with a semiempirical core potential, DFCP-Dirac-Fock with a semiempirical core potential), with ab initio methods (RMBPT-SD-relativistic many-body perturbation theory with single and double contributions, R(L)CCSD(T)-relativistic (linearized) coupled cluster method with single, double (and partial triple) contributions), and with experimental works (SA-spectral analysis, DFI-delayed field ionization, RESIS-resonant excitation Stark ionization spectroscopy).", "cite_spans": [], "ref_spans": [{"start": 185, "end": 201, "text": "Tables IV and V.", "ref_id": "TABREF0"}]}, {"section": "Dipole polarizabilities", "text": "The ground (n + 1)s 1/2 dipole polarizabilities involve n \u2032 p 1/2,3/2 intermediate states. They are dominated by the resonant (n+1)s 1/2 \u2192 (n+1)p j transitions, and their accuracy is largely dependent on the accuracy of the transition matrix elements connecting these states. Excellent consistency is found with RCICP [3] and DFCP [4] for Ca + (n = 3) and with RCICP [9] for Sr + (n = 4), while no reference value is available with these approaches for Ba + (n = 5). The agreement with ab initio calculations is satisfactory, although the present method tends to underestimate \u03b1 S 1 by a few percents. This is also true for the RCICP and DFCP methods, and is a direct consequence of the slightly different line strengths for the resonant transitions in these two types of calculations. [6, 7] .", "cite_spans": [], "ref_spans": []}, {"section": "Dipole polarizabilities", "text": "The (n + 1)p j dipole polarizabilities involve Method \u03b1 [8] 76.1(11) 32.0(11) Expt. SA [73] 75.3(4) Sr [10] 91.3(9) 62.0(5) Expt. DFI [74] 86(11) Ba [11] 124.15 Expt. RESIS [75] 123.88(5) [14] 906(5) \u22123706(75) RMBPT-SD [5] 871(4) Sr [14] 1366(9) \u22121732(41) RMBPT-SD [12] 1370.0(28) Expt. DFI [74] 1.1(10)\u00d710 [11] 4182(34) Expt. RESIS [75] 4420(250)", "cite_spans": [], "ref_spans": []}, {"section": "Quadrupole polarizabilities", "text": "The ground (n + 1)s 1/2 quadrupole polarizabilities involve n \u2032 d 3/2,5/2 states. The present values agree very well (< 1% differences) with DFCP [4] for Ca + and with RCICP [9] for Sr + , while no reference value is available with these approaches for Ba + . The comparison with ab initio methods shows that the present values are a few percents lower, for the same reason as for dipole polarizabilities. The Sr + experimental value from Ref. [74] is clearly incompatible with the theoretical works, while for Ba + the experimental result from Ref. [75] is in favor of the ab initio number, matching within the experimental uncertainties.", "cite_spans": [], "ref_spans": []}, {"section": "Quadrupole polarizabilities", "text": "The", "cite_spans": [], "ref_spans": []}, {"section": "Quadrupole polarizabilities", "text": "states, and additional n \u2032 g 9/2 states for nd 5/2 . Hence, nd j intermediate states must be excluded from the sum over n \u2032 in the nd j polarizability. The present values for Ca + differ from the DFCP result by 4%, and do not match with RCICP within the theoretical uncertainties for Sr + . The agreement with other semiempirical approaches is thus poor. Ab initio values are only available for nd 5/2 states. The level of agreement ranges from 5% to 9% for Ca + , and below 5% for Sr + . No reference number is available for Ba + . Hence, around 5% uncertainty should be assigned to the present values for Ba + . The (n + 1)p j quadrupole polarizabilities involve n \u2032 p 3/2 , n \u2032 f 5/2 states, and additional n \u2032 p 1/2 , n \u2032 f 7/2 states for (n + 1)p 3/2 . Hence, (n + 1)p 3/2 intermediate states must be excluded from the sum over n \u2032 in the (n + 1)p 3/2 polarizability. Excellent consistency (0.2% differences) with DFCP and RCICP is obtained for Ca + , and the values agree very well within the theoretical uncertainties for Sr + . Neither semiempirical nor ab initio calculations are available for Ba + . Table VI As for Tables IV  and V , using the second set of core dipole polarizabilities enables to estimate theoretical uncertainties on the a Corrected values [76] ; a factor 1/2 is missing in Ref. [38] .", "cite_spans": [], "ref_spans": [{"start": 1110, "end": 1118, "text": "Table VI", "ref_id": "TABREF0"}, {"start": 1119, "end": 1142, "text": "As for Tables IV  and V", "ref_id": "TABREF0"}]}, {"section": "D. Calculations of decay rates and lifetimes", "text": "DHFCP-LMM values displayed in Table VI . As mentioned in Sec. I, only one prior calculation has been carried out in these ions [38] , using the ab initio relativistic single-double all-order method. The comparison with the present results enabled to detect that a factor 1/2 was missing in Table I of Ref. [38] . Indeed, both approaches led to comparable differential decay rates, dW 2E1 /d\u03c9 1 , and the only source of error was a wrong choice of bounds for the integration over \u03c9 1 . A corrigendum has recently been published in Ref. [76] .", "cite_spans": [], "ref_spans": [{"start": 30, "end": 38, "text": "Table VI", "ref_id": "TABREF0"}, {"start": 290, "end": 297, "text": "Table I", "ref_id": "TABREF0"}]}, {"section": "D. Calculations of decay rates and lifetimes", "text": "The DHF-LMM results agree very well with corrected reference values, since both calculations are based on an ab initio method. The differences range from 0.4% to 0.5%, apart from 0.8% for the 5d 5/2 \u2192 6s 1/2 transition in Ba + . By contrast, differences between the DHFCP-LMM results and corrected all-order values are one order of magnitude higher, ranging from 1.4% to 6.0% depending on the studied ion. However, overall agreement is highly satisfying, keeping in mind that semiempirical results are compared to an ab initio method that explicitly includes single and double electron excitations to all orders of perturbation theory. Besides, the present study leads to the same conclusion as in Ref. [38] , i.e., that the DHF values of the 2E1 decay rates are strongly modified by the inclusion of electron correlation. Indeed, the DHF calculation overestimates the rates by factors of 10 \u2212 50. Table VII Table VII . Again, an estimation of theoretical uncertainties on the values displayed in Table VII is obtained by using the second set of core dipole and quadrupole polarizabilities.", "cite_spans": [], "ref_spans": [{"start": 898, "end": 907, "text": "Table VII", "ref_id": "TABREF0"}, {"start": 908, "end": 917, "text": "Table VII", "ref_id": "TABREF0"}]}, {"section": "D. Calculations of decay rates and lifetimes", "text": "DHFCP-LMM results of the total lifetimes \u03c4 are compared with other theory and with observation in order to study the accuracy of the present approach. While the cited theoretical references only report on calculations of E2 and M 1 contributions to the lifetimes of the nd j states, the present work also includes the 2E1 contributions.", "cite_spans": [], "ref_spans": []}, {"section": "D. Calculations of decay rates and lifetimes", "text": "While the nd 3/2 states can only decay via nd 3/2 \u2192 (n + 1)s 1/2 channels, the nd 5/2 states decay via nd 5/2 \u2192 (n + 1)s 1/2 and nd 5/2 \u2192 nd 3/2 channels. 2E1 decay rates being proportional to \u03c9 6 , their contribution is negligible for nd 5/2 \u2192 nd 3/2 (< 10 \u221213 s \u22121 ) but not for nd j \u2192 (n + 1)s 1/2 . E2 decay rates, proportional to \u03c9 5 , are dominant for nd j \u2192 (n + 1)s 1/2 . They are negligible for nd 5/2 \u2192 nd 3/2 in Ca + and Sr + , but they become comparable to 2E1 contributions for 5d 5/2 \u2192 5d 3/2 in Ba + . M 1 decay rates, proportional to \u03c9 3 , are negligible for nd 3/2 \u2192 (n + 1)s 1/2 but not for nd 5/2 \u2192 nd 3/2 . However, their contribution is only significant to the 5d 3/2 lifetime in Ba + . Taking the inverse of the total decay rates W (in s \u22121 ) yields the total lifetimes \u03c4 (in s). The DHFCP-LMM results agree very well (< 1% differences) with DFCP [4] for Ca + and RCICP [9] for Sr + , and good consistency is found with various ab initio calculations for these two ions. Among them, 0.5% \u2212 5% differences are obtained with the very recent work using the relativistic all-order method [34] . For each nd j lifetime of Ca + and Sr + , the present results lie within the uncertainties of at least one experiment, and the discrepancies with the other experimental values are not high. It should be noticed that discrepancies also occur among theoretical and experimental values, as well as between the two of them. Lifetimes are longer in Ba + than in Ca + and Sr + . Comparison of the present calculation of 5d j lifetimes with Ref. [34] yields 0.9% \u2212 5% differences, in the same range as in Ca + and Sr + . Values vary from one to two units between ab initio calculations, and the large experimental uncertainties due to the long lifetimes do not allow to discriminate between the different works.", "cite_spans": [], "ref_spans": []}, {"section": "V. CONCLUSIONS", "text": "This work presents DHFCP-LMM calculations of polarizabilities, one-and two-photon decay rates, and associated lifetimes in Ca + , Sr + , and Ba + ions. Two integration methods are devised to compute two-electron Slater integrals, and the comparison of their results allows to assess the precision of the values displayed in the tables. In addition, the effect of variations in the values of the core dipole and quadrupole polarizabilities on the final results is studied, which enables to estimate theoretical uncertainties on the latter.", "cite_spans": [], "ref_spans": []}, {"section": "V. CONCLUSIONS", "text": "The core orbitals are defined by a closed-shell DHF calculation with the grasp2k package, and are projected on Lagrange bases. The single valence electron is described in the frozen-core approximation by a Dirac-like Hamiltonian involving a CP potential to simulate the core-valence electron correlation. Comparing with grasp2k results, the accuracy on core energies is \u223c 10 \u22127 , while the one on DHF valence energies is \u223c 10 \u22125 for the five lowest states of each ion. With the inclusion of V CP , calculated energies are fitted with relative errors < 10 \u22127 in comparison with observation.", "cite_spans": [], "ref_spans": []}, {"section": "V. CONCLUSIONS", "text": "Turning to dipole and quadrupole polarizabilities, the agreement with other semiempirical approaches is excellent for Ca + and Sr + , while no such reference value exists for Ba + . Overall good agreement is obtained with ab initio methods and observation, although semiempirical approaches underestimate the ground-state polarizabilities by a few percents. The principal limitation of the accuracy on polarizabilities with such approaches lies in the accuracy of the core polarizabilities, that has to be computed with an independent method.", "cite_spans": [], "ref_spans": []}, {"section": "V. CONCLUSIONS", "text": "For the 2E1 nd j \u2192 (n + 1)s 1/2 decay rates, a comparison with Refs. [38, 76] shows that both DHF results agree very well with each other, and that a satisfying agreement is obtained between the DHFCP-LMM and all-order values. Both works conclude that the DHF values are strongly modified by the inclusion of electron correlation.", "cite_spans": [], "ref_spans": []}, {"section": "V. CONCLUSIONS", "text": "The lifetimes estimation of the metastable nd j states involves the study of the competition between the E2, M 1, and 2E1 decay channels. The present results agree very well with other semiempirical approaches for Ca + and Sr + , and overall good consistency is found with ab initio calculations and experiments. Results vary more significantly between calculations for Ba + , and the few existing experiments are associated with large uncertainties. Moreover, the contribution of the 2E1 processes to the total decay rates of nd j states is negligible (0.001 \u2212 0.01%) at the present level of theoretical and experimental accuracy. This conclusion had already been done in Ref. [38] . Estimating more accurate lifetimes for the nd j metastable states in these three ions currently represents a difficult task. Other decay processes are expected to compete with the E2, M 1, and 2E1 channels, such as magnetic-field induced transitions (MIT), and hyperfine induced transitions (HFI) for odd-A isotopes of these three ions. These processes are likely to modify the existing theoretical lifetimes values. Besides, new highprecision experimental results are urgently needed to test the theoretical predictions of the 5d j lifetimes in Ba + . Our work is based on a fully relativistic version of the semiempirical-core-potential approach. As such, it is an approximate method, where the comparison with experiments and other theories should in principle provide an assessment of the errors due to physical effects that are not included in the model. As illustrated by Tables IV-VII, estimating more realistic theoretical uncertainties based on such comparisons would be statistically meaningless, due to the dispersion of ab initio and experimental values.", "cite_spans": [], "ref_spans": []}, {"section": "V. CONCLUSIONS", "text": "Comparison with other theory and observation shows that the DHFCP-LMM method provides a simple and efficient way for evaluating properties of alkali-like ions involving an infinite number of intermediates states, such as relativistic polarizabilities and two-photon decay rates. For the first time, a semiempirical-core-potential calculation of two-photon decay rates is performed, and results from relativistic computations in the Ba + ion are reported with such an approach. By using the LMM, which allows a simple computation of one-body matrix elements, and by developing Gauss-quadrature-based methods to accurately evaluate the two-electron Slater integrals, precise results are obtained with small computing times and memory requirements. Besides, the use of the grasp2k package for core orbitals calculations reduces the code-development effort to only single valenceelectron calculations. The present approach can play a role in further improvement of theoretical nd j lifetimes in these three ions. It can also be used to study a variety of heavy alkali-like systems, such as Cs, Fr, Ra + and Yb + , for which theoretical results and experimental data are available for comparison, or others for which information is not available. Dynamic polarizabilities, hyperpolarizabilities and dispersion coefficients involved in long-range interactions between pairs of atoms, can be studied in various alkali-like systems. From a methodological point of view, the LMM could also offer some computational advantages for estimating other properties involving an infinite number of intermediate states, such as atomic electric dipole moments and parity nonconservation amplitudes. (A.7)", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF28": {"title": "Sinclair", "authors": [{"first": "V", "middle": [], "last": "Letchumanan", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Wilson", "suffix": ""}, {"first": "P", "middle": [], "last": "Gill", "suffix": ""}, {"first": "A", "middle": ["G"], "last": "", "suffix": ""}], "year": 2005, "venue": "Phys. Rev. A", "link": null}, "BIBREF29": {"title": "Eleventh International Conference on Laser Spectroscopy", "authors": [{"first": "G", "middle": ["P"], "last": "Barwood", "suffix": ""}, {"first": "C", "middle": ["S"], "last": "Edwards", "suffix": ""}, {"first": "P", "middle": [], "last": "Gill", "suffix": ""}, {"first": "H", "middle": ["A"], "last": "Klein", "suffix": ""}, {"first": "W", "middle": ["R"], "last": "Rowley", "suffix": ""}], "year": 1993, "venue": "", "link": null}, "BIBREF38": {"title": "Relativistic Quantum Theory of Atoms and Molecules", "authors": [{"first": "I", "middle": ["P"], "last": "Grant", "suffix": ""}], "year": 2007, "venue": "", "link": "99000191"}, "BIBREF52": {"title": "Computational Atomic Structure: An MCHF Approach", "authors": [{"first": "C", "middle": [], "last": "Fischer", "suffix": ""}, {"first": "T", "middle": [], "last": "Brage", "suffix": ""}, {"first": "P", "middle": [], "last": "J\u00f6nsson", "suffix": ""}], "year": 1997, "venue": "", "link": "116372038"}, "BIBREF64": {"title": "Handbook of Mathematical Functions", "authors": [{"first": "M", "middle": [], "last": "Abramowitz", "suffix": ""}, {"first": "I", "middle": ["A"], "last": "Stegun", "suffix": ""}], "year": 1965, "venue": "", "link": "117843805"}, "BIBREF65": {"title": "Orthogonal polynomials", "authors": [{"first": "G", "middle": [], "last": "Szeg\u00f6", "suffix": ""}], "year": 1967, "venue": "Am. Math. Soc, Providence", "link": null}, "BIBREF68": {"title": "The calculation of Atomic Structures", "authors": [{"first": "D", "middle": ["R"], "last": "Hartree", "suffix": ""}], "year": 1957, "venue": "", "link": null}}, "ref_entries": {"FIGREF1": {"text": "the normalization of P v (r) and Q v (r) at the Gauss- quadrature approximation.", "type": "figure"}, "FIGREF2": {"text": "pq exc is given by Eq. (10), where the integral R k pq (ic, cj) reads, according to Eq. (5),", "type": "figure"}, "FIGREF3": {"text": "\u03ba v . The corresponding eigenvectors contain the coefficients p v \u2032 j and q v \u2032 j of the components P v \u2032 (r) and Q v \u2032 (r) of the intermediate states. The latter are calculated with \u03b1", "type": "figure"}, "FIGREF4": {"text": "the origin. Accurate calculations of Eqs.", "type": "figure"}, "FIGREF5": {"text": "with a Gauss-Laguerre quadrature are possible by choosing a third meshhx i whereh = 2h v h \u2032 v /(h v +h \u2032 v ). In the two-photon case, h v corresponds to h i or h f . Thex i correspond to the weight function x\u1fb1e \u2212x with \u03b1 = (\u03b1 v + \u03b1 \u2032 v )/2, and the corresponding weights are de- noted as\u03bb i . Approximate scalar polarizabilities \u03b1 S \u03bb (v) are obtained from Eq.", "type": "figure"}, "FIGREF6": {"text": "terms of the 2E1 de- cay rates (16) are obtained from Eq. (17) as", "type": "figure"}, "FIGREF7": {"text": "with \u03ba = \u03ba \u2032 = \u03ba c and k = 0. Using a basis of N c = 50 Lagrange functions for Ca 2+ , Sr 2+ , and Ba 2+ , all relative errors with respect to grasp2k are in the range 10 \u22127 \u2212 10 \u22126 .", "type": "figure"}, "FIGREF8": {"text": "\u03bac p c for the one-electron integrals (4), where p c = (p c1 , \u00b7 \u00b7 \u00b7 , p cNc , q c1 , \u00b7 \u00b7 \u00b7 , q cNc ) T , and the 2N c \u00d72N c matrix H \u03bac is given by Eq. (29) with \u03ba c instead of \u03ba v . Accord- ing to Eq. (3), the total one-electron energy of the core is expressed as I tot = c q c I(c, c). The two-electron Slater integrals (4) are computed using methods M I and M II. The Appendix provides expressions on Lagrange meshes for the valence case. Similar expressions can be derived for the Slater integrals", "type": "figure"}, "FIGREF9": {"text": "I and M II. Increasing the number of Lagrange functions beyond N c = 50 does not improve the accu- racy of the results.", "type": "figure"}, "FIGREF10": {"text": "polarizabilities (in a.u.) are given for the j v > 1/2 states. Core dipole and quadrupole polariz- abilities from Ref. [71] are added to the valence-LMM results are computed with N c = N v = N \u2032 = 50 Lagrange functions, where N \u2032 denotes the number of functions used to describe the intermediate states. Significant digits are estimated by increasing N \u2032 from 50 to 80. The LMM calculations are performed with M I and M II, and the comparison of their results allows to assess the precision of the values displayed in", "type": "figure"}, "FIGREF11": {"text": "displays 2E1 decay rates, W 2E1 (in s \u22121 ), of the nd j \u2192 (n + 1)s 1/2 transitions in Ca + (n = 3), Sr + (n = 4), and Ba + (n = 5) ions. The nd 3/2 \u2192 (n + 1)s 1/2 transitions involve n \u2032 p 1/2,3/2 intermediate states while the nd 5/2 \u2192 (n + 1)s 1/2 transitions only involve n \u2032 p 3/2 states. The DHF-LMM and DHFCP-LMM results are computed in the length gauge with N c = N v = N \u2032 = 50 Lagrange functions. The integral over \u03c9 1 is evaluated with N \u03c91 = 50 mesh points. Significant digits are esti- mated by increasing N \u2032 from 50 to 80 and by compar- ing results from M I and M II. Better agreement be- tween M I and M II is obtained for DHFCP-LMM re- sults, since DHF-LMM energies differ more significantly between both integration methods.", "type": "figure"}, "FIGREF12": {"text": "displays lifetimes, \u03c4 (in s), and multipole contributions to the transition rates, W (in s \u22121 ), of the nd j states in Ca + (n = 3), Sr + (n = 4), and Ba + (n = 5) ions. The DHFCP-LMM values of the 2E1 decay rates are taken from Table VI. The DHFCP-LMM values of the E2 decay rates are computed in the length gauge with N c = N v = 50, and M 1 decay rates are computed with the same parameters. Significant digits of the E2 and M 1 results are estimated by comparison with N v = 60 considering M I and M II, and the comparison of the re- sults from M I and M II allows to assess the precision of the values displayed in", "type": "figure"}, "FIGREF13": {"text": "(jc; r) is recov- ered by adding back Y 0 q (jc; \u221e) (1\u2212e \u2212r ) to the solution of the modified algebraic system. Once Y k q (jc; r) is known, integral (34) is expressed using a Gauss quadrature with the same parameters as in (A.M II, let us start with the integral over r in Eq. (37). Definingh \u2261 2h v h c /(h v + h c ), the integrand reads (r + r 2 ) \u03b1v +\u03b1c 2 \u2212k P Nv +Nc\u22121 (r + r 2 ) e \u2212(r+r2)/h , (A.4) where P Nv+Nc\u22121 is a polynomial of degree N v + N c \u2212 1 and the first factor is non-polynomial. Expression (A.4) suggests that computing the integral over r by the Gauss- Laguerre quadrature with weight function exp (\u2212r/h) and N G > (N v + N c )/2 points should be efficient. Denot- ing the abscissae and weights of this Gauss quadrature byhx m andh\u03bb m (with m = 1 to N G )m + r 2 )/h v ]P c (hx m + r 2 ) (hx m + r 2 ) k+1 . (A.5) For each term of the sum over index m, the integrand of the integral over r 2 can be written as (hx m + r 2 )+2Nc+k\u22121 is a polynomial of degree 2N v + 2N c + k \u2212 1 andh \u2261h/2. This expression incites us to evaluate the integral over r 2 by a Gauss-Laguerre quadrature with weight function r> N v + N c + k/2 points. Let us denote byhx m \u2032 andh\u03bb m \u2032 (with m \u2032 = 1 to N \u2032 G ), the abscissae and weights of this Gauss quadrature. The integral R k pq (ic, cj) given by Eq. (37) reads, finally,m \u2032 /h v )Q c (hx m \u2032 )hx m +hx m \u2032 )/h v ]P c (hx m +hx m \u2032 ) (hx m +hx m \u2032 ) k+1 .", "type": "figure"}, "TABREF0": {"text": "Ecore (in a.u.). LMM M I and M II values are compared with grasp2k re- sults. Powers of 10 are indicated within brackets.(in a.u.), of the five lowest states in Ca + , Sr + , and Ba + . Energies are given relative to the energy of the core. DHF-LMM values are compared with results from grasp2k.", "type": "table"}, "TABREF1": {"text": "DHF and DHFCP energies, \u03b5N c = N v = 50 Lagrange functions. The values of the scaling parameter h v are 0.10 for nd j states, 0.11 for (n + 1)s 1/2 states and 0.12 for (n + 1)p j states. In practice, all values between 0.1 and 0.2 are acceptable for these states. DHF-LMM values, obtained by neglecting V CP (r) in Eq.", "type": "table"}, "TABREF2": {"text": "2+ ) = 10.61 a.u. The \u03c1 \u03bav -values (in a.u.), listed in Table III, ensure that the relative error on \u03b5 DHFCP v with respect to experimental NIST data [70] is below 10 \u22127 for all states presented in Table II, considering both M I and M II. The obtained \u03c1 \u03bav -numbers show good agreement with the ones pro- vided by Ref. [4] for Ca", "type": "table"}, "TABREF3": {"text": "", "type": "table"}, "TABREF4": {"text": "spect to the first set of values are respectively 0.9%, 1.1% and 1.7%. A second set of core quadrupole values is pro- vided by Ref. [14] for CaThe relative differences with respect to the first set of values are respectively 11.3%, 15.5% and 4.3%, thus substantially higher than for the core dipole values.", "type": "table"}, "TABREF5": {"text": "Good agreement with observation is found for Ca + , while the large uncertainty of the experimental value for Srcannot be used to discriminate between theoretical esti- mates. By contrast, ab initio calculations are more con- sistent with experiment than the present one for Ba + . The nd j dipole polarizabilities involve n", "type": "table"}, "TABREF6": {"text": "and nd j . For 4p j states in Ca + , cancella- tions in the sum lead to small \u03b1 S 1 values, and consistency with RCICP and DFCP is poor. Moreover, the ab initio works do not agree with each other. Better agreement is found between \u03b1 T 1 values of 4p 3/2 . For 5p j states in Sr + , excellent consistency is obtained with RCICP. Results are in good agreement with ab initio methods for \u03b1value of 5p 3/2 is around 8% smaller because the matrix element of 5s 1/2 \u2192 5p 3/2 is smaller. Only one ab initio calculation is available for 6p j states", "type": "table"}, "TABREF7": {"text": "Static scalar dipole (\u03b1) polarizabilities (in a.u.) are given for the jv > 1/2 states. Core polarizabilities from Ref. [71] are added to the DHFCP- LMM valence \u03b1 S 1 (v) results. Comparison with other theory and experiment. Uncertainties in the last digits are given within parentheses.", "type": "table"}, "TABREF11": {"text": "results. Comparison with other theory and experiment. Uncertainties in the last digits are given within parentheses.", "type": "table"}, "TABREF13": {"text": "2E1", "type": "table"}, "TABREF14": {"text": "Lifetimes, \u03c4 (in s), and multipole contributions to the transition rates, W (in s \u22121 ), of the ndj states in Ca + (n = 3), Sr + (n = 4), and Ba + (n = 5). DHFCP-LMM results of the total lifetimes \u03c4 are compared with other theory and experiment. Uncertainties in the last digits are given within parentheses. Powers of 10 are indicated within brackets for W .", "type": "table"}}}
{"paper_id": "119424854", "_pdf_hash": "10c491989c95c5d29dfd98342dcebdebfbb63354", "abstract": [], "body_text": [], "bib_entries": {"BIBREF1": {"title": "The m atrix representatives d$m ( | jt) for the", "authors": [{"first": "C", "middle": ["J"], "last": "Bradley", "suffix": ""}], "year": 1961, "venue": "", "link": null}, "BIBREF2": {"title": "Society Depository of Unpublished Tables, file no. 79. W ashington: Library of Congress collection", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF5": {"title": "Angular momentum in quantum mechanics", "authors": [{"first": "A", "middle": ["R"], "last": "Edmonds", "suffix": ""}], "year": 1957, "venue": "", "link": "119711409"}, "BIBREF6": {"title": "Higher transcendental functions", "authors": [{"first": "A", "middle": [], "last": "Erdelyi", "suffix": ""}, {"first": "W", "middle": [], "last": "Magnus", "suffix": ""}, {"first": "F", "middle": [], "last": "Oberhettinger", "suffix": ""}, {"first": "F", "middle": ["G"], "last": "Tricomi", "suffix": ""}], "year": 1953, "venue": "Bateman Manuscipt P r o j e c t", "link": "119551296"}, "BIBREF7": {"title": "2 , 207. M cIntosh, H . V. i960", "authors": [{"first": "I", "middle": ["M"], "last": "Gevfand", "suffix": ""}, {"first": "Z", "middle": ["Y"], "last": "Shapiro", "suffix": ""}], "year": 1956, "venue": "Amer. Math. Soc. Transl", "link": null}, "BIBREF8": {"title": "Group theory and its applications to the quantum mechanics o f atomic spectra", "authors": [{"first": "P", "middle": ["M"], "last": "Morse", "suffix": ""}, {"first": "H", "middle": [], "last": "Feshbach", "suffix": ""}], "year": 1953, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "119425236", "_pdf_hash": "1eab7df32c89de81f34091f6331165a4bca9facf", "abstract": [{"section": "Abstract", "text": "A search for new high-mass resonances in proton-proton collisions having final states with an electron or muon and missing transverse momentum is presented. The analysis uses proton-proton collision data collected in 2016 with the CMS detector at the LHC at a center-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 35.9 fb \u22121 . The transverse mass distribution of the charged lepton-neutrino system is used as the discriminating variable. No significant deviation from the standard model prediction is found. The best limit, from the combination of electron and muon channels, is 5.2 TeV at 95% confidence level for the mass of a W boson with the same couplings as those of the standard model W boson. Exclusion limits of 2.9 TeV are set on the inverse radius of the extra dimension in the framework of split universal extra dimensions. In addition, model-independent limits are set on the production cross section and coupling strength of W bosons decaying into this final state. An interpretation is also made in the context of an R parity violating supersymmetric model with a slepton as a mediator and flavor violating decay.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "The standard model (SM) of particle physics describes the properties of all known elementary particles and the forces between them. Five decades of experimental studies have verified its predictions to very high precision. Despite the great success of the SM, theories beyond the SM (BSM) have been invoked to address a variety of open issues. Many SM extensions predict additional heavy gauge bosons, including models with extended gauge sectors [1] , and theories with extra spatial dimensions [2, 3] .", "cite_spans": [{"start": 447, "end": 450, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Introduction", "text": "The search presented in this paper is sensitive to deviations from the SM prediction in the transverse mass spectrum of events with a charged lepton (electron or muon) and a neutrino. Interpretations of the observations are made in the context of several theoretical models: the production and decay of a W boson in the sequential standard model (SSM) [4] , the production and flavor violating decay of a slepton in an R-parity violating supersymmetry (RPV SUSY) model [5, 6] , and the production and decay of a Kaluza-Klein (KK) excitation of the W boson in a model with split universal extra dimensions (split-UED) [7] .", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The shape of the distribution is studied using a binned likelihood method. This approach is especially powerful as the examined theories predict different signal event distributions. Although the details differ, all models predict that the signal of a high-mass resonance is present at large transverse masses where SM backgrounds are very small.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The present analysis uses data corresponding to an integrated luminosity of 35.9 fb \u22121 of protonproton collisions at a center-of-mass energy of 13 TeV, recorded in 2016 with the CMS detector at the CERN LHC. The analysis improves upon the sensitivity of its predecessors [8, 9] , benefiting from the increased energy and luminosity of the LHC. Previous searches [10, 11] have not found evidence for deviations from the SM prediction for the transverse mass distribution.", "cite_spans": [], "ref_spans": []}, {"section": "The CMS detector", "text": "The central feature of the CMS apparatus is a superconducting solenoid of 6 m internal diameter, providing a magnetic field of 3.8 T. Within the solenoid volume are a silicon pixel and strip tracker, a lead tungstate crystal electromagnetic calorimeter (ECAL), and a brass and scintillator hadron calorimeter (HCAL), each composed of a barrel and two endcap sections. Extensive forward calorimetry complements the coverage provided by the barrel and endcap detectors.", "cite_spans": [], "ref_spans": []}, {"section": "The CMS detector", "text": "The silicon tracker measures charged particles within the pseudorapidity range |\u03b7| < 2.5. It consists of silicon pixel and silicon strip detector modules. The electromagnetic calorimeter consists of 75 848 lead tungstate crystals that provide coverage in pseudorapidity |\u03b7| < 1.48 in a barrel region and 1.48 < |\u03b7| < 3.00 in two endcap regions. The ECAL energy resolution for electrons with a transverse momentum p T \u2248 45 GeV from Z \u2192 ee decays is better than 2% in the central region of the ECAL barrel (|\u03b7| < 0.8), and is between 2% and 5% elsewhere [12] . For high energies, which are relevant for this analysis, the electron energy resolution slightly improves [13] .", "cite_spans": [], "ref_spans": []}, {"section": "The CMS detector", "text": "Muons are measured in gas-ionization detectors embedded in the steel flux-return yoke outside the solenoid, in the pseudorapidity range |\u03b7| < 2.4. Detection is provided using three technologies: drift tube (DT), cathode strip chamber (CSC), and resistive plate chamber (RPC). While the barrel region of |\u03b7| \u2264 1.1 is instrumented with DT and RPC, the forward endcaps (1.1 < |\u03b7| < 2.4) are equipped with CSC and RPC. A muon from the interaction point will cross four layers of muon chambers, interleaved with steel forming the return yoke of the magnetic field. Every chamber provides reconstructed hits on several detection planes, which are then combined into local track segments, forming the basis of muon reconstruction inside the muon system. Matching muons track segments to tracks measured in the silicon tracker results in a relative transverse momentum (p T ) resolution in the barrel of about 1-2% for muons with p T 200 GeV and better than 10% for high momentum muons of p T \u223c 1 TeV [14] .", "cite_spans": [], "ref_spans": []}, {"section": "The CMS detector", "text": "Jets are reconstructed offline from the energy deposits in the calorimeter towers, clustered using the anti-k T algorithm [15, 16] with a distance parameter of 0.4. In this process, the contribution from each calorimeter tower is assigned a momentum, the absolute value and the direction of which are given by the energy measured in the tower, and the coordinates of the tower. The raw jet energy is obtained from the sum of the tower energies, and the raw jet momentum by the vectorial sum of the tower momenta, which results in a nonzero jet mass. The raw jet energies are then corrected to establish a relative uniform response of the calorimeter in \u03b7 and a calibrated absolute response in transverse momentum p T .", "cite_spans": [{"start": 127, "end": 130, "text": "16]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "The CMS detector", "text": "The CMS experiment has a two-level trigger system [17] . The level-1 trigger, composed of custom hardware processors, selects events of interest using information from the calorimeters and muon detectors and reduces the readout rate from the 40 MHz bunch-crossing frequency to a maximum of 100 kHz. The software based high-level trigger uses the full event information, including that from the inner tracker, to reduce the event rate to the 1 kHz that is recorded.", "cite_spans": [{"start": 50, "end": 54, "text": "[17]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "The CMS detector", "text": "A more detailed description of the CMS detector can be found in Ref. [18] .", "cite_spans": [{"start": 69, "end": 73, "text": "[18]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Physics models and event simulation", "text": "Many BSM scenarios predict the existence of new particles that decay with the experimental signature of a charged lepton, , and missing transverse momentum, p miss T , where the latter may flag the presence of a non-interacting particle. The missing transverse momentum, p miss T , is defined as \u2212 \u2211 p T of all reconstructed particles, with p miss T being the modulus of p miss T .", "cite_spans": [], "ref_spans": []}, {"section": "Physics models and event simulation", "text": "The analysis is performed in two channels: e + p miss T and \u00b5 + p miss T . New particles may be detected as an excess of events in the observed spectrum of transverse mass, defined as", "cite_spans": [], "ref_spans": []}, {"section": "Physics models and event simulation", "text": "where \u2206\u03c6( , p miss T ) is the azimuthal opening angle (in radians) between the directions of the missing transverse momentum and the charged lepton. Several new-physics models predict the production of high-p T leptons, which should be identifiable as an excess in the region of high M T values where little SM background is expected.", "cite_spans": [], "ref_spans": []}, {"section": "Physics models and event simulation", "text": "This section summarizes the new physics models used for interpretation of the observations, along with model-specific assumptions and details of the generator programs used for production of simulated signal event samples. All generated events are processed through a full simulation of the CMS detector based on GEANT4 [19] , a trigger emulation, and the event reconstruction chain.", "cite_spans": [{"start": 320, "end": 324, "text": "[19]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Physics models and event simulation", "text": "All simulated event samples are normalized to the integrated luminosity of the recorded data. The simulation of pileup is included in all event samples by superimposing simulated minimum bias interactions onto all simulated events. For the data set used, the average number of interactions per bunch-crossing after selection is about 20, with a maximum of 55. ", "cite_spans": [], "ref_spans": []}, {"section": "Sequential standard model W boson", "text": "The SSM [4] has been used as a benchmark model for experimental W boson searches for more than two decades. The Feynman diagram for the production and decay of a W boson is depicted in Fig. 1 (left) . In accordance with previous analyses, no interference with the SM W boson is considered.", "cite_spans": [], "ref_spans": [{"start": 185, "end": 198, "text": "Fig. 1 (left)", "ref_id": "FIGREF0"}]}, {"section": "Sequential standard model W boson", "text": "In the SSM, the W boson is considered to be a heavy analogue of the SM W boson, with similar decay modes and branching fractions. These are modified by the presence of the tb decay channel, which opens up for W boson masses above 180 GeV. Dedicated searches in the tb channel are described in Refs. [20] [21] [22] . For this search, the given assumptions yield a predicted branching fraction (B) of about 8.5% for each of the leptonic channels studied. The width of a 1 TeV W boson would be about 33 GeV. Decays of the W boson via WZ are assumed to be suppressed. Dedicated searches for these decays can be found in Refs. [23, 24] .", "cite_spans": [{"start": 299, "end": 303, "text": "[20]", "ref_id": "BIBREF5"}, {"start": 304, "end": 308, "text": "[21]", "ref_id": "BIBREF6"}, {"start": 309, "end": 313, "text": "[22]", "ref_id": "BIBREF7"}, {"start": 622, "end": 626, "text": "[23,", "ref_id": "BIBREF8"}, {"start": 627, "end": 630, "text": "24]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Sequential standard model W boson", "text": "The signature of a W boson is a Jacobian peak in the transverse mass distribution, similar to that of the SM W boson, but at a higher mass. Because of constraints from the parton distribution functions (PDF) the phase space for production of very massive W bosons in pp collisions at 13 TeV is reduced, leading to a large fraction of such W bosons being produced off-shell, at lower masses.", "cite_spans": [], "ref_spans": []}, {"section": "Sequential standard model W boson", "text": "The simulation of data samples in the SSM is performed at leading order (LO) with PYTHIA 8.212 [25] , using the NNPDF2.3 PDF set [26, 27] and tune CUETP8M1 [28] . The simulated masses range from 400 GeV to 6 TeV, where the lower mass matches the beginning of the sensitive region as determined by the trigger thresholds. A W boson mass-dependent K-factor is used to correct for next-to-next-to-leading order (NNLO) QCD multijet cross sections, calculated using FEWZ 3.1 [29, 30] . The K-factor varies from 1.363 to 1.140.", "cite_spans": [{"start": 95, "end": 99, "text": "[25]", "ref_id": "BIBREF10"}, {"start": 129, "end": 133, "text": "[26,", "ref_id": "BIBREF11"}, {"start": 134, "end": 137, "text": "27]", "ref_id": "BIBREF12"}, {"start": 156, "end": 160, "text": "[28]", "ref_id": "BIBREF13"}, {"start": 470, "end": 474, "text": "[29,", "ref_id": "BIBREF14"}, {"start": 475, "end": 478, "text": "30]", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "Varying coupling strength", "text": "The W boson coupling strength, g W , is usually given in terms of the SM weak coupling strength g W . If the W is a copy of the SM W boson, their coupling ratio is g W /g W = 1 and the SSM W theoretical cross sections, signal shapes, and widths apply. However, different couplings are possible. Because of the dependence of the width of a particle on its coupling, and the consequent effect on the M T distribution, a limit can also be set on the coupling strength. For this study, signal samples for a range of coupling ratios, g W /g W = 10 \u22122 to 3, are simulated in LO with MADGRAPH 5 (v1.5.11) [31] . These signals exhibit different widths as well as different cross sections. The generated distributions of the PYTHIA samples are reweighted to take into account the decay width dependence, thus providing the appropriate reconstructed M T distributions. For g W /g W = 1 the theoretical LO cross sections apply and this coupling strength was used to compare the standard SSM samples with the reweighted ones, allowing the reweighting method to be verified. For g W /g W = 1 the theoretical cross sections scale with the coupling strength squared.", "cite_spans": [], "ref_spans": []}, {"section": "Split-UED model", "text": "The leptonic final states under study may also be interpreted in the framework of universal extra dimensions with fermions propagating in the bulk, known as split-UED model [7, 32] . This is a model based on an extended space-time with an additional compact fourth spatial dimension of radius R, and a bulk mass parameter of the fermion field in five dimensions, \u00b5. In this model all SM particles have corresponding Kaluza-Klein (KK) partners, for instance W (n) KK , where the superscript denotes the n th KK excitation mode. Only KK-even KK modes of W (n) KK couple to SM fermions, owing to KK-parity conservation. In the split-UED model the parameter \u00b5 is assumed to be non-zero, following Refs. [7, 32] . The mass of the W KK from approximately 400 to 6000 GeV.", "cite_spans": [], "ref_spans": []}, {"section": "RPV SUSY with scalar lepton mediator", "text": "This model assumes a SUSY scalar lepton ( ) as a mediator, with subsequent R-parity and lepton flavor violating decay to a charged lepton and a neutrino [5, 6] . The analysis studies the cases where a tau slepton decays to e + \u03bd \u00b5 or to \u00b5 + \u03bd e . The Feynman diagram is depicted on the right of Fig. 1 for the two decay channels under study. While on the production side, the coupling is always a version of the hadronic-leptonic RPV coupling \u03bb 3ij (which is the coupling to the third generation, in this case the tau slepton), the decay is governed by the leptonic RPV coupling \u03bb 231 for the decay to e + \u03bd \u00b5 , and by \u03bb 132 for the decay to \u00b5 + \u03bd e . The values of the couplings may be identical. Signal samples for a range of tau slepton masses, M( \u03c4), are simulated with MADGRAPH 5 (v1.5.14) at LO and no higher order effects are considered. Signals are simulated with the parameters \u03bb 231 , \u03bb 132 and \u03bb 3ij =0.05 to 0.5 for M( \u03c4) = 400 to 6000 GeV.", "cite_spans": [], "ref_spans": [{"start": 295, "end": 301, "text": "Fig. 1", "ref_id": "FIGREF0"}]}, {"section": "Event reconstruction", "text": "The models described in the previous section provide an event signature of a single high-p T lepton (electron or muon) and a particle that cannot be detected directly, giving rise to the exper-imentally observed p miss T . This quantity is measured using a particle-flow (PF) technique [33] , that combines measurements from all components of the CMS detector in order to produce particle candidates. The modulus of the vector p T sum of these candidates defines p miss T , which is corrected for the jet energy calibration [34, 35] . At high mass, the p miss T is mainly determined by the high-p T lepton in the event.", "cite_spans": [], "ref_spans": []}, {"section": "Event reconstruction", "text": "Electrons are reconstructed as ECAL clusters that are matched to a central track and their identification has been optimized for high-p T values [36] . Electron candidates are required to be isolated, have an electron-like shape, and be within the acceptance region of the barrel (|\u03b7| < 1.44) or the endcaps (1.56 < |\u03b7| < 2.50). This acceptance region avoids the transition region between barrel and endcap parts of the ECAL. Electron isolation in the tracker is ensured by requiring the sum of p T to be less than 5 GeV for all tracks that are in close proximity to the track of the electron candidate and to originate from the same primary vertex. Only tracks that are within a cone of \u2206R = \u221a (\u2206\u03c6) 2 + (\u2206\u03b7) 2 < 0.3 around the electron candidate's track are considered. The reconstructed vertex with the largest value of summed physics-object p 2 T is taken to be the primary pp interaction vertex. The physics objects are the jets, clustered using the jet finding algorithm [15, 16] with the tracks assigned to the vertex as inputs, and the associated missing transverse momentum, taken as the negative vector sum of the p T of those jets. As in the tracker isolation calculation, in the calorimeters the sum of energy deposits within a cone \u2206R < 0.3 around the electron candidate's direction is used as a measure of isolation. It is corrected for the mean energy contribution from additional pp collisions occurring within the same bunch crossing (pileup) [37] . To obtain sufficiently isolated electrons, this calorimeter isolation is required to be below a threshold of 3% of the electron's transverse momentum. Additionally, the energy deposits in the hadron calorimeter within a cone of \u2206R = 0.15 around the electron's direction must be less than 5% of the electron's energy deposit in the ECAL. In order to differentiate between electrons and photons, properties of the track matched to the calorimeter measurement must be consistent with those of an electron originating from the primary vertex. Specifically, there must be \u22641 hit missing in the innermost tracker layers, and the transverse distance to the primary vertex must be <0.02 cm (barrel) or <0.05 cm (endcap).", "cite_spans": [{"start": 981, "end": 984, "text": "16]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Event reconstruction", "text": "The muon system covers the pseudorapidity region |\u03b7| < 2.4. The reconstruction of muons is optimized for high-p T values [36] . Information from the inner tracker and the outer muon system are used together. Each muon track is required to have at least one hit in the pixel detector, at least six tracker layer hits, and segments with hits in two or more muon detector stations. Since segments are typically in consecutive layers separated by thick layers of steel, the latter requirement significantly reduces the amount of hadronic punch-through [38] . To reduce background from cosmic ray muons, each muon is required to have a transverse impact parameter of less than 0.02 cm and a longitudinal distance parameter of less than 0.5 cm with respect to the primary vertex. In order to suppress muons with mismeasured p T , an additional requirement \u03c3 p T /p T < 0.3 is applied, where \u03c3 p T is the p T uncertainty from the muon track reconstruction. Muon isolation requires that the scalar p T sum of all tracks originating from the interaction vertex within a \u2206R < 0.3 cone around its direction, excluding the muon itself, is less than 10% of the muon's p T .", "cite_spans": [], "ref_spans": []}, {"section": "Event reconstruction", "text": "In order to determine any differences in the selection efficiencies between observed and simulated data, the efficiencies for both channels are measured using the \"tag-and-probe\" method [39], with samples of dilepton events from high-p T Z boson decays and high-mass Drell-Yan pairs. The overall efficiency in each case includes contributions from the trigger and the lepton reconstruction and identification criteria. The ratio of the efficiencies for data and simulation, denoted as the scale factor (SF), is determined for each channel separately. The SFs that match the electron identification and reconstruction efficiencies in data and simulation are 0.972 \u00b1 0.006 (barrel) and 0.983 \u00b1 0.007 (endcap). The muon scale factors are also sensitive to differences between simulated samples and data, caused by radiative processes associated with muon interactions in the material of the detector. The corresponding SFs are applied as a function of \u03b7, with uncertainties covering possible lower efficiencies in data and dependent on the muon momentum that, for a muon momentum of 5 TeV, range from 3% for |\u03b7| < 1.6 and up to 20% for 1.6 < |\u03b7| < 2.4.", "cite_spans": [], "ref_spans": []}, {"section": "Event selection", "text": "The event selection follows the approach used in previous CMS analyses [8, 9] . Events are triggered with a single-electron (muon) trigger with trigger thresholds of lepton p T > 115(50) GeV. In addition, high-p T electrons may be triggered by a single-photon trigger with a threshold of 175 GeV for the photon p T , which is used in a logical \"OR\" with the single-electron trigger. For the electron channel, the trigger SF is determined to be 0.989 \u00b1 0.003 (barrel) and 0.996 \u00b1 0.003 (endcap), respectively, for the combination of the single-electron and single-photon triggers. The muon trigger SF accounts for observed differences between the efficiencies in simulation and in data for particular regions of the detector, such as the transition region between the barrel and endcap muon detectors. The SF values, applied as a function of \u03b7, range from 0.92 to unity.", "cite_spans": [], "ref_spans": []}, {"section": "Event selection", "text": "The minimum offline lepton p T must be above the lepton trigger threshold. For offline reconstruction, electrons are required to have p T > 130 GeV and to have |\u03b7| < 1.44 or 1.56 < |\u03b7| < 2.50. Muons must have p T > 53 GeV and |\u03b7| < 2.4. Signal events are identified by the presence of an isolated high-p T lepton. Events with a second lepton with p T > 25 GeV are rejected. In the electron channel, p miss T is required to be above 150 GeV to avoid the mismodeled low-p miss T region.", "cite_spans": [], "ref_spans": []}, {"section": "Event selection", "text": "In the muon channel, the contribution from tt events is further reduced by rejecting events containing six or more jets or events with the leading jet having p T > 25 GeV and |\u03b7| < 2.5, consistent with originating from a bottom quark, using the standard CMS b-tagging tools [40] .", "cite_spans": [], "ref_spans": []}, {"section": "Event selection", "text": "In the considered models, the lepton and p miss T are expected to be nearly back-to-back in the transverse plane, and balanced in transverse momentum. To incorporate these characteristics in the analysis, additional kinematic criteria select events based on the ratio of the lepton p T to p miss T , requiring 0.4 < p T /p miss T < 1.5, and on the angular difference between the lepton and p miss T , with \u2206\u03c6( , p miss T ) > 2.5 \u2248 0.8\u03c0. The distributions of the lepton p T and p miss T are depicted in Fig. 2 separately for the electron (upper panels) and muon (lower panels) channels.", "cite_spans": [], "ref_spans": [{"start": 502, "end": 508, "text": "Fig. 2", "ref_id": "FIGREF2"}]}, {"section": "Event selection", "text": "For simulated events passing all the selection criteria, the signal efficiency for an SSM W with no requirement on the reconstructed M T in the event, is maximal at a value of 0.75 (for both decay channels) for a W boson mass range 1.5-2.5 TeV, and decreases gradually to \u22480.60 for larger and smaller masses. For larger masses, the increasing off-shell production displaces events to lower M T , where the background is larger.", "cite_spans": [], "ref_spans": []}, {"section": "Event selection", "text": "The resulting M T distributions for the analyzed data sets are shown in Fig. 3 for the electron and muon channels. The minimum value of M T is determined by the trigger thresholds, resulting in a choice of \u223c250 and \u223c100 GeV in the electron and muon channels, respectively. Included in Fig. 3 are the predicted M T distributions for the accepted SM events, separated into contributions from each background process, along with example signal distributions for the SSM W , split-UED, and SUSY models. For the muon channel, a variable binning commensurate with the energy-dependent M T -resolution is used. The expected systematic uncertainties in the pre- (right), for the electron (upper row) and muon (lower row) for data and for expected SM backgrounds, after applying complete selection criteria. The QCD multijet background in the electron channel is derived from data. The background labelled as \"diboson\" includes WW, ZZ, and WZ contributions. Also shown are SSM W signal examples for the two indicated masses. The last bin shows the total overflow. The lower panel shows the ratio of data to prediction and the shaded band includes the systematic uncertainties. dicted M T distributions are also shown. The numbers of signal and background events for a selected set of M T thresholds are shown in Table 1 .", "cite_spans": [], "ref_spans": [{"start": 72, "end": 78, "text": "Fig. 3", "ref_id": "FIGREF3"}, {"start": 285, "end": 291, "text": "Fig. 3", "ref_id": "FIGREF3"}, {"start": 1303, "end": 1310, "text": "Table 1", "ref_id": "TABREF2"}]}, {"section": "Event selection", "text": "No significant excess over the SM expectation is observed in the M T spectrum. The highest transverse mass events observed have M T \u223c 2.6 and M T \u223c 2.9 TeV in the electron and muon channels, respectively.", "cite_spans": [], "ref_spans": []}, {"section": "35.9fb", "text": "\u22121 (13 TeV)", "cite_spans": [], "ref_spans": []}, {"section": "35.9fb", "text": "CMS e + p miss ", "cite_spans": [], "ref_spans": []}, {"section": "Background", "text": "Searching for deviations from the steeply falling M T spectrum requires an accurate background estimate at very high transverse masses. For the majority of background sources, the estimate is determined from simulation, based on samples with large event counts at high M T . The primary source of background for all signals is the presence of off-peak, high transverse mass tails of the SM W \u2192 \u03bd decays. Other backgrounds arise from multijet events from QCD processes, tt and single top quark production, and from Drell-Yan events. Contributions from dibosons (WW, WZ, ZZ) decaying to e or \u00b5 are also considered.", "cite_spans": [], "ref_spans": []}, {"section": "Background", "text": "The dominant and irreducible background is W\u2192 \u03bd with = e, \u00b5, and \u03c4. The W \u2192 \u03c4\u03bd process mostly contributes to the region of lower M T values in comparison to decays into the other lepton channels, because of the large fraction of the momentum carried away by the two neutrinos from the tau lepton decay. Top quark pair and single top quark production are other sources of high-p T leptons and p miss T , and these are generated with POWHEG 2.0 [44-47] in combination with PYTHIA 8.212, except for the s-channel of single top quark production, which is generated with MADGRAPH5 aMC@NLO in combination with PYTHIA 8.212. The tt category includes both semileptonic and dileptonic decay modes samples. A NNLO cross section calculation from Ref. [48] is used to rescale the NLO predictions. These events are largely rejected by requiring compatibility with a two body decay, but the remaining events can extend into the region of high M T , as seen in Fig. 3 .", "cite_spans": [{"start": 740, "end": 744, "text": "[48]", "ref_id": "BIBREF19"}], "ref_spans": [{"start": 946, "end": 952, "text": "Fig. 3", "ref_id": "FIGREF3"}]}, {"section": "Background", "text": "Drell-Yan production of dileptons ( = e, \u00b5) constitutes a background when one lepton escapes detection. High mass Drell-Yan samples are generated with POWHEG at NLO, with parton showering and hadronization described by PYTHIA, using the CUETP8M1 tune and NNPDF3.0 PDF set.", "cite_spans": [], "ref_spans": []}, {"section": "Background", "text": "Contributions from dibosons are derived from inclusive samples (WZ, ZZ, including all possible final states), generated with PYTHIA 8.2.1.2 with the tune CUETP8M1 and the NNPDF2.3 LO PDF set, and exclusive samples (WW \u2192 \u03bdqq, WW \u2192 4q, WW \u2192 \u03bd\u03bd, with = e, \u00b5, \u03c4), generated with POWHEG. The inclusive (exclusive) normalizations are scaled to NLO (NNLO) cross sections [49] [50] [51] .", "cite_spans": [{"start": 364, "end": 368, "text": "[49]", "ref_id": "BIBREF20"}, {"start": 369, "end": 373, "text": "[50]", "ref_id": "BIBREF21"}, {"start": 374, "end": 378, "text": "[51]", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "Background", "text": "In the electron channel, a \u03b3+jet event sample, generated with MADGRAPH 5 MLM [52] at LO, is used to estimate the effects of photons misidentified as electrons.", "cite_spans": [{"start": 77, "end": 81, "text": "[52]", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Background", "text": "The misidentification of jets as leptons is a possible source of background for this search. While the contribution of QCD multijet events to the muon channel is negligible, a small contribution to the electron channel remains after event selection. For the latter, the shape and normalization of the QCD multijet background is derived from data and included in the final background estimate shown in Fig. 3. A QCD multijet template is obtained from the events in which the electron candidate fails the isolation requirement but where all other event requirements are met. QCD multijet template events are scaled with normalization factors from an independent control region, defined by the requirement p T /p miss T > 1.5, where multijet production is dominating. In this region, the ratio of 'tight' events (electron candidates that passes all requirements of a well-isolated electron) to 'loose' events (all events in the region) is measured as a function of electron p T . The resulting normalization factor for QCD multijet template events is applied to non-QCD subtracted data. This procedure results in ratios from about 10% for p T =200 GeV down to 1% for p T > 600 GeV, and represents the percentage of jets that are misreconstructed as electrons. An uncertainty of 40% in this estimate is obtained by comparing data to predictions from simulation, and is assigned to this small background contribution.", "cite_spans": [], "ref_spans": [{"start": 401, "end": 408, "text": "Fig. 3.", "ref_id": "FIGREF3"}]}, {"section": "Systematic uncertainties", "text": "The mismeasurement of lepton energy or momentum, arising from both detector resolution and imperfect scale calibration, will result in a smearing of the M T spectrum. For each source of uncertainty, shifts of \u00b11\u03c3 are applied to the simulated data. The kinematic distributions of the objects (e, \u00b5, p miss T ) and M T are recalculated, and the kinematic selection is reapplied. The systematic uncertainty in the electron energy scale is estimated to be 0.4 (0.8)% in the barrel (endcaps). For the electron energy resolution uncertainty, an additional Gaussian smearing of 1.2 (2.4)% for the barrel (endcap) region is applied to the simulation [53] to reflect the observed behaviour of the calorimeter.", "cite_spans": [{"start": 642, "end": 646, "text": "[53]", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Systematic uncertainties", "text": "The muon transverse momentum scale uncertainty is estimated by studying the curvature of muon tracks in different regions of \u03b7 and \u03c6, using high-p T muons from cosmic ray data [38] and dimuon events from high-p T Z boson decays from collision data, together with corresponding simulation samples. These studies indicate the absence of a significant curvature bias in the central \u03b7 region (|\u03b7| < 1.2), within an uncertainty of 0.025/ TeV. In more forward regions, especially for |\u03b7| > 2.1, and in particular muon \u03c6 zones, values of the scale bias different from zero are found. The mean value of the modification in the simulated p T coming from these scale biases is used as an estimate of the uncertainty, for p T > 200 GeV. This uncertainty is propagated to p miss T and M T .", "cite_spans": [], "ref_spans": []}, {"section": "Systematic uncertainties", "text": "The uncertainty in the muon momentum measurement derives from the smallness of curvature of tracks for high-p T muons, while the energy of the electrons, measured in the crystal calorimeter, has a smaller uncertainty. The muon p T resolution in data at high-p T values is well reproduced by the simulation within an uncertainty of \u00b11(2)% in the barrel (endcap) region and no additional smearing is implemented.", "cite_spans": [], "ref_spans": []}, {"section": "Systematic uncertainties", "text": "The overall uncertainty in the determination of p miss T in each event is derived from the individual uncertainties assigned to the objects (jets, e, \u00b5, \u03c4, \u03b3, and unclustered energy) obtained from the PF algorithm. The contribution of each object type is varied according to its uncertainty. In addition, an uncertainty of 10% in the p T is used for the unclustered energy. This uncertainty is propagated to the PF p miss T [35] . The quadratic sum of the individual uncertainties gives the overall uncertainty in the PF p miss T . In addition to the cross section uncertainties, two further contributions play a role in the background prediction uncertainties. For the dominant W boson production, the uncertainties associated with the method chosen to calculate the K-factor are considered, amounting to \u00b15%. The effect of even higher order corrections is expected to be small and therefore is not considered. For the QCD multijet background prediction, an uncertainty of 40% is used as described in Section 6.", "cite_spans": [], "ref_spans": []}, {"section": "Systematic uncertainties", "text": "The theoretical uncertainty related to the choice of PDF set was estimated using the PDF4LHC recommended procedure [54] . After reweighting the background samples with different PDF sets, the envelopes of their error bands are taken as the uncertainty. The values increase with M T , ranging from an uncertainty of 1% at M T =300 GeV to 20% at M T \u2248 3 TeV.", "cite_spans": [{"start": 115, "end": 119, "text": "[54]", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "Systematic uncertainties", "text": "The efficiency scale factors defined in Section 4 are assigned uncertainties that take into account the determination method and the extrapolation to high M T .", "cite_spans": [], "ref_spans": []}, {"section": "Systematic uncertainties", "text": "The simulated distribution of pp collision vertices per bunch crossing is reweighted to the distribution measured in data. The uncertainty due to this reweighting method is treated as the systematic uncertainty of the pileup simulation. The effect on the background event yield from this uncertainty is smaller than 5%.", "cite_spans": [], "ref_spans": []}, {"section": "Systematic uncertainties", "text": "The estimated uncertainty in the integrated luminosity measurement is 2.5% [55] .", "cite_spans": [{"start": 75, "end": 79, "text": "[55]", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "Interpretation of the results", "text": "No significant deviation from the SM expectation is observed in either channel and exclusion limits on the production cross sections of the theoretical models from Section 3 are calculated. All limits presented here are at 95% CL.", "cite_spans": [], "ref_spans": []}, {"section": "Interpretation of the results", "text": "The signal search is performed using the binned M T distribution, obtained after the complete event selection, taking into account the shape and normalization of the signal and backgrounds. As shown in Fig. 3 , signal events are expected to be particularly prominent at the upper end of their M T distribution, where the expected SM background is low. The final M T distributions are presented in Fig. 3 for electron and muon channels, and together with the detailed systematic uncertainties described in Section 7.", "cite_spans": [], "ref_spans": [{"start": 202, "end": 208, "text": "Fig. 3", "ref_id": "FIGREF3"}, {"start": 397, "end": 403, "text": "Fig. 3", "ref_id": "FIGREF3"}]}, {"section": "Statistical analysis", "text": "Upper limits on the product of the production cross section and branching fraction \u03c3 W B(W \u2192 \u03bd), with = e or \u00b5, are determined using a Bayesian method [56] with an uniform positive prior probability distribution for the signal cross section. Systematic uncertainties in the expected signal and background yields are included either via nuisance parameters with log normal prior distributions or with the shape of the distribution included through the use of a binned likelihood (multi-bin counting). For the SSM W and split-UED models, the limits are obtained from the entire M T spectrum for M T > 220 GeV, as displayed in Fig. 3 , using the multi-bin counting method. This procedure is performed for different values of parameters of each signal, to obtain limits in terms on these parameters, such as the W boson mass.", "cite_spans": [{"start": 151, "end": 155, "text": "[56]", "ref_id": "BIBREF27"}], "ref_spans": [{"start": 624, "end": 630, "text": "Fig. 3", "ref_id": "FIGREF3"}]}, {"section": "Statistical analysis", "text": "To determine a model-independent upper limit on the product of the cross section and branching fraction, all events above a threshold M min T are summed. From the number of background events, signal events, and observed data events, the cross section limit can be calculated. When the background is low, this method has good sensitivity, comparable to that of the multi-bin approach. The resulting limit can be reinterpreted for other models with a lepton and p miss T in the final state. One example application is given in this paper, where limits on specific RPV SUSY processes are derived.", "cite_spans": [], "ref_spans": []}, {"section": "Model-independent cross section limit", "text": "A model-independent cross section limit is determined using a single bin ranging from a lower threshold on M T to infinity. No assumptions on the shape of the signal M T distribution have to be made other than that of a flat product A of acceptance and efficiency as a function of W mass. In order to determine any limit for a specific model from the model-independent limit shown here, only the model-dependent part of the efficiency needs to be applied. The experimental efficiencies for the signal are already taken into account, including the effect of the kinematic selection (the cuts on p T /p miss T and \u2206\u03c6), the geometrical acceptance (cut on \u03b7), and the trigger threshold.", "cite_spans": [], "ref_spans": []}, {"section": "Model-independent cross section limit", "text": "A factor f M T that reflects the effect of the threshold M min T on the signal is determined by counting the events with M T >M min T and dividing it by the number of generated events. For M T > 400 GeV the reconstruction efficiency is nearly constant, therefore f M T can be evaluated at generator level. For lower M T , a very slight (<1%) difference is expected due to the single-lepton trigger threshold (in particular the 130 GeV threshold for electrons). A limit on the product of the cross section and branching fraction (\u03c3 B A ) excl can be obtained by dividing the excluded cross section of the model-independent limit (\u03c3 B A ) MI given in Fig. 4 by the calculated frac-", "cite_spans": [], "ref_spans": [{"start": 649, "end": 655, "text": "Fig. 4", "ref_id": "FIGREF5"}]}, {"section": "Model-independent cross section limit", "text": ".", "cite_spans": [], "ref_spans": []}, {"section": "Model-independent cross section limit", "text": "Models with a theoretical cross section (\u03c3B) theo larger than (\u03c3B) excl can be excluded. The procedure described here can be applied to models that exhibit back-to-back kinematics similar to those of a generic W , which is a reasonable assumption for a two-body decay of a massive state. If the kinematic properties are different, the fraction of events f M T (M min T ) needs to be determined for the model considered. The results for the electron and muon channels are shown separately in Fig. 4 ", "cite_spans": [], "ref_spans": [{"start": 491, "end": 497, "text": "Fig. 4", "ref_id": "FIGREF5"}]}, {"section": "Limits on an SSM W boson", "text": "The search for an SSM W boson yields limits on the product of the cross section and branching fraction for the electron and muon channels. The multi-bin method is used to determine the 95% CL upper cross section limits, shown in Fig. 5 . The indicated theoretical cross sections are the NNLO values for the lepton+p miss T channel, as detailed in Section 3, and are the same for both channels. The PDF uncertainties are shown as a thin band around the NNLO cross section.", "cite_spans": [], "ref_spans": [{"start": 229, "end": 235, "text": "Fig. 5", "ref_id": "FIGREF6"}]}, {"section": "Limits on an SSM W boson", "text": "The central value of the product of the theoretical cross section and branching fraction is used for deriving the mass limit. Values of the W mass below 4.9 TeV (expected limit is 5.0 TeV) and 4.9 TeV (expected limit is 4.9 TeV) are excluded in the electron and muon channel, respectively. Also shown in Fig. 5 are theoretical cross sections for a number of interpretations. For the benchmark SSM model, the displayed NNLO theoretical cross section includes the branching fraction to an electron or muon, as appropriate.", "cite_spans": [], "ref_spans": [{"start": 304, "end": 310, "text": "Fig. 5", "ref_id": "FIGREF6"}]}, {"section": "Limits on an SSM W boson", "text": "When combining both channels, the exclusion limit increases to 5.2 TeV (expected limit is 5.2 TeV), as depicted in Fig. 6 . This is a significant improvement over the previous 13 TeV result [9] of 3.6 TeV and 3.9 TeV in the electron and muon channels, respectively. For high W masses (around 5 TeV and higher), the mass limit becomes less stringent because of the increasing fraction of off-shell production. For high masses, the search sensitivity is limited by the amount of data available at present and will improve in future. The one and two standard deviation bands in the figures represent the systematic uncertainties as described in Section 7. In addition, the LO cross section for the SSM model is shown. For the split-UED model, NNLO cross sections are displayed for two extreme values of the bulk mass parameter \u00b5 corresponding to a \u00b5 = 0.05 TeV (boson mass limit of 2.4 TeV) and a \u00b5 = 10 TeV (boson mass limit of 5.6 TeV).", "cite_spans": [], "ref_spans": [{"start": 115, "end": 121, "text": "Fig. 6", "ref_id": "FIGREF7"}]}, {"section": "Limits on the coupling strength", "text": "The limit on the cross section depends on both the mass range of a potential excess and the width. Because of the relation between the coupling of a particle and its width, a limit can also be set on the coupling strength.", "cite_spans": [], "ref_spans": []}, {"section": "Limits on the coupling strength", "text": "In order to compute the limit for couplings other than g W /g W = 1, reweighted samples are used that take into account the appropriate signal width and the differences in reconstructed M T shapes. For g W /g W = 1 the theoretical LO cross sections apply.", "cite_spans": [], "ref_spans": []}, {"section": "Limits on the coupling strength", "text": "Based on the M T distribution of data after all selections, shown in Fig. 3 , a cross section limit as a function of the coupling is determined for each mass point. The procedure is repeated for the full range of W masses and the corresponding intersection points provide the input for ", "cite_spans": [], "ref_spans": [{"start": 69, "end": 75, "text": "Fig. 3", "ref_id": "FIGREF3"}]}, {"section": "Interpretation in the split-UED model", "text": "The UED model is parameterized by the quantities R and \u00b5, which are the radius of the extra dimension and the bulk mass parameter of the fermion field in five dimensions. The lower limits on the mass for n = 2 can be directly translated from the SSM W limit into bounds on the split-UED parameter space (1/R, \u00b5), as the signal shape and signal efficiency are identical to the SSM W signal. The split-UED limits are displayed in ", "cite_spans": [], "ref_spans": []}, {"section": "Limits on RPV SUSY", "text": "An alternative interpretation assumes a \u03c4 slepton as a mediator, with distinct RPV SUSY couplings at the production and decay vertices, as detailed in Section 3.4. This result is obtained using the model-independent limit, and illustrates its power. The couplings are defined in Fig. 1 . While \u03bb 3ij is common to both decay channels, the coupling at the decay is either \u03bb 231 (for e + \u03bd \u00b5 ) or \u03bb 132 (for \u00b5 + \u03bd e ). This signal has a slightly different shape compared to the SSM W , a sharper Jacobian peak and essentially no off-shell part at high mediator masses affecting the signal efficiency. In particular at low masses, the tau slepton signal efficiency is higher. Applying the procedure from Section 8.2, the fraction of events f M T is determined for the \u03c4 slepton model at generator level and a correction with respect to the SSM W is applied. ", "cite_spans": [], "ref_spans": [{"start": 279, "end": 285, "text": "Fig. 1", "ref_id": "FIGREF0"}]}, {"section": "Summary", "text": "A search for high-mass resonances in the lepton plus the missing transverse momentum final state in proton-proton collisions at \u221a s = 13 TeV has been performed, using a data sample corresponding to an integrated luminosity of 35.9 fb \u22121 . No evidence for new physics is observed when examining the transverse mass distributions in the electron and muon channels. These observations are interpreted as 95% confidence limits on the parameters of several models.", "cite_spans": [], "ref_spans": []}, {"section": "Summary", "text": "The exclusion limits on a sequential standard model-like W are calculated to be 4.9 (4.9) TeV in the individual electron (muon) channels. A combination of both channels increases the limit to 5.2 TeV, assuming standard model couplings. Additionally, variations in the coupling strength are studied and couplings above 2 \u00d7 10 \u22122 are excluded for low W masses. These results are also applied to the split universal extra dimension model, and the inverse radius of the extra dimension 1/R is constrained by this analysis to be above 2.9 TeV. These results are presented in a model-independent form, making possible their interpretation in a number of other models. An example of this application is given using a supersymmetric model with R-parity violation, and a tau slepton mediator with flavor-violating decays into either e + \u03bd \u00b5 or \u00b5 + \u03bd e . Limits on the coupling strengths at the decay vertex have been derived as a function of the mediator mass, for various values of the coupling at the production vertex \u03bb 3ij .", "cite_spans": [], "ref_spans": []}, {"section": "Acknowledgments", "text": "We congratulate our colleagues in the CERN accelerator departments for the excellent performance of the LHC and thank the technical and administrative staffs at CERN and at other CMS institutes for their contributions to the success of the CMS effort. In addition, we gratefully acknowledge the computing centers and personnel of the Worldwide LHC Computing Grid for delivering so effectively the computing infrastructure essential to our analyses. Finally, we acknowledge the enduring support for the construction and operation of the LHC and the CMS detector provided by the following funding agencies: BMWFW and FWF (Aus [34] CMS Collaboration, \"Performance of missing energy reconstruction in 13 TeV pp collision data using the CMS detector\", (2016). CMS Physics Analysis Summary CMS-JME-16-004.", "cite_spans": [], "ref_spans": []}, {"section": "Acknowledgments", "text": "[35] CMS Collaboration, \"Missing transverse energy performance of the CMS detector\", JINST 6 (2011) P09001, doi:10.1088/1748-0221/6/09/P09001, arXiv:1106.5048. 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The coupling strength, g, may vary. In RPV SUSY, a tau slepton ( \u03c4) could also act as a mediator (right) with corresponding \u03bb couplings for the decay that are different for the two final states, denoted by \u03bb 231 and \u03bb 132 for the electron and muon final states, respectively.", "type": "figure"}, "FIGREF1": {"text": ", a larger radius (R) corre- sponds to smaller KK masses. The mass of KK fermions depends on the bulk mass parameter \u00b5. The product of the cross section of the W (n) KK production and the branching fraction to standard model fermions goes to zero as \u00b5 goes to zero. For the mode n = 2, the decay of W (2) KK to leptons is kinematically identical to the SSM W boson decay, and the observed limits obtained from the W \u2192 e\u03bd and W \u2192 \u00b5\u03bd searches can be reinterpreted directly in terms of the W (2) KK boson mass, taking into account the difference in widths in the simulation. The Feynman diagram in Fig. 1 (left) shows this process. The simulation is performed at leading order with PYTHIA 8.212. The mass-dependent K-factors from the SSM W interpretation are used. This is possible since the signal shapes of a W (2) KK and a SSM W correspond to each other. The signal samples are generated with the parameters 1/R = 200 to 3000 GeV and \u00b5 = 50 to 10 000 GeV. The 1/R range corresponds to the mass of W (2)", "type": "figure"}, "FIGREF2": {"text": "Figure 2: Distributions in p T (left) and p miss T", "type": "figure"}, "FIGREF3": {"text": "Figure 3: Observed M T distributions for the electron (left) and muon (right) channels after all selections. Signal examples for W masses of 1.8 and 3.8 TeV, including detector simulation, are shown in both channels. In addition, signal examples for RPV SUSY and split-UED are depicted. The lower panel shows the ratio of data to prediction and the hatched band includes the systematic uncertainties. The last bin shows the total overflow.", "type": "figure"}, "FIGREF4": {"text": ". The results depend strongly on the threshold M min T . In both channels, cross section values \u03c3 B A between 40-50 fb (for M", "type": "figure"}, "FIGREF5": {"text": "Figure 4: Cross section upper limits at 95% CL on the effective cross section \u03c3(W ) B(W \u2192 \u03bd) A above a threshold M min T for the individual electron (left) and muon (right) channels. Shown are the observed limit (solid line), expected limit (dashed line), and the expected limit \u00b11 and \u00b12 standard deviation (s.d.) intervals.", "type": "figure"}, "FIGREF6": {"text": "Figure 5: Expected (dashed line) and observed (solid line) 95% CL limits in the SSM interpretation for the electron (left) and muon (right) channels. The shaded bands represent the one and two standard deviation (s.d.) uncertainty bands. Also shown are theoretical cross sections for the SSM benchmark model (black with a grey band for the PDF uncertainties) and split-UED (red and blue solid lines) interpretations.", "type": "figure"}, "FIGREF7": {"text": "Figure 6: Expected (dashed line) and observed (solid line) 95% CL limits on the product of the cross section and branching fraction, in the SSM W model (left) and the model-independent interpretation (right). Shown are the combination of the electron and muon channels, with the shaded bands corresponding to one and two standard deviations (s.d.). For comparison, the results from Ref. [9] for the regions investigated in 2015 are shown as dotted lines. the exclusion limit on the coupling strength g W /g W as a function of the W mass, as shown in Fig. 7. Everything above the experimental limit is excluded. For low masses, weak couplings down to nearly 10 \u22122 are excluded.", "type": "figure"}, "FIGREF9": {"text": "Figure 7: Expected (dashed line) and observed (solid line) 95% CL limits on the coupling strength g W /g W as a function of the W mass, for the electron (left) and muon (right) channels. The area above the limit line is excluded. The shaded bands represent the one and two standard deviation (s.d.) uncertainty bands. The SSM W couplings are shown as a dotted line.", "type": "figure"}, "FIGREF10": {"text": "Figure 8: Exclusion limit in the plane (\u00b5, 1/R) for the split-UED interpretation for the n = 2 case in the electron (left) and muon (middle) channels, respectively. On the right, the result for the combination of both channels is shown. The expected limit is depicted as a dashed line and the experimentally excluded region as a solid black line (filled as a yellow area). For comparison, the 8 TeV result from Ref. [8] is given as a red, dotted line.", "type": "figure"}, "FIGREF11": {"text": "For a \u03c4 slepton mass of 3.6 TeV, as a function of M min T , representative values are: f M T is 0GeV). Exclusion limits on \u03bb 231 and \u03bb 123 as a function of the mediator mass for a number of coupling values \u03bb 3ij are shown in Fig. 9.", "type": "figure"}, "FIGREF13": {"text": "Figure 9: Observed (solid line) and expected (dashed line) exclusion limits for different couplings in the model with a \u03c4 slepton as a mediator. The couplings \u03bb 3ij , \u03bb 231 , and \u03bb 132 are defined in Fig. 1. Results are shown for the final states consisting of e + \u03bd \u00b5 on the left and \u00b5 + \u03bd e on the right.", "type": "figure"}, "FIGREF14": {"text": "- tria); FNRS and FWO (Belgium); CNPq, CAPES, FAPERJ, and FAPESP (Brazil); MES (Bulgaria); CERN; CAS, MoST, and NSFC (China); COLCIENCIAS (Colombia); MSES and CSF (Croatia); RPF (Cyprus); SENESCYT (Ecuador); MoER, ERC IUT, and ERDF (Estonia); Academy of Fin- land, MEC, and HIP (Finland); CEA and CNRS/IN2P3 (France); BMBF, DFG, and HGF (Ger- many); GSRT (Greece); NKFIA (Hungary); DAE and DST (India); IPM (Iran); SFI (Ireland); INFN (Italy); MSIP and NRF (Republic of Korea); LAS (Lithuania); MOE and UM (Malaysia); BUAP, CINVESTAV, CONACYT, LNS, SEP, and UASLP-FAI (Mexico); MBIE (New Zealand); PAEC (Pakistan); MSHE and NSC (Poland); FCT (Portugal); JINR (Dubna); MON, RosAtom, RAS, RFBR and RAEP (Russia); MESTD (Serbia); SEIDI, CPAN, PCTI and FEDER (Spain); Swiss Funding Agencies (Switzerland); MST (Taipei); ThEPCenter, IPST, STAR, and NSTDA (Thai- land); TUBITAK and TAEK (Turkey); NASU and SFFR (Ukraine); STFC (United Kingdom); DOE and NSF (USA). Individuals have received support from the Marie-Curie program and the European Research Council and Horizon 2020 Grant, contract No. 675440 (European Union); the Leventis Foun- dation; the A. P. Sloan Foundation; the Alexander von Humboldt Foundation; the Belgian Fed- eral Science Policy Office; the Fonds pour la Formation\u00e0 la Recherche dans l'Industrie et dans l'Agriculture (FRIA-Belgium); the Agentschap voor Innovatie door Wetenschap en Technologie (IWT-Belgium); the F.R.S.-FNRS and FWO (Belgium) under the \"Excellence of Science -EOS\" - be.h project n. 30820817; the Ministry of Education, Youth and Sports (MEYS) of the Czech Re- public; the Lend\u00fclet (\"Momentum\") Program and the J\u00e1nos Bolyai Research Scholarship of the Hungarian Academy of Sciences, the New National Excellence Program\u00daNKP, the NKFIA re- search grants 123842, 123959, 124845, 124850 and 125105 (Hungary); the Council of Science and Industrial Research, India; the HOMING PLUS program of the Foundation for Polish Science, cofinanced from European Union, Regional Development Fund, the Mobility Plus program of the Ministry of Science and Higher Education, the National Science Center (Poland), contracts Harmonia 2014/14/M/ST2/00428, Opus 2014/13/B/ST2/02543, 2014/15/B/ST2/03998, and 2015/19/B/ST2/02861, Sonata-bis 2012/07/E/ST2/01406; the National Priorities Research Program by Qatar National Research Fund; the Programa Estatal de Fomento de la Investi- gaci\u00f3n Cient\u00edfica y T\u00e9cnica de Excelencia Mar\u00eda de Maeztu, grant MDM-2015-0509 and the Pro- grama Severo Ochoa del Principado de Asturias; the Thalis and Aristeia programs cofinanced by EU-ESF and the Greek NSRF; the Rachadapisek Sompot Fund for Postdoctoral Fellowship, Chulalongkorn University and the Chulalongkorn Academic into Its 2nd Century Project Ad- vancement Project (Thailand); the Welch Foundation, contract C-1845; and the Weston Havens Foundation (USA).", "type": "figure"}, "FIGREF15": {"text": "N. 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Also shown are the total systematic uncertainties in the estimate of the event numbers. The signal yields are based on NNLO cross sections.", "type": "table"}, "TABREF3": {"text": "NLO electroweak precision. The resulting K-factors depend on M T , being around 1.1 for M T =400 GeV and decreasing to around 0.8 for M T =3 TeV.", "type": "table"}}}
{"paper_id": "119426140", "_pdf_hash": "bde28b0177a56bf7b3ee80d04e65801dc0a5f0c2", "abstract": [{"section": "Abstract", "text": "We have measured the c-axis angular-dependent magnetoresistance \u0351AMR\u0352 of a Na 0.48 CoO 2 single crystal, with a magnetic field of 10 T rotating within Co-O planes. Below the metal-insulator transition temperature at 40 K, the AMR is dominated by a twofold oscillation due to the charge ordering. The fourfold and sixfold oscillations in AMR become pronounced below 25 K. The presence of this fourfold oscillation is consistent with the picture proposed by Choy et al. \u0351cond-mat/0502164\u0352 that the Co lattice will split into two orthogonal sublattices with one occupied by Co 3+ ions and the other by Co 4+ ions in low temperatures. Embedded in these orthogonal sublattices, a hexagonal lattice, formed by Co 4+ spins, leads to the sixfold oscillation in AMR. DOI: 10.1103/PhysRevB.73.212414 PACS number\u0351s\u0352: 71.20.Be, 72.20.Ht, 75.30.Fv Recently great attention has been attracted to the investigation of physical properties of Na 0.35 CoO 2 \u00b7 1.3H 2 O, 1 which is one of the few known layered transition metal oxides exhibiting superconductivity other than high-T c cuprates. The nonhydrated host oxide Na x CoO 2 is known for its large thermoelectric power.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "2,3 It is a quasi-two-dimensional material and Co atoms form a triangular lattice. The Co-O planes are composed of the edge sharing O octahedra with a Co atom lying at the center of each O-octahedron. Na atoms or H 2 O molecules lie between two neighboring Co-O planes.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "The phase diagram of Na x CoO 2 is very rich. This cobalt oxide is a paramagnetic metal around x \u03f3 0.35 and a CurieWeiss metal \u0351a metal with a Curie-Weiss-like magnetic susceptibility\u0352 around x \u03f3 0.66. 6 However, at about x = 0.5, it becomes a charge-ordered insulator in low temperatures. In particular, Na 0.5 CoO 2 exhibits three successive phase transitions at 88, 50, and 25 K, respectively.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "5-10 The phase transition at 88 K is likely to be induced by magnetic ordering. The recent SR and neutron scattering experiments showed that there is a static magnetic order below 88 K.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "7-9 The transition at 50 K results from the formation of charge stripes of Co 3+ and Co 4+ ions. A weak magnetic transition was observed at 25 K in the resistivity as well as low field \u0351a few G\u0352 magnetic susceptibility measurements.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Recently, the c-axis magnetoresistance of Na 0.5 CoO 2 was measured.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "11,12 It was found that a magnetic field applied along the c axis has almost no effect on the metal-insulator transition temperature up to 43 T. On the contrary, if a magnetic field is applied parallel to the Co-O planes, the charge ordering is suppressed and the metal-insulator transition disappears above 40 T. It was further found that the system changes from the twofold to the sixfold rotational symmetry when the in-plane field increases from 25 to 45 T at 0.6 K.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "In this paper, we report the measurement data of the c-axis AMR of a Na 0.48 CoO 2 single crystal, with a rotating magnetic field of 10 T applied parallel to Co-O planes, from 5 to 50 K. The AMR measurement is a useful technique for analyzing electronic structures, especially the Fermi-surface topology of a layered material. [13] [14] [15] The Na 0.48 CoO 2 sample is prepared by sodium deintercalation from a Na 0.85 CoO 2 single phased single crystal, synthesized by the floating-zone technique. 16, 17 The crystal of Na 0.85 CoO 2 was immersed in a Br 2 and CH 3 CN solution for more than two weeks for sodium deintercalation. The sodium concentration determined by ICP is 0.48\u00b1 0.02. From the x-ray measurements, we found that Na 0.48 CoO 2 is in a single phase and the c axis lattice constant c is 11.144 \u00c5. The magnetoresistance was measured using the standard four-probe low frequency ac method in a PPMS system of Quantum Design. The measurement resolution of resistance is 10 \u22125 \u2340. Figure 1\u0351a\u0352 shows the temperature dependence of the c-axis resistance R c \u0351T\u0352 of Na 0.48 CoO 2 . In the whole temperature range R c \u0351T\u0352 behaves similarly as for Na 0.5 CoO 2 .", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "5,6 Initially, R c increases gradually with decreasing temperature. It then shows a dramatic increase below 40 K, as a result of metal-insulator phase transition. Here the metal-insulator transition temperature is lower than the corresponding transition temperature for Na 0.5 CoO 2 . This difference is due to the difference of the Na concentration. Figure 1\u0351b\u0352 compares the temperature dependence of R c at zero field with that in an external magnetic field of 10 T applied along the Co-O planes. The corresponding c-axis Fig. 1\u0351c\u0352 . The applied field has almost no effect on the metal-insulator transition temperature, but suppresses the resistivity in the charge ordered phase. R c exhibits a weak hump structure around 25 K. A similar R c hump exists in Na 0.5 CoO 2 between 25 and 40 K. \u2426R c increases with increasing T in low temperatures. It shows a noticeable deep just below 40 K. This deep is caused by the metal-insulator transition. Figure 2 shows the c-axis AMR of Na 0.48 CoO 2 at different temperatures. At low temperatures, the AMR shows a clear periodical oscillation with fine structures as a function of rotating angle . However, in high temperatures, the oscillation becomes weaker and some of the fine structures disappear.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "Recently great attention has been attracted to the investigation of physical properties of Na 0.35 CoO 2 \u00b7 1.3H 2 O, 1 which is one of the few known layered transition metal oxides exhibiting superconductivity other than high-T c cuprates. The nonhydrated host oxide Na x CoO 2 is known for its large thermoelectric power. 2, 3 It is a quasi-two-dimensional material and Co atoms form a triangular lattice. The Co-O planes are composed of the edge sharing O octahedra with a Co atom lying at the center of each O-octahedron. Na atoms or H 2 O molecules lie between two neighboring Co-O planes. 4, 5 The phase diagram of Na x CoO 2 is very rich. This cobalt oxide is a paramagnetic metal around x \u03f3 0.35 and a CurieWeiss metal \u0351a metal with a Curie-Weiss-like magnetic susceptibility\u0352 around x \u03f3 0.66. 6 However, at about x = 0.5, it becomes a charge-ordered insulator in low temperatures. In particular, Na 0.5 CoO 2 exhibits three successive phase transitions at 88, 50, and 25 K, respectively. [5] [6] [7] [8] [9] [10] The phase transition at 88 K is likely to be induced by magnetic ordering. The recent SR and neutron scattering experiments showed that there is a static magnetic order below 88 K. [7] [8] [9] The transition at 50 K results from the formation of charge stripes of Co 3+ and Co 4+ ions. A weak magnetic transition was observed at 25 K in the resistivity as well as low field \u0351a few G\u0352 magnetic susceptibility measurements. 10 Recently, the c-axis magnetoresistance of Na 0.5 CoO 2 was measured. 11, 12 It was found that a magnetic field applied along the c axis has almost no effect on the metal-insulator transition temperature up to 43 T. On the contrary, if a magnetic field is applied parallel to the Co-O planes, the charge ordering is suppressed and the metal-insulator transition disappears above 40 T. It was further found that the system changes from the twofold to the sixfold rotational symmetry when the in-plane field increases from 25 to 45 T at 0.6 K.", "cite_spans": [], "ref_spans": []}, {"section": "11", "text": "In this paper, we report the measurement data of the c-axis AMR of a Na 0.48 CoO 2 single crystal, with a rotating magnetic field of 10 T applied parallel to Co-O planes, from 5 to 50 K. The AMR measurement is a useful technique for analyzing electronic structures, especially the Fermi-surface topology of a layered material. [13] [14] [15] The Na 0.48 CoO 2 sample is prepared by sodium deintercalation from a Na 0.85 CoO 2 single phased single crystal, synthesized by the floating-zone technique. 16, 17 The crystal of Na 0.85 CoO 2 was immersed in a Br 2 and CH 3 CN solution for more than two weeks for sodium deintercalation. The sodium concentration determined by ICP is 0.48\u00b1 0.02. From the x-ray measurements, we found that Na 0.48 CoO 2 is in a single phase and the c axis lattice constant c is 11.144 \u00c5. The magnetoresistance was measured using the standard four-probe low frequency ac method in a PPMS system of Quantum Design. The measurement resolution of resistance is 10 \u22125 \u2340. Figure 1\u0351a\u0352 shows the temperature dependence of the c-axis resistance R c \u0351T\u0352 of Na 0.48 CoO 2 . In the whole temperature range R c \u0351T\u0352 behaves similarly as for Na 0.5 CoO 2 . 5, 6 Initially, R c increases gradually with decreasing temperature. It then shows a dramatic increase below 40 K, as a result of metal-insulator phase transition. Here the metal-insulator transition temperature is lower than the corresponding transition temperature for Na 0.5 CoO 2 . This difference is due to the difference of the Na concentration. Figure 1\u0351b\u0352 compares the temperature dependence of R c at zero field with that in an external magnetic field of 10 T applied along the Co-O planes. The corresponding c-axis Fig. 1\u0351c\u0352 . The applied field has almost no effect on the metal-insulator transition temperature, but suppresses the resistivity in the charge ordered phase. R c exhibits a weak hump structure around 25 K. A similar R c hump exists in Na 0.5 CoO 2 between 25 and 40 K. \u2426R c increases with increasing T in low temperatures. It shows a noticeable deep just below 40 K. This deep is caused by the metal-insulator transition. Figure 2 shows the c-axis AMR of Na 0.48 CoO 2 at different temperatures. At low temperatures, the AMR shows a clear periodical oscillation with fine structures as a function of rotating angle . However, in high temperatures, the oscillation becomes weaker and some of the fine structures disappear.", "cite_spans": [], "ref_spans": [{"start": 993, "end": 1004, "text": "Figure 1\u0351a\u0352", "ref_id": "FIGREF0"}, {"start": 1521, "end": 1532, "text": "Figure 1\u0351b\u0352", "ref_id": "FIGREF0"}, {"start": 1694, "end": 1703, "text": "Fig. 1\u0351c\u0352", "ref_id": "FIGREF0"}]}, {"section": "11", "text": "In order to reveal the hidden periodicities associated with the oscillation of the AMR, we perform a Fourier analysis on the experimental data. The Fourier transformation of R c \u0351\u0352 is defined as", "cite_spans": [], "ref_spans": []}, {"section": "11", "text": "where j =2j / N and n =0,1, ... ,N \u22121. N\u0351\u03f3450\u0352 is the total number of data points measured at each circle of rotation of the magnetic field. F n is the nth coefficient of the Fourier expansion. Its absolute value \u0349F n \u0349 measures the contribution of the conduction channel with n-fold symmetry. Figure 3 shows the Fourier power spectra \u0349F n \u0349 at different temperatures from 5 to 50 K. Here we concentrate on the components that are physically most relevant, i.e., n =2-8 and 12. We find that F 2 , F 4 , and F 6 are the three most important components. Among them, the component of twofold oscillation \u0351F 2 \u0352 is the most distinctive one. Figure 4 shows the temperature dependence of the absolute values of F 2 , F 4 , and F 6 .", "cite_spans": [], "ref_spans": []}, {"section": "11", "text": "The Fourier power spectra indicate that a two-fold oscillation contributes most to the c-axis AMR. Below the charge ordering temperature, this is clearly due to the formation of charge stripes. In Na 0.48 CoO 2 , there are both Co 3+ and Co", "cite_spans": [], "ref_spans": []}, {"section": "4+", "text": "ions. These ions will form alternating charge stripes in the insulating phase, 5, 6, 18, 19 induced probably by the orthorhombic superstructure of Na atoms. 5, 18 A similar twofold AMR oscillation was observed in lightly doped high-T c cuprates La 2\u2212x Sr x CuO 4 . 20 In that material, it is also believed that a charge stripe exists.", "cite_spans": [], "ref_spans": []}, {"section": "4+", "text": "Above the charge ordering temperature, a weak but noticeable twofold oscillation is also observed. In our measurements, the sample is adhered to a \"L-shaped\" sample holder which can rotate in a magnetic field. A sketch of the rotating apparatus is shown in Fig. 5 . Ideally, the magnetic field should run parallel to the Co-O planes during the rotating process. However, in real measurements, a small tilted angle between the applied field and the Co-O planes exists since the L-shaped sample holder may not be in a perfect right angle. In our measurement, this angle was controlled less than 3\u00b0. Other effects, such as the uneven interface between the holder and the sample, may further enlarge this angle. It is difficult to determine accurately the extra angle induced by these effects, but we believe that the total angle between the Co-O planes and the field is less than 5\u00b0. During the rotating process, this tilted angle will lead to an oscillating field along the c axis. The maximum field caused by a 5\u00b0angle is 0.87 T if a 10 T magnetic field is applied. Such an oscillating field along the c axis could cause a relative weak twofold component in AMR. With the present experimental technique, we cannot distinguish whether the weak twofold oscillation above the charge ordering temperature is an intrinsic property of Na 0.48 CoO 2 or caused by the misalignment between the ab plane of Na 0.48 CoO 2 crystal and the applied field.", "cite_spans": [], "ref_spans": []}, {"section": "4+", "text": "The observation of strong fourfold and sixfold oscillations in the AMR below 25 K \u0351see Fig. 4\u0352 implies that the low temperature electronic structure of Na 0.48 CoO 2 contains orthogonal and hexagonal symmetries in addition to the twofold rotational symmetry. This result is consistent with the picture recently proposed by Choy et al. for Na 0.5 CoO 2 based on the calculation of the Hubbard model \u0351see Fig. 6\u0352 , 21 and can be understood as follows. Below the charge ordering temperature, the triangular Co lattice will split into two orthogonal sublattices with one occupied by Co 3+ ions and the other by Co 4+ ions. Co 4+ has a magnetic moment of S =1/2. Below 25 K, Co 4+ spins undergo a weak magnetic transition and form an antiferromagnetic order. Embedded in this fourfold symmetric structure, there exists a sixfold rotational symmetry formed by purely up or down spins. The recent SR measurement also suggested that there is a rearrangement of Co 4+ spins below 25 K. 7 In summary, we have measured the c axis AMR of a Na 0.48 CoO 2 single crystal. We find that the oscillation of the AMR is dominated by a two-fold rotational symmetry below the metal-insulator transition temperature. This is consistent with the observation that the metal-insulator transition is induced by the charge ordering of Co ions. Below 25 K, strong fourfold and sixfold oscillations in the AMR appear in addition to the twofold oscillation. It suggests the charge ordered Co 4+ spins will further become antiferromagnetic correlated in this temperature regime. 5 . Sketch of the rotating apparatus in the AMR experiments. The sample is glued to the sample holder which rotates around O\u0408O\u0409 axis in a static magnetic field H. Ideally, the magnetic field should run parallel to the Co-O planes during the whole rotating process. However, in real measurements, there exits a small angle between the applied field and the Co-O planes. This will induce a twofold oscillating field along the c axis. The inset shows the induced magnetic field as a function of rotating angle assuming = 5\u00b0and the applied field H =10 T. ", "cite_spans": [], "ref_spans": [{"start": 403, "end": 410, "text": "Fig. 6\u0352", "ref_id": "FIGREF2"}]}], "bib_entries": {}, "ref_entries": {"FIGREF0": {"text": "FIG. 1. \u0351Color online\u0352 \u0351a\u0352 Temperature dependence of the c-axis resistivity R c of Na 0.48 CoO 2 . \u0351b\u0352 R c versus T at 0 T \u0351open triangles\u0352 and 10 T applied parallel to the Co-O planes \u0351solid squares\u0352, respectively. \u0351c\u0352 Temperature dependence of the c-axis magnetoresistance \u2426R c = \u0353R c \u035110 T\u0352 \u2212 R c \u03510 T\u0352\u0354 / R c \u03510 T\u0352.", "type": "figure"}, "FIGREF1": {"text": "FIG. 4. \u0351Color online\u0352 Temperature dependence of \u0349F n \u0349 / R \u0351n = 2, 4, and 6\u0352, for Na 0.48 CoO 2 . The inset shows the temperature dependence of \u0349F 2 \u0349 / R around 40 K.", "type": "figure"}, "FIGREF2": {"text": "FIG. 6. A possible low temperature \u0351\u03fd25 K\u0352 electronic structure of Na 0.5 CoO 2 . The circles represent cobalt ions. The triangular lattice is broken into two orthogonal sublattices with one occupied by Co 3+ ions and the other by Co 4+ spins with antiferromagnetic correlation. A hexagonal sublattice of ferromagnetic ordered Co 4+", "type": "figure"}}}
{"paper_id": "119426258", "_pdf_hash": "49ec60f77ee82d671cf699273a09b6ee0486f2aa", "abstract": [{"section": "Abstract", "text": "We use a recent scaling analysis of the quasielastic electron scattering data from 12 C to predict the quasielastic charge-changing neutrino scattering cross sections within an uncertainty band. We use a scaling function extracted from a selection of the (e, e \u2032 ) cross section data, and an effective nucleon mass inspired by the relativistic mean-field model of nuclear matter. The corresponding super-scaling analysis with relativistic effective mass (SuSAM*) describes a large amount of the electron data lying inside a phenomenological quasielastic band. The effective mass incorporates the enhancement of the transverse current produced by the relativistic mean field. The scaling function incorporates nuclear effects beyond the impulse approximation, in particular meson-exchange currents and short range correlations producing tails in the scaling function. Besides its simplicity, this model describes the neutrino data as reasonably well as other more sophisticated nuclear models.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "I. INTRODUCTION", "text": "The analysis of modern accelerator-based neutrino oscillation experiments requires a precise knowledge of the intermediate-energy neutrino-nucleus scattering cross section [1, 2] . The inclusive cross section involves contributions from different channels, which can be grouped into quasielastic (QE) one-nucleon emission, multi-nucleon (2p-2h, . . . ) emission, pion production and other inelastic processes. In particular, QE interactions are key processes for these experiments, but the nuclear models for these neutrino and antineutrino cross sections have large uncertainties [3] . There are processes which appear as QE-like in the neutrino detectors, produced by final-state interactions, direct multi-nucleon emission, and others which are not under total control from the theoretical point of view, and require relativistic modeling of complex hadronic final states in the continuum. They therefore limit the reach of current and future oscillation experiments such as T2K [4] [5] [6] , NOvA [7] or DUNE [8] . Recent attempts to reduce the model uncertainties have been made by measuring the proton multiplicity of the final states in the T2K [6] and ArgoNEUT [9, 10] experiments and also the measurement of neutron multiplicity in ANNIE [11] is planned.", "cite_spans": [{"start": 1169, "end": 1172, "text": "[9,", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "Within this state of afairs the acquaintance of the inclusive (e, e \u2032 ) cross sections of nuclei becomes a valuable starting point; its prior description should be a very convenient requisite for the neutrino-nucleus interaction models. In fact, the isovector component of the electromagnetic nuclear responses can be related to the vectorvector (VV) component of the weak charged-current responses contributing to the neutrino cross sections for the same intermediate energies. The contribution of the * Electronic address: ruizsig@ugr.es \u2020 Electronic address: amaro@ugr.es \u2021 Electronic address: earriola@ugr.es axial current might, in principle, be inferred by starting from any available model capable of describing electron scattering. While results from different groups including effects beyond the impulse approximation have allowed to explain the recent neutrino and antineutrino data [12] [13] [14] [15] , systematic differences still persist between these theoretical predictions. It is therefore reasonable to suspect that these differences might be attributed to systematic differences in the description of the (e, e \u2032 ) data by the same models.", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "The goal of this paper is to provide predictions for neutrino cross sections with their systematic error inherited directly from the available (e, e \u2032 ) data in the superscaling model with relativistic effective mass (SuSAM*) [16, 17] . The scaling approaches [18] [19] [20] are an alternative to more sophisticated microscopical models for predicting the neutrino QE cross section. They use a phenomenological scaling functions extracted from the (e, e \u2032 ) data, which encode many effects and assume that the same scaling functions can be used to compute the neutrino cross section [21, 22] by just replacing the electromagnetic currents with the vector and axial ones.", "cite_spans": [{"start": 583, "end": 587, "text": "[21,", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "The SuSAM* approach used in this paper is an interesting new alternative to the more traditional superscaling analysis approach (SuSA) of refs. [23, 24] , using different assumptions and definitions for the scaling functions and variables. SuSAM* is based on the relativistic mean field or Walecka model of nuclear matter [25] , containing basic theoretical and phenomenological ingredients such as relativity, gauge invariance and dynamical enhancement of lower Dirac components of the nucleon in the medium due to the scalar and vector potentials. These are known to be good enough to describe the electromagnetic nuclear responses in the QE peak [26] .", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "Recently, we have applied SuSAM* to extract a phenomenological scaling function directly from the cross section (e, e \u2032 ) data in the QE region within an uncertainty band [27] . In [27, 28] we have shown that the extracted scaling function f * (\u03c8 * ) is an universal function valid for all the nuclei, provided that a relativistic effective mass M * and Fermi momentum k F are fitted to the data for each nucleus. These two parameters, k F and M * , have been determined in [27] from the (e, e \u2032 ) database representing a first direct extraction of the Fermi-momentum dependence of relativistic effective mass below saturation from finite nuclei. We find that a subset of a third of the about 20000 existing data approximately scales to an universal superscaling function. The resulting scaling function and its uncertainty band have been parameterized and can thus be easily and directly applied to predict the neutrino QE cross sections within a corresponding uncertainty.", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "Before proceeding further a qualitying remark regarding interpretation of the present work is in order. From our point of view the SuSAM* band can be understood as the uncertainty in the theoretical description of the QE data due to processes violating the scaling model assumptions. Namely, those interactions which are beyond the impulse approximation and break the factorization of the cross section, but that imply small corrections to the center value and therefore can be regarded as QE-like interactions. The uncertainties obtained in this work for the neutrino cross sections can then be considered most likely as an upper limit to the systematic error expected from nuclear modeling of the QE processes, because all the models aiming to describe the (e, e \u2032 ) data should lie inside the phenomenological uncertainty bands for the pertinent kinematics.", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "The structure of this work is as follows. In Sect. II we describe the theoretical formalism of the SuSAM* model and the parameters of the phenomenological superscaling function f * (\u03c8 * ). In Sect. III we give our results for the neutrino and antineutrino cross sections and theoretical uncertainties and compare with most of the available data sets. In sect. IV we give our summary and conclusions. In the appendices we show some technical details on the calculation of selected differential cross sections.", "cite_spans": [], "ref_spans": []}, {"section": "II. FORMALISM OF QUASIELASTIC NEUTRINO SCATTERING", "text": "A. Cross section and responses", "cite_spans": [], "ref_spans": []}, {"section": "II. FORMALISM OF QUASIELASTIC NEUTRINO SCATTERING", "text": "In this paper we are interested in the charged-current quasielastic (CCQE) reactions in nuclei induced by neutrinos. In particular we compute the (\u03bd \u00b5 , \u00b5 \u2212 ) cross section. The total energies of the incident neutrino and detected muon are \u01eb = E \u03bd , \u01eb \u2032 = m \u00b5 + T \u00b5 , and their momenta are k, k \u2032 . The four-momentum transfer is", "cite_spans": [], "ref_spans": []}, {"section": "II. FORMALISM OF QUASIELASTIC NEUTRINO SCATTERING", "text": "If the lepton scattering angle is \u03b8 \u00b5 , the doubledifferential cross section can be written as [21, 22] ", "cite_spans": [{"start": 95, "end": 99, "text": "[21,", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "II. FORMALISM OF QUASIELASTIC NEUTRINO SCATTERING", "text": "where we have defined the cross section", "cite_spans": [], "ref_spans": []}, {"section": "II. FORMALISM OF QUASIELASTIC NEUTRINO SCATTERING", "text": "Here G = 1.166\u00d710", "cite_spans": [], "ref_spans": []}, {"section": "II. FORMALISM OF QUASIELASTIC NEUTRINO SCATTERING", "text": "p is the Fermi constant, \u03b8 c is the Cabibbo angle, cos \u03b8 c = 0.975, and the kinematic factor v 0 = (\u01eb + \u01eb \u2032 ) 2 \u2212 q 2 . The nuclear structure is implicitly written as a linear combination of five nuclear response functions, R K (q, \u03c9), where the fifth response function R T \u2032 is added (+) for neutrinos and subtracted (\u2212) for antineutrinos). The V K coefficients depend only on the lepton kinematics and are independent on the details of the nuclear target. They are defined by", "cite_spans": [], "ref_spans": []}, {"section": "II. FORMALISM OF QUASIELASTIC NEUTRINO SCATTERING", "text": "Here we have defined the dimensionless factors \u03b4 = m \u00b5 / Q 2 , proportional to the muon mass m \u00b5 , \u03c1 = Q 2 /q 2 , and \u03c1 \u2032 = q/(\u01eb + \u01eb \u2032 ). We evaluate the five nuclear response functions R K , K = CC, CL, LL, T, T \u2032 (C=Coulomb, L=longitudinal, T =transverse) using a coordinate system with the z-axis pointing along q and the x-axis along the transverse component of the incident neutrino. The nuclear response functions in this frame are given by the following components of the hadronic tensor:", "cite_spans": [], "ref_spans": []}, {"section": "II. FORMALISM OF QUASIELASTIC NEUTRINO SCATTERING", "text": "B. Nuclear matter responses in the RMF", "cite_spans": [], "ref_spans": []}, {"section": "II. FORMALISM OF QUASIELASTIC NEUTRINO SCATTERING", "text": "The starting point in this work is the relativistic mean field (RMF) theory of nuclear matter [25] , and its reasonable description of the electromagnetic nuclear response in the quasielastic region [26] . This model [25] describes the nuclear interaction in terms of vector and scalar potentials whose effect is encoded into a relativistic effective mass m * N of the nucleon in the medium. In this model the hadronic tensor for one particle-one hole (1p-1h) excitations with momentum q and energy \u03c9 can be written as", "cite_spans": [], "ref_spans": []}, {"section": "II. FORMALISM OF QUASIELASTIC NEUTRINO SCATTERING", "text": "where E = p 2 + m * N 2 is the initial nucleon energy in the mean field. The final momentum of the nucleon is p \u2032 = p + q and its energy is E \u2032 = p \u20322 + m * ", "cite_spans": [], "ref_spans": []}, {"section": "II. FORMALISM OF QUASIELASTIC NEUTRINO SCATTERING", "text": "where J \u00b5 * is the weak current matrix element between positive energy Dirac spinors with mass m * N and normalized to uu = 1. This single nucleon current is the sum of vector and axial-vector terms", "cite_spans": [], "ref_spans": []}, {"section": "II. FORMALISM OF QUASIELASTIC NEUTRINO SCATTERING", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "II. FORMALISM OF QUASIELASTIC NEUTRINO SCATTERING", "text": "are the isovector form factors of the nucleon. The axial current is", "cite_spans": [], "ref_spans": []}, {"section": "II. FORMALISM OF QUASIELASTIC NEUTRINO SCATTERING", "text": "Note that the free nucleon mass enters in the current operator, which is not modified in the medium. However the initial and final spinors u s (p), and u s \u2032 (p \u2032 ), correspond to nucleons with relativistic effective mass m * N . This modifies the values of the above matrix elements in the nuclear medium with respect to the free values. Thus the vector current operator used in this work, Eq. (15) corresponds to the CC2 prescription for the off-shell extrapolation of the electromagnetic current operator [29] .", "cite_spans": [], "ref_spans": []}, {"section": "II. FORMALISM OF QUASIELASTIC NEUTRINO SCATTERING", "text": "The present RMF theory of nuclear matter treats exactly relativity, gauge invariance and translational invariance. It differs with respect to the well known RFG in that the nucleon mass is replaced by the effective mass both in the spinors and in the energy-momentum relation. As a consequence, equations similar to the RFG responses are obtained by replacing m N by m * N and rescaling some of the form factors.", "cite_spans": [], "ref_spans": []}, {"section": "II. FORMALISM OF QUASIELASTIC NEUTRINO SCATTERING", "text": "The resulting nuclear response function R K is proportional to a single-nucleon response function U K times the scaling function f * (\u03c8 * )", "cite_spans": [], "ref_spans": []}, {"section": "II. FORMALISM OF QUASIELASTIC NEUTRINO SCATTERING", "text": "where N is the number of neutrons/protons for neutrino/antineutrino scattering, \u03b7 * F = k F /m * N , and \u03be * F = 1 + \u03b7 * 2 F \u2212 1. This factorization of the scaling function inspires the scaling models of [18] [19] [20] , by using a phenomenological scaling function instead of the well-known scaling function of the Fermi gas", "cite_spans": [], "ref_spans": []}, {"section": "II. FORMALISM OF QUASIELASTIC NEUTRINO SCATTERING", "text": "where \u03b8 is the step function and \u03c8 * is the scaling variable. In this work we use a phenomenological scaling function extracted in [17] from the (e, e \u2032 ) quasielastic data of 12 C. In contrast to traditional approaches where the lepton interacts with a free nucleon, here we use a modified scaling variable incorporating the effective mass", "cite_spans": [], "ref_spans": []}, {"section": "II. FORMALISM OF QUASIELASTIC NEUTRINO SCATTERING", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "II. FORMALISM OF QUASIELASTIC NEUTRINO SCATTERING", "text": "The single-nucleon responses U K are obtained analytically by performing the traces in Eq. (14) and the integration in Eq. (13) .", "cite_spans": [], "ref_spans": []}, {"section": "II. FORMALISM OF QUASIELASTIC NEUTRINO SCATTERING", "text": "The K = CC response is the sum of vector and axial pieces. The vector part implements the conservation of the vector current (CVC), i.e. it vanishes by contracting with q \u00b5 . The axial part can be written as the sum of conserved (c.) plus non conserved (n.c.) parts. Then", "cite_spans": [], "ref_spans": []}, {"section": "II. FORMALISM OF QUASIELASTIC NEUTRINO SCATTERING", "text": "For the vector CC response we have", "cite_spans": [], "ref_spans": []}, {"section": "II. FORMALISM OF QUASIELASTIC NEUTRINO SCATTERING", "text": "where G * V E and G * V M are the new isovector electric and magnetic nucleon form factors that get modified in the medium through the effective mass:", "cite_spans": [], "ref_spans": []}, {"section": "II. FORMALISM OF QUASIELASTIC NEUTRINO SCATTERING", "text": "For the free Dirac and Pauli form factors, F The definition of the quantity \u2206 in Eq. (21) is The axial-vector CC responses are", "cite_spans": [], "ref_spans": []}, {"section": "II. FORMALISM OF QUASIELASTIC NEUTRINO SCATTERING", "text": "where G A is the nucleon axial-vector form factor and G * P is the new pseudo-scalar axial form factor, also modified in the medium. From partial conservation of the axial current (PCAC), the new and re-scaled pseudo-scalar form factor are now", "cite_spans": [], "ref_spans": []}, {"section": "II. FORMALISM OF QUASIELASTIC NEUTRINO SCATTERING", "text": "Note that the axial form factor G A is not modified in the medium because in its definition in the axial current, Eq. (16), the nucleon mass does not appear explicitly.", "cite_spans": [], "ref_spans": []}, {"section": "II. FORMALISM OF QUASIELASTIC NEUTRINO SCATTERING", "text": "Using current conservation we have for K = CL, LL", "cite_spans": [], "ref_spans": []}, {"section": "II. FORMALISM OF QUASIELASTIC NEUTRINO SCATTERING", "text": "The n.c. parts are", "cite_spans": [], "ref_spans": []}, {"section": "II. FORMALISM OF QUASIELASTIC NEUTRINO SCATTERING", "text": "Finally, the transverse responses are given by ", "cite_spans": [], "ref_spans": []}, {"section": "II. FORMALISM OF QUASIELASTIC NEUTRINO SCATTERING", "text": "C. SuSAM* scaling function", "cite_spans": [], "ref_spans": []}, {"section": "II. FORMALISM OF QUASIELASTIC NEUTRINO SCATTERING", "text": "One of the inputs of our model is the phenomenological scaling function f * (\u03c8 * ). This has been determined from a scaling analysis of the quasielastic electron scattering data [16, 17] based on the RMF formulae of the previous section, with an effective mass for the nucleon, in contrast to all previous investigations made with M * = 1 [19] [20] [21] . This analysis allows to select a subset of \"quasielastic\" data which merge into a thick band that can be separated from the rest of data. This subset turns out to be a large fraction (about a third) of the total 20000 data and approximately scales to an universal superscaling function with uncertainties. The central value of the phenomenological quasielastic band has been parameterized as a sum of two Gaussian functions", "cite_spans": [{"start": 349, "end": 353, "text": "[21]", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "II. FORMALISM OF QUASIELASTIC NEUTRINO SCATTERING", "text": "The coefficients encoding the band and their ranges are provided in [30] .", "cite_spans": [], "ref_spans": []}, {"section": "II. FORMALISM OF QUASIELASTIC NEUTRINO SCATTERING", "text": "The present SuSAM* model provides a landmark representation of the intermediate energy quasielastic data, in the sense that any model aiming to describe these quasielastic data should lie inside the uncertainty band. It gives a fair and simple description of the selected data band. Besides the scaling function f * (\u03c8 * ), it only includes two parameters: the effective mass and the Fermi momentum.", "cite_spans": [], "ref_spans": []}, {"section": "II. FORMALISM OF QUASIELASTIC NEUTRINO SCATTERING", "text": "In the present work we will apply this model to neutrino and antineutrino quasielastic scattering from 12 C and 16 O, assuming the same uncertainty band in the scaling function as determined in (e, e \u2032 ). In ref. [17] we showed the results of our model for the doubly differential 12 C(e, e \u2032 ) cross section, with a fair global description of data. In Fig. 1 we compare our model with the 16 O data. We remark that only six kinematics are available for this nucleus. We use the values M * = 0.8 and", "cite_spans": [], "ref_spans": [{"start": 353, "end": 359, "text": "Fig. 1", "ref_id": "FIGREF2"}]}, {"section": "II. FORMALISM OF QUASIELASTIC NEUTRINO SCATTERING", "text": "MeV/c, taken from the recent A-dependent super-scaling analysis of [27] , while the scaling function band is the same as that of 12 C determined in [17] and given in Table I .", "cite_spans": [], "ref_spans": [{"start": 166, "end": 173, "text": "Table I", "ref_id": "TABREF0"}]}, {"section": "II. FORMALISM OF QUASIELASTIC NEUTRINO SCATTERING", "text": "As it can be observed most of the data around the quasielastic region are well described. Note that our model does not include the pion emission or inelastic channels and therefore the higher energy data lie, as expected, outside our uncertainty band. The quality of our description is similar to the one of the SuSAv2 model [23, 24] . In addition, we provide an estimation of the theoretical error in the cross section, that will be translated to neutrino cross section error bands in the results of the next section.", "cite_spans": [], "ref_spans": []}, {"section": "III. NUMERICAL PREDICTIONS", "text": "In this section we present our results for the quasielastic neutrino and antineutrino cross sections on 12 C and 16 O within the SuSAM* model. The parameters of the model are the effective mass M * = 0.8 and the Fermi momentum k F = 225, 230 MeV/c, for carbon and oxygen, respectively. The other input of the model is the phenomenological scaling function f * (\u03c8 * ), extracted from (e, e \u2032 ) data as described in the previous section.", "cite_spans": [], "ref_spans": []}, {"section": "A. MiniBooNE", "text": "We start with the discussion of the MiniBooNE results [33, 34] . In Fig. 2 we show our results for the fluxaveraged double differential cross section", "cite_spans": [], "ref_spans": []}, {"section": "A. MiniBooNE", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "A. MiniBooNE", "text": "dT\u00b5d cos \u03b8\u00b5 (E \u03bd ) is the computed cross section for fixed neutrino energy E \u03bd . The neutrino flux \u03a6(E \u03bd ) corresponds to the MiniBooNE experiment on 12 C nucleus [33] .", "cite_spans": [], "ref_spans": []}, {"section": "A. MiniBooNE", "text": "In the figure the band predictions and the central cross section values are compared to the experimental data of Ref [33] , which are given in bins of cos \u03b8 \u00b5 and T \u00b5 . In each panel of Fig. 2 we fix the cos \u03b8 \u00b5 to the corresponding experimental bin and the cross section is plotted as a function of T \u00b5 . In each panel we perform an integration over the corresponding angular window in cos \u03b8 \u00b5 and divide by the bin width \u2206 cos \u03b8 \u00b5 = 0.1.", "cite_spans": [], "ref_spans": []}, {"section": "A. MiniBooNE", "text": "We observe that the strength and peak position are reasonably well described by our model, and that the band thickness is similar to the experimental errors. The data are slightly above our central curves, except for very forward angles (cos \u03b8 \u00b5 \u223c 0.95 panel). Thus, we find that, in general, the data are consistent with the band within the experimental errors. Note that, by construction, the band contains by definition the purely QE nuclear effects coming from the (e, e \u2032 ) data. This is a very rewarding result which essentially confirms in a quantitative way the underlying hypothesis of the scaling analysis, namely, the fact that around the QE the main difererence between electron and neutrino scattering is mainly due to the different currents and not so much on the intricacies of nuclear effects. Of course, such a description has limitations and is subjected to improvements. Actually, the experimental neutrino data above the QE band indicate the existence of QE-like effects without pions, as 2p-2h meson-exchange currents (MEC) and short-range correlations or \u03c0-emission and reabsorption. Besides, the neutrino data falling slightly below the band for low muon energy in the top left panel point to low-q mechanisms which are, in general, overestimated by the scaling model. All these effects are known to violate scaling and are expected to produce additional contributions to the band results. Our goal here is limited to study the implications of the (e, e \u2032 ) band when directly translated to neutrino scattering. The inclusion of these effects, while extremely interesting, is beyond the scope of this work and is left for future research.", "cite_spans": [], "ref_spans": []}, {"section": "A. MiniBooNE", "text": "The antineutrino double differential cross sections for the kinematics of the MiniBooNE experiment [34] are shown in Fig. 3 . Again a good description of data is observed. In general the data are above our central curves, leaving room for additional nuclear effects not included in the SuSAM* model.", "cite_spans": [], "ref_spans": []}, {"section": "A. MiniBooNE", "text": "Our results on Figs. 2 and 3 are quantitatively slightly larger than those of the RMF model of Udias et al. [35, 36] , but it is apparent that the RMF is closely inside our uncertainty band. This was to be expected because both models are based on the same theoretical Walecka model [25] . The main difference between both approaches is that the model of Udias et al. describes finite nuclei with local vector and scalar potentials, while here our potentials are constant and generate a fixed effective mass inside the volume containing the RFG. In our case the scaling function takes into account the finite [33, 34] size of the nucleus and, besides, it is phenomenological, what accounts for the differences between both models.", "cite_spans": [], "ref_spans": []}, {"section": "A. MiniBooNE", "text": "Despite the fact that our model is not including 2p-2h explicitly, it is remarkable that the agreement of our central curve with the MiniBooNE data is similar to that obtained with more sophisticated models as those by authors Nieves et al. [41, 42] , Martini et al. [43, 44] , and Mosel et al. [14] . This is so because the RMF includes some dynamical relativistic effects like enhancement of transverse response due to lower components of nucleon spinors and other nuclear effects hidden into the phenomenological scaling function f * (\u03c8 * ).", "cite_spans": [], "ref_spans": []}, {"section": "A. MiniBooNE", "text": "The uncertainty imposed by the QE (e, e \u2032 ) data over neutrino scattering can be globally appreciated in the single differential cross sections of Fig. 4 , obtained by integration of the double differential ones. In general the data are within the SuSAM* band. Our central curves are systematically slightly below the data, in agreement with the results of the previous Figs. 2 and 3 . The thickness of the band seems larger than in the (e, e \u2032 ) cross sections. This appears to be due to the integration over the neutrino flux, which mixes the bands for different kinematics.", "cite_spans": [], "ref_spans": [{"start": 147, "end": 153, "text": "Fig. 4", "ref_id": "FIGREF6"}]}, {"section": "A. MiniBooNE", "text": "A closer insight into our results is considered in Fig. 5 . Here we show the separate contributions of the L, T and T \u2032 responses to the cross section for several kinematics. The contribution of L response is considerably smaller than the transverse channels. The T response gives the largest contribution. This indicates that the axial contribution to the transverse cross section is larger than the V V one. For large scattering angle the T and T \u2032 responses tend to be almost equal. This produces a large cancellation in the antineutrino cross section, which is therefore very small for large angles. Due to this cancellation one would expect the antineutrino cross section to be more sensitive to the details of the longitudinal responses. The results of . The experimental data nicely fall inside the QE uncertainty band except for very forward angles, where the data are overestimated around the maximum of the cross section. This is related to the limitations of the SuSAM* model to describe the low momentum transfer region.", "cite_spans": [], "ref_spans": []}, {"section": "A. MiniBooNE", "text": "In contrast to the MiniBooNE experiment, the T2K data bins are not equally-spaced in cos \u03b8 \u00b5 , and the forward angle dependence is probed in some more detail than in the MiniBooNE analysis. Note that in all the calculations we average the cross section over the corresponding angular bin. The neutrino energy distribution of the T2K experiment is also different from that of the MiniBooNE experiment, the former being narrower around the maximum value \u223c 0.5 GeV. Both neutrino fluxes are compared in Fig. 8 .", "cite_spans": [], "ref_spans": [{"start": 500, "end": 506, "text": "Fig. 8", "ref_id": "FIGREF12"}]}, {"section": "A. MiniBooNE", "text": "The flux folding of the cross section, Eq. (38), implies an integration over the incident neutrino energy, which produces a smearing of the cross section for different energies. This results in a mild model dependence of the QE neutrino cross sections. Being the flux narrower than the MiniBooNE one, one would expect the T2K experiment to be more suited for discriminating over different theoretical models of the reaction. Note also that the T2K angular bins are smaller for small angles (cos \u03b8 \u00b5 > 0.8), but for large angles (cos \u03b8 \u00b5 < 0.6) the bins are embracing a large angular sector, thus acquiring a larger additional smearing of angular cross sections. For all these reasons, the T2K and MiniBooNE cross sections are not directly comparable because they explore different energy and angular regions of the QE peak by selected integrations.", "cite_spans": [], "ref_spans": []}, {"section": "A. MiniBooNE", "text": "In Fig. 8 we analyze in more detail the smearing effect produced by the folding with the neutrino flux. We show the QE cross section for fixed neutrino energies E \u03bd = 0.5, . . . , 2.5 GeV, as a function of the muon momentum for the kinematics 0.98 < cos \u03b8 \u00b5 < 1 (corresponding to the last panels in Figs. 6 and 7) . For fixed neutrino energy, the cross section is a narrow peak contributing to the flux-folded cross section only in a narrow region in p \u00b5 . As E \u03bd increases the allowed muon energy increases and the peak position moves to the right, and its width increases, as a function of p \u00b5 . From this figure we can infer that the error of the reconstruction of the neutrino energy from the flux-folded cross section is related to the width of these peaks for fixed neutrino energy -or more precisely for fixed T \u00b5 , which is of the same order.", "cite_spans": [], "ref_spans": [{"start": 3, "end": 9, "text": "Fig. 8", "ref_id": "FIGREF12"}, {"start": 299, "end": 313, "text": "Figs. 6 and 7)", "ref_id": "FIGREF9"}]}, {"section": "A. MiniBooNE", "text": "It is interesting to see that the strength of the cross section increases with E \u03bd . This is in contrast to the electron scattering QE cross section, which decreases with the incident electron energy. The reason is because in the electromagnetic interaction there is a photon propagator squared 1/Q 4 , which decreases with Q 2 , while in the weak CC case there is a W \u00b1 propagator squared \u2243 1/M 4 W which is almost constant for the low Q 2 -values considered here. Therefore the neutrino cross section increases with E \u00b5 . This increase is partially balanced with a decrease of the neutrino flux inside the folding. Accidentally, this balance turns out to be almost perfect in the case of the T2K experiment for the kinematics of Fig. 8 and that is the reason why for large p \u00b5 the flux-folded cross section does not fall to zero and is almost constant in the last panels of Figs. 6 and 7.", "cite_spans": [], "ref_spans": [{"start": 731, "end": 737, "text": "Fig. 8", "ref_id": "FIGREF12"}]}, {"section": "A. MiniBooNE", "text": "To complete the comparison with T2K data, in Figs. 9 and 10 we compare our model with the data of total inclusive cross sections for \u03bd \u00b5 [39] and \u03bd e CC scattering from 12 C [40] . Up to now we have compared with inclusive data without pions in the final state (CCQE-0\u03c0), corresponding to QE-like events, but they are not restricted to one-nucleon emission because these semi-inclusive cross sections contain multi-nucleon emission, mainly from 2p-2h final states. Our model accounts for this multi-nucleon emission, at least partially, because the effective mass and scaling function is extracted directly from cross section data. The width of the band should account for those processes that violate scaling, but remain close to the QE peak. In particular, the tail in the scaling function is produced by nucleons with large momentum (compared to k F ) inside the ground state, which are mainly produce by short-range correlations. Other mechanisms such as meson-exchange currents also should contribute partially to the uncertainty band. In addition to this, the inclusive neutrino data in Figs. 9 and 10 contain also explicit pion emission and other inelasticities, which do not scale and have been disregarded in our selection of QE (e, e \u2032 ) data. That is why our results underestimate the inclusive cross sections, as it is more apparent in the case of \u03bd e , shown in Fig. 10 .", "cite_spans": [], "ref_spans": [{"start": 1375, "end": 1382, "text": "Fig. 10", "ref_id": "FIGREF2"}]}, {"section": "C. MINERvA", "text": "In Fig. 11 we show the flux-folded CCQE singledifferential cross section d\u03c3/dQ 2 QE for (\u03bd \u00b5 , \u00b5 \u2212 ) and (\u03bd \u00b5 , \u00b5 + ) scattering from 12 C and CH respectively, compared to the MINERvA experiment [45] . This cross section is presented as a function of the reconstructed variable Q 2 QE , which is not the true Q 2 , but it is computed from the reconstructed neutrino energy assuming quasielastic scattering from a nucleon at rest. In Appendix A we show details on how this cross section is computed. The cross section data for antineutrino scattering contain the H contribution from the target. In Appendix B we show how we evaluate this cross section within our formalism. As we can see in Fig. 11 , all the MINERvA data fall with our uncertainty band and, moreover, they are very close to the central value of the SuSAM* model predictions.", "cite_spans": [], "ref_spans": [{"start": 3, "end": 10, "text": "Fig. 11", "ref_id": "FIGREF2"}, {"start": 690, "end": 697, "text": "Fig. 11", "ref_id": "FIGREF2"}]}, {"section": "C. MINERvA", "text": "To finish our discussion, in Fig. 12 we show the double differential antineutrino cross section for QE scattering on CH (hydrocarbon) corresponding to the recent measurements in the MINERvA detector [3] .", "cite_spans": [], "ref_spans": [{"start": 29, "end": 36, "text": "Fig. 12", "ref_id": "FIGREF2"}]}, {"section": "C. MINERvA", "text": "The double-differential measurements of antineutrino QE scattering in the MINERvA detector provide a complete description of observed muon kinematics with respect to the muon longitudinal and transverse momentum with respect to the incident neutrino. These are related to the variables p \u00b5 , cos \u03b8 \u00b5 by", "cite_spans": [], "ref_spans": []}, {"section": "C. MINERvA", "text": "It is then straightforward to compute the Jacobian of the transformation to the usual cross section variables E \u00b5 , cos \u03b8 \u00b5 dp dp Therefore we compute the MINERvA double-differential cross section as d 2 \u03c3 dp dp", "cite_spans": [], "ref_spans": []}, {"section": "C. MINERvA", "text": "Our calculation in Fig. 12 is compared with the 'true' CCQE data from tables XXII, XXIII and XXIV of ref. [3] . Most of the data are within the uncertainty band and slightly above the central SuSAM* results. This may indicate the presence of some non-QE events in the data. The hydrogen contribution is also included in the calculation from hydrocarbon. It is found to provide a small correction which slightly increases the cross section, but it could be safely ignored without sensibly modifying the uncertainty band of Fig. 12 . Note that in each panel of the figure the parallel component of the muon momentum is averaged over the corresponding experimental bin as indicated. By plotting the cross section as a function of the perpendicular muon momentum not only the total muon momentum increases, but also the angle, opposite to the usual E \u00b5 -plots where the cos \u03b8 \u00b5 bins are kept constant.", "cite_spans": [], "ref_spans": [{"start": 19, "end": 26, "text": "Fig. 12", "ref_id": "FIGREF2"}, {"start": 522, "end": 529, "text": "Fig. 12", "ref_id": "FIGREF2"}]}, {"section": "IV. CONCLUSIONS", "text": "Summarizing, in this work we have provided predictions for the CCQE neutrino and antineutrino cross sections and their theoretical uncertainties. These uncertainties are extracted directly from the (e, e \u2032 ) data and can be considered upper limits to the expected systematic errors coming from the nuclear modeling of the reaction.", "cite_spans": [], "ref_spans": []}, {"section": "IV. CONCLUSIONS", "text": "We have compared our model with the available QE neutrino and antineutrino double-differential and differential cross section data from MiniBooNE, T2K and MINERvA experiments, with a reasonable agreement. The theoretical uncertainty bands are around 20% \u2212 30% and, in general, of the same order as the experimental errors.", "cite_spans": [], "ref_spans": []}, {"section": "IV. CONCLUSIONS", "text": "The agreement of our central results with data is similar to that obtained with much more sophisticated theoretical models. We emphasize that the results were obtained without any tuning of model parameters except the relativistic effective mass and the Fermi momentum, extracted from a large body of (e, e \u2032 ) data around the QE. The accord with data over different experiments, different nuclei, and spanning a wide range of neutrino and antineutrino energies, shows that the SuSAM* uncertainty bands faithfully encode intricate nuclear effects and qualify as a suitable tool for the validation of models of QE-like interactions. We plan to explore ways to reduce the systematic errors, for instance by combining the SuSAM* model with explicit additional contributions from meson-exchange currents, which only are partially included in the phenomenological scaling function, or by extending the model to account for the inelastic channels. A quantity of interest in the experiments is the reconstructed neutrino energy assuming quasielastic scattering on a nucleon at rest. By energy-momentum conservation, it is given by [3, 33, 46 ]", "cite_spans": [{"start": 1132, "end": 1134, "text": "46", "ref_id": "BIBREF45"}], "ref_spans": []}, {"section": "IV. CONCLUSIONS", "text": "where m \u2032 n = m n \u2212 E b , and E b = 34 MeV is an effective binding energy for an initial neutron at rest in 12 C. For the inverse reaction case of antineutrinos one should exchange the neutron and proton masses in the formula and ", "cite_spans": [], "ref_spans": []}, {"section": "IV. CONCLUSIONS", "text": "Note that the reconstructed variable Q 2 QE is not the true Q 2 because the true neutrino energy is unknown. It is a function of (cos \u03b8 \u00b5 , E \u00b5 ). It is a convenient variable to present results in a representation similar to the neutrinonucleon cross section. The definition of the cross section d\u03c3/dQ 2 QE is the following", "cite_spans": [], "ref_spans": []}, {"section": "IV. CONCLUSIONS", "text": "were the cross section in the numerator, is the fluxfolded double-differential cross section. The denominator is the Jacobian in the change of variables (cos \u03b8 \u00b5 , E \u00b5 ) \u2192 (Q 2 QE , E \u00b5 ). Therefore inside the integral the cos \u03b8 \u00b5 variable is computed from Eqs. (A1-A2) by solving for cos \u03b8 \u00b5 in terms of the independent variables (Q 2 QE , E \u00b5 ):", "cite_spans": [], "ref_spans": []}, {"section": "IV. CONCLUSIONS", "text": "The Jacobian in the denominator is then given by", "cite_spans": [], "ref_spans": []}, {"section": "IV. CONCLUSIONS", "text": "The resulting differential cross section has been computed using (A3) when we compare with the MINERvA data. fore, when comparing with such experiments, such as the MINERvA data, the individual proton cross sections have to be added incoherently to the 12 C one in proportion to the relative number of protons in each species of the target.", "cite_spans": [], "ref_spans": []}, {"section": "IV. CONCLUSIONS", "text": "Here we compute this contribution as a particular case of the RFG formalism for k F = 0, Z = 1 and M * = 1. For the flux averaged antineutrino cross section we have", "cite_spans": [], "ref_spans": []}, {"section": "IV. CONCLUSIONS", "text": "where the elastic single nucleon responses U K (E \u2032 , 0) are evaluated for a nucleon at rest using Eqs. (20, 28, 29, 32, 35) , for k F = 0, or equivalently, by simply setting \u2206 =\u2206 = 0 in those equations. Being a nucleon at rest, the values of q and \u03c9 are calculated from the kinematics inside the integral. To integrate over the neutrino energy using the Dirac delta, we take into account that the final nucleon energy, E \u2032 , depends on the antineutrino energy through E \u20322 = m \u03c3/dp || /dp d 2 \u03c3 dp dp \u22a5 for antineutrino CCQE scattering from CH (hydrocarbon) compared to the MINERvA experiment. The H contribution is obtained from the elastic antineutrino-proton cross section divided by A = 13. The data are from [3] .", "cite_spans": [], "ref_spans": []}, {"section": "IV. CONCLUSIONS", "text": "Differentiating we can write", "cite_spans": [], "ref_spans": []}, {"section": "IV. CONCLUSIONS", "text": "Now it is straightforward to integrate the Dirac delta, obtaining", "cite_spans": [], "ref_spans": []}, {"section": "IV. CONCLUSIONS", "text": "where we have taken the absolute value of the Jacobian and replaced in the denominator E \u03bd \u2212 E \u2032 = E \u00b5 \u2212 m p . The value of the antineutrino energy is", "cite_spans": [], "ref_spans": []}, {"section": "IV. CONCLUSIONS", "text": "and E \u2032 = E \u03bd \u2212 E \u00b5 + m p . This solves the doubledifferential cross section problem. Finally, to compute the single differential cross section d\u03c3/dQ 2 QE for the proton we apply again the method explained in Appendix A, for E b = 0.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF8": {"title": "JPS Conf. Proc", "authors": [{"first": "O", "middle": [], "last": "Palamara", "suffix": ""}], "year": 2016, "venue": "", "link": null}, "BIBREF20": {"title": "Donnelly A. Molinari, and I. Sick", "authors": [{"first": "J", "middle": ["E"], "last": "Amaro", "suffix": ""}, {"first": "M", "middle": ["B"], "last": "Barbaro", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Caballero", "suffix": ""}, {"first": "T", "middle": ["W"], "last": "", "suffix": ""}], "year": 2005, "venue": "Phys. Rev. C", "link": null}, "BIBREF45": {"title": "Measurement of the Antineutrino DoubleDifferential Charged-Current Quasi-Elastic Scattering Cross Section at MINERvA Springer Theses", "authors": [{"first": "C", "middle": ["E"], "last": "Patrick", "suffix": ""}], "year": 2018, "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Note that the initial and final nucleons have the same effective mass m * N . The volume V = 3\u03c0 2 N /kof the system is re- lated to the Fermi momentum k F and proportional to the number N = N (Z) of neutrons (protons) participating in the process for CC neutrino (antineutrino) scattering. Finally the single-nucleon tensor is written in terms of the CC current", "type": "figure"}, "FIGREF2": {"text": "FIG. 1: Comparison of inclusive 16 O (e, e \u2032 ) cross section and predictions of the SuSAM* model. The solid lines have been obtained with the central parameterization of the scaling function,l while the green band represents the theoretical uncertainty. Data are from [31, 32].", "type": "figure"}, "FIGREF4": {"text": "FIG. 2: (Color online) Flux-integrated double-differential cross section per target neutron for the CCQE (\u03bd\u00b5, \u00b5 \u2212 ) reaction on 12 C in the SuSAM* model. Each panel is labeled by the mean value of cos \u03b8\u00b5 in each experimental bin. The experimental data are from [33]", "type": "figure"}, "FIGREF6": {"text": "FIG. 4: (Color online) Flux-integrated single-differential cross sections per target neutron (proton) for the CCQE neutrino (antineutrino) reactions on 12 C in the SuSAM* model. Left panels are for neutrinos and right ones for antineutrinos. The experimental data are from [33, 34]", "type": "figure"}, "FIGREF7": {"text": "Fig. 5 are useful to further be compared with those of the RMF model of Udias et al. (see Figs. 2 and 3 of ref. [35]), being in fair agreement with our findings. This comparison again ensures the similitudes between the SuSAM* and the RMF in finite nuclei for intermediate energies.", "type": "figure"}, "FIGREF8": {"text": "FIG. 5: (Color online) Flux-integrated double-differential cross section per target neutron (proton) for the CCQE neutrino (antineutrino) reaction on 12 C in the SuSAM* model (neutrino left and antineutrino right). The separate contributions of the L, T and T' responses are highlighted for two selected kinematics. The experimental data are from [33, 34]", "type": "figure"}, "FIGREF9": {"text": "FIG. 6: T2K flux-folded double differential CCQE cross section per nucleon for \u03bd\u00b5 scattering on 12 C in the SuSAM* model. Experimental data are from [37].", "type": "figure"}, "FIGREF10": {"text": "FIG. 7: T2K flux-folded double differential CCQE cross section per neutron for \u03bd\u00b5 scattering on 16 O in the SuSAM* model. Experimental data are from [38].", "type": "figure"}, "FIGREF12": {"text": "FIG. 8: (color online) Top panel: Comparison of MiniBooNE and T2K neutrino fluxes. Bottom panel: Double-differential CCQE 16 O (\u03bd\u00b5, \u00b5 \u2212 ) cross section for fixed neutrino energies computed for the angular bin 0.975 < cos \u03b8\u00b5 < 1.", "type": "figure"}, "FIGREF13": {"text": "has been partially supported by the Spanish Ministerio de Economia y Competitividad (grants Nos. FIS2014-59386-P and FIS2017-85053-C2-1-P) and by the Junta de Andalucia (grant No. FQM-225). V.L.M.C. acknowledges a contract with Universidad de Granada funded by Junta de Andalucia and Fondo Social Europeo.", "type": "figure"}, "FIGREF14": {"text": "FIG. 9: T2K flux-folded double differential CC inclusive cross section per nucleon for \u03bd\u00b5 scattering on 12 C in the SuSAM* model. Experimental data are from [39].", "type": "figure"}, "FIGREF15": {"text": "FIG. 10: T2K flux-folded single differential CC inclusive cross section per nucleon for \u03bde scattering on 12 C in the SuSAM* model. Experimental data are from [40]. The neutron binding energy for this case is EB = 25 MeV.", "type": "figure"}, "FIGREF16": {"text": "FIG. 11: (color online) Flux-folded CCQE (\u03bd\u00b5, \u00b5 \u2212 ) and (\u03bd\u00b5, \u00b5 + ) scattering from 12 C and CH scattering compared to the MINERvA experiment. The H contribution is obtained from the elastic antineutrino-proton cross section divided by Z = 7. The data are from [45].", "type": "figure"}, "FIGREF17": {"text": "\u2212 2E \u03bd p \u00b5 cos \u03b8 \u00b5 (B2)", "type": "figure"}, "FIGREF18": {"text": "FIG. 12: (color online) Flux-folded double-differential cross section", "type": "figure"}, "TABREF0": {"text": "Parameters of our fit of the phenomenological scal- ing function central value, f * (\u03c8 * ), and of the lower and upper boundaries (min and max, respectively).", "type": "table"}, "TABREF1": {"text": "table I. The lower and upper limits of the phenomenological band have been parameterized as sum of two Gaussians as well, with coefficients a, given in table I too. Note that the new scal- ing function f * (\u03c8 * ) is different to the phenomenological scaling function used in the SuSA formalism", "type": "table"}}}
{"paper_id": "119426456", "_pdf_hash": "9160a9ab0d0feef000ff95a85751ef140d860faa", "abstract": [{"section": "Abstract", "text": "Observations of synchrotron polarization at multiple frequencies in the presence of Faraday rotation can provide a way to reconstruct the 3D magnetic field distribution. In this paper we compare the well known Faraday Tomography (FT, Burn 1966) technique to the new approach named Synchrotron Polarization Gradients (SPG, Lazarian & Yuen 2018b). We compare the strengths and limitations of the two techniques, and describe their synergy. In particular, we show that in the situations when FT technique fails, e.g. due to insufficient frequency coverage, the SPG can still trace the 3D structure of magnetic field.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION", "text": "Magnetic field structure is very important for key astrophysical processes in interstellar media (ISM) such as the formation of stars (see McKee & Ostriker 2007; Mac Low & Klessen 2004) , the propagation and acceleration of cosmic rays (see Jokipii 1966; Yan & Lazarian 2008) , the regulation of heat and mass transfer between different ISM phases (see Draine 2009 for the list of the different ISM phases). Polarized radiation arising from the presence of the magnetic field is also important to explain the enigmatic CMB B-modes (Zaldarriaga & Seljak 1997; Caldwell et al. 2017; Kandel et al. 2017a ).", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "Synchrotron polarization is widely used in study magnetic fields structure in the sky. However, in the presence of the Faraday rotation it is not trivial to compensate for the distortion from the 2D polarization pattern within the volume emitting synchrotron radiation. The tracing of the actual threedimensional (3D) magnetic field structure presents both a big attraction and an outstanding challenge. Potentially, by combining synchrotron data at different frequencies, one can try to obtain the magnetic field variation along the line-of-sight. Burn (1966) first suggested that the Faraday Tomography (FT), i.e. multi-layer plane-of-sky magnetic field structures, can be obtained through proper Fourier transform from the polarized synchrotron emissions (See Brentjens & de Bruyn 2005, hereafter BB05) . A number of works are coming out based on the depolarization of the synchrotron emissions (Robitaille et al. 2017; Dickey et al. 2018; Jelic, V. et al. 2018; Haverkorn 2018; Farnes et al. 2018) .", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "A recently suggested alternative technique of magnetic field tracing employs the Synchrotron Polarization Gradients (SPGs, Lazarian & Yuen 2018b, LY18b) . As discussed in the latter paper, the foundations of the SPGs are routed in the properties of MHD turbulence and turbulent reconneckyuen2@wisc.edu tion Goldreich & Sridhar 1995; Lazarian & Vishniac 1999 . As a result, the SPGs trace the local magnetic field through observationally resolved eddies. The applicability of the SPGs to the interstellar medium (ISM) arises form the fact that ISM is turbulent Armstrong et al. (1995) ; Chepurnov & Lazarian (2009 ; Burkhart et al. (2015) . In the presence of Faraday Rotation, only a certain deepness of the synchrotron emission is effectively collected into the Stokes parameters. That means the synchrotron polarization map for a specific emitting frequency f corresponds to the plane-of-sky magnetic field variation accumulated up to a certain depth along the line of sight.The theory of this effect in the presence of magnetic turbulence is given in Lazarian & Pogosyan (2016) . As a result, one can try to obtain the 3D magnetic field structure by utilizing multi-frequency synchrotron emissions. LY18b pointed out that by considering the differences of SPGs of polarized synchrotron maps obtained with multifrequency observations, one can reconstruct the 3D magnetic field structure.", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "While the two proposals of tracing 3D magnetic field both rely on the multi-frequency synchrotron emission in the presence of Faraday Rotation, there are significant differences between the foundations of the two methods. One may wonder:", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "(1) What are the limitations of the techniques? (2) How precise can the 3D B-field distributions can be traced with these techniques? (3) Are the methods self-consistent?. This paper is the first attempt to answer these important questions.", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "On one hand, the method of SPGs relies on the fact that turbulence is ubiquitous while the FT provides the selfconsistent 3D mapping of the underlying regular magnetic field. On the other hand, the method of FT has a much higher requirement on the number of frequencies compared to the SPG (e.g. Li et.al 2011b) . In addition, the line-of-sight magnetic field strength information is not available for the FT but possible to obtain using SPG (see LY18b).", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "We would therefore like to compare the two techniques in this paper through numerical simulations. Instead of confronting the techniques we search for their synergy. In what follows, we briefly describe the numerical code and setup for simulation in \u00a72, the performance of two method in \u00a73 & \u00a74, the discussion of the synergy of two method in \u00a75 and summary in \u00a76.", "cite_spans": [], "ref_spans": []}, {"section": "NUMERICAL SIMULATIONS Simulation setup.", "text": "The numerical 3D MHD simulations were used already in Lazarian & Yuen (2018a) and LY18b by setting up a 3D, uniform, isothermal turbulent medium. We use a range of Alfv\u00e9nic Mach number", "cite_spans": [], "ref_spans": []}, {"section": "NUMERICAL SIMULATIONS Simulation setup.", "text": "where V L is the injection velocity; V A and V s are the Alfv\u00e9n and sonic velocities respectively. The numerical parameters are listed in Table 1 in sequence of ascending values of media magnetization \u03b2 = 2(M A /M S ) 2 .", "cite_spans": [], "ref_spans": []}, {"section": "NUMERICAL SIMULATIONS Simulation setup.", "text": "Faraday Tomography. The concept of Faraday Tomography was first suggested by Burn (1966) . The method utilizes the fact that the Faraday rotation integral of synchrotron polarization along the line of sight is effectively a Fourier transform of the complex polarized brightness per unit Faraday depth F (\u03c6) :", "cite_spans": [], "ref_spans": []}, {"section": "NUMERICAL SIMULATIONS Simulation setup.", "text": "where \u03bb is the observed wavelength, P (\u03bb 2 ) is the complex polarized surface brightness in terms of Stoke parameters Q and U , and \u03c6 is the Faraday depth. Performing the inverse Fourier transform one can easily acquire F (\u03c6):", "cite_spans": [], "ref_spans": []}, {"section": "NUMERICAL SIMULATIONS Simulation setup.", "text": "which provides the 3D Magnetic field information as a function of \u03c6. Since \u03bb 2 only lies in the positive real space, the inverse Fourier transform cannot be computed accurately unless the negative part of \u03bb 2 is provided. BB05 provided a solution to the problem by introducing the window function W (\u03bb 2 ) to reconstruct F (\u03c6). The window function is nonzero in the range of observed \u03bb 2 and is otherwise zero. BB05 then defined the observed polarized surface brightness as:", "cite_spans": [], "ref_spans": []}, {"section": "NUMERICAL SIMULATIONS Simulation setup.", "text": "As a result, the complex polarized brightness that includes the windowF (\u03c6) can be written as", "cite_spans": [], "ref_spans": []}, {"section": "NUMERICAL SIMULATIONS Simulation setup.", "text": "where R(\u03c6) is the rotation measure transfer function (RMTF):", "cite_spans": [], "ref_spans": []}, {"section": "NUMERICAL SIMULATIONS Simulation setup.", "text": "The function K is", "cite_spans": [], "ref_spans": []}, {"section": "NUMERICAL SIMULATIONS Simulation setup.", "text": "and a parameter \u03bb 0 is introduced to Eq. (4) & (5) in order to improve the the behavior of RMTF. The optimal \u03bb 2 0 is the mean of \u03bb 2 sample values obtained by the telescope. This technique introduced by BB05 is referred to as the Rotation Measure (RM) synthesis. It shows promising in obtaining the 3D tomography magnetic field structure. The requirement for the technique to work is to have enough synchrotron polarization measurements at different frequencies.", "cite_spans": [], "ref_spans": []}, {"section": "NUMERICAL SIMULATIONS Simulation setup.", "text": "To calculate F (\u03c6) in numerical simulations, we consider a column of data along the line of sight (LOS) in a 3D MHD numerical data cube and divide this column into n segments. Each segment contains the information from density, magnetic field (such as Q & U ), and rotation measurement \u03c6. In this setting the polarization can be calculated as", "cite_spans": [], "ref_spans": []}, {"section": "NUMERICAL SIMULATIONS Simulation setup.", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "NUMERICAL SIMULATIONS Simulation setup.", "text": "The Faraday dispersion function can then be expressed as", "cite_spans": [], "ref_spans": []}, {"section": "NUMERICAL SIMULATIONS Simulation setup.", "text": "Although we cannot get the information of P (\u03bb 2 ) when \u03bb 2 < 0, it is still useful to assume Eq. 8 holds by assuming P (\u03bb 2 < 0) = 0 :", "cite_spans": [], "ref_spans": []}, {"section": "NUMERICAL SIMULATIONS Simulation setup.", "text": "which suggests that |F (\u03c6)| can be decomposed into n delta functions \u03b4(\u03c6 \u2212 \u03c6 k ) peaked at \u03c6 k . It is important to notice that Eq. 9 and the reconstructed Faraday dispersion functionF (\u03c6) are not equivalent but share many similarities.", "cite_spans": [], "ref_spans": []}, {"section": "NUMERICAL SIMULATIONS Simulation setup.", "text": "Synthesis of Position-Position-Frequency (PPF) cubes. We synthesize the PPF cubes following the procedures in LY18b. We use the definition of synchrotron polarization in Lazarian & Pogosyan (2016) thus ignoring the wavelength dependences of synchrotron polarization arising from the cosmic ray spectrum. This means the source term P i (X, z) will be wavelength-independent while the observed polarization will be wavelength-dependent due to Faraday rotation only. Similar to LY18b, we assume the cosmic ray index \u03b3 = 2 since Lazarian & Pogosyan (2012) showed marginal effect of \u03b3 on the spatial variations in the Stokes parameters. That means we can express the Stokes Q and U as:", "cite_spans": [], "ref_spans": []}, {"section": "NUMERICAL SIMULATIONS Simulation setup.", "text": "where p is the polarization fraction, which is assumed to be constant, and n e is the density of relativistic electrons. The definitions of the Stokes parameters above correspond to the synchrotron intensity at the source", "cite_spans": [], "ref_spans": []}, {"section": "NUMERICAL SIMULATIONS Simulation setup.", "text": "Effective measurable distance due to the Faraday screening effect. In LP16 and LY18b the effective measurable distance L ef f arising from Faraday depolarization is introduced, refers to the line-of-sight distance over which the Faraday rotation phase of the synchrotron emission source is less than unity. Mathematically,", "cite_spans": [], "ref_spans": []}, {"section": "NUMERICAL SIMULATIONS Simulation setup.", "text": "where L is the cloud thickness. Synchrotron polarization from distances larger than L ef f contributed as noise in the resultant Stokes maps (see LY18b).", "cite_spans": [], "ref_spans": []}, {"section": "NUMERICAL SIMULATIONS Simulation setup.", "text": "Block averaging for gradient calculations. Gradients of polarization are calculated by taking the values of polarization in the neighboring points and dividing them over the distances between the points following the recipe of Yuen & Lazarian (2017a) . In this work, we focus on the smallest scale contribution as we did in Lazarian & Yuen (2018a) . LY18b provides the criteria for the gradients to be perpendicular to the magnetic field by investigating the indexes of the power spectrum and correlation function anisotropy. As we are using the same set of simulations used in LY18b, the criteria in LY18b are automatically satisfied.", "cite_spans": [], "ref_spans": []}, {"section": "NUMERICAL SIMULATIONS Simulation setup.", "text": "Alignment Measure (AM). To quantify how good two vector fields are aligned, we employ the alignment measure that is introduced in analogy with the grain alignment studies (see Lazarian 2007) : To use the Faraday tomography method, we use the reconstructed Faraday dispersion functionF (\u03c6) instead of Faraday dispersion function F (\u03c6) because (i) as explained above, it is only possible to obtainF (\u03c6) from observational data, (ii) both functions share similar spiky features with respect to the Faraday rotation measure, and (iii) the corresponding \u03c6-values of those peaks are similar for both functions. To demonstrate the points, Fig 1 showsF (\u03c6) from a simulation sample and compare with F (\u03c6). They match the properties that Eq. 9 describes. The functionF (\u03c6) still contains the spiky feature we observed in F (\u03c6). Moreover, the positions of the spikes inF (\u03c6) are consistent to those in F (\u03c6). Therefore, we can use Eq.9 and describe the features we calculated using theF (\u03c6).", "cite_spans": [], "ref_spans": [{"start": 632, "end": 637, "text": "Fig 1", "ref_id": "FIGREF1"}]}, {"section": "NUMERICAL SIMULATIONS Simulation setup.", "text": "The reconstruction of Faraday dispersion function in simulation is rather trivial since the number of segments n in Eq.9 corresponds to the number of frequency measurements in observations. Potentially it should be possible to obtain the magnetic field distributions exactly provided that one has sufficiently large n in Eq.9. However, increasing the number of measurements is very costly as the Nyquist condition for the reconstruction of Faraday dispersion function grows with the square root of n; that means to increase the signalto-noise by a factor of 2 one has to increase the number of measurements four times.", "cite_spans": [], "ref_spans": []}, {"section": "NUMERICAL SIMULATIONS Simulation setup.", "text": "In Fig. 1 we observed a lot of \u03b4-like structures sparsely Figure 2 . Illustration of the difference between simulation data and observation spaced across \u03c6. We would refer the spaces between the \u03b4-like structures as \"gaps\" while the \u03b4-like structures themselves are referred as \"peaks\". Fig. 2 shows a simple illustration on how the number of \"peaks\" would affect the detection accuracy of the Faraday tomography method. In observations (orange shaped region) one can only obtain a continuous distribution of the Faraday dispersion function in the Fourier space. However in numerical simulations the respective Faraday dispersion function is often composed of a number of discrete peaks, which correspond to different magnetic field values along the line of sight. The differences of the shape of the Faraday dispersion function between observations and simulations bring one very important question while applying the FT method in observation: How to determine the peaks in observation? To answer the aforementioned question, we performed a synthetic studies using numerical simulation and trying to mimic the observational settings. In observations the number of frequency channels n is often limited, which makes the peak determination difficult. We therefore test whether the change of n would result in different peak locations in the F (\u03c6) \u2212 \u03c6 plot. Fig.1 shows how the change of frequency channel resolution would alter the positions of peaks of the Faraday dispersion function. We see that positions of peaks are similar in both cases, showing that the resolution along the frequency axis does not affect locating the peaks of the Faraday dispersion function.", "cite_spans": [], "ref_spans": [{"start": 3, "end": 9, "text": "Fig. 1", "ref_id": "FIGREF1"}, {"start": 1356, "end": 1361, "text": "Fig.1", "ref_id": "FIGREF1"}]}, {"section": "Determining the magnetic field orientation using Faraday Tomography", "text": "The advantage of the Faraday Tomography over other methods is the high precision in determining the plane-of-sky component of the magnetic field as long as there are enough frequency channels that satisfy the Nyquist criterion. With a correct selection of frequency band in observation, one can determine the peaks in the Faraday dispersion function without difficulties. We would like to illustrate the power of Faraday Tomography using the numerical simulations listed in Table 1 . Table 2 shows the AM of the FT reconstructed plane-ofsky component magnetic field compared to the true magnetic field in numerical simulations. To get these results, we first convert the numerical cube to a Position-Position-Frequency (PPF) cube using the approach in \u00a72 and then we compute theF . After that, we locate the most significant three peaks for which the real and imaginary part represent the Stokes parameters Q & U. The three peaks we located in the \u03c6 space are converted to the magnetic field measurements that we compare with the real magnetic field using the AM (See \u00a72). When we are computing the AM we randomly select 300 columns 1 We also use the \u03c6 value found from those three peaks and compare to the the exact value of the polarization angle available from the simulations. Finally, we compare both angles and get the AM values for each of them. There are subtle differences between the cases whether the mean field or the turbulent field dominates along the line of sight (Lazarian & Pogosyan 2016) and careful studies have to be done these cases. To test this, we perform tests in both cases with ordered and chaotic LOS B-fields. For the ordered Bfield case, we rotate the simulation cube such that the mean field direction is pointing to the observer. For the chaotic field case, we further rotate the cube so that the mean field direction would be parallel to plane of sky. One can see that for both cases of ordered and chaotic LOS B-field the AM is pretty high, with an average value of \u223c 0.7 -0.8, if we pick the correct frequency band.", "cite_spans": [], "ref_spans": []}, {"section": "Possible improvement of Faraday Tomography and its impact", "text": "1 The whole process for FT is expensive since a two-step process is required to convert the simulation cubes to Faraday dispersion function, namely from the position-position-position (PPP) cubes to the PPF cubes and finally to PP\u03c6 cubes. Both processes are having the computational complexity of O(N 3 \u00d7 N f ) and O(N 3 \u00d7 N \u03c6 ), where N , N f and N \u03c6 are the resolutions of simulations , number of frequency bands and number of rotation measure channels, respectively. We assume the N f = N \u03c6 in this study. Apart from that, to compute the AM, it also requires the computational complexity of O(N 3 \u00d7 N \u03c6 ) to trace back the local maximum. So, checking pixels randomly provides a more efficient approach in checking the accuracy of FT. It is worth mentioning that we do not apply the technique involving a multiplicative factor of e 2i\u03c6\u03bb 2 0 in the calculation of theF as suggested in BB05. BB05 thought that this factor could influence the phase rotation ofF in both real and imaginary space thus affecting the tracing power of FT. However, we have shown that FT performs well even without this factor. Also, with the extra factor, Eq.13 will become:", "cite_spans": [], "ref_spans": []}, {"section": "Possible improvement of Faraday Tomography and its impact", "text": "Comparing to Eq.9, Eq.13 contains an extra term e 2i\u03c6 k \u03bb 2 0 . This term will not affect the features we explained about the |F (\u03c6)| at \u03c6 space since e 2i\u03c6 k \u03bb 2 0 will be canceled during the calculation by its conjugate term. So, the peak value and the location of the \u03b4 function will not be changed. However, if we use the same treatment as we did on ", "cite_spans": [], "ref_spans": []}, {"section": "The performance of SPG in tracing 3D magnetic field", "text": "To compare the performance of the SPG tomography proposed in LY18b with the FT , we divide the axis along LOS into 20 slides, which corresponds to L ef f /L as from 0.05 to 1.0 with a separation of 0.05. This allows us to trace the 2D magnetic field structure at different depth. The frequencies required are computed from the Eq.11.", "cite_spans": [], "ref_spans": []}, {"section": "The performance of SPG in tracing 3D magnetic field", "text": "It is important to note that the rule to choose the frequency band is different for SPG and FT. Suppose we get two measurements from P (f i ) and P (f i+1 ) at any two neighbouring frequency points f i and f i+1 , with the definition that the frequency width is defined as the difference of frequencies \u2206f = f i \u2212 f i+1 . In the case of SPG, since the relation L ef f \u223c f 2 \u03c6 from the Eq.11 holds for all frequencies, the effective line of sight thickness \u03b4L ef f is also related to the frequency width following Eq.11 that \u03b4L ef f \u223c \u03b4f", "cite_spans": [], "ref_spans": []}, {"section": "The performance of SPG in tracing 3D magnetic field", "text": ". If one wants \u03b4L ef f to be fixed, then the differences of frequency bands follows quadratically with the above relation. In the case of FT, since we are performing Fourier transform with the term e 2i\u03c6\u03bb 2 in \u03bb 2 space, the selection of frequency bands would then depend on the fact that the differences of wavelengths have to be constant \u03bb The dependencies of frequency bands as a result is inversely quadratically. We would discuss more in \u00a74.3 .", "cite_spans": [], "ref_spans": []}, {"section": "The performance of SPG in tracing 3D magnetic field", "text": "After a correct selection of frequency bands, which corresponds to a set of effective line of sight thicknesses, we can then get the synchrotron polarization derivative map from calculating the difference of polarized intensity\u03a6 = \u2206Q 2 + \u2206U 2 by:", "cite_spans": [], "ref_spans": []}, {"section": "The performance of SPG in tracing 3D magnetic field", "text": "where f i+1 and f i are two neighboring frequencies. The two maps contain the information of cumulative magnetic morphology in the corresponding depth and computing the differences of gradient orientation would determine the 3D magnetic morphology between the two line of sight depths", "cite_spans": [], "ref_spans": []}, {"section": "The performance of SPG in tracing 3D magnetic field", "text": "We use the block averaging technique (see YL17) to obtain the statistical measurement of gradient orientation within a sampling region. In our calculations we choose the block size to be 30 \u00d7 30 pixels. Table 3 shows the AM from different numerical cubes following our treatment. A clear trend seen from the table is that SPG traces the magnetic morphology with higher accuracy compared to that for the chaotic LOS field. This follows from the differences in the localization of L ef f for the case of regular and chaotic field (Lazarian & Pogosyan 2016) . For the ordered LOS magnetic field case we get the AM around 0.2 to 0.3 which agrees well with the results in LY18b. All gradient techniques share the same foundation of anisotropic MHD turbulence, i.e. the turbulent eddies are elongated along local magnetic field directions which were described in Goldreich & Sridhar (1995) and Lazarian & Vishniac (1999) . The property of anisotropy will affect the structure of other observables, e.g. integrated intensities, velocity centroids, velocity channels and also synchrotron intensities. The performance of gradient techniques are highly related to whether the environment is dominated by turbulence or not, and how anisotropic the system it is. In our case of ordered B-field, the mean magnetic field direction is pointing along the LOS. Since the turbulent eddies are all aligned to the local field and most of our numerical cubes are having strong magnetization, when observing along the mean field only a weak or even no anisotropy can be detected. This also explains why the model with lower M A traces magnetic field better.", "cite_spans": [], "ref_spans": []}, {"section": "WHAT TECHNIQUES SHOULD WE SELECT? 4.1. LOS information along the \u03c6 axis", "text": "In order to know the information of magnetic field from different depths ofF (\u03c6), we should first study the relation between the \u03b4 functions at \u03c6 and LOS axes. On the scale of the resolution, one can see that the correct identification of the position of \u03b4 function is closely related to how ordered is the LOS B-field. Depending on the strength of the mean and fluctuating magnetic field, we can classify the magnetic field conditions into two cases. If the LOS B-field is highly ordered, e.g. when the B-field direction is pointing either towards or away from the LOS observer, each \u03c6 k is unique and we can relate the order in the location of the \u03b4 function in the reconstructed distribution and the order in the location of emitters in the source. If the LOS B-field is chaotic, i.e. is pointing both towards and away from observer, this relation fails. Figure 3 illustrates both cases. In a magnetized environment, the LOS magnetic field structure is usually determined by the orientation of the mean field in respect to the observer. For the SPGs problems arise when the mean field is directed exactly either towards or away form the observer. o solve the problem that there is a complicated dependence of \u03c6 to LOS, a physical model of local interstellar medium should be built up to relate the two physical quantities (Jelic, V. et al. 2015; Van Eck et al. 2017) . However, it requires other measurements for building it up.", "cite_spans": [], "ref_spans": [{"start": 858, "end": 866, "text": "Figure 3", "ref_id": "FIGREF2"}]}, {"section": "Synergy of SPGs & FT", "text": "The SPGs is a very new technique and therefore the corresponding procedures of restoring the 3D structure do require refinement and improvements. We expect that the AM in Table 3 will improve as the technique is getting mature. Nevertheless, even at this point we can clearly see the synergy of the SPGs and the FT.", "cite_spans": [], "ref_spans": []}, {"section": "Synergy of SPGs & FT", "text": "As we showed in section 3.1.1, the LOS B-field structure is critical for determining the positions of synchrotron emission sources in theF (\u03c6). Since the LOS B-field is turbulent in the ISM, tracing 3D B-field structure with FT is difficult in many cases, especially if the mean field is close to perpendicular to the line of sight. This is exactly the case, however, when the SPGs can be most useful. As we discussed above the SPGs have difficulty with tracing magnetic field structure when the mean field is nearly parallel to the line of sight. At the same time, SPG performs the best way when the mean magnetic field is perpendicular to the line of sight.", "cite_spans": [], "ref_spans": []}, {"section": "Synergy of SPGs & FT", "text": "The traditional polarization method that used widely in the astronomical community provides one polarization angle vector per pixel. It is usually being interpreted to be the 2D B-field direction at that pixel. However , this polarization direction that we measured is actually a sum of the Stokes parameters of that column and the direction of polarization is affected by the Faraday rotation (see Eq.7). While the Faraday rotation effect can be minimized by observing the polarization at high frequencies, even in this case the angle that we measure is a mean angle of synchrotron emission from multiple synchrotron sources along the LOS. If the LOS emission is dominated by one bright emission source, the measured polarization angle is close to the polarization angle at the source. In an extreme case where we have multiple sources with comparable brightness, the measured polarization angle may be misleading. As a simple example let us consider two synchrotron polarization sources of similar brightness having 0 and \u03c0 4 polarization angle, which is illustrated by Fig 4. The angle measured in this case is \u223c \u03c0 8 and this fails to represent the underlying magnetic field information for either of the source. The situation of having multiple bright sources along the line of sight is very common. Unfortunately, it is impossible to tell how many sources are there along the line of sight with their respective weight by simply increasing the observing frequency.", "cite_spans": [], "ref_spans": [{"start": 1072, "end": 1078, "text": "Fig 4.", "ref_id": "FIGREF5"}]}, {"section": "Synergy of SPGs & FT", "text": "On the contrary, the FT method (Burn 1966, BB05) has ability to detect the number of the emission sources along the LOS. The amplitude of \u03b4(\u03c6) functions at the Faraday dispersion function representing the brightness of each source. By counting the number of peaks of the Faraday dispersion function, not only we know the numbers of intensive sources along the LOS, also the 2D magnetic field structure within the source.", "cite_spans": [], "ref_spans": []}, {"section": "Synergy of SPGs & FT", "text": "The mathematical nature of the FT method provides the ability to depolarize emission along the LOS. We can even know the intensity distribution along LOS from this method. It also gives a high AM to trace the magnetic field orientation whichever direction the mean field points to. However, the result from FT was limited in the scale of pixel that explained in Section 3.1.1. We lose the positional information during the process from \u03bb 2 to \u03c6 space. We cannot get any information about the magnetic field morphology of different depth even in the local scale. Nevertheless, we cannot construct the 3D field information due to the lack of the LOS B-field information. In this sense, the FT method acts like a probe that allows one to obtain precise 2D field information for each source but fails to provide any of the positional nor line-of-sight B-field information.", "cite_spans": [], "ref_spans": []}, {"section": "Synergy of SPGs & FT", "text": "On the other hand, SPG depicts the magnetic field structure quite well. It can map the 2D magnetic morphology in different depths and even the 3D structure shown in LY18b. Unlike FT which is applied to all the environment, this method comes with requirements of the environment. In principle the method of SPG requires the system to have anisotropic turbulence satisfying the spectral conditions suggested by LY18b, namely the spectral slope has to be steeper than \u22121 and the local anisotropy has to be along local magnetic field direction. In fact, the electron spectrum studies from Armstrong et al. (1995) and later extended by Chepurnov & Lazarian (2010) showed that turbulence spectrum is \u22125/3 for 15 orders of magnitudes, including the scale where synchrotron emissions are significant. Moreover, the anisotropy of the statistical measures available through observations is a well established fact proven with both synthetic observations and actual observational data (see Lazarian et al. 2002; Esquivel & Lazarian 2005; Heyer et al. 2008; ).", "cite_spans": [{"start": 979, "end": 1000, "text": "Lazarian et al. 2002;", "ref_id": "BIBREF52"}], "ref_spans": []}, {"section": "2", "text": "As a result, even though both techniques advertised themselves that they can provide magnetic field information tomographically, their products are different and it is difficult to have direct comparisons between them. For instance, one can identify the bright sources using FT while constructing the 3D field morphology using SPG. The information acquired by both methods are complementary but a side-byside comparison requires further conversion between the two methods.", "cite_spans": [], "ref_spans": []}, {"section": "Frequency sampling between the SPG and FT", "text": "2 The anisotropy of MHD turbulence has been has been known for a while (see Higdon 1984) . It is also a part of Goldreich & Sridhar (1995) picture. It is essential for the SPGs, however, that the anisotropy is present not in terms of mean magnetic field, but in terms of local magnetic field, i.e. the magnetic field at the location of turbulent eddies. This concept is not a part of the original Goldreich & Sridhar (1995) model, but it was introduced in later publications. It follows from turbulent reconnection theory (Lazarian & Vishniac 1999) ", "cite_spans": [], "ref_spans": []}, {"section": "Frequency sampling between the SPG and FT", "text": "The \u03b4\u03bb 2 term controls the maximum \u03c6 that is not affected by the m\u03c0 ambiguities problem. To maximize the usable range of \u03c6, the robust way is to narrow the frequency width. Sometimes it is necessary for observer to narrow the width if the synchrotron emission along LOS is lining on a large |\u03c6|. Therefore, the FT requires more data points to keep its accuracy.", "cite_spans": [], "ref_spans": []}, {"section": "Frequency sampling between the SPG and FT", "text": "For the SPG technique, we can get the relation from Eq. 11 and bring out the result", "cite_spans": [], "ref_spans": []}, {"section": "Frequency sampling between the SPG and FT", "text": "The width of the frequency band controls how thick is the layer along LOS. Increasing the number of data points within the frequency band can get us a more detailed morphology within the region. One of the advantages of this method is that the result will not be affected by m\u03c0 ambiguities problem. Observers have the flexibility to choose the frequency band width.", "cite_spans": [], "ref_spans": []}, {"section": "Frequency sampling between the SPG and FT", "text": "5. DISCUSSION 5.1. Requirements for the instruments It has been shown in \u00a74.2 that SPG and FT techniques are actually complementary to each other. The SPG method requires far less data points compared to FT, and it can be used to scan though the whole region. The method can then provide a 2D magnetic field structure of the whole environment with good accuracy (AM 0.6-0.7). Apart from tracing the direction of magnetic field, the SPG can be used to test the magnetization information. The corresponding technique of obtaining a distribution of Alfvenic Mach numbers M A was demonstrated in LY18a.", "cite_spans": [], "ref_spans": []}, {"section": "Frequency sampling between the SPG and FT", "text": "FT technique (Burn 1966 , BB05, see also Dickey et al. 2018; Jelic, V. et al. 2018; Haverkorn 2018; Farnes et al. 2018 ) provides a high accuracy restoration of magnetic field (AM 0.8-0.9) in ideal case. However, it requires more frequency measurements to keep the high resolution. From BB05, It brings out the resolution of the Faraday dispersion function as,", "cite_spans": [], "ref_spans": []}, {"section": "Frequency sampling between the SPG and FT", "text": "One can easily see that the resolution of the Faraday dispersion function is very sensitive to the frequency density by combining Eq. 15 and Eq. 17.", "cite_spans": [], "ref_spans": []}, {"section": "Frequency sampling between the SPG and FT", "text": "where N = \u2206\u03bb 2 \u03b4\u03bb 2 is the frequency density in a certain frequency band, meaning the total number of N measurements observed in a particular frequency band \u2206\u03bb 2 with frequency width \u03b4\u03bb 2 . The resolution would then affect the accuracy of the FT technique to probe the direction of the magnetic field. To test how the frequency density affects the accuracy, we perform a test for both techniques with different frequency density in Fig.5 .", "cite_spans": [], "ref_spans": []}, {"section": "Frequency sampling between the SPG and FT", "text": "There is a clear trend that the accuracy of the FT technique would drop with respect to the frequency density in all of our simulations. For instance, when the frequency density drops to 250, the accuracy of FT drops to the range of 0.5\u22120.7. It is worth noticing that the SPG technique can achieve the same accuracy with only 20 frequency points. The performance of FT becomes worse when one further decreases the frequency density to 125 frequency points. On the other hand, SPG shows a very stable result with only small fluctuation even in the very low-frequency density measurement like 5 and 10 frequency points.", "cite_spans": [], "ref_spans": []}, {"section": "Frequency sampling between the SPG and FT", "text": "We have demonstrated in \u00a73.2 that SPG is flexible when applying to data with different frequency resolution and plausible in constructing 3D magnetic field morphology with high precision. To better resolve the Faraday depth structure, FT requires high precision instrument like The LowFrequency Array(LOFAR). In view of this, it is more favorable to use the SPG in tracing the 3D magnetic field due to the low-frequency band and the limited frequency resolution we have in current observation since the resolution is comparable to the maximum detectable scale in FT. (Jelic, V. et al. 2015; John M. Dickey et al. 2018) ", "cite_spans": [{"start": 591, "end": 618, "text": "John M. Dickey et al. 2018)", "ref_id": "BIBREF35"}], "ref_spans": []}, {"section": "The future of FT and SPGs", "text": "As a member of VGT family, SPG also based on the same property of anisotropic MHD turbulence. Recently VGT is getting more mature especially in the case of extracting field information from molecular clouds. For instance, a new technique like Moving Window Method was developed to correct the gradient direction and improve the alignment between the gradient direction and magnetic field direction (Lazarian & Yuen 2018a ). In addition, the extraction of magnetization using the dispersion of velocity gradients in diffuse HI media are developed recently . Those methods were already applyed to both diffuse interstellar media and self-gravitating molecular clouds and provide reliable result (Hu et al. 2019) . Likewise, those techniques applied to VGT could also migrate to SPG in the future. By obtaining the multi-frequency synchrotron emission, SPG could construct a 3D magnetization distribution of the interstellar media, by analyzing the gradient distribution in different effective depth of SPG. The accuracy of such predictions can be improved through the Moving Window Method. In the near future, SPGs could provide not only the high precision 3D magnetic field morphology but more physical information along the line of sight.", "cite_spans": [], "ref_spans": []}, {"section": "The future of FT and SPGs", "text": "The use of FT is also combined with other recently developed technique to provide further analysis of the observation data, e.g., combining the Rolling Hough Transform (RHT, Clark et al. 2015) with FT (Jelic, V. et al. 2018) .", "cite_spans": [], "ref_spans": []}, {"section": "The future of FT and SPGs", "text": "In the paper, they are using RHT to characterize the properties of the straight depolarization canals from the LOFAR observation data. As the result, they provide the relative orientation analysis of the Faraday dispersion Map. Moreover, it is worth mentioning that the similar analysis of relative orientation can be obtained also by SPG with a much higher accuracy and a possible 3D morphological structure based on the data provided. We believe that the aforementioned filamentary pattern/structure are the result of velocity crowding and related to the velocity gradient. In the future, SPG itself could also be combining with FT in observation data to obtain the orientation analysis.", "cite_spans": [], "ref_spans": []}, {"section": "The future of FT and SPGs", "text": "6. SUMMARY The present paper compares the two techniques named Faraday Tomography and Synchrotron Polarization Gradients that are plausible to trace the 3D magnetic field using polarized synchrotron emission. We have explored numerically the performance of these techniques and analyzed their strengths and limitations. The FT method can provide high accuracy in magnetic field tracing provided that a high frequency coverage is available and the mean magnetic field are not close to perpendicular to the line of sight. It is advantageous that the SPGs, on the other hand, provide a better accuracy in tracing the 3D magnetic field when the magnetic field is nearly perpendicular to the line of sight. Moreover, we demonstrated that the SPGs require less frequencies when restoring the magnetic field structure. As a result, we claim that combining the two techniques for acquiring the 3D structure of interstellar magnetic field is advantageous, especially as the SPG technique matures and gets more accurate.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF2": {"title": "Galactic Structure and Stellar Populations", "authors": [{"first": "R", "middle": [], "last": "Beck", "suffix": ""}, {"first": "R", "middle": [], "last": "Wielebinski", "suffix": ""}], "year": 2013, "venue": "", "link": null}, "BIBREF4": {"title": "The plot of the AM (y-axis) and frequency density(x-axis) in difference numerical simulation listed in section 2. Every color line represents a numerical simulation. The left panel is represent the plot of FT and right panel is SPG", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF27": {"title": "prep Haverkorn, M. 2018, Peering towards Cosmic Dawn", "authors": [{"first": "D", "middle": ["F"], "last": "Gonz\u00e1lez-Casanova", "suffix": ""}, {"first": "A", "middle": [], "last": "Lazarian", "suffix": ""}], "year": 2018, "venue": "", "link": null}, "BIBREF35": {"title": "Advancing Astrophysics with the Square Kilometre Array (AASKA14)", "authors": [{"first": "John", "middle": ["M"], "last": "Dickey", "suffix": ""}, {"first": "T", "middle": ["L"], "last": "Landecker", "suffix": ""}, {"first": "A", "middle": ["J M"], "last": "Thomson", "suffix": ""}, {"first": "M", "middle": [], "last": "Johnston-Hollitt", "suffix": ""}, {"first": "F", "middle": [], "last": "Govoni", "suffix": ""}, {"first": "R", "middle": [], "last": "Beck", "suffix": ""}], "year": 2015, "venue": "", "link": null}, "BIBREF52": {"title": "Seeing Through the Dust: The Detection of HI and the Exploration of the ISM in Galaxies", "authors": [{"first": "A", "middle": [], "last": "Lazarian", "suffix": ""}, {"first": "D", "middle": [], "last": "Pogosyan", "suffix": ""}, {"first": "A", "middle": [], "last": "Esquivel", "suffix": ""}], "year": 2002, "venue": "", "link": null}}, "ref_entries": {"FIGREF1": {"text": "Figure 1. Comparison plot of between the actual P k andF . The samples are randomly chosen from a column of pixels along the line of sight in a 3D MHD simulation Ms3.2Ma0.32.", "type": "figure"}, "FIGREF2": {"text": "Figure 3. Illustration of two types of LOS B-field and how they affect the order of the \u03b4 function .", "type": "figure"}, "FIGREF3": {"text": "not be cancelled but induce extra Faraday rotation. In fact, there is a similar mathemati- cal origin for the expressions from Faraday rotation ewould make the polarization angle more physically justified.", "type": "figure"}, "FIGREF5": {"text": "Figure 4. Illustration of how multi emission source with similar intensity change the result of the emission angle measurement .", "type": "figure"}, "FIGREF6": {"text": "and is supported by numerical simulations Cho & Vishniac (2000); Maron & Goldreich (2001); Cho et al. (2002).", "type": "figure"}, "TABREF4": {"text": "Table to summarize the difference between SPG and FT method", "type": "table"}}}
{"paper_id": "119426660", "_pdf_hash": "5673ffe08cdd502944c3e38f8b4e16adb35f9e39", "abstract": [{"section": "Abstract", "text": "Abstract. Fitting the multi-wavelength spectral energy distributions (SEDs) of galaxies is a widely used technique to extract information about the physical properties of galaxies. However, a major difficulty lies in the numerous uncertainties regarding almost all ingredients of the SED modeling of galaxies. The Bayesian methods provide a consistent conceptual basis for dealing with the problem of inference with many uncertainties. While the Bayesian parameter estimation method have become quite popular in the field of SED fitting of galaxies, the Bayesian model comparison method, which is based on the same Bayes' rule, is still not widely used in this field. With the application of Bayesian model comparison method in a series of papers, we show that the results obtained with Bayesian model comparison are understandable in the context of stellar/galaxy physics. These results indicate that Bayesian model comparison is a reliable and very powerful method for the SED fitting of galaxies.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "As shown in a series of papers with the same title by Conroy and collaborators (Conroy et al. 2009 , there are many important uncertainties in the stellar population synthesis modeling. To obtain the synthetic spectra of simple stellar populations (SSPs), we need to employ a library of stellar evolutionary tracks, a library of stellar spectra, and assumption about the stellar initial mass function (IMF), all of which suffer from some important uncertainties. It is still challenging to model the complex effects of convection, rotation and a binary companion in stellar evolution (Paxton et al. 2013) . Some not well understood phases of stellar evolution, such as the thermally pulsating AGB stars (Marigo & Girardi 2007; Marigo et al. 2008; Rosenfield et al. 2016) , horizontal branch stars (Heber 2009; Cassisi & Salaris 2013) , and blue straggler stars (Boffin et al. 2014) , have important contributions to the integrated light from a galaxy. On the other hand, the empirical libraries (e.g., Vazdekis et al. 2010 ) of stellar spectra are limited in the coverage in the parameter space, possible errors in the estimation of physical parameters, finite SNR, while the theoretical ones (e.g., Leitherer et al. 2010) suffer from shortcomings of atomic and molecular data, inappropriate abundance ratios, non-LTE, etc. Futhermore, the stellar initial mass functions (IMFs) may not be universal as traditionally assumed, but could be variable in the galaxy's for-2 Yunkun Han mation history (Kroupa 2001; Bastian et al. 2010; Cappellari et al. 2012) . Consequently, the numerous uncertainties in the ingredients of the modeling have led to the diversity of stellar population synthesis (SPS) models \u2020. Except for the SSPs given by SPS modelings, we need models about the star formation history (SFH) and chemical evolution history of the interstellar medium, which are even more uncertain.", "cite_spans": [{"start": 810, "end": 833, "text": "Cassisi & Salaris 2013)", "ref_id": "BIBREF4"}, {"start": 861, "end": 881, "text": "(Boffin et al. 2014)", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Bayesian model comparison", "text": "Given the numerous uncertainties regarding almost all ingredients of the SED modelings of galaxies, we need to find a method to allow a reasonable comparison of the many possible assumptions about them. While the Bayesian parameter estimation method has been widely used in the field of SED fitting galaxies, the Bayesian model comparaison method, which is based on the same Bayes' rule as Bayesian parameter estimation, is still rarely used in this field. A main reason for this situation is that the computation of Bayesian evidence, which is critical for Bayesian model comparison, is generally much more computationally expansive than the posterior sampling in Bayesian parameter estimation. However, with the advent of state-of-the-art Bayesian inference tool, such as MultiNest (Feroz et al. 2009) , it has become possible to achieve efficient and robust computation of Bayesian evidence. The Bayesian evidence can be thought as a quantified Occam's razor such that a model with a better balance between its goodness-of-fit to the data and its complexity will be more favored (Gregory 2005) .", "cite_spans": [{"start": 1082, "end": 1096, "text": "(Gregory 2005)", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Bayesian model comparison", "text": "A major difficulty for the application of Bayesian model comparison method to the comparison of different SED modelings lies in the fact that the computation of the SED modeling itself could be even more computationally expansive. In Han & Han (2012) , we have employed the artificial neural network (ANN) technique to allow a rather rapid computation of model SEDs. With the building-up of a pre-released version of our BayeSED code, we have applied the Bayesian model comparison to the study of a sample of hyper-luminous infrared galaxies (HLIRGs) (Ruiz et al. 2010) . We found that the more complicated Starburst+AGN model has larger Bayesian evidence than the simpler pure Starburst or pure AGN model. This result supports the idea that HLIRGs represent an important phase in the formation and evolution of galaxies where both the star formation and SMBH accretion are very active. In Fan et al. (2016a,b) , we have applied the similar methods to the infrared SED decomposition of a sample of WISE-selected, hyperluminous hot dust-obscured galaxies. We found that the more complicated AGN torus+Greybody model has larger Bayesian evidence than the simpler pure AGN torus or pure Greybody model for these galaxies.", "cite_spans": [], "ref_spans": []}, {"section": "Bayesian model comparison", "text": "In Han & Han (2014) , we have presented the first version of our BayeSED code. The performance of BayeSED for the estimation of physical parameters, such as stellar mass and star formation rate, has been extensively tested with a mock sample of galaxies and the comparaison with the results obtained with the FAST code (Kriek et al. 2009 ). With BayeSED V1.0, we have presented the first Bayesian comparison of SPS models. For a Ks-selected sample of 5467 low-z galaxies given by Muzzin et al. (2013) , we found that the simpler BC03 model has larger Bayesian evidence than the M05 model. However, this comparison of SPS models has some important limitations. For example, we have only considered the most popular BC03 and M05 models, while there are many others. The SFH of galaxies is fixed to the commonly used Exp-dec form, and the dust attenuation law (DAL) is fixed to the Calzetti law. Since the SFH and DAL of different galaxies could be very different, the above assumption about them could introduce serious bias to the results of Bayesian SPS model comparaison.", "cite_spans": [], "ref_spans": []}, {"section": "Bayesian model comparison", "text": "In Han & Han (2019) , we have presented a more comprehensive Bayesian Discrimination of SPS models, where 16 SSP models, 5 forms of SFH and 4 forms of DAL have been considered. We have introduced a method to define the Bayesian evidence for the SED modeling of a sample of galaxies with a universal and fixed SSP, but object-dependent and free SFH and DAL. Since the Bayesian evidence is defined for a sample of galaxies instead of an individual galaxy and the results are obtained with the marginalization over the different choices of SFH and DAL for different galaxies, we can achieve a much more robust comparison of SPS models. We found that the most widely used BC03 has much larger Bayesian evidence than many other more updated SPS models, including the CB07 model from the same authors. Our results indicate that the contribution of TP-AGB stars is still not properly considered in current SPS models. On the other hand, we found that the version of BPASS V2.0 model (Eldridge et al. 2008 ) without binaries has a slightly larger Bayesian evidence than the BC03 models. However, the version of BPASS V2.0 model with binaries actually has the lowest Bayesian evidence. For the two models with the consideration of binaries, the Yunnan-II model (Zhang et al. 2005 ) is more favored than the BPASS V2.0 model. Our results indicate that the effects of binaries are still not well considered in current SPS models, which is not surprising, given the uncertainties about the period and mass-ratio distributions of binary stars (Moe & Di Stefano 2017) and other not well understood complex physics in binary stellar evolution.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "With the MultiNest-like Bayesian inference tools and methods for rapid generation of model SEDs, it has become possible to reliably and efficiently compute the Bayesian evidence for a large set of SED models. In a series of papers, we show that the results obtained with Bayesian model comparison are understandable in the context of stellar/galaxy physics. So, we believe that Bayesian model comparison is a reliable and very powerful method, and it should be more extensively used in the field of SED fitting and the study of galaxies. We have built the BayeSED code \u2020 for this kind of studies. The public version of the code is in a compiled binary format, which is generally faster than other interpreted language code (e.g. Python). The code is directly runable on MAC/LINUX platform and does not require users to resolve the often annoying library dependency problems. In the future, more and more sophisticated SED models will be added gradually to BayeSED. The suggestions about adding new SED models and other new features, and the reports about bugs are very welcome.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF1": {"title": "Ecology of Blue Straggler Stars", "authors": [{"first": "H", "middle": [], "last": "Boffin", "suffix": ""}, {"first": "G", "middle": [], "last": "Carraro", "suffix": ""}, {"first": "G", "middle": [], "last": "Beccari", "suffix": ""}], "year": 2014, "venue": "", "link": "118118652"}, "BIBREF4": {"title": "Old Stellar Populations: How to Study the Fossil Record of Galaxy Formation", "authors": [{"first": "S", "middle": [], "last": "Cassisi", "suffix": ""}, {"first": "M", "middle": [], "last": "Salaris", "suffix": ""}], "year": 2013, "venue": "", "link": "117024426"}, "BIBREF12": {"title": "Bayesian Logical Data Analysis for the Physical Sciences", "authors": [{"first": "P", "middle": [], "last": "Gregory", "suffix": ""}], "year": 2005, "venue": "", "link": "60150778"}}, "ref_entries": {}}
{"paper_id": "119426844", "_pdf_hash": "29290e13d0d7783f7c9517fb1ab36b7652783c8e", "abstract": [{"section": "Abstract", "text": "String scenarios generically predict that we live in a so called axiverse: the Universe with about a hundred of light axion species which are decoupled from the Standard Model particles. However, the axions can couple to the inflaton which leads to their production after inflation. Then, these axions remain in the expanding Universe contributing to the dark radiation component, which is severely bounded from present cosmological data. We place a general constraint on the axion production rate and apply it to several variants of reasonable inflaton-to-axion couplings. The limit merely constrains the number of ultralight axions and the relative strength of inflaton-to-axion coupling. It is valid in both large and small field inflationary models irrespectively of the axion energy scales and masses. Thus, the limit is complementary to those associated with the Universe overclosure and axion isocurvature fluctuations. In particular, a hundred of axions is forbidden if inflaton universally couples to all the fields at reheating. In the case of gravitational sector being responsible for the reheating of the Universe (which is a natural option in all inflationary models with modified gravity), the axion production can be efficient. We find that in the Starobinsky R 2 -inflation even a single axion (e.g. the standard QCD-axion) is in tension with the Planck data, making the model inconsistent with the axiverse. The general conclusion is that an inflation with inefficient reheating mechanism and low reheating temperature may be in tension with the presence of light scalars.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "In order to solve several problems of the hot Big Bang cosmology, the inflationary stage of the Universe evolution has been proposed [1, 2] . The simplest way to organize the close-toexponential expansion of the Universe is to exploit the scalar field (inflaton) slowly rolling towards the minimum of the potential [3, 4] . Recent data from the Planck satellite put such strong constraints on the inflaton potential that the simplest quartic and quadratic cases turn out to be excluded [5] . The best agreement with the data is still exhibited by the large field inflation provided by the exponentially flat potential. Such a potential naturally arises in different models with the modified gravitational sector [1, 6, 7] as well as in the supergravity framework [8] [9] [10] . All these models, being non-renormalizable, require an ultraviolet completion which is often thought to be a string theory.", "cite_spans": [{"start": 767, "end": 770, "text": "[9]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Introduction", "text": "However, the common prediction of many string scenarios is the existence of a plenty of light scalars (axions) arising as zero modes of antisymmetric gauge fields on the compactified dimensions [11] . They inherit a perturbative shift symmetry violated by instanton contributions [12, 13] . One of these scalars can play a role of QCD axion explaining the zero value of the QCD \u03b8-angle. The number of light axions is determined by the topology of extra dimensions and is likely to be about hundred [14] . Many potentially observable consequences of the string axiverse were discussed in literature [14, 15] . Here we explore whether many light scalars are compatible with inflationary models. String axions can contribute to dark matter component, see e.g. [16] . In order to avoid overproduction and suppress isocurvature fluctuations, one constrains the axion masses, couplings and initial conditions at the inflationary stage. At the same time, light scalars produced at reheating can contribute to the dark radiation, which implies an additional bound on the model parameters. Dark radiation amount at Big Bang Nucleosynthesis (BBN) and recombination is now strictly bounded by the Planck data [18] . In generic string scenarios, the number of effective relativistic degrees of freedom at these epochs is predicted to be much larger than the Planck results [18] allow, the discrepancy is mostly due to the contribution of moduli decays [15] . One can suppose, however, that the supersymmetry breaking scale, as well as the masses of all moduli, are larger than the Hubble parameter at inflation. In this case, the moduli are not produced and the axions are created only by the inflaton decay. We show that in this case, if the inflaton couples to SM particles only through the gravity (i.e. via suppressed by Planck mass operators, which is natural, e.g. for F (R) inflationary models), then even one light scalar is in tension with the recent Planck data. Thus, in the axiverse the inflaton must couple to matter much stronger. In that case, we put a lower bound on the reheating temperature which makes the existence of hundreds of light scalars consistent with the Planck data.", "cite_spans": [], "ref_spans": []}, {"section": "Reheating in the axiverse", "text": "In each model, the inflationary stage must be followed by the reheating process eventually populating the Universe with the hot plasma of SM particles. Therefore, the energy of the inflaton field must be somehow transformed into the usual matter. In general, during this process axion-like particles can well be produced. Let the production rate of each axion be \u0393 a while that of the SM particles be \u0393 SM . Then, the number of additional degrees of freedom at BBN and recombination written traditionally as the number of additional neutrino components is", "cite_spans": [], "ref_spans": []}, {"section": "Reheating in the axiverse", "text": "Here N is the number of axion species, g \u03bd = 2 \u00b7 7/8, g reh and g BBN are the effective number of relativistic degrees of freedom at reheating and nucleosynthesis stages, respectively. Their SM values are g reh = 106.75 and g BBN = 10.75. According to the latest Planck data, within the concordance \u039bCDM cosmological model the effective number of relativistic species N eff is bounded as [18] N eff = 3.15 \u00b1 0.23.", "cite_spans": [], "ref_spans": []}, {"section": "Reheating in the axiverse", "text": "This parameter is expected to be measured in future CMB polarization experiments with much higher accuracy [19, 20] . One can observe from (1) that if the reheating is due to some universal mechanism (i.e. inflaton decays to all scalars including the SM Higgs with the comparable rates \u0393 a \u223c \u0393 SM /4) then \u2206N eff \u223c 0.7 N which is clearly incompatible with bound (2) in the axiverse. This is the main finding of the present paper.", "cite_spans": [], "ref_spans": []}, {"section": "Reheating in the axiverse", "text": "The bound (1), (2) constrains axion coupling to inflaton and the number of axions ultrarelativistic at BBN and recombination. It is applicable to both large-and small-field inflation with any mass pattern in the axion sector, as far as the axions remain ultrarelativistic. Thus, the obtained constraint is complementary to another bounds on the axion energy scales, masses and on the energy scale of inflation. These bounds are inferred from the Universe overclosure argument and absence of the axion isocurvature fluctuations [16, 17] . Formula (1) is exact if the axion branching ratio \u0393 a /\u0393 SM is constant in time at the reheating epoch. Otherwise it is corrected by a numerical factor of order one, which is the case if the inflaton couplings to the axion and SM-particles are of the different nature, e.g. provided by the operators of different dimensions. Then \u0393 SM in eq. (1) defines the age of the Universe at reheating, t U \u223c 1/\u0393 SM and \u0393 a /\u0393 SM \u223c \u0393 a t U \u226a 1 refers to the fraction of inflaton energy transfered to axions.", "cite_spans": [], "ref_spans": []}, {"section": "Reheating in the axiverse", "text": "The case when moduli decay is responsible for the reheating provides an example of the universal reheating mechanisms, which has been studied in Ref. [15] . Below we consider several other examples of models with universal reheating mechanisms relevant to the problem with axiverse.", "cite_spans": [], "ref_spans": []}, {"section": "The Starobinsky model", "text": "The Starobinsky model of inflation historically was the first successful model suggested for the exponential stage of the Universe expansion [1] . However, it still provides the predictions which are in a perfect agreement with the present cosmological data [18] . In a Jordan frame, the model is described by the following action:", "cite_spans": [], "ref_spans": []}, {"section": "The Starobinsky model", "text": "Here the reduced Planck mass is", "cite_spans": [], "ref_spans": []}, {"section": "The Starobinsky model", "text": "GeV and S matter denotes the action for all matter fields in the theory. The value of m, which is actually mass of an additional scalar degree of freedom (scalaron) responsible for inflation, is determined by the amplitude of scalar perturbations as m = 1.3 \u00d7 10 \u22125 M P [23] . After the Weyl transformation of the metric to the Einstein frame,", "cite_spans": [], "ref_spans": []}, {"section": "The Starobinsky model", "text": "action ( ", "cite_spans": [], "ref_spans": []}, {"section": "The Starobinsky model", "text": "HereS matter is the Weyl transformed action of the matter fields. Thus, conformal noninvariance in the matter sector naturally implies the interaction between scalaron \u03c6 and all other particles. Fermions and vector fields are Weyl invariant at the tree level in the high energy limit. Therefore, a key role in the process of reheating is played by the light scalars: SM Higgs boson and axions in the discussed framework (see Ref. [26] for dilaton). Axions a i , i = 1, . . . , N, unlike the Higgs, due to the perturbative shift symmetry [13] can not be non-minimally coupled to the gravity via terms Ra 2 i . Thus, their kinetic terms are canonical in the Jourdan frame (3), yielding the universal couplings to the inflaton. The decay rates of scalaron to Higgs pair and to axion pair are [22, 27] ", "cite_spans": [], "ref_spans": []}, {"section": "The Starobinsky model", "text": "respectively, with the SM Higgs boson possibly non-minimally coupled to gravity via lagrangian term L = \u03be h Rh 2 /2. One observes that the decay rates to the axions and to the SM particles (Higgs bosons) are comparable.", "cite_spans": [], "ref_spans": []}, {"section": "The Starobinsky model", "text": "The ultrarelativistic axions produced at reheating remain in the late Universe contributing to the energy density and pressure at BBN and recombination as additional", "cite_spans": [], "ref_spans": []}, {"section": "The Starobinsky model", "text": "neutrino flavors (we put (7) with \u03be h = 0 into (1)). Hence, even one additional light scalar (for example, standard QCD axion) is already in tension with the Planck bound (2) in the Starobinsky model.", "cite_spans": [], "ref_spans": []}, {"section": "The Starobinsky model", "text": "To resolve the situation one can add some new N s scalars to the matter content of the SM. Then the r.h.s. of (8) gets suppressed by a factor 4/(4 + N s ), which makes the Starobinsky model in the axiverse populated by N \u223c 100 axions consistent with the present cosmological bounds (2) if N s \u223c 200 scalars are added.", "cite_spans": [], "ref_spans": []}, {"section": "Inflation with non-minimal kinetic terms", "text": "Another way to obtain the favored by the Planck results exponentially flat potentials in a natural way is connected with the modification of the kinetic term of the inflaton. This idea is widely discussed in the context of supergravity [8, 9, 24, 32] where non-trivial kinetic terms come from the Kahler potential. In particular, it was realised as \u03b1-attractors in Refs. [28, 29] , where the inflationary region corresponds to the pole in the kinetic term of the inflaton. In all these models the inflaton may be canonically normalized upon an appropriate field transformation. In general, one can expect that the kinetic terms of additional scalars (axions) are also non-minimal. Thus, the action consistent with the shift symmetry of axions a i reads", "cite_spans": [{"start": 240, "end": 242, "text": "9,", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Inflation with non-minimal kinetic terms", "text": "where f i (\u03c6) are some functions of the inflaton field.", "cite_spans": [], "ref_spans": []}, {"section": "Inflation with non-minimal kinetic terms", "text": "Similarly one may expect non-renormalizable couplings to the SM fields yielding the most relevant for reheating two-body decays of inflaton,", "cite_spans": [], "ref_spans": []}, {"section": "Inflation with non-minimal kinetic terms", "text": "Terms in the last set in (10) are proportional to the fermion masses through the equation of motion and hence their role in the reheating is negligible. Near the minimum of V (\u03c6) (we take it to be zero) one may anticipate the expansions", "cite_spans": [], "ref_spans": []}, {"section": "Inflation with non-minimal kinetic terms", "text": "From the point of view of the effective theory considered after inflation such terms suppressed by cutoff scale \u039b < M P are naturally expected with \u03b2,\u03b3, \u03b4 \u223c 1 from quantum corrections since the potential of the inflaton (as well as the gravity) is non-renormalizable. However, during inflation f i (\u03c6) \u2248 1 because of the approximate shift symmetry of the inflaton field with Planck-favored plateau-like potential providing no significant physical effects. But after inflation the expansions (11) start to work leading to the inflaton decay. For example, with \u03b3 = 0 the reheating process can go through the decay of the inflaton to the Higgs bosons. If the coupling to gauge bosons is suppressed for some reason we are left with the similar case as in the Starobinsky model where the dark radiation production is highly efficient (8) . This model is cosmologically forbidden. If the inflaton couples to the kinetic terms of all the matter fields in the model with \u03b3, \u03b4 i \u223c 1, then all the bosons will be produced roughly at equal amounts. In this case one can get an estimate for the axion contribution to the effective relativistic degrees \u2206N eff by putting \u0393 a /\u0393 SM \u223c 1/30 in (1). In this way one obtains \u2206N eff \u223c N/10, which is certainly cosmologically forbidden for N \u223c 100 given the constraint (2).", "cite_spans": [], "ref_spans": []}, {"section": "Inflation with non-minimal kinetic terms", "text": "The problem of axion overproduction may be avoided if the inflaton couples to the SM particles stronger than to the axions. The former may be parametrized by means of the time of reheating (as we discuss at the beginning of Sec. 2) or the reheating temperature T reh , i.e. the temperature of the SM plasma at the moment when a half of the total energy density is already in the form of radiation. Then, if the inflaton mass is m, one obtains from Eqs. (9), (11),", "cite_spans": [], "ref_spans": []}, {"section": "Inflation with non-minimal kinetic terms", "text": "Substituting (12) into the equation (1) we obtain for the amount of dark radiation:", "cite_spans": [], "ref_spans": []}, {"section": "Inflation with non-minimal kinetic terms", "text": "For the reheating temperature high enough one can see that N \u223c 100 may still be allowed by the Planck constraints. On the contrary, inefficient reheating with low T reh can easily throw the model out of the viable range (2) . Note in passing that the terms of the first order in the expansion (11) may be forbidden due to some symmetry (the simplest one is Z 2 , \u03c6 \u2192 \u2212\u03c6). In this case, the production of axions would be inefficient if the Universe is reheated due to the other inflaton couplings to matter provided by a lower order operators.", "cite_spans": [], "ref_spans": []}, {"section": "Inflation with non-minimal kinetic terms", "text": "We discuss this case in more details in the next Section using the inflaton non-minimally coupled to gravity as a realistic example.", "cite_spans": [], "ref_spans": []}, {"section": "Inflation driven by the scalar field non-minimally coupled to gravity", "text": "Although inflation models with reasonable (e.g. renormalizable without gravity) power-law potentials are disfavoured by the Planck data, switching on the non-minimal coupling of the inflaton to gravity can provide with the flat potential suppressing the tensor modes. Models of such type are widely discussed in the literature (see e.g., [28, 30, 31] ) and include the Higgs inflation [7] . The action for the inflaton field \u03c6 reads (here we neglect the possible mass term for the inflaton at large field values),", "cite_spans": [], "ref_spans": []}, {"section": "Inflation driven by the scalar field non-minimally coupled to gravity", "text": "One can get rid of the non-minimal coupling by making use of the metric redefinition", "cite_spans": [], "ref_spans": []}, {"section": "Inflation driven by the scalar field non-minimally coupled to gravity", "text": "After that, the action in the Einstein frame takes the form", "cite_spans": [], "ref_spans": []}, {"section": "Inflation driven by the scalar field non-minimally coupled to gravity", "text": "where canonically normalized field \u03c7 is defined by", "cite_spans": [], "ref_spans": []}, {"section": "Inflation driven by the scalar field non-minimally coupled to gravity", "text": "The kinetic term of axion gets coupled to the inflaton in the Einstein frame:", "cite_spans": [], "ref_spans": []}, {"section": "Inflation driven by the scalar field non-minimally coupled to gravity", "text": "At first sight, this coupling is quadratic in inflaton and seems to be strongly suppressed by squared Planck scale. However, at and some time after inflationary epoch the inflaton field takes large values, \u03c6 \u223c M P . This makes the second term in parenthesis in (18) important to the extent which depends on the value of nonminimal coupling \u03be. Taking into account this fact we study two different cases for the value of \u03be which finally yield different results.", "cite_spans": [], "ref_spans": []}, {"section": "Inflation driven by the scalar field non-minimally coupled to gravity", "text": "Large non-minimal coupling, \u03be \u226b 1. This case includes the model of Higgs inflation [7] . In this limit for large field values of \u03c6 > M P / \u221a \u03be one obtains from (17)", "cite_spans": [], "ref_spans": []}, {"section": "Inflation driven by the scalar field non-minimally coupled to gravity", "text": "Inflation in models of this type is followed by harmonic oscillations with frequency \u03c9 = \u03bb/3M P /\u03be: the scalar potential is effectively quadratic while the amplitude of \u03c7 is large enough,", "cite_spans": [], "ref_spans": []}, {"section": "Inflation driven by the scalar field non-minimally coupled to gravity", "text": "The Universe is expanding as at the stage of matter domination: a \u221d t 2/3 . In the original", "cite_spans": [], "ref_spans": []}, {"section": "Inflation driven by the scalar field non-minimally coupled to gravity", "text": "Higgs inflation [7] the reheating happens at this stage due to decays of Higgs to the SM particles [25] . The interaction lagrangian between the inflaton and any additional scalar a coming from the Weyl transformation (15) takes the same form as in the Starobinsky model of Sec. 2.1:", "cite_spans": [], "ref_spans": []}, {"section": "Inflation driven by the scalar field non-minimally coupled to gravity", "text": "If the reheating happens at this stage (Eqs. (19) , (21), (20)) then the decay rates of the inflaton are actually given by eq. (12) . Here T reh is the temperature of the SM plasma at the moment of equality between energy densities of radiation and inflaton excitations. For the Higgs inflation T reh \u2243 6 \u00d7 10 13 GeV [25] . Let us evaluate the amount of dark radiation given the reference values of the Higgs inflation:", "cite_spans": [], "ref_spans": []}, {"section": "Inflation driven by the scalar field non-minimally coupled to gravity", "text": "One can observe that the axiverse with N \u223c 10 2 is safe from the overproduction of dark radiation in models with high enough reheating temperature. Such models require nongravitational couplings between the inflaton and SM particles, like gauge and Yukawa interactions between the inflaton (Higgs) and the SM fields in the example of Higgs inflation.", "cite_spans": [], "ref_spans": []}, {"section": "Inflation driven by the scalar field non-minimally coupled to gravity", "text": "A side remark concerns models with the axions coupled to the SM particles in plasma that provide with more efficient mechanisms of the dark radiation production. The QCD axion with the decay constant in the range f a \u223c 10 10 \u2212 10 12 GeV is a realistic example. Such axion couples to the SM particles via dimension-5 operators suppressed by \u039b = f a rather than \u039b = M Pl . Therefore, it thermalizes in the SM plasma of temperature above 10 9 GeV which is the case for the Higgs inflation. Thus, the amount of dark radiation in this case is defined by the axion number density in thermal equilibrium. This leads to the value [33] \u2206N ef f = 0.026,", "cite_spans": [], "ref_spans": []}, {"section": "Inflation driven by the scalar field non-minimally coupled to gravity", "text": "which can be measured in future CMB polarization experiments [19, 20] . At the same time, the thermal production of string axions with f a \u223c 10 16 GeV is still inefficient.", "cite_spans": [], "ref_spans": []}, {"section": "Inflation driven by the scalar field non-minimally coupled to gravity", "text": "It is worth noting that the reference value of the reheating temperature in (22) corresponds to the final amplitude of the inflaton oscillations of order \u03c7 \u223c M P /\u03be [25] 1 . In other words, for a quartic inflation with non-minimal coupling to gravity, the reheating temperature cannot be lower than the reference value in (22) , if the system is still at the effective matter domination stage provided by (20) . Hence eq. (22) imposes a kind of upper limit on the impact of axions in the model with efficient reheating. If the reheating is less efficient than in the Higgs inflation, the evolution comes to the second stage. There the inflaton amplitude drops down to the value \u03c7 \u223c M P /\u03be before the reheating started, and the potential and interactions of the canonically normalized inflaton field \u03c7 change the forms:", "cite_spans": [], "ref_spans": []}, {"section": "Inflation driven by the scalar field non-minimally coupled to gravity", "text": "1 We do not consider values of \u03be much larger than those of the Higgs inflation (\u03be \u223c 10 5 ) because it would lead to strong coupling for the inflaton self-coupling, \u03bb 1 .", "cite_spans": [], "ref_spans": []}, {"section": "Inflation driven by the scalar field non-minimally coupled to gravity", "text": "After this moment the axion production becomes inefficient because, instead of the inflaton decay, we deal with the inflaton scattering suppressed by the squared Planck mass. Moreover, the scattering rate dilutes as 1/a 3 due to the Universe expansion providing with negligible overall axion production.", "cite_spans": [], "ref_spans": []}, {"section": "Inflation driven by the scalar field non-minimally coupled to gravity", "text": "Therefore at this stage, the axion production actually terminates providing the overall impact of axions to be of order (22) calculated for the reference value of the reheating temperature T reh \u2243 6 \u00d7 10 13 GeV. One can see that for all reasonable parameter choices we are left with a negligible amount of axion dark radiation. Note that the real reheating, that is a production of the SM plasma, may happen much later, than the reference temperature indicates, but it does not change this estimate in the slightest. Inflaton couplings to the SM particles must be of another form than the kinetic one of Eq. (24), the latter is not sufficient for successful reheating.", "cite_spans": [], "ref_spans": []}, {"section": "Inflation driven by the scalar field non-minimally coupled to gravity", "text": "Small non-minimal coupling \u03be \u226a 1. Here the change of variables (17) may be simplified:", "cite_spans": [], "ref_spans": []}, {"section": "Inflation driven by the scalar field non-minimally coupled to gravity", "text": "The potential (14) transforms to", "cite_spans": [], "ref_spans": []}, {"section": "Inflation driven by the scalar field non-minimally coupled to gravity", "text": "Near the minimum, conformal factor (15) can be approximated as \u2126 2 = 1+\u03be\u03c7 2 /M 2 P providing the leading interaction term with scalars to be", "cite_spans": [], "ref_spans": []}, {"section": "Inflation driven by the scalar field non-minimally coupled to gravity", "text": "Potential (26) is symmetric with respect to \u03c7 \u2192 \u2212\u03c7 so no linear terms are expected. The production of axions in that case is inefficient due to the M 2 P suppression of interaction (27) in accord with the expectations we discussed right below eq. (18).", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "In this paper, we investigate the validity of inflationary models in the string axiverse. Many light scalars can be produced at reheating and later contribute to the dark radiation component of the Universe which is strictly bounded by the recent Planck data. We found the general conditions for the efficient production of the light scalars at the Universe reheating. Namely, if the inflaton decays to two axions via the dimension-5 Planck-scale suppressed operators then the amount of the dark radiation is controlled by the reheating temperature. For example, inflationary models with reheating via Planck suppressed couplings of the inflaton to the SM particles (which seems to be common in the supergravity framework) predict too much dark radiation making them inconsistent with the cosmological observations. We should stress that our results are directly applicable not only in the string framework but for any light scalars (Nambu-Goldstone bosons, dilaton) which may appear in a concrete cosmological model.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "However, there are two ways how to make the inflation consistent with the presence of extra light scalars. The first way is to provide the additional couplings between the inflaton and SM fields which are not suppressed by the Planck mass. It would raise the reheating temperature leaving no time for the axions production after inflation. Another way around is to deal with models possessing a symmetry which either forbids or strongly suppresses the inflaton decay to axions (the symmetry must not prevent the successful reheating, of course).", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF1": {"title": "Nonsingular model of the Universe with the quantum-gravitational de Sitter stage and its observational consequences", "authors": [{"first": "A", "middle": ["A"], "last": "Starobinsky", "suffix": ""}], "year": 1981, "venue": "Proc. of the Second Seminar \"Quantum Theory of Gravity", "link": "117034521"}, "BIBREF9": {"title": "Erratum", "authors": [{"first": "J", "middle": [], "last": "Ellis", "suffix": ""}, {"first": "D", "middle": ["V"], "last": "Nanopoulos", "suffix": ""}, {"first": "K", "middle": ["A"], "last": "Olive", "suffix": ""}], "year": 2013, "venue": "Phys. Rev. Lett", "link": null}}, "ref_entries": {"FIGREF0": {"text": "3) takes the form [21]", "type": "figure"}}}
{"paper_id": "119427373", "_pdf_hash": "1abcbcf5798a3736564e4463be33c10b0f7b7626", "abstract": [{"section": "Abstract", "text": "The off-line \u03b3-spectrometry was carried out after the end of bombardment (EOB) to measure the activity of the radionuclides produced in each foil and cross sections were calculated. Measured cross-sectional data were analyzed in terms of compound and precompound model calculations. Conclusions: Theoretical estimations confirmed that major production yields are mostly contributed by the compound reaction process. Preequilibrium emissions contributed at the high energy tail of the 3n channel for both the reactions. Moreover, an indirect signature of a direct reaction influence was also observed in the 90m Y production. ", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "I. INTRODUCTION", "text": "were also studied by our group to produce NCA 97 Ru [26] [27] [28] [29] [30] .", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "On the other hand, low-lying high intense \u03b3-rays of 101m Rh help in the in vivo monitoring by using a scintillation camera, while emission of Auger, Coster-Kronig electrons and X-rays aid in therapeutic applications. The 101m Rh (4.34 d) decays mainly by electron capture (92.8 %) to stable 101 Ru by emitting 306.9 keV (81 %) and 545.1 keV (4.3 %) \u03b3-rays and by isomeric transition (IT) (7.2 %) to 101 Rh (3.3 a), which finally decays to 101 Ru.", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "So far, production of 101m Rh has been studied using light ion (p, d, 3 He, 4 He) induced reactions only. 101m Rh was produced through the decay of its precursors 101 Pd and 101 Ag, which were populated in p-induced reactions on the 103 Rh, nat Pd, and nat Ag targets [31] [32] [33] [34] [35] [36] [37] .", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "In the deuteron-induced reactions, production of 101m Rh using 103 Rh target was measured by Hermanne et at., Detr\u00f3i et al. in different energy regions [38] [39] [40] . Direct and cumulative production of 101m Rh in the d+ nat Pd reaction was also experimented by Detr\u00f3i et al. [41] , however the production was significantly low. Apart from these, production of 101m Rh isomer was reported by Skakun et al. [42] Thus we have gone through the current interest to study the heavy ion induced reactions and the production of 97 Ru and 101m Rh radionuclides in those reactions. The experimental procedure and brief review of the nuclear model calculations are described in Secs. II and III, respectively. Section IV discusses the results and Sec. V finally concludes the report.", "cite_spans": [], "ref_spans": []}, {"section": "II. EXPERIMENT", "text": "The experiment was performed at the BARC-TIFR Pelletron facility, Mumbai, India. Spectroscopically pure (99.99%) natural yttrium and niobium foils were procured from the Alfa Aesar. Self-supporting thin foils of those metals were made by uniform rolling in a machine. Thicknesses of the thin Y-and Nb-foils were between 0.84-2.9 mg/cm 2 and 1.2-2.1 mg/cm 2 , respectively. The Al-backing foils had thickness between 1.5-2 mg/cm 2 . Annular aluminum holders with an inner and outer diameter 12 and 20 mm, respectively, were used to mount the foils. The large area of Al foil ensures the complete collection of recoiled the residues, if recoiled any, in the beam direction. The Al-foils also served the purpose of an energy damper so that suitable energy separation between consecutive target foils could be achieved. Energy degradation of the projectile in each foil was estimated by Stopping and", "cite_spans": [], "ref_spans": []}, {"section": "Stacked foil activation technique was used to explore", "text": "Range of Ions in Matter (SRIM) code [43] . The 11 B energy at a target is typically the average of the incident and outgoing beam energy.", "cite_spans": [], "ref_spans": []}, {"section": "Stacked foil activation technique was used to explore", "text": "After the end of bombardment (EOB), the residual radionuclides produced in each target foil (Y and Nb) were identified and quantified with the help of \u03b3-ray spectrometry using a broad energy germanium (BEGe) based detector attached with a PC operating with the The activity of the residuals was measured in a fixed geometry over a longer period of time in the regular intervals to follow their decay profile. The activity of the residuals at the EOB was measured from the background-subtracted peak area count rate (counts/sec).", "cite_spans": [], "ref_spans": []}, {"section": "Stacked foil activation technique was used to explore", "text": "Production cross section of the residues at each incident energy was calculated from the activation formula. The detail description of the activity and cross-section measurement is available in our previous reports [26, 44, 45] . Nuclear spectroscopic data of the residual radionuclides are listed in Table I [46].", "cite_spans": [], "ref_spans": [{"start": 301, "end": 308, "text": "Table I", "ref_id": "TABREF6"}]}, {"section": "Stacked foil activation technique was used to explore", "text": "The error introduced in the cross section measurement was mainly due to non-uniformity of samples and in measuring its thickness (\u223c5%), fluctuation of beam current (\u223c5%), efficiency calibration of the detector (\u223c2%). Some other sources such as the branching intensity of characteristic \u03b3-rays, counting statistics, beam energy degradation while traversing through the successive target foils (straggling effects) etc. are also responsible; however, these were negligible in this case [47, 48] . The total uncertainty associated with the cross section measurement was determined considering all those factors and the data was presented in this article up to 95% confidence level.", "cite_spans": [], "ref_spans": []}, {"section": "Stacked foil activation technique was used to explore", "text": "III. ANALYSIS OF MEASURED DATA", "cite_spans": [], "ref_spans": []}, {"section": "PACE4", "text": "Compound reaction contribution in the produced residues at different bombarding en- ", "cite_spans": [], "ref_spans": []}, {"section": "PACE4", "text": "where \u03bb (= \u03bb/2\u03c0) is the wavelength of incident projectile; s, I and J represent projectile, target and compound nucleus spin, respectively, and l is orbital angular momentum of the projectile. T \u03b1jl (E \u03b1 , J, \u03a0) stands for the transmission coefficient having channel energy E \u03b1 and orbital angular momentum l, which together with particle spin s couples to the channel angular momentum j used to select in target nucleus spin I populated for a given compound nucleus spin J and parity \u03a0. Similarly, T \u03b2j \u2032 l \u2032 (E \u03b2 , J, \u03a0) and T \u03b3j \u2032\u2032 l \u2032\u2032 (E \u03b3 , J, \u03a0) indicate transmission coefficients for \u03b2 and \u03b3 channels with emitting energies E \u03b2 , E \u03b3 and orbital angular momenta l \u2032 , l \u2032\u2032 couple with emitting particle spins gives channel spins j \u2032 , j \u2032\u2032 , respectively.", "cite_spans": [], "ref_spans": []}, {"section": "PACE4", "text": "The quantity in the first square bracket indicates the compound nucleus formation/fusion cross section in a state of total spin (J) and parity (\u03a0) associated to the incident channel \u03b1 which reduces to a simple form for spin less target (I = 0),", "cite_spans": [], "ref_spans": []}, {"section": "PACE4", "text": "The quantity in the second square bracket represents the decay probability of the compound nucleus in the channel \u03b2 having ejectile particle energy E \u03b2 .", "cite_spans": [], "ref_spans": []}, {"section": "PACE4", "text": "PACE4 uses Bass model potential [50] for the calculation of transmission coefficient, although it is not well suited near/below the barrier as well as for very heavy ion projectiles.", "cite_spans": [], "ref_spans": []}, {"section": "PACE4", "text": "Fission is considered as a decay mode, and modified rotating liquid drop fission barrier (by A.", "cite_spans": [], "ref_spans": []}, {"section": "PACE4", "text": "J. Sierk) is selected. Evaporation of seven light particles/nuclei in the order n, p, \u03b1, d, t, 3 He, 6 Li is considered whose transmission coefficients are determined by optical model potential, where optical model parameter is taken from Ref [51] . Gilbert Cameron (GC) nuclear level density parameter and GC spin cutoff parameter are adopted for the calculation. Little a ratio, a f /a \u03b3 , is taken as unity. In order to simulate \u03b3 multiplicity and corresponding energy, a non-statistical yrast cascade gamma decay chain is artificially included.", "cite_spans": [], "ref_spans": []}, {"section": "EMPIRE3.2", "text": "EMPIRE considers all three major nuclear reaction formalisms -Direct (DIR), Preequilibrium (PEQ) and Compound (EQ). DIR processes are estimated either by coupled channels approach or distorted wave Born approximation (DWBA) [52, 53] . There are various PEQ phenomenological and quantum models for light-ion induced reactions. However, PEQ emissions in the heavy-ion induced reactions are not well tested for phenomenological hybrid Monte Carlo simulation as well as quantum mechanical multi-step direct (MSD) and multi-step compound (MSC) models, and therefore ignored by the code. PEQ emission for heavy ion projectiles is calculated using the exciton model, which has the capability to treat the cluster emission built on the Iwamotto Harada model [54] . The differential cross section of the PEQ emission has a form", "cite_spans": [{"start": 224, "end": 228, "text": "[52,", "ref_id": "BIBREF50"}, {"start": 229, "end": 232, "text": "53]", "ref_id": "BIBREF51"}], "ref_spans": []}, {"section": "EMPIRE3.2", "text": "where \u03c3 CF (\u01eb \u03b1 ) is the composite nucleus formation cross section and defined as \u03c3", "cite_spans": [], "ref_spans": []}, {"section": "EMPIRE3.2", "text": ", a difference of reaction and direct reaction cross section. \u03c4 (n) is lifetime of n exciton configuration. W \u03b2 (E, n, \u01eb \u03b2 ) represents the emission rate of a cluster \u03b2 with energy \u01eb \u03b2 , spin s \u03b2 and reduced mass \u00b5 \u03b2 from a state with n (= p + h) excitons and can be given as,", "cite_spans": [], "ref_spans": []}, {"section": "EMPIRE3.2", "text": "where \u03c3 inv \u03b2 (\u01eb \u03b2 ) is the inverse reaction cross section; \u03c9(p, h, E) is particle-hole state density, calculated by Williams formula [55] . Q lm \u03b2 (p, h) is a factor accounting for the probability of the outgoing cluster \u03b2 being formed with l particles situated above and m below the Fermi surface (\u03b2 = l + m) and factor F \u03b2 lm (\u01eb \u03b2 ) denotes formation probability of the cluster \u03b2 as a function of its energy.", "cite_spans": [], "ref_spans": []}, {"section": "EMPIRE3.2", "text": "EQ processes are calculated from the Hauser-Feshbach model, including width fluctuations and the optical model for fission. However, heavy ion fusion cross section is estimated with the help of a simplified coupled channel model (CCFUS) [56] . In CCFUS, collision between two nuclei is considered in the presence of coupling of the relative motion r of the projectile to a nuclear collective motion \u03b6. The Hamiltonian of such system is written as [57] ", "cite_spans": [], "ref_spans": []}, {"section": "EMPIRE3.2", "text": "where \u00b5 is the reduced mass of the system and V (r) is the sum of Coulomb and nuclear Woods-Saxon potential. H 0 (\u03b6) and H \u2032 (r, \u03b6) stand for the intrinsic and coupling Hamiltonian, respectively. The coupled-channels equations for the radial part of the total wave function can be written from such Hamiltonian as", "cite_spans": [], "ref_spans": []}, {"section": "EMPIRE3.2", "text": "where n represents a n th quantum state and \u01eb n is the energy eigenvalue of the intrinsic Hamiltonian. J is the total angular momentum, the sum of relative orbital angular momentum l and the angular momentum of intrinsic motion I. H \u2032 nn \u2032 = n H \u2032 n \u2032 is the coupling matrix element. Diagonalizing this matrix element at the barrier, the matching wave functions can be uncoupled roughly. The total transmission probability is obtained by summing over the distribution of transmission probabilities for the eigenbarriers, with weight given by the overlap of the initial state with eigenchannels,", "cite_spans": [], "ref_spans": []}, {"section": "EMPIRE3.2", "text": "where I \u2032 is the angular momentum of collective motion in the entrance channel. Thus the fusion cross section can be calculated by using Eq. 2 except that the transmission probability is now affected by each reaction channel.", "cite_spans": [], "ref_spans": []}, {"section": "EMPIRE3.2", "text": "In the present calculation, the value of the mean free path parameter for the exciton model is chosen as 1. ", "cite_spans": [], "ref_spans": []}, {"section": "IV. RESULTS AND DISCUSSION", "text": "A methodical investigations of radioisotopes produced in the 11 B-induced reaction on Table II and Table III In general, measured cross section data is well reproduced by EMPIRE over PACE4. In the low energy region, a gradual increase in the theoretical cross sections of the radionuclides is observed in EMPIRE calculations compared to the steep increment in PACE4. It might be due to the more accurate treatment of fusion cross section (CCFUS) calculation and a general consideration of Ignatyuk energy-dependent level density parameter in EMPIRE.", "cite_spans": [], "ref_spans": [{"start": 86, "end": 108, "text": "Table II and Table III", "ref_id": "TABREF6"}]}, {"section": "IV. RESULTS AND DISCUSSION", "text": "Moreover, EMPIRE successfully explained the PEQ emission of particles in both the reactions using exciton model over the compound process. Though the effectiveness of the level density models (EGSM/GSM/GC) could not be concluded precisely from this study, yet GSM/EGSM explains satisfactory most of the reaction channels. It is true that heavy ion reactions cannot compete with the light ion production routes (of 97 Ru, 101m ) in terms of the production yield. However, sufficient production of those radionuclides is possible to conduct the experiments in the laboratory scale. A good quantity of those radionuclides could be produced using a high current heavy ion accelerator.The The comparisons of the theoretical model calculations suggest that the compound reaction mechanism is the dominant route for the production of residues. Like other heavy-ion induced reactions, PEQ emission of neutrons was observed in the 3n channels for both the reactions. A signature of PEQ emission was also evident in the p2n and p3n channel in ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF50": {"title": "Optical-Model and Coupled-Channel Calculations in Nuclear Physics", "authors": [{"first": "J", "middle": [], "last": "", "suffix": ""}], "year": 1972, "venue": "International Atomic Energy Agency Report IAEA-SMR", "link": null}, "BIBREF51": {"title": "Computing as a Language of Physics", "authors": [{"first": "J", "middle": [], "last": "", "suffix": ""}], "year": 1972, "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "89 Y+ 11 B and 93 Nb+ 11 B reactions. A stack of targets was prepared by placing 2-3 target foils each one of which was backed by an aluminum (Al) catcher foil so that target and backing appear in an alternative fashion. A typical experimental setup to irradiate the stack foil arrangement is shown in Fig 1. Each target stack was bombarded by the 11 B 5+ beam for a stipulated time. Beam current was kept almost constant during the experiment. The total charge passed through the target was measured by an electron suppressed Faraday cup placed at the back of the target assembly during the beam-on period. The time of irradiation was decided by the projectile flux and the half-lives of the product radioisotopes. A total of 4-5 such stack was irradiated individually for each target-projectile combination varying the incident energy of 11 B with a slight overlap between them.", "type": "figure"}, "FIGREF1": {"text": "5 and the equilibrium exciton number varies between 10-14 for 25-65 MeV energy range of the projectile. The complete fusion cross section is calculated up to 21- 46 l max value for 25-65 MeV energy range using Christensen-Winther potential [58]. Various nuclear level density options: Gilbert Cameron (GC) level density with Ignatyuk systematic, Generalized Superfluid Model (GSM), and Enhanced Generalized Superfluid Model (EGSM) have been used. In all the three level density model, Ignatyuk level density parameter, which consists of two independent parameters: asymptotic value of the level density parameter (\u00e3) and shell effect damping parameter (\u03b3 s ), is used. In GC model, Ignatyuk systematic is used in which a = 0.154A + 6.3\u00d710 \u22125 A 2 and \u03b3 s = -0.054. GSM and EGSM use\u00e3 = \u03b1A + \u03b2A 2/3 and \u03b3 s = \u03b3 0 A 1/3 where \u03b1 = 0.103, \u03b2 = -0.105, \u03b3 0 = 0.375 are used for GSM and \u03b1 = 0.0748, \u03b2 = 0.0, \u03b3 0 = 0.5609 are used for EGSM.", "type": "figure"}, "FIGREF2": {"text": "significance of the heavy ion induced production route of 97 Ru and 101m Rh from the target matrices Y and Nb, respectively, and their subsequent chemical separation procedures have been discussed in detail in our recent articles [30, 59].", "type": "figure"}, "FIGREF3": {"text": "support was provided in order to extract information about their produc- tion mechanism. It might be helpful to optimize the production parameters of medically relevant radionuclides: 97 Ru, 101m Rh. A comparative study of the various level density mod- els (GSM/EGSM/GC) used in EMPIRE is reported in this article. Although, no specific level density model could be suggested to explain the 11 B+ 89 Y and 11 B+ 93 Nb reaction data, EGSM/GSM calculations reproduced the measured data in many channels. In general, EM- PIRE calculations show better reproduction of the cross sections in most of the channels.", "type": "figure"}, "FIGREF4": {"text": "FIG. 1. A schematic diagram of a typical stack foil activation setup.", "type": "figure"}, "FIGREF5": {"text": "FIG. 6. Same as Fig. 5 for 96 Tc.", "type": "figure"}, "FIGREF6": {"text": "FIG. 7. Same as Fig. 5 for 95 Tc.", "type": "figure"}, "FIGREF7": {"text": "FIG. 8. Same as Fig. 5 for 94 Tc.", "type": "figure"}, "FIGREF8": {"text": "FIG. 9. Same as Fig. 5 for 93m Mo.", "type": "figure"}, "FIGREF9": {"text": "FIG. 10. Same as Fig. 5 for 90m Y.", "type": "figure"}, "FIGREF10": {"text": "FIG. 11. Comparison of measured excitation function (symbols) of 101 Pd from the 11 B+ 93 Nb reaction and those computed from theory (curves) using EMPIRE and PACE4", "type": "figure"}, "FIGREF11": {"text": "FIG. 13. Same as Fig. 11 for 99 Pd.", "type": "figure"}, "FIGREF12": {"text": "FIG. 14. Cumulative production of 101m Rh, via its higher charge isobar, 101 Pd (8.47 h) with the passage of time at various incident energies.", "type": "figure"}, "FIGREF13": {"text": "FIG. 15. Same as Fig. 11 for 101m Rh.", "type": "figure"}, "FIGREF14": {"text": "FIG. 16. Same as Fig. 11 for 100 Rh.", "type": "figure"}, "FIGREF15": {"text": "FIG. 17. Same as Fig. 11 for 99m Rh.", "type": "figure"}, "FIGREF16": {"text": "FIG. 18. Same as Fig. 11 for 97 Ru.", "type": "figure"}, "TABREF3": {"text": "89 Y and 93 Nb targets were carried out for each target foils at various incident energies. Two typical \u03b3-ray spectra collected 38.3 and 37.9 minutes after the EOB from the 11 B+ 89 Y and 11 B+ 93 Nb reactions at 50.8 and 51 MeV incident energies are shown in Figs 2 andNb target matrix are confirmed and are presented in Figs 4-10, and Figs 11-18, respectively. Measured data points are indicated by symbols with an uncertainty and the theoretical estimations are shown by curves. The measured cross sections are compared with the theoretical model calculations from PACE4 and EMPIRE3.2 utilizing different nuclear level density options. A list of the radionuclides and the possible contributing reactions are listed in Table I [46]. Experimental cross section data are tabulated in", "type": "table"}, "TABREF4": {"text": "A. Radionuclides produced in 11 B+ 89 Y 1. 97,95 Ru The measured excitation function of 97 Ru, presented in the Fig 4, is compared with the PACE and EMPIRE calculation. Experimental data are well reproduced by both the model codes in the lower energy region (\u223c28-42 MeV), however, PACE estimation sharply decreases compared to the measured data at higher energies and becomes about 20 times smaller than the experimental cross section at 58.7 MeV energy. The experimental results are in good agreement with those computed from the EMPIRE at the high energy region. It certainly indicates the emission of PEQ neutrons, along with evaporated neutrons in the 3n reaction channel, as observed in various heavy-ion induced reactions [8, 9, 26]. Reproduction of the data describes the necessity of the PEQ exciton model used in EMPIRE for heavy projectiles. Although all the level densities show a good agreement between each other, GSM level density reproduces the measured data more accurately in comparison to the EGSM and GC level densities at high energy tail of the excitation function. Figure 5 shows a comparison between the measured cross sections of 95 Ru in the 45- 60 MeV energy range and the theoretical evaluation. Experimental cross sections are best explained by EMPIRE with GSM level density throughout the energy range, while other two calculations with EGSM and GC level density overestimate the measured data in the high energy range (\u223c52-60 MeV). On the other hand, PACE result underpredicts the experimental data below 52 MeV and overpredicts above it. Independent productions of 97,95 Ru are measured due to the absence of any precursor.with the theoretical excitation functions. The measured data are satisfactorily reproduced by the EMPIRE and PACE4 in the higher energy region, while PACE underpredicts them in the lower energy range. EMPIRE calculation corresponding to EGSM and GC has shown the best reproduction of measured data throughout the estimated energy range.EMPIRE calculations. Experimental data are well reproduced by the EMPIRE with the EGSM level density option throughout the energy range considered. Calculations of EMPIRE using other two level densities are found satisfactory below 47 MeV projectile energy and underpredict the data above it. As the code PACE calculates the cross section of 93 Mo, the sum of isomeric and ground state, it overpredicts the experimental data throughout (up to 55 MeV) the energy.Pd at different incident energies are indicated in Fig 12 and Fig 13, respectively, to compare with the theoretical results. It is evident from the Fig 12 that PACE calculation underpredicts the data at the lower energies and overpredicts at the higher energy range. Experimental data are well reproduced by the EMPIRE calculation with EGSM level density throughout the energy range within the experimental error. EMPIRE estimation with GC level density overestimates the measured data, while that with the GSM level density well reproduces up to 43 MeV energy and underestimates beyond it. On the other hand, in the Fig 13, none of the model calculation explained the experimental observations, although EMPIRE calculations mimic the trend well.the passage of time, as expected. On an average, \u223c55% increment in the cross section of 101m Rh is observed for all the energies at the first half-life of 101 Pd after the EOB. However, independent production cross-sections of 101m Rh is measured in this work and the excitation function is shown in Fig 15. PACE explains the data up to 51 MeV incident energy and underpredicts above it. EMPIRE calculations with EGSM and GC level density reproduce the experimental data within the error bar over the energy region, while GSM overestimates beyond 40 MeV projectile energy. Nevertheless, EMPIRE calculation shades light on the role of the PEQ reaction mechanism to 101m Rh at the high energy tail.tions satisfactorily predict the experimental results, while PACE calculation shows a small deviation both in lower and higher energy side. EMPIRE with EGSM has best reproduced the experimental results. Although decay of 100 Pd (3.63 d) could add to the cross section of 100 Rh, this possibility was avoided recording the \u03b3-ray spectrum immediately after the EOB.99m Rh is shown in the Fig 17 and compared the isomeric production obtained from EMPIRE along with the PACE that calculates the sum of isomeric and ground state production. EMPIRE with GC explains the experimental result slightly better than EGSM and GSM level density calculation. PACE grossly underestimates the measured excitation function throughout the entire energy range.estimations. Measured results are best described by the EMPIRE with EGSM level density.", "type": "table"}, "TABREF6": {"text": "Spectoscopic decay data [46] for the observed radioisotopes and list of contributing process in the 11 B + 89 Y and 11 B + 93 Nb reactionsa E th denotes threshold energy. b IT denotes isomeric transition.", "type": "table"}, "TABREF7": {"text": "Cross section (mb) of radioisotopes at various incident energies in the 11 B + 89 Y reaction.TABLE III. Cross section (mb) of radioisotopes at various incident energies in the 11 B + 93 Nb reaction.FIG. 3. A \u03b3-ray spectrum of the 11 B+ 93 Nb reaction at 51 MeV energy after 37.9 minute of EOB.FIG. 4. Comparison of measured excitation function (symbols) of 97 Ru from the 11 B+ 89 Y reaction and those computed from the theory (curves) using EMPIRE and PACE4FIG. 5. Comparison of measured (symbols) and computed (curves) excitation functions for pro- duction of 95 Ru.", "type": "table"}}}
{"paper_id": "119428228", "_pdf_hash": "a51e490c680347d807c4e230a36a101a942a96a8", "abstract": [{"section": "Abstract", "text": "Abstract. Using data from the NEMO-3 experiment, we have measured the two-neutrino double beta decay (2\u03bd\u03b2\u03b2) half-life of 82 Se as T 2\u03bd 1/2 = [9.39 \u00b1 0.17 (stat) \u00b1 0.58 (syst)]\u00d710 19 y under the single-state dominance hypothesis for this nuclear transition. The corresponding nuclear matrix element is M 2\u03bd = 0.0498\u00b10.0016.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "In addition, a search for neutrinoless double beta decay (0\u03bd\u03b2\u03b2) using 0.93 kg of 82 Se observed for a total of 5.25 y has been conducted and no evidence for a signal has been found. The resulting half-life limit of T 0\u03bd 1/2 > 2.5 \u00d7 10 23 y (90% C.L.) for the light neutrino exchange mechanism leads to a constraint on the effective Majorana neutrino mass of m\u03bd < (1.2 \u2212 3.0) eV, where the range reflects 0\u03bd\u03b2\u03b2 nuclear matrix element values from different calculations. Furthermore, constraints on lepton number violating parameters for other 0\u03bd\u03b2\u03b2 mechanisms, such as right-handed currents, majoron emission and R-parity violating supersymmetry modes have been set. arXiv:1806.05553v1 [hep-ex]", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "The observation of neutrino oscillations has provided proof that the neutrino has non-zero mass [1] [2] [3] . However the absolute mass of the neutrino and its fundamental Dirac or Majorana nature remain undetermined. Neutrinoless double beta decay (0\u03bd\u03b2\u03b2) is the only practical way to establish the full lepton number violation required by many grand unification models and if the decay proceeds via a light neutrino exchange mechanism, would be one of the most sensitive probes of absolute neutrino mass [4] .", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The half-life of 0\u03bd\u03b2\u03b2 is given by:", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "where g A is the axial-vector coupling constant, G 0\u03bd is a phase-space factor, M 0\u03bd is a nuclear matrix element (NME) and \u03be is a lepton number violating parameter. In the most commonly discussed mechanism of 0\u03bd\u03b2\u03b2, the decay proceeds via the exchange of a light Majorana neutrino ( \u03be \u2261 m \u03bd /m e , where m e is the mass of the electron). However, other mechanisms are possible, such as the admixture of right-handed currents in the electroweak interaction, majoron emission and R-parity violating supersymmetry (SUSY). In all mechanisms, 0\u03bd\u03b2\u03b2 violates lepton number conservation and is a direct probe of physics beyond the Standard Model. To date, no evidence for 0\u03bd\u03b2\u03b2 has been found, with the best half-life limits in the 10 24 \u2212 10 26 y range [5] [6] [7] [8] [9] [10] [11] . Two-neutrino double beta decay (2\u03bd\u03b2\u03b2) is a rare second order process that is allowed in the Standard Model. It has been observed in 12 isotopes with half-lives ranging from 10 19 to 10 24 y [12, 13] . Measurement of the 2\u03bd\u03b2\u03b2 halflife provides experimental determination of the NME for this process, M 2\u03bd , which can be used to improve NME calculations for the 0\u03bd\u03b2\u03b2 mode. The precision with which \u03be can be measured depends crucially on knowledge of M 0\u03bd . In addition, 2\u03bd\u03b2\u03b2 is an irreducible background component to 0\u03bd\u03b2\u03b2 and therefore precise measurements of 2\u03bd\u03b2\u03b2 rates and spectral shapes are important.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "One of the most promising double beta decay (\u03b2\u03b2) candidates is 82 Se due to its high Q-value (2997.9(3) keV [14] ), above most common backgrounds from natural radioactivity, relatively high isotopic abundance (8.83% [15] ) and existing robust technologies of isotopic enrichment through centrifugation. It has been selected as the isotope of choice for a number of planned 0\u03bd\u03b2\u03b2 decay experiments [16, 17] .", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The first measurement of \u03b2\u03b2 in 82 Se was made in 1967 with a geochemical experiment, extracting a halflife of 0.6 +0.6 \u22120.3 \u00d7 10 20 y [18] . This result was later confirmed by many other geochemical measurements (see reviews [19] [20] [21] ). Such geochemical experiments are not able to distinguish between 0\u03bd\u03b2\u03b2 and 2\u03bd\u03b2\u03b2 modes and the conclusion that 2\u03bd\u03b2\u03b2 had been observed was drawn using complementary theoretical and experimental arguments. Whilst the precision of any individual measurement was reasonably good, the spread of the results was quite high. Nevertheless, the combination of many experiments led to a half-life value of (1.0 \u2212 1.3) \u00d7 10 20 y [19] [20] [21] .", "cite_spans": [{"start": 225, "end": 229, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 230, "end": 234, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 659, "end": 663, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 664, "end": 668, "text": "[20]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "Introduction", "text": "Correspondence to: jmott@hep.ucl.ac.uk, r.saakyan@ucl.ac.uk", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The isotope of 82 Se was in fact the first nucleus in which 2\u03bd\u03b2\u03b2 was directly observed in a counter experiment in 1987 [22] . A total of 36 candidate 2\u03bd\u03b2\u03b2 events were observed yielding a half-life of 1.1 +0.8 \u22120.3 \u00d7 10 20 y. A more precise direct measurement was later carried out by NEMO-2, [8.3 \u00b1 1.0 (stat) \u00b1 0.7 (syst)] \u00d7 10 19 y [23] . The most precise result to date was obtained by NEMO-3 after analysing a subset of its data, [9.6 \u00b1 0.3 (stat) \u00b1 1.0 (syst)]\u00d7 10 19 y [24] . The same data set was also used to obtain a stringent lower limit on the half-life for the 0\u03bd\u03b2\u03b2 decay of 82 Se, T 0\u03bd 1/2 > 1.0 \u00d7 10 23 y at 90% C.L.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "We present the results of the 82 Se 2\u03bd\u03b2\u03b2 measurement and 0\u03bd\u03b2\u03b2 searches with the full data set collected by the NEMO-3 detector, representing a five-fold increase in exposure compared to the previously published result [24] .", "cite_spans": [], "ref_spans": []}, {"section": "NEMO-3 Detector and", "text": "82 Se Source NEMO-3 was a detector composed of a tracker and a calorimeter capable of reconstructing the full topology of \u03b2\u03b2 events. It was installed in the Modane Underground Laboratory (LSM) with an overburden of 4800 m.w.e. to shield against cosmic rays. The detector housed seven enriched \u03b2\u03b2 isotopes in the form of thin (about 50 mg/cm 2 ) source foils. These were arranged in a cylindrical geometry subdivided into 20 [8, [24] [25] [26] [27] [28] . Charged particle ionisation tracks are reconstructed from hits in 50 cm deep and 270 cm long wire chambers on each side of the source foils composed of 6180 Geiger cells operating in helium with the addition of ethanol as a quencher (4%), argon (1%) and water vapour (0.15%). The transverse and longitudinal resolution of individual tracker cells was 0.5 mm and 8.0 mm (\u03c3) respectively. The tracker was enclosed by calorimeter walls assembled from plastic scintillator blocks coupled to low background photomultipliers (PMT). The energy resolution of the calorimeter blocks was 5.8 \u2212 7.2% and the time resolution was 250 ps, both \u03c3 at 1 MeV. The detector was surrounded by a solenoid which generated a 25 G magnetic field parallel to the cell wires. The magnetic field allows the rejection of approximately 95% of positrons at 1 MeV. The detector was placed in passive shielding consisting of a 19 cm thick layer of iron to suppress the external gamma ray background, as well as borated water, paraffin and wood to moderate and absorb the environmental neutron background. A detailed description of the detector and its performance can be found in [8, 29] .", "cite_spans": [{"start": 421, "end": 423, "text": "20", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "NEMO-3 Detector and", "text": "The 82 Se source foils had a composite structure. Enriched 82 Se powder was mixed with polyvinyl alcohol (PVA) glue and deposited between 23 \u00b5m (2.2 mg/cm 2 ) thick Mylar foils. Enriched selenium from two production runs was used, attaining enrichment factors of 97.02 \u00b1 0.05% for run 1 and 96.82 \u00b1 0.05% for run 2. Selenium from run 1, which was also used in the NEMO-2 experiment [23] , was placed in a single detector sector, while the isotope from run 2 was in an adjacent sector. The total mass of the 82 Se isotope in NEMO-3 was (0.932 \u00b1 0.005) kg, with 0.464 kg from run 1 and 0.468 kg from run 2. NEMO-3 took data from February 2003 to January 2011. A standard set of criteria define high quality runs, where the detector was operating stably and the calorimeter was calibrated [8] . The accepted live-time of the detector is 5.252 y, resulting in an exposure of 4.90 kg\u00b7y for 82 Se.", "cite_spans": [], "ref_spans": []}, {"section": "NEMO-3 Detector and", "text": "During the first 18 months of data-taking, the radon ( 222 Rn) level inside the detector was higher than anticipated. This was caused by the diffusion of radon from the air of the laboratory into the tracking gas. To lower the radon level inside the detector, an anti-radon tent containing filtered air was built around the detector reducing the radon level in the tracker volume by a factor of about 6 [30] . The higher radon activity data-taking period, lasting 1.06 y, is referred to as phase 1 and the lower activity period, with a duration of 4.19 y, as phase 2.", "cite_spans": [], "ref_spans": []}, {"section": "Particle Identification and Event Selection", "text": "One of the major strengths of the NEMO-3 approach amongst \u03b2\u03b2 experiments is its ability to use multiple observables and a combination of tracking and calorimetry information for particle identification and reconstruction of different event topologies. By separating data events into different channels based on the number of electrons, \u03b3-rays and \u03b1-particles that they contain, a pure \u03b2\u03b2 signal channel can be defined along with a series of background channels that may be used to normalise the different background contributions to this signal channel.", "cite_spans": [], "ref_spans": []}, {"section": "Particle Identification and Event Selection", "text": "Electrons and positrons are identified by ionisation traces that can be extrapolated to an energy deposit in the calorimeter, and are distinguished by their curvature in the magnetic field. By contrast, \u03b3-rays are identified as an energy deposit in the calorimeter without an associated track. A 1 MeV photon has a 50% probability of interaction with a scintillator block. Therefore neighbouring calorimeter hits are clustered together and attributed to a single \u03b3-ray interaction event with an energy equal to the energy sum of the individual hits. Due to their heavy ionisation energy losses, \u03b1-particles from radioactive decays can not travel more than about 35 cm in the NEMO-3 tracker and are identified by their short, straight tracks.", "cite_spans": [], "ref_spans": []}, {"section": "Particle Identification and Event Selection", "text": "Both data and Monte Carlo simulations (MC) of signal and background are processed by the same reconstruction algorithm. The DECAY0 event generator [31] is used for generation of initial kinematics and particles are tracked through a detailed GEANT3 based detector simulation [32] .", "cite_spans": [], "ref_spans": []}, {"section": "Particle Identification and Event Selection", "text": "Candidate \u03b2\u03b2 signal events are selected to contain two electron tracks, each with an energy deposit > 300 keV. The tracks must originate from the 82 Se source foil and have a common vertex (i.e. the distance between the track intersections with the foil should be \u2206 XY < 2 cm (transversely) and \u2206 Z < 4 cm (vertically), set by the resolution of the tracking detector). There should be no \u03b1-particle tracks in the event. The timing of the calorimeter hits must be consistent with an internal event defined as two electrons simultaneously emitted from a common vertex in the foil [8] .", "cite_spans": [], "ref_spans": []}, {"section": "Particle Identification and Event Selection", "text": "Backgrounds are constrained using specific event topologies and timing characteristics. Single electron candidate events (1e) must have one electron track originating from a 82 Se source foil. The position of these intersections are used to identify areas in the source foils with higher than average contaminations as shown in Figure 1 . Areas with an event rate more than 5\u03c3 higher than the mean rate for the foil strip in which it is housed are excluded from the data analysis.", "cite_spans": [], "ref_spans": [{"start": 328, "end": 336, "text": "Figure 1", "ref_id": "FIGREF1"}]}, {"section": "Particle Identification and Event Selection", "text": "The 1e1\u03b1N \u03b3 channel events contain a single electron track and a delayed \u03b1-particle track emitted from a common vertex, with no constraints on the number of \u03b3-rays present. The \u03b1-particle track must be registered in the range of (10 \u2212 650) \u00b5s after the electron track, such that it is consistent with 214 Bi \u2192 214 Po \u2192 210 Pb sequential decays from the 238 U radioactive series. These decays predominantly originate from radon in the tracker as outlined in Section 4.", "cite_spans": [], "ref_spans": []}, {"section": "Particle Identification and Event Selection", "text": "Events with a single electron track and a number of \u03b3-ray hits (1eN \u03b3) are used to constrain different backgrounds depending on the number of \u03b3-rays and their timing characteristics. As with electron candidates, \u03b3-ray hits must have an energy deposit > 300 keV to be accepted. Events containing electron and \u03b3-ray hits consistent with simultaneous emission from the same location in a 82 Se foil are used to measure internal contamination by radioactive isotopes. Conversely, those containing hit times consistent with a \u03b3-ray first interacting with a calorimeter block before producing an electron in the foil are used to measure the external \u03b3-ray flux. Finally, crossing-electron events, where a single electron crosses from one side of the detector to the other, are selected using the same cuts as for the \u03b2\u03b2 channel but with a requirement that the timing of the calorimeter hits be consistent with an external origin of the event. Further details on using topological, timing and energy cuts for background identification can be found in [30] .", "cite_spans": [], "ref_spans": []}, {"section": "Background and Control Measurements", "text": "Any event containing two reconstructed electrons from an origin other than the decay of 82 Se can be misidentified as a \u03b2\u03b2 event. The main source of background events are trace amounts of naturally-occurring radioactive isotopes that come from the 238 U and 232 Th radioactive series. Only (\u03b2, \u03b3)-emitting radioactive isotopes with high Q-values are potential backgrounds to a 0\u03bd\u03b2\u03b2 search. The two main isotopes of concern are 214 Bi and 208 Tl with Qvalues of 3.27 and 4.99 MeV respectively.", "cite_spans": [], "ref_spans": []}, {"section": "Background and Control Measurements", "text": "The largest background contribution comes from internal contamination of the source foils. Isotopes that undergo \u03b2-decay can mimic two electron events via the processes of \u03b2-decay with M\u00f8ller scattering, \u03b2-decay to an excited state followed by internal conversion, or by subsequent Compton scattering of the de-excitation photon.", "cite_spans": [], "ref_spans": []}, {"section": "Background and Control Measurements", "text": "Other background events may be classified as coming from an origin external to the source foils. These usually Figure (b) shows the same region after removing events originating from neighbouring foils, calibration tubes and areas with activity more than 5\u03c3 higher than the mean for the particular 82 Se foil strip. This is the fiducial area used in the analysis. The higher activity strip in sector 8 is contaminated with 210 Bi which does not affect the \u03b2\u03b2 analyses due to its low Q-value.", "cite_spans": [], "ref_spans": []}, {"section": "Background and Control Measurements", "text": "involve a \u03b3-ray that interacts with the source foil causing pair production, Compton interaction followed by M\u00f8ller scattering or double Compton scattering. The sources of external \u03b3-rays are predominantly radioactive decays within the rock surrounding the laboratory, neutron capture and decays within the detector components or shielding.", "cite_spans": [], "ref_spans": []}, {"section": "Background and Control Measurements", "text": "A subset of the external backgrounds is identified as radon backgrounds, coming from 222 Rn, which is a gaseous isotope in the 238 U chain. Due to its long half-life of 3.82 days 222 Rn can be introduced via a number of mechanisms, notably emanation from detector materials, contamination of the tracker gas or of other detector surfaces, or via diffusion through detector seals. Once inside the detector, the radon decays to predominantly positive ions. These charged progenies drift towards the source foils or tracker wires where they settle, leaving deposits of 214 Bi near the source material [30] . Once on or near the source foils, this 214 Bi is then capable of producing background events in the same way as internal contaminants.", "cite_spans": [], "ref_spans": []}, {"section": "Background and Control Measurements", "text": "The background model is defined by the activity of each isotope in specific locations. In all background sources, 214 Pb is assumed to be in secular equilibrium with 214 Bi and likewise for 228 Ac, 212 Bi and 208 Tl. The fitting procedure extracts the different isotope activities using a binned log-likelihood maximisation. The distributions from the six background channels (1e, 1e1\u03b1N \u03b3, 1e1\u03b3, 1e2\u03b3, external 1\u03b31e and crossing-electron) and a \u03b2\u03b2 signal channel are fitted simultaneously to extract the most likely activity parameters.", "cite_spans": [], "ref_spans": []}, {"section": "External backgrounds", "text": "The external \u03b3-ray flux incident on the detector is quantified using the external 1\u03b31e and crossing-electron channels. In the former, a \u03b3-ray deposits energy in the calorimeter before interacting with the source foil to produce an outgoing electron. In the latter, the \u03b3-ray interacts close to the surface of a calorimeter, producing an electron that crosses the whole tracking chamber including the source foil. Data from these channels constrain the number of events in the \u03b2\u03b2 channel from the external \u03b3-ray flux.", "cite_spans": [], "ref_spans": []}, {"section": "External backgrounds", "text": "The external background model is an effective model of the \u03b3-ray flux incident on the detector, with components similar to the model in [30] . It is dominated by 40 The model reproduces the data accurately as can be seen from the distributions of energy deposited in the calorimeter for the external 1\u03b31e and crossing-electron channels shown in Figure 2 .", "cite_spans": [], "ref_spans": [{"start": 345, "end": 353, "text": "Figure 2", "ref_id": "FIGREF3"}]}, {"section": "External backgrounds", "text": "The external background model presented here is constructed using data from the 82 Se sectors only. It is consistent with the average external background model in [30] , where all sectors are used, within 10% \u2212 20%. This is the expected level of sector-to-sector variation in the external background model.", "cite_spans": [], "ref_spans": []}, {"section": "Radon backgrounds", "text": "The radon level inside the detector can be measured by studying 214 Bi \u2192 214 Po \u2192 210 Pb sequential decay events in the 1e1\u03b1N \u03b3 channel. The distribution of the length of the \u03b1-particle tracks is used to reconstruct the location of 214 Bi. For example, the \u03b1 track length is sensitive to whether the \u03b1-particle originated from the surface of a tracker wire or inside the bulk of the source foil.", "cite_spans": [], "ref_spans": []}, {"section": "Radon backgrounds", "text": "Using the reconstructed position of the events, an extensive radon model has been developed with 214 Bi on the surface of the tracker wires, source foils and scintillators varying from sector-to-sector and, in the case of the surface of the wires, with tracker layer [30] . Distribution of the sum of the incoming and outgoing electron energies in the crossing-electron channel. In both figures, the energy spectra from data are compared to the total MC prediction (top panels) and as a ratio of data to the total MC prediction (bottom panels). The Other MC histograms contain the small contributions from internal and radon background sources. Distributions of \u03b1-particle track length from the 1e1\u03b1N \u03b3 channel, which are used to extract the 214 Bi activities, can be seen in Figure 3 . The contribution from internal foil contamination has the shortest track lengths as these \u03b1-particles must traverse the most material before entering the tracking gas while the surface of tracker wires sample has the longest tracks. The shape of the distributions is an artefact of the tracker geometry. The lower number of events between 20 and 30 cm is a result of a gap in the layers of tracker cells at this distance due to the presence of calorimeter blocks in the detector end caps [29] .", "cite_spans": [], "ref_spans": []}, {"section": "Radon backgrounds", "text": "The difference between phases 1 and 2 is apparent, with a higher proportion of events from surfaces of the tracker wires and source foils during phase 1. In these cases, 214 Bi has been deposited on exposed surfaces as a result of radon decay in the tracker gas. In phase 2 there is a larger contribution from the internal and Mylar components. This originates from 214 Bi decays from contamination with 226 Ra and has therefore remained constant whilst the radon level inside the tracker gas has decreased.", "cite_spans": [], "ref_spans": []}, {"section": "Radon backgrounds", "text": "The small discrepancies observed between MC and data distributions are due to a strong sensitivity of the \u03b1-particle range to the location of the 214 Bi. For example, the distributions can be altered significantly by transferring 214 Bi between the surface of the foils and the surface of the wires or between different wires within the tracker. The detection efficiency for electrons from 214 Bi is much less sensitive to these small changes in decay location and so the systematic uncertainty from this discrepancy that propagates through to the \u03b2\u03b2 channel is negligible. ", "cite_spans": [], "ref_spans": []}, {"section": "Internal backgrounds", "text": "The main backgrounds in the low energy region come from \u03b2-decaying isotopes. The 1e channel electron energy distributions, shown in Figure 4a , are dominated by 210 Bi, 40 K and 234m Pa. In the higher energy region, the contributions from the external 208 Tl and 214 Bi backgrounds become significant and at energies above 2.7 MeV, 214 Bi from the internal and surface of tracker wire contaminations are the only remaining contributions.", "cite_spans": [], "ref_spans": [{"start": 132, "end": 141, "text": "Figure 4a", "ref_id": "FIGREF7"}]}, {"section": "Internal backgrounds", "text": "The 1e1\u03b3 channel constrains isotopes decaying to excited states, most notably Distributions of the length of \u03b1-particle tracks from the 1e1\u03b1N \u03b3 channel, which contains events with one electron track and one delayed \u03b1-particle track, with no constraints on the number of \u03b3-rays present. The length is measured as the distance from the electron vertex on the foil to the furthest hit in the \u03b1-particle track. internal origin. At high energies, the distribution contains events from internal contamination with 208 Tl. A more sensitive probe for the 208 Tl internal contamination is the 1e2\u03b3 channel with one \u03b3-ray above 1.7 MeV, shown in Figure 5 . Any contributions from 214 Bi are heavily suppressed by this cut on the \u03b3 energy such that the channel is dominated by the internal contributions of 208 Tl, with a 10% contribution from the 208 Tl in the tracker wires.", "cite_spans": [], "ref_spans": []}, {"section": "Internal backgrounds", "text": "The measured activities for the internal contaminations are summarised in Table 1 . The levels of contamination are similar for both enrichment runs with the exception of 234m Pa where there is a four-fold increase in the activity in run 2. The results are compared with measurements made with a high purity germanium (HPGe) detector carried out prior to the installation of the 82 Se foils in the detector. The results are consistent across all isotopes.", "cite_spans": [], "ref_spans": [{"start": 74, "end": 81, "text": "Table 1", "ref_id": "TABREF3"}]}, {"section": "Two-neutrino double beta decay", "text": "Candidate \u03b2\u03b2 signal events are selected using the criteria outlined in Section 3. A total of 8936 candidate events were selected, with 4350 and 4586 from source foils from enrichment runs 1 and 2 respectively. Table 2 shows the contribution expected from simulations of individual back- 82 Se foils from enrichment runs 1 and 2 were measured together in the HPGe detector, so the NEMO-3 combined values are the mean values of the specific activities from each enrichment run. All error bars are statistical only and are at the 1\u03c3 level. The limit shown is at the 2\u03c3 level. The HPGe measurements are taken from [29] . Table 2 : Predicted number of events in the two electron channel for different event sources. The expected numbers of events in the energy region relevant to 0\u03bd\u03b2\u03b2 are also given. Isotopes denote the internal contaminations of the 82 Se foils and the numbers are assigned to whether the tracks originated from foils from enrichment run 1 or 2. Multiple isotopes listed on the same line indicates the assumption of secular equilibrium.", "cite_spans": [], "ref_spans": []}, {"section": "Event Source", "text": "Etot > 0.6 MeV 2.6 MeV < Etot < 3. the majority of events from \u03b3-ray transitions of 208 Tl and 214 Bi. The radon backgrounds make up 2% with a dominant contribution from 214 Bi, and a secondary contribution from 210 Bi. The majority of these events come from the surface of the tracker wires, but some are also present on the surface of the foil. There are more expected radon background events in phase 1 compared to phase 2 despite its much shorter exposure period.", "cite_spans": [], "ref_spans": []}, {"section": "Event Source", "text": "NEMO-3 has the unique capability of reconstructing the full kinematics of the \u03b2\u03b2 decay final states. The individual energies of each electron can be seen in Figure 6 , where the higher degree of contamination from 234m Pa in the run 2 foils leads to a much larger contribution from the internal backgrounds. There is a discrepancy between data and MC in the region of 0.5 \u2212 0.7 MeV caused by a peak from the emission of a 694 keV internal conversion electron from 234m Pa. This discrepancy is significantly stronger in the run 2 foils due to their higher contamination with 234m Pa. The discrepancy is most likely caused by inaccuracies in the internal conversion electron transition probabilities obtained from the existing nuclear data sheets [33, 34] . Given this large uncertainty associated with the 234m Pa background contribution, the enrichment run 2 foils are excluded from the analysis to enable a more precise measurement of the 2\u03bd\u03b2\u03b2 half-life, as further discussed in 5.2.", "cite_spans": [], "ref_spans": [{"start": 157, "end": 165, "text": "Figure 6", "ref_id": "FIGREF9"}]}, {"section": "Higher-state vs single-state dominated transistions", "text": "For the purpose of the nuclear matrix element calculation, the decay of 82 Se to 82 Kr is modelled as two virtual [35] , suggesting that the SSD scenario could be realised. The shape of the distribution of the sum of electron energies, which is used for the 2\u03bd\u03b2\u03b2 halflife measurement, is very similar in both scenarios. However, the sub-division of energy between the electrons is different in the two cases and therefore a precise highstatistics study of single-electron energy distributions can be used to distinguish between the two models [36] . Moreover, the choice of the model affects the measured half-life of the 2\u03bd\u03b2\u03b2 transition. This is because the increased number of lower energy electrons in the SSD model reduces the detection efficiency and therefore the extracted halflife. The selection efficiency for the 2\u03bd\u03b2\u03b2 signal calculated from MC using the event selection criteria described above is [2.971 \u00b1 0.002 (stat)] % under the HSD hypothesis and [2.623 \u00b1 0.002 (stat)] % in the SSD case.", "cite_spans": [], "ref_spans": []}, {"section": "Higher-state vs single-state dominated transistions", "text": "The largest difference between the SSD and HSD singleelectron energy spectra is at the low end of the distribution [36] . However, due to the previously identified issues with the 234m Pa conversion electron branching ratios, the individual electron energy distributions for the HSD and SSD models were compared to data after applying a cut on the sum of the electron energy of E tot > 1.6 MeV. This reduces the contamination from 234m Pa to below 2%. Figure 7 shows a good agreement with data for the SSD hypothesis (\u03c7 2 /ndf = 12.3/16) while the HSD hypothesis is disfavoured (\u03c7 2 /ndf = 35.3/16) at a level equivalent to 2.1\u03c3. The SSD scenario is therefore assumed for the remainder of the analysis, unless explicitly stated otherwise.", "cite_spans": [], "ref_spans": []}, {"section": "Extraction of 2\u03bd\u03b2\u03b2 half-life", "text": "A binned log-likelihood fit to the distribution of the sum of the two electron energies of the 4350 \u03b2\u03b2 events selected from the data and originating from enrichment run 1 foils is performed together with a fit to the six background channels, as described in Section 4. The fit assuming the SSD hypothesis, shown in Figure 8 , yields 3472.4 \u00b1 75.7 signal events, with a signal-to-background ratio of 4.0. The distribution of the opening angle between the two tracks is shown in Figure 9 .", "cite_spans": [], "ref_spans": []}, {"section": "Extraction of 2\u03bd\u03b2\u03b2 half-life", "text": "In addition to the statistical uncertainty obtained from the log-likelihood fit, the 2\u03bd\u03b2\u03b2 half-life measurement is affected by a number of systematic uncertainties. The most important source of systematic error is the uncertainty on the detector acceptance and reconstruction and selection efficiency. This uncertainty is quantified using dedicated runs with 207 Bi sources introduced into the detector and Table 2 . The largest background category is internal contamination of the source foil (blue), but this is still much smaller than the contribution from the 2\u03bd\u03b2\u03b2 signal, with a signal-tobackground ratio of 4.0. Fig . 9 : Distribution of the cosine of the angle between two electron tracks at the point of emission from the run 1 source foil in the \u03b2\u03b2 channel. As expected, more events are observed with electrons emitted to back-to-back than with smaller opening angles. This angular distribution has been reweighted based on data from 207 Bi calibration sources. is compared with activities independently measured by an HPGe detector. Taking into account the systematic error on the HPGe measurement (5%) the uncertainty on the signal efficiency is determined to be 5% [8] .", "cite_spans": [], "ref_spans": []}, {"section": "Extraction of 2\u03bd\u03b2\u03b2 half-life", "text": "Other sources of systematic uncertainty are listed in Table 3 . The systematic error due to the background modelling is dominated by the uncertainty on the 234m Pa conversion electron branching ratio discussed above. This uncertainty translates into a 2.3% error on the 2\u03bd\u03b2\u03b2 half-life for the run 1 foils and increases to 4.5% if the analysis is performed on both enrichment samples due to the higher 234m Pa levels in the run 2 foils. The uncertainty on the 2\u03bd\u03b2\u03b2 half-life measurement is systematics dominated and therefore the overall precision of the measurement is improved by excluding the run 2 foils.", "cite_spans": [], "ref_spans": [{"start": 54, "end": 61, "text": "Table 3", "ref_id": "TABREF6"}]}, {"section": "Extraction of 2\u03bd\u03b2\u03b2 half-life", "text": "The individual systematic errors are assumed to be uncorrelated and are added in quadrature to obtain the total systematic uncertainty of 6.3%. This yields the final measurement of N = 3472 \u00b1 76 (stat) \u00b1 218 (syst) for the number of signal events obtained with (0.464 \u00b1 0.002) kg of 82 Se from enrichment run 1 over 5.25 y of observation. This can be converted to the 82 Se 2\u03bd\u03b2\u03b2 half-life using", "cite_spans": [], "ref_spans": []}, {"section": "Extraction of 2\u03bd\u03b2\u03b2 half-life", "text": "where is the selection efficiency (2.623%), N A is Avogadro's number, The half-life measurement allows the experimental determination of the NME for the 2\u03bd\u03b2\u03b2 decay mode of 82 Se using the equation", "cite_spans": [], "ref_spans": []}, {"section": "Extraction of 2\u03bd\u03b2\u03b2 half-life", "text": "where g A is the axial-vector coupling constant and G 2\u03bd is the phase space for the 82 Se 2\u03bd\u03b2\u03b2 0", "cite_spans": [], "ref_spans": []}, {"section": "Extraction of 2\u03bd\u03b2\u03b2 half-life", "text": "as calculated in [37, 38] and assuming g A = 1.27 [3] we obtain for the matrix element under the SSD hypothesis", "cite_spans": [], "ref_spans": []}, {"section": "Extraction of 2\u03bd\u03b2\u03b2 half-life", "text": "and under the HSD hypothesis", "cite_spans": [], "ref_spans": []}, {"section": "Extraction of 2\u03bd\u03b2\u03b2 half-life", "text": "where the quoted errors include both statistical and systematic uncertainties, which are assumed to be uncorrelated.", "cite_spans": [], "ref_spans": []}, {"section": "Neutrinoless double beta decay", "text": "A search for 0\u03bd\u03b2\u03b2 is carried out by selecting \u03b2\u03b2 events as outlined in Section 3. Due to the higher energies of electrons emitted in the 0\u03bd\u03b2\u03b2 decay the uncertainties due to the 234m Pa background model reported earlier are negligible. Consequently, both enrichment samples are included in the 0\u03bd\u03b2\u03b2 analysis. Alongside backgrounds from natural radioactivity, 0\u03bd\u03b2\u03b2 has an additional background contribution from 2\u03bd\u03b2\u03b2 events. The following results assume the SSD hypothesis, but the same results are also found if the HSD case is taken. We considered four lepton number violating mechanisms for 0\u03bd\u03b2\u03b2: light Majorana neutrino exchange, the admixture of right-handed currents in electroweak interactions, 0\u03bd\u03b2\u03b2 decay accompanied by a majoron emission and R-parity violating SUSY models. No evidence for a 0\u03bd\u03b2\u03b2 signal is found for any of these mechanisms and therefore corresponding limits on the half-lives are set. The background contributions to 0\u03bd\u03b2\u03b2 in the [2.6 \u2212 3.2] MeV energy region, where most of the signal from the light Majorana neutrino exchange and right-handed current mechanisms is expected, are shown in Table 2 .", "cite_spans": [], "ref_spans": []}, {"section": "Neutrinoless double beta decay", "text": "The electron energy sum distribution is used to set the limits using a modified frequentist method based on a binned log-likelihood ratio test statistic (CL s ) [39] . The statistic is calculated over the entire energy range above 0.6 MeV and takes into account the shape of the energy distribution.", "cite_spans": [], "ref_spans": []}, {"section": "Neutrinoless double beta decay", "text": "In order to estimate the effect of systematic uncertainties on the limit, the background and signal distributions are scaled by random factors drawn from Gaussian distributions with widths defined by the systematic errors of the experiment [40] , which are given in Table 4 . Similarly to 2\u03bd\u03b2\u03b2, the most significant contribution comes from the error on the selection efficiency. Table 4 : Values of the 1\u03c3 systematic errors included when setting limits on 0\u03bd\u03b2\u03b2 decay modes using the COLLIE software package [40] . The estimated errors shown are on the systematic quantity and are therefore significantly reduced when transferred through the \u03b2\u03b2 selection, with the exception of the dominating 0\u03bd\u03b2\u03b2 efficiency uncertainty. ", "cite_spans": [], "ref_spans": []}, {"section": "Light Majorana Neutrino Exchange", "text": "Light Majorana neutrino exchange is the most commonly discussed mechanism of 0\u03bd\u03b2\u03b2 decay. It has an experimental signature characterised by a peak in the distribution of the electron energy sum at the Q \u03b2\u03b2 value. The background, signal and data distributions shown in Figure 10a are used to set the limit. There are 7.20 [5.09 \u2212 10.66] events expected to be excluded at the 90% C.L., where the \u00b11\u03c3 range is given in brackets. The systematic errors from Table 4 are included in the expected limit and only reduce it by 2%. Taking into account the detector efficiency of 9.80% for this 0\u03bd\u03b2\u03b2 mechanism and the 82 Se exposure of 4.90 kg\u00b7y, the 90% C.L. expected halflife limit is 3.39 [2.29\u22124.80]\u00d710", "cite_spans": [], "ref_spans": [{"start": 267, "end": 277, "text": "Figure 10a", "ref_id": "FIGREF1"}]}, {"section": "Light Majorana Neutrino Exchange", "text": "23 y. From the data sample, 9.67 events are excluded at 90% C.L. leading to an upper limit on the half-life of", "cite_spans": [], "ref_spans": []}, {"section": "Light Majorana Neutrino Exchange", "text": "which is within the 1\u03c3 range of the expected sensitivity. Equation 1 is used to convert the half-life limit into an upper bound on the effective Majorana neutrino mass. The phase space is taken as G 0\u03bd = 1.016 \u00d7 10 \u221214 y \u22121 [37] (in agreement with G 0\u03bd = 1.014 \u00d7 10 \u221214 y \u22121 from [38] ). Several nuclear models are used to calculate the NME for the 82 Se 0\u03bd\u03b2\u03b2 transition to the ground state. The most recent calculations from [41] [42] [43] [44] [45] [46] have been used and g A is taken in the range 1.25 \u2212 1.27 to correspond with the assumptions of the different calculations. As a result, the constraint on the effective neutrino mass is", "cite_spans": [], "ref_spans": []}, {"section": "Right-handed Currents", "text": "Right-left symmetric models can provide an alternative mechanism for 0\u03bd\u03b2\u03b2 due to the presence of right-handed currents (RHC) in the electroweak Lagrangian [47, 48] . The lepton number violation mechanism is characterised by the coupling between right-handed currents of quarks and leptons, \u03bb , and right-handed quark and left-handed lepton currents, \u03b7 .", "cite_spans": [], "ref_spans": []}, {"section": "Right-handed Currents", "text": "The \u03bb mechanism leads to very different angular and single energy distributions of the final state electrons and can therefore be distinguished from other mechanisms in an experiment capable of reconstructing the full topology of the process, such as NEMO-3 [16] . In addition to the electron energy sum, further discrimination between the RHC \u03bb mechanism and background can be achieved with the energy asymmetry between the individual electron energies, A, defined as A = (E max \u2212 E min ) / (E max + E min ).", "cite_spans": [], "ref_spans": []}, {"section": "Right-handed Currents", "text": "The expected sensitivity in the RHC \u03bb mode has been studied by MC and is maximised with a cut of A > 0.26. This selection is therefore applied when searching for this particular decay mode as shown in Figure 10b . Cutting on the energy asymmetry variable provides no improvement in sensitivity for the \u03b7 mode and so the standard \u03b2\u03b2 selection criteria are used in this case.", "cite_spans": [], "ref_spans": [{"start": 201, "end": 211, "text": "Figure 10b", "ref_id": "FIGREF1"}]}, {"section": "Right-handed Currents", "text": "For the \u03bb mode, 7.34 events are excluded from the data sample leading to a lower limit on the half-life of 1.63 \u00d7 10 23 y at 90% C.L. This result is in agreement with the median expected sensitivity of the experiment of 2.16 [1.46 \u2212 3.01] \u00d7 10 23 y. For the \u03b7 mode, the halflife lower limit is 2.19 \u00d7 10 23 y at 90% C.L. and also agrees with the expected sensitivity.", "cite_spans": [], "ref_spans": []}, {"section": "Right-handed Currents", "text": "These half-life limits are translated into upper bound on the coupling between right-handed quark and lepton currents, \u03bb < (2.2 \u2212 2.6) \u00d7 10 \u22126 , and into the coupling between right-handed quark and left-handed lepton currents, \u03b7 < (1.7\u22122.1)\u00d710 \u22128 . The constraints are obtained using NME calculations from [48] [49] [50] .", "cite_spans": [], "ref_spans": []}, {"section": "Majoron Emission", "text": "A 0\u03bd\u03b2\u03b2 decay accompanied by a majoron, a light or massless boson that weakly couples to the neutrino, has a continuous spectrum of the energy sum of the two decay electrons, E tot , up to Q \u03b2\u03b2 [51] . The phase space of the process depends on the spectral index n, as G 0\u03bd \u221d (Q \u03b2\u03b2 \u2212 E tot ) n , and determines the shape of the distribution. Decays with higher n have broader E tot distributions peaking at lower energy values. Such events are harder to separate from 2\u03bd\u03b2\u03b2 and other backgrounds. Therefore only the result of the search for majoron induced 0\u03bd\u03b2\u03b2 decay with n = 1 is shown here. The corresponding half-life limit is T 0\u03bd 1/2 > 3.7 \u00d7 10 22 y at 90% C.L., which translates into an upper limit on the majoron-neutrino coupling of g ee < (3.2 \u2212 8.0) \u00d7 10 \u22125 . The range is due to a spread in NME calculations, which are taken from [41] [42] [43] [44] [45] [46] , while the phase space is taken from [52] . ,", "cite_spans": [], "ref_spans": []}, {"section": "Majoron Emission", "text": "where \u039b SUSY is a general SUSY breaking scale parameter. The above limits assume g A = 1.25. The spread in the limits is due to NME uncertainties associated with differences in the form of the Argonne and Charge Dependent Bonn (CD-Bonn) nucleon-nucleon potentials [55] .", "cite_spans": [], "ref_spans": []}, {"section": "Summary and Conclusions", "text": "The results of 82 Se \u03b2\u03b2 decay studies obtained with the full set of NEMO-3 data are presented. The 82 Se 2\u03bd\u03b2\u03b2 decay half-life for the ground state transition has been measured using foils from the first enrichment run only, due to higher levels of 234m Pa contamination in the foils from the second run and associated uncertainties in the 234m Pa conversion electron branching ratios. With the corresponding exposure of 2.4 kg\u00b7y, the HSD transition hypothesis is disfavoured at the 2.1\u03c3 level, whilst the SSD hypothesis is supported. In the SSD scenario, the half-life has been measured to be T 19 y. This is the most precise measurement for this isotope to date and allows the experimental extraction of the corresponding NME, M 2\u03bd = 0.0498 \u00b1 0.0016. This single result is more precise than and consistent with the world average reported in [12, 13] . The SuperNEMO experiment is based on the same design principles as the NEMO-3 detector and will have lower backgrounds and improved energy resolution. A demonstrator module is currently being commissioned, which will house 7 kg of 82 Se. The SuperNEMO demonstrator module will have the sensitivity to distinguish between the SSD and HSD scenarios at a > 5\u03c3 level.", "cite_spans": [], "ref_spans": []}, {"section": "Summary and Conclusions", "text": "A search for 0\u03bd\u03b2\u03b2 decay has been carried out for a number of different mechanisms, with foils from both enrichment runs, giving an exposure of 4.9 kg\u00b7y. No evidence for any neutrinoless double beta decay transition is found and therefore upper limits on the corresponding lepton number violating parameters have been set. The results of the 0\u03bd\u03b2\u03b2 search are summarised in Table 5 . The most stringent half-life limit for 82 Se is obtained for the light neutrino exchange mechanism of 0\u03bd\u03b2\u03b2, T The constraints on the RHC parameters, \u03bb and \u03b7 , on the majoron-neutrino coupling constant, g ee , and on R-parity violating SUSY parameters, \u03bb 1ij , shown in Table 5 are the best for 82 Se and are comparable with the best available limits from other isotopes [8] despite a much lower exposure. ", "cite_spans": [], "ref_spans": [{"start": 371, "end": 378, "text": "Table 5", "ref_id": "TABREF8"}]}], "bib_entries": {"BIBREF18": {"title": "Nuclear Beta Decays and Neutrino. Proc. Int. Symp. Osaka", "authors": [{"first": "T", "middle": [], "last": "Kirsten", "suffix": ""}, {"first": "E", "middle": [], "last": "Heusser", "suffix": ""}, {"first": "D", "middle": [], "last": "Kather", "suffix": ""}, {"first": "J", "middle": [], "last": "Ohm", "suffix": ""}, {"first": "E", "middle": [], "last": "Pernicka", "suffix": ""}, {"first": "H", "middle": [], "last": "Richter", "suffix": ""}], "year": 1986, "venue": "", "link": null}, "BIBREF19": {"title": "Nuclear Beta Decays and Neutrino. Proc. Int. Symp. Osaka", "authors": [{"first": "O", "middle": ["K"], "last": "Manuel", "suffix": ""}], "year": 1986, "venue": "", "link": null}}, "ref_entries": {"FIGREF1": {"text": "Fig. 1: The sectors of the detector containing the 82 Se source foils, imaged in the 1e channel. Figure (a) shows the reconstructed vertex from all single electron events. Figure (b) shows the same region after removing events originating from neighbouring foils, calibration tubes and areas with activity more than 5\u03c3 higher than the mean for the particular 82 Se foil strip. This is the fiducial area used in the analysis. The higher activity strip in sector 8 is contaminated with 210 Bi which does not affect the \u03b2\u03b2 analyses due to its low Q-value.", "type": "figure"}, "FIGREF3": {"text": "Fig. 2: (a) Distribution of the sum of the energies of the electron and \u03b3-ray in the external 1\u03b31e channel. (b) Distribution of the sum of the incoming and outgoing electron energies in the crossing-electron channel. In both figures, the energy spectra from data are compared to the total MC prediction (top panels) and as a ratio of data to the total MC prediction (bottom panels). The Other MC histograms contain the small contributions from internal and radon background sources.", "type": "figure"}, "FIGREF4": {"text": "Fig. 3: Distributions of the length of \u03b1-particle tracks from the 1e1\u03b1N \u03b3 channel, which contains events with one electron track and one delayed \u03b1-particle track, with no constraints on the number of \u03b3-rays present. The length is measured as the distance from the electron vertex on the foil to the furthest hit in the \u03b1-particle track. Figure (a) shows data from phase 1, which had a higher radon level in the tracker and Figure (b) shows the same distribution for phase 2 data. In the top panels, data are overlaid on stacked histograms of the MC prediction from 214 Bi contaminations in the source foils (red), Mylar backing film (yellow), deposits on the tracker wires (green) and on the surface of the source foils (blue). The bottom panels show the ratio of data to the total MC prediction.", "type": "figure"}, "FIGREF5": {"text": "Fig. 3: Distributions of the length of \u03b1-particle tracks from the 1e1\u03b1N \u03b3 channel, which contains events with one electron track and one delayed \u03b1-particle track, with no constraints on the number of \u03b3-rays present. The length is measured as the distance from the electron vertex on the foil to the furthest hit in the \u03b1-particle track. Figure (a) shows data from phase 1, which had a higher radon level in the tracker and Figure (b) shows the same distribution for phase 2 data. In the top panels, data are overlaid on stacked histograms of the MC prediction from 214 Bi contaminations in the source foils (red), Mylar backing film (yellow), deposits on the tracker wires (green) and on the surface of the source foils (blue). The bottom panels show the ratio of data to the total MC prediction.", "type": "figure"}, "FIGREF6": {"text": "to the \u03b2\u03b2 signal channel, with the lower energy threshold column relevant to a 2\u03bd\u03b2\u03b2 measurement. The largest background contribution comes from in- ternal contamination of the source foils with 15.1% of the total number of events for run 1 foils and 29.1% of those from run 2 foils. Among the internal contaminants, 234m Pa is the most prominent, accounting for 7.9% of events orig- inating in run 1 foils and 23.0% of events from run 2 foils. The external backgrounds account for 3% of the total with", "type": "figure"}, "FIGREF7": {"text": "Fig. 4: (a) Energy spectrum of electrons in events containing a single electron selected in the 1e channel compared to the MC prediction. At energies below 1 MeV the dominant contributions are from 40 K contamination and from 210 Bi deposited on the surfaces of the source foils and tracker wires. The contribution from 234m Pa becomes significant in an intermediate region at 1.2 \u2212 2.2 MeV. Above this energy the spectrum is composed of events from 214 Bi originating from source foil contamination and radon backgrounds. The small numbers of events at the highest energies are a result of external neutron flux. They do not contribute significantly to any other channel. (b) Distribution of the sum of electron and \u03b3-ray energies for events selected in the 1e1\u03b3 channel comparing data to the MC prediction. Below 2.5 MeV the distributions are mainly composed of events from the external \u03b3-ray flux. Above this energy the spectrum contains events from contamination of the source foil with 208 Tl.", "type": "figure"}, "FIGREF9": {"text": "Fig. 6: Energy distribution of individual electrons in the \u03b2\u03b2 channel for foils from each enrichment run, showing a comparison of the data to the predicted spectrum from MC. The two electrons in each event are entered separately into this distributions. The higher level of 234m Pa contamination in the run 2 foils leads to a larger contribution from the internal backgrounds. These foils are removed from the 2\u03bd\u03b2\u03b2 analysis due to poor modelling of this isotope (see text).", "type": "figure"}, "FIGREF10": {"text": "Fig. 7: Energy distribution of individual electrons in the \u03b2\u03b2 channel for foils from enrichment run 1, after removing events where \u03a3E e < 1.6 MeV to reduce the effect of contamination by 234m Pa. The data are compared to the predicted spectrum from MC under the HSD and SSD hypotheses. There is good agreement between the data and SSD hypothesis (\u03c7 2 /ndf = 12.3/16), but the HSD hypothesis is disfavoured (\u03c7 2 /ndf = 35.3/16).", "type": "figure"}, "FIGREF12": {"text": "is the number of moles of 82 Se and t is the total exposure time. The resulting half-life, assuming the SSD hypothesis, is T 2\u03bd 1/2 = [9.39 \u00b1 0.17 (stat) \u00b1 0.58 (syst)] \u00d7 10 19 y . (3) An identical analysis under the HSD hypothesis gives T 2\u03bd 1/2 = [10.63 \u00b1 0.19 (stat) \u00b1 0.66 (syst)] \u00d7 10 19 y . (4)", "type": "figure"}, "FIGREF13": {"text": "Fig. 10: Distribution of the summed electron energies in the \u03b2\u03b2 channel and the ratio between the observed and MC predicted data. The inset plot shows the highest energy events on a linear scale. The solid histograms represent the backgrounds and 2\u03bd\u03b2\u03b2 predictions and the open histogram shows a hypothetical 0\u03bd\u03b2\u03b2 signal corresponding to the limit at 90% C.L. Figure (a) contains events selected in the \u03b2\u03b2 channel and Figure (b) contains a subset of these events that also pass the energy asymmetry cut for the right-handed current \u03bb mode, A > 0.26, where A is defined in the text.", "type": "figure"}, "FIGREF14": {"text": "= [9.39 \u00b1 0.17 (stat) \u00b1 0.58 (syst)] \u00d7 10", "type": "figure"}, "FIGREF15": {"text": "C.L. corresponding to an effective Majorana neu- trino mass of m \u03bd < (1.2 \u2212 3.0) eV. It should be noted that the CUPID-0 collaboration recently published their first limit for 0\u03bd\u03b2\u03b2 of 82 Se with a value T", "type": "figure"}, "TABREF0": {"text": "identical sectors. The two isotopes with the largest mass were", "type": "table"}, "TABREF2": {"text": "Bi. The for- mer is a product of 220 Rn decay and was measured using 1e2\u03b3 and 1e3\u03b3 channels where the electron track starts away from the foil [30]. The latter is caused by 210 Pb from 222 Rn deposited on the surfaces of detector components during construction. This isotope has a half-life of 22.3 y and supplies 210 Bi over the lifetime of the experiment. It is therefore not in equilibrium with 222 Rn observed in the detector. In a similar manner to the 214 Bi activities, a map of relative 210 Bi activities divided by sector and tracker layer has been developed [30].", "type": "table"}, "TABREF3": {"text": "Measurements of the specific activity of 82 Se source foils for different isotopes, made with the NEMO-3 detector and independently with an HPGe detector. Equal numbers of", "type": "table"}, "TABREF4": {"text": "Tl. Data are compared to the MC prediction, which is dominated by internal 208 Tl con- tamination with a small contribution from 208 Tl in the tracker wires.", "type": "table"}, "TABREF5": {"text": "Kr. If one single intermediate 1 + state dominates the transition, then the process is said to be single-state dominated (SSD). Alternatively, if the process proceeds through many higher intermediate excited states, it is said to be higher-state dominated (HSD). Previously, it has been assumed that", "type": "table"}, "TABREF6": {"text": "", "type": "table"}, "TABREF8": {"text": "Limits from 0\u03bd\u03b2\u03b2 searches for different decay modes in 82 Se. The signal efficiency and the 90% C.L. limits for half-lives and lepton number violating (LNV) parameters are shown. The ranges in the expected half-life limits are the \u00b11\u03c3 range of systematic uncertainties on the background model and signal efficiency. The ranges in the LNV parameter are due to the spread in NME calculations. The R-parity violating SUSY LNV parameters correspond to sparticle masses and energy scale \u039b SUSY in TeV.", "type": "table"}}}
{"paper_id": "119428908", "_pdf_hash": "bc8feab79485ca6ca6c9f28cfae190f2f81bfff7", "abstract": [{"section": "Abstract", "text": "We present BVRI photometry of supernova (SN) 2016coj in NGC 4125 from 9 days before to 57 days after its B-band maximum light. Our light curves and color curves suggest that this event belongs to the \"normal\" class of type Ia SNe, with a decline rate parameter \u2206m 15 (B) = 1.32 \u00b1 0.10, and that it suffers little extinction. Adopting a distance modulus to its host galaxy of (m\u2212 M ) = 31.89 mag, we compute extinction-corrected peak absolute magnitudes of M B = \u221219.01, M V = \u221219.05, M R = \u221219.03, and M I = \u221218.79. The explosion occurred close enough to the nucleus of NGC 4125 to hinder the measurement of its brightness. We describe our methods to reduce the effect of such host-galaxy contamination, but it is clear that our latest values suffer from systematic bias.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION", "text": "Supernova (SNe) of type Ia are thought to originate in close binary systems, consisting of either a single white dwarf and a main-sequence companion, or two white dwarfs. When one white dwarf accretes enough material to exceed the Chandrasekhar limit (Chandrasekhar 1931) , either by long-term transfer from a main sequence companion, or by a violent merger with another white dwarf, a runaway thermonuclear reaction propagates through it, disrupting the entire white dwarf, heating the ejecta to hundreds of thousands of degrees and blowing it out into space at thousands of kilometers per second. The expanding cloud of hot gas radiates energy for several months, reaching absolute magnitudes in the optical of order -18 to -20. Many (but not all) type Ia SNe exhibit similar properties, with a correlation between the shape of the light curve and the absolute magnitude at peak (Phillips 1993) . When events are observed in sufficient detail, one can use the shape of the light curve to compute the absolute magnitude (Prieto, Rest & Suntzeff (2006) ; Guy et al. (2005) ), and so use these SNe as \"standard-izable candles\" to determine distances.", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "Supernova 2016coj in the galaxy NGC 4125, a peculiar elliptical of class E6 (de Vaucouleurs et al. 1991) , was discovered by the Lick Observatory Supernova Search (Filippenko et al. 2001; Leaman et al. 2011 ) on UT 2016 May 28 (Zheng et al. 2016) and quickly identified as a type Ia explosion. Since its host galaxy is relatively close to our Milky Way, at a redshift of only z = 0.004523 according to NED, 1 this event promised to provide a wealth of high-precision information. However, since the supernova occurred not far from the galaxy's nucleus, disentangling its light from that of the surrounding stars turns out to be a difficult task.", "cite_spans": [{"start": 76, "end": 104, "text": "(de Vaucouleurs et al. 1991)", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "In this paper, we describe photometry of SN 2016coj in the BVRI passbands acquired at two locations, starting on UT 2016 May 30 and ending UT 2016 Aug 4, an interval of 66 days. Section 2 describes our observational methods, the cleaning of the raw CCD images, and the techniques we used to extract instrumental magnitudes. We explain our photometric calibration of the raw measurements onto the standard Johnson-Cousins system in Section 3. The light curves and color curves of the event are shown in Section 4; we comment briefly on their properties and the effect of extinction along the line of sight. We present our conclusions in Section 5. In an appendix, we discuss the difficulties of measuring the light of a point source immersed in a non-uniform background, and use simple simulations to estimate the nature of systematic biases that appear in our data.", "cite_spans": [], "ref_spans": []}, {"section": "OBSERVATIONS", "text": "We present herein data acquired at the RIT Observatory, near Rochester, New York, and at the Northern Skies Observatory (NSO), in Peacham, Vermont. We will describe below the procedures by which we acquired and reduced the images from each observatory in turn.", "cite_spans": [], "ref_spans": []}, {"section": "OBSERVATIONS", "text": "The RIT Observatory is located on the southeastern corner of the Rochester Institute of Technology campus, at longitude 77:39:53 West, latitude +43:04:33 North, and an altitude of 168 meters. Our Meade LX200 f/10 30-cm telescope provides a plate scale of 1.", "cite_spans": [], "ref_spans": []}, {"section": "OBSERVATIONS", "text": "\u2032\u2032 38 per pixel at the focus of our SBIG ST-9 camera, which has BVRI filters built to the Bessell prescription. When observing SN 2016coj, we acquired a series of 5 to 20 short exposures (exposure times 30 seconds each up to 2016 July 19 = JD 2457588, 120 seconds each after that date), discarding those with trailing or extinction by clouds. We acquired dark and flatfield images each night, creating master frames from the median of 10 individual images. Flatfields were based on images of the twilight sky, with the exception of UT June 13, when bad conditions forced us to use dome flats. After subtracting the master dark from each target frame and dividing it by the normalized master flatfield, we examined each resulting \"clean\" image by eye, discarding those with poor quality. Before extracting instrumental magnitudes, we combined all the images in a particular passband using a median technique, in order to increase the signal-to-noise ratio and eliminate cosmic rays. Figure 1 shows an example of such a combined image, with labels indicating stars used for calibration. The Point Spread Function (PSF) of these combined images had a typical Full Width at Half Maximum (FWHM) of 3.", "cite_spans": [], "ref_spans": [{"start": 982, "end": 990, "text": "Figure 1", "ref_id": "FIGREF0"}]}, {"section": "OBSERVATIONS", "text": "\u2032\u2032 5 to 4. \u2032\u2032 1.", "cite_spans": [], "ref_spans": []}, {"section": "OBSERVATIONS", "text": "Since the supernova lies only about 12 arcseconds from the nucleus of its host galaxy (Zheng et al. 2016) , simple aperture photometry will yield poor results. A systematic error can appear in such measurements due to imperfect background subtraction; the size of the error will grow as the supernova fades. A standard technique in such cases is to match each target image to a template of the same galaxy taken some time before or after the event, in which the supernova does not appear, and then to subtract the template from the target image. However, since we lacked template images, we adopted a technique which does not require them; the drawback is that its results are less accurate, and can still suffer from systematic effects. See the Appendix for a detailed explanation. The basic idea of the method is to use the symmetry of the elliptical galaxy host to provide a pseudo-template. We identified the center of the host galaxy, rotated the image by 180", "cite_spans": [], "ref_spans": []}, {"section": "East", "text": "\u2022 around this point, then subtracted the rotated version from the original. An example of the results, starting with the same image shown in Figure 1 , is displayed in Figure 2 ; we have zoomed in to show details near the nucleus more clearly. The subtraction is not perfect: small positive and negative residuals remain near the center of the galaxy. However, the residuals decrease rapidly with radius, and near the position of the supernova they are typically much smaller than the peak of the supernova's light. Moreover, the background around and underneath the supernova is much more uniform than in the original image, removing the main source of error in the aperture photometry.", "cite_spans": [], "ref_spans": [{"start": 141, "end": 149, "text": "Figure 1", "ref_id": "FIGREF0"}]}, {"section": "East", "text": "After creating these residual images, we performed standard aperture photometry of the SN and reference stars, using the XVista (Treffers & Richmond 1989 ) routines stars and phot. We chose to measure light within circular apertures of a fixed radius, a bit larger than the usual FWHM: 4 pixels = 5.", "cite_spans": [], "ref_spans": []}, {"section": "East", "text": "\u2032\u2032 5. A local sky background was estimated for each star using an annulus with radii of 6. \u2032\u2032 9 and 13. U16M CCD camera; we bin the chip 2x2 to produce a plate scale of 1.", "cite_spans": [], "ref_spans": []}, {"section": "East", "text": "\u2032\u2032 26 per pixel. We acquire new flatfield images for each observing session, but re-use bias and dark frames for a month or so. We acquired 5 unguided images in each passband, using exposure times of 45 to 60 seconds each. After using MaximDL to subtract master bias and master dark frames, and divide by a master flatfield frame, we combined the images in each passband using a median technique. These combined images typically had a FWHM ranging between 3. \u2032\u2032 1 and 3. \u2032\u2032 9, with most lying near the low end of this range. A sample composite R-band image is shown in Figure 3 . We applied the rotation technique described above to each combined image before extracting photometry using circular apertures of radius 3 pixels = 3.", "cite_spans": [], "ref_spans": [{"start": 569, "end": 577, "text": "Figure 3", "ref_id": "FIGREF2"}]}, {"section": "East", "text": "\u2032\u2032 8. The local background was measured for each star using an annulus of radii 12. \u2032\u2032 6 and 25. \u2032\u2032 2. Figure   4 shows one such residual image from the NSO dataset. In order to transform our instrumental measurements onto the standard Johnson-Cousins BVRI system, we used a set of local reference stars provided by the AAVSO 2 in their sequence X18345FX. These stars are labelled in all figures showing the supernova and its surroundings. Given our relatively small fields of view and shallow limiting magnitudes, we did not select comparison stars on the basis of color, but accepted them all. The color range covered is relatively small: 0.598 \u2264 (B \u2212 V ) \u2264 1.065. SN 2016coj has a color of (B \u2212 V ) \u2243 0.0 near maximum light, and does not redden to match the comparison stars until about 15 days later. Of course, the spectrum of this type Ia SN is so distinct from that of the comparison stars that color corrections must be approximate in any case.", "cite_spans": [], "ref_spans": [{"start": 103, "end": 113, "text": "Figure   4", "ref_id": "FIGREF3"}]}, {"section": "East", "text": "In order to convert the RIT measurements to the Johnson-Cousins system, we analyzed images of the standard fields PG1633+009 and PG2213-006 (Landolt 1992 ) taken on five nights between June and August, 2016. Comparing our instrumental values to the standard magnitudes, we determined transformation equations", "cite_spans": [], "ref_spans": []}, {"section": "East", "text": "(1) ", "cite_spans": [], "ref_spans": []}, {"section": "East", "text": "In the equations above, lower-case symbols represent instrumental magnitudes, upper-case symbols Johnson-Cousins magnitudes, terms in parentheses the uncertainties in each coefficient, and Z the zeropoint in each band. The relatively small field of view of the RIT images allowed us to use only a few stars for calibration: B, C, J, and, in some cases, K. In mid-June 2016, we noticed that images in the B-band from RIT had a low signal-to-noise ratio, even after coaddition; this is largely a function of the relatively low sensitivity of our camera's sensor at short wavelengths. The B-band measurements showed a large scatter from night to night, making real trends in the light curve hard to discern. Therefore, after UT 2016 June 20, we stopped taking images at RIT in the B-band.", "cite_spans": [], "ref_spans": []}, {"section": "East", "text": "We present our calibrated measurements of SN 2016coj made at RIT in Table 2 . The first column shows the mean Julian Date of all the exposures taken during each night; we have subtracted the arbitrary constant 2457530 from all Julian Dates for convenience. The uncertainties listed in Table 2 incorporate the uncertainties in instrumental magnitudes and in the offset to shift the instrumental values to the standard scale, added in quadrature.", "cite_spans": [], "ref_spans": [{"start": 68, "end": 75, "text": "Table 2", "ref_id": "TABREF1"}, {"start": 285, "end": 292, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "East", "text": "We determined linear transformations between the instrumental NSO measurements and the standard scale using images of the open cluster M67 and photometry provided by the AAVSO. The transformation equations for NSO were", "cite_spans": [], "ref_spans": []}, {"section": "East", "text": "In the equations above, lower-case symbols represent instrumental magnitudes, upper-case symbols Johnson-Cousins magnitudes, terms in parentheses the uncertainties in each coefficient, and Z the zeropoint in each band. We list two equations for the V -band; on nights when we acquired R images, we used the (v \u2212 r) equation; but on nights when we measured only B and V , we used the (b \u2212 v) version. Table 3 lists our calibrated measurements of SN 2016coj made at Northern Skies Observatory.", "cite_spans": [], "ref_spans": [{"start": 400, "end": 407, "text": "Table 3", "ref_id": "TABREF2"}]}, {"section": "LIGHT CURVES", "text": "In order to determine the time and magnitude at peak brightness, we fit polynomials of order 3 to the light curves near maximum, using data from the period 0 < (JD \u2212 2457530) < 30 in each passband, weighting the fits by the uncertainties in each measurement. We list the results in Table 4 . For the secondary maximum in I-band, we found that polynomials of order 2 provided better fits; we averaged the results from several intervals during during the period 30 < (JD \u2212 2457530) < 50 to produce the value in the table. Note that the I-band magnitude at its primary maximum is particularly uncertain, as it falls farther within the gap in our measurements than the peaks in other passbands.", "cite_spans": [], "ref_spans": [{"start": 282, "end": 289, "text": "Table 4", "ref_id": "TABREF3"}]}, {"section": "LIGHT CURVES", "text": "Using a second-order polynomial to interpolate in the B-band observations exactly 15 days after the time of B-band maximum light, we compute \u2206 15 (B) = 1.32 \u00b1 0.10. By this measure, SN 2016coj lies in the range of \"normal\" type Ia SNe, such as 1980N (Hamuy et al. 1991 ), 1989B (Wells et al. 1994 ), 1994D (Richmond et al. 1995 ), 2003du (Stanishev et al. 2007 , and 2011fe (Richmond & Smith 2012; Parrent et al. 2012 ). The secondary peak in I-band, which lies 22.8 \u00b1 1.0 days after and 0.27 \u00b1 0.07 mag below the primary peak, is also typical of \"normal\" type Ia events.", "cite_spans": [], "ref_spans": []}, {"section": "LIGHT CURVES", "text": "Our values of the apparent magnitude at B-band maximum light and the \u2206 15 (B) parameter agree with those measured by Zheng et al. (2016) . Those authors also provide spectroscopic evidence to support a \"normal\" classification for SN 2016coj.", "cite_spans": [], "ref_spans": []}, {"section": "LIGHT CURVES", "text": "In order to compute absolute magnitudes and intrinsic colors for SN 2016coj, we must remove the extinction due to any intervening material. Fortunately, there appears to be very little dust in its direction. Our own Galaxy's contribution is small: Schlegel, Finkbeiner & Davis (1998) use infrared maps of the Milky Way to estimate E(B \u2212 V ) MW = 0.017 in the direction of Prieto, Rest & Suntzeff (2006) After removing this extinction from each passband, we calculate the evolution of the event in each color; see Figure 6 for (B \u2212 V ), Figure 7 for (V \u2212 R), and Figure 8 for (R \u2212 I). The (B \u2212 V ) color shows a value of zero at maximum light, typical for a normal type Ia. In the same figure, we have drawn a line which represents the late-time (B \u2212 V ) evolution of a set of normal type Ia SNe with little or no extinction (Lira (1995) ; Phillips et al. (1999) ). Although our measurements are sparse and noisy at late times, due to the low signal in the B band, they suggest that SN 2016coj followed the same evolution as other normal events. In Figure 7 , we see that SN 2016coj reaches a minimum (V \u2212 R) color about 10 days after B-band maximum, then increases to a maximum (V \u2212 R) = 0.35. The time of minimum is a few days earlier in (R \u2212 I), which then rises to a maximum of (R \u2212 I) = 0.35. All these properties are similar to those in the color curves of the normal SNe Ia 1994D (Richmond et al. 1995) , 2003du (Stanishev et al. 2007 ), 2009an (Sahu et al. 2013) , and 2011fe (Richmond & Smith 2012) . The only significant difference in the late-time behavior of SN 2016coj is in (R \u2212 I), which appears to have a relatively constant value of (R \u2212 I) \u223c 0.2. However, we believe that this color in particular suffers from a systematic bias in the RIT I-band measurements (see the Appendix); note the position of the single late-time NSO datum, at a negative color more typical of normal SNe.", "cite_spans": [{"start": 824, "end": 836, "text": "(Lira (1995)", "ref_id": "BIBREF7"}], "ref_spans": [{"start": 513, "end": 521, "text": "Figure 6", "ref_id": "FIGREF6"}, {"start": 536, "end": 544, "text": "Figure 7", "ref_id": "FIGREF7"}, {"start": 562, "end": 570, "text": "Figure 8", "ref_id": "FIGREF8"}, {"start": 1048, "end": 1056, "text": "Figure 7", "ref_id": "FIGREF7"}]}, {"section": "ABSOLUTE MAGNITUDES", "text": "What was the absolute magnitude of SN 2016coj? In order to convert our apparent magnitudes to the absolute scale, we need to account for extinction and the distance to the host galaxy. As mentioned earlier, Zheng et al. (2016) place only upper limits on the extinction due to material in the host galaxy. In the discussion which follows, we will compute two values of absolute magnitude, one assuming no extinction in the host galaxy, the other corresponding to the upper limit of E(B \u2212 V ) = 0.05 derived in Zheng et al. (2016) . The distance to NGC 4125 has been measured a number of times, but none are very recent. We will adopt the measurement based on Surface Brightness Fluctuations (SBF) by Tonry et al. (2001) of (m \u2212 M ) = 31.89 \u00b1 0.25. A connection between the absolute magnitude of a type Ia SN and its rate of decline after maximum was first noted by Phillips (1993) and has since been refined by a number of authors (Hamuy et al. 1996 ; Riess, Press & Kirshner 1996 ; Perlmutter et al. 1997) . We choose the relationships derived by Prieto, Rest & Suntzeff (2006) which are based on the fading in B-band in the first 15 days after maximum light, the \u2206m 15 (B) parameter. In the case of SN 2016coj, we measure \u2206m 15 (B) = 1.32 \u00b1 0.10. Inserting that into the equations in Table 3 of Prieto, Rest & Suntzeff (2006) for events in environments with low extinction, we derive the absolute magnitudes shown in the rightmost column of Table 5 . With the exception of the B-band measurement assuming no host extinction, all measurements agree with the predictions of the decline-rate method, supporting further the classification of SN 2016coj as normal. The slight improvement offered by assuming a small host extinction provides weak evidence that it may be close to the upper limits derived by Zheng et al. (2016) .", "cite_spans": [], "ref_spans": [{"start": 1285, "end": 1292, "text": "Table 3", "ref_id": "TABREF2"}]}, {"section": "CONCLUSION", "text": "Our measurements of SN 2016coj show that its photometric behavior at early times (within 60 days of maximum light) follows that of \"normal\" type Ia SNe. We compute a decline parameter of \u2206m 15 (B) = 1.32 \u00b1 0.10 mag, placing it in the middle of the distribution of normal events. Adopting a distance modulus to NGC 4125 of (m \u2212 M ) = 31.89 and correcting for a total of E(B \u2212 V ) = 0.067 of extinction, we derive absolute magnitudes of M B = \u221219.01, M V = \u221219.05, M R = \u221219.03 and M I = \u221218.79.", "cite_spans": [], "ref_spans": []}, {"section": "CONCLUSION", "text": "We have shown that correcting for contamination of SN measurements by the background light of the host galaxy is a difficult issue for this event. While our measurements at early times -upon which the above conclusions are based -are reliable, those at late times must be treated with caution. The simple procedure we used for this dataset does not require template images of the host galaxy alone, but can leave a systematic error which grows as the target object fades.", "cite_spans": [], "ref_spans": []}, {"section": "CONCLUSION", "text": "We thank the staff at AAVSO for their finding charts, sequences of comparison stars, and endless support of observers. MWR is grateful for the continued support of the RIT Observatory by RIT and its College of Science. BV thanks the Northeast Kingdom Astronomy Foundation for allowing him to use their facility. The Lick Observatory Supernova Search noticed this event and quickly alerted the rest of the community, permitting us to begin our study while the supernova was still on the rise. This research has made use of the \"Aladin Sky Atlas\" and SIMBAD database (Wenger et al. 2000) , developed and operated at the CDS, Strasbourg Observatory, France, We have also made use of the NASA/IPAC Extragalactic Database (NED) which is operated by the Jet Propulsion Laboratory, California Institute of Technology, under contract with the National Aeronautics and Space Administration. This paper (and many others) has made use of NASA's Astrophysics Data System.", "cite_spans": [], "ref_spans": []}, {"section": "Facility: AAVSO APPENDIX A. BIAS IN PHOTOMETRY", "text": "The location of SN 2016coj in its host galaxy presents the observer with good news and bad news. The good news is that NGC 4125 is an elliptical galaxy, and therefore likely contains relatively little gas and dust, as the spectroscopic measurements of Zheng et al. (2016) confirm. It is therefore not necessary to make large corrections for extinction. But the bad news is that the supernova is close enough to the bright core of its host, offset by only 5.", "cite_spans": [], "ref_spans": []}, {"section": "Facility: AAVSO APPENDIX A. BIAS IN PHOTOMETRY", "text": "\u2032\u2032 0 east and 10. \u2032\u2032 8 north (Zheng et al. 2016) , that the light of the nucleus and the surrounding stars provides a significant background to measurements of the SN. Moreover, at this location, the light of the galaxy has a strong radial gradient, making it very difficult to subtract its contribution accurately. Since other observers may encounter similar situations, we describe in some detail below our investigation of the likely systematic errors that can arise when one attempts to perform photometry on such images.", "cite_spans": [], "ref_spans": []}, {"section": "Facility: AAVSO APPENDIX A. BIAS IN PHOTOMETRY", "text": "It became clear to us that simple aperture photometry methods would yield poor results in this case. Since we did not have template images of the galaxy to use as references for subtraction in the standard manner, we settled upon a method which would provide better (but not perfect) results: making a copy of each image, rotating the copy by 180", "cite_spans": [], "ref_spans": []}, {"section": "Facility: AAVSO APPENDIX A. BIAS IN PHOTOMETRY", "text": "\u2022 around the center of the galaxy, then subtracting the copy from the original. As shown in Figure 2 , the resulting residual image has a background near the location of the supernova which is both much lower, and much more uniform, than the original image. We used these residual images to derive the measurements presented in this paper.", "cite_spans": [], "ref_spans": []}, {"section": "Facility: AAVSO APPENDIX A. BIAS IN PHOTOMETRY", "text": "However, we suspected that there remained a sometimes significant systematic error in the photometry produced by this method, for two reasons. noticed that this event faded less quickly at late times -by an amount which appeared to grow with time. Second, we noticed a difference between measurements from our two sites: measurements from NSO, which typically have a smaller PSF and higher signal-to-noise than those from RIT, showed the SN as slightly fainter, and this difference also grew with time.", "cite_spans": [], "ref_spans": []}, {"section": "Facility: AAVSO APPENDIX A. BIAS IN PHOTOMETRY", "text": "Could there be a reason why measurements of faint point sources immersed in a noisy (and possibly non-uniform) background should show a systematic error? Our technique of identifying and measuring both reference stars and the supernova in images was a simple one: we searched through each image independently to identify peaks above the local sky background, measured their properties, and kept as \"good\" sources those which had shapes consistent with the expected PSF. We used the pixels around each of these sources to compute its center, placed a circular aperture at this position, and integrated the light within the aperture; finally, we subtracted the contribution from the local background light within the aperture.", "cite_spans": [], "ref_spans": []}, {"section": "Facility: AAVSO APPENDIX A. BIAS IN PHOTOMETRY", "text": "The important feature of this standard method is that the position of the aperture used to measure the SN (and reference stars) is not fixed in any way: it may be influenced independently by noise in each image, especially when the source is faint and the noise is high. A better technique, one which is natural when using a template, is to align images, co-add them to improve signal-to-noise, and measure relative positions for the SN and several reference stars; then, in each individual image, measure the position of bright reference stars and use them to infer the position of the SN using a fixed offset, rather than computing it based on the possibly noisy data at its location in each image. The method we employed is likely to shift the center of the SN's aperture slightly to follow positive noise peaks, which could yield measurements slightly higher than they ought to be.", "cite_spans": [], "ref_spans": []}, {"section": "Facility: AAVSO APPENDIX A. BIAS IN PHOTOMETRY", "text": "In short, we suspect that our measurements, especially those made at RIT, contain a systematic positive bias: the SN appears brighter than it actually is, by an amount which increases as the SN fades.", "cite_spans": [], "ref_spans": []}, {"section": "Facility: AAVSO APPENDIX A. BIAS IN PHOTOMETRY", "text": "To test this hypothesis, we created a set of simulated images with properties similar to those acquired at RIT, and subjected them to exactly the same measurement methods as we used on our actual images. We started with a simplified situation: a set of reference stars of identical brightness on a uniform background, and a single \"supernova\" immersed in a \"square galaxy\" region of uniform higher intensity; see Figure 9 . The stars are modeled as gaussians of FWHM 3.0 pixels, matching the typical seeing at RIT, and the gain in the image is set to 2.2 electrons per count, matching the properties of the SBIG ST-9E camera. The brightness of the \"square galaxy\" is set to 620 counts, typical for the region near SN 2016coj in R-band images. Note that the stars are placed at intervals with small random variations, ensuring that they appear at a wide range of sub-pixel locations. We Figure 9 . Simulated image with 19 reference stars in a low background and a \"supernova\" immersed in a \"square galaxy\". ran a number of instances of each simulation, shifting both the reference stars and the \"supernova\" by small random sub-pixel positions each time.", "cite_spans": [], "ref_spans": []}, {"section": "Facility: AAVSO APPENDIX A. BIAS IN PHOTOMETRY", "text": "In this simplified situation, we chose as the center of rotation the geometric center of the image. After making a copy and rotating it around this center by 180", "cite_spans": [], "ref_spans": []}, {"section": "Facility: AAVSO APPENDIX A. BIAS IN PHOTOMETRY", "text": "\u2022 , we subtracted the copy from the original, leaving both reference stars and \"supernova\" in a near-zero background; but the pixels surrounding the supernova might be noisier than those surrounding the reference stars. As a sanity check that our software was not introducing errors of its own, we ran simulations in which no photon noise was added to the images: the background value was some fixed value in all pixels, and the model gaussian for each star was similarly exact. Over a series of trials, the reference stars and \"supernova\" were all set to the same input brightness, increasing gradually throughout the trials until their centers reached a value of 30,000 counts (similar to the limit of linearity on our camera). We would expect the stars and \"supernova\" all to have exactly the same magnitude in this noiseless simulation. The magenta symbols in Figure 10 show that the difference between the average reference star magnitude, and the \"supernova\" magnitude, is indeed zero under these conditions. However, when we add photon noise to our simulations, we find some differences between the magnitude of the reference stars and the \"supernova.\" We ran simulations with two background levels, 100 and 1000 counts per pixel, roughly bracketing the range of sky levels in real RIT images (which varies due to clouds, haze, and the aspect of the Moon). Consider first the SN peak counts (intensity) sky=100, photon noise sky=1000, photon noise sky=1000, no photon noise Figure 10 . Results of photometry after rotation and subtraction of the simulated images with a \"square galaxy.\" red asterisk symbols, which show the results under low sky conditions: when the SN and stars are bright, there is no significant difference in their measured magnitudes. But when the stars are faint, noise in the sky background and in their own signal leads both to increased scatter and to discrepancy between the average value of the reference stars and that of the \"supernova;\" the SN tends to be measured as brighter than the reference stars. The amplitude of the difference grows to roughly 0.1 magnitude by the time the stars are too faint to detect reliably. The blue circular symbols, corresponding to higher and so noisier background sky levels, show the same trend, but at an increased amplitude.", "cite_spans": [], "ref_spans": [{"start": 864, "end": 873, "text": "Figure 10", "ref_id": "FIGREF0"}, {"start": 1481, "end": 1490, "text": "Figure 10", "ref_id": "FIGREF0"}]}, {"section": "Facility: AAVSO APPENDIX A. BIAS IN PHOTOMETRY", "text": "We conclude that point sources simply immersed in a higher background of light will suffer from a systematic bias under our measurement procedure, appearing brighter than they ought to be. However, the situation of SN 2016coj is even worse: not only is it in a region of higher background level than the comparison stars, but it sits in a strong spatial gradient. What effect will this additional complication have on our measurements?", "cite_spans": [], "ref_spans": []}, {"section": "Facility: AAVSO APPENDIX A. BIAS IN PHOTOMETRY", "text": "We performed a very simple test by creating a toy model of our real images. We created an artificial galaxy by superposing a central gaussian (FWHM = 3.0 pixels) and an extended and flattened component (FWHM = 8.0 pixels, convolved with a kernel of FWHM = 6 along rows and FWHM = 12 along columns), scaling the result so that it resembled the appearance of NGC 4125 in our R-band images. We then placed the \"supernova\" at an offset from the galaxy similar to its actual offset. Both the galaxy and the \"supernova\" were shifted in position by small random sub-pixel amounts in each realization of our simulations. Figure  11 shows an example of these artificial images, one in which the reference stars and SN are all at the maximum brightness.", "cite_spans": [], "ref_spans": [{"start": 613, "end": 623, "text": "Figure  11", "ref_id": "FIGREF0"}]}, {"section": "Facility: AAVSO APPENDIX A. BIAS IN PHOTOMETRY", "text": "We then carried out a series of instances, changing the brightness of the stellar objects over a wide range; at each level of brightness, we ran 10 realizations, varying the positions of each source at the sub-pixel level and generating different random values of photon noise. For each realization, we carried out exactly the same measurement procedure as we used for the real images:", "cite_spans": [], "ref_spans": []}, {"section": "Facility: AAVSO APPENDIX A. BIAS IN PHOTOMETRY", "text": "\u2022 a copy of the image was displayed on a computer screen", "cite_spans": [], "ref_spans": []}, {"section": "Facility: AAVSO APPENDIX A. BIAS IN PHOTOMETRY", "text": "\u2022 the user moved a cursor to the center of the galaxy, pressed a key to initiate a calculation of the local centroid and display a radial profile, made adjustments to initial position until satisfied that the center had been found correctly", "cite_spans": [], "ref_spans": []}, {"section": "Facility: AAVSO APPENDIX A. BIAS IN PHOTOMETRY", "text": "\u2022 a copy of the image was rotated around this position Figure 11 . Simulated image with 19 reference stars in a low background and a \"supernova\" placed close to an artificial galaxy.", "cite_spans": [], "ref_spans": [{"start": 55, "end": 64, "text": "Figure 11", "ref_id": "FIGREF0"}]}, {"section": "Facility: AAVSO APPENDIX A. BIAS IN PHOTOMETRY", "text": "\u2022 the copy was subtracted from the original image", "cite_spans": [], "ref_spans": []}, {"section": "Facility: AAVSO APPENDIX A. BIAS IN PHOTOMETRY", "text": "\u2022 point sources in the residual image were automatically found and measured via aperture photometry An example of one residual image is shown in Figure 12 . There is clearly imperfect subtraction of the galaxy's light at its very center, as is seen in most of the real images after this procedure.", "cite_spans": [], "ref_spans": [{"start": 145, "end": 154, "text": "Figure 12", "ref_id": "FIGREF0"}]}, {"section": "Facility: AAVSO APPENDIX A. BIAS IN PHOTOMETRY", "text": "The results of photometry on these images are display in Figure 13 . In this case, we fixed the brightness of the overall sky background to 100 counts for all realizations, so it represents the optimistic end of the spectrum of real conditions. The general trend is similar to that in the \"square galaxy\" simulations: measurements of the SN appear brighter than those of the reference stars, by an amount which increases as the SN fades. However, there are important differences: first, this systematic difference appears even in the absence of photon noise; this indicates that the software used to perform the image analysis (XVista Treffers & Richmond 1989 ) is unable to compute the center of the galaxy accurately enough, or perform the image rotation accurately enough, or both. Second, note that the amplitude of the systematic difference is much larger than in the \"square galaxy\" simulations: the SN can appear about 1.0 magnitude brighter it ought to be, instead of just 0.1 magnitude.", "cite_spans": [], "ref_spans": [{"start": 57, "end": 66, "text": "Figure 13", "ref_id": "FIGREF0"}]}, {"section": "Facility: AAVSO APPENDIX A. BIAS IN PHOTOMETRY", "text": "In order to reduce these systematic errors, one must improve the method of subtracting the background contribution to the total light within the photometric aperture. Given the large FWHM of our images, we could not decrease the size of the photometric Figure 12 . Simulated image with artificial galaxy after rotation and subtraction. aperture significantly; given the location of the SN, close to the galaxy's nucleus, increasing the size of the background annulus would make matters worse, and, given the large FWHM, decreasing the size of the background annulus is not possible. Rather than choosing some constant value per pixel for the background contribution, one could do better by making a model of the galaxy's light within the photometric aperture. We will investigate this technique in the future; it would require a substantial effort to modify the existing software. The difficulty of proper background subtraction is, of course, the reason that many astronomers adopt the \"template subtraction\" method. Now, in light of this information, let us review the light curves shown in Figure 5 . When the SN is bright, measurements from RIT and NSO agree well; but as the SN fades, an offset between the two datasets appears, with the NSO measurements slightly fainter. The offset is largest in the I-band and smallest in the B-band; we ascribe this trend with wavelength to the color of the galaxy's light. The starlight of NGC 4125 is more prominent at long wavelengths, making the background at the location of SN 2016coj brightest (relative to the SN) in the I-band. Since the NSO data have both a smaller PSF and a higher signal-to-noise ratio, they suffer from less contamination by the galaxy's light.", "cite_spans": [], "ref_spans": [{"start": 253, "end": 262, "text": "Figure 12", "ref_id": "FIGREF0"}, {"start": 1093, "end": 1101, "text": "Figure 5", "ref_id": "FIGREF4"}]}, {"section": "Facility: AAVSO APPENDIX A. BIAS IN PHOTOMETRY", "text": "At early times, the SN was bright enough that any systematic bias was at most comparable to the random uncertainties in each measurement; but that is certainly not true for the late times. We recommend that readers use with caution the latest measurements presented here. We suggest that greater weight be given to the NSO values at late times; it might be profitable to \"warp\" the RIT measurements at late times to match the final NSO magnitudes.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF1": {"title": "Third Reference Catalog of Bright Galaxies Filippenko, A", "authors": [{"first": "G", "middle": [], "last": "De Vaucouleurs", "suffix": ""}], "year": 1991, "venue": "ASPC", "link": null}, "BIBREF7": {"title": "Master's thesis", "authors": [{"first": "P", "middle": ["; J T"], "last": "Lira", "suffix": ""}], "year": 1995, "venue": "ApJ", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Figure 1. A R-band composite (16 images of 30 seconds each) of SN 2016coj from RIT, showing stars used to calibrate measurements. North is up, East to the left. The field of view is roughly 12 by 12 arcminutes.", "type": "figure"}, "FIGREF1": {"text": "Figure 2. The residual after rotation and subtraction of an image from RIT taken UT 2016 June 24. Positive residuals are bright and negative dark. North is up, East to the left; the galaxy's nucleus appears at the center. The field of view is roughly 7 by 7 arcminutes.", "type": "figure"}, "FIGREF2": {"text": "Figure 3. A R-band composite (5 images of 45 seconds each) of SN 2016coj from NSO, showing stars used to calibrate measurements. North is up, East to the left. The field of view is roughly 30 by 30 arcminutes.", "type": "figure"}, "FIGREF3": {"text": "Figure 4. The residual after rotation and subtraction of an image from NSO taken UT 2016 June 26. Positive residuals are bright and negative dark. North is up, East to the left; the galaxy's nucleus appears at the center. The field of view is roughly 10 by 10 arcminutes.", "type": "figure"}, "FIGREF4": {"text": "Figure 5. Light curves of SN 2016coj in BVRI. The data for each passband have been offset vertically for clarity. Small symbols represent measurements from RIT, large symbols those from NSO; uncertainties in the latter are smaller than the symbols.", "type": "figure"}, "FIGREF6": {"text": "Figure 6. (B-V) color evolution of SN 2016coj, after correcting for extinction.", "type": "figure"}, "FIGREF7": {"text": "Figure 7. (V-R) color evolution of SN 2016coj, after correcting for extinction.", "type": "figure"}, "FIGREF8": {"text": "Figure 8. (R-I) color evolution of SN 2016coj, after correcting for extinction.", "type": "figure"}, "FIGREF10": {"text": "photon noise no photon noise", "type": "figure"}, "TABREF0": {"text": "Photometry of comparison stars", "type": "table"}, "TABREF1": {"text": "RIT photometry of SN 2016coj33.60 14.535 \u00b1 0.088 13.650 \u00b1 0.024 13.675 \u00b1 0.057 13.723 \u00b1 0.087 36.59 15.166 \u00b1 0.222 13.865 \u00b1 0.048 13.656 \u00b1 0.088 13.608 \u00b1 0.085 clouds 37.59 15.129 \u00b1 0.091 13.964 \u00b1 0.052 13.670 \u00b1 0.066 13.572 \u00b1 0.099 fewer images 39.60 15.400 \u00b1 0.115 14.061 \u00b1 0.030 13.737 \u00b1 0.069 13.516 \u00b1 0.086 40.60 15.370 \u00b1 0.069 14.155 \u00b1 0.043 13.795 \u00b1 0.061 13.418 \u00b1 0.104", "type": "table"}, "TABREF2": {"text": "NSO photometry of SN 2016coj", "type": "table"}, "TABREF3": {"text": "Apparent magnitudes at maximum light", "type": "table"}}}
{"paper_id": "119429683", "_pdf_hash": "95e99aceeba157b393789f870a59d82aa05a524f", "abstract": [{"section": "Abstract", "text": "Abstract. Current cosmological data favour inflationary models non-minimally coupled to gravity. In this work we study the implications of the metastability of the electroweak vacuum in this framework. We consider an inflaton field with a non-minimal coupling to Ricci curvature and a portal coupling between the Higgs field and the inflaton and find that the ratio of the two couplings is severely constrained from stability during inflation and reheating dynamics, with constraints becoming more severe for weaker non-minimal coupling as during inflation Higgs fluctuations are amplified by inflationary expansion and after inflation by parametric resonance due to an oscillating inflaton background.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Since its discovery in 2012 [1, 2] the Higgs field has remained the subject of a vibrant area of research, both in the context of collider physics and wider implications for the universe as a whole. One of the most interesting aspects of Higgs physics is that the values of Standard Model parameters are such that our universe appears 1 to occupy a metastable vacuum state which will eventually decay into a true vacuum at high field values [5, 6] . This aspect has received much attention in recent years, especially in the context of early universe cosmology (for a recent review, see [7] ).", "cite_spans": [{"start": 28, "end": 31, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 32, "end": 34, "text": "2]", "ref_id": "BIBREF1"}, {"start": 441, "end": 444, "text": "[5,", "ref_id": "BIBREF4"}, {"start": 445, "end": 447, "text": "6]", "ref_id": "BIBREF5"}, {"start": 587, "end": 590, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Introduction", "text": "While the lifetime of our metastable vacuum far exceeds the age the universe, it remains unclear how this energetically disfavoured situation was reached. During high-scale inflation, fluctuations in light fields are amplified by deSitter dynamics and as such the Higgs field would have been driven to its true vacuum [8] [9] [10] [11] . This suggests that either the scale of inflation must not have been very high or that some new physics come to the rescue and stabilize the Higgs during inflation. One can stabilize the Higgs potential by introducing new fields which change the running of the Higgs self-coupling at high energies [12, 13] . A particularly minimal approach is to couple the Higgs fields to the inflaton which is already necessitated by inflation or to couple it non-minimally to gravity [14] . The coupling to the inflaton can stabilize the vacuum by either mixing with the Higgs at low energies [15] or by inducing a large effective mass for the Higgs at inflationary scales [9] . In the latter case, while stabilization is achieved during inflation, the vacuum may again become destabilized during reheating as the very same couplings which stabilized the field result in copious production of Higgs quanta due to parametric and tachyonic resonance of the oscillating inflaton field [16] [17] [18] [19] .", "cite_spans": [{"start": 318, "end": 321, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 322, "end": 325, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 326, "end": 330, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 331, "end": 335, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 635, "end": 639, "text": "[12,", "ref_id": "BIBREF11"}, {"start": 640, "end": 643, "text": "13]", "ref_id": "BIBREF12"}, {"start": 808, "end": 812, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 917, "end": 921, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 997, "end": 1000, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 1306, "end": 1310, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 1311, "end": 1315, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 1316, "end": 1320, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 1321, "end": 1325, "text": "[19]", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Introduction", "text": "Many of the earlier works assumed a simple quadratic model for the inflaton which has become increasingly disfavoured by cosmological measurements [20] . Non-minimal couplings are expected on general grounds as they generically appear via radiative corrections even if absent at tree level [21] [22] [23] [24] [25] . In this work we study the stability of the EW vacuum in the non-minimally coupled quartic model which is in excellent agreement with the data. We focus on the quadratic portal coupling between the inflaton and the Higgs and find that vacuum stability during inflation and reheating impose severe constraints on the couplings. Thus, the stability of the electroweak vacuum may, in fact, prove an important criterion in discriminating between inflationary models. This paper is organized as follows. In Section 2 we introduce the model and review the inflationary dynamics arising from a scalar non-minimally coupled to gravity. In Section 3 we study the behaviour of the Higgs during inflation and present constraints arising from stability in the inflationary epoch. In Section 4 we examine Higgs dynamics during the oscillatory phase of the inflaton and derive constraints arising from parametric resonance. We present the numerical calculations in Section 5 and conclude in Section 6 with a discussion of the results.", "cite_spans": [{"start": 147, "end": 151, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 290, "end": 294, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 295, "end": 299, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 305, "end": 309, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 310, "end": 314, "text": "[25]", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Non-minimally coupled inflation", "text": "We consider a model with a quartic inflaton potential where the inflaton is non-minimally coupled to gravity. This setup is similar to the Higgs inflation 2 scenario [27] only now inflation is driven by a new scalar while the Higgs remains a spectator. The action in the Jordan frame is", "cite_spans": [{"start": 166, "end": 170, "text": "[27]", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "Non-minimally coupled inflation", "text": "which can be transformed into the Einstein frame by a conformal transformation", "cite_spans": [], "ref_spans": []}, {"section": "Non-minimally coupled inflation", "text": "and the field redefinition", "cite_spans": [], "ref_spans": []}, {"section": "Non-minimally coupled inflation", "text": "to make the kinetic term of the inflaton canonical. This can be integrated to give [28] ", "cite_spans": [{"start": 83, "end": 87, "text": "[28]", "ref_id": "BIBREF27"}], "ref_spans": []}, {"section": "Non-minimally coupled inflation", "text": "Inflation happens in the large-field plateau \u221a \u03be\u03c6 J M pl and the inflationary observables can be shown to be 3", "cite_spans": [], "ref_spans": []}, {"section": "Non-minimally coupled inflation", "text": "These values are in excellent agreement with the current cosmological constraints and the tensor-to-scalar ratio lies in the region that will be probed by the next-generation polarization experiments 4 [31] . The measured amplitude of the power spectrum [20] constraints the ratio \u03bb/\u03be 2 \u2248 5 \u00d7 10 \u221210 .", "cite_spans": [{"start": 202, "end": 206, "text": "[31]", "ref_id": "BIBREF30"}, {"start": 254, "end": 258, "text": "[20]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "Higgs during inflation", "text": "If the Standard Model is valid all the way up to inflationary scales then the Higgs is a light field and therefore its fluctuations obtain a spectrum P \u03b4h \u223c H 2 inf /(2\u03c0) 2 on superhorizon scales. Furthermore, the renormalization group running of the Higgs self coupling predicts that \u03bb h becomes negative around the energy scale \u00b5 c \u223c 10 10 GeV. In order for the vacuum to not be destabilized by inflationary amplification of fluctuations, the Higgs must remain heavy during inflation 5 . This is achieved through coupling to the inflaton which has a large amplitude during inflation. The equation of motion for the Higgs in the Einstein frame is", "cite_spans": [], "ref_spans": []}, {"section": "Higgs during inflation", "text": "3 This is in fact equivalent to the Starobinsky model", "cite_spans": [], "ref_spans": []}, {"section": "Higgs during inflation", "text": ". 4 However, even those future constraints can be evaded in Palatini gravity [30] . 5 Strictly speaking this requirement can be relaxed somewhat -for a light Higgs the average field value performs a random walk which may end up subcritical in our observable patch [11] . However, this depends on the initial field value and the duration of inflation. We take the heaviness of the Higgs as a conservative bound.", "cite_spans": [{"start": 2, "end": 3, "text": "4", "ref_id": "BIBREF3"}, {"start": 77, "end": 81, "text": "[30]", "ref_id": "BIBREF29"}, {"start": 84, "end": 85, "text": "5", "ref_id": "BIBREF4"}, {"start": 264, "end": 268, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Higgs during inflation", "text": "During slow-roll inflation we can estimate", "cite_spans": [], "ref_spans": []}, {"section": "Higgs during inflation", "text": "In non-minimally coupled inflation we have \u223c \u03b7 2 \u223c 1/N 2 so that the additional friction term coming from the conformal transformation is unimportant 6 .", "cite_spans": [], "ref_spans": []}, {"section": "Radiative corrections", "text": "We must take care that the addition of the Higgs does not spoil the successful inflationary predictions. In particular, quantum corrections from Higgs loops must not dominate over the inflationary potential. The effective mass of the canonical variableh \u2261 h/\u2126 is", "cite_spans": [], "ref_spans": []}, {"section": "Radiative corrections", "text": "and the corresponding Coleman-Weinberg correction due to Higgs loops is", "cite_spans": [], "ref_spans": []}, {"section": "Radiative corrections", "text": "From the slow-roll evolution we can estimate", "cite_spans": [], "ref_spans": []}, {"section": "Radiative corrections", "text": "Therefore the potential induced by the conformal factor alone, V \u223c m 4 \u2126 , is suppressed compared to the inflationary potential by e \u22122 2 3 \u03c6/M pl and by the small ratio \u03bb \u03c6 /\u03be 2 \u223c 10 \u221210 and can be neglected. On the other hand, the contribution from Higgs-inflaton coupling alone is of the same form as the original inflationary potential and so can be absorbed in the redefinition of \u03bb \u03c6 . This leaves the cross term between the two", "cite_spans": [], "ref_spans": []}, {"section": "Radiative corrections", "text": "Requiring that this contribution is subdominant gives the constraint", "cite_spans": [], "ref_spans": []}, {"section": "Radiative corrections", "text": "Thus, radiative corrections to the inflationary potential are always negligible, being suppressed by the exponential flatness of the potential.", "cite_spans": [], "ref_spans": []}, {"section": "Vacuum stability", "text": "In the Standard Model the self-coupling of the Higgs \u03bb h turns negative above the critical scale \u00b5 c \u223c 10 10 GeV. In order for the vacuum to remain stable against inflationary amplification of Higgs fluctuations the Higgs field must be heavy. The effective potential for the Higgs is 7 6 Note that this is the case during inflation, but not necessarily during reheating. We shall discuss this issue further in the next section.", "cite_spans": [{"start": 286, "end": 287, "text": "6", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Vacuum stability", "text": "7 Note that it is scaled by \u2126 \u22122 rather than \u2126 \u22124 because of non-minimal kinetic coupling. Alternatively one can think of \u2126 \u22124 V h as the effective potential for the canonical variableh.", "cite_spans": [], "ref_spans": []}, {"section": "Vacuum stability", "text": "The coupling to the inflaton introduces a large effective mass for the Higgs and the new instability scale defined as the location of the potential barrier becomes h 2 c = |\u03bb h | \u22121 \u03bb h\u03c6 \u03c6 2 J . The condition for V = 0 of the vanishing fluctuation mass is h 2 c /3. The Higgs is heavy during inflation if", "cite_spans": [], "ref_spans": []}, {"section": "Vacuum stability", "text": "As long as this is satisfied and initially 3h 2 0 < h 2 c we have sufficient conditions for stability. Requiring that the Higgs is heavy gives the constraint", "cite_spans": [], "ref_spans": []}, {"section": "Vacuum stability", "text": "where the estimate is for around 55 e-folds. Thus, we find that the coupling to the inflaton successfully stabilizes the vacuum without introducing radiative corrections to the inflationary potential.", "cite_spans": [], "ref_spans": []}, {"section": "Higgs after inflation", "text": "After inflation is over the inflaton starts to oscillate, first with a quadratic and then with a quartic potential of Equation (2.", "cite_spans": [], "ref_spans": []}, {"section": "5). The equation of motion for the Higgs modes in the Hartree approximation is", "text": "whereh \u2261 h 2 . The coupling to the inflaton induces an oscillating mass term for the Higgs which results in amplification of Higgs fluctuations via parametric resonance [32, 33] .", "cite_spans": [{"start": 169, "end": 173, "text": "[32,", "ref_id": "BIBREF31"}, {"start": 174, "end": 177, "text": "33]", "ref_id": "BIBREF32"}], "ref_spans": []}, {"section": "Constraints from the quartic stage", "text": "Before we consider the oscillation in the quadratic regime let us examine what happens once the inflaton oscillation reaches the quartic regime. This happens when \u03c6 \u223c M pl /\u03be. At this point the Einstein and Jordan frames agree and the dynamics can be described by the usual \u03c6 4 theory preheating [34] . The expansion of the universe is radiation-domination-like and the situation is conformal to the Minkowski case. Changing to conformal time and rescaling both fields by a, the inflaton oscillates as", "cite_spans": [{"start": 296, "end": 300, "text": "[34]", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "Constraints from the quartic stage", "text": "where cn(x; k) is the Jacobi elliptic cosine, while the Higgs modes obey the equatio\u00f1", "cite_spans": [], "ref_spans": []}, {"section": "Constraints from the quartic stage", "text": "The resonance parameter is now", "cite_spans": [], "ref_spans": []}, {"section": "Constraints from the quartic stage", "text": "Since the effects of expansion factor out, modes don't exit resonance bands and so the production cannot be shut down by the expansion of the universe. Therefore if resonance is significant nothing can stop the Higgs from being destabilized unless inflaton decays before this via other interactions. Therefore we get a constraint", "cite_spans": [], "ref_spans": []}, {"section": "Constraints from the quartic stage", "text": "Recall that stability during inflation required that \u03bb \u03c6h /\u03be 4 \u00d7 10 \u221211 . Thus, for large \u03be 1 this still leaves a sizeable window for stability both during inflation and the quartic stage. Now let us consider the intermediate, quadratic regime.", "cite_spans": [], "ref_spans": []}, {"section": "Constraints from the quadratic stage", "text": "In the quadratic regime the Einstein frame inflaton oscillates in a harmonic potential with", "cite_spans": [], "ref_spans": []}, {"section": "Constraints from the quadratic stage", "text": "We define a new time variable \u03c4 \u2261 mt. The Jordan frame inflaton, which is what the Higgs is coupled to, then can be approximated by", "cite_spans": [], "ref_spans": []}, {"section": "Constraints from the quadratic stage", "text": "being the amplitude of the Einstein frame inflaton field. The equation of motion for the rescaled Higgs fluctuations", "cite_spans": [], "ref_spans": []}, {"section": "Constraints from the quadratic stage", "text": "where the effective masses induced respectively by Higgs-inflaton interaction and gravity are", "cite_spans": [], "ref_spans": []}, {"section": "Constraints from the quadratic stage", "text": "Note that these are measured in units of m. We have separated the ratio \u03bb \u03c6h /\u03be because the quantity \u03be\u03c6 2 J behaves independently of \u03be for large non-minimal coupling and so this ratio will determine the strength of particle production. The gravitationally induced mass m grav can be estimated to be (see Appendix A for details)", "cite_spans": [], "ref_spans": []}, {"section": "Constraints from the quadratic stage", "text": "Far away from the zero-crossing it contributes a tachyonic term. However, for the parameter range relevant for stability, \u03bb \u03c6h /\u03be 10 \u221210 , the mass induced by the Higgs-inflaton coupling dominates and so m grav can be neglected. In contrast, close to the zero-crossing, when m \u03c6h is small, the gravitationally induced term exhibits a large spike-like feature \u223c \u03be\u03a6 2 /M 2 pl . The behaviour is illustrated in Figure 1 . This can lead to particle production even in the absence of an explicit coupling to the inflaton as was pointed out in [35] . As we shall see, however, destabilization occurs around \u03bb \u03c6h /\u03be > 10 \u22128 . For such values effect of the spike is too brief and is well within the region adiabaticity violation so that it does not change the evolution of the (4.9). The right panel shows a close vicinity around the fourth zero-crossing (when corrections due to the conformal factor have decayed sufficiently).", "cite_spans": [{"start": 538, "end": 542, "text": "[35]", "ref_id": "BIBREF34"}], "ref_spans": [{"start": 408, "end": 416, "text": "Figure 1", "ref_id": "FIGREF0"}]}, {"section": "Constraints from the quadratic stage", "text": "modes. We have checked numerically that m grav does not alter the dynamics for the coupling ranges relevant for destabilization. Thus, in the present case, this effect is unimportant and particle production is dominated by parametric resonance due to the Higgs-inflaton coupling.", "cite_spans": [], "ref_spans": []}, {"section": "Parametric resonance", "text": "The production of Higgs quanta proceeds via the non-perturbative process of broad parametric resonance which has been extensively studied in the literature [32] [33] [34] . The case of non-minimal coupling to gravity has been considered in [28, 36] in the context of Higgs inflation and decay into gauge bosons and in [37] [38] [39] for general multi-field models. Far away from the zero-crossings of the inflaton the Higgs modes can be approximated by a WKB solution, so that before the jth zero-crossing", "cite_spans": [{"start": 156, "end": 160, "text": "[32]", "ref_id": "BIBREF31"}, {"start": 161, "end": 165, "text": "[33]", "ref_id": "BIBREF32"}, {"start": 166, "end": 170, "text": "[34]", "ref_id": "BIBREF33"}, {"start": 240, "end": 244, "text": "[28,", "ref_id": "BIBREF27"}, {"start": 245, "end": 248, "text": "36]", "ref_id": "BIBREF35"}, {"start": 318, "end": 322, "text": "[37]", "ref_id": "BIBREF36"}, {"start": 323, "end": 327, "text": "[38]", "ref_id": "BIBREF37"}, {"start": 328, "end": 332, "text": "[39]", "ref_id": "BIBREF38"}], "ref_spans": []}, {"section": "Parametric resonance", "text": "and after the zero crossing an equivalent one with \u03b1 j+1 k , \u03b2 j+1 k . The mapping between the Bogolyubov coefficients can be obtained by solving the equations of motion near the zerocrossing and then matching the solution to the incoming and outgoing WKB modes. See Appendix B for more details. The occupation numbers after the jth zero crossing can be shown to be ", "cite_spans": [], "ref_spans": []}, {"section": "Parametric resonance", "text": "Here A and B refer to the Airy functions The numerically obtained occupation number spectra are plotted in Figure 2 . In the large occupation number limit we can estimate n The phase term \u03b8 tot can result in either enhancement of particle production or even in a decrease of particle numbers. However, it effectively behaves stochastically for large \u03bb \u03c6h /\u03be in analogy to the m 2 \u03c6 2 case [33] . Therefore, we take it to be zero on average so that", "cite_spans": [{"start": 389, "end": 393, "text": "[33]", "ref_id": "BIBREF32"}], "ref_spans": [{"start": 107, "end": 115, "text": "Figure 2", "ref_id": "FIGREF1"}]}, {"section": "Parametric resonance", "text": "With the use of the saddle-point approximation we can then estimate the variance of Higgs fluctuations (see Appendix C for details)", "cite_spans": [], "ref_spans": []}, {"section": "Parametric resonance", "text": "where q = q j j is the initial value of the resonance parameter. The numerical solution for the Higgs variance in the absence of self-interaction can be seen in Figure 3 .", "cite_spans": [], "ref_spans": [{"start": 161, "end": 169, "text": "Figure 3", "ref_id": "FIGREF4"}]}, {"section": "Stability", "text": "The Higgs fluctuations are amplified exponentially due to parametric resonance induced by the Higgs-inflaton coupling. If this continues long enough the Higgs will be driven into the true vacuum at large field values. Note that even for q \u223c 1, h 2 1/2 is above the instability scale of the pure standard model \u00b5 SM c \u223c 10 \u221210 GeV so that the contribution of the Higgs self-coupling is negative (\u03bb h < 0) throughout preheating, contributing a tachyonic mass to the Higgs modes. The vacuum remains stable as long as the resonance terminates before this contribution overpowers the stabilizing effect of the Higgs-inflaton coupling. Taking into account the self-coupling at the level of Hartree approximation, the frequency of Higgs modes around the zero-crossing is", "cite_spans": [], "ref_spans": []}, {"section": "Stability", "text": "Near the zero-crossing the stabilizing effect of the inflaton temporarily disappears and the tachyonic term due to self-interaction dominates for the time interval", "cite_spans": [], "ref_spans": []}, {"section": "Stability", "text": "For stability we require that m tach \u2206\u03c4 tach < 1 which translates to", "cite_spans": [], "ref_spans": []}, {"section": "Stability", "text": "Therefore the stability condition is", "cite_spans": [], "ref_spans": []}, {"section": "Stability", "text": "Requiring that the resonance terminates before the instability condition becomes violated j end \u223c q < j inst we get q < 1 log This translates to a constraint on couplings", "cite_spans": [], "ref_spans": []}, {"section": "Stability", "text": "where we have taken |\u03bb h | \u223c 10 \u22122 . Meanwhile, recall that the stability condition during inflation was", "cite_spans": [], "ref_spans": []}, {"section": "Stability", "text": "Thus, only the range \u03bb \u03c6h /\u03be \u223c 10 \u221210 ..10 \u22128 is viable in terms of stability both during and after inflation. A numerical comparison of h 2 to the instability scale can be seen in Figure 4 . We can observe that self-coupling leads to explosive destabilization; however, in terms of whether h 2 exceeds the barrier it does result in a qualitative change. In our analytic estimates, we have not taken into account the phase factor which makes the dependence of the resonance on coupling non-monotonic. Numerical solution shows regions of enhanced and diminished resonance in the parameter space, as can be seen in Figure 5 . In particular, resonance is very strong for \u03bb \u03c6h /\u03be \u223c 2 \u00d7 10 \u22128 and weaker for larger couplings. However, resonance continues as long as q j > 1 which decays rather slowly, q j \u221d j \u22121 , as a result of the fact that the Higgs is coupled to \u03c6 J rather than the \u03c6 field 8 . Therefore the duration of resonance is proportional to \u03bb \u03c6h /\u03be and so destabilization occurs even in the weaker regions of Figure 5 as long as \u03bb \u03c6h /\u03be > 10 \u22128 . We have also checked that the effect of m grav is unimportant.", "cite_spans": [], "ref_spans": [{"start": 181, "end": 189, "text": "Figure 4", "ref_id": "FIGREF5"}]}, {"section": "Backreaction", "text": "So far we have considered the case where the resonance is shut down by the expansion of the universe. If enough Higgs quanta are produced, however, they can backreact on the inflaton dynamics, changing its equation of motion. For large couplings this can shut down the resonance while it is still broad. In this section we will estimate the significance of backreaction for the results presented above. The gradient of the inflaton potential is", "cite_spans": [], "ref_spans": []}, {"section": "Backreaction", "text": "where the backreaction of Higgs fluctuations is given by", "cite_spans": [], "ref_spans": []}, {"section": "Backreaction", "text": "The derivative term \u2202 \u00b5 h\u2202 \u00b5 h \u223c \u2212\u03bb \u03c6h \u03c6 2 J h 2 is subdominant since during preheating we have \u03be\u03c6 Therefore, backreaction is unimportant for the ranges of couplings discussed in the previous sections. However, one might consider the possibility that for very large couplings \u03bb \u03c6h 10 \u22125 \u03be backreaction shuts down the resonance before destabilization can occur thus rescuing the Higgs. However, at the time of backreaction a significant part the inflaton condensate decays thus removing the stabilizing effect of the Higgs-inflaton coupling. Detailed investigation of such dynamics requires non-linear analysis using lattice simulations and is beyond the scope of the present work. Furthermore, as discussed in the next section, the large coupling regime raises questions of unitarity because large momenta are amplified by parametric resonance so that the model assumed above may not be sufficient to described the dynamics.", "cite_spans": [], "ref_spans": []}, {"section": "Unitarity", "text": "The subject of unitarity in non-minimaly coupled theories has gained much attention, especially in the context of Higgs inflation [40] [41] [42] [43] [44] [45] . The UV cutoff of the theory depends on the amplitude of the background field so that when \u03c6 2 J M 2 pl /\u03be the cutoff is given by \u039b \u223c M pl allowing for a robust effective field theory description [43] [44] [45] . In the small field regime \u03c6 J M pl /\u03be the cutoff is \u039b \u223c M pl /\u03be. In the intermediate regime the cutoff depends on the field amplitude, interpolating between these two values.", "cite_spans": [{"start": 130, "end": 134, "text": "[40]", "ref_id": "BIBREF39"}, {"start": 135, "end": 139, "text": "[41]", "ref_id": "BIBREF40"}, {"start": 140, "end": 144, "text": "[42]", "ref_id": "BIBREF41"}, {"start": 145, "end": 149, "text": "[43]", "ref_id": "BIBREF42"}, {"start": 150, "end": 154, "text": "[44]", "ref_id": "BIBREF43"}, {"start": 155, "end": 159, "text": "[45]", "ref_id": "BIBREF44"}, {"start": 357, "end": 361, "text": "[43]", "ref_id": "BIBREF42"}, {"start": 362, "end": 366, "text": "[44]", "ref_id": "BIBREF43"}, {"start": 367, "end": 371, "text": "[45]", "ref_id": "BIBREF44"}], "ref_spans": []}, {"section": "Unitarity", "text": "As discussed in [35, 38] , we take the effective theory description to be valid as long as momenta do not exceed the UV cutoff. Parametric resonance produces quanta with typical momenta k \u223c q 1/3 m. Requiring that these stay below the cutoff M pl /\u03be gives the following unitarity bound for the couplings:", "cite_spans": [{"start": 16, "end": 20, "text": "[35,", "ref_id": "BIBREF34"}, {"start": 21, "end": 24, "text": "38]", "ref_id": "BIBREF37"}], "ref_spans": []}, {"section": "Unitarity", "text": "Thus, unless \u03be is extremely large, unitarity is not violated for the ranges relevant for Higgs destabilization (\u03bb \u03c6h \u223c 10 \u22128 \u03be). Furthermore, this constraint may be too conservative because the Higgs stays subdominant and the amplitude of the inflaton is large \u03c6 J M pl /\u03be. Consequently the cutoff is also higher than M pl /\u03be. On the other hand, in the strong coupling regime where backreaction becomes important before destabilization the inflaton is expected to transfer most of its energy to Higgs quanta decreasing the amplitude of the field and Figure 5 : Occupation numbers after 100 zero-crossings. The interplay of phases causes constructive and destructive interference making the strength of resonance non-monotonic. For example, particle production is very strong around \u03bb \u03c6h /\u03be \u223c 2 \u00d7 10 \u22128 and less so for higher coupling values. However, for higher coupling values the resonance also lasts much longer (beyond 100 zero-crossings).", "cite_spans": [], "ref_spans": []}, {"section": "Unitarity", "text": "lowering the cutoff. Therefore in this range a UV complete description may be necessary for obtaining the correct dynamics. The unitarity bound is shown in Figure 6 where we summarize the model constraints. It should also be noted that in the region of large ratio \u03bb \u03c6h /\u03be the portal coupling \u03bb \u03c6h becomes large, changing the running of \u03bb h , making the vacuum more stable. If it is increased further it becomes non-perturbative at low-energy which is problematic in terms of experimantally verified Higgs phenomenology.", "cite_spans": [], "ref_spans": [{"start": 156, "end": 164, "text": "Figure 6", "ref_id": "FIGREF7"}]}, {"section": "Numerical analysis", "text": "To complement the analytic investigation of the previous sections, we have also studied the dynamics of the Higgs numerically. The equations of motion for the inflaton in the Einstein frame are\u03c6", "cite_spans": [], "ref_spans": []}, {"section": "Numerical analysis", "text": "However, because there is no closed form expression for the potential in terms of the Einstein frame field we instead solve the dynamics of the variable \u03c6 J , obeying the equations", "cite_spans": [], "ref_spans": []}, {"section": "Numerical analysis", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "Numerical analysis", "text": "Note, however, that time and the Hubble parameter are still measured in the Einstein frame. We solve the inflaton dynamics with 55 e-folds of inflation and then use the obtained solution to get the evolution of the Higgs fluctuations whose equation of motion is given by (4.1). We take the self-coupling of the Higgs into account at the Hartree level. This is implemented as follows. We solve the evolution of Higgs modes one inflaton half-cycle at a time for different momenta and then integrate to obtain h 2 . This is then used to evolve the modes across the next half-cycle of inflaton oscillation. This procedure is sufficient for finding the bounds from stability as destabilization occurs long before backreaction and rescattering become important as long as \u03bb \u03c6h \u03be < 10 \u22123 .", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "We have studied the behaviour of the Standard Model Higgs in a theory of inflation where the inflaton is non-minimally coupled to gravity. This is a well-motivated model both theoretically, as non-minimal couplings are generically radiatively generated, and experimentally, with its cosmological prediction falling squarely in the middle of current observational bounds. We find that the stability of the electroweak vacuum during and immediately after inflation severely constrains the possible parameter space. During inflation, the pure SM Higgs is a light field whose fluctuations are amplified by de Sitter expansion leading to destabilization. If, on the other hand, the Higgs is stabilized during inflation via coupling to the inflaton its fluctuations are amplified after inflation by parametric resonance resulting from an oscillating inflaton background. The dynamics of the inflaton is largely independent of the non-minimal coupling to gravity during inflation and a period of harmonic oscillation following it as long as the amplitude is rescaled by \u221a \u03be. As a result, the relevant coupling for the Higgs is the ratio \u03bb \u03c6h /\u03be. We find that early universe vacuum stability is realized if this ratio is in the range \u03bb \u03c6h /\u03be \u223c 10 \u221210 ..10 \u22128 .", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "During inflation a ratio of \u03bb \u03c6h /\u03be 10 \u221210 is needed in order to make the Higgs heavy and roll to the vacuum at low field values. During preheating with large \u03be the inflaton oscillates in harmonic potential and parametric amplification of Higgs quanta ends due to expansion before destabilization for \u03bb \u03c6h /\u03be 10 \u22128 . For moderate values of the non-minimal coupling the system soon transitions from a harmonic potential to quartic where the effects of the expansion factor out and so cannot end the resonance. It will instead be terminated by the backreaction of produced quanta.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "The backreaction effects are not important when the couplings are in the above range. For very large couplings backreaction may come into play at comparable scales to the destabilization, necessitating the use of non-linear solutions including rescattering effects. However, in such a regime quanta with momenta higher that the UV cutoff of the theory are easily amplified indicating that a UV complete treatment may be necessary. This is beyond the scope of the current analysis. The constraints are summarized in Figure 6 .", "cite_spans": [], "ref_spans": [{"start": 515, "end": 523, "text": "Figure 6", "ref_id": "FIGREF7"}]}, {"section": "Conclusions", "text": "Since an inflaton field must couple to the SM in order to facilitate reheating Higgs portal coupling is expected to be a generic feature of scalar field models of inflation. Thus, the tight constraints imposed by vacuum metastability can in fact prove an important discriminator between inflationary models. whose solutions are Airy functions. Before the zero-crossing these are", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "and after the zero-crossing", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "Far away from the zero crossing the solution is given by the WKB form (4.10). Using the large-argument expansions for Airy functions", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "and matching the incoming and outgoing WKB modes one can obtain the mapping between Bogolyubov coefficients before and after the zero-crossing", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "with the relevant components given by ", "cite_spans": [], "ref_spans": []}, {"section": "C Calculation of the Higgs variance", "text": "This section describes the details of Higgs production during parametric resonance. Taking the typical value for the Floquet index, corresponding to \u03b8 tot = 0, the occupation numbers after j zero-crossings are where q \u2261 jq j and a 0 \u2261 a j j \u22122/3 . The occupation number is We estimate the integral using the saddle-point method. Write \u03ba 2 e \u2212\u03bc j \u03ba 2 = e f (\u03ba) . Expanding around the maximum \u03ba 2 max =\u03bc Thus for broad resonance q j 1 the mass term dominates over the momentum contribution: ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Observation of a new boson at a mass of 125 GeV with the CMS experiment at the LHC", "authors": [{"first": "S", "middle": [], "last": "Chatrchyan", "suffix": ""}], "year": 2012, "venue": "Phys. Lett", "link": null}, "BIBREF1": {"title": "Observation of a new particle in the search for the Standard Model Higgs boson with the ATLAS detector at the LHC", "authors": [{"first": "G", "middle": [], "last": "Aad", "suffix": ""}], "year": 2012, "venue": "Phys. Lett", "link": null}, "BIBREF2": {"title": "The top quark and Higgs boson masses and the stability of the electroweak vacuum", "authors": [{"first": "A", "middle": [], "last": "S. 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Yellow indicates early times, red late times.", "type": "figure"}, "FIGREF2": {"text": "\u03c4 j d\u03c4 \u03c9 k is the phase accrued by the jth zero-crossing.", "type": "figure"}, "FIGREF4": {"text": "Figure 3: h 2 for different resonance parameters \u03bb \u03c6h /\u03be with \u03bb h = 0. In the left panel, solid lines denote \u03be = 10 4 and dashed lines \u03be = 10 6 , showing that for large non-minimal coupling preheating dynamics is indeed largely insensitive to \u03be and is determined by the ratio \u03bb \u03c6h /\u03be. The right panel shows the case of small non-minimal coupling \u03be = 5 where the system enters the quadratic regime early and Higgs modes continue to be amplified as discussed in Section 4.1, even for rather modest values \u03bb \u03c6h .", "type": "figure"}, "FIGREF5": {"text": "Figure 4: Comparison to the Higgs variance to the location of the potential barrier. The left panel shows only the amplification from parametric resonance. The right panel shows the case where the Higgs self-coupling was taken into account.", "type": "figure"}, "FIGREF6": {"text": ". Also the last term is subdominant until destabilization. From equation (4.19), at the time of destabilization h 2 \u223c q", "type": "figure"}, "FIGREF7": {"text": "Figure 6: Constraints from stability during and after inflation.", "type": "figure"}, "FIGREF8": {"text": "\u2261 \u03c4 \u2212 \u03c4 j and \u03b8 j k \u2261 \u03c4 j d\u03c4 \u03c9 k (\u03c4 ). The equation of motion close to the zero-", "type": "figure"}, "FIGREF9": {"text": "AA \u2212 BB ) + i(A B + AB ) (B.11) where A and B referring to the two Airy functions with argument \u2212", "type": "figure"}, "TABREF0": {"text": "and where \u03ba \u2261 k/m. Then the dispersion of Higgs fluctuations far away from the zero-crossing can be obtained as", "type": "table"}}}
{"paper_id": "119429889", "_pdf_hash": "2845ea6c48986120e462785c062bcc72136eecd1", "abstract": [{"section": "Abstract", "text": "Both continuum and emission line flickering are phenomena directly associated with the mass accretion process. In this work we simulate accretion disk Doppler maps including the effects of winds and flickering flares. Synthetic flickering Doppler maps are calculated and the effect of the flickering parameters on the maps is explored. Jets and winds occur in many astrophysical objects where accretion disks are present. Jets are generally absent among the cataclysmic variables (CVs), but there is evidence of mass loss by wind in many objects. CVs are ideal objects to study accretion disks and consequently to study the wind associated with these disks. We also present simulations of accretion disks including the presence of a wind with orbital phase resolution. Synthetic H\u03b1 line profiles in the optical region are obtained and their corresponding Doppler maps are calculated. The effect of the wind simulation parameters on the wind line profiles is also explored. From this study we verified that optically thick lines and/or emission by diffuse material into the primary Roche lobe are necessary to generate single peaked line profiles, often seen in CVs. The future accounting of these effects is suggested for interpreting Doppler tomography reconstructions.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Cataclysmic variables (CVs) are close binary systems composed by a white dwarf (primary) and a red dwarf or subgiant star (secondary). The secondary star fills its Roche lobe and matter is transferred to the white dwarf. Due to the angular momentum of the system (and if the magnetic field of the primary is not strong enough) there is the formation of an accretion disk around the primary.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The flickering (rapid variability) is observed as stochastic fluctuations in the emitted radiation, with timescales ranging from seconds to tenth of minutes and amplitudes from cents of magnitude to more than one magnitude.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Flickering is not exclusive to CVs, but it is also observed in symbiotic stars (e.g. CH Cyg, Mikolajewski, Mikolajewska & Khudiakova 1990 ), X-ray binaries (Reynolds, Callanan & Filippenko 2007 , Malzac et al. 2003 , Baptista, Bortoletto & Harlaftis 2002 and pre-main sequence stars (Kenyon et al. 2000 , Clarke et al. 2005 . The flickering cannot be related only to accretion disks as it is observed in magnetic systems (Thackeray, Wesselink & Oosterhoff 1950) ; an early model to describe the flickering in the polar AM Her was proposed by Panek (1980) . On a wide perspective, the presence of flickering seems associated to the process of mass accretion itself.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The first CV where flickering was observed is UX UMa (Linnell 1949 ). Since then, many studies were made aiming to locate the flickering source region on many objects. The flickering can be originated in many regions of the system. Warner & Nather (1971) observed that the U Gem flickering disappeared during the eclipse, and as the inner parts of the disk were not occulted during the eclipse, the flickering source was associated with the hot spot. Vogt, Kreminski & Podersen (1981) observed that OY Car flickering persisted during the hot spot eclipse, the same behavior was observed on HT Cas by Patterson (1981) and Z Cha by Wood et al. (1986) . Horne, K. & Stiening (1985) identified the flickering in some eclipsing systems as originated in the inner part of the accretions disk, Horne et al. (1994) also associated the OY Car flickering with this disk region. Bruch (1996) associated the flickering source in Z Cha with the region near to the white dwarf, but with other flickering sources appearing in other photometric states.", "cite_spans": [{"start": 232, "end": 254, "text": "Warner & Nather (1971)", "ref_id": "BIBREF40"}], "ref_spans": []}, {"section": "Introduction", "text": "As the CVs cannot be spatially resolved, indirect imaging methods are used. One of these methods is the Doppler tomography (Marsh & Horne 1988) , where the system emissivity is reconstructed from the observed line profiles. Diaz (2001) proposed an extension of the Doppler tomography, the flickering tomography, where the line profile variability is mapped. In this method, we start calculating the variance of the observed line profiles into phase bins. Then, the instrumental, orbital, and secular components are subtracted from such variance, remaining only the intrinsic variance component. The instrumental component of the variance is calculated as a combination of the Poisson noise plus a Gaussian readout noise. The [Vol. , orbital component contribution is considered negligible if the data is sampled into small phase bins. The secular component is the remaining long term variability of the system. The effect of this later component was found to be negligible by replacing the long term average profiles by profiles computed from individual runs. From these intrinsic variance line profiles Doppler tomograms are calculated, mapping the line emission variability in the system. This technique was applied to V442 Oph (Diaz 2001) , where an isolated flickering source was not identified, and V3885 Sgr (Ribeiro & Diaz 2007) , where the main flickering source seems to be associated with reprocessed UV radiation on the illuminated face of the secondary star.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The association between accretion disks and jets is observed in many astrophysical objects, as young stellar objects (YSO), low-mass and high-mass X-ray binaries, microquasars and active galactic nuclei. Concerning disks around white dwarfs, jets are observed in super-soft binaries (SSS) and some V Sge systems. Among the CVs, jets are not detected, except during the evolution of classical novae explosions (Retter 2004) , where the jet formation is related to the additional energy available due to the nuclear reactions on the primary surface. Soker & Lasota (2004) explained the absence of jets in CVs using the jet launching thermal model (Torbett 1984) , originally developed to explain jets in YSO. According to these authors, the CVs accretion rates are not high enough to produce jets. On the other hand, some CVs have mass loss by wind, and the mechanism that best describes the wind production in these systems is the line opacity (line driven winds) (Proga 2005) .", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Ultraviolet observations allowed the identification of mass loss by wind in CVs. UV ressonant lines (e.g. CIV \u03bb1548, \u03bb1551, NV \u03bb1239, \u03bb1243, Si \u03bb1397) are observed with a component in absorption displaced to the blue in classical novae remnants and nova-like systems with high accretion rate. The fact that wind is detected only in systems with high accretion rates relates the wind emission to the accretion process. The P-Cygni profiles are observed only in systems where the orbital inclination is approximately lower than 65.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "\u2022 (eg. Warner 1995; Shlosman & Vitello 1993) , indicating that the geometry of the line formation region could be bipolar. Models from Drew (1987) indicate that, even if the emission of the accretion disk is bipolar, the wind also must be a bipolar geometry.", "cite_spans": [{"start": 7, "end": 19, "text": "Warner 1995;", "ref_id": "BIBREF40"}], "ref_spans": []}, {"section": "Introduction", "text": "Most of the studies about winds in CVs are based on UV ressonant lines. They basically follow two research lines: cinematic models fitted to observed profiles (Long & Knigge 2002) , or hydrodynamic numerical modeling (Proga, Stone & Drew 1999) . A major disagreement between the modeled line profiles and the observed ones appears in the fit of the P-Cyg emission component. Most of the wind models make use the standard disk model (Shakura & Sunyaev 1973 , Pringle 1981 . Disk models with temperature given by the standard model are optically thick in Balmer lines, but the outer parts could be optically thick in Balmer lines and optically thin in the continuum (Williams 1980) . Following this model the lines must be formed in the outer parts of the disk, but the observations show that the disk line emissivity are centrally concentrated. Absorption lines are obtained from optically thick disk simulations under LTE while NLTE effects must be considered to simulate emission lines. Ko et al. (1996) presented a model where the accretion disk vertical structure and NLTE effects are considered, where a chromosphere is superposed to a standard model disk. A selfconsistent model for accretion disk extended atmosphere is still an open issue.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The main wind features are detected in UV, but wind effects can also appear in the optical region. In a brief survey, Kafka & Honeycutt (2004) noticed P-Cyg profiles in the HeI \u03bb5876, HeI \u03bb7065 and H\u03b1 line profiles of BZ Cam, Q Cyg, HR Del, DI Lac, BT Mon and AC Cnc. They presented a few spectra of each object showing P-Cyg features and extended H\u03b1 line wings, that are signatures of mass loss by wind. Studies analyzing the behavior of these features with the orbital phase in the optical region were not presented until now. Disk spectral synthesis and eclipse mapping studies suggest that gas in the primary Roche lobe (e.g. Baptista & Catalan 2001) contribute with scattering free-free and recombination continuum photons.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The presence of wind in CVs is a hypothesis raised to explain the emission at low velocities seen in many Doppler maps and the single peaked line profiles observed even on systems were a double peak line profile is expected (e.g. high inclination systems) (Murray & Chiang 1997) .", "cite_spans": [], "ref_spans": []}, {"section": "Accretion Disk Simulations", "text": "The simulation procedure is divided into two parts. First, a steady accretion disk emission is simulated, later, the flickering and/or wind is added. The simulated disk is geometrically thin and limited by the white dwarf at the inner rim and by the tidal radius at the outer rim. The emissivity of the disk is assumed to follow a power law with radial dependence", "cite_spans": [], "ref_spans": []}, {"section": "Accretion Disk Simulations", "text": "where F j is each element flux, r j its radial coordinate, \u03b8 its angular coordinate, a the power law proportionality constant, b the power law index, i the orbital inclination and \u03bb the emission wavelength calculated from the velocity Doppler shift calculated from equation 2. For each disk element the emission is calculated, the corresponding velocity is computed (eq. 2) and the contribution of each disk element is put into the spectra.", "cite_spans": [], "ref_spans": []}, {"section": "Accretion Disk Simulations", "text": "In equation 2, \u03b3 is the systemic velocity, v K the Keplerian disk velocity, and a K the system's stellar components separation. This procedure is repeated until all elements of the disk were computed. There is also the possibility of simulate a hot spot or a boundary layer. These regions are geometrically restricted on the disk surface and their emissivity is given as a fraction of the total disk emissivity.", "cite_spans": [], "ref_spans": []}, {"section": "Accretion Disk Simulations", "text": "Aiming to test our simulation method, a disk with an enhanced emission in a region similar to the hot spot at the outer parts of the disk and a disk with an enhanced emission in the inner disk parts were simulated. From the synthetic spectra generated by the simulations, Doppler maps were constructed. In the first case, the hot spot-like emission appears on the expected region of the synthetic Doppler maps, but the emission of the inner parts of the disk does not appear on the tomograms. From this we conclude that the Doppler tomography method is appropriated to study emission from the outer parts of the accretion disks but not for emission from the inner parts of the disk. In this later case, the information concentrated on a small region in position space is spread on a large region on the velocity space, due to the Jacobian of this transformation.", "cite_spans": [], "ref_spans": []}, {"section": "Flickering Simulations", "text": "The emission line flickering is simulated as a set of discrete flares on the accretion disk. Each flare is generated at a random position inside a pre-defined region (the hot spot, for example), allowing us to simulate flickering from different regions of the disk or from the secondary star. The flickering flare has a random intensity between a maximum intensity (simulation parameter) and zero. This maximum intensity is given in disk total line flux units, aiming to quantify the flare energy.", "cite_spans": [], "ref_spans": []}, {"section": "Flickering Simulations", "text": "When flickering is observed in an object, the resulting data comprises a sum of all flickering flares events during each integration time. Aiming to reproduce this observational effect on the simulations, the flickering flares are represented along a temporal grid with bins much smaller than the integration time. The sum along many bins is made to synthetize the effect of flickering on each spectrum. As the flickering flares are not instantaneous events but they present a temporal evolution, the flares are simulated as having instantaneous rise and exponential decay", "cite_spans": [], "ref_spans": []}, {"section": "Flickering Simulations", "text": "where I(t) f lare is the flare intensity on each bin, I(t 0 ) f lare its intensity on the previous bin, \u03c4 the characteristic decay time and t the temporal variable. The study of CVs light curves by Bruch (1989) indicate an assimetry on the flickering flare temporal evolution, with the flare rise faster than its decay. A fiducial flare description is not a critical issue on our simulations as the integration times are often longer than the individual flare timescale.", "cite_spans": [], "ref_spans": []}, {"section": "Flickering Simulations", "text": "As the flickering flares are not produced with a fixed periodicity, an occurrence probability is attributed to the flare on each time bin. This probability together with the integration time give us the averaged number of expected flares on each simulated line profile. The time of occurrence of the flare inside a particular temporal bin is a random value.", "cite_spans": [], "ref_spans": []}, {"section": "Flickering Simulations", "text": "This procedure is repeated for all bins inside the integration time. The Doppler shift of the flares are calculated based on the position of each flare, assuming a Keplerian disk, and the flare contribution is added to the line profile. Aiming to simulate line profiles with noise, we introduced a Gaussian noise in the simulations, this noise is quantified by a continuum signal-to-noise ratio. The standard deviation of the noise distribution is calculated by the ratio between the continuum intensity and the signal-to-noise ratio desired for the line profile. The introduced noise is symmetric around zero average and it is added to each wavelength resolution element of the resulting line profile. An averaged disk line profile and its corresponding RMS is shown in figure 1. Here the flickering simulations were held without noise. The disk was simulated on a 200x200 bins spatial grid. The addopted simulation parameters were the followings: orbital period of 5 hours, primary mass of 1 solar mass, mass ratio of 0.7 and integrated line flux of 9 \u00d7 10 \u221211 erg s \u22121 cm \u22122 . The flickering source region is a small region restricted between 0.75 and 0.85 disk radii units, centered at an angle of 120.", "cite_spans": [], "ref_spans": []}, {"section": "Flickering Simulations", "text": "\u2022 (measured from the line that join the stellar centres) and with an angular range of 1.", "cite_spans": [], "ref_spans": []}, {"section": "Flickering Simulations", "text": "\u2022 . This region has a location similar to the one of the impact of the stream on the disk considering free particles and a disk radius of approximately 2/3 of the primary Roche lobe radius. The flickering temporal evolution is calculated in a grid with 5 times more elements than the predicted number of flares on each integration time. The total decay time addopted for each flare was 1 minute. The maximum amplitude of the flares into each exposition was 10% of the disk total flux. The flare occurrence mean frequency is 0.025 s \u22121 , which corresponds to a flare at each 40 seconds on average. The relative intensity between the line profile and its RMS is dependent on these parameters. The flickering was restricted to a hot-spot-like region, the effect of this assumption is seen on figure 1, as the RMS profile lacking high velocity wings. The noise on the RMS profile is produced by the finite number of phase bins where the variance is calculated. This behavior tends to be minimized when a large number of phase bins is used.", "cite_spans": [], "ref_spans": []}, {"section": "Flickering Simulations", "text": "Other simulations with flickering originating on the hot spot region were held. The simulation parameters were varied one by one to verify the effect on the synthetic tomograms. The addopted simulation parameters were the same of the last paragraph, but with an integrated flux of 10 \u22129 erg s \u22121 cm \u22122 , flickering maximum amplitude of 1% of the total line flux and including noise in the line profiles.", "cite_spans": [], "ref_spans": []}, {"section": "Flickering Simulations", "text": "The addopted quality criterion to quantify the detection of a flickering feature was the ratio between the maximum intensity in the flickering occurrence region and the RMS of a region without flickering, affected only by the noise. We addopted as a feature detection criterion a quality factor (max/RM S) higher than 10.", "cite_spans": [], "ref_spans": []}, {"section": "Flickering Simulations", "text": "In the figures 2 and 3, the effect of each flickering parameter of our simulation is presented. The error bars for all the simulations were calculated from the standard deviation of the quality factors obtained from a series of 11 simulations.", "cite_spans": [], "ref_spans": []}, {"section": "Flickering Simulations", "text": "[Vol. , From figure 2a one can see that, higher the number of spectra used to calculate the flickering Doppler map, better is the structure detection capability. The flickering amplitude also affects the structure detection, as features with higher amplitude are detected more clearly. If we consider that features with max/RM S > 10 are detected, it can be noticed that, even using a high number of spectra to calculate the maps, the flickering with lowest amplitude could not be detected. On figure 3, the synthetic flickering maps of two particular points from figure 2 are shown. One can see that the feature detection is better for figure 3b (S/N = 20) than for figure 3a (S/N = 11). The flickering amplitude effect on the Doppler maps is shown in figure 2b . It is clear that the detection is better for the case of higher flickering amplitudes. One also can see that low amplitude flickering information is lost more easily than the high amplitude flickering one. The effect of the flare occurrence frequency is presented in figure 2c . We notice a decrease on the detection quality for high frequencies, where the combination of discrete flares tends to form a continuum emission instead of a series of discrete events. It is important to observe that, in the case where the frequency is small than 1 flare per integration time, the variance calculated in each phase box may not represent the variability properly. The integration time effect upon the synthetic flickering maps is shown in figure 2d . One can see from this graph that the detection is better for small integration times (with many flares on each integration time). For longer integration times, the flickering information is lost. We have not found any significative variation of the quality factor with the decay time-scale of each flickering flare.", "cite_spans": [], "ref_spans": [{"start": 13, "end": 22, "text": "figure 2a", "ref_id": "FIGREF1"}, {"start": 753, "end": 762, "text": "figure 2b", "ref_id": "FIGREF1"}, {"start": 1032, "end": 1041, "text": "figure 2c", "ref_id": "FIGREF1"}, {"start": 1498, "end": 1507, "text": "figure 2d", "ref_id": "FIGREF1"}]}, {"section": "Flickering Simulations", "text": "On these simulations the flickering source can be also In (a) the filled circles correspond to simulations with 1000 spectra and flickering amplitude 1%, the triangles were found with 500 spectra and amplitude of 0.5% of the total line flux and the empty circles correspond to simulations with 1000 spectra and amplitude of 0.5%.", "cite_spans": [], "ref_spans": []}, {"section": "Flickering Simulations", "text": "attributed to the reprocessing of radiation at the illuminated face of the secondary star. The application of this particular source model to the observations of V3885 Sgr was already made (Ribeiro & Diaz 2007) . In this case, the secondary is considered spherical and the flickering source geometry is approximate. These assumptions are reasonable, due to the typical resolution of Doppler tomograms. The velocity field in this case is given by eq. 2 without the Keplerian velocity term.", "cite_spans": [], "ref_spans": []}, {"section": "Wind Simulations", "text": "The wind is implemented in a 3d grid, below and above the disk. The wind emission process is chosen to be radiative recombination, with emissivity given by", "cite_spans": [], "ref_spans": []}, {"section": "Wind Simulations", "text": "where I is the wind emissivity, \u03bd the frequency, \u03b1 ef f the effective recombination coefficient and N e the electron density. For simplicity, the wind is considered isothermal. As only H\u03b1 line profiles are simulated, other emission processes as scattering are not considered. If the temperature variation along the wind were considered, then a detailed temperature stratification on the disk must also be taken into account. The wind addopted geometry is biconic ( figure 4) , and its velocity law is given by the Castor & Abbott velocity field (Long & Knigge 2002) ", "cite_spans": [], "ref_spans": []}, {"section": "Wind Simulations", "text": "where \u03b2 the wind terminal velocity scale factor, M 1 the primary mass, v 0 the initial wind velocity, R av the effective acceleration scale, l is the distance of each wind element along the wind streamlines, \u03b1 the acceleration coefficient and r is the distance between a point in the wind and the white dwarf. The ionization was considered to be partial for H and He and up to the CNO elements. The disk angular momentum conservation through the wind is also considered by", "cite_spans": [], "ref_spans": []}, {"section": "Wind Simulations", "text": "where r d is the radius of each wind element projected over the disk and \u03b8 v is the elevation angular coordinate. As the single peaked line profiles often seen in some CVs could not be generated only by varying the wind parameters, an optically thick wind was implemented. The line self-absorption through the wind was parameterized by the line optical depth \u03c4 , which relates to the emitted radiation by", "cite_spans": [], "ref_spans": []}, {"section": "Wind Simulations", "text": "where I \u03bd (s 0 ) is original the wind emission and I(s) the attenuated wind emission. Scattering effects were not considered.", "cite_spans": [], "ref_spans": []}, {"section": "Wind Simulations", "text": "The velocity of each wind element projected on the line of sight is calculated. If the element is not occulted by the optically thick disk, its emissivity is added to the disk Fig. 4 . Illustration of the wind biconic geometry. The white dwarf is the open circle at the center, the disk is the black thick line. The impact parameter d is the distance between the white dwarf and the wind focus at each side of the disk. The wind cone is limited by the inner and outer disk rim, and it is presented as the gray gradient region. The wind cone at the other disk side is limited by the dashed line.", "cite_spans": [], "ref_spans": []}, {"section": "Wind Simulations", "text": "spectra. If the wind has \u03c4 = 0 the absorption along the wind region of the disk emission is also considered.", "cite_spans": [], "ref_spans": []}, {"section": "Wind Simulations", "text": "The result of these simulations are line profiles of Keplerian accretion disks with wind inside the primary's Roche lobe. The simulation can be repeated at many orbital phases, allowing us to construct Doppler maps with these synthetic spectra.", "cite_spans": [], "ref_spans": []}, {"section": "Wind Simulations", "text": "In this work the line profiles were simulated considering only the wind, i.e, the disk emission is not included, varying only the optical thickness to verify the effect of this parameter over the line profiles (figure 5). From figure  5 one can see that, as optical thickness is increased the line profile changes from double-peaked to single-peaked. In this simulation, we find that the line profile becomes single-peaked for \u03c4 values higher than 10. The effect of optically an thick wind on the Doppler maps is presented on figure 6 . The optically thin Doppler map (figure 6a) is not filled at low velocities, while the optically thick wind Doppler map (figure 6b) presents a significant low velocity emission.", "cite_spans": [], "ref_spans": [{"start": 227, "end": 236, "text": "figure  5", "ref_id": "FIGREF3"}]}, {"section": "Wind Simulations", "text": "The effect of the other wind simulation parameters (see eq. 6) on the optically thick wind line profiles are presented on figure 7. These simulations were held with a fixed line optical depth \u03c4 = 12.5. The impact parameter d v is what determine the collimation of the wind. Higher the d v value is, more collimated is the wind. From figure 7a one can see that a more collimated wind produces a smaller flux and a narrower profile. The acceleration coefficient \u03b1 controls the wind acceleration. In figure 7b one can see that a more accelerated wind generates most intense line profiles. One interesting point about this parameter is that, for low values of \u03b1, a deficit in the emission at the red side of the line profile is perceived. This can be understood as the wind region opposite to the observer (redshifted mainly by the poloidal velocity component) having its radiation more attenuated by the absorption than the side in the direction of the observer (blueshifted). If only the Keplerian wind velocity is considered, the attenuation would be equal in both red and blue sides. The effect of terminal velocity scale factor \u03b2 on the line profiles (figure 7c) is that a higher value of \u03b2 yields line profiles [Vol. , with higher flux. A higher line flux is also the result of an increase of the effective acceleration scale R av ( figure  7d ) and a decrease on the initial wind velocity v 0 (figure 7e). In these last three cases the line profile shape does not present a significant change with the variation of each parameter, only the line flux does. Another physical scenario that produces single-peaked line profiles and consequently low velocity emission on Doppler maps is the emission by stationary material inside the Roche lobe. In this case, the only velocity component is orbital and the density of the material inside the Roche lobe is assumed to be constant. The line profiles generated by emission of stationary material inside the primary's Roche lobe are similar to the ones produced by high optical depth winds. In the present simulations wind and/or emission by stationary material can be considered.", "cite_spans": [], "ref_spans": []}, {"section": "Wind Simulations", "text": "A test application was performed to verify the plausibility of the wind hypothesis to produce low velocity emission on observed Doppler maps. Wind Doppler maps were simulated with some different values of line optical depth. From each map a velocity profile was obtained by calculating the mode along rings centered on the primary. These velocity profiles were compared to the V3885 Sgr Doppler map velocity profile (Ribeiro & Diaz 2007) (figure 8) . From figure 8 one can see that the V3885 Sgr H\u03b1 velocity profile has a shape similar to the simulated wind map velocity profile for high line optical depth The velocity of the peak does not coincide because it depends on the dynamical parameters of the wind.", "cite_spans": [], "ref_spans": []}, {"section": "Wind Simulations", "text": "We also analyzed the effect of the line optical depth on the radial emissivity profiles. We generated a series of simulated wind line profiles calculated with some fixed values for the line optical depth. Using those series Doppler maps were computed for each case. The disk contribution to the total emissivity was not included. The Doppler maps were transformed to the position space assuming a Keplerian velocity regime to obtain the radial emissivity profiles. The modal emissivity value was then calculated along several rings centered on the primary. Finally, a power law was fitted to these points (figure 9). The indexes of these radial power laws as a function of the line optical depth are given on table 1.", "cite_spans": [], "ref_spans": []}, {"section": "Wind Simulations", "text": "From table 1 we can conclude that the radial emissivity gets less centrally concentrated as we have higher line optical depths in the wind. From figure 9 one can see that, as expected, the flux is smaller for higher optical depths, but it is rather low for the \u03c4 line =15 case. This is expected as the emission measure gets too small in the high optical [Vol. , depth regime. The flux is also dependent on the other parameters considered on the simulations, as the electronic density or the dynamical parameters of the wind. The next step of our work is analyze the behavior of the simulated velocity and radial emissivity profiles with these parameters and compare the real data profiles with the simulated ones to constrain these dynamical parameters using a multiparametric optimization.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "In all flickering tomography studies the integration time must be small enough to preserve the flickering information. On the other hand, it must be long enough to ensure a good S/N ratio. One limitation of the Doppler tomography technique is that the flickering from the inner parts of the accretion disk could not be mapped with this method, as the information from a proportionally small accretion disk region is spread over a large region on the Doppler map. In addition, most of the emission from the inner parts of the accretion disk falls on the line wings, the profile region that is most affected by noise and continuum subtraction errors.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "One possible extension of the flickering simulation study is to compare the observed flickering maps and simulated ones aiming to constrain the flare energy. The difficult of this study is that the flickering simulation has many parameters and that the noise is superposed to the intrinsic stochastic variation on the observed data. The flickering in the present work is simulated considering only one occurrence frequency, more frequencies can be included in future studies.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "When the flickering from the secondary star is simulated, it is supposed to be due to the flickering from the disk being reprocessed on the illuminated face of the companion. To produce a more fiducial simulation, the effect of the illumination itself must be considered on the code. The effects of the illumination over the disk line profile is not included in the present version of the code.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "On both the wind and flickering simulations, the disk emission is given by a power law emissivity radial profile. The present simulation code can be combined with an disk model code to improve the description of the disk emission properties. One obstacle to do this is that longer computational times will be necessary to simulate the spectra used on the construction of the synthetic Doppler maps. On the wind simulations, the wind was considered isothermal. In the case of a disk model combined with the code, the temperature stratification of the wind can be otherwise included.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "The SW Sex stars are cataclysmic variables with peculiar characteristics. Among others, they present single peaked line profiles where a double peaked line profile is expected and their Doppler maps are dominated by emission at low velocity. This is occasionally observed even on systems which are not classified as SW Sex CVs. Many scenarios have been proposed to explain this behavior: accretion disk winds (Horne 1986) , magnetic accretion and mass loss via a propeller mechanism (Horne 1999 ), a gas stream that does not impact the disk completely at the hot spot region and flyby over the disk (Hellier & Robinson 1994) , accretion on the magnetic poles of a synchronous primary (Casares et al. 1996) and shock along the stream trajectory over the disk (Groot, Rutten & van Paradijs 2000) . The present simulations and their comparison with observed Doppler maps may help to identify the origin of SW Sex phenomenon. In particular, the reconstructions of a disk with an optically thick wind suggest that disk mass loss should be at least part of the solution to the SW Sex problem.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "A method for simulating accretion disk Doppler maps including wind and flickering is presented. The detection quality of the flickering raising from a small region of the disk was analyzed. High S/N and high time resolution spectra are needed to obtain information from flickering tomograms. The information from low amplitude and high frequency flickering is lost first. The flickering information is also lost if long integration times are used. The flickering from the inner part of the accretion disk could not be mapped with the Doppler tomography technique.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "Wind simulations were also held, and the effect of each simulation parameter over the wind line profiles is presented. It was necessary to consider an optically thick wind, with optical depth higher than 10 to generate single peaked H\u03b1 line profiles. Diffuse emission inside the primary Roche lobe is other mechanism that generate these single peaked profiles and centrally concentrated Doppler maps.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF40": {"title": "Cataclysmic variable stars", "authors": [{"first": "B", "middle": [], "last": "Warner", "suffix": ""}, {"first": "B", "middle": [], "last": "Warner", "suffix": ""}, {"first": "R", "middle": ["E"], "last": "Nather", "suffix": ""}], "year": 1971, "venue": "MNRAS", "link": "118278247"}}, "ref_entries": {"FIGREF0": {"text": "Fig. 1. Averaged simulated line profile (solid line) and its flickering RMS (dotted line) line profile. The simulations parameters are given on the text.", "type": "figure"}, "FIGREF1": {"text": "Fig. 2. Behavior of the quality factor with (a) S/N ratio, (b) flickering amplitude, (c) flickering frequency and (d) integration time. In (a) the filled circles correspond to simulations with 1000 spectra and flickering amplitude 1%, the triangles were found with 500 spectra and amplitude of 0.5% of the total line flux and the empty circles correspond to simulations with 1000 spectra and amplitude of 0.5%.", "type": "figure"}, "FIGREF2": {"text": "Fig. 3. Two synthetic flickering Doppler maps for 1000 spectra, flickering maximum amplitude of 0,5% the total line flux and (a) S/N = 11 and (b) S/N = 20. Notice that the feature detection is much better on the second case. The crosses are, from top to bottom, the secondary's center of mass, the L1 Lagrange point, the system's center of mass and the primary's center of mass.", "type": "figure"}, "FIGREF3": {"text": "Fig. 5. Effect of optical depth on the wind line profiles. For optical depths higher than approximately 10 the lines are single peaked.", "type": "figure"}, "FIGREF4": {"text": "Fig. 6. Doppler maps for accretion disk simulations including (a) an optically thin wind and (b) an optically thick wind with \u03c4 line = 20 (see text).", "type": "figure"}, "FIGREF5": {"text": "Fig. 8. Velocity profiles from (a) H\u03b1 (solid curve) and HeI \u03bb6678 (dashed curve) V3885 Sgr Doppler maps and from (b) simulated wind Doppler maps. On (b) the profiles are presented for some line optical depth values: \u03c4 = 0 (solid black curve), \u03c4 = 10 (dotted black curve), \u03c4 = 15 (dashed black curve), \u03c4 = 20 (solid gray curve) and \u03c4 = 25 (dashed gray curve). The V3885 Sgr H\u03b1 line velocity profile has a shape similar to those simulated with 15 < \u223c \u03c4 < \u223c 20.", "type": "figure"}}}
{"paper_id": "17780091", "_pdf_hash": "b1e91dfa6aed4b1ad31a4abd8688eabe3f8bee00", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Cache coherence protocols: Evaluation using a multiprocessor simulation model", "authors": [{"first": "J", "middle": [], "last": "Archibald", "suffix": ""}, {"first": "Jean-Loup", "middle": [], "last": "Baer", "suffix": ""}], "year": 1986, "venue": "ACM Trans. on Comp. Sys", "link": "713808"}, "BIBREF1": {"title": "Overview of the KSR1 computer system", "authors": [{"first": "H", "middle": [], "last": "Burkhardt", "suffix": ""}], "year": 1992, "venue": "", "link": "60448319"}, "BIBREF2": {"title": "Synchronization, coherence and event ordering in multiprocessors", "authors": [{"first": "M", "middle": [], "last": "Dubois", "suffix": ""}, {"first": "C", "middle": [], "last": "Scheurich", "suffix": ""}], "year": 1988, "venue": "IEEE Computer", "link": "1749330"}, "BIBREF3": {"title": "1-.2: Logical layer specifications", "authors": [{"first": "Futurebus+", "middle": [], "last": "Ieee", "suffix": ""}, {"first": "", "middle": [], "last": "P896", "suffix": ""}], "year": 1990, "venue": "", "link": null}, "BIBREF4": {"title": "DDM A cache-only memory architecture", "authors": [{"first": "E", "middle": [], "last": "Hagersten", "suffix": ""}, {"first": "S", "middle": [], "last": "Haridi", "suffix": ""}, {"first": "D", "middle": ["H D"], "last": "Warren", "suffix": ""}], "year": 1992, "venue": "IEEE Computer", "link": "15771581"}, "BIBREF5": {"title": "Implementing a cache consistency protocol", "authors": [{"first": "R", "middle": [], "last": "Katz", "suffix": ""}], "year": 1984, "venue": "Proc. 12th Annual Int. Symp. On Comp. Arch", "link": "62169625"}, "BIBREF6": {"title": "A comparison of shared memory architectures for shared-bus multiprocessors", "authors": [{"first": "J", "middle": [], "last": "Kong", "suffix": ""}, {"first": "G", "middle": [], "last": "Lee", "suffix": ""}], "year": 1995, "venue": "", "link": null}, "BIBREF7": {"title": "An assessment of COMA multiprocessors", "authors": [{"first": "G", "middle": [], "last": "Lee", "suffix": ""}], "year": 1995, "venue": "9th International Parallel Processing Symposium", "link": null}, "BIBREF8": {"title": "DICE Prototype Specification", "authors": [{"first": "G", "middle": [], "last": "Lee", "suffix": ""}, {"first": "B", "middle": [], "last": "Quattlebaum", "suffix": ""}, {"first": "S", "middle": [], "last": "Jamil", "suffix": ""}, {"first": "M", "middle": [], "last": "Agarwal", "suffix": ""}, {"first": "L", "middle": [], "last": "Kinney", "suffix": ""}, {"first": "D", "middle": [], "last": "Lilja", "suffix": ""}], "year": 1993, "venue": "", "link": null}, "BIBREF9": {"title": "The directory-based cache coherence protocol for the DASH multiprocessor", "authors": [{"first": "D", "middle": [], "last": "Lenoski", "suffix": ""}], "year": 1990, "venue": "Proc. 17th Annual Int. Symp. on Comp. Arch", "link": "20008194"}, "BIBREF10": {"title": "The Symmetry multiprocessor system", "authors": [{"first": "T", "middle": [], "last": "Lovett", "suffix": ""}, {"first": "S", "middle": [], "last": "Thakkar", "suffix": ""}], "year": 1987, "venue": "Sequent Computer Systems", "link": "35816298"}, "BIBREF11": {"title": "Distributed shared memory: A survey of issues and algorithms", "authors": [{"first": "B", "middle": [], "last": "Nitzberg", "suffix": ""}, {"first": "V", "middle": [], "last": "Lo", "suffix": ""}], "year": 1991, "venue": "IEEE Computer", "link": null}, "BIBREF12": {"title": "Comparative performance evaluation of cachecoherence NUMA and COMA architectures", "authors": [{"first": "T", "middle": [], "last": "Per Stenstom", "suffix": ""}, {"first": "A", "middle": [], "last": "Joe", "suffix": ""}, {"first": "", "middle": [], "last": "Gupta", "suffix": ""}], "year": 1992, "venue": "Proc. 19th Annnual Int Symp. on Comp. Arch", "link": null}, "BIBREF13": {"title": "A survey of cache coherence schemes for multiprocessors", "authors": [{"first": "Per", "middle": [], "last": "Stenstrom", "suffix": ""}], "year": 1990, "venue": "IEEE Computer", "link": "20004221"}, "BIBREF14": {"title": "A class of compatible cache consistency protocols and their support by the IEEE Futurebus", "authors": [{"first": "P", "middle": [], "last": "Sweazey", "suffix": ""}, {"first": "", "middle": [], "last": "Smith", "suffix": ""}], "year": 1986, "venue": "Proc. 13th Annual Int. Symp. on Comp. Arch", "link": "9713683"}, "BIBREF15": {"title": "Futurebus+ Interface Family, (Rev. 5.1), Texas Instruments, Linear Products Div", "authors": [], "year": 1993, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "17780169", "_pdf_hash": "70264d18acfffb7e8a60533a2a13d8ea5a3aa642", "abstract": [{"section": "Abstract", "text": "Intrathoracic gastric volvulus in the neonatal period is a rare surgical emergency. Delays in diagnosis and treatment are life-threatening due to progressive deterioration of the gastric walls. Presentation in this period can be confused with the possibility of esophageal atresia or esophageal web. The upper gastrointestinal tract contrast study is diagnostic in this disease. The authors report a case of acute intrathoracic gastric volvulus diagnosis by radiologic-contrast-study in 1-day-old girl that was confirmed at surgery. The physiopathology, classification and different presentations of this entity are briefly reviewed", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Primary gastric volvulus in the neonatal period is extremely rare, potentially life-threatening condition, which is difficult to diagnose. This case of acute gastric volvulus in neonates with the aim of describing this rare disease and its varied clinical manifestations", "cite_spans": [], "ref_spans": []}, {"section": "Patient and observation", "text": "A 1-day old girl normally delivered after an uneventful pregnancy, weighing 3.200 Kg referred to us with a suspected diagnosis of esophageal atresia due to excessive salivation, regurgitation with an impossibility to pass a nasogastric tube. Physical examination did not reveal any overt signs, but an orogastric tube was arrested at 12 cm from the gum margin. Plain X-ray of the chest with orogastric tube in situ demonstrated the presence of tip of the tube at 6 thoracic vertebral level as well as the presence of an abnormal gas shadow in the chest (Figure 1) . Subsequent contrast study ruled out esophageal atresia and demonstrated partial herniation of the stomach through a large hiatal hernia, and organoaxial gastic volvulus (Figure 2) . The patient underwent emergency surgical repair via laparotomy because of distress respiratory and the risk of gastric perforation. At exploration, the stomach was found herniated into the chest through a large hiatal defect, twisted but not ischemic, gastroperitoneal attachments and gastric ligaments were absent with mobile spleen, there was no abdominal malformation. After untwisting, the stomach was reduced into the abdominal, the hiatal defect was repaired and a Thal fundoplication was performed, and a gastropexy was added to the procedure. The postoperative course was uncomplicated. At 1-year follow-up she is asymptomatic and growing well.", "cite_spans": [], "ref_spans": [{"start": 553, "end": 563, "text": "(Figure 1)", "ref_id": "FIGREF0"}]}, {"section": "Discussion", "text": "The normal gastric attachments within the abdomen include four ligaments: gastrohepatic, gastrophrenic, gastrosplenic and gastrocolic, these attachments result in the relative fixation of the stomach in the left upper quadrant, and intact diaphragmatic crus prevent herniation. For intrathoracic herniation of stomach to occur, the ligamentous attachements must be lax and the diaphragmatic hiatus must be deficient [1] , and congenital esophageal shortening is also a feature of some infants with intrathoracic stomach. This abnormality predispose to a sliding hiatus hernia as opposed to a herniation secondary rotation or volvulus of the stomach [2, 3] . Gastric volvulus is defined as an abnormal rotation of the stomach of more than 180, creating a closed loop obstruction that can result incarceration and strangulation. According to the axis around which the stomach rotates, gastric volvulus is classified as follows [4] : organoaxial, the stomach rotates around an axis that connects the gastroesophageal junction and pylorus. The antrum rotates in opposite direction to the fundus of the stomach, this is the most common type in both children and is usually associated with diaphragmatic defects, strangulation and necrosis commonly occur with this type. Mesentericoaxial is the type in which the axis bisects both lesser and greater curvatures. The antrum rotates anteriorly and superiorly so that the posterior surface of the stomach lies anteriorly, the rotation is usually incomplete and occurs intermittently. Vascular compromise is uncommon. Patients with this type usually present without diaphragmatic defects and usually chronic symptoms. The third type of volvulus is a combination of the first and second type in which the stomach twists both mesentericoaxially and organoaxially. In the majority of neonates with gastric volvulus the stomach remains in the abdominal cavity, although a gastric volvulus also can occur into the chest. According to etiology, gastric volvulus can be classified as either type 1(idiopathic) or type 2 (congenital or acquired) [4] . Some of the anomalies associated with gastric volvulus included congenital diaphragmatic hernia, wandering spleen, diaphragmatic eventration and asplenia-polysplenia syndrome, the gastroperitoneal attachments and gastric ligaments are often absent in patient with there anomalies making them susceptible to gastric volvulus. A variety of symptom may occur, but it is common that the symptom complex is indicative of upper alimentary tract obstruction, with or without cyanotic episode. In patient with intrathoracic gastric volvulus, the symptomatolgy may indicate an esophageal atresia as was suspected in our patient. In these neonates an orogastric tube gets arrested from the gum margin, a level lower than that usually seen in esophageal atresia [5] . Sever epigastric pain and distension, violent unproductive retching and inability to pass a nasogastric tube comprises the classical tried of borchardt [6] , the features result from obstruction at the cardia and/or pylorus. Sawaguchi has attributed vomiting in young infants to the maldeveloppement of hiatal function. Intermittent or chronic gastric volvulus my cause diverse gastrointestinal and chest symptoms in children [7] A plain X-ray of chest needs to be viewed carefully as the gastric shadow can be seen in lower chest, by the side of esophagus and separate from the pulmonary shadow. The contrast study will be performed for delineation of anatomy of esophagus and stomach, and a correct preoperative diagnosis could be made.", "cite_spans": [{"start": 416, "end": 419, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 649, "end": 652, "text": "[2,", "ref_id": "BIBREF1"}, {"start": 653, "end": 655, "text": "3]", "ref_id": "BIBREF2"}, {"start": 925, "end": 928, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 2078, "end": 2081, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 2835, "end": 2838, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 2993, "end": 2996, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 3267, "end": 3270, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Discussion", "text": "Acute gastric volvulus is a surgical emergency as delay in recognition and treatment can cause strangulation and perforation. Chronic volvulus however should be initially treated conservatively by keeping the patient in the prone position. Gastroscopic decompression for chronic gastric volvulus is also reported. Anterior gastropexy supplemented with a gastrostomy is a satisfactory solution to this life threatening problem. Percutaneous gastrostomy using anchoring devices and laparoscopic guided gastroscopy are newer modalities reported [8] . The need for an antireflux operation after hiatal hernia repair in patients with intrathoracic gastric volvulus remains controversial. [4] ", "cite_spans": [{"start": 542, "end": 545, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 683, "end": 686, "text": "[4]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Conclusion", "text": "Intrathoracic gastric volvulus is seen at all ages through life, but rarely present in the neonatal period. The purpose of this paper is to draw attention to the possibility of gastric volvulus at the newborn and to suspect this disease entity when its inability to pass a nasogastric tube confused with esophageal atresia", "cite_spans": [], "ref_spans": []}, {"section": "Competing interests", "text": "The author declares he has no competing interest. ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Intrathoracic gastric volvulus in infancy", "authors": [{"first": "Al-Salem", "middle": [], "last": "", "suffix": ""}, {"first": "A", "middle": ["H"], "last": "", "suffix": ""}], "year": 2000, "venue": "Pediatr Radiol", "link": null}, "BIBREF1": {"title": "Prenatal diagnosis of intrathoracic stomach(gastric herniation)", "authors": [{"first": "A", "middle": [], "last": "Al-Assiri", "suffix": ""}, {"first": "N", "middle": [], "last": "Wiseman", "suffix": ""}, {"first": "M", "middle": [], "last": "Bunge", "suffix": ""}], "year": 2005, "venue": "J Ped Surg", "link": "23788551"}, "BIBREF2": {"title": "Gastric volvulus in the childhood", "authors": [{"first": "Aep", "middle": [], "last": "Cameron", "suffix": ""}, {"first": "E", "middle": ["R"], "last": "Howard", "suffix": ""}], "year": 1988, "venue": "J Pediatr Surg", "link": null}, "BIBREF3": {"title": "Primary intrathoracic gastric volvulus in a newborn", "authors": [{"first": "K", "middle": ["H"], "last": "Mutabagani", "suffix": ""}, {"first": "S", "middle": [], "last": "Teich", "suffix": ""}, {"first": "F", "middle": ["R"], "last": "Long", "suffix": ""}], "year": 1999, "venue": "J Ped Surg", "link": null}, "BIBREF4": {"title": "Paraesophageal hernia in the neonatal period: another differential diagnosis of esophageal atresia", "authors": [{"first": "K", "middle": [], "last": "Yadav", "suffix": ""}, {"first": "N", "middle": ["A"], "last": "Myers", "suffix": ""}], "year": 1997, "venue": "Pediatr Surg International", "link": "9093647"}, "BIBREF5": {"title": "Kur pathologie and therapie des magen volvulus", "authors": [{"first": "M", "middle": [], "last": "Borchardt", "suffix": ""}], "year": 1904, "venue": "Arch Kin Chir", "link": null}, "BIBREF6": {"title": "Idiopatic gastric volvulus in infancy and childhood", "authors": [{"first": "S", "middle": [], "last": "Sawaguchi", "suffix": ""}, {"first": "H", "middle": [], "last": "Ohkawa", "suffix": ""}], "year": 1989, "venue": "Z Kinderchir", "link": null}, "BIBREF7": {"title": "Laparoscopic reduction of gastric volvulus and repair of giant hiatal hernia in a neonate. Pediatric endosurgery & Innovative Techniques", "authors": [{"first": "D", "middle": [], "last": "Timothy", "suffix": ""}, {"first": "M", "middle": ["D"], "last": "Kane", "suffix": ""}, {"first": "M", "middle": [], "last": "Carroll", "suffix": ""}, {"first": "M", "middle": ["D"], "last": "Harmon", "suffix": ""}, {"first": "E", "middle": [], "last": "Keith", "suffix": ""}, {"first": "M", "middle": ["D"], "last": "Georgeson", "suffix": ""}], "year": 2003, "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Figures Figure 1: Neonatal chest X-ray showing catheter in esophagus at T6 vertebral level and intrathoracic gastric bubble in the mediastinum", "type": "figure"}, "FIGREF1": {"text": "Figure 2: Upper gastrointestinal contrast study showing organoaxial volvulus of stomach", "type": "figure"}}}
{"paper_id": "17780220", "_pdf_hash": "9b97c7a278ec21e754d8a808971f05a3c51aa7a7", "abstract": [{"section": "Abstract", "text": "Background. Tissue oxygenation is the primary determinant of wound infection risk. Mild hypercapnia markedly improves cutaneous, subcutaneous (s.c.), and muscular tissue oxygenation in volunteers and patients. However, relative contributions of increased cardiac output and peripheral vasodilation to this response remains unknown. We thus tested the hypothesis that increased cardiac output is the dominant mechanism.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "Wound infections are among the most common serious complications of anaesthesia and surgery. 1 All wounds become contaminated. Contamination progresses to a clinical infection when host defence fails. This process occurs during a 'decisive period' lasting several hours after contamination; 2 in other words, during the immediate perioperative period. Oxidative killing by neutrophils is the primary determinant of host resistance to bacterial contamination. 3 It is thus unsurprising that factors which increase subcutaneous (s.c.) tissue oxygenation reduce infection risk. 4 Determinants of s.c. oxygen availability include arterial oxygen pressure, 4 haemoglobin concentration, 5 cardiac output, 6 local perfusion, 7 fraction of fat in s.c. tissue, 8 hydration status 9 and autonomic responses to pain. 10 Mild-to-moderate hypercapnia also improves tissue oxygen availability. 11 For example, s.c. oxygenation increased from 63 (14) to 89 (19) mm Hg (P=0.01) when arterial PCO 2 increased from 35 to 50 mm Hg. 11 This 26 mm Hg increase is likely to be clinically important. 12 There are two mechanisms by which hypercapnia might improve tissue oxygenation. The first is activation of central 13 and peripheral 14 chemoreceptors, which promotes release of catecholamines. 15 16 Catecholamines, in turn, increase cardiac output, 11 17 enhance systemic vascular conductance 14 18 and increase venous return. 13 19 20 Interestingly, hypercapnia is not associated with increased blood pressure, 11 at least not during anaesthesia, because baroreflex-mediated parasympathetic activity reduces systemic vascular resistance (SVR) and heart rate. 17 21 The second mechanism by which hypercapnia might improve tissue oxygenation is direct, locally medicated peripheral vasodilation that may overwhelm sympathetic vasoconstriction. 22 23 The relative contribution of increased cardiac output and direct peripheral vasodilation remains unknown; that is, peripheral capacitance vessels could dilate to absorb increased cardiac output or cardiac output could increase in response to systemic vasodilation. Normally, it would be difficult to separate peripheral vasodilation caused by the local action of CO 2 from mechanisms that involve increased cardiac output and central autonomic regulation of the circulation. An exception, though, is during cardiopulmonary bypass when the bypass pump can control systemic perfusion. We, therefore, tested the hypothesis that mild hypercapnia increases peripheral tissue and cerebral oxygenation during cardiopulmonary bypass even when the pump flow (cardiac output) remains constant.", "cite_spans": [{"start": 93, "end": 94, "text": "1", "ref_id": "BIBREF0"}, {"start": 459, "end": 460, "text": "3", "ref_id": "BIBREF2"}, {"start": 575, "end": 576, "text": "4", "ref_id": "BIBREF3"}, {"start": 652, "end": 653, "text": "4", "ref_id": "BIBREF3"}, {"start": 681, "end": 682, "text": "5", "ref_id": "BIBREF4"}, {"start": 699, "end": 700, "text": "6", "ref_id": "BIBREF5"}, {"start": 718, "end": 719, "text": "7", "ref_id": "BIBREF6"}, {"start": 752, "end": 753, "text": "8", "ref_id": "BIBREF7"}, {"start": 771, "end": 772, "text": "9", "ref_id": "BIBREF8"}, {"start": 806, "end": 808, "text": "10", "ref_id": "BIBREF9"}, {"start": 880, "end": 882, "text": "11", "ref_id": "BIBREF10"}, {"start": 931, "end": 935, "text": "(14)", "ref_id": "BIBREF13"}, {"start": 942, "end": 946, "text": "(19)", "ref_id": "BIBREF18"}, {"start": 1013, "end": 1015, "text": "11", "ref_id": "BIBREF10"}, {"start": 1077, "end": 1079, "text": "12", "ref_id": "BIBREF11"}, {"start": 1195, "end": 1197, "text": "13", "ref_id": "BIBREF12"}, {"start": 1213, "end": 1215, "text": "14", "ref_id": "BIBREF13"}, {"start": 1493, "end": 1495, "text": "11", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "", "text": "Among the various systems currently used for tissue oxygen monitoring, the Clark-type electrode-based method is considered the gold standard. The disadvantage of this method is that the Clark-type electrode consumes oxygen itself, which can decrease the system's accuracy, especially at lower tissue oxygen tensions. Ruthenium-based fluorescent oxygen probe (optode) systems do not have this disadvantage, but have not been fully validated for clinical use. We thus took this opportunity to validate a new fluorescence optode oxygen-monitoring system by comparing it with the standard polarographic electrode (Clark-type) method and evaluating practical factors related to its use.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "With the approval of Human Studies Committee at the University of Louisville and written informed consent of patients, we enrolled 10 ASA physical status III patients aged 40-65 yr, undergoing heart surgery on cardiopulmonary bypass. Patients were excluded if they were morbidly obese (BMI>35), had diabetes or peripheral vascular disease of any type, or were taking a 2 -agonists or other vasoactive drugs. Patients who smoked were included, but were not permitted to smoke during the 8 h before surgery because smoking reduces tissue oxygenation for 1 h. 24 Using a crossover study design, we compared s.c. tissue oxygen pressure and cerebral oxygen saturation during normocapnia and mild hypercapnia. Based on previous data, 11 we expected that mild hypercapnia (a 15-20 mm Hg increase in arterial PCO 2 ) would increase s.c. tissue oxygen pressure by at least 15 mm Hg. Assuming, as in our previous studies, that the SD would be 15 mm Hg, we estimated that a sample size of 10 would provide an 80% power to detect a statistically significant effect of hypercapnia at an alpha level of 0.05.", "cite_spans": [{"start": 557, "end": 559, "text": "24", "ref_id": "BIBREF23"}, {"start": 728, "end": 730, "text": "11", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Protocol", "text": "Anaesthesia was induced with etomidate (0.3 mg kg \u00c01 ), succinylcholine (%1 mg kg \u00c01 ), and fentanyl (3-4 mg kg \u00c01 ), and maintained with pancuronium (0.01 mg kg \u00c01 as needed), fentanyl (%10 mg kg \u00c01 bolus before sternotomy then 2-3 mg kg \u00c01 as needed) and isoflurane. Hypovolaemia reduces s.c. perfusion; 9 therefore, patients were kept well hydrated, especially during the pre-bypass period, by an infusion of crystalloid at a rate of 6-8 ml kg \u00c01 h \u00c01 . Patients were actively warmed to maintain core temperature near 36 C before and after the bypass procedure. Because local warming influences tissue oxygenation, the upper arm tonometer site (described below) was protected from active surface warming.", "cite_spans": [{"start": 306, "end": 307, "text": "9", "ref_id": "BIBREF8"}, {"start": 521, "end": 523, "text": "36", "ref_id": "BIBREF35"}], "ref_spans": []}, {"section": "Protocol", "text": "After initiation of cardiopulmonary bypass, pump flow was set to maintain sufficient perfusion with a constant flow at a target mean arterial pressure of 60 mm Hg. Once set, pump outflow was kept constant until the end of the bypass period. Patients were alternately exposed to a Pa CO 2 of 35 and 50 mm Hg during bypass, using a crossover design. Each designated Pa CO 2 tension was maintained for about 30 min. CO 2 was added to the oxygenator circuit by the perfusionist, as necessary, to maintain the designated Pa CO 2 . Treatment order was randomly assigned and based on computer-generated codes that were maintained in sealed, sequentially numbered opaque envelopes until the beginning of the bypass procedure. Intraoperatively (including the bypass period), the inspired oxygen concentration (F I O 2 ) was kept constant for each patient [average of all patients was 0.85 (0.10)].", "cite_spans": [], "ref_spans": []}, {"section": "Measurements", "text": "Demographic and morphometric characteristics and potential confounding factors, including preoperative haemoglobin, smoking status, type and duration of surgery, total amount of crystalloids given and intraoperative core temperature were recorded. Core temperature was measured from the distal oesophagus (Mallinckrodt Anaesthesiology Products, St Louis, MO, USA) and Swan-Ganz catheter. Bladder temperature, which was recorded from the urinary catheter, was used to represent core temperature during the bypass period because the chest cavity was open.", "cite_spans": [], "ref_spans": []}, {"section": "Measurements", "text": "After induction of anaesthesia, 5-6 cm of a 15 cm-long Silastic tonometer (1 mm outer diameter, 0.8 mm inner diameter) was inserted s.c. on the lateral aspect of one upper arm, which was then gently tucked at the patient's side. S.C. tissue oxygen tension (Psq O 2 ) was measured with a polarographic electrode system (Licox Medical Systems, Corp., Greenvale, NY, USA). 25 The polarographic oxygen electrode was calibrated on room air at the beginning of each surgery (154 mm Hg), and then positioned within the Silastic tonometer described above. A thermocouple was inserted into the opposite lumen of the tonometer and positioned approximately 1 cm from the oxygen electrode. The system was filled with hypoxic saline to remove air from the catheter.", "cite_spans": [{"start": 370, "end": 372, "text": "25", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Measurements", "text": "Calibration and stabilization of the polarographic system required 20-30 min. In vitro accuracy of the polarographic electrodes (in a water bath at 37 C) is \u00b13 mm Hg for 0-100 mm Hg O 2 and \u00b15% for 100-360 mm Hg O 2 . Temperature sensitivity is 0.25% per degree centigrade, but temperature-compensation is included in the Psq O 2 calculations. Polarographic electrode calibration remains stable (within 8% of baseline value for room air) in vivo for at least 8 h. Consequently, polarographic electrodes measure oxygen tension accurately and reliably over a broad range of s.c. temperatures and PO 2 values. 25 S.C. tissue oxygen tension was also measured from the same silicon tubing with the FOXY fluorescence system (Ocean Optics Inc., Dunedin, FL, USA), a relatively new technology. The FOXY-PI600 oxygen probe was simultaneously inserted into the silicon catheter. The fibre-optic probe conveys excitation light produced by a blue light emitting diode (LED) to a sol-gel thin film coating on the membrane at the probe tip. Fluorescence quenching of this probe is related to the partial pressure of oxygen by the Stern-Volmer equation. 26 Fluorescence generated at the tip is collected by the probe and carried by optical fibre to the detector. 27 We performed a two-point calibration of the optode at 0 and 154 mm Hg (F I O 2 : 0 and 0.21) before insertion.", "cite_spans": [{"start": 607, "end": 609, "text": "25", "ref_id": "BIBREF24"}, {"start": 1139, "end": 1141, "text": "26", "ref_id": "BIBREF25"}, {"start": 1248, "end": 1250, "text": "27", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "Measurements", "text": "Cerebral oxygen saturation was monitored by a non-invasive near-infrared reflectance spectroscopic oximeter (INVOS 3100, Somanetics, Troy, MI, USA). 28 Cerebral oximetry reflects the balance between regional oxygen supply and demand. 29 ", "cite_spans": [{"start": 149, "end": 151, "text": "28", "ref_id": "BIBREF27"}, {"start": 234, "end": 236, "text": "29", "ref_id": "BIBREF28"}], "ref_spans": []}, {"section": "Data analysis", "text": "The major outcomes of our study were s.c. oxygen tension, as measured by two different systems, and cerebral oxygen saturation.", "cite_spans": [], "ref_spans": []}, {"section": "Data analysis", "text": "Intraoperative values were recorded at 5 min intervals. Tissue oxygenation values were monitored continuously and recorded at the end of each 30 min interval. The average values of the tissue oxygen gathered at the end of each 30 min interval were then compared between the periods. Demographic and morphometric factors were recorded.", "cite_spans": [], "ref_spans": []}, {"section": "Data analysis", "text": "Outcomes were compared between the groups with paired, two-tailed t-tests. Non-normally distributed results were analysed by Wilcoxon signed-rank tests. Results are presented as means (SDs or 95% confidence intervals), actual values, median (range), or percentages; P<0.05 was considered statistically significant. Additionally, two-period crossover methodology described by Hills and Armitage 30 was used to investigate treatment effects and possible period effects for the three major outcomes.", "cite_spans": [{"start": 394, "end": 396, "text": "30", "ref_id": "BIBREF29"}], "ref_spans": []}, {"section": "Data analysis", "text": "Linear regression and Bland-Altman analysis were used to compare tissue oxygen tensions obtained from the polarographic electrode (Licox) and fluoroscopic optode (Foxy) systems.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "The patients were 56 (42-62) yr old and three were women. Three of the ten were obese (BMI between 30 and 35 kg m \u00c02 ). The duration of surgery averaged 3.5 h, which included 1-1.5 h of cardiopulmonary bypass. Five patients had coronary artery bypass graft (CABG) surgery, five had valve replacement surgery, and one had both arterial grafting and a valve replacement. All but one of the patients had a history of cigarette smoking. Preoperative haemoglobin and other laboratory values were within normal range (Table 1) .", "cite_spans": [], "ref_spans": [{"start": 511, "end": 520, "text": "(Table 1)", "ref_id": "TABREF0"}]}, {"section": "Results", "text": "During bypass, measurements of F I O 2 , Pa O 2 , pump outflow, mean arterial pressure, core (bladder) temperature, and s.c. tissue temperature were similar during the normocapnic and hypercapnic periods ( Table 2 ). Arterial CO 2 Fig. 1) .", "cite_spans": [], "ref_spans": [{"start": 206, "end": 213, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "Results", "text": "On the other hand, hypercapnia caused a clinically important and statistically significant increase in the cerebral oxygen saturation despite constant bypass pump flow and mean arterial pressure [55 (14)% vs 64 (17)%, P=0.025, Table 2 and Fig. 2] .", "cite_spans": [], "ref_spans": [{"start": 227, "end": 234, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "Results", "text": "Using the two-period crossover methodology, 30 Psq O 2 , as measured with Licox, had a non-significant treatment effect of 4.9 mm Hg (P=0.213, 95% CI \u00c03.3 to 13.1) and a nonsignificant period effect of 5.1 mm Hg (P=0.194, 95% CI ", "cite_spans": [{"start": 44, "end": 46, "text": "30", "ref_id": "BIBREF29"}], "ref_spans": []}, {"section": "\u00c03.1 to 13.3).", "text": "Psq O 2 , as measured with the Foxy system, had similar results with a non-significant treatment effect of 3.8 mm Hg (P=0.562, 95% CI \u00c010.3 to 17.9) and a nonsignificant period effect of 11.4 mm Hg (P=0.100, 95% CI \u00c02.7 to 25.5). On the contrary, in cerebral oxygen saturation there was a statistically significant treatment effect of 9.5% (P=0.007, 95% CI 4.1-14.9) with a non-significant period effect of 3.4% (P=0.204, 95% CI \u00c02.0 to 8.8).", "cite_spans": [], "ref_spans": []}, {"section": "\u00c03.1 to 13.3).", "text": "Tissue oxygenation recorded from the tissue oxygenmonitoring systems correlated well (r=0.92, Fig. 3) . The difference between the polarographic and fluoroscopic systems (accuracy, bias) averaged 6.8 (15.0) mm Hg. The precision (2 SDs of the difference between the systems) was 30 mm Hg (Fig. 4) . The Foxy system proved difficult to use because it was light sensitive, subject to substantial motion artifact, and lacked a small-calibre temperature sensor.", "cite_spans": [], "ref_spans": [{"start": 287, "end": 295, "text": "(Fig. 4)", "ref_id": "FIGREF1"}]}, {"section": "Discussion", "text": "It is well established that mild hypercapnia improves peripheral perfusion and increases tissue PO 2 . Our main question was whether peripheral vasodilation is a direct effect of the CO 2 or a secondary result of increased cardiac output and related central autonomic homeostatic responses. We found that mild hypercapnia did not increase s.c. tissue oxygenation when systemic blood flow and mean arterial pressure remained constant during cardiopulmonary bypass. Increased tissue oxygenation during mild hypercapnia thus most likely results from a hyperdynamic circulatory response and shifting oxyhaemoglobin dissociation curve rather than direct peripheral vasodilation.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Even mild systemic hypercapnia provokes sympathoexcitation 15 which increases cardiac output, enhances systemic vascular conductance, 18 19 and-because of active venoconstriction-increases venous return. 19 20 The increase in capacitance vessel tone is mediated via peripheral and central chemoreceptors and does not necessarily parallel changes in overall vascular resistance 18 -and, as our results demonstrate, does not increase s.c. perfusion. Venoconstriction nonetheless increases venous return and is, thus, invariably associated with a sustained increase in cardiac output, 14 18 19 31 an effect that dominates a small direct depressant effect of hypercapnic acidosis on the isolated myocardium. 32 33 Hypercapnia increases both sympathetic and cardiac vagus nerve activity in anaesthetized dogs. Such co-activation of vagus and sympathetic systems, which can be initiated reflexively or by action on higher centres, has been shown to be of distinct physiological benefit in controlling reactions that relate cardiac function to body need. As the sympathetic and parasympathetic systems are co-activated during systemic hypercapnia, blood pressure and heart rate response depends on the functional balance between these two systems. We were unable to evaluate heart rate during bypass, but have previously shown that both mean arterial blood pressure and heart rate remained essentially unchanged during hypercapnia even though cardiac output increases 25%. 11 Recent evidence indicates that both the sympathetic and parasympathetic nervous systems contribute to regulation of peripheral microcirculation. 34 The presence of parasympathetic-related, high-frequency microvascular oscillations has been recently documented in adrenergically rich peripheral regions-even during nonpulsatile perfusion 34 -and has important implications for local flow homeostasis. Interestingly, nonpulsatile flow in the systemic circulation, as during cardiopulmonary bypass, progressively increases sympathetic nerve activity, 35 leading to arterial vasoconstriction and increased SVR. 35 This increase in sympathetic nerve activity is attributable to suppression of baroreflex-mediated inhibition of the vasomotor centre and is associated with local parasympathetic activation 34 in an effort to preserve tissue perfusion. Mild hypercapnia during constant systemic blood flow did not increase tissue oxygenation; however, we cannot exclude the possibility of a differential action of CO 2 in regional vascular resistance, 36 which could have diverted systemic perfusion to areas other than s.c. tissues. 37 Our results provided data only from the s.c. tissue. If any perfusion improvements occurred because of a change in vascular resistance, we missed them because of a lack of monitoring. Potential redistribution cannot be excluded either.", "cite_spans": [{"start": 59, "end": 61, "text": "15", "ref_id": "BIBREF14"}, {"start": 377, "end": 379, "text": "18", "ref_id": "BIBREF17"}, {"start": 1466, "end": 1468, "text": "11", "ref_id": "BIBREF10"}, {"start": 1614, "end": 1616, "text": "34", "ref_id": "BIBREF33"}, {"start": 1806, "end": 1808, "text": "34", "ref_id": "BIBREF33"}, {"start": 2017, "end": 2019, "text": "35", "ref_id": "BIBREF34"}, {"start": 2076, "end": 2078, "text": "35", "ref_id": "BIBREF34"}, {"start": 2268, "end": 2270, "text": "34", "ref_id": "BIBREF33"}, {"start": 2513, "end": 2515, "text": "36", "ref_id": "BIBREF35"}, {"start": 2595, "end": 2597, "text": "37", "ref_id": "BIBREF36"}], "ref_spans": []}, {"section": "Discussion", "text": "In striking contrast to the unchanged s.c. oxygenation during constant systemic blood flow, mild hypercapnia markedly improved cerebral regional oxygen saturation. And the magnitude of the increase was similar to that we have previously observed in patients undergoing elective non-cardiac surgery. 31 This finding is consistent with the fact that sympathetic control of the cerebral vessels is weaker than of other vascular beds, 38 and the contractile state of the cerebrovascular smooth muscle appears to depend mainly on local metabolic factors including the partial pressure of CO 2 . Thus, the vasodilator effect of CO 2 is particularly marked in the cerebral circulation where a CO 2 concentration of 7-10% nearly doubles cerebral blood flow (CBF) in humans, 39 while mild hypercapnia (Pa CO 2 $50 mm Hg) impairs autoregulation of CBF and is associated with an overall increase in cerebral oxygenation. 11 40 A similar cerebrovascular response during cardiopulmonary bypass leads to an increase in CBF 41 that is associated with a reduction in cerebral oxygen consumption. 42 On the other hand, peripheral vasomotor tone during hypercapnia is essentially the result of a balance between the direct effects of CO 2 and the level of sympathetic activity. 38 Of course, because neither cerebral nor other vital organ blood flows were monitored in the study, it was not possible to exclude any role of redistribution of blood flow between the organ systems.", "cite_spans": [{"start": 299, "end": 301, "text": "31", "ref_id": "BIBREF30"}, {"start": 431, "end": 433, "text": "38", "ref_id": "BIBREF37"}, {"start": 766, "end": 768, "text": "39", "ref_id": "BIBREF38"}, {"start": 1009, "end": 1011, "text": "41", "ref_id": "BIBREF40"}, {"start": 1080, "end": 1082, "text": "42", "ref_id": "BIBREF41"}, {"start": 1260, "end": 1262, "text": "38", "ref_id": "BIBREF37"}], "ref_spans": []}, {"section": "Discussion", "text": "The mechanism by which CO 2 exerts its direct effects on the cerebral vasculature seems to involve nitric oxide (NO), ATP-sensitive potassium channels, and cyclooxygenasedependent pathways. The CO 2 -NO axis is considered a cardinal pathway for CBF regulation in humans. Thus, although ATP-sensitive and Ca", "cite_spans": [], "ref_spans": []}, {"section": "2+", "text": "-activated potassium channels are also major systems that respond to hypercapnic acidosis, their response is incomplete in the absence of NO donors. In both animals 43 and humans, 44 hypercapnic vasodilatation is mediated by inhibition of NO synthase-the enzyme responsible for NO synthesis. It is probable that the vasodilation to hypercapnic acidosis is mediated either by increased synthesis of NO or increased sensitivity to NO.", "cite_spans": [{"start": 165, "end": 167, "text": "43", "ref_id": "BIBREF42"}, {"start": 180, "end": 182, "text": "44", "ref_id": "BIBREF43"}], "ref_spans": []}, {"section": "2+", "text": "A secondary goal of our study was to compare a new fluoroscopic optode based oxygen-monitoring system (Foxy) with the current standard, polarographic electrode system (Licox). The fluorescence optode system is known to be more accurate in lower tissue oxygen environments than the polarographic one, because it does not consume oxygen. However, increased bias and impaired linearity of the relationship between the oxygen-monitoring systems when Psq O 2 was above 150 mm Hg indicates reduced accuracy of the fluorescence optode at high tissue oxygenation. Other drawbacks of the fluorescence method include substantial light sensitivity, sensitivity to movement and the lack of a small-calibre temperature probe. These limitations make its use in the clinical setting impractical.", "cite_spans": [], "ref_spans": []}, {"section": "2+", "text": "Another potential limitation of our study was that we allowed only a 30 min equilibration period at each designated arterial PCO 2 concentration. (A period of 30 min was chosen because the bypass period sometimes lasted only an hour.) However, 20-30 min is sufficient to obtain stable tissue oxygen values with tonometric systems that accommodate tissue oxygen probes. A further potential limitation of our study was that three of our 10 patients were obese and obesity is known to influence tissue oxygenation. 8 However, because of our crossover design, the effect on tissue oxygenation should have been the same at both concentrations of CO 2 . And lastly, we did not provide a positive control by increasing the bypass pump outflow during the study, which would have simulated increased cardiac output. Although we initially thought about putting this in our protocol, because we were working with patients as study subjects, we decided that it would be risky to include it. The clinical importance of the relationship between the bypass pump outflow and weaning the patient off the pump is just too fragile. In summary, mild hypercapnia-which normally markedly increases s.c. tissue oxygenation-failed to do so during cardiopulmonary bypass when the bypass pump controlled systemic blood flow. In contrast, cerebral oxygen saturation increased as usual. The increase in s.c. oxygen partial pressure that normally accompanies mild hypercapnia thus results largely from increased cardiac output and compensatory autonomic circulatory responses. 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"suffix": ""}], "year": 1997, "venue": "Am J Physiol", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Fig 2 Mean cerebral oximeter saturation values obtained at the end of 30 min normocapnia (35 mm Hg Pa CO2 ) and hypercapnia (50 mm Hg Pa CO2 ) periods. Cerebral oxygen saturation was significantly greater during hypercapnia (P=0.025).", "type": "figure"}, "FIGREF1": {"text": "Fig 4 Bland-Altman analysis comparing the polarographic electrode (Licox) and fluoroscopic optode (Foxy) systems. The bias (average difference of Foxy minus Licox method) is plotted on the y-axis and the average of the Foxy and Licox values is plotted on the x-axis. The centre line represents the bias [6.8 (15.0)] whereas the top and bottom lines represent \u00b12 SDs of the bias.", "type": "figure"}, "TABREF0": {"text": "Patient characteristics and potential confounding factors. Data pre- sented as means (range or SDs) or actual values. *SI units [conventional units]Although the relationship is not known to be linear, s.c. oxygen partial pressure (Psq O 2 ) was approximately one-third that of the Pa O 2 (%120 mm Hg vs 365 mm Hg). Psq O 2 during normocapnia (PCO 2 of 35 mm Hg) was similar to that during hypercapnia (PCO 2 of 50 mm Hg), whether measured by the Licox or Foxy system (Table 2 and", "type": "table"}, "TABREF1": {"text": "Major outcomes with normocapnia and hypercapnia during cardiopul- monary bypass. Data presented as means (SDs) and median [range]; paired two-tailed t-tests were used to compare values for each 30 min crossover period except where asterisk (*) denotes Wilcoxon signed-rank test was used. Licox PsqO", "type": "table"}}}
{"paper_id": "17780241", "_pdf_hash": "d466fabed53c31d9325ae02da5b4c9ba8170c233", "abstract": [{"section": "Abstract", "text": "We here give a brief survey of our new many-body theory for composite excitons, as well as some of the results we have already obtained using it. In view of them, we conclude that, in order to fully trust the results one finds, interacting excitons should not be bosonized: Indeed, all effective bosonic Hamiltonians (even the hermitian ones !) can miss terms as large as the ones they generate; they can even miss the dominant term, as in problems dealing with optical nonlinearities.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "We have recently developed a new many-body theory for interacting composite bosons [1] [2] [3] [4] [5] [6] [7] [8] , which is actually an important break-through: Indeed, up to now, the existing many-body theories were appropriate to interactions between fermions or bosons [9] [10] [11] .", "cite_spans": [{"start": 274, "end": 277, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 278, "end": 282, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 283, "end": 287, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "", "text": "Although essentially all bosons known in physics are composite bosons, there were no many-body procedures adapted to them, most probably because it is far more subtil to handle composite bosons properly than to handle true bosons or true fermions.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "In order to \"do something\" in problems in which interactions between composite bosons obviously play a role, it is a common practice to replace composite bosons by true bosons, provided that their interactions are \"dressed by exchange\" -which is considered as a way to take care of their composite nature. The production of such effective bosonic Hamiltonians is the aim of the wide literature on bosonization [12, 13] .", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "This pragmatic idea is after all perfectly acceptable. The real (major) trouble in semiconductor physics, is that the effective bosonic Hamiltonian which has been produced [14, 15] -and widely used -to treat interactions between excitons, should have been rejected long ago because it is not even hermitian: This failure, which comes from unconsistent manipulations in producing this effective Hamiltonian, has apparently been missed by everyone for 35 years ! As we were the first to point it out, it is easy to understand why our new theory for interacting composite excitons has not been welcomed by the experts in the field.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "With a first line -the Hamiltonian -physically unacceptable, there is no reason for the last line -the deduced results -to be correct, except if some cancellations in the missed terms miraculously take place. Unfortunately, they don't ! Even if hermiticity is forced -which is always possible -essentially the same amount of terms is missing. In all the physical quantities we have studied up to now using our new theory for composite excitons, the missed terms are as large as the ones which appear. In some cases, in particular the ones in which photons are involved, i. e., in optical nonlinearities, the missed terms can even be the dominant ones, as obvious from a dimensional argument explained below.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Excitons are deeply made of two fermions; there is no way to get rid of their composite nature, as we do when we bosonize them.", "cite_spans": [], "ref_spans": []}, {"section": "Survey of our new many-body theory", "text": "Our new many-body theory for composite bosons relies on four nicely simple commu-tators [1, 3] :", "cite_spans": [], "ref_spans": []}, {"section": "Survey of our new many-body theory", "text": "To calculate these matrix elements, we first push f (H) to the right, to end with f (H)|v = f (0)|v , if the vacuum energy is taken as zero. This is done using eq. (1). In the simplest case, f (H) = H, we have", "cite_spans": [], "ref_spans": []}, {"section": "Survey of our new many-body theory", "text": "V \u2020 i being then pushed to the right according to eq. (2). Another f (H) of interest can be (a \u2212 H) \u22121 . It appears in correlation effects or in optical nonlinearities, a then being (\u03c9 + i\u03b7). In this case, we use [4]", "cite_spans": [], "ref_spans": []}, {"section": "Survey of our new many-body theory", "text": "which follows from eq. (1), as easy to show by multiplying eq. (10) by (a \u2212 H) on the left", "cite_spans": [], "ref_spans": []}, {"section": "Survey of our new many-body theory", "text": "It appears in problems dealing with time evolution. We then use [16] ", "cite_spans": [], "ref_spans": []}, {"section": "Survey of our new many-body theory", "text": "which follows from eq. (10) when inserted in the integral representation of the exponential,", "cite_spans": [], "ref_spans": []}, {"section": "Survey of our new many-body theory", "text": "valid for t and \u03b7 positive.", "cite_spans": [], "ref_spans": []}, {"section": "Survey of our new many-body theory", "text": "Once f (H) is pushed to the right, we start pushing the B's to the right, according to eqs. (3, 4) , to end with B m |v = 0 and D mi |v = 0, which follows from eq. (4) applied to |v .", "cite_spans": [], "ref_spans": []}, {"section": "Survey of our new many-body theory", "text": "In problems dealing with many excitons, most of them are usually in the same state 0. It is then convenient to note that the iteration of eqs. (1,4) leads to [17] H, B \u2020N 0", "cite_spans": [], "ref_spans": []}, {"section": "Survey of our new many-body theory", "text": "The real -challenging -difficulties in problems dealing with interacting excitons, is not so much the calculation of these matrix elements, which after all, can be tedious but ", "cite_spans": [], "ref_spans": []}, {"section": "Survey of our new many-body theory", "text": "Since the electrons (holes) are undistinguishable, there is no way to know ! Actually, the quantity V \u2020 i , defined in eq. (1), plays the role of this interacting potential. It however has the dimension of a pair creation operator, this is why we have called it \"Coulomb creation potential\". To support this idea, we can note that the first terms of the right hand side of eqs. (9,10,11), which contain (H + E i ), are in fact the \"zero order terms\" of the left hand side of these equations, i. e., the terms in the absence of Coulomb interaction between the exciton i and the rest of the system.", "cite_spans": [], "ref_spans": []}, {"section": "Survey of our new many-body theory", "text": "The real difficulty to get the physics of interacting excitons, is thus to write the quantities we look for, not in terms of V , as we usually do, but in terms of the Hamiltonian H. The Hamiltonian a priori contains all the necessary informations on the interactions existing in the system. Consequently, even if this may not appear as obvious at first, there should be a way to write all quantities dealing with interacting excitons in terms of H only. (Note that, since there is no V , there is no H 0 -because its existence would mean that we could define V -so that there is no \"unperturbed state\" |0 ).", "cite_spans": [], "ref_spans": []}, {"section": "Survey of our new many-body theory", "text": "As an example of such a possible new writing, we have recently considered the lifetime and scattering rates of excitons [18] . In the usual case, when H = H 0 + V , they are given by the Fermi golden rule, which reads in terms of V . We have shown that the lifetime of an initial state |\u03c8 0 can also be written as", "cite_spans": [], "ref_spans": []}, {"section": "Survey of our new many-body theory", "text": "being the usual delta function of width (2/t). It is easy to check that, for H = H 0 + V and |\u03c8 0 = |0 , with (H \u2212 E n )|n = 0, the Fermi golden rule follows from eq. (15): Indeed, as\u0124|\u03c8 0 = (1 \u2212 |0 0|) V |0 is just n =0 |n |V |0 , we do recover", "cite_spans": [], "ref_spans": []}, {"section": "Survey of our new many-body theory", "text": "Diagrams associated to this new many-body theory", "cite_spans": [], "ref_spans": []}, {"section": "Survey of our new many-body theory", "text": "The construction of a new many-body theory has for final goal, to write all processes in which enter interactions, at any order. Of course, to reach this goal, we always start in a pedestrian way, by generating the corresponding terms, through some kind of recursion procedure, in order to obtain their mathematical expressions. However, if we go to high orders, most of the time, these expressions become so complicated that we do not \"see\"", "cite_spans": [], "ref_spans": []}, {"section": "Survey of our new many-body theory", "text": "their physical meaning anymore. This is why many-body theories are usually associated to diagrams which are just the visual representation of these mathematical quantities.", "cite_spans": [], "ref_spans": []}, {"section": "Survey of our new many-body theory", "text": "These diagrams are really useful because they allow to \"see\" the physics involved in the corresponding terms, in an easy way.", "cite_spans": [], "ref_spans": []}, {"section": "Survey of our new many-body theory", "text": "In our new many-body theory for interacting excitons, enter two conceptually different Using eq. (14), we can in particular show that", "cite_spans": [], "ref_spans": []}, {"section": "Survey of our new many-body theory", "text": "where A (N ) 00 = N!F N has already been calculated in references [5, 7] , while C (N ) mi is given by ", "cite_spans": [], "ref_spans": []}, {"section": "Survey of our new many-body theory", "text": "Its replacement by", "cite_spans": [], "ref_spans": []}, {"section": "Survey of our new many-body theory", "text": "would have allowed the effective Hamiltonian to be at least hermitian.", "cite_spans": [], "ref_spans": []}, {"section": "Survey of our new many-body theory", "text": "This hermiticity is however not enough to get correct results on interacting excitons, because \u03be dir and \u03bb e,h are conceptually independent scatterings: They may appear in many other ways than the ones written in eqs. (19, 20) . In particular, in problems dealing with photons, \u03bb e,h can appear alone [16, 19] , so that the corresponding terms are simply missed by any effective bosonic Hamiltonian, whatever these scatterings are. Indeed, V mnij must have the dimension of an energy, while \u03bb e,h is dimensionless. Moreover, Coulomb processes which may enter these physical effects, have to appear with energy denominators, in order to have the same dimension as the pure Pauli terms, which contain \u03bb e,h only. In problems dealing with photons, these energies are in fact the exciton detunings, so that the Coulomb processes are negligible in front of the pure Pauli terms -missed by the effective bosonic", "cite_spans": [], "ref_spans": []}, {"section": "Survey of our new many-body theory", "text": "Hamiltonians -in the large detuning limit.", "cite_spans": [], "ref_spans": []}, {"section": "2) Scattering rates and lifetime of excitons", "text": "We have shown that the lifetime of an exciton state in which all the excitons are in the same state 0, is related to the scattering rates towards other exciton states in which two excitons differ from 0, by the relation [18] ", "cite_spans": [], "ref_spans": []}, {"section": "2) Scattering rates and lifetime of excitons", "text": "where \u03b1 = 1 if the excitons are bosonized and \u03b1 = 1/2 if their composite nature is kept. This shows that it is impossible to find effective scatterings for the effective bosonic", "cite_spans": [], "ref_spans": []}, {"section": "2) Scattering rates and lifetime of excitons", "text": "Hamiltonian, giving both the lifetime and scattering rates correctly.", "cite_spans": [], "ref_spans": []}, {"section": "2) Scattering rates and lifetime of excitons", "text": "This type of sum rule comes from closure relation. We have shown that, while the one for bosonized excitons is of course the standard closure relation for elementary particles,", "cite_spans": [], "ref_spans": []}, {"section": "2) Scattering rates and lifetime of excitons", "text": "a closure relation also exists for composite excitons, in spite of the fact that these states form a non-orthogonal overcomplete set [20] . It actually reads [21] ", "cite_spans": [], "ref_spans": []}, {"section": "2) Scattering rates and lifetime of excitons", "text": "Consequently, all sum rules will appear differently for exact and boson excitons, making the corresponding quantities irretrievably different.", "cite_spans": [], "ref_spans": []}, {"section": "2) Scattering rates and lifetime of excitons", "text": "3) The trion as an exciton interacting with a carrier", "cite_spans": [], "ref_spans": []}, {"section": "2) Scattering rates and lifetime of excitons", "text": "This new many-body theory for excitons interacting with excitons can be adapted to excitons interacting with free carriers [22] [23] [24] .", "cite_spans": [], "ref_spans": []}, {"section": "2) Scattering rates and lifetime of excitons", "text": "The simplest of these problems is surely the trion: The exciton interacts with one electron either by Coulomb interaction or by electron exchange. Using this approach, we can calculate the trion oscillator strength in a quite easy way [25] . We have shown that it is one exciton volume divided by one sample volume smaller than the exciton one, making the trion impossible to see in the linear response of a macroscopic semiconductor sample.", "cite_spans": [{"start": 235, "end": 239, "text": "[25]", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "2) Scattering rates and lifetime of excitons", "text": "This approach should allow us to face the much harder problem of the linear response of a doped semiconductor quantum well. Our old work on this problem [26] is quite unsatisfactory, not at all because Coulomb screening is missing, but because the electronelectron repulsion has been neglected. In order to include it, i. e., in order to study the rearrangement of a Fermi sea to the sudden appearance of an exciton -not simply to a hole, as we did -we have to handle not only Coulomb interaction between the exciton and the Fermi sea electrons, but also all possible electron exchanges. This again makes our new many-body theory for interacting excitons rather unavoidable.", "cite_spans": [], "ref_spans": []}, {"section": "4) Optical nonlinearities", "text": "The optical nonlinearities come from interactions with the virtual excitations induced in the matter by the photons. In the case of semiconductors, these excitations are the excitons. Consequently, in order to derive the optical nonlinearities in semiconductors properly, it is necessary to know how to handle interactions between excitons in a secure way. This is why our new many-body theory for composite excitons is going to be all the most useful for semiconductor optical nonlinearities.", "cite_spans": [], "ref_spans": []}, {"section": "4) Optical nonlinearities", "text": "We have first reconsidered the calculation of the third order susceptibility \u03c7 (3) [16] .", "cite_spans": [], "ref_spans": []}, {"section": "4) Optical nonlinearities", "text": "This calculation contains a major difficulty, unsolved before our work, which comes from the fact that \u03c7 (3) appears as the sum of 16 terms which all increase linearly with the sample volume. Of course, as the susceptibility is an intensive quantity, these volume-linear terms have to cancel. However, this cancellation has to be shown very carefully in order to get the correct volume-free terms which remain once the volume-linear terms are removed.", "cite_spans": [], "ref_spans": []}, {"section": "4) Optical nonlinearities", "text": "Our many-body theory allows to calculate these 16 terms explicitly and to combine them in order to show that the volume-linear terms do disappear as expected. However, this clean cancellation in fact generates volume-free terms missed by the previous approaches, which come from pure Pauli interactions between the virtual excitons coupled to the photons. Again, these missed pure Pauli terms are the dominant ones at large detuning.", "cite_spans": [], "ref_spans": []}, {"section": "4) Optical nonlinearities", "text": "Another nonlinear effect in semiconductor physics is the exciton optical Stark effect [27] . The seeds of our new many-body theory were actually in our old works on this effect, in particular the Coulomb creation potential V \u2020 i . The introduction of the two scatterings \u03be dir and \u03bb e,h however make the study of this exciton optical Stark effect quite easy, in particular if we are interested in subtle polarization effects.", "cite_spans": [], "ref_spans": []}, {"section": "4) Optical nonlinearities", "text": "Our many-body theory is also very convenient to study spin manipulations by laser pulse [19] . We have recently predicted the spin precession of an electron bound to an impurity, when the sample is irradiated by a pump beam tuned in the transparency region. This precession, which is due to exchanges between the electron bound to the impurity and the electron of the virtual exciton coupled to the pump photon, lasts as long as the laser pulse, so that it can be used for ultrafast spin manipulation.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "\u2022 We have developed a new many-body theory adapted to interactions between composite excitons.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "\u2022 It relies on two \"scatterings\": One is associated to Coulomb processes, the other is associated to carrier exchanges induced by Pauli exclusion. This Pauli scattering can appear alone or mixed with Coulomb processes, in many more subtle ways than the one appearing in the effective bosonic Hamiltonian for excitons. When it appears alone, the corresponding terms are a priori missed by the effective bosonic Hamiltonians, whatever are the scatterings they use. These missed terms are often the dominant ones, due to dimensional arguments.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "\u2022 We have generated a diagrammatic representation of this theory. The direct Coulomb scattering gives rise to diagrams similar to the Feynman diagrams. On the opposite, the Pauli scattering gives rise to diagrams which are conceptually new: Pauli exclusion being N-body \"at once\", the corresponding \"skeleton Pauli diagrams\" show all possible carrier exchanges between 2,3,4. . . excitons, in a quite transparent way.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "\u2022 This new many-body theory is going to be of great interest for all problems dealing with interactions between excitons and between excitons and free carriers, as well as for all optical nonlinearities in semiconductors, because, for the first time, it allows a clean treatment of the possible carrier exchanges.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "\u2022 This new theory is also going to be of importance in many other fields than semiconductor physics, because essentially all particles considered as bosons, are in fact composite bosons. 2 , the sign being linked to the parity of the number of carrier exchanges, as usual.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF8": {"title": "Methods of quantum field theory in statistical physics", "authors": [{"first": "A", "middle": [], "last": "Abrikosov", "suffix": ""}, {"first": "L", "middle": [], "last": "Gorkov", "suffix": ""}, {"first": "I", "middle": [], "last": "Dzyaloshinski", "suffix": ""}], "year": 1963, "venue": "", "link": null}, "BIBREF9": {"title": "Quantum theory of many-particle systems", "authors": [{"first": "A", "middle": [], "last": "Fetter", "suffix": ""}, {"first": "J", "middle": [], "last": "Walecka", "suffix": ""}], "year": 1971, "venue": "", "link": null}, "BIBREF10": {"title": "Many-particle Physics", "authors": [{"first": "G", "middle": [], "last": "Mahan", "suffix": ""}], "year": 1990, "venue": "", "link": "123137466"}, "BIBREF24": {"title": "Solid State Com", "authors": [{"first": "M", "middle": [], "last": "Combescot", "suffix": ""}, {"first": "J", "middle": [], "last": "Tribollet", "suffix": ""}], "year": 2003, "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "the Coulomb scattering between free carriers. It gives rise to diagrams which look very much like the Feynman diagrams. On the opposite, the Pauli scatterings,the conceptually new part of our theory. Although they appear as scatterings between two excitons (i, j), transforming them into (m, n), they originate from Pauli exclusion, which makes the excitons close-to-bosons only, as can be seen from eqs. (3,4). However, Pauli exclusion being N-body \"at once\" -an additional exciton having to be made with carriers in states different from all the ones involved in the excitons already present -it is clear that these Pauli scatterings between two excitons only, cannot be the quantities which appear at the end, in physical effects in which N excitons are involved. Nevertheless, they are quite convenient in the intermediate stages of the theory, because they allow to write recursion relations between scalar products of N, (N \u2212 1), (N \u2212 2), \u00b7 \u00b7 \u00b7 exciton states.", "type": "figure"}, "FIGREF1": {"text": "If we iterate this equation and perform the sums over the dumb indices (p, j, . . .), through closure relations, we end with the \"skeleton Pauli diagrams\" [8] shown in fig.2. This figure essentially says that the scalar product of one exciton m along with (N \u22121) excitons 0 on the left, and one exciton i along with (N \u2212 1) excitons 0 on the right, can be separated into a term in which the excitons 0 do not play any role, and terms in which one, two, . . . excitons 0 out of N, exchange their carriers with the excitons m and i, in any possible way. The N-dependent prefactors are just the number of ways to choose these excitons 0 among (N \u2212 1), on each side, while the sign is related to the parity of the number of exchanges involved in the diagram, as usual. This diagrammatic representation of the matrix element of N-exciton states with one exciton different from 0 on each side, can be extended to any other scalar products [17] having more than one exciton different from 0. Although this extension may appear as reasonable, it did not appear to us obvious, at first ! It in fact relies on heavy calculations which use recursion relations similar to the one of eq. (17). This \"reasonable\" extension has actually been made possible due to the introduction of the \"skeleton Pauli diagrams\" [8], which allow to get rid of the relative positions of the Pauli scatterings \u03bb mnij , and which make disappearing all the awkward factors 2 due to \u03bb e (these \"skeleton Pauli diagrams\", in which can possibly enter some additional direct Coulomb scatterings between two exciton lines, due to possible H contributions to the matrix elements of interest, we can represent any quantity we wish, dealing with interacting excitons, in a transparent way. Some applications of this new many-body theory We have used this new many-body theory in a few problems in which interacting excitons are involved: 1) Link with the effective bosonic Hamiltonian for excitons In order to make the link with the results obtained from the usual effective bosonic Hamiltonian for excitons, we have shown [1] that the scattering V mnij which appears in the interaction term of this Hamiltonian, (1/2) mnij V mnijB \u2020 mB \u2020 nB iBj , where theB i", "type": "figure"}, "FIGREF2": {"text": "Figure 1: (a) Direct Coulomb scattering \u03be dir n m j i between the \"in\" excitons (i, j) and the \"out\"", "type": "figure"}}}
{"paper_id": "17780285", "_pdf_hash": "2647fefadefa1d0feb239500e53004cfccac3243", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "17780609", "_pdf_hash": "a605667d6feebbdfc49ab4c7338ac41ae64d6802", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Designing a Dynamometer Test Stand with an Emulated Gasoline/Diesel Engine Power Source: A White Paper", "authors": [{"first": "B", "middle": ["T"], "last": "Boulter", "suffix": ""}], "year": 2000, "venue": "ApICS LLC", "link": null}, "BIBREF1": {"title": "Laboratory Set-up for Wind Turbine Emulation", "authors": [{"first": "M", "middle": [], "last": "Chinchilla", "suffix": ""}, {"first": "S", "middle": [], "last": "Arnaltes", "suffix": ""}, {"first": "J", "middle": ["L"], "last": "Rodriguesamenedo", "suffix": ""}], "year": 2004, "venue": "Proc. of 2004 IEEE International Conference on Industrial Technology", "link": "28893608"}, "BIBREF2": {"title": "Real-Time Wind Turbine Emulator Suitable for Power Quality and Dynamic Control Studies", "authors": [{"first": "D", "middle": [], "last": "Dolan", "suffix": ""}, {"first": "P", "middle": ["W"], "last": "Lehn", "suffix": ""}], "year": 2005, "venue": "Proc. of International Conference on Power Systems Transients", "link": null}, "BIBREF3": {"title": "A Multilanguage Environment for Interactive Simulation and Development of Controls for Power Electronics", "authors": [{"first": "R", "middle": ["A"], "last": "Dougal", "suffix": ""}, {"first": "T", "middle": [], "last": "Lovett", "suffix": ""}, {"first": "A", "middle": [], "last": "Monti", "suffix": ""}, {"first": "E", "middle": [], "last": "Santi", "suffix": ""}], "year": 2001, "venue": "IEEE PESC", "link": "18456448"}, "BIBREF5": {"title": "Digital Control of Dynamic Systems", "authors": [{"first": "L", "middle": [], "last": "Workman", "suffix": ""}], "year": 1997, "venue": "", "link": "53911820"}, "BIBREF6": {"title": "Fundamentals of Fluid Mechanics", "authors": [{"first": "P", "middle": ["R"], "last": "Gerhart", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Gross", "suffix": ""}, {"first": "J", "middle": ["I"], "last": "Hochstein", "suffix": ""}], "year": 1992, "venue": "", "link": null}, "BIBREF7": {"title": "Fundamental of Engineering Thermodynamics", "authors": [{"first": "M", "middle": ["J"], "last": "Moran", "suffix": ""}, {"first": "H", "middle": ["N"], "last": "Shapiro", "suffix": ""}, {"first": "J", "middle": ["I"], "last": "Hochstein", "suffix": ""}], "year": 2000, "venue": "", "link": null}, "BIBREF8": {"title": "Digital Control of Electrical Drives", "authors": [{"first": "S", "middle": ["N"], "last": "Vukosavi\u0107", "suffix": ""}], "year": 2007, "venue": "", "link": "107151459"}}, "ref_entries": {}}
{"paper_id": "17780768", "_pdf_hash": "7ce9e5cc008c95e665b518e5b7436cbfede3060d", "abstract": [{"section": "Abstract", "text": "Motivation: Many RNAs, such as riboswitches, can fold into multiple alternate structures and perform different biological functions. These biologically functional structures usually have low free energies in their local energy landscapes and are very stable such that they cannot easily jump out of the current states and fold into other stable conformations. The conformational space of feasible RNA secondary structures is prohibitively large, and accurate prediction of functional structure conformations is challenging. Because the stability of an RNA secondary structure is determined predominantly by energetically favorable helical regions (stacks), we propose to use configurations of putative stacks to represent RNA secondary structures. By considering a reduced conformational space of local optimal stack configurations instead of all feasible RNA structures, we first present an algorithm for enumerating all possible local optimal stack configurations. In addition, we present a fast heuristic algorithm for approximating energy barriers encountered during folding pathways between each pair of local optimal stack configurations and finding all the stable local optimal structures. Results: Benchmark tests have been conducted on several RNA riboswitches, whose alternate secondary structures have been experimentally verified. The benchmark results show that our method can successfully predict the native 'on' and 'off' secondary structures, and better rank them compared with other state-of-art approaches.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION", "text": "RNA molecules play important roles in many biological activities. The structures of RNAs are key to understanding their functionalities. The native secondary structures of RNA molecules are usually the minimum free energy (MFE) structures. However, many regulatory RNAs may form multiple alternate metastable structures, each of which, performs a different function (Baumstark et al., 1997; Schultes and Bartel, 2000) . For example, the cis-regulatory RNAs (called as riboswitches) are widely present at the non-coding regions of mRNAs in bacteria, and regulate both transcriptional and translational expression of their cognate * To whom correspondence should be addressed. metabolic genes and thus comprise a metabolite-sensing system. Riboswitches can selectively bind with small metabolites and form alternative structure conformations, in order to exert control over translation initiation or formation of a transcription terminator (or an anti-terminator) helix and thus turn 'off' (or 'on') the gene transcription (Mandal and Breaker, 2004; Wakeman et al., 2007) .", "cite_spans": [{"start": 366, "end": 390, "text": "(Baumstark et al., 1997;", "ref_id": "BIBREF2"}, {"start": 391, "end": 417, "text": "Schultes and Bartel, 2000)", "ref_id": "BIBREF32"}, {"start": 1021, "end": 1047, "text": "(Mandal and Breaker, 2004;", "ref_id": "BIBREF20"}, {"start": 1048, "end": 1069, "text": "Wakeman et al., 2007)", "ref_id": "BIBREF39"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "Alternate structure conformations of RNA riboswitches can be experimentally verified using in-line probing (Mandal and Breaker, 2004) , X-ray crystallography (Batey et al., 2004) or Nuclear Magnetic Resonance (NMR) spectroscopy (Noeske et al., 2005) . However, these methods are usually time consuming and expensive. Computational approaches for accurately predicting alternate conformations are in need. The alternate functional structures are usually also energetically favored and are stable in their local energy landscapes. The conformational transitions between any pair of alternate structures may involve high-energy barriers, such that RNAs can easily become kinetically trapped by these structures. Accurate predictions of alternate structures of an RNA molecule should be conducted by exploiting the energy landscape and the folding dynamics of the RNA, in combination with the binding of the target metabolites. The ideal approach is to construct an exact energy landscape on all possible suboptimal secondary structures, then analyze every possible local optimal structures as well as all possible folding pathways in the landscape, and finally determine the most significant structures. In the following, we will briefly review existing methods for enumerating suboptimal structures and predicting alternate structures for RNA molecules. Zuker (1989) devised the first algorithm, mfold, for predicting the MFE structure and multiple suboptimal structures. For a given sequence, it generates, for each admissible base pair, the energetically best structure containing that base pair. For a sequence of length n, mfold produces at most n(n\u22121)/2 suboptimal structures, which are a very small fraction of all the candidate suboptimal structures, and may miss some of the functional structures. In addition, mfold uses a filter based on the base pair metric to remove structures that are similar to one another. The filter is based on base pair difference, while it might be better to infer stability of structures in the context of energy landscape and remove unstable structures. Wuchty et al. (1999) proposed the first exact solution, RNAsubopt, for predicting all possible suboptimal structures between the MFE and an arbitrary upper limit using a mathematical model proposed by Waterman and Byers (1985) based on the Turner energy model (Freier et al., 1986; He et al., 1991; Jaeger et al., 1989; Turner et al., 1988) . Parisien and Major (2008) devised MC-Fold, a similar solution to the same problem that takes into account both non-canonical base pairings and pseudoknotted structures. In addition, Flamm et al. (2002) presented BARRIERS, an algorithm for constructing the exact energy landscape on all possible suboptimal structures produced by RNAsubopt. BARRIERS is able to distinguish all the local optimal structures and can build a barrier tree representing the energy landscape. However, the number of feasible structures grows quickly with the length of the RNA sequence and the energy range, and RNAsubopt enumerates enormous solutions for even a short sequence with a small energy range. For example, the free energies of the native 'off' and 'on' structures of the 110 nt long adenine riboswitch of ydhL from B.subtilis are \u221232.3 and \u221214.8 (kcal/mol), respectively. The number of feasible structures grows quickly as free energy increases (which is shown in Supplementary Figure S1) , and the number of structures with free energies between the two native structures exceeds 10 9 . Therefore, it is very difficult and time consuming to find a few alternate structures from an enormous collection of candidates. Applications of these algorithms are generally limited to very short RNA sequences with a small energy range.", "cite_spans": [{"start": 107, "end": 133, "text": "(Mandal and Breaker, 2004)", "ref_id": "BIBREF20"}, {"start": 158, "end": 178, "text": "(Batey et al., 2004)", "ref_id": "BIBREF1"}, {"start": 228, "end": 249, "text": "(Noeske et al., 2005)", "ref_id": "BIBREF27"}, {"start": 1352, "end": 1364, "text": "Zuker (1989)", "ref_id": "BIBREF45"}, {"start": 2091, "end": 2111, "text": "Wuchty et al. (1999)", "ref_id": "BIBREF41"}, {"start": 2292, "end": 2317, "text": "Waterman and Byers (1985)", "ref_id": "BIBREF40"}, {"start": 2351, "end": 2372, "text": "(Freier et al., 1986;", "ref_id": "BIBREF10"}, {"start": 2373, "end": 2389, "text": "He et al., 1991;", "ref_id": "BIBREF13"}, {"start": 2390, "end": 2410, "text": "Jaeger et al., 1989;", "ref_id": "BIBREF16"}, {"start": 2411, "end": 2431, "text": "Turner et al., 1988)", "ref_id": "BIBREF37"}, {"start": 2434, "end": 2459, "text": "Parisien and Major (2008)", "ref_id": "BIBREF29"}, {"start": 2616, "end": 2635, "text": "Flamm et al. (2002)", "ref_id": "BIBREF9"}], "ref_spans": [{"start": 3386, "end": 3410, "text": "Supplementary Figure S1)", "ref_id": "FIGREF0"}]}, {"section": "INTRODUCTION", "text": "The conformational space of feasible structures not only is prohibitively large, but also renders redundant information, because many structures in the space are similar to one other. Thus, researchers have also proposed alternative approaches, which investigate reduced conformational spaces instead of the space of feasible suboptimal structures. Pipas and McMahon (1975) presented an algorithm that can construct the best k structures composed of compatible stacks (i.e. sharing no base in common and forming no pseudoknot). Nakaya et al. (1996) used a search tree for generating suboptimal structures by selecting a subset of stacking regions that can coexist, from the set of all possible stacking regions. The search tree is composed of m level of nodes, where m is the number of possible stacks and nodes at depth i determine whether the i-th stacking region is selected. Evers and Giegerich (2001) provided an algorithm that can enumerate all possible saturated structures such that no unpaired base can be paired without affecting the validity of the structures (Zuker, 1984) . They employed a dynamic programming similar to that of Wuchty et al. (1999) and incorporated a saturation check to ensure that structures are saturated. Giegerich and his cooperators also presented RNAShapes (Giegerich et al., 2004; Steffen et al., 2006) , an approach that first extracts RNA abstract shapes based on juxtaposition and embedding of stacks, and then clusters structures with the same shape together, and finally represents all the structures in a cluster by the 'shrep' of the cluster (i.e. the secondary structure with the lowest free energy in the cluster). One shortcoming of the stack-based approaches is that they may exclude incompatible stacks that overlap by only one or a few bases. If we consider shortening one of the stacks by cutting off the overlapping bases, it will result in a pair of compatible stacks. Another drawback of these approaches is that it is hard to infer the stability of RNA secondary structures in the context of energy landscape and thus is hard to accurately predict native structures. Recently, Lorenz and Clote (2011) proposed an approach, RNAlocopt, that can sample a user-defined number of structures from the space of locally optimal structures. A locally optimal structure has the lowest free energy compared with its neighboring structures (obtained by adding or deleting a single base pair). One shortcoming is that when the sample size is small, RNAlocopt may fail to predict the native structures, and when the sample size is large, it would be difficult to identify the significant structures from a large number of candidates.", "cite_spans": [{"start": 349, "end": 373, "text": "Pipas and McMahon (1975)", "ref_id": "BIBREF30"}, {"start": 528, "end": 548, "text": "Nakaya et al. (1996)", "ref_id": "BIBREF26"}, {"start": 879, "end": 905, "text": "Evers and Giegerich (2001)", "ref_id": "BIBREF7"}, {"start": 1071, "end": 1084, "text": "(Zuker, 1984)", "ref_id": "BIBREF44"}, {"start": 1142, "end": 1162, "text": "Wuchty et al. (1999)", "ref_id": "BIBREF41"}, {"start": 1295, "end": 1319, "text": "(Giegerich et al., 2004;", "ref_id": "BIBREF12"}, {"start": 1320, "end": 1341, "text": "Steffen et al., 2006)", "ref_id": "BIBREF35"}, {"start": 2134, "end": 2157, "text": "Lorenz and Clote (2011)", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "We are interested in finding stable local optimal (SLOpt) structures that conform to the following criteria. First, a SLOpt structure should be local optimal (LOpt) in that it resides at the bottom of a basin in the energy landscape (i.e. has the lowest free energy compared with all its neighbors). None local optimal structures are unlikely to be biologically functional, because they can continuously transit to their lower energy neighboring structures, like climbing down a hill until a local optimum (the bottom of a basin in the energy landscape) is reached. Second, a SLOpt structure should be stable in that the minimal energy barrier between this structure and any other SLOpt structures should be high. This criterion is proposed because secondary structures with lower free energies are not guaranteed to be more stable than those with higher energies. This criterion ensures that the RNA molecule can be 'trapped' by the energy basin where the SLOpt structure resides, without being able to getting out of the basin easily. Figure 1 illustrates a schematic representation of the energy landscape of an RNA molecule. Each LOpt structure (e.g. the local optimum, number 5) can represent a set of none LOpt structures in its associated energy basin (e.g. the dot). In addition, although both 1 and 3 are local optima and 1 has even lower energy than 3, 1 is still less stable. This is because the conformational transition from 1 to 2 involves a lower energy barrier, while the transitions from 3 to any lower free energy LOpt structures yield higher energy barriers.", "cite_spans": [], "ref_spans": [{"start": 1037, "end": 1045, "text": "Figure 1", "ref_id": "FIGREF0"}]}, {"section": "INTRODUCTION", "text": "We formalize the problem as follows: given an RNA sequence A, an energy range E and an energy barrier cutoff B, find all the stable and local optimal structures, of which (i) the free energies are within E of the MFE and (ii) the minimal energy barrier between any pair of SLOpt structures is \u2265 B. We will describe our approach (RNASLOpt) for addressing the problem in Section 2. In Section 3, we will compare RNASLOpt against the state-ofart methods and show benchmark tests on known riboswitches. In Section 4, we will discuss possible applications of our approach and conclude the article.", "cite_spans": [], "ref_spans": []}, {"section": "METHODS", "text": "First, we introduce configurations of stacks to represent scaffolds of RNA secondary structures. RNA secondary structures involve both stacking base pairs and isolated base pairs, where stacking base pairs contribute significantly to the stabilization of RNA secondary structures (Yakovchuk et al., 2006) . Structures with isolated base pairs are usually unrealistic and the removal of these structures from the search space may yield more significant structures (Zuker, 1989) . Since LOpt structures reside at bottoms of basins in the energy landscape, and each can represent a set of similar secondary structures, we introduce LOpt stack configurations to approximate LOpt structures. LOpt stack configurations are configurations that have a maximal number of putative stacks such that no stacks can be added rendering lower energy structures. We then present algorithms for finding all possible LOpt stack configurations based on both the Nussinov model (Nussinov et al., 1978) and the Turner energy model (Freier et al., 1986; He et al., 1991; Jaeger et al., 1989; Mathews et al., 1999; Turner et al., 1988) , using the mathematical scheme advocated by Wuchty et al. (1999) . Next, we describe a fast heuristic algorithm for computing pairwise energy barriers among LOpt stack configurations. The energy barrier between a pair of LOpt stack configurations indicates the amount of additional energy required for the RNA molecule to fold from one structure to the other, and can be used to filter out unstable LOpt structures. Finally, we employ a simple neighbor joining algorithm to cluster unstable LOpt structures, obtain stable local optimal structures and assign rank accordingly.", "cite_spans": [{"start": 280, "end": 304, "text": "(Yakovchuk et al., 2006)", "ref_id": "BIBREF42"}, {"start": 463, "end": 476, "text": "(Zuker, 1989)", "ref_id": "BIBREF45"}, {"start": 957, "end": 980, "text": "(Nussinov et al., 1978)", "ref_id": "BIBREF28"}, {"start": 1009, "end": 1030, "text": "(Freier et al., 1986;", "ref_id": "BIBREF10"}, {"start": 1031, "end": 1047, "text": "He et al., 1991;", "ref_id": "BIBREF13"}, {"start": 1048, "end": 1068, "text": "Jaeger et al., 1989;", "ref_id": "BIBREF16"}, {"start": 1069, "end": 1090, "text": "Mathews et al., 1999;", "ref_id": "BIBREF22"}, {"start": 1091, "end": 1111, "text": "Turner et al., 1988)", "ref_id": "BIBREF37"}, {"start": 1157, "end": 1177, "text": "Wuchty et al. (1999)", "ref_id": "BIBREF41"}], "ref_spans": []}, {"section": "RNA secondary structures and stack configurations", "text": "Consider an RNA sequence as a string A = a 1 \u00b7\u00b7\u00b7a n of n letters over alphabet ={A,U,G,C}. A pair of nucleotides a i and a j (i < j) can interact with each other and form a base pair (denoted by (i,j)), if they are complementary to each other. In this article, we only consider the canonical base pairings (G-C and A-U) and the wobble base pairing (G-U). A secondary structure of an RNA can be represented by an ensemble of pairing bases. A secondary structure is pseudoknotted if it contains two base pairs (i,j) and (i ,j ) such that i < i < j < j . In this article, we only consider pseudoknot-free secondary structures.", "cite_spans": [], "ref_spans": []}, {"section": "RNA secondary structures and stack configurations", "text": "The stability of an RNA secondary structure is determined predominantly by energetically favorable helical regions, where both base pair stacking and hydrogen bonding provide stabilizing energy contributions (Yakovchuk et al., 2006) . We denote a helical region by a stack. A stack p = (p b ,p e ,p l ) has p l consecutive base pairs, where (p b ,p e ) is the outmost base pair and (p b +p l \u22121,p e \u2212p l +1) is the innermost base pair. Without loss of generality, p l can be 0. We define two arbitrary stacks as compatible with each other if they are parallel or one stack encloses the other. We define partial orders < P and < I between compatible stacks as follows. If a stack p is parallel to a stack q, and p resides to the 5 of q (i.e. p e < q b ), then", "cite_spans": [{"start": 208, "end": 232, "text": "(Yakovchuk et al., 2006)", "ref_id": "BIBREF42"}], "ref_spans": []}, {"section": "RNA secondary structures and stack configurations", "text": "We denote the ensemble of all possible putative stacks of an RNA sequence by P. We can compute P using the algorithm of Bafna et al. (2006) in O(n 2 ) time. Following their work, we score hydrogen bonds between pairing bases G-C, A-U and G-U by 3, 2 and 1, respectively, and set the minimum length of putative stacks ( min ) as 4 and the minimum score of hydrogen bonds (h min ) as 8, because statistics show that the fraction of true stacks missed is <10% with the cutoff (Bafna et al., 2006) . The number of putative stacks predicted is usually much less than the number of feasible pairing bases. This yields a faster algorithm for enumerating suboptimal structures, which recursively branches when a putative stack (instead of a feasible base pair) is encountered. In addition, the typical lengths of riboswitches are around 100\u2212200, and the number of putative stacks predicted for an RNA of similar length may even be smaller than the sequence lengths. For example, we predicted 62 putative stacks for the 110 nt long adenine riboswitch of ydhL gene from B.subtilis.", "cite_spans": [{"start": 120, "end": 139, "text": "Bafna et al. (2006)", "ref_id": "BIBREF0"}, {"start": 473, "end": 493, "text": "(Bafna et al., 2006)", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "RNA secondary structures and stack configurations", "text": "In order to elucidate the basic idea, we define a notion of stack configuration. A stack configuration of an RNA sequence is composed of a set of putative stacks in P that are pairwisely compatible. Figure 2 shows a schematic representation of a stack configuration. A stack configuration \u03d5 is local optimal if there does not exist any stack p in P that p can be added to \u03d5 without affecting the validity of \u03d5 (i.e. forming a pseudoknot or paring a base with more than one partner). Next, let p and q be putative stacks and q is enclosed with p, we also define the following terms:", "cite_spans": [], "ref_spans": []}, {"section": "RNA secondary structures and stack configurations", "text": "|p|: the length of the subsequence covered by p (i.e. p e \u2212p b +1). ", "cite_spans": [], "ref_spans": []}, {"section": "Stack-based folding using Nussinov model", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Computing the maximum number of base pairs", "text": "The RNA folding problem was formulated as a loop matching problem by Nussinov et al. (1978) and solved using dynamic programming. In the Nussinov model, the energy contribution of each base pair is 1, while base pair stacking and loop entropies have no energetic contributions. Given an arbitrary stack p, we define N(p) as the maximal number of base pairs of all the stack configurations in N (p). The recursive formula for computing N(p) is shown in Equation (1). If F I (p) is an empty set, then no putative stack is enclosed with p and N(p) = p l (the number of base pairs in p). Otherwise, we can divide the sequence covered by p into three parts: (i) the stacking base pairs in p, (ii) an arbitrary stack q in F I (p) and (iii) a stack l p,q which is enclosed with p and to the 5 of q. In this case, N(p) is the sum of base pairs in the three parts. The time complexity for computing N(p) is O(|P(p)| 2 ). In addition, we denote the entire RNA sequence by a stack p * = (1,n,0) and can obtain the maximum number of base pairs over all possible stack configurations on the sequence by computing N(p * ). Figure 3 an exact algorithm for enumerating all possible LOpt stack configurations with at least n \u03b8 base pairs. We keep an array of partial stack configurations in R. Each partial stack configuration \u03d5 in R comprises an ordered list of stacks, which are labeled with either finished or unfinished.", "cite_spans": [{"start": 69, "end": 91, "text": "Nussinov et al. (1978)", "ref_id": "BIBREF28"}], "ref_spans": []}, {"section": "Generating all possible LOpt stack configurations We present in", "text": "The label finished indicates that we have finished processing p and p should appear on all the stack configurations \u03d5 represents. The label unfinished means that the structures on the subsequence covered by p is not determined yet and p needs to be dealt with in the future. Each partial stack configuration \u03d5 can represent a set of LOpt stack configurations that contain all the finished stacks in \u03d5. And, a partial stack configuration (p * ,unfinished) can represent all possible LOpt stack configurations on the entire RNA sequence. Besides, when all the stacks in \u03d5 are labeled with finished, \u03d5 only represents exactly one stack configuration. The algorithm is as follows. First, we push (p * , unfinished) to R. Then, we repeatedly pop up the last partial stack configuration \u03d5 from R and process \u03d5 according to the following procedures until R is empty. Given \u03d5, we pop", "cite_spans": [], "ref_spans": []}, {"section": "Generating all possible LOpt stack configurations We present in", "text": "if (x \u2265 n \u03b8 ) then output \u03d5 end if end if end while Fig. 3 . An algorithm enumerate(A,n \u03b8 ) for enumerating all possible local optimal stack configurations on an RNA sequence A with at least n \u03b8 base pairs. The meaning of \u21d2, \u21d2 and \u21d0 are pushing back an element to the end of an array, inserting an element to the beginning of an array, and popping up the last element from an array, respectively. the last element (a stack p) from the array of \u03d5 and check its associated label. If the label of p is finished, then all the stacks in \u03d5 should have been processed. (Because we always insert stacks labeled with finished to the front of the array of \u03d5 and push stacks labeled with unfinished to the end.) In this case, we output the only stack configuration that \u03d5 represents. Otherwise, we decompose the unfinished stack p into three disjoint components: (i) the stacking base pairs of p, (ii) a stack q \u2208 F I (p) and (iii) a stack l p,q . We can construct a stack configuration on the subsequence covered by p by combining (i) the stack p, (ii) a stack configuration taken from N (q) and (iii) a stack configuration taken from N (l p,q ). If q is determined, we can construct |N (q)|\u00d7|N (l p,q )| possible new stack configurations. And, for each stack q in F I (p), we construct a new stack configuration \u03d5 by pushing (p,finished) to the end of \u03d5 and inserting (l p,q ,unfinished) and (q,unfinished) to the beginning of \u03d5. We can compute the size of N (p) using Equation (2).", "cite_spans": [], "ref_spans": []}, {"section": "Generating all possible LOpt stack configurations We present in", "text": "Next, we push all the new partial stack configurations that have at least n \u03b8 base pairs to the end of R. We denote the maximal number of base pairs of a partial stack configuration \u03d5 by N(\u03d5). As shown in Equation (3), N(\u03d5) is the sum of N(p) over all stacks p in \u03d5. Each stack labeled with finished contributes exactly p l base pairs, and each stack labeled with unfinished contributes at most N(p) base pairs [where N(p) can be computed using Equation (1)].", "cite_spans": [], "ref_spans": []}, {"section": "Stack-based RNA folding using the Turner model", "text": "According to the Turner model, the free energy of a stack configuration is the additive sum of energy contributions of all the stacking base pairs, hairpin loops, bulges, interior loops, multiloops and dangling bases (Mathews et al., 1999) . We describe the energy parameters and terminal symbols used in the following: M c : offset penalty for opening a multibranched loop. ", "cite_spans": [{"start": 217, "end": 239, "text": "(Mathews et al., 1999)", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "Computing the minimum free energy", "text": "The recursive formula for computing the minimum free energy is shown in Equation (4), with a time complexity of O(|P(p)| 3 ) [which is O(n 6 ) with a small factor]. For the sake of simplicity, we do not discuss dangling energy contributions in the recursive formula, but take them into account in the implementation.", "cite_spans": [], "ref_spans": []}, {"section": "Generating all possible LOpt stack configurations", "text": "In this section, we describe an algorithm for numerating all possible local optimal stack configurations of an RNA sequence A within E of the MFE. The detailed procedures are described in Supplementary Figures S4-S8 . We denote the free energy upper limit for stack configurations by e \u03b8 , where e \u03b8 is equivalent to the MFE of all possible stack configurations plus E. We keep an array of paired objects R ={(\u03d5,E(\u03d5)),(\u03d5 ,E(\u03d5 )),...}. Each paired object of R comprises of a partial stack configuration \u03d5 and its associated minimum free energy E(\u03d5). Each partial stack configuration \u03d5 comprises an ordered list of stacks, each with a label (i.e. \u03d5 ={(p,label),(p ,label ),...}). There are five types of labels, including finished, F, C, FM1 and FM. The label finished indicates that we have finished processing stack p, and p will appear on all the stack configurations that \u03d5 represents. The remaining labels correspond to the following cases: FM1(p) , and FM(p), respectively. The algorithms starts with a partial stack configuration \u03d5 0 = (p * = (1,n,0),F) and its associated minimum free energy E(\u03d5 0 ). \u03d5 0 represents all possible stack configurations on A, and E(\u03d5 0 ) is the minimum free energy of \u03d5 0 (i.e. E(\u03d5 0 ) = F(p * )). We push (\u03d5 0 ,E(\u03d5 0 )) to R and repetitively process the last element of R according to the following procedure until R is empty. Let (\u03d5,E(\u03d5)) be the last partial stack configuration and its associated energy in R, and let (p,label) be the last stack and its associated label in \u03d5. First, we check the label of p. Similar to the algorithm based on the Nussinov model, we also ensure that stacks labeled with finished are inserted to the front of the array of \u03d5 and other stacks are pushed back to the end of the array. If the label of p is finished, then all the stacks should have been processed. In this case, we output \u03d5 if E \u03d5 is less than e \u03b8 . Otherwise, we will construct a set of new partial stack configurations according to the label. Each new partial stack configuration \u03d5 is constructed by combining all the remaining stacks other than p in \u03d5 (denoted by \u03d5 \u2212 , where \u03d5 \u2212 = \u03d5 \u2212{(p,label)}) with stacks enclosed with p. Next, we compute E(\u03d5 ) for each new partial stack configuration \u03d5 , and push them to the end of R if E(\u03d5 ) is less than or equal to e \u03b8 , as described in the following:", "cite_spans": [], "ref_spans": [{"start": 188, "end": 215, "text": "Supplementary Figures S4-S8", "ref_id": "FIGREF1"}]}, {"section": "Generating all possible LOpt stack configurations", "text": "Case F: p (p b = 1 and p l = 0) is a stack. For each stack q in F I (p), we construct a new partial stack configuration \u03d5 by pushing (q,C) and (l p,q ,F) to the end of \u03d5 \u2212 . E(\u03d5 ) is given by Equation (5).", "cite_spans": [], "ref_spans": []}, {"section": "Generating all possible LOpt stack configurations", "text": "Case C: p (p l = 0) should appear on all the stack configurations that \u03d5 represents. We construct a set of new partial stack configurations according to Cases C.1, C.2 and C.3. C.1: p closes a hairpin loop. We construct a new partial stack configuration \u03d5 by inserting (p,finished) to the front of \u03d5 \u2212 . E(\u03d5 ) is given by Equation (6).", "cite_spans": [], "ref_spans": []}, {"section": "E(\u03d5 ) = E(\u03d5)\u2212C(p)+S(p)+H(p)", "text": "C.2: p closes a stack q and forms an interior loop (or a bulge) with q. For each stack q < I p, we construct a partial stack configuration \u03d5 by inserting (p,finished) to the front of \u03d5 \u2212 and then pushing (q,C) to the end. E(\u03d5 ) is given by Equation (7).", "cite_spans": [], "ref_spans": []}, {"section": "E(\u03d5 ) = E(\u03d5)\u2212C(p)+S(p)+I(p,q)+C(q)", "text": "C.3: p closes a multibranched loop. For each stack q \u2208 F I (p), we construct a new partial stack configuration \u03d5 by inserting (p,finished) to the front of \u03d5 \u2212 , and then pushing (q,C) and (l p,q ,FM1) to the end. E(\u03d5 ) is given by Equation (8).", "cite_spans": [], "ref_spans": []}, {"section": "E(\u03d5 ) = E(\u03d5)\u2212C(p)+S(p)+I(p,q)+C(q)", "text": "Case FM1: p (p l = 0) is directly enclosed with a multibranched loop, and there exists at least a stack q such that q l = 0 and q < I p. For each stack q in F I (p), we construct a new partial stack configurations \u03d5 by pushing (q,C) and (l p,q ,FM) to the end of \u03d5 \u2212 . E(\u03d5 ) is given by Equation (9).", "cite_spans": [], "ref_spans": []}, {"section": "E(\u03d5 ) = E(\u03d5)\u2212C(p)+S(p)+I(p,q)+C(q)", "text": "Case FM: p (p l = 0) is directly enclosed with a multibranched loop. We construct a set of new partial stack configurations according to cases FM.1 and FM.2. FM.1: all the bases covered by p are unpaired. We construct a partial stack configuration \u03d5 = \u03d5 \u2212 . E(\u03d5 ) is computed as Equation (10).", "cite_spans": [], "ref_spans": []}, {"section": "E(\u03d5 ) = E(\u03d5)\u2212C(p)+S(p)+I(p,q)+C(q)", "text": "FM.2: there exists a stack q (q l = 0) enclosed with p. For each stack q < I p, we construct a partial stack configuration \u03d5 by pushing (q,C) and (l p,q ,FM) to the end of \u03d5 \u2212 . E(\u03d5 ) is given by Equation (11).", "cite_spans": [], "ref_spans": []}, {"section": "E(\u03d5 ) = E(\u03d5)\u2212C(p)+S(p)+I(p,q)+C(q)", "text": "2.3.3 Redefining partial orders < I and < P Stack configurations produced by our approach consist of pairwisely compatible stacks, therefore incompatible stacks that overlap one another by only a few bases cannot coexist in a structure. To solve this problem, we use looser definitions of partial orders < I and < P , which allow compatible stacks to share a small portion of bases in common. RNASLOpt is able to produce stack configurations containing incompatible stacks overlapping by a few (by default, no >20%) bases.", "cite_spans": [], "ref_spans": []}, {"section": "Obtaining SLOpt structures", "text": "Using the algorithm described above, we can produce a set of all possible LOpt stack configurations on an RNA sequence, and denote it by R. However, although the conformational space of LOpt stack configurations is dramatically reduced compared with the space of feasible secondary structures, the number of structures considered may still be enormous. In literature, many distance metrics, such as base pair metrics (Zuker, 1989; Zuker et al., 1991) , tree metrics (Shapiro and Zhang, 1990) , mountain metrics (Moulton et al., 2000) , metrics based on base pairing probability matrices (Hofacker et al., 2004) and metrics using the Lempel-Ziv algorithm (Liu and Wang, 2006; Zhang and Wang, 2010) have been proposed for filtering out similar structures and reducing the number of structures considered. In contrast, we are only interested in stable local optimal (SLOpt) structures. And, we will filter out unstable structures from the space instead of removing similar structures that share base pairs, shapes or pairing probabilities in common. The SLOpt structures should be difficult for an RNA molecule to escape, and the associated energy barrier between any pair of SLOpt structures should be greater than or equal to a certain threshold B. Using pairwise energy barriers among LOpt stack configurations as a distance matrix, we can evaluate the stability of RNA secondary structures in the context of energy landscape. The problem of determining the minimal energy barrier between two conformational structures has been well studied, and it is usually solved in conjunction with finding the optimal folding pathways with the minimal energy barrier. Many approaches have been proposed to address the problem. These approaches can either be based on the Nussinov model [e.g. an exact algorithm proposed by Thachuk et al. (2010) and a greedy algorithm by Morgan and Higgs (1998) ] or the Turner model [e.g. an exact solution devised by Flamm et al. (2002) and heuristic algorithms developed by Morgan and Higgs (1998) , Flamm et al. (2001) , Voss et al. (2004) , Geis et al. (2008) and Dotu et al. (2010) ]. In this article, we focus on using energy barriers to find SLOpt stack configurations (instead of determining the optimal folding pathways). Therefore, here, we propose a fast heuristic for computing pairwise energy barriers among LOpt stack configurations. Upon these pairwise energy barriers, we cluster unstable LOpt stack configurations using a simple neighbor joining algorithm, and obtain all the SLOpt stack configurations with the minimal pairwise energy barrier no less than B. Finally, we rank these SLOpt structures either according to their free energies or their minimal associated energy barriers.", "cite_spans": [{"start": 417, "end": 430, "text": "(Zuker, 1989;", "ref_id": "BIBREF45"}, {"start": 431, "end": 450, "text": "Zuker et al., 1991)", "ref_id": "BIBREF46"}, {"start": 466, "end": 491, "text": "(Shapiro and Zhang, 1990)", "ref_id": "BIBREF33"}, {"start": 511, "end": 533, "text": "(Moulton et al., 2000)", "ref_id": "BIBREF25"}, {"start": 587, "end": 610, "text": "(Hofacker et al., 2004)", "ref_id": "BIBREF15"}, {"start": 654, "end": 674, "text": "(Liu and Wang, 2006;", "ref_id": "BIBREF18"}, {"start": 675, "end": 696, "text": "Zhang and Wang, 2010)", "ref_id": "BIBREF43"}, {"start": 1812, "end": 1833, "text": "Thachuk et al. (2010)", "ref_id": "BIBREF36"}, {"start": 1860, "end": 1883, "text": "Morgan and Higgs (1998)", "ref_id": "BIBREF24"}, {"start": 1941, "end": 1960, "text": "Flamm et al. (2002)", "ref_id": "BIBREF9"}, {"start": 1999, "end": 2022, "text": "Morgan and Higgs (1998)", "ref_id": "BIBREF24"}, {"start": 2025, "end": 2044, "text": "Flamm et al. (2001)", "ref_id": "BIBREF8"}, {"start": 2047, "end": 2065, "text": "Voss et al. (2004)", "ref_id": "BIBREF38"}, {"start": 2068, "end": 2086, "text": "Geis et al. (2008)", "ref_id": "BIBREF11"}, {"start": 2091, "end": 2109, "text": "Dotu et al. (2010)", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Approximating barrier energy", "text": "Consider secondary structures S and S , the folding pathway between S and S involves a series of intermediate structures, among which, the saddle point structure S * is the one with the highest free energy (e.g. in Fig. 1 , a is the saddle point for the folding pathway from local optima 1 to 2). We denote the energy barrier from S to S by B(S \u2192 S ) and denote the energy barrier between S and S by B(S S ). B(S \u2192 S ) is equivalent to the absolute difference in the free energies of S and S * [i.e. |E(S)\u2212E(S * )|] and B(S S ) can be computed using Equation (12).", "cite_spans": [], "ref_spans": [{"start": 215, "end": 221, "text": "Fig. 1", "ref_id": "FIGREF0"}]}, {"section": "B(S S", "text": "We list our assumptions for approximating barrier energy B(S \u2192 S ) in the following. The saddle point S * between S and S can be achieved when all the base pairs in S are opened or shifted such that S can be formed without opening more base pairs. The amount of additional energy required for opening an entire stack p is roughly S(p), and the amount for opening a base pair in p is about 1 p l * S(p), while the amount for sliding one endpoint of a base pair in p is \u03b1 p l * S(p), (0 \u2264 \u03b1 \u2264 1, by default, \u03b1 is 0.5). Given a base pair (i,j) in S and an arbitrary stack p in S , we determine the necessary operation to apply to (i,j) (i.e. operations that can make the formation of p possible) according to the positional relationship between (i,j) and p . Let w ((i,j) ,p ) denote the additional energy associated with the operation. We describe the four types of positional relationships and the corresponding w ((i,j) ,p ) in Table 1 . Case 1 (i,j) is compatible to p (i.e. either be nested or juxtapose to each other). In this case, we cannot infer the operation to apply to the base pair, because the stack can be formed anyway. Case 2, (i,j) is consistent with p [(i,j) is in p ]. We do not apply any operation to the base pair so as to keep it intact during the folding. Case 3 (i,j) partially conflicts to p [i.e. there exist two base pairs (i,i ) and (j ,j) in p ]. In this case, we may slide either ((i,j) ,p ) over all the stacks p in S , to represent the least amount of additional energy required so as to form S . If (i,j) is compatible with all the stacks in S , we have to delete (i,j), which requires 1 p l * S(p) additional energy. We present the approximated algorithm for computing B(S \u2192 S ) in Equation (13). ", "cite_spans": [], "ref_spans": [{"start": 928, "end": 935, "text": "Table 1", "ref_id": "TABREF2"}]}, {"section": "B(S", "text": "\u2192 S ) = p\u2208S (i,j)\u2208p min p \u2208S {w((i,j),p ) * S(p)}(13)", "cite_spans": [], "ref_spans": []}, {"section": "Pairwise energy barrier-based clustering", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Reducing the conformational space", "text": "The number of feasible secondary structures within a certain energy range of the MFE can be enormous. Len, lengths of riboswitches. SubOpt, the percentage suboptimality.", "cite_spans": [], "ref_spans": []}, {"section": "Predicting alternative structures for riboswitches", "text": "We will show that although the conformational space of SLOpt stack configurations is greatly reduced compared with the space of feasible structures, it does not miss native structures for all the benchmark tests. Therefore, we can predict alternate structures for riboswitches by exploring the space of SLOpt stack configurations. We performed benchmark tests on seven riboswitches, including the adenine riboswitch of the ydhL gene from B.subtilis (Mandal and Breaker, 2004 ) (denoted by adenine-BS), the adenine riboswitch of add gene from Vibrio vulnificus (Lemay et al., 2011) (denoted by adenine-VV), the guanine riboswitch of xpt-pbuX operon from B.subtilis (Mandal et al., 2003) , the S-adenosylmethionine (SAM) riboswitch of metE from Thermoanaerobacter tencongensis (Epshtein et al., 2003) , the c-di-GMP riboswitch of tfoX from Candidatus desulforudis (Smith et al., 2009) , the lysine riboswitch of lysC from B.subtilis (Blouin et al., 2011) and the thiamin pyrophosphate (TPP) riboswitch of thiamin from B.subtilis (Mironov et al., 2002; Rentmeister et al., 2007) . We describe the parameters used in the tests as follows. By default, the minimum length of putative stacks (i.e. min ) is 4, and the minimum score for hydrogen bonds (i.e. h min ) is 8. However, min is 3 for the SAM riboswitch and c-di-GMP riboswitch, because a large proportion of stacks in the native structures of both cases are of lengths \u2264 3. Percentage suboptimality is a parameter that determines the free energy upper limit for the predicted structures. If percentage suboptimality is x%, then only structures that have free energies \u2264 (1\u2212x%) of the MFE will be computed. The default value is 20%, since usually the native structures are within a lower energy range from the MFE. However, for the adenine-BS riboswitch and the guanine riboswitch, suboptimality is assigned a greater value (i.e. 55%), because the free energies of the 'on' structures for both riboswitches are >20% of the MFE. The default energy barrier cutoff B is 12 (kcal/mol), which is empirically chosen to reflect the stability of alternative structures, and it can be changed by users.", "cite_spans": [{"start": 449, "end": 474, "text": "(Mandal and Breaker, 2004", "ref_id": "BIBREF20"}, {"start": 560, "end": 580, "text": "(Lemay et al., 2011)", "ref_id": "BIBREF17"}, {"start": 664, "end": 685, "text": "(Mandal et al., 2003)", "ref_id": "BIBREF21"}, {"start": 775, "end": 798, "text": "(Epshtein et al., 2003)", "ref_id": "BIBREF6"}, {"start": 862, "end": 882, "text": "(Smith et al., 2009)", "ref_id": "BIBREF34"}, {"start": 931, "end": 952, "text": "(Blouin et al., 2011)", "ref_id": "BIBREF3"}, {"start": 1027, "end": 1049, "text": "(Mironov et al., 2002;", "ref_id": "BIBREF23"}, {"start": 1050, "end": 1075, "text": "Rentmeister et al., 2007)", "ref_id": "BIBREF31"}], "ref_spans": []}, {"section": "Predicting alternative structures for riboswitches", "text": "First, we compare the number of structures produced by mfold (v3.5), the number of 'shreps' by RNAShapes (v2.1.6) and the numbers of LOpt and SLOpt stack configurations by RNASLOpt in Table 2 . The number of SLOpt produced by RNASLOpt is less than that of RNAShapes in all the cases. It reveals that although the number of candidates considered by both methods are exponential, the space of RNASLOpt is reduced compared with the space of RNAShapes. Interestingly, the number of candidates produced by RNASLOpt is even less than that of mfold [which generates O(n 2 ) structures at most], when the RNA sequence is short (e.g. the adenine riboswitch). The running time for all the test cases on a 32 bit PC with 2.4 GHz Quad-processor, 3.2 GB memory (running Fedora 11) are 0.04, 0.04, 6, 2.4, 1.5, 227.6 and 15.8 s, respectively (see Supplementary Table S1 ). Usually, RNASLOpt can be applied on RNAs of around 200 nt long and finish the computation within a few minutes.", "cite_spans": [], "ref_spans": [{"start": 184, "end": 191, "text": "Table 2", "ref_id": "TABREF5"}, {"start": 833, "end": 855, "text": "Supplementary Table S1", "ref_id": "TABREF2"}]}, {"section": "Predicting alternative structures for riboswitches", "text": "Next, we compare the ranks of the best structures corresponding to the native structures produced by mfold, RNAShapes, RNAlocopt and RNASLOpt in Table 3 . The best structures should share the most backbone structures in common with the native structures. RNASLOpt can rank predicted structures both according to their free energies and minimal associated energy barriers. In all the cases, RNASLOpt ranks the best structures corresponding to the native 'on' and 'off' structure conformations among the top. And, in six out of seven cases, RNASLOpt provides better ranks than the others.", "cite_spans": [], "ref_spans": []}, {"section": "Predicting alternative structures for riboswitches", "text": "For example, Figure 4 show both the native 'on' and 'off' structures of adenine riboswitch from the ydhL gene of B.subtilis (Breaker, 2004) and the best stack configurations produced by RNASLOpt. RNAsubopt produces >10 9 feasible secondary structures, mfold selects 43 representative structures and RNAShapes predicts 25 shreps (with the most abstract option). In contrast, RNASLOpt enumerates 19 LOpt stack configurations within 55% of the MFE, filters out 14 unstable stack configurations, and obtains 5 SLOpt stack configurations. Two SLOpt stack configurations among the five have the similar backbone structures to the native conformations and are ranked among the top according to both free energies (i.e. ranked 1 and 4, respectively) and the minimal associated energy barriers (i.e. ranked 1 and 2, respectively). Since the 'on' and 'off' structures predicted by RNASLOpt are LOpt stack configurations, an extra stack was predicted for each configuration (Fig. 4C and D) without affecting the backbone structure. We also list the native 'on' or 'off' conformations of the seven riboswitches, together with the best structures produced by mfold, RNAShapes, RNAlocopt and RNASLOpt in Supplementary Figures S10-S16.", "cite_spans": [{"start": 124, "end": 139, "text": "(Breaker, 2004)", "ref_id": "BIBREF4"}], "ref_spans": [{"start": 13, "end": 21, "text": "Figure 4", "ref_id": "FIGREF1"}, {"start": 963, "end": 978, "text": "(Fig. 4C and D)", "ref_id": "FIGREF1"}]}, {"section": "CONCLUSION", "text": "In this article, we designed an approach RNASLOpt for predicting stable local optimal stack configurations of an RNA molecule. We first predict all possible local optimal stack configurations that are significantly different from one another. With each stack configuration representing a set of similar RNA secondary structures, we are able to greatly reduce the size of the conformational space considered, and make applications on longer sequences with a higher energy range possible. 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Lower-case characters a,b,c and d are saddle points (i.e. structures with the highest free energies) of folding pathways between local optima 1&2, 2&3, 3&4 and 4&5, respectively. Bars represent the minimal additional energy required for the RNA molecule to 'jump' out of the corresponding energy basins.", "type": "figure"}, "FIGREF1": {"text": "Fig. 4. The native and predicted 'on' and 'off' structure conformations of the adenine riboswitch from the ydhL gene of B.subtilis. (A) and (B) show the native 'on' and 'off' structure conformations; (C) and (D) plot the best corresponding stack configurations predicted by RNASLOpt.", "type": "figure"}, "TABREF0": {"text": "P(p): the set of all possible putative stacks on a subsequence covered by p (i.e. a p b ...a pe ).Fig. 2. A schematic representation of a stack configuration. Filled arcs represent putative stacks p,q,u and v. The relationships between these putative stacks are as follows: p < P v, u < P q, u < I p, q < I p and q \u2208 F I (p). Dashed arcs represent l p,q and r p,q , respectively. N (p): all possible LOpt stack configurations composed of putative stacks in P(p). F I (p): a subset of putative stacks in P(p), where \u2200q \u2208 F I (p), q such that q < I p and ((q < P q ) or (q < I q )). l p,q : a stack (p b +p l ,q b \u22121,0) that is enclosed by p and juxtaposes to the 5 end of q, provided that q < I p. r p,q : a stack (q e +1,p e \u2212p l ,0) that is enclosed by p and juxtaposes to the 3 end of q, provided that q < I p. In the next two subsections, we will describe algorithms for generating all possible LOpt stack configurations based on the Nussinov model and the Turner model, respectively.", "type": "table"}, "TABREF1": {"text": "stabilizing energies of all the stacking base pairs in a stack p. M c , M b and M i are constant energy parameters. H(p) and I(p,q) can be obtained from the tabulated energy parameters, and S(p) can be computed as the sum of tabulated stacking energies of adjacent stacking base pairs in p. All the free energy parameters are taken from the work of Mathews et al. (1999). We also define the following non-terminal symbols as follows:", "type": "table"}, "TABREF2": {"text": "Positional relationships between a base pair (i,j) and a stack p", "type": "table"}, "TABREF3": {"text": "A LOpt stack configuration \u03d5 is considered as stable if the minimal energy barrier between \u03d5 and any other stable structures is no less than B. \u03d5 can be seen as a representative of all the unstable structures in the energy basin it resides. Let R * denote the set of SLOpt stack configurations. We describe the procedure for constructing R * from the set of LOpt stack configurations R in Supplementary Figure S9. First, we sort LOpt stackWe analyze each LOpt stack configuration \u03d5 in R. If the energy barrier between \u03d5 and any SLOpt stack configuration in R * is less than B, we consider \u03d5 as unstable, and discard it. Otherwise, we push \u03d5 to R * as a SLOpt stack configuration and update M * accordingly. When M * is constructed completely, we stepwisely neighbor join SLOpt stack configurations in R * which have the lowest pairwise energy barrier in M * , and obtain a cluster tree. Finally, we rank SLOpt structures in R * either by their free energies or by their associated minimal energy barriers.", "type": "table"}, "TABREF4": {"text": "the number of which is greatly reduced compared with that of feasible structures. In addition, we can further reduce the number of candidates to consider by filtering out unstable structures and only investigate SLOpt stack configurations. Note that the reduced space still grows exponentially with the RNA length and the energy range. Comparisons of sizes of different conformational spaces are shown in Supplementary Figures S2 and S3.", "type": "table"}, "TABREF5": {"text": "The numbers of structures produced by mfold, RNAShapes and RNASLOpt", "type": "table"}}}
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{"paper_id": "17781218", "_pdf_hash": "027d2db20f5accaf147f3b685d7f7be443de927f", "abstract": [{"section": "Abstract", "text": "Performing intensity-modulated radiotherapy (IMRT) on head and neck cancer patients (HNCPs) requires robust training and experience. Thus, in 2011, the Head and Neck Cancer Working Group (HNCWG) of the Italian Association of Radiation Oncology (AIRO) organized a study group with the aim to run a literature review to outline clinical practice recommendations, to suggest technical solutions and to advise target volumes and doses selection for head and neck cancer IMRT. The main purpose was therefore to standardize the technical approach of radiation oncologists in this context. The following paper describes the results of this working group. Volumes, techniques/strategies and dosage were summarized for each head-and-neck site and subsite according to international guidelines or after reaching a consensus in case of weak literature evidence.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Performing intensity-modulated radiotherapy (IMRT) in head and neck cancer patients (HNCPs) requires training [1] and experience. For example, in the 02-02 Trans Tasman Radiation Oncology Group (TROG) trial, comparing cisplatin (P) and radiotherapy (RT) with or without tirapazamine, a major quality defect of the irradiation approach in terms of dose and target volume selection and delineation was found in 12% of patients and was associated with a 24% lower locoregional control rate at 2 years [2] . Hence, in 2011, the Head and Neck Cancer Working Group (HNCWG) of the Italian Association of Radiation Oncology (AIRO) organized a study group to outline clinical practice recommendations regarding techniques, treatment volumes and doses to be employed during head and neck IMRT. The main purpose was to standardize technical approaches of professionals participating into AIRO head and neck cancer trials.", "cite_spans": [{"start": 110, "end": 113, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 498, "end": 501, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Material and methods", "text": "The first participants (AM, DA, AM, LL, RM, GG, OC, FM, FD and RC) were chosen on a voluntary basis among the HNCWG members. The group was coordinated by an expert head and neck radiation oncologist (RC). Each member was in charge of a specific topic. At the end of the first draft (February 2012) the whole document was reviewed by all the HNCWG members in order to discuss critical issues and to homogenize the manuscript structure. The revised draft was again reviewed by 5 radiation oncologists with particular expertise in head and neck IMRT (RVT, PF, SP, ER and GS).", "cite_spans": [], "ref_spans": []}, {"section": "General aspects Treatment strategy", "text": "RT is one of the mainstay treatment options for head and neck cancers (HNCs), along with chemotherapy (ChT) and surgery (S). In general, RT \u00b1 ChT is the preferred approach for head and neck squamous cell carcinomas (HN-SCC) whenever organ preservation is desired or the tumor is unresectable at presentation (cT4b) or the patient is considered not amenable to surgery. For early T-stage lesions (cT1 and selected cT2) without lymph nodes involvement (cN0), treatment should be monomodal (RT vs S), while for locally advanced disease (cT3-cT4 or any T,cN+), treatment is usually multimodal (S followed by RT \u00b1 ChT vs RT and concomitant ChT \u00b1 S). Concomitant ChT (usually platinum-based) has been shown to increase overall survival (OS) in stage III and IV disease over RT alone [3] . Recently published long-term results of the RTOG 91-11 trial in larynx cancer failed to show such an advantage over sequential ChT-RT because of an increased number of non-cancer-related deaths in the concomitant arm, suggesting a higher longterm toxicity rate for ChT-RT [4] . Induction and adjuvant ChT are less effective than concomitant ChT [3, 5] . However, within an organ preservation strategy, induction ChT may become an option to select responders who might potentially benefit from an organ preservation approach, driving eventual further treatments (S vs RT) on the basis of response to neoadjuvant ChT [6, 7] . Recent published trials found no benefit from the addition of Taxotere(T)-Platinum (P)-5Fluorouracil(F) induction ChT to concomitant ChT/RT or cetuximab-RT compared to concomitant ChT/RT or RT alone [8] [9] [10] . Another alternative to concomitant ChT is cetuximab, an epidermal growth factor receptor inhibitor, which, combined to RT, has been shown to provide a better OS than RT alone in HN-SCC [11] . However, Erbitux has never been tested against the standard treatment (concomitant platinum-based ChT-RT) and consequently its role is somewhat unclear. Moreover, when Erbitux was added to concomitant ChT-RT, no additional benefit was found [12] . After concomitant ChT-RT, S is usually reserved for eventual locoregional disease persistence. Regarding neck management, most Institutions nowadays use FDG-PET/CT at 10-12 weeks to select patients at risk of for residual nodal disease [13] . The decision to add adjuvant treatments after upfront surgery is made once the pathology report is available. RT is usually added for high risk features including positive resection margins (PRMs), advanced T stage (selected pT3 and all pT4), perineural invasion, lymph-vascular invasion, any nodal stage higher than pN1, and extra-capsular lymph-nodal extension (ECE); ChT is added for PRM and ECE. Therefore, treatment is usually multidisciplinary and any decision should be discussed within the tumor board involving all specialties. Aspects such as nutrition, oral care and restoration/preservation of swallowing and phonatory function (speech therapy) are also important and should be considered whenever feasible.", "cite_spans": [{"start": 777, "end": 780, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 1055, "end": 1058, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 1128, "end": 1131, "text": "[3,", "ref_id": "BIBREF2"}, {"start": 1132, "end": 1134, "text": "5]", "ref_id": "BIBREF4"}, {"start": 1398, "end": 1401, "text": "[6,", "ref_id": "BIBREF5"}, {"start": 1402, "end": 1404, "text": "7]", "ref_id": "BIBREF6"}, {"start": 1606, "end": 1609, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 1610, "end": 1613, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 1614, "end": 1618, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 1806, "end": 1810, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 2054, "end": 2058, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 2297, "end": 2301, "text": "[13]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "IMRT (Intensity-Modulated Radiation Therapy)", "text": "Though few Institutions pioneered IMRT for HN-SCC during mid-90s, this technique has become widespread during the last decade. The aim of IMRT is to achieve more conformal dose distribution over standard 3D conformal RT (3DCRT) and this in turn allows for better sparing of normal structures (i.e. parotid glands). This potentially translates into fewer late side effects (xerostomia) and improved quality of life [14] . With IMRT, the physician identifies the target volumes(s) and the organs at risk (OARs) appropriate for a given clinical condition. The dose to the target is usually proportional to the estimated tumour burden (Table 1 and Figure 1 ).", "cite_spans": [{"start": 414, "end": 418, "text": "[14]", "ref_id": "BIBREF13"}], "ref_spans": [{"start": 631, "end": 639, "text": "(Table 1", "ref_id": "TABREF0"}, {"start": 644, "end": 652, "text": "Figure 1", "ref_id": "FIGREF0"}]}, {"section": "IMRT (Intensity-Modulated Radiation Therapy)", "text": "It should be noted that the maximum prescribed dose has empirically evolved as the highest tolerated dose taking into account the surrounding normal structures. A 'definitive' treatment typically includes 2-3 dose levels within the same patient. Using IMRT a different dose to different targets can be delivered with sequential plans (as for 3DCRT) or with a simultaneous integrated boost (SIB). It has been shown that the latter approach provides better dose conformity compared to several consecutive plans [15] . When a single plan is prescribed, CTV1 receives both a higher total dose and a higher dose/fraction (d./f.) compared to the other CTVs. This results in an even higher biologically equivalent dose (BED) compared to other CTVs. However, since all dose levels are delivered throughout the same number of fractions, targets must receive different fractionations.", "cite_spans": [{"start": 509, "end": 513, "text": "[15]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "IMRT (Intensity-Modulated Radiation Therapy)", "text": "Two solutions have been proposed [16] (see Table 1 ). The first approach is to maintain conventionally fractionated doses to the highest dose CTV (1.8-2 Gy per fraction) (Table 1 ) whereas the elective targets receive a lower d./f. (1.6-1.8 Gy). The choice of the latter is made taking into consideration the normalized total dose in 2 Gy fractions (NTD). The second strategy is to deliver a slightly hypofractionated dose to the GTV and standard fraction doses to the CTVs [17] . Each strategy has pros and cons and no universally accepted schedule has been developed. The former solution may lead to the use of a very low d./f. according to current standards; a daily d./f. below 1.6 Gy should be avoided. Notably, in one study, 58.1 Gy in 35 fractions were able to control the microscopic low-risk disease [18] . The latter approach has the disadvantage of using a higher d./f. (up to 2.5 Gy) than the standard fractionation for the GTV potentially exposing normal tissues embedded within the high dose CTV to the risk of increased late toxicity. Moreover, this results in a higher than standard weekly total dose to normal tissues (i.e. mucosa) within the high dose region. According to some authors [19] , 66 Gy/ 30 f. (2.2 Gy) should not be used in the context of concomitant CT. On the other hand, a d./f. up to 2.12 Gy is used in the context of concomitant CT (P, 100 mg/m2 x 3 cycles) for nasopharyngeal cancer [20] . Recently some authors have reported initial experience in advanced HNC with a d./f. up to 2.25 Gy in 30 fractions concomitantly to CT. This schedule seems feasible with an acceptable but not negligible acute toxicity rate, while a *Depending from anatomic barrier; \u00a7 though one prospective study failed to show a benefit for 66 Gy over 60 Gy in the high risk post-operative region [78] , this is the dose recommended by some cooperative groups (EORTC [79] ); PTB: postoperative tumour bed;^definition of the high-risk region is controversial [18] ; D = Definitive RT; Post-S = postoperative. CTV HD : High Disease; CTV HR= High Risk; LR = Low risk. \u00c7 in case of muscular infiltration (i.e. sternocleidomastoid muscle) at least the portion of the muscle surrounding the node [47] should be included. # Similarly, it would be appropriate to include the whole muscle (i.e. sternocleidomastoid muscle) in CTV3/LR or when grossly infiltrated at some level.", "cite_spans": [{"start": 33, "end": 37, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 474, "end": 478, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 809, "end": 813, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 1204, "end": 1208, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 1420, "end": 1424, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 1808, "end": 1812, "text": "[78]", "ref_id": "BIBREF77"}, {"start": 1878, "end": 1882, "text": "[79]", "ref_id": "BIBREF78"}, {"start": 1969, "end": 1973, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 2201, "end": 2205, "text": "[47]", "ref_id": "BIBREF46"}], "ref_spans": [{"start": 43, "end": 50, "text": "Table 1", "ref_id": "TABREF0"}, {"start": 170, "end": 178, "text": "(Table 1", "ref_id": "TABREF0"}]}, {"section": "IMRT (Intensity-Modulated Radiation Therapy)", "text": "longer follow-up is needed to fully evaluate late effects [21, 22] . In conclusion, hereinafter we will refer to IMRT as a SIB approach. The choice of the fractionation schedule (d./f.) is left to each Institution taking into account the aforementioned considerations. Whenever available, we will refer, for each primary site, to the fractionation schedules that have been tested clinically. We encourage each Institution to follow patients and investigate its own pattern of failure.", "cite_spans": [{"start": 58, "end": 62, "text": "[21,", "ref_id": "BIBREF20"}, {"start": 63, "end": 66, "text": "22]", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Practical implications of induction/concomitant CT", "text": "HNCs are typically treated once a day, i.e. 5 fractions per week (f/w) (standard fractionation). Although a few studies, and one meta-analysis, have shown better locoregional control rates, and even improved survival, when multiple fractions per day are delivered [23] [24] [25] , it is doubtful whether the treatment acceleration (more than 5 f/w) is beneficial also in the context of concomitant CT. Two randomized studies [26, 27] failed to show an advantage of concomitant chemo/accelerated-RT over standard CT/RT. Moreover, there are practical limitations in the number of treatment sessions that can be delivered per day with IMRT due to its workload intensiveness (each treatment session typically takes more than 15 minutes). RTOG [26] adopted a mildly accelerated radiation schedule (6 f/w) with concomitant CT as a standard, delivering the 6th fraction as a second daily dose on Friday (at least with a 6 hour gap) or on Saturday. In the context of concomitant CT there are no clinical data showing the benefit of multiple fractions per day (or more than 5 f/w) or a single fraction per day higher than 2 Gy.", "cite_spans": [{"start": 264, "end": 268, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 269, "end": 273, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 274, "end": 278, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 425, "end": 429, "text": "[26,", "ref_id": "BIBREF25"}, {"start": 430, "end": 433, "text": "27]", "ref_id": "BIBREF26"}, {"start": 739, "end": 743, "text": "[26]", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "Practical implications of induction/concomitant CT", "text": "Regarding induction CT, one potential advantage/pitfall is the potential downsizing of the primary tumour and lymph nodes. This can be successfully exploited in selected situations where the delivery of the highest dose level is limited by the tolerance of the surrounding normal structures (i.e. optic pathways for T4 NPC) [28] . On the other hand, it has been recommended that the initial rather than the post-chemo volume should encompass the high-dose region during contouring and planning [29] . With this in mind, the planning session should be carried out both before and after induction CT, if possible using the same immobilization device.", "cite_spans": [{"start": 324, "end": 328, "text": "[28]", "ref_id": "BIBREF27"}, {"start": 494, "end": 498, "text": "[29]", "ref_id": "BIBREF28"}], "ref_spans": []}, {"section": "Practical implications of upfront surgery", "text": "Extensive surgery can disrupt normal anatomy and violate tissues that generally are not considered at risk of microscopic disease. In general, the whole operative bed is considered at some/low risk after surgery, with the initial site of disease at highest risk. This implies that, when a flap reconstruction is performed, the whole flap should be included at least in the lowest dose volume. Regarding the whole operative bed, doses in the order of 50-54 Gy (2 Gy per fr) have been used [30, 31] . It should be noted that the 'classical' recommendation is to include any surgically violated sites regardless of final pathology (i.e. the dissected neck that is found to be negative, pN0, should still be included in the lowest dose level) ( Table 1) . Regarding the initial site of disease, its identification is best based on pre-surgery imaging studies and operative notes. When incomplete resection is suspected, a repeated PET/CT at > 1 month after surgery has been shown to detect macroscopic residual disease in a significant proportion of patients [32] . Postoperative treatment should be started as soon as healing takes place (usually 2 weeks) and not later than 6-8 weeks after surgery [31] . Patients who fail after surgery may have a peculiar lymphnode-invasion pattern due to the distortion of normal lymphatic flow. Therefore, in this setting, lymph node involvement may be less predictable than in the previously untreated setting and hence deviate from the recommendations here provided.", "cite_spans": [{"start": 488, "end": 492, "text": "[30,", "ref_id": "BIBREF29"}, {"start": 493, "end": 496, "text": "31]", "ref_id": "BIBREF30"}, {"start": 1055, "end": 1059, "text": "[32]", "ref_id": "BIBREF31"}, {"start": 1196, "end": 1200, "text": "[31]", "ref_id": "BIBREF30"}], "ref_spans": [{"start": 741, "end": 749, "text": "Table 1)", "ref_id": "TABREF0"}]}, {"section": "Pre-treatment evaluation", "text": "The following procedures are recommended before starting RT: FDG-PET/CT scan for locally advanced disease and for unknown primary sites (integration of both high resolution contrastenhanced CT and dedicated PET acquisition through the head and neck region are strongly suggested; as an alternative, CT of the chest \u00b1 abdomen, in particular for salivary gland tumours); 9.3 Head-and-neck MRI with gadolinium including T1-and T2-weighted sequences in at least 2 different planes (strongly suggested for tumours involving the tongue base, salivary glands and nasopharyngeal cancer). 10. Audiogram is recommended if the inner ear is to be irradiated at mean dose \u2265 40 Gy. 11. Post-operative MRI/CT, pre and post-operative PET (optional); 12. Testing the tumour specimen for Human Papilloma Virus (HPV) is also strongly recommended via in-situ hybridization or, indirectly, via p16 IHC (Immunohistochemistry) for oropharyngeal cancer, WHO-Type 1 nasopharyngeal cancer, and unknown primary tumours [33] . Testing the tumour specimen for Epstein Barr Virus (EBV) is strongly recommended for both nasopharyngeal and unknown primary tumours.", "cite_spans": [{"start": 992, "end": 996, "text": "[33]", "ref_id": "BIBREF32"}], "ref_spans": []}, {"section": "Simulation", "text": "1. The patient is usually set up on the treatment table in supine position. The immobilization device is generally a thermoplastic mask immobilizing both head and shoulders [34] . A mouth piece is also indicated for all non-edentulous patients. A tongue depressor is generally not recommended except for tumours of the nasal cavity and paranasal sinuses (to move the tongue and the mouth floor away from the irradiated volume) or for tumours of the bottom of the oral cavity (to displace the upper part of the oral cavity). Dental prostheses have to be removed. The position of the head is usually neutral and comfortable except in selected situations detailed in each section. The patient is instructed to breath normally/quietly and not to swallow during scanning. Scars are usually wired. A 3-5 mm bolus over the larynx is also optional depending on the beam energy and the patient's thickness when the larynx is part of the target (especially for lesions involving the anterior commissure and beyond). A 3-5 mm bolus is also to be considered over areas of skin infiltration and/or after surgery in case of nodal extra-capsular extension (ECE). 2. Treatment planning CT scan should be performed having the patient in the treatment position. I.V. contrast liquid administration at the time of simulation is also recommended. MRI-scan planning is optional. 3. CT-scan thickness should be 0.3 cm or less through the region that contains the primary target volumes. The regions above and below the target volume may be scanned with slice thickness up to 0.5 cm. MRI and PET/CT scans may be included to assist in defining target volumes as appropriate.", "cite_spans": [{"start": 173, "end": 177, "text": "[34]", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "Simulation", "text": "4. The GTV, CTV and PTV and normal tissues are outlined on all the appropriate CT slices. 5. Patients should be trained to avoid swallowing in order to reduce organ motion during treatment.", "cite_spans": [], "ref_spans": []}, {"section": "Volume and ICRU reference point definitions", "text": "The definition of volumes is in accordance with ICRU Reports n\u00b050 [35] and n\u00b083 [36] :", "cite_spans": [{"start": 66, "end": 70, "text": "[35]", "ref_id": "BIBREF34"}, {"start": 80, "end": 84, "text": "[36]", "ref_id": "BIBREF35"}], "ref_spans": []}, {"section": "Volume and ICRU reference point definitions", "text": "1. The Gross Tumour Volume (GTV) is defined as all known gross disease determined by CT, clinical information, endoscopic findings and MRI in case of tumours treated after biopsy alone. Functional information can be used to define sub-GTVs that are to receive some additional absorbed dose [37] . Typically, different GTVs are defined for the primary tumour (GTV-T) and the regional node(s) (GTV-N). Yet in those clinical situations in which the metastatic node cannot be distinguished from the primary tumour, a single GTV encompassing both the primary tumour and the node(s) may be contoured (GTV-TN) [38] . Furthermore, in consideration of adaptive RT, any changes occurring within the GTV during treatment can be quantified with anatomic-and/or functional-imaging techniques, allowing for the definition of a modified GTV in order to adjust the absorbed-dose distribution [39, 40] . Thus, because GTV contouring can vary according to the diagnostic modality used (e.g. clinical examination, anatomic and/or functional imaging) and the time/dose of acquisition with respect to the start of treatment (e.g. in the case of adaptive RT), a clear annotation is required. For example, ICRU 83 recommends specifying the imaging technique and pre-delivered dose: e.g. GTV-T (MRI-T2, 30 Gy), GTV-T (clin, 0 Gy).", "cite_spans": [{"start": 290, "end": 294, "text": "[37]", "ref_id": "BIBREF36"}, {"start": 603, "end": 607, "text": "[38]", "ref_id": "BIBREF37"}, {"start": 876, "end": 880, "text": "[39,", "ref_id": "BIBREF38"}, {"start": 881, "end": 884, "text": "40]", "ref_id": "BIBREF39"}], "ref_spans": []}, {"section": "2.", "text": "The Clinical Target Volume (CTV) is contoured by the treating physician and is defined as a volume of tissue that contains a demonstrable GTV and/or subclinical malignant disease with a certain probability of occurrence considered relevant for therapy [38] . The notion of subclinical malignant disease includes the microscopic tumour spread at the boundary of the primary-tumour GTV, the possible regional infiltration into lymph nodes, and the potential metastatic involvement of other tissues. (Figure 1a ,b) (e.g. regional lymph nodes, N0) at a distance from a GTV also need to be considered for therapy [42] . In this situation the prescription is based on the assumption that in some anatomically definable tissues/organs, there may be cancer cells at a given probability level, even though they cannot be detected as they are subclinical. The level of probability is based on clinical experience from adequately documented treatments and follow-up. For the purpose of treatment prescription, it can usually be described in terms of frequency of risk for later detectable manifestations (failure rate), when untreated adequately in the subclinical setting [43] . There is no general consensus on which probability is considered relevant for therapy [18, 38, 44] , but typically a probability of occult disease higher than 5-10% is assumed to require treatment. However, the volume could be defined as at \"high-risk\" (CTVHR or CTV2) or \"low-risk\" (CTVLR or CTV3) (Figure 1a /b) in consideration of the probability and entity of microscopic infiltration and could be targeted at different dose levels [18, 41, 44] . Moreover, in HNC the probability of pathologic lymph-node involvement has been well described, and the distribution follows a predictable pattern allowing clinicians to tailor the CTV to the primary-tumour location and extent [18, [45] [46] [47] . In postoperative cases, the CTV includes the operative bed and adequate margins according to an assessment of the risk of subclinical disease. The contouring of GTV and CTV are based on purely anatomic-topographic and biological considerations (morphology, such as ulcerative or exophytic, infiltrative or pushing front) with no regard to technical treatment factors [35, 43] . Consequently, rather than simply expanding the GTV uniformly, it is recommended that the CTV should be contoured on a slice-by-slice basis [48] . Hereinafter, peri-GTV, CTVHR and CTVLR will be respectively defined CTV1 (e.g. CTV-T 1; CTV-N 1; CTV-TN 1), CTV2 and CTV3.", "cite_spans": [{"start": 252, "end": 256, "text": "[38]", "ref_id": "BIBREF37"}, {"start": 608, "end": 612, "text": "[42]", "ref_id": "BIBREF41"}, {"start": 1162, "end": 1166, "text": "[43]", "ref_id": "BIBREF42"}, {"start": 1255, "end": 1259, "text": "[18,", "ref_id": "BIBREF17"}, {"start": 1260, "end": 1263, "text": "38,", "ref_id": "BIBREF37"}, {"start": 1264, "end": 1267, "text": "44]", "ref_id": "BIBREF43"}, {"start": 1605, "end": 1609, "text": "[18,", "ref_id": "BIBREF17"}, {"start": 1610, "end": 1613, "text": "41,", "ref_id": "BIBREF40"}, {"start": 1614, "end": 1617, "text": "44]", "ref_id": "BIBREF43"}, {"start": 1846, "end": 1850, "text": "[18,", "ref_id": "BIBREF17"}, {"start": 1851, "end": 1855, "text": "[45]", "ref_id": "BIBREF44"}, {"start": 1856, "end": 1860, "text": "[46]", "ref_id": "BIBREF45"}, {"start": 1861, "end": 1865, "text": "[47]", "ref_id": "BIBREF46"}, {"start": 2235, "end": 2239, "text": "[35,", "ref_id": "BIBREF34"}, {"start": 2240, "end": 2243, "text": "43]", "ref_id": "BIBREF42"}, {"start": 2385, "end": 2389, "text": "[48]", "ref_id": "BIBREF47"}], "ref_spans": [{"start": 497, "end": 507, "text": "(Figure 1a", "ref_id": "FIGREF0"}, {"start": 1468, "end": 1478, "text": "(Figure 1a", "ref_id": "FIGREF0"}]}, {"section": "2.", "text": "3. The Planning Target Volume (PTV) will provide a margin around each CTV to compensate for the uncertainties of treatment set-up and tissue deformation. An isotropic expansion of 5 mm is typically added around the CTV to define each respective PTV. For patients undergoing daily IGRT, the margins are sometimes cut down to 3 mm, though this is controversial [49] . Margins can be further expanded in special situations (i.e. concerns on set-up error). Nevertheless, institution specific margins are strongly recommended. 4. In patients who receive neoadjuvant CT, the post-CT GTV will differ from what is seen on diagnostic images and the former should be outlined. The CTV, however, should be tailored to encompass the preCT GTV [29] (see Figure 2 ). 5. To facilitate planning a suffix indicating the prescribed dose to each CTV should be used, e.g. CTV70, CTV60, CTV50, etc. 6. Unless otherwise specified, here we will refer to the 3 definitive and 2 postoperative dose levels as reported in Table 1 .", "cite_spans": [{"start": 359, "end": 363, "text": "[49]", "ref_id": "BIBREF48"}, {"start": 731, "end": 735, "text": "[29]", "ref_id": "BIBREF28"}], "ref_spans": [{"start": 741, "end": 749, "text": "Figure 2", "ref_id": "FIGREF1"}, {"start": 995, "end": 1002, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Primary-tumour contouring (GTV-T): high dose volume (CTV-T 1)", "text": "The GTV is usually defined based on physical examination and imaging findings. While the addition of MRI to CT contributes to improve tumour detection and observer consistency, the role of functional imaging to define the GTV is less established. Some authors disregard the information from FDG PET-CT [50] . Once identified, the GTV is usually expanded to its corresponding CTV (CTV1) by 0-10 mm depending on the presence of anatomic barriers, image quality and the presence of artefacts (dentures). With 3DCRT the whole portion of the sub-site, or a major part of it, is included in the CTV1 (e.g. the whole larynx and the whole rinopharynx in the case respectively of laryngeal and nasopharyngeal primaries). Conversely, with IMRT and according to ICRU directions, there is the tendency to limit the high dose region to the part of the sub-site, involved by disease.", "cite_spans": [{"start": 302, "end": 306, "text": "[50]", "ref_id": "BIBREF49"}], "ref_spans": []}, {"section": "Positive neck nodes (GTV-N): high dose volume (CTV-N 1)", "text": "Lymph node stations or levels in the neck follow the surgical nomenclature. Cervical nodes are usually considered positive on contrast-enhanced CT scans if they show one or more of the following features: maximum axial diameter > 1 cm (5 mm if retropharyngeal); oval/ round as opposed to reniform shape; suspected focal necrotic hypodensity; irregular enhancement pattern; presence of extra-capsular penetration as judged by spiculated margins [51] and clusters of 3 or more borderline nodes [52] . A station is considered positive if it contains positive lymph nodes. For positive nodes, a 'full' radiation dose is usually recommended. However, in this case, only the positive lymph node(s) and not the whole station is (are) contoured as GTV. Moreover, expansion from GTV to CTV1 does not imply that the whole level would be part of CTV1. Some authors would add 5 [41]-10 [53]mm around the GTV of lymph nodes to account for potential subclinical (extracapsular) spread [41] .", "cite_spans": [{"start": 444, "end": 448, "text": "[51]", "ref_id": "BIBREF50"}, {"start": 492, "end": 496, "text": "[52]", "ref_id": "BIBREF51"}, {"start": 971, "end": 975, "text": "[41]", "ref_id": "BIBREF40"}], "ref_spans": []}, {"section": "Intermediate dose volume: high risk volume (CTV 2)", "text": "Within a definitive treatment, the definition of the intermediate dose region is highly subjective, variable across Institutions [18] and considered optional. Ideally it would correspond to the regions at high risk of containing microscopic disease (>10-20% [54, 55] ), preferential regions of diffusion around the primary tumour [56] or lymph nodes that are borderline or suspicious. (i.e. between 7-9 mm in greatest axial dimension in neck levels III through IV; with a rounded appearance defined as a width to length ratio greater than 0.5; lack of fatty hilum or a cluster of three or more borderline nodes) [51, 57] . The factors affecting this risk should be taken into account for each case: tumour stage, size, thickness (3 mm or more is associated with a high metastatic risk for oral cavity tumours), differentiation, keratinization status, lymphatic vessel invasion in the tumour specimen, and whether other neck levels are involved [16] .", "cite_spans": [{"start": 129, "end": 133, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 258, "end": 262, "text": "[54,", "ref_id": "BIBREF53"}, {"start": 263, "end": 266, "text": "55]", "ref_id": "BIBREF54"}, {"start": 330, "end": 334, "text": "[56]", "ref_id": "BIBREF55"}, {"start": 612, "end": 616, "text": "[51,", "ref_id": "BIBREF50"}, {"start": 617, "end": 620, "text": "57]", "ref_id": "BIBREF56"}, {"start": 944, "end": 948, "text": "[16]", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "Intermediate dose volume: high risk volume (CTV 2)", "text": "Again, as for positive nodes, it is unclear whether the whole level at risk should be included within a given higher dose or only the suspicious node. We usually favour the latter, since in one study all neck failures originated from pre-treatment suspicious nodes [18] .", "cite_spans": [{"start": 265, "end": 269, "text": "[18]", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "Elective neck contouring: low risk volume (CTV 3)", "text": "There are several definitions available for neck nodal levels and here we will refer to the one used by cooperative groups (RTOG/EORTC). Accordingly, there are several papers and atlases that have reported guidelines for nodal level contouring both without and after surgery [47, 58, 59] . Compared to volumes treated with 3DCRT, current definitions of neck levels provide only partially overlapping volumes and the mismatch is particularly evident for some levels (i.e. levels IB and V) [59] . However, once identified, it is possible to irradiate precisely and selectively different node levels wit IMRT. Hereafter we will refer to the neck nodal levels ipsi-and contralateral to the primary site for each subsite.", "cite_spans": [{"start": 275, "end": 279, "text": "[47,", "ref_id": "BIBREF46"}, {"start": 280, "end": 283, "text": "58,", "ref_id": "BIBREF57"}, {"start": 284, "end": 287, "text": "59]", "ref_id": "BIBREF58"}, {"start": 488, "end": 492, "text": "[59]", "ref_id": "BIBREF58"}], "ref_spans": []}, {"section": "Elective neck contouring: low risk volume (CTV 3)", "text": "Finally, it would be appropriate to include the whole muscle (i.e. sternocleidomastoid muscle) in CTV3/LR or when grossly infiltrated at some level.", "cite_spans": [], "ref_spans": []}, {"section": "Organ at risk (OAR) Definition", "text": "Several OARs and tissues are routinely contoured on each patient planning CT as follows: mandible/TM joints, brain, brainstem, cord, parotid glands, upper gastrointestinal mucosa, larynx, oesophagus, brachial plexuses, inner ears, optic chiasm, optic nerves, ocular bulbs, lenses, major lacrimal glands, pituitary gland, submental connective tissue. For planning purposes, the cord and brainstem are usually expanded (by 5 mm) as well as the optic pathway structures (optic chiasm, optic nerves and both retinas) to form a PRV (planning reference volume). PRV expansion, as PTV expansion, depends on set-up accuracy and set-up errors as well as on the IGRT technique.", "cite_spans": [], "ref_spans": []}, {"section": "Organ at risk (OAR) Definition", "text": "Optional (that are usually not constrained) OARs include: submandibular glands, thyroid gland, masticatory spaces, upper, middle, and inferior constrictor muscles, crico-pharyngeal muscle, carotid arteries, lung apexes.", "cite_spans": [], "ref_spans": []}, {"section": "OARs dose (volume) objectives", "text": "Dose volume objectives are summarized in the Table 2 .", "cite_spans": [], "ref_spans": [{"start": 45, "end": 52, "text": "Table 2", "ref_id": "TABREF3"}]}, {"section": "OARs dose (volume) objectives", "text": "Contouring indications and structured atlases [60, 61] can be herein found:", "cite_spans": [{"start": 46, "end": 50, "text": "[60,", "ref_id": "BIBREF59"}, {"start": 51, "end": 54, "text": "61]", "ref_id": "BIBREF60"}], "ref_spans": []}, {"section": "OARs dose (volume) objectives", "text": "http://groups.eortc.be/radio/res/gregoiratlas/ ln_levels_neck.pdf; http://www.rtog.org/LinkClick.aspx?fileticket = TjrmNiHXly8%3d&tabid = 229. Dose and constraints reporting and recording should be standardized according to Institution guidelines.", "cite_spans": [], "ref_spans": []}, {"section": "OARs dose (volume) objectives", "text": "The tolerance parameters reported here have only an indicative value since they may vary significantly among individual patients based on genetic factors, co-morbidities, concurrent or previous treatments, clinical status, habits and supportive treatments. Moreover, it should be noted that dose fractionation may influence the risk of both acute (weekly total dose) and late (d./f.) reactions. The doses reported below should to be considered equivalent to 2 Gy d./f.; their use at a lower d./f. would be conservative, or allow for extra safety.", "cite_spans": [], "ref_spans": []}, {"section": "PTV dose (volume) objectives", "text": "The process of developing a treatment plan consists of 3 components: (1) the definition and description of the \"planning aims\" and the desired absorbed-dose levels; (2) a complex beam delivery \"optimization\" process to achieve and, if needed, modify the initial \"planning aims\"; (3) a complete set of finally accepted values, which becomes the \"prescription\". When optimized, the absorbed-dose distribution is accepted by the physician.", "cite_spans": [], "ref_spans": []}, {"section": "PTV dose (volume) objectives", "text": "In the Literature different parameters regarding PTV prescription and dose homogeneity are reported [62] [63] [64] .", "cite_spans": [{"start": 100, "end": 104, "text": "[62]", "ref_id": "BIBREF61"}, {"start": 105, "end": 109, "text": "[63]", "ref_id": "BIBREF62"}, {"start": 110, "end": 114, "text": "[64]", "ref_id": "BIBREF63"}], "ref_spans": []}, {"section": "PTV dose (volume) objectives", "text": "Hereinafter, the prescription dose is defined as the isodose encompassing at least 95% of the PTV.", "cite_spans": [], "ref_spans": []}, {"section": "PTV dose (volume) objectives", "text": "Target dose restrictions include the followings: no more than 20% of any PTV could receive >110% of its prescribed dose, no more than 1% of any PTV would receive <93% of the prescribed dose, and no more than 1% or 1 cc of the tissue outside the PTV would receive >110% of the dose prescribed to the primary target [17] . [67] , but no clear advantage (and possibly disadvantage) in terms of target coverage and OAR sparing. Although this is a rapidly evolving field, the impression is that VMAT/RA may not offer the same dose distribution of IMRT/Tomotherapy for complicated cases [67] . Within this uncertainty, it seems reasonable to implement VMAT/RA, at least initially, in simple cases and with a dosimetric comparison to standard IMRT. Tissue deformation during treatment. Most patients undergoing RT \u00b1 CT for HNC may lose a significant proportion of their weight (on averages 6% to 12% of pre-treatment body weight [68] ) during a 7-week course. Sometimes, large nodal masses show a dramatic shrinkage [69] ; especially when adjacent to surrounding normal structures (cord, parotids), the dose distribution during treatment may deviate significantly during treatment compared to initial planning [70] . Finally, it has been shown that almost all OARs undergo significant changes during treatment, with about 30% of shrinkage for major salivary glands, 10% for muscles (with the exception of constrictors) and 15% increase for larynx and constrictors [71] . The cord, the brain and other nervous tissue structures seem unaffected. An adequate supportive/nutritional treatment (including enteral feeding) has proven to limit weight loss during treatment, increase patient compliance and ultimately patient's quality of life [72] . Which is the role of daily IGRT and adaptive re-planning in this setting is still undefined. Daily IGRT may reduce both systematic and random errors and thus may be preferable over weekly KV orthogonal films that address only the former [73] , though no firm clinical data support this recommendation. One issue with the HN district is the relative motion of structures, i.e. the mandible and shoulders relatively to the neck and the deformability of structures (i.e. neck curvature). These limit the success of corrections using translations. Re-planning should be currently limited to cases where the changes in anatomy jeopardize the clinical outcome, i.e. increase in dose to the cord due to shrinking neck masses [70] . Fortunately, only a minority of cases (<5%) show such modifications during treatment, and overall most patients still fail within the high dose region suggesting that geographic misses both at planning and during treatment are not a prevalent cause of failure. At present, rescanning of the patient during treatment (with subsequent recalculation of the dose distribution on the new planning CT \u00b1 re-optimization) is considered at some Institutions mainly in patients with significant (>10%) weight loss or (nodal) tumour changes. Dental artefacts and tissue heterogeneity calculation. Metal artefacts, in form of fixed intracavitary dental alloys, may induce dose alterations with dose enhancement that can lead to adverse tissue complications in OARs in contact to or near PTVs, and dose attenuation that may potentially spare cells within the target volume. Two methods have been proposed to limit tissue heterogeneity. A method that uses a model with four different material classes: air, soft tissue, bone, and metal. Pixels belonging to the same class are assigned to the same representative Hounsfield unit (HU). The HU of the pixels in the streaks resulting from the presence of metal are replaced as much as possible by the Hounsfield units of the soft tissue class or bone class [74] , thus reducing artefact influence on dose calculation. Another method uses MV-CT imaging obtained with the treatment machine, with the patient in the treatment position, that can be registered with the simulation kV-CT scan for the purposes of structure delineation, dose calculation, and treatment planning [75] . Alternatively, a simple/basic empirical method is to override tissue density in the metal region after contouring. In this setting it is always prudent to rerun the dose calculation with the original tissue heterogeneity to better appreciate significant deviations.", "cite_spans": [{"start": 314, "end": 318, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 321, "end": 325, "text": "[67]", "ref_id": "BIBREF66"}, {"start": 581, "end": 585, "text": "[67]", "ref_id": "BIBREF66"}, {"start": 922, "end": 926, "text": "[68]", "ref_id": "BIBREF67"}, {"start": 1009, "end": 1013, "text": "[69]", "ref_id": "BIBREF68"}, {"start": 1203, "end": 1207, "text": "[70]", "ref_id": "BIBREF69"}, {"start": 1457, "end": 1461, "text": "[71]", "ref_id": "BIBREF70"}, {"start": 1729, "end": 1733, "text": "[72]", "ref_id": "BIBREF71"}, {"start": 1973, "end": 1977, "text": "[73]", "ref_id": "BIBREF72"}, {"start": 2454, "end": 2458, "text": "[70]", "ref_id": "BIBREF69"}, {"start": 3750, "end": 3754, "text": "[74]", "ref_id": "BIBREF73"}, {"start": 4064, "end": 4068, "text": "[75]", "ref_id": "BIBREF74"}], "ref_spans": []}, {"section": "PTV dose (volume) objectives", "text": "PTV and skin. Whenever the tumour or clinical target volume approaches the surface of the skin, part of the PTV can extend into the build-up region of incident photon beams or even into the surrounding air (so-called in-air PTV). Most dose-computation algorithms cannot accurately compute absorbed dose in build-up regions. This will lead to a convergence error, i.e., the optimizer does not reach a global minimum for the objective function [76] . Two solution are usually proposed: i. The PTVs are cropped so that they are restricted to 3 mm below the contoured body surface to prevent optimization issues in the build-up region except for areas where the skin is considered a part of the CTV. In the latter situation, a bolus is suggested, as stated in the \"simulation\" chapter. In addition, the PTV receiving lower dose is cropped from the overlapping higher dose PTV to facilitate optimization. After optimization, a skin flash region (virtual bolus) is used to obtain a sufficient fluence in surrounding air to cover the original PTV. ii. Planning-target-volumes are subdivided and a relaxation of the planning aims is used (ICRU 83). PTV overlapping OARs. The second solution proposed in previous situation is the preferred one when there is a PTV/PRV overlapping knowing that it is a trade-off between the coverage of the PTV with the aimed dose and the saving of OARs within the constraints.", "cite_spans": [{"start": 442, "end": 446, "text": "[76]", "ref_id": "BIBREF75"}], "ref_spans": []}, {"section": "Oral cavity", "text": "Cancers of the oral cavity are usually managed by upfront surgery and postoperative (chemo)RT. RT can be used as primary therapy for small (T1, T2) tumours of the oral cavity. Best results are with a combination of external beam radiation and brachytherapy. IMRT is often used for oral cavity SCC to limit the dose to OARs and primarily to the parotid glands. However, compared to 3DCRT, it is associated with longer delivery or treatment session time. This may not be an ideal option for patients, who, especially after extensive surgeries, due to accumulation of secretions in the mouth, may not tolerate the supine position. Sometimes suctioning secretions before treatment delivery helps to maintain the treatment position during IMRT. Furthermore some initial reports with IMRT register marginal failure especially in patients with perineural invasion raising the question whether conventional opposed lateral fields might be a better option, also highlighting the importance of target delineation [82] [83] . Table 3 shows the commonly used fractionation regimens in the curative setting. Table 4 shows the commonly used fractionation regimens in the post-operatve setting:", "cite_spans": [{"start": 1003, "end": 1007, "text": "[82]", "ref_id": "BIBREF81"}, {"start": 1008, "end": 1012, "text": "[83]", "ref_id": "BIBREF82"}], "ref_spans": [{"start": 1015, "end": 1022, "text": "Table 3", "ref_id": "TABREF4"}, {"start": 1095, "end": 1102, "text": "Table 4", "ref_id": "TABREF5"}]}, {"section": "Dose/fractionation remarks", "text": "Primary-tumour contour Definitive treatment 1. Table 5 describes anatomical landmarks in contouring various oral subsites 2. At least a 1 cm margin around the GTV should always be added. In cases where the extent of the tumour is difficult to visualise it's preferable to use a 15 mm margins. CTV to PTV expansion also need to consider the local motility of the target (i.e. oral tongue) with respect also to the use of immobilization devices (i.e. tongue depressor) and their reproducibility. Anisotropic expansions (up to 10 mm) are often used to accommodate regions at higher motility (i.e. the oral tongue).", "cite_spans": [], "ref_spans": [{"start": 47, "end": 54, "text": "Table 5", "ref_id": "TABREF7"}]}, {"section": "Postoperative treatments", "text": "A positive margin on the oral tongue can be an indication for re-resection. Even when converted to negative, an initial positive margin carries a worse prognosis than an initially negative one [84] and thus should be considered at high risk of failure. In oral tongue cancers, perineural invasion (PNI) is an adverse feature that qualifies for adjuvant treatment at the primary site; moreover, in case of PNI, the value of a negative margin is somewhat questionable due to the possibility of a skip metastasis along the nerve route. In case of direct nerve invasion, e. g. if the inferior alveolar nerve is positive, the infratemporal fossa should be included in the radiation field because cancer can spread retrograde through the nerve into infratemporal fossa and to the skull base. The infratemporal fossa should also be included in the radiation field for tumour adjacent to this nerve with extensive perineural invasion and for tumour invading the pterygoid muscle, which is most commonly seen in patients with retromolar trigone cancers [82] . The CTV3 includes the whole operative bed and reconstruction site (i.e. free flap, mandibular reconstruction).", "cite_spans": [{"start": 193, "end": 197, "text": "[84]", "ref_id": "BIBREF83"}, {"start": 1044, "end": 1048, "text": "[82]", "ref_id": "BIBREF81"}], "ref_spans": []}, {"section": "Lymph-node station contour", "text": "The neck (at least on the side of the disease) is often dissected during the removal of the primary tumour. As such, it is usually included in the lowest dose level regardless of pathology findings (just because part of the operative bed and thus potentially contaminated). A further dose is best judged based on the final pathology findings (high risk features, see above). Sometimes the clinically negative neck is not dissected (usually when the indication for RT is based on other findings that are already known at the time of surgery-i.e. contralateral to cN+). When dissected, indications for adjuvant treatment include: pN > 1 (multiple pathologically involved nodes/multiple levels); single node with extracapsular extension; incomplete neck dissection (i.e. lack of level IV dissection in patients with pathologically positive level III); atypical node location (i.e. skip metastasis in level III) (see Table 1 ) for dose level definitions).", "cite_spans": [], "ref_spans": [{"start": 913, "end": 920, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Lymph-node station contour", "text": "Treatment of the neck can be unilateral for well lateralized lesions (i.e. buccal mucosa), in absence of cN2-N3 ipsilateral neck nodes [85] (see Table 6 ).", "cite_spans": [{"start": 135, "end": 139, "text": "[85]", "ref_id": "BIBREF84"}], "ref_spans": [{"start": 145, "end": 152, "text": "Table 6", "ref_id": "TABREF8"}]}, {"section": "Lymph-node station contour", "text": "Oral tongue primaries carry a higher risk of contralateral nodal disease than other oral cavity sites because of the rich bilateral lymphatic drainage [86] , therefore the bilateral neck should be irradiated in all oral tongue cancer patients with involved ipsilateral nodes, especially in high grade tumours or advanced T stages [82] .", "cite_spans": [{"start": 151, "end": 155, "text": "[86]", "ref_id": "BIBREF85"}, {"start": 330, "end": 334, "text": "[82]", "ref_id": "BIBREF81"}], "ref_spans": []}, {"section": "Lymph-node station contour", "text": "1. Oral tongue drainage is to ipsilateral level Ib and level II, III and even level IV with an incidence of skip metastasis of 10-15% [87] . An adequate elective neck dissection for oral tongue SCC includes levels Ib-IV. Five to ten percent of oral tongue cancers have bilateral lymph node metastases [88, 89] . 2. For oral cavity SCC, the risk of positive nodes is strictly correlated with the depth of primary tumour invasion. Three to 9 mm tumours have a 44% risk of positive nodes and a 7% risk of local recurrence; >9 mm thickness is associated with a 53% risk of subclinical nodes and 24% of local recurrence [90, 91] .", "cite_spans": [{"start": 134, "end": 138, "text": "[87]", "ref_id": "BIBREF86"}, {"start": 301, "end": 305, "text": "[88,", "ref_id": "BIBREF87"}, {"start": 306, "end": 309, "text": "89]", "ref_id": "BIBREF88"}, {"start": 615, "end": 619, "text": "[90,", "ref_id": "BIBREF89"}, {"start": 620, "end": 623, "text": "91]", "ref_id": "BIBREF90"}], "ref_spans": []}, {"section": "Lymph-node station contour", "text": "3. The floor of mouth and tip of the tongue drain to levels Ia, Ib and II. The incidence of bilateral lymph node involvement is relatively high because many lesions are near or cross the midline [88, 89] . 4. Tumours of the buccal mucosa and hard palate not exceeding midline drain to ipsilateral level Ib. 5. For well-lateralized lesions (at least 1.5 cm from midline) only the ipsilateral neck should be considered for treatment, especially in absence of N2-N3 disease (except for oral tongue, see above). 6. In general, for cN0-1, elective nodal stations include Ib-III with the exceptions of IIb (Table 6) . The addition of level Ia is for lesions of the floor of mouth, oral tongue and lower gingiva. Adding level IV is for lesions of the oral tongue, especially if in the posterior 2/3. 7. The likelyhood that an oral cavity cancer involving cervical lymph nodes of levels I to III would also involve level IV is generally stated as 7% to 17%, and the corresponding rate for level V is 0 to 6% [92, 93] ; 8. For cN2-3, elective irradiation of level V is advised; in case of extension to the tonsillar region, also retropharyngeal nodes should be included.", "cite_spans": [{"start": 195, "end": 199, "text": "[88,", "ref_id": "BIBREF87"}, {"start": 200, "end": 203, "text": "89]", "ref_id": "BIBREF88"}, {"start": 1000, "end": 1004, "text": "[92,", "ref_id": "BIBREF91"}, {"start": 1005, "end": 1008, "text": "93]", "ref_id": "BIBREF92"}], "ref_spans": [{"start": 600, "end": 609, "text": "(Table 6)", "ref_id": "TABREF8"}]}, {"section": "Nasopharynx (NPX)", "text": "Standard treatment of nasopharyngeal carcinoma is definitive RT \u00b1 CT. Target definition remarks (Table 7) 1. CTV1 = GTV+ a margin of \u2265 5 mm should be given circumferentially but can be 0-1 mm if anatomical barriers are present. CT and MRI should be used to A surgery-to-RT interval of <6 weeks improves local-regional control.", "cite_spans": [], "ref_spans": [{"start": 96, "end": 105, "text": "(Table 7)", "ref_id": "TABREF10"}]}, {"section": "Nasopharynx (NPX)", "text": "identify the primary tumour location [20, 94] (Figure 2) . Indeed, the clivus and nerves are best seen on MRI. 2. CTV 2 = whole NPX (Table 7) should be included in high risk volume regardless T site [20, 95, 96] . Indeed Sham observed that only 7% of patients had involvement of one subsite regardless of T site [95] .", "cite_spans": [{"start": 37, "end": 41, "text": "[20,", "ref_id": "BIBREF19"}, {"start": 42, "end": 45, "text": "94]", "ref_id": "BIBREF93"}, {"start": 199, "end": 203, "text": "[20,", "ref_id": "BIBREF19"}, {"start": 204, "end": 207, "text": "95,", "ref_id": "BIBREF94"}, {"start": 208, "end": 211, "text": "96]", "ref_id": "BIBREF95"}, {"start": 312, "end": 316, "text": "[95]", "ref_id": "BIBREF94"}], "ref_spans": [{"start": 46, "end": 56, "text": "(Figure 2)", "ref_id": "FIGREF1"}, {"start": 132, "end": 141, "text": "(Table 7)", "ref_id": "TABREF10"}]}, {"section": "Nasopharynx (NPX)", "text": "The most outer boundary of CTV2 should be at least 10 mm from the GTV.", "cite_spans": [], "ref_spans": []}, {"section": "Pathology remarks", "text": "Histological subtypes: the old WHO classification of nasopharyngeal carcinomas [98] , yet widely used in literature, should be replaced by the new one [99] [104] . c) Of note, the same radiation dose is prescribed for all variants. Table 8 shows the commonly used fractionation regimens:", "cite_spans": [{"start": 79, "end": 83, "text": "[98]", "ref_id": "BIBREF97"}, {"start": 151, "end": 155, "text": "[99]", "ref_id": "BIBREF98"}, {"start": 156, "end": 161, "text": "[104]", "ref_id": "BIBREF103"}], "ref_spans": [{"start": 232, "end": 239, "text": "Table 8", "ref_id": "TABREF9"}]}, {"section": "Dose/fractionation remarks", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Primary-tumour contour", "text": "Anatomic considerations (see also Table 7 ).", "cite_spans": [], "ref_spans": [{"start": 34, "end": 41, "text": "Table 7", "ref_id": "TABREF10"}]}, {"section": "Primary-tumour contour", "text": "1. NPX is usually divided into 3 subsites: a) posterosuperior wall: extends from the level of the junction of To mandible/medial pterygoid muscle on both sides.", "cite_spans": [], "ref_spans": []}, {"section": "Primary-tumour contour", "text": "Includes both parapharyngeal spaces. 1. Induction CT is sometimes used for neoadjuvant purposes to shrink and downsize the tumour especially when it is abutting OARs whose tolerance is inferior to the prescribed GTV dose (i.e. brainstem). In this case, the pre-induction target should receive full dose [29, 109] (Figure 2 ), but the dose to the original site of disease is often limited to The patient should be simulated supine with the head hyperextended [110] to provide adequate separation between the primary lesion/retropharyngeal lymph node and the upper neck field and to avert eyes from the primary volume, or in neutral position.", "cite_spans": [{"start": 303, "end": 307, "text": "[29,", "ref_id": "BIBREF28"}, {"start": 308, "end": 312, "text": "109]", "ref_id": "BIBREF108"}, {"start": 458, "end": 463, "text": "[110]", "ref_id": "BIBREF109"}], "ref_spans": [{"start": 313, "end": 322, "text": "(Figure 2", "ref_id": "FIGREF1"}]}, {"section": "Lymphnode-level contour", "text": "Anatomic considerations. There are three distinct pathways of lymphatic drainage from the nasopharynx: i. Postero-inferiorly to the retropharyngeal nodes (including the node of Rouviere); ii. Directly to superior deep cervical nodes; iii. Laterally to mastoid and spinal accessory nodes (level V). The initial lymphatics (including capillary network and precollectors) arise in the wall of the nasal fossae and the nasopharynx.", "cite_spans": [], "ref_spans": []}, {"section": "Lymphnode-level contour", "text": "The lymphatic collectors run into the parapharyngeal space to the lateral pharyngeal and retropharyngeal lymph nodes. They run through the lateral wall of the nasopharynx and form two lymph collectors (lateral and medial) that descend laterally to the pharyngeal wall in the parapharyngeal fat tissue:", "cite_spans": [], "ref_spans": []}, {"section": "Lymphnode-level contour", "text": "i. the lateral one is situated on the lateral side of the external carotid artery; ii. the medial is located one medially along the external carotid artery.", "cite_spans": [], "ref_spans": []}, {"section": "Lymphnode-level contour", "text": "The lateral group provides lymphatic drainage from the lateral walls (including Rosenmuller Fossa) directly into deep nodes of the posterior triangle (upper level V) while the medial trunk drains to the superior deep cervical nodes (levels II and III) [111, 112] .", "cite_spans": [{"start": 252, "end": 257, "text": "[111,", "ref_id": "BIBREF110"}, {"start": 258, "end": 262, "text": "112]", "ref_id": "BIBREF111"}], "ref_spans": []}, {"section": "Lymphnode-level contour", "text": "Neoplastic-behaviour considerations 1. The primary lymphatic drainage of nasopharyngeal carcinoma is to retropharyngeal, II and Va nodal levels. Setting the cranial border of level IIb node at the skull base should be considered when delineating nodal target volume [113] . 2. The secondary lymphatic drainage is to levels III and Vb [114] . 3. Level IV is involved in 10% of the cases [115] . 4. Level Ib is rarely involved; it has to be included only in case of clinical adenopathy evidence [115] . It should be noted, however, that the posterior part of level Ib was routinely irradiated in the old days [59] . 5. Lymphatic drainage is bilateral. Therefore, both sides of the neck are at risk [41] (Table 9 ). 6. Retropharyngeal nodes (top of C1 to bottom of C2, sometimes C3 [108, 116] ) should be always included in the CTV2.", "cite_spans": [{"start": 266, "end": 271, "text": "[113]", "ref_id": "BIBREF112"}, {"start": 334, "end": 339, "text": "[114]", "ref_id": "BIBREF113"}, {"start": 386, "end": 391, "text": "[115]", "ref_id": "BIBREF114"}, {"start": 493, "end": 498, "text": "[115]", "ref_id": "BIBREF114"}, {"start": 607, "end": 611, "text": "[59]", "ref_id": "BIBREF58"}, {"start": 696, "end": 700, "text": "[41]", "ref_id": "BIBREF40"}, {"start": 779, "end": 784, "text": "[108,", "ref_id": "BIBREF107"}, {"start": 785, "end": 789, "text": "116]", "ref_id": "BIBREF115"}], "ref_spans": []}, {"section": "Lymphnode-level contour", "text": "Few studies have investigated the option to withhold elective treatment for cN0 patients. One of them found a high regional salvage rate with either surgery or RT [117] . It should be noted, however, that patients with residual persistent disease in the neck or who fail in the neck have a higher risk of distant metastases than patients who do not fail in the neck. Therefore, comprehensive neck irradiation (including levels II-V) is always advocated for NP.", "cite_spans": [{"start": 163, "end": 168, "text": "[117]", "ref_id": "BIBREF116"}], "ref_spans": []}, {"section": "Oropharynx", "text": "The oropharynx is usually divided into 4 sub-sites: tonsil, base of tongue, pharyngeal walls and soft palate. While sub-site only is not a predictor of treatment outcome, HPV related tumours, with a more favourable prognosis compared to their alcohol and tobacco counterparts, usually originate from the base of tongue or tonsils. Currently there are no practical implications or differences between HPV positive and negative tumours. Table 10 shows the common fractionation regimen.", "cite_spans": [], "ref_spans": [{"start": 435, "end": 443, "text": "Table 10", "ref_id": "TABREF0"}]}, {"section": "Dose/fractionation remarks", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Primary-tumour contour", "text": "Historical perspective:", "cite_spans": [], "ref_spans": []}, {"section": "Primary-tumour contour", "text": "1. In the standard 3-field era, the whole oropharynx was included in the low dose region and the primary tumour boosted to the final dose. Whether the whole oropharynx should be included in the low risk region is somewhat controversial and no definitive recommendations can be made. However, some Authors, especially in presence of HPV related tumours (that seem to have a lower risk of field cancerization) tend to limit the low risk volume (CTV3) to the sub-site involved or, at most, the adjacent one (i.e. in Table 9 Guidelines for contouring bilateral neck levels (negative on imaging) case of a tonsillar tumour, CTV3 would include the involved tonsil and the tongue base but not the contralateral tonsil). 2. In the old days, a typical initial field for a tonsillar tumour included the whole pterygoid plates up to the base of skull; therefore it is recommended that CTV3 cover the whole pterygoids as well.", "cite_spans": [], "ref_spans": []}, {"section": "Primary-tumour contour", "text": "Clinical and anatomical considerations 1. Trismus is a surrogate of medial pterygoid muscle invasion and in this case a generous margin along with the medial pterygoid muscle should be contoured during CTV1 definition; 2. The anterior extent of the GTV in the tongue base is best evaluated via contrasted CT or even better with MRI; due to subclinical anterior extension, especially for infiltrative primary tongue base tumours, a generous margin (1.5-2 cm) around both CTV1 and CTV3 should be added anteriorly; 3. Patients with dentures that are likely to create visual artefacts should be positioned with the head in a different position (more flexed or extended); moreover, the location of the primary tumour should be driven by a different study, i.e. MRI; 4. After primary tumour (surgical) removal, unless the original location of the primary is clearly available and visible on a dedicated study, the whole sub-site should be part of CTV; 5. Parapharyngeal space is a locus minoris resistentiae and needs to be included in the CTV in the case of possible/suspected local extension and/or retro/ parapharyngeal node involvement ( Figure 3 ).", "cite_spans": [], "ref_spans": [{"start": 1136, "end": 1144, "text": "Figure 3", "ref_id": "FIGREF2"}]}, {"section": "Lymphnode-level contour", "text": "1. The primary lymphatic drainage of oropharyngeal SCC is to levels II, III and retropharyngeal nodes. Bilateral spread is fairly common for lesions that approach midline (such as in the case of the tongue base and soft palate), while it is relatively rare for well lateralized lesions (at least 1.5 cm from midline as in the case of tonsil primaries) in absence of multiple or large (>3 cm) lymph nodes; in addition, lesions arising or involving the soft palate have an increased risk of level I (Ib) involvement; 2. When the primary tumour is well lateralized (e.g. tonsil) and the ipsilateral neck shows limited involvement (N0-1, questionable N2a), contralateral neck coverage can be omitted; 3. Some Authors [59, 119] would limit level IB coverage to its most posterior part. The anterior extent of the contour of level IB when included in CTV3 would stop at the anterior extent of the submandibular gland and, therefore, exclude the triangular fat space lateral to the deep extrinsic muscles of the tongue. 4. Retropharyngeal nodes (top of C1 to bottom of C2, sometimes C3) should be always included in the CTV3 unless suspicious (>5 mm). 5. In case of suspicious neck nodes (as previously defined) and lymph node enlargement in other sites than ipsilateral levels II and III, the suspicious finding and not the whole level should be contoured as CTV2. 6. Table 11 provides some indications for contouring ipsilateral and contralateral neck levels that are negative at imaging.", "cite_spans": [{"start": 713, "end": 717, "text": "[59,", "ref_id": "BIBREF58"}, {"start": 718, "end": 722, "text": "119]", "ref_id": "BIBREF118"}], "ref_spans": [{"start": 1362, "end": 1370, "text": "Table 11", "ref_id": "TABREF0"}]}, {"section": "Hypopharynx", "text": "SCC of the hypopharynx is usually diagnosed at a later/advanced stage. Moreover, due to local (submucosal) invasion, it is usually considered more aggressive/less radioresponsive than its laryngeal counterpart. Concomitant CT is usually indicated for T3-4 or anyT N+ [120] [121] [122] [123] , but some Authors in monoinstitutional experience [124, 125] claim the use of concomitant CT also for earlier T stage (T2) lesions even if the only two large randomized trials specifically addressing the hypopharyngeal cancer subset [126, 127] with few T2 patients included, used sequential or alternate ChT and RT and not concomitant treatments. In patient unfit for standard concomitant CT, induction CT or the concomitant association with Erbitux can be considered [11] . Due to concerns regarding treatment-related late toxicities, hypofracionation delivered with SIB is not recommended [122, 128] .", "cite_spans": [{"start": 267, "end": 272, "text": "[120]", "ref_id": "BIBREF119"}, {"start": 273, "end": 278, "text": "[121]", "ref_id": "BIBREF120"}, {"start": 279, "end": 284, "text": "[122]", "ref_id": "BIBREF121"}, {"start": 285, "end": 290, "text": "[123]", "ref_id": "BIBREF122"}, {"start": 342, "end": 347, "text": "[124,", "ref_id": "BIBREF123"}, {"start": 348, "end": 352, "text": "125]", "ref_id": "BIBREF124"}, {"start": 525, "end": 530, "text": "[126,", "ref_id": "BIBREF125"}, {"start": 531, "end": 535, "text": "127]", "ref_id": "BIBREF126"}, {"start": 760, "end": 764, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 883, "end": 888, "text": "[122,", "ref_id": "BIBREF121"}, {"start": 889, "end": 893, "text": "128]", "ref_id": "BIBREF127"}], "ref_spans": []}, {"section": "Target definition remarks", "text": "CTV2. After surgery, CTV2 would include the whole laryngo-pharynx bed with particular attention to the cranial and caudal extent of resection (i.e. cervical oesophagus) and the site of dissected positive lymph nodes;", "cite_spans": [], "ref_spans": []}, {"section": "Dose/fractionation remarks Primary-tumour contour", "text": "Historical perspective: In the old days, the lower extent of tumour coverage (cricoid cartilage) needed a low neck junction that was particularly troublesome in patients with a short neck; nowadays with IMRT, the issue about adequate coverage of the caudal part of the CTV is overcome [128] . Clinical and anatomical considerations The hypopharynx consists of the pyriform sinuses, postcricoid region and posterior pharyngeal wall. The anatomic boundaries of the hypopharynx include the ariepiglottic folds (superiorly), the cricoid cartilage (inferiorly), the prevertebral fascia (posteriorly) and the larynx (anteriorly). Unlike the larynx, the hypopharynx has no clear barriers to cancer extension. The boundary between the oropharynx and hypopharynx is theoretical and the boundaries between different subregions are more anatomical landmarks that real barriers. Because submucosal extensions are hardly visible, it is preferable to have larger volumes to reduce the risk of recurrence. Therefore, CTV2 would encompass 1-1.5 cm of normal mucosa cranial and caudal to CTV1 [129] . The lower extent of the tumour is best evaluated with a dedicated esophagoscopy.", "cite_spans": [{"start": 285, "end": 290, "text": "[128]", "ref_id": "BIBREF127"}, {"start": 1076, "end": 1081, "text": "[129]", "ref_id": "BIBREF128"}], "ref_spans": []}, {"section": "Dose/fractionation remarks Primary-tumour contour", "text": "Especially for lesions involving the medial wall of the pyriform sinus, the posterior part of the larynx (arytenoids and interarytenoid region) should be part of the CTV1 as well. Involvement and violation of the prevertebral fascia can be appreciated clinically (tumour fixation) and on imaging (MRI); in case of prevertebral space invasion, the lesion becomes unresectable and the margins for cranio-caudal microscopic tumor spread would be wider than usual. Indications to boost the stomal region after major surgery basically duplicate those for laryngeal primaries.", "cite_spans": [], "ref_spans": []}, {"section": "Dose/fractionation remarks Primary-tumour contour", "text": "Lymphnode-level contour Table 12 reports the most used fractionation schemes for laryngeal cancer. The standard dose for T1N0 of the glottic larynx is 66 Gy /33 fxs/6.5 weeks. For T1 glottic lesions, the d./f. used within 3DCRT has been up to 3.43 Gy [131] (Total dose 55Gy/16 fractions); there is limited experience with IMRT for this fractionation, and thus the recommendation is to limit the d./f. to 2.25 Gy to 56.25-63 Gy [132] in the context of IMRT. For T2 glottic lesions, RTOG 9512 found only trend in favour of hyperfractionation over standard fractionation [133] .", "cite_spans": [{"start": 251, "end": 256, "text": "[131]", "ref_id": "BIBREF130"}, {"start": 427, "end": 432, "text": "[132]", "ref_id": "BIBREF131"}, {"start": 568, "end": 573, "text": "[133]", "ref_id": "BIBREF132"}], "ref_spans": [{"start": 24, "end": 32, "text": "Table 12", "ref_id": "TABREF0"}]}, {"section": "Larynx", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Dose/fractionation remarks", "text": "For more advanced lesions (T3-4) of the larynx, there are consolidated data on the benefit of altered fractionation in terms of both local control and survival; the best outcome is reached with hyperfractionation [134] . However, hyperfractionation hardly fits into an IMRT technique for reasons that have been previously discussed; moreover with the advent of ChT, RT alone is rarely used for T3-4 lesions.", "cite_spans": [{"start": 213, "end": 218, "text": "[134]", "ref_id": "BIBREF133"}], "ref_spans": []}, {"section": "Dose/fractionation remarks", "text": "In the postoperative setting, the most used schedule is: 66 Gy in 33 fractions (2 Gy daily) to CTV1, 59.4 Gy in 33 fractions (1.8 Gy daily) to CTV2 (optional) and 54,12/56,1 in 33 fractions (1.64-1.7 Gy daily) to CTV3.", "cite_spans": [], "ref_spans": []}, {"section": "Dose/fractionation remarks", "text": "After subtotal laryngectomies (horizontal supraglottic laryngectomy-HSL, near total laryngectomy, hemilaryngectomy) there is the concern that adjuvant RT (\u00b1ChT) may jeopardize the functional outcome of the residual or surgically spared larynx [135] . For example, after HSL (horizontal supraglottic laryngectomy), it has been found that 60 Gy radiation significantly increases the risk of laryngeal edema (over 50 Gy) [136] . Therefore, unless specifically indicated (positive resection margins) and after careful discussion with the patient, the dose to the larynx should be kept within 50 Gy (see also below) [137, 138] .", "cite_spans": [{"start": 243, "end": 248, "text": "[135]", "ref_id": "BIBREF134"}, {"start": 418, "end": 423, "text": "[136]", "ref_id": "BIBREF136"}, {"start": 611, "end": 616, "text": "[137,", "ref_id": "BIBREF137"}, {"start": 617, "end": 621, "text": "138]", "ref_id": "BIBREF138"}], "ref_spans": []}, {"section": "Primary-tumour contour", "text": "The larynx is divided into three anatomic regions: Supraglottis -suprahyoid epiglottis, infrahyoid epiglottis, aryepiglottic folds (laryngeal aspect), arytenoids, and ventricular bands (false cords). Glottis -true vocal cords, including anterior and posterior commissures. Subglottissubglottis, extending from lower boundary of the glottis to the lower margin of the cricoid cartilage [139] .", "cite_spans": [{"start": 385, "end": 390, "text": "[139]", "ref_id": "BIBREF139"}], "ref_spans": []}, {"section": "Definitive treatments", "text": "Anatomical considerations 1. Target volumes are defined according to the pathways of cancer extension in the larynx (Figure 3) . Cancer of the larynx mainly spreads by direct extension (following the line of least resistance), prior to lymphatic spread and more rarely follows the vascular and neurological routes.", "cite_spans": [], "ref_spans": [{"start": 116, "end": 126, "text": "(Figure 3)", "ref_id": "FIGREF2"}]}, {"section": "Definitive treatments", "text": "The main way of diffusion of laryngeal cancer is to para-glottic and to the pre-epiglottic spaces through the anterior commissure, the thyro-epiglottic and thyro-arytenoid ligaments (upper and lower), the ligament and crico-thyroid membrane, the perforations of the sub-hyoid epiglottis, the bottom of the ventricle and laterally through the thyroid cartilage. These two spaces also play an important role for the T classification, as neoplastic invasion of these spaces upstages laryngeal cancer to T3. Therefore, if these structures are directly encompassed by GTV, CTV1 should include also pre-epiglottic and para-glottic space.", "cite_spans": [], "ref_spans": []}, {"section": "Definitive treatments", "text": "Historical perspective 1. In the 3DCRT era the whole larynx or the majority of it was included in the CTV1; nowadays there is the tendency to include in the CTV1 only the expanded GTV; however, careful considerations about the depth of invasion, the natural history of disease, the presence/absence of anatomical barriers (i.e. continuity between pre-epiglottic and para-glottic spaces ( Figure 3 ) and the quality of the imaging should always be taken into consideration; the use of anatomic compartments to define CTV boundaries is more adequate than the use of any arbitrary uniform expansion around the GTV, unless such boundaries are not well-defined, such as the anterior boundary in case of base of the tongue involvement [50] . Thus, the CTV1 corresponds to the GTV plus a margin of 5 mm to 1 cm or more, depending on the ways of diffusion or anatomical barriers (i.e. supraglottic tumours extending to the aryepiglottic folds will be outlined extending the superior margin of the CTV to 2 cm above the GTV; in case of infiltration of the base of tongue, a structure that does not present anatomical barriers, a margin of 1.5-2 cm is appropriate) and should not be modified according to a possible response to induction ChT. [140] . In correspondence of anatomical barriers GTV to CTV expansion should not exceed those structures (eg, prevertebral fascia, bone). In case of doubt of submucosal extension, it is better to enlarge the volumes to reduce the risk of recurrence. 2. The level of complexity required for the irradiation of laryngeal cancer is highly variable and IMRT may provide distinct advantages over 3DCRT in sparing OARs (parotids, especially when level IIb is part of the target, carotids for early stage lesions) and covering the target (avoiding field junctions and irradiating the subglottis especially in patients with a 'short' neck'). Though there are several dosimetric and even preliminary clinical experience with IMRT for T1-2 glottic cancers [141, 142] or for locoregionally advanced glottic and supraglottic cancers [121] [122] [123] , the clinical benefits of IMRT are usually speculative and the standard of care remains 3DCRT. Table 14 provides guidelines for contouring primary tumor CTVs on planning imaging:", "cite_spans": [{"start": 729, "end": 733, "text": "[50]", "ref_id": "BIBREF49"}, {"start": 1233, "end": 1238, "text": "[140]", "ref_id": "BIBREF140"}, {"start": 1979, "end": 1984, "text": "[141,", "ref_id": "BIBREF141"}, {"start": 1985, "end": 1989, "text": "142]", "ref_id": "BIBREF142"}, {"start": 2054, "end": 2059, "text": "[121]", "ref_id": "BIBREF120"}, {"start": 2060, "end": 2065, "text": "[122]", "ref_id": "BIBREF121"}, {"start": 2066, "end": 2071, "text": "[123]", "ref_id": "BIBREF122"}], "ref_spans": [{"start": 388, "end": 396, "text": "Figure 3", "ref_id": "FIGREF2"}, {"start": 2168, "end": 2176, "text": "Table 14", "ref_id": "TABREF0"}]}, {"section": "Postoperative treatments", "text": "In the postoperative setting, features that are usually considered predictors of local relapse are: i. close or positive margins; ii. pT4; iii. extracapsular extension of the neck nodes. Other features (i.e. perineural spread) are less recognized and need to be considered on a caseto-case basis. In order to outline postoperative volumes, pre-surgery imaging studies and operative note(s) should be carefully reviewed. Moreover, the natural history of the disease plays also an important role.", "cite_spans": [], "ref_spans": []}, {"section": "Postoperative treatments", "text": "In case of subglottic or soft tissue extension, the region of the stoma should be included in CTV2, while for upward lesions (i.e. lesions with significant anterior extension in the pre-epiglottic space) the base of tongue needs to be included in CTV2.", "cite_spans": [], "ref_spans": []}, {"section": "Postoperative treatments", "text": "After subtotal laryngectomy, the decision to include the larynx within the low dose level (even in absence of high risk features), simply because it has been part of the operative bed, is controversial [135] . However, regardless whether the larynx is included or not, careful planning should avoid unnecessary overdosing of the larynx (>50 Gy) in absence of specific indication (e.g. if the decision to irradiate a removed level II node with extracapsular extension is made, the larynx should not receive a dose higher than 50 Gy even though the lymph-nodal area at risk needed a dose higher than 60 Gy). For high risk patients (R1 and pT4) CTV1 should include the whole remnant larynx with cranial and caudal extent of resection (e.g. subglottic extension) and the site of dissected positive lymph-nodes.", "cite_spans": [{"start": 202, "end": 207, "text": "[135]", "ref_id": "BIBREF134"}], "ref_spans": []}, {"section": "Lymphnode-level contour", "text": "Anatomical considerations.", "cite_spans": [], "ref_spans": []}, {"section": "Supraglottic larynx", "text": "The lymphatic drainage terminates in the ipsilateral level II nodes while a second component extends lateral and drains into nodes located at the junction of Levels II and III. There is occasionally a third component that drains into the nodes located in Level III nodes.", "cite_spans": [], "ref_spans": []}, {"section": "Supraglottic larynx", "text": "Tumours involving the supraglottic larynx are at risk of crossing lymphatic drainage. The risk of palpable lymph nodes at presentation is higher for epi-laryngeal tumours than for the rest of supraglottic one [143] .", "cite_spans": [{"start": 209, "end": 214, "text": "[143]", "ref_id": "BIBREF143"}], "ref_spans": []}, {"section": "Glottic larynx", "text": "The true vocal cords (TVC) form a natural barrier between the supraglottic and infraglottic larynx due to its paucity of lymphatic draining. At any rate, the lymphatic drainage of sovraglottic or subglottic larynx can be involved by advanced TVC carcinoma.", "cite_spans": [], "ref_spans": []}, {"section": "Subglottic larynx", "text": "Lymphatics from the subglottic larynx drain to the mid and lower jugular lymph nodes (levels III and IV) and to the prelaryngeal (cricothyroid or Delphian) node. Subsequently, the pretracheal and paratracheal lymph nodes can be involved [144] . Tables 15 and 16 provide guidelines for contouring neck levels either in the case of negative or positive nodes on the imaging:", "cite_spans": [{"start": 237, "end": 242, "text": "[144]", "ref_id": "BIBREF144"}], "ref_spans": [{"start": 245, "end": 261, "text": "Tables 15 and 16", "ref_id": "TABREF0"}]}, {"section": "Subglottic larynx", "text": "Historical perspectives", "cite_spans": [], "ref_spans": []}, {"section": "Subglottic larynx", "text": "1. For T2N0 of the glottis, the standard recommendation is to treat the larynx only, but the actual results are based on pre-IMRT cases. Conventional RT used to irradiate with two lateral opposing fields. Authors showed that portions of the neck lymphatic chain where inadvertently treated [59, 133] . Therefore, it is advisable, in common practice, to irradiate levels II-III and III-IV especially when lesions extend into the supra or sub-glottis. 2. For primary lesions with subglottic involvement and clinically detectable lower neck nodes, the upper mediastinum (down to the level of the carina) was prophylactically covered with AP/PA fields. Therefore, inclusion of level VII in the CTV3 is advised in case of subglottic extension with significant and lower neck disease. 3. In the case of No, level IIb should not be irradiated.", "cite_spans": [{"start": 290, "end": 294, "text": "[59,", "ref_id": "BIBREF58"}, {"start": 295, "end": 299, "text": "133]", "ref_id": "BIBREF132"}], "ref_spans": []}, {"section": "Planning remarks", "text": "1. In case of suspicious neck nodes (as previously defined) it is unclear whether only the suspicious finding or the whole level should be included in the CTV2. For nodes belonging to lymph node stations different from ipsilateral levels II and III, the suspicious finding and not the whole level should be contoured as CTV2. , it is recommended to include at least the portion of the muscle surrounding the node [47] . Similarly, it would be appropriate to include the whole muscle (i.e. sternocleidomastoid muscle) in the lowest dose level when grossly infiltrated at some level. 3. After surgical removal of a lymph-node with extracapsular extension, the initial location of the node needs to be identified; careful planning should avoid underdosing of the surgical scar close to the pre-surgery location of the node (sometimes 3-5 mm skin bolus is necessary). 4. Subglottic cancer, transglottic cancer, and glottic cancer with subglottic extension have a higher risk of para-tracheal nodes involvement; for T > 2 even in N0 patients, this level should be included in CTV3 [57, 145] . 5. Ipsilateral Ib nodal level and parapharyngeal space extending to retrostyloid space should be included if level II nodes are positive.", "cite_spans": [{"start": 413, "end": 417, "text": "[47]", "ref_id": "BIBREF46"}, {"start": 1076, "end": 1080, "text": "[57,", "ref_id": "BIBREF56"}, {"start": 1081, "end": 1085, "text": "145]", "ref_id": "BIBREF145"}], "ref_spans": []}, {"section": "Paranasal sinuses and nasal cavity", "text": "Target definition remarks RT may be indicated as postoperative (i.e. adenocarcinomas) or definitive treatment with or without concomitant CT. Whereas the definitive treatment leads to the irradiation of the usual 3 CTVs as described in the general part, the previous surgical approach (midfacial degloving, lateral rhinotomy, craniofacial, or endoscopic) Detailed description of the surgical procedure and pathology report is mandatory. In the postoperative setting, there is no identifiable GTV and thus CTV1 is not available. CTV is represented by all areas at risk of containing residual microscopic disease and the choice between HR and LR depends on the risk for each sub-volume. Table 17 shows the commonly used fractionation regimens:", "cite_spans": [], "ref_spans": [{"start": 685, "end": 693, "text": "Table 17", "ref_id": "TABREF0"}]}, {"section": "Dose/fractionation remarks", "text": "Primary-tumour contour Table 18 describes the limits of the CTV2 for ethmoid and maxillary regions, according the suggestions of Stratt et al. [149] .", "cite_spans": [{"start": 143, "end": 148, "text": "[149]", "ref_id": "BIBREF149"}], "ref_spans": [{"start": 23, "end": 31, "text": "Table 18", "ref_id": "TABREF0"}]}, {"section": "Planning remarks", "text": "1. In regions where the GTV is flanked by anatomic barriers (i.e. intact bone), no margin is usually added.", "cite_spans": [], "ref_spans": []}, {"section": "Planning remarks", "text": "In regions where GTV involves compartments enclosed by bone (i.e. maxillary sinus), the whole compartment is contoured as CTV1. 2. When the tumour is in proximity of radiologically defined spaces known to poorly resist to invasion (i.e. masticator or para-pharyngeal spaces) either the entire space or at least part of it should be contoured as CTV2/3. The former is usually reserved for the part close/next to the tumour while the latter for the remaining part. 3. Similarly, when the tumour is abutting the medial wall of the orbit or there is minimal orbital invasion, the medial part (including the rectus medialis muscle) of the orbit has to be included into the CTV2/3. 4. The choice of the regions at risk for microscopic disease depends on the location of the primary tumour, its extension/stage, and pathology. In general, the palate, alveolar ridge, nasal cavity, and the nasopharynx are included in the CTV2/3 in case of maxillary sinus tumours, and the medial orbit in maxillary/ethmoid-sinus cancers. The pterygopalatine fossa and infratemporal fossa, frequently at risk of subclinical disease, are included in the CTV2/LR. Superior lesions require CTV extension to the sphenoid sinus and foramen rotundum at the base of skull to accommodate potential involvement of the maxillary nerve. 5. If MRI suggests neural involvement, the CTV2/3", "cite_spans": [], "ref_spans": []}, {"section": "Planning remarks", "text": "should be extended to include the cavernous sinus. For lesions in the upper nasal cavity and ethmoid sinuses, the cribriform plate and a rim of the frontal lobe are included in the CTV2/LR. The anterior cranial fossa is included in case of intracranial extension [16] .", "cite_spans": [{"start": 263, "end": 267, "text": "[16]", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "Planning remarks", "text": "6. As a general rule, after induction CT, the original location of the tumour (and not the residual) represents the CTV1. 7. In the postoperative setting, CTV2 consists of the resection cavity plus a variable margin according to the principles of a \"compartment-related CTV\" as described above. All surgically violated regions should be included in the lowest dose level CTV. 8. In case of adenoid cystic carcinoma, attention should be paid to the neural spread and, hence, RT volumes must encompass the afferent and efferent local nerves up to the skull base. 9. Esthesioneuroblastomas arise in the superior nasal cavity and, even at early stages, tend to invade the cribriform plate and anterior cranial fossa, and therefore, these regions should be encompassed in the target volume.", "cite_spans": [], "ref_spans": []}, {"section": "Planning remarks", "text": "Lymphnode-level contour", "cite_spans": [], "ref_spans": []}, {"section": "Planning remarks", "text": "1. Lymph node metastases are unusual, thus elective treatment of the neck is not mandatory (excluded in the cases of esthesioneuroblastomas, high-grade/ high-stage SCC or whenever the next anatomical regions (e.g. nasopharynx, cheek, gingiva or alveolus) are involved. 2. Lymphatic drainage from the paranasal sinuses is to the retropharyngeal, submandibular, and jugodigastric nodes [57] . Cervical metastases are below 10% at presentation thus not justifying elective dissection. For the same reason lymphnodes are usually not included in any CTV unless involved or at risk. The risk of involvement usually depends on the location of the primary tumour and the pathology. Adenocarcinomas and sinonasal undifferentiated cancers (SNUC) rarely spread to lymph nodes; some Authors claim prophylactic neck treatment for esthesioneuroblastomas [150] or SCC of the maxillary sinus [151, 152] . 3. Once prophylactic neck treatment is indicated, the side of the neck and the levels to be contoured depend on both the location of the tumour and its pathology. For maxillary sinus, levels IB and II represent the first echelon; for esthesioneuroblastomas, a comprehensive neck irradiation (levels IB-V) is the rule. Bilateral retropharyngeal nodes irradiation should be considered.", "cite_spans": [{"start": 384, "end": 388, "text": "[57]", "ref_id": "BIBREF56"}, {"start": 840, "end": 845, "text": "[150]", "ref_id": "BIBREF150"}, {"start": 876, "end": 881, "text": "[151,", "ref_id": "BIBREF151"}, {"start": 882, "end": 886, "text": "152]", "ref_id": "BIBREF152"}], "ref_spans": []}, {"section": "Planning remarks", "text": "1. After CTV to PTV expansion, overlap between PTV and OAR is frequent and optimal target coverage is often challenging.", "cite_spans": [], "ref_spans": []}, {"section": "Planning remarks", "text": "2. In general planning priorities are set to avoid a risk of late toxicity >10% on selected OARs as brain, brainstem, chiasm and optic nerves.In the planning process, any attempt should be made to maintain coverage of CTV1 while compromising the coverage of PTV in order to allow minor variations in selected OAR irradiation (i.e. V95% of CTV1 is >95% while PTV1 coverage is 93% and optic nerve Dmax is 59.9 Gy). 3. Proton Beam Therapy has shown good results and acceptable toxicity especially in locally advanced inoperable paranasal tumours [153, 154] .", "cite_spans": [{"start": 543, "end": 548, "text": "[153,", "ref_id": "BIBREF153"}, {"start": 549, "end": 553, "text": "154]", "ref_id": "BIBREF154"}], "ref_spans": []}, {"section": "Salivary glands", "text": "Target definition remarks Salivary gland tumours are usually treated with surgery. Curative RT alone is an option (even if the odds' local control is relatively low) for patients with technically unresectable disease or inoperable for medical reasons or who refuse surgery.", "cite_spans": [], "ref_spans": []}, {"section": "Salivary glands", "text": "Risk factors that support postoperative RT include T3/ T4 disease and or any of the following [155, 156] :", "cite_spans": [{"start": 94, "end": 99, "text": "[155,", "ref_id": "BIBREF155"}, {"start": 100, "end": 104, "text": "156]", "ref_id": "BIBREF156"}], "ref_spans": []}, {"section": "Salivary glands", "text": "Incomplete or close resection margins High grade histology Recurrent disease Peri-neural invasion Nodal involvement", "cite_spans": [], "ref_spans": []}, {"section": "Pathology remarks", "text": "Salivary gland tumours include a variety of both benign and malignant tumours that can involve both minor and major salivary glands. In major salivary glands the most frequent benign tumour is pleomorphic adenoma, whereas the most frequent malignant hystology is mucoepidermoid carcinoma; adenoid cystic carcinoma is the most frequent malignant tumour in minor salivary glands. Diagnosis is often difficult and experienced pathologist is needed to interpret fine needle aspiration cytology. Table 19 summarizes the most important pathology variants and the role of RT:", "cite_spans": [], "ref_spans": [{"start": 491, "end": 499, "text": "Table 19", "ref_id": "TABREF0"}]}, {"section": "Pathology remarks", "text": "External beam RT with photons is rarely a curative option since local control in malignant salivary gland tumours is dose dependent. Considering that high doses are needed to achieve local control, most malignant salivary gland tumours would probably benefit from the use of particle therapy. However, although locoregional control after neutron therapy seems to be higher than Ethmoid Cribriform plate should be included.", "cite_spans": [], "ref_spans": []}, {"section": "Pathology remarks", "text": "The inferior turbinate; In the case that the inferior border of the GTV allows a 10-mm margin around the original disease, the entire hard palate does not need to be included.", "cite_spans": [], "ref_spans": []}, {"section": "Pathology remarks", "text": "The nasal cavity, ethmoid sinuses, and the ipsilateral maxillary sinus and when indicated the volume should extend to the rectus muscle.", "cite_spans": [], "ref_spans": []}, {"section": "Pathology remarks", "text": "Include the sphenoid sinus. The retropharyngeal lymph nodes should be encompasses if the tumour extended close to the nasopharynx or if there are metastatic neck nodes from an ethmoidal carcinoma.", "cite_spans": [], "ref_spans": []}, {"section": "Pathology remarks", "text": "In the case it was been resected the margin should encompass all the initial GTV including the dura or the dural graft.", "cite_spans": [], "ref_spans": []}, {"section": "Maxillary", "text": "The inferior border of the maxilla and the hard palate but should encompass a 10-mm margin around the initial GTV.", "cite_spans": [], "ref_spans": []}, {"section": "Maxillary", "text": "Medial aspect should be the nasal septum, unless violation of midline structures occurs.", "cite_spans": [], "ref_spans": []}, {"section": "Maxillary", "text": "The pterygopalatine and the infratemporal fossa should be included, paying special attention to encompass the masticator space and the infraorbital fissure.", "cite_spans": [], "ref_spans": []}, {"section": "Maxillary", "text": "after photon irradiation, severe late toxicity has been observed while OS was equal. Promising results were found in a dose escalation study in locally advanced adenoid cystic carcinoma. Patients were treated with stereotactically guided or photon IMRT (45-54Gy) and a carbon ion boost of 18 GyE. The results are similar to those obtained with neutrons alone but with lower late toxicity profile [157] . ", "cite_spans": [{"start": 396, "end": 401, "text": "[157]", "ref_id": "BIBREF157"}], "ref_spans": []}, {"section": "Dose/fractionation remarks", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Neck metastases from unknown primary (cTx)", "text": "General remarks Metastatic cervical nodes of unknown primary origin represent a very heterogeneous entity. Squamous cell carcinoma is the more frequent histological type, followed by adenocarcinoma and undifferentiated carcinoma.", "cite_spans": [], "ref_spans": []}, {"section": "Neck metastases from unknown primary (cTx)", "text": "When pathology is different from squamous cell carcinoma (eg melanoma, lymphoma, adenocarcinoma), a primary arising in the chest, thyroid or salivary gland cancer should be suspected and treatment should be planned accordingly (the following guidelines would not apply).", "cite_spans": [], "ref_spans": []}, {"section": "Neck metastases from unknown primary (cTx)", "text": "Here we consider only SCC or undifferentiated carcinoma.", "cite_spans": [], "ref_spans": []}, {"section": "Neck metastases from unknown primary (cTx)", "text": "There are some correlations between the location of the node and the primary site:", "cite_spans": [], "ref_spans": []}, {"section": "Neck metastases from unknown primary (cTx)", "text": "1. superficial parotid: skin; 2. level Ib: oral cavity; 3. level Va: NPC; 4. level IV: chest (or abdomen)", "cite_spans": [], "ref_spans": []}, {"section": "Neck metastases from unknown primary (cTx)", "text": "More than 50% of primaries are discovered by physical examination and assessment under anaesthesia conducted by experienced ENTs (this data refers to pre-PET era) [161] ; 50-80% of primaries are found in the oropharynx; there is a strong correlation between HPV, cystic nodes and oropharyngeal primary [162] , but up to 25% of patients may have primary disease below the clavicles (lungs). EBV testing may help determine possible primary location. There is no advantage for repeated Direct Laryngoscopy if negative initially [163] .", "cite_spans": [{"start": 163, "end": 168, "text": "[161]", "ref_id": "BIBREF161"}, {"start": 302, "end": 307, "text": "[162]", "ref_id": "BIBREF162"}, {"start": 525, "end": 530, "text": "[163]", "ref_id": "BIBREF163"}], "ref_spans": []}, {"section": "Neck metastases from unknown primary (cTx)", "text": "More than FNA (e.g. incisional/excisional biopsy) is considered 'neck violation' and should be avoided. Injudicious removal of a metastatic node causes surgical scarring which may prevent or preclude subsequent surgical dissection of the lymph node bearing area. Above all, this procedure may delay the proper treatment.", "cite_spans": [], "ref_spans": []}, {"section": "Neck metastases from unknown primary (cTx)", "text": "Unilateral or bilateral tonsillectomy should be performed including excision of eventual remnant tonsillar tissue. In the absence of panendoscopic detectable lesions, ipsilateral tonsillectomy can discover carcinoma in about a quarter of the patients [164] . If physical examination shows mucosal abnormalities the detection rate rises to 40%. It is still controversial if tonsillectomy should be bilateral or unilateral. In favour of bilateral tonsillectomy, some Authors report that the rate of contralateral spread of metastatic cancer from occult tonsil lesions may approach 10%. A more convincing reason is to avoid asymmetric FDG uptake in the oropharyngeal region by removing only one tonsil that may confound follow up studies. For these reasons, bilateral tonsillectomy is recommended as a routine step in the search for the occult primary in patients presenting with cervical metastasis of SCC and palatine tonsils intact [165] . The discovery of the primary lesion may help the radiation oncologist to better define volumes to be treated and their respective dose. This ultimately would help to increase the odds of cure and minimize the risk of side effects. If physical examination and other imaging modalities are negative, PET may discover new primaries in an additional 25% of patients (5-73%), nodes in \u2248 15% and distant metastases in \u2248 10% [166] . Because FDG-PET detects increased metabolic activity, inflammation induced by biopsies may contribute to false-positive results if PET is obtained after direct laryngoscopy/ biopsy [167] .", "cite_spans": [{"start": 251, "end": 256, "text": "[164]", "ref_id": "BIBREF164"}, {"start": 932, "end": 937, "text": "[165]", "ref_id": "BIBREF165"}, {"start": 1358, "end": 1363, "text": "[166]", "ref_id": "BIBREF166"}, {"start": 1547, "end": 1552, "text": "[167]", "ref_id": "BIBREF167"}], "ref_spans": []}, {"section": "General treatment strategy", "text": "There are 2 main clinical scenarios: In general the radiosensitivity of salivary gland tumours depends on their pathology; doses for SCC are similar to SCC of other districts; for adenoid cystic doses in the order of 66 Gy and 60 Gy (at 2 Gy per fr) are recommended for CTV2 and CTV3, respectively [155] A dose of 60 Gy for postoperative treatment of high grade tumours has been suggested also by Chen et al. [158] . In favour of neck surgery stand the following remarks:", "cite_spans": [{"start": 298, "end": 303, "text": "[155]", "ref_id": "BIBREF155"}, {"start": 409, "end": 414, "text": "[158]", "ref_id": "BIBREF158"}], "ref_spans": []}, {"section": "MACROSCOPIC TUMOUR RESIDUAL AFTER INITIAL EVALUATION: Surgery vs RT \u00b1 CT", "text": "1. If the patient most likely needs surgery after RT or chemoRT (i.e. bulky node); 2. If the patient may be potentially cured by surgery alone (i.e. small <3 cm/single node); 3. Surgery permits concomitant teeth extractions and Direct Laringoscopy; 4. Surgery allows for a better staging of the neck and pathology of node level involvement; 5. If more tissue is required and pathology of nodal diffusion is uncertain.", "cite_spans": [], "ref_spans": []}, {"section": "MACROSCOPIC TUMOUR RESIDUAL AFTER INITIAL EVALUATION: Surgery vs RT \u00b1 CT", "text": "However, surgery may add extra morbidity especially if subsequent RT is necessary.", "cite_spans": [], "ref_spans": []}, {"section": "MACROSCOPIC TUMOUR RESIDUAL AFTER INITIAL EVALUATION: Surgery vs RT \u00b1 CT", "text": "In favour of RT \u00b1 CT stand the following remarks:", "cite_spans": [], "ref_spans": []}, {"section": "MACROSCOPIC TUMOUR RESIDUAL AFTER INITIAL EVALUATION: Surgery vs RT \u00b1 CT", "text": "1. If RT or CT-RT are potentially curative in patient that would need postoperative RT anyhow (i.e. multiple small nodes); 2. The use of RT or CT-RT without surgery on the neck allows for a better oxygenation of the potential mucosal site of primary;", "cite_spans": [], "ref_spans": []}, {"section": "MACROSCOPIC TUMOUR RESIDUAL AFTER INITIAL EVALUATION: Surgery vs RT \u00b1 CT", "text": "3. It permits better evaluation of tumour response (especially if CT is used); leaving salvage surgery for non-responders.", "cite_spans": [], "ref_spans": []}, {"section": "NO RESIDUAL MACROSCOPIC DISEASE AFTER INITIAL EVALUATION", "text": "If pN1 AND no ECE (AND no previous neck violation), observation can be appropriate; otherwise, if pN > 1 or ECE or neck violation, postoperative RT should be recommended.", "cite_spans": [], "ref_spans": []}, {"section": "Target definition remarks", "text": "CTV1 or high disease volume that encompasses the gross tumour volume in the neck if present with a margin; CTV2 that typically includes the putative primary site(s) considered at high risk of containing microscopic disease; moreover, after surgery, this would include the site of dissected positive lymph nodes; CTV3 includes the nodal stations that do not contain positive or suspicious nodes after appropriate imaging;", "cite_spans": [], "ref_spans": []}, {"section": "Transversal section", "text": "Coronal section Figure 4 Parapharyngeal space (transversal and coronal sections). moreover, it would include the putative primary site(s) considered at low risk of containing microscopic disease. Tables 22 and 23 show the commonly used fractionation regimens in definitive (macroscopic nodal disease present) and in postoperative settings:", "cite_spans": [], "ref_spans": [{"start": 196, "end": 212, "text": "Tables 22 and 23", "ref_id": "TABREF3"}]}, {"section": "Dose/fractionation remarks", "text": "Primary-tumour contour 1. According to classical teaching, the putative primary tumour may be located in the pharyngeal axis and thus the mucosa of the whole pharynx (nasopharynx, oropharynx and hypopharynx) as well as the larynx would be included in the subclinical dose level; the oral cavity should NOT be routinely included. The extent of the pharynx to be irradiated must be determined on a case-by-case basis [169] : a. Irradiation of oropharynx alone might be sufficient for an HPV+ patient. b. Irradiation of nasopharynx alone might be sufficient for an EBV+. 2. The larynx and hypopharynx are considered at low risk if levels III and IV are not involved and PET/CT is negative and level V is positive and pathology is suspicious for a nasopharyngeal primary or the tumour stains for HPV and/or EBV. In these cases, the dose to the larynx can be lowered to CTV3 or even dropped from any CTV [168, [170] [171] [172] [173] .", "cite_spans": [{"start": 415, "end": 420, "text": "[169]", "ref_id": "BIBREF169"}, {"start": 899, "end": 904, "text": "[168,", "ref_id": "BIBREF168"}, {"start": 905, "end": 910, "text": "[170]", "ref_id": "BIBREF170"}, {"start": 911, "end": 916, "text": "[171]", "ref_id": "BIBREF171"}, {"start": 917, "end": 922, "text": "[172]", "ref_id": "BIBREF172"}, {"start": 923, "end": 928, "text": "[173]", "ref_id": "BIBREF173"}], "ref_spans": []}, {"section": "Dose/fractionation remarks", "text": "Lymphnode-level contour", "cite_spans": [], "ref_spans": []}, {"section": "Dose/fractionation remarks", "text": "1. Traditionally, all neck levels ipsilateral to the positive nodal disease are included in the target volume. 2. With regard to the bilateral neck irradiation, currently there are two points of view: a. Considering the morbidity induced by extensive irradiation, some Authors consider irradiation of the contralateral neck indicated for a defined subset of patients, e.g., those with bilateral nodal metastases, extensive unilateral involvement with regard to number and levels of nodal metastases (cN2b+), unfavourable grading [164] . b. Other Authors, reporting local control rates with median neck relapse rate ranging from 31 to 63% after unilateral RT group, compared with a median neck relapse rate ranging from 8 to 49% in bilateral and pharyngeal mucosa RT group, advocate bilateral neck irradiation [174] . In this case contralateral neck levels II-IV and the retropharyngeal nodes could be included in CTV3 [169] . 3. Bilateral retropharyngeal nodes should be included. 4. 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The Question mark \"?\" refers to the uncertainty of the tumour-cell density.", "type": "figure"}, "FIGREF1": {"text": "Figure 2 Nasopharynx. Countered volumes (before and after ChT).", "type": "figure"}, "FIGREF2": {"text": "Figure 3 Laryngeal anatomy.", "type": "figure"}, "FIGREF3": {"text": "For lymph nodes that show gross extracapsular disease, a margin of 5[41]-10[53]mm around the visible GTV is usually added; in case of muscular infiltration by a pathological lymph node (i.e. sternocleidomastoid muscle)", "type": "figure"}, "FIGREF4": {"text": "the defintion of the volume boundaries.", "type": "figure"}, "TABREF0": {"text": "Volumes at risk in HNC", "type": "table"}, "TABREF3": {"text": "Organs at riskLinac-based volumetric IMRT, VMAT or Rapid Arc, offers the advantage of less monitor units and shorter delivery times over static IMRT", "type": "table"}, "TABREF4": {"text": "Suggested fractionation regimens for definitive treatment of oral cavity cancers", "type": "table"}, "TABREF5": {"text": "Suggested fractionation regimens for postoperative setting of oral cavity cancers", "type": "table"}, "TABREF6": {"text": "in order to avoid confounding factors:While subsite only is not a predictor of treatment out- come, histological subtypes are strongly variables by race and strongly influence prognosis:", "type": "table"}, "TABREF7": {"text": "Anatomical landmarks in contouring various oral subsites", "type": "table"}, "TABREF8": {"text": "Guidelines for contouring neck levels [57]", "type": "table"}, "TABREF9": {"text": "Suggested fractionation regimens for NPX", "type": "table"}, "TABREF10": {"text": "Standard anatomic limits of Nasopharynx", "type": "table"}, "TABREF12": {"text": "Suggested fractionation regimen for oropharyngeal cancer", "type": "table"}, "TABREF13": {"text": "guidelines for contouring ipsilateral and contralateral neck levels negative at imaging", "type": "table"}, "TABREF14": {"text": "The risk of subclinical disease in lymph nodes is not strictly correlated to the stage of the primary tumour. 3. Stations at risk are reported in Table 13 [57,130]. 4. Lymph node level VI has to be encompassed if oesophageal extension is present. 5. Ipsilateral retrostyloid lymph nodes should be included if clinical or radiological level II involvement is present.", "type": "table"}, "TABREF15": {"text": "Guidelines for contouring neck levels when negative at imaging in hypopharyngeal cancer", "type": "table"}, "TABREF16": {"text": "", "type": "table"}, "TABREF17": {"text": "Guidelines for contouring larynx (according to subsites)", "type": "table"}, "TABREF18": {"text": "Guidelines for contouring neck levels (negative on the imaging)", "type": "table"}, "TABREF19": {"text": "", "type": "table"}, "TABREF20": {"text": "Suggested fractionation regimens for para-nasal sinus and nasal cavity", "type": "table"}, "TABREF21": {"text": "Suggested CTV2 for ethmoid and maxillary sites", "type": "table"}, "TABREF22": {"text": "summarizes the most commonly used post- operative fractionation regimens: Primary tumour contour 1. A bolus over the scar region is indicated in the case of skin invasion, for superficially located tumours of the parotid or submandibular glands and/or in case of tumour spillage/ capsular rupture. 2. Adenoid cystic tumours have the distinct propensity for perineural infiltration (facial, trigeminal, hypoglossal, lingual nerve) and skull base involvement; in case of 'named' nerve invasion, CTV3 must track the course of the nerve as back as to its entry in the skull (base of skull). The addition of concomitant adjuvant CT is still investigational. 3. The CTV is a function of the location of the tumour (Table 21), its extension and histological risk factors; for low grade tumours, only the tumour site (i.e. parotid bed) is at risk; for high grade tumours, CTV2 includes the initial site of disease, while CTV3 should cover the whole surgical bed. 4. For parotid gland tumours, a document online describes target volume definition of the parotid bed and indications for ipsilateral neck irradiation for patients entering the COSTAR trial (COchlear Sparing Therapy And Conventional Radiation: A Multicentre Randomised Study Of Cochlear Sparing Intensity Modulated RT Versus Conventional RT In Patients With Parotid Tumours) http://aktinotherapeutis.gr/wp-content/uploads/doc- tors/COSTAR_Outlining_Guidelines.pdf 4. The parotid gland extends from the zygomatic arch superiorly to beyond the lower border of the mandible inferiorly. Posteriorly, the gland dips in the space between the mandible and the mastoid, with the adjoining external auditory meatus intimately surrounded by the gland in its free borders, that is, anteriorly and inferiorly. On a deeper plane, the parotid is related to the styloid process and the muscles connected to it (Figure 4). Local infiltration of tissues adjacent to the parotid gland is the main pattern of spread. This follows the anatomical borders of the parotid gland and in cases of perineural invasion, the facial nerve to the stylomastoid foramina. 5. CTV2 for parotid tumours includes: the parotid bed and any adjacent tissues at risk of microscopic spread. a. Areas at risk of soft tissue extension are: infratemporal fossa, parapharyngeal space, masseter and digastric muscle, skin. b. Bone infiltration-at risk areas include: lateral part of the floor of middle cranial fossa, neck of man- dible, external auditory meatus, inferior surface of styloid process. Lymphnode-level contour 1. Elective nodal irradiation should be considered in any of the following [158]: a. High grade tumours b. T3/T4 stage c. Histological subtype i. Squamous cell carcinomas ii. Adenocarcinomas iii. Undifferentiated carcinomas, iv. High grade mucoepidermoid carcinomas v. Salivary duct carcinomas 2. In case of risk of subclinical disease, if the primary tumour is dissected, the lymph node levels at risk should be dissected as well (surgical/pathological staging of the neck is usually preferred to elective treatment of undissected neck). 3. After surgery, planning should avoid underdosing of the skin especially when capsular rupture is present (bolus over the scar). 4. Levels Ib, IIa IIb, RP ipsilateral nodal stations (commonly in tumor bed) should be included in CTV2 for parotid tumors. 5. Levels III, IV and V ipsilateral nodal stations should be included in CTV3 for parotid tumors when high grade features are present, T3-T4, and the histological type listed in point 1 if neck is undissected [159,160]. 6. There is no indication for bilateral elective neck treatment.", "type": "table"}, "TABREF23": {"text": "Summary of the most important pathology variants in salivary gland tumoursAlways postop RT except in adenoid cystic carcinoma and mucoepdermoid in absence of risk factors. Adenocarcinoma", "type": "table"}, "TABREF24": {"text": "Commonly used postoperative regimens", "type": "table"}, "TABREF25": {"text": "Suggested volumes (surgical bed) at high riskFollow clips if leaved by surgeon otherwise and use the contralateral submandibular gland as a guide.", "type": "table"}, "TABREF26": {"text": "Suggested fractionation regimens for Unknown Primary (macroscopic disease present)", "type": "table"}, "TABREF27": {"text": "Suggested fractionation regimens for Unknown Primary (postoperative setting)", "type": "table"}}}
{"paper_id": "17781243", "_pdf_hash": "410354570f0cc93d3d9ff70b82f15fffc58cb622", "abstract": [{"section": "Abstract", "text": "Background: Fourteen African countries are scaling up voluntary medical male circumcision (VMMC) for HIV prevention. Several devices that might offer alternatives to the three WHO-approved surgical VMMC procedures have been evaluated for use in adults. One such device is PrePex, which was prequalified by the WHO in May 2013. We utilized data from one of the PrePex field studies undertaken in Zimbabwe to identify cost considerations for introducing PrePex into the existing surgical circumcision program.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "In 2005-2007, three randomized controlled clinical trials demonstrated that voluntary medical male circumcision (VMMC) reduced male acquisition of HIV through heterosexual intercourse by approximately 60% [1] [2] [3] . Since then mathematical modeling studies have suggested that scaling up VMMC in 13 Eastern and Southern African countries to 80% coverage over five years and maintaining that coverage through 2025 could avert 3.4 million HIV infections over that time period and save approximately $16.5 billion in the cost of HIV treatment and care [4] .", "cite_spans": [{"start": 205, "end": 208, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 209, "end": 212, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 213, "end": 216, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 552, "end": 555, "text": "[4]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Introduction", "text": "Despite the promise of VMMC to substantially impact the HIV epidemic in these settings, scale-up of VMMC programs has been challenged by issues related to demand creation and service availability in remote and resource-constrained areas [5] [6] [7] . New adult VMMC devices are currently being assessed for safety, effectiveness, cost, and client and provider acceptability [8, 9] . Devices could potentially simplify the procedure, enabling nonphysician providers to conduct the surgery in a wider array of settings. The availability of devices might also offer an alternative mode of VMMC for men who have fears related to conventional surgery.", "cite_spans": [{"start": 241, "end": 244, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 245, "end": 248, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 374, "end": 377, "text": "[8,", "ref_id": "BIBREF7"}, {"start": 378, "end": 380, "text": "9]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Introduction", "text": "One adult VMMC device, PrePex, developed by Circ MedTech (Herzelia, Israel), works by compressing the foreskin between a fitted ring and elastic band, leading to distal tissue necrosis. In most cases, PrePex does not require the use of injected anesthesia and does not require suturing. Clients who undergo VMMC using the PrePex device are required to wear the device for seven days and then return to the clinic for removal on the seventh day. In a Rwanda field study, the PrePex procedure took 4.3 minutes for device application (including preparation) and 3.8 minutes for device removal seven days later [10] , compared with 23-30 minutes for conventional surgery (from scrubbing the patient in preparation for the operation to cleaning the wound after suturing) in a multi-country study [11] .", "cite_spans": [{"start": 607, "end": 611, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 791, "end": 795, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Introduction", "text": "A series of three studies (safety case study, comparative study, and field study) of the PrePex device was first completed in Rwanda [10, 12, 13] . This same series of studies was subsequently completed independently in Zimbabwe. The information generated from these six studies informed the WHO decision in May 2013 to add PrePex to its prequalification list [14, 15] .", "cite_spans": [{"start": 133, "end": 137, "text": "[10,", "ref_id": "BIBREF9"}, {"start": 138, "end": 141, "text": "12,", "ref_id": "BIBREF11"}, {"start": 142, "end": 145, "text": "13]", "ref_id": "BIBREF12"}, {"start": 360, "end": 364, "text": "[14,", "ref_id": "BIBREF13"}, {"start": 365, "end": 368, "text": "15]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Introduction", "text": "Claims have been advanced that the PrePex procedure would result in significantly decreased unit costs per VMMC compared with conventional surgery; this has not been borne out in analyses published to date. Using hypothetical costing information from Kenya, Obiero and colleagues derived a unit cost of $44.54-$49.02 for PrePex, not including the device cost, and $54.52-$55.29 for forceps-guided surgical VMMC [16] . Duffy and colleagues collected costs of PrePex-based and surgical VMMC at a high-volume urban hospital in Uganda and found a unit cost of $30.55 for PrePex-based and $22.65 for surgical VMMC, using a PrePex device price of $20 and excluding demand creation costs [17] .", "cite_spans": [{"start": 411, "end": 415, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 681, "end": 685, "text": "[17]", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Introduction", "text": "Countries in Eastern and Southern Africa have already begun scaling up VMMC using conventional surgical approaches. Because of age and other exclusions (PrePex is only qualified for use with men over the age of 18), programs that wish to introduce PrePex will need to continue to make conventional surgery available. Therefore, we sought to examine potential cost implications of integrating the PrePex device into an existing VMMC program. Instead of estimating a unit cost specifically for PrePex-based VMMC vs. surgical VMMC, as others have [16, 17] , we examined the site-level unit cost of VMMC at a highthroughput public facility providing only routine surgical VMMC (''routine surgery site'') and at a similar facility in which staff and equipment were added to also conduct PrePex-based circumcisions for a research study (''mixed study site''). We used data collected during routine surgical implementation in Zimbabwe and as part of the Zimbabwe PrePex field study, respectively. Because of the differing staffing pattern and equipment used at each site, the unit costs of the two sites are not comparable. Therefore, to enable comparison of the unit costs, we also created a hypothetical mixed site scenario that retained the same staffing pattern and number of beds as the routine surgery site.", "cite_spans": [{"start": 544, "end": 548, "text": "[16,", "ref_id": "BIBREF15"}, {"start": 549, "end": 552, "text": "17]", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Introduction", "text": "This study poses several questions: (1) What are the major drivers of unit costs in each type of site (routine surgery and the two different mixed sites)? (2) How would the unit cost at a mixed site change with varying ratios of surgical to PrePex-based circumcisions? (3) How would unit costs change with varying levels of site utilization? (4) What impact would different device prices have on the unit cost?", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Implementation models", "text": "Three implementation models were evaluated ( Figure 1 ): a routine surgery site based on the configuration (staffing, equipment) of the Bulawayo VMMC Centre, a mixed study site based on the configuration of the Harare PrePex Field Study Site, and a hypothetical mixed site with a configuration comparable to that of the routine surgery site. The Bulawayo and Harare sites are dedicated VMMC sites, where efficiencies such as task sharing, use of VMMC kits with disposable surgical instruments for the conventional surgery, and use of multiple surgical beds for each surgeon are being implemented.", "cite_spans": [], "ref_spans": [{"start": 45, "end": 53, "text": "Figure 1", "ref_id": "FIGREF0"}]}, {"section": "Implementation models", "text": "The routine surgery site had a four-bed capacity and employed one medical doctor, six nurses, three theatre assistants, and one receptionist. The doctors had overall responsibility for the surgical procedure, provided local anesthesia, removed the foreskin, stopped bleeding either using sutures or electrocauterization, and attended to post-operative complications and treatment of adverse events involving wound revisions or severe infections with abscesses. The nurses conducted group education sessions, conducted pre-operative examination and counseling, conducted HIV testing and counseling, assisted with circumcisions, conducted post-operative examination and counseling, and conducted post-operative review of the client on day 2,day 7 and day 42 postsurgery. The theatre assistant was responsible for cleaning the operation room, cleaning instruments after the operation, preparing instruments and operation room in case of adverse events, and cleaning the waiting area, counseling and examination rooms. The receptionist was responsible for taking clients' personal details, explaining the procedure, and booking the client for operation and follow-up review.", "cite_spans": [], "ref_spans": []}, {"section": "Implementation models", "text": "The mixed study site had a six-bed capacity and employed one medical doctor, eight nurses (an additional two nurses and two beds to conduct PrePex circumcisions), three theatre assistants, and one receptionist. In addition to the responsibilities outlined above for the surgery site, the doctor supervised the nurses conducting PrePex circumcisions, handled device-related complications, and conducted surgery in case of displacement of the device. The nurses conducted the PrePex procedure: fitting the PrePex device size, placing the device, removing the dried foreskin, inner ring, and elastic band on day 7, dressing the wound, and conducting post-operative review of the client after removal of the device on day 7 and day 42. The theatre assistant sterilized instruments used for removal of the foreskin and device. All staff at the mixed site were qualified to conduct both types of circumcisions based on client demand.", "cite_spans": [], "ref_spans": []}, {"section": "Implementation models", "text": "The hypothetical mixed site had a four-bed capacity and employed the same staff as the routine surgery site.", "cite_spans": [], "ref_spans": []}, {"section": "Implementation models", "text": "Data on service delivery were collected between May 8 and July 9, 2012, at the Harare site for the mixed study site model and at the Bulawayo site for the routine surgery site model. For PrePexbased circumcisions, clients who presented for placements were counted as PrePex VMMCs conducted. All devices were removed at day 7. The median number of daily circumcisions per site during this period was used in all of the unit cost calculations except the analysis that examined different levels of site capacity utilization, which used the observed minimum, first quartile, median, third quartile, maximum, and theoretical maximum (explained in the Results section) numbers of clients per day. The population to be circumcised included males ages 10 to 49 years; those under 18 years of age, those declining to participate in the study, and those with exclusions such as HIV infection, cracked foreskin, phimosis, short or tight frenulum, or preputial adhesions were not eligible to be circumcised using PrePex and were offered conventional surgery. Those with active genital infections were treated and asked to come back for circumcision at a later date. In the mixed study sites during the period of data collection, 84% of the circumcisions were conducted using conventional surgery and 16% were conducted using PrePex. This ratio was applied as described below when calculating the unit cost at the mixed study site.", "cite_spans": [], "ref_spans": []}, {"section": "Cost Model", "text": "All analyses were performed using Microsoft Excel 2010 (Microsoft Corporation, Redmond, WA). All costs are presented in USD.", "cite_spans": [], "ref_spans": []}, {"section": "Cost Model", "text": "Unit costs per circumcision (regardless of site type) comprised seven cost categories: consumables, device, supply chain management, staff, durable equipment, training, and waste management. Indirect costs, costs for demand creation, and costs for complications were not included in this analysis. Unit costs represent costs to the service provider and do not include costs to clients, such as transport to and from the intervention sites. The VMMC unit cost for the mixed sites is the average unit cost of all circumcisions provided, including both conventional surgical VMMCs and PrePex-based VMMCs; we did not disaggregate unit costs by modality. Site-level unit costs were derived by calculating the per circumcision cost for each of the seven cost categories and then adding the costs of all the categories: [18] s is the annual staff cost at that type of site e is the annual durable equipment cost at that type of site t is the annual training cost at that type of site m is the median number of circumcisions performed per day at that type of site, multiplied by 220 working days per year w is the cost of waste management per circumcision Details about each cost category follow. Consumables. Lists of required consumables for both surgical VMMC using the forceps-guided technique and PrePexbased circumcisions were provided by the Zimbabwe PrePex Field Study team, as defined in the study protocol. Consumables prices were provided by the PEPFAR funded through USAID Partnership for Supply Chain Management System (SCMS) project and are available in Table S1 and Table S2 . For conventional surgical VMMC, the study utilized pre-sterilized, disposable commodities bundled into kits (market price sourced by SCMS as of February 15, 2013) , while a combination of disposable and reusable commodities was used for the PrePex procedure. The commodity costs for the PrePex procedure were derived from average SCMS pricing from procurements in 2009-2012, with data compiled on January 10, 2013, or from a quotation obtained from Circ MedTech on December 19, 2012, as indicated in Table S2 . The actual PrePex device is disposable/single-use. Each reusable commodity cost was divided across 150 procedures to derive the unit cost, based upon experience in the field study.", "cite_spans": [{"start": 813, "end": 817, "text": "[18]", "ref_id": "BIBREF17"}], "ref_spans": [{"start": 1560, "end": 1581, "text": "Table S1 and Table S2", "ref_id": "TABREF1"}, {"start": 2084, "end": 2092, "text": "Table S2", "ref_id": "TABREF2"}]}, {"section": "Cost Model", "text": "Device. The baseline PrePex device cost applied was USD $20 per unit based on a quotation from Circ MedTech to SCMS on December 19, 2012. This is not the price that was used in the series of clinical studies in Zimbabwe, but it was the price quoted by the manufacturer for pilot implementation studies in several countries.", "cite_spans": [], "ref_spans": []}, {"section": "Cost Model", "text": "Supply chain management. Based on a study of the existing supply chain management system in Zimbabwe conducted by the USAID DELIVER Project in 2010, supply chain costs per circumcision were calculated by multiplying the costs of consumables (including device) by 31.4%, comprising 11.4% for procurement costs plus 20% for logistics expenses [18] .", "cite_spans": [{"start": 341, "end": 345, "text": "[18]", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "Cost Model", "text": "Staff Table S3 . Equipment costs were allocated uniformly over three years based on estimated life span.", "cite_spans": [], "ref_spans": [{"start": 6, "end": 14, "text": "Table S3", "ref_id": "TABREF4"}]}, {"section": "Cost Model", "text": "Training. All nurses and doctors in the routine surgery and mixed sites received the same initial competency-based team training. Staff turnover was approximately 50% per year, so on average an entirely new cohort of staff would need to be retrained every 3.6 years. Therefore, training costs were allocated uniformly over 3.6 years.", "cite_spans": [], "ref_spans": []}, {"section": "Cost Model", "text": "At the routine surgery site, the training cost in 2012 was USD $884 per trainee for a 6-day course that included 2.5 days of theory and 3.5 days of applied work. For the mixed sites, the training cost was USD $1,252 per trainee for an 8.5-day course that included an additional 2.5 days for applied training with PrePex. All nurses and doctors at the mixed site were trained in both surgical and PrePex-based circumcision.", "cite_spans": [], "ref_spans": []}, {"section": "Cost Model", "text": "Waste management. At the routine surgery site, according to 2012 site records, the cost of waste management of USD $1.00 per kg of waste was based on current program generation of 25 kg of waste per week, resulting from 130 circumcisions per week. The same unit cost for waste management per VMMC was applied to the mixed sites.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Key cost drivers", "text": "The unit cost per VMMC for the routine surgery site was $55.83, for the mixed study site it was $60.58, and for the hypothetical mixed site it was $57.45 (Table 1 ). The two largest contributors to the unit cost were consumables and staff. At the routine surgery site, consumables ($30.36) and staff ($14.90) contributed a combined 81% to the unit cost; in the mixed study site, consumables ($30.87), including device, and staff ($17.83) contributed a combined 80% to the unit cost; in the hypothetical mixed site, consumables ($30.87), including device, and staff ($14.90) contributed a combined 80% to the unit cost. Training, durable equipment, and waste management contributed negligibly to the unit costs at all three sites.", "cite_spans": [], "ref_spans": [{"start": 154, "end": 162, "text": "(Table 1", "ref_id": "TABREF1"}]}, {"section": "Impact of ratio of conventional surgical to PrePex-based circumcisions at mixed site", "text": "At the mixed study site between May 8 and July 9, 2012, 28% of the clients were ineligible for PrePex due to being less than 18 years old, and 5.6% were ineligible for physiological reasons such as phimosis or tight foreskin. Since acceptability of the PrePex device in Zimbabwe outside the study environment is currently unknown, we looked at the effect on the unit cost of varying the ratio of conventional surgical circumcisions to PrePex-based circumcisions. The maximum percentage of PrePex-based circumcisions with 100% acceptability would be 68%, given age and physiological exclusions. We kept the staffing and the total number of circumcisions per day constant in this analysis: although in theory both the staffing and the total number of circumcisions per day might change with different ratios of the different types of circumcisions, we did not have robust data upon which to base changes in these variables for this analysis. The unit cost in this analysis ranged from $60 per circumcision when 100% of circumcisions were performed using conventional surgery to $63 per circumcision when 68% of circumcisions were performed using PrePex ( Table 2 ).", "cite_spans": [], "ref_spans": [{"start": 1153, "end": 1160, "text": "Table 2", "ref_id": "TABREF2"}]}, {"section": "Utilization of site capacity", "text": "Generating, maintaining, and predicting fluctuations in demand for VMMC over time can be challenging. In some countries scaling up VMMC, sites have been fully staffed and equipped, only to experience suboptimal utilization during some periods. We examined the impact of different levels of site utilization on the unit cost. In these analyses the daily costs for staffing, durable equipment, and training were held constant, while consumables, device, supply chain management, and waste management costs varied by number of circumcisions. The distribution of numbers of circumcisions per day was based on site utilization data from the routine surgery and mixed study sites between May 8 and July 9, 2012. Because the sites were not operating at full capacity, a theoretical maximum number of circumcisions per day was estimated based on the complement of staff and equipment at each type of site in an eight-hour day if demand for circumcisions met or exceeded supply. The median number of VMMC procedures per day was 26 at both the routine surgery site and the mixed study site. The theoretical maximum number of daily VMMCs was 80 at the routine surgery site and 120 at the mixed study site. VMMC unit cost was highly sensitive to the level of site utilization in both types of sites, ranging at the mixed study site from $45 at the theoretical maximum utilization to $98 when the site performed only nine VMMCs per day (the minimum observed during the two-month period at this site). Similarly, at the routine surgery site, the unit cost ranged from $45 at theoretical maximum site utilization to $122 when only five VMMCs (the minimum observed during the two-month period at this site) were performed per day (Table 3) .", "cite_spans": [], "ref_spans": [{"start": 1714, "end": 1723, "text": "(Table 3)", "ref_id": "TABREF5"}]}, {"section": "Impact of device price", "text": "The price of the PrePex device outside of small procurements for research studies has not been negotiated. Because only 16% of circumcisions used PrePex at the mixed sites, we modeled the variations in unit cost as a function of a variety of PrePex device prices using a fictional scenario in which 68% of the circumcisions were performed using PrePex (the maximum possible in this population given age and physiological exclusions), in order to see the maximum possible impact of variations in device price. Under these assumptions, the unit cost ranged from $50 at a device price of $2.00 (device 3% of the unit cost) to $63 at a device price of $20 (device 22% of unit cost) (Table 4) . Therefore, the unit cost is sensitive to variations in the device price.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "In this analysis we sought to examine the impact on VMMC unit costs of introducing PrePex into an existing routine surgical VMMC program in Zimbabwe. Introduction of PrePex at the study site did not have a large impact on the overall unit cost. The key cost drivers for both the routine surgery and the mixed sites were consumables and staff salary costs, suggesting areas of focus for lowering the price per VMMC. At the mixed study site, the unit cost only increased by $3 when the ratio of surgical and PrePex-based circumcisions was hypothetically varied from 100% surgery to 32% surgery and 68% PrePex. Unit costs were highly sensitive to potential variations in the device price when 68% of the circumcisions were performed using the device; therefore, a responsibly low public-sector price could result in cost savings and avail VMMC services to more people in need, if acceptability of PrePex turns out to be high.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "The largest impact on the unit cost was underutilization of site capacity. At the mixed study site, the minimum observed daily service utilization resulted in unit costs twice those of maximum observed service utilization. Similar cost increases were seen from underutilization at the routine surgery sites. The negative impact of underutilization would be even greater if overhead costs had been included in the analysis. This result highlights the importance of optimal demand creation and a balanced relationship between service supply (availability) and demand for VMMC services, regardless of the circumcision method used.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Further research examining alternative service delivery models in different settings and country contexts might find unit costs that are different from those presented in this study. For example, if implementation is carried out in a site dedicated entirely to VMMC, rather than co-located or integrated within a public health care facility, increased costs for waste transportation and disposal and supply chain management might be expected with either the routine surgery or mixed site model. If circumcisions are outsourced to the private sector, staff salaries, facility rental or construction, and profit may increase or decrease the unit costs. The use of temporary or locum staff to adjust capacity to accommodate fluctuations in demand could change the cost structure. Different implementation models-for example, those involving mobile teams and outreach campaigns-might include additional or higher costs for expenses such as transportation. If a new supply chain management system needs to be created or the existing one strengthened, supply chain management costs would likely be higher, at least temporarily. If commodity transportation requires air freight rather than ocean freight, procurement costs will be higher. The teams in Zimbabwe were highly experienced and efficient, so they could conduct many circumcisions per day. Newly trained teams usually need more time to conduct each circumcision, reducing productivity and driving up unit costs. It is also reasonable to speculate that unit costs could decrease as a result of PrePex availability. At the point that they are no longer experimental, PrePex circumcisions provided as a routine service could be reduced in cost due to potential reductions in consumables and supply chain costs and higher service utilization. A responsible public-sector price for the PrePex device when purchased in large volumes, which reflects the costs of materials and production plus a reasonable mark-up for profit, should reduce the overall consumables cost. Because supply chain costs are related to consumables costs, by extension they might also decrease.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "In Zimbabwe, nurses are not allowed to perform certain aspects of the surgical male circumcision procedure, but the PrePex Field Study demonstrated that nurses are able to conduct the entire PrePex VMMC procedure. Different staffing patterns can affect the overall unit cost. For countries without task shifting, instituting a task-shifting policy is one way to significantly decrease staff costs and therefore decrease unit costs of VMMC.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "This study has several limitations. The per-VMMC unit costs provided did not include all cost components, and they were based on limited data using a single service delivery model. PrePex procedures were performed as part of a study, and thus the costs of those procedures do not reflect routine service delivery conditions (for example, in Zimbabwe the mixed sites employed more staff than those sites offering routine circumcision, but did not observe an increase in the total number of circumcisions. In routine service delivery, it is doubtful that such additional staff would be hired without any increase in uptake). Conventional surgical circumcisions, on the other hand, were provided as a routine service, in a model perfected over years. Actual unit costs should be determined by careful costing studies in a large number of sites once routine implementation of both circumcision methods is well under way. The unit costs did not include indirect costs or costs for demand creation, each of which might contribute significantly to the unit cost. Other groups have attempted to derive unit costs for demand creation for VMMC in other settings, but they have found too much variation in implementation and costs to be able to produce a standard unit cost [19] . Because of the importance of demand creation, this question merits further research. At this time, little is known about the acceptability of the PrePex device outside of research settings, either in Zimbabwe or in other cultural contexts. Costs of supervision, community engagement, and program management were not included in this analysis. These costs should be collected as the introduction of PrePex is rolled out on a larger scale in a number of different settings.", "cite_spans": [{"start": 1263, "end": 1267, "text": "[19]", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Discussion", "text": "This study provides new data on the cost of introducing the PrePex device into an existing surgery-based VMMC program and highlights the importance of controlling consumable and staff costs and ensuring high levels of site utilization through effective demand creation strategies. We found no evidence in these analyses that introducing the PrePex device would result in increased efficiency of the VMMC program in terms of reducing the unit cost. To assist countries that wish to incorporate PrePex into their VMMC scale-up plans, it will be necessary to collect a broader diversity of actual cost data from different implementation models, across different countries. Table 4 . Sensitivity analysis of device price on unit cost at mixed study site with 68% of circumcisions conducted using the PrePex device. 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Key characteristics of the different implementation models. The routine surgery site and the hypothetical mixed site employed 1 medical doctor, 6 nurses, 3 theatre assistants, and 1 receptionist in a 4-bed facility, and the mixed study site employed 1 medical doctor, 8 nurses, 3 theatre assistants, and 1 receptionist in a 6-bed facility. doi:10.1371/journal.pone.0082533.g001", "type": "figure"}, "TABREF0": {"text": "cost~c s p s zc p p p |fflfflfflfflfflffl ffl{zfflfflfflfflfflffl ffl}where c s is the per circumcision cost of consumables for conventional surgical circumcisions p s is the percentage of conventional surgical circumcisions at the site (for the routine surgery site, p s = 100%) c p is the per circumcision cost of consumables for PrePex-based circumcisions p p is the percentage of PrePex-based circumcisions at the site (for the routine surgery site, p p = zero) d is the device price 31.4% of the cost of consumables (including device) constitutes the supply chain cost", "type": "table"}, "TABREF1": {"text": "Cost drivers for unit cost of different implementation models.", "type": "table"}, "TABREF2": {"text": "Effect of proportion of conventional surgical versus PrePex-based circumcisions on unit cost at the mixed study site.", "type": "table"}, "TABREF3": {"text": "Itemized consumables costs for forceps- guided routine surgical circumcisions. (DOCX) Table S2 Itemized consumables costs for PrePex-based circumcisions. (DOCX)", "type": "table"}, "TABREF4": {"text": "Durable equipment costs for the routine surgery site, mixed study site, and hypothetical mixed site. (DOCX)", "type": "table"}, "TABREF5": {"text": "Effect of site capacity utilization on unit cost at routine surgery site and mixed study site.# circ/day Unit cost # circ/day Unit cost", "type": "table"}, "TABREF6": {"text": "22% doi:10.1371/journal.pone.0082533.t004", "type": "table"}}}
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{"paper_id": "17781487", "_pdf_hash": "01d5cbfcec01b61f6c5428b547b55fb7a05053fb", "abstract": [{"section": "Abstract", "text": "Many Histoplasma capsulatum strains have a-(1,3)-glucan in their cell walls and spontaneously produce variants that lack this polymer. The variants, in contrast to the parents, exist in aberrant shapes within macrophages. Here, the ultrastructure of the parental and variant cell walls was examined. All yeasts had identical electron-lucent, thick walls when grown in broth culture. However, ingestion by either macrophages or hamster trachea epithelial (HTE) cells caused the walls of variants to become electron-dense, thin, and sinuous. Parental strains remained unchanged in macrophages. Within HTE cells inoculated with parental strains, some organisms retained a thick wall and a-(1,3)-glucan but appeared to be degrading. In contrast, apparently intact intracellular yeasts had thin, wavy walls lacking a- (1,3) 6 -9]. Because parents and variants differ in both their a-(1,3)-glucan composition and their clump in liquid culture and form rough-textured colonies on solid medium. Chemotype II strains, which include isolates morphology inside macrophages, we investigated whether the cell wall ultrastructure of the yeasts also deviates either during from three different continents and several different evolutionary classes [2], spontaneously produce variant yeasts that lack growth in broth or while resident in macrophages. In contrast to the situation in macrophages, variants infecting HTE cells a-(1,3)-glucan, grow in a dispersed fashion in broth, and form smooth colonies. One method for isolating these organisms retain the same morphology as their parents [5] . However, when the parental strain is used to inoculate HTE cells, only entails enriching for yeasts that sediment slowly in liquid cultures. These isolates are designated ''smooth'' variants, and variant yeasts are harvested [4]. In an attempt to understand these observations, we have also examined the ultrastructure the suffix ''S'' is added to the strain name to identify them as such [3] . A method developed later requires passage of parental of yeasts inside HTE cells. strains through hamster trachea epithelial (HTE) cells [4]. These ''HTE variants'' (designated by the suffix HTE added Materials and Methods to the strain name) consistently have a slight difference in colony texture and color compared with the S variants, sugYeast strains. H. capsulatum G186A-R, -S, and -HTE as well gesting that they represent a distinctive phenotype (unpublished as strains UCLA 531-R, -S, and -HTE were acquired and mainobservation). 7.4 (see [13]; contains sucrose rather than glucose and 6.0 rather The Journal of Infectious Diseases 1997;175:1538-44 than 8.0 g/mL NaCl). Pelleted yeasts were postfixed at 4\u040aC in \u1b67 1997 by The University of Chicago. All rights reserved.", "cite_spans": [{"start": 1574, "end": 1577, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 1969, "end": 1972, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": []}], "body_text": [{"section": "", "text": "Chemotype II strains of Histoplasma capsulatum, a fungus culture [4] , albeit in a variety of aberrant morphologies (allomorphs) [5] reminiscent of those found in tissues of persistently that causes respiratory disease in mammals, have a-(1,3)-glucan within the cell walls of the yeast form [1] . These yeasts infected patients and animals [6 -9] . Because parents and variants differ in both their a-(1,3)-glucan composition and their clump in liquid culture and form rough-textured colonies on solid medium. Chemotype II strains, which include isolates morphology inside macrophages, we investigated whether the cell wall ultrastructure of the yeasts also deviates either during from three different continents and several different evolutionary classes [2] , spontaneously produce variant yeasts that lack growth in broth or while resident in macrophages. In contrast to the situation in macrophages, variants infecting HTE cells a-(1,3)-glucan, grow in a dispersed fashion in broth, and form smooth colonies. One method for isolating these organisms retain the same morphology as their parents [5] . However, when the parental strain is used to inoculate HTE cells, only entails enriching for yeasts that sediment slowly in liquid cultures. These isolates are designated ''smooth'' variants, and variant yeasts are harvested [4] . In an attempt to understand these observations, we have also examined the ultrastructure the suffix ''S'' is added to the strain name to identify them as such [3] . A method developed later requires passage of parental of yeasts inside HTE cells. strains through hamster trachea epithelial (HTE) cells [4] . These ''HTE variants'' (designated by the suffix HTE added Materials and Methods to the strain name) consistently have a slight difference in colony texture and color compared with the S variants, sugYeast strains. H. capsulatum G186A-R, -S, and -HTE as well gesting that they represent a distinctive phenotype (unpublished as strains UCLA 531-R, -S, and -HTE were acquired and mainobservation). surrounded by a thin, convoluted layer that was presumed to but not to smooth variants, which lack a-(1,3)-glucan [15] . After be the cell wall ( figure 1D ). As expected, no a-(1,3)-glucan 2 more washes, samples were incubated for 30 min with goat was detected in these walls (not shown). Electron microscopy anti-mouse IgM coupled to 15-nm gold particles (Zymed, San revealed similar shapes for parental and variant yeasts despite Francisco) for 30 min. Samples were then washed and examined the fact that fluorescence microscopy shows that variants are for gold particles.", "cite_spans": [{"start": 129, "end": 132, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 291, "end": 294, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 1098, "end": 1101, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 1494, "end": 1497, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": [{"start": 2185, "end": 2194, "text": "figure 1D", "ref_id": "FIGREF1"}]}, {"section": "", "text": "allomorphic [5] . This apparent paradox is probably a result of while the thin-walled fungi did not.", "cite_spans": [{"start": 12, "end": 15, "text": "[5]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Results Discussion", "text": "Parent and variant (S or HTE) strains appear to have similar Yeasts in suspension. Knowing that parental and variant yeasts differ in their cell wall compositions, we looked first at cell wall ultrastructure when the yeasts are cultured in broth. However, this ultrastructure becomes drastically altered when the ultrastructure of broth-grown yeasts. Ruthenium red staining revealed an outermost carbohydrate layer ( figure 1A) in H. capsulatum variants are grown in either macrophages or epithelial cells. The same alterations are seen in variants prethe cell wall of all yeasts; organisms from different strains and their variants were indistinguishable (G186A-R, -S, and -HTE; treated with glutaraldehyde, indicating that no active response is required from the yeasts. Instead, the variant cell wall may UCLA 531-R and -S). As expected, immunogold staining localized a-(1,3)-glucan to the walls of G186A-R (figure 1B) and be particularly sensitive to some enzymatic or other activity within the phagolysosome. Alternatively, the nonprotein por-UCLA 531-R. In the absence of ruthenium red, the cell wall was electron-lucent. With regards to survival in macrophages, tion of the wall may have a passive physicochemical response to the microenvironment within the host cells. ability to kill these phagocytes, and tendency to form allo- Fluorescence microscopy of macrophages infected with vari-HTE cells, profound changes can occur in the phagocytized parental strain yeasts. Some of these yeasts appear to undergo ants reveals a variety of allomorphic shapes, including simple enlarged spheres, barbells, gourds, and kidney beans [5] , which degradation within the first day after inoculation. Those that do not have acquired thin, wavy cell walls that are indistinare similar to forms found in the tissues of infected mammals and patients. This variety of shapes may relate to the thin, guishable from those of the variants. Thus, the parental phenotype seems unfavorable for survival in HTE cells. sinuous cell wall seen ultrastructurally. For example, if the thinned walls reflect less rigidity, perhaps osmotic stress could", "cite_spans": [{"start": 1633, "end": 1636, "text": "[5]", "ref_id": "BIBREF4"}], "ref_spans": [{"start": 417, "end": 427, "text": "figure 1A)", "ref_id": "FIGREF1"}]}, {"section": "Results Discussion", "text": "The differences between the microenvironment facing H. capsulatum within macrophages and HTE cells are unknown, explain allomorphism. As might be expected in such a scenario, enlarged spherical forms predominate. The additional shapes yet probably influence the yeast morphology and cell wall architecture. In both cases, the fungi are enclosed in membraneobserved might result from uneven stress, perhaps due to local variations in the rigidity of the cell wall with consequent herniabound vesicles. These have been identified as phagolysosomes of neutral pH in macrophages [17] but have yet to be charactertion at weaker sites. Consistent with this idea, allomorphs do not form inside cells if the walls of the variants are protected ized in HTE cells. Levels of other ions may also differ within the hosting vesicles of these cells, as may the transport of from potential osmotic effects as a result of cross-linking with glutaraldehyde.", "cite_spans": [{"start": 575, "end": 579, "text": "[17]", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Results Discussion", "text": "nutrients from the medium or host cell cytoplasm. The purpose of this study was to compare an experimental regimen of atovaquone plus proguanil with the standard regimen of quinine plus tetracycline for the treatment of uncomplicated falciparum malaria. The study was designed as an open, randomized study of men presenting with symptoms of uncomplicated malaria and thick-smear slide confirmation of parasitemia (1000 -100,000 ring forms/mL). Subjects were hospitalized for 28 days to insure medication compliance and to rule out the possibility of reinfections. With 77 patients in each group, the cure rates were 98.7% and 100% for atovaquone plus proguanil and quinine plus tetracycline, respectively. The parasite clearance times (mean, 56 h) and fever clearance times (mean, 19 h) were significantly shorter in the atovaquone plus proguanil group, and there were significantly fewer side effects in the atovaquone plus proguanil group. Atovaquone plus proguanil is an efficacious, easily administered, safe regimen for the treatment of uncomplicated, multidrug-resistant falciparum malaria in Brazil.", "cite_spans": [], "ref_spans": []}, {"section": "Results Discussion", "text": "Multidrug-resistant falciparum malaria continues to be a madisseminate resistant strains throughout the region. During the past decades, parasite drug resistance to chloroquine, pyrimethjor public health problem in developing countries, requiring new treatment regimens nearly every decade. The problem is amine-sulfadoxine, and to some extent, quinine [2] has developed at an alarming rate. Currently, the recommended regimens especially severe in Brazil, which has experienced a 3-fold rise for uncomplicated falciparum malaria in order of priority are in malaria during the past decade, to nearly 600,000 infections quinine plus tetracycline for 7 days, quinine alone for 10 days, annually, approximately half of which are falciparum [1] .", "cite_spans": [{"start": 737, "end": 740, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Results Discussion", "text": "and a single dose of mefloquine [3] . The first two regimens Nearly all of the malaria is confined to the Amazon region, in have problems with poor compliance and many side effects. which migrant populations, great distances, and poor access to Half the patients do not comply for \u00fa3 days (de Alencar FEC, diagnosis and treatment are major obstacles to malaria control. unpublished data). Mefloquine is expensive, and because of its Presumptive treatment without diagnosis has led to overuse of long half-life, resistance may develop rapidly through reinfecantimalarials and is probably a significant factor in the generations in malaria-endemic areas. tion of parasite resistance. Migrant populations can rapidly As in other areas of the world faced with multidrug resistance, the options for alternatives are few and problematic. Increasing the dose of existing regimens may lead to toxicity and only delay the development of resistance. Combining dif-", "cite_spans": [{"start": 32, "end": 35, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Serial enzymatic hydrolysis of cell walls of two serotypes of yeast-form Histoplasma capsulatum with a-(1-3)-glucanase, b-(1-3)-selecting for a few a-(1,3)-glucan -negative variants already glucanase, pronase, and chitinase", "authors": [{"first": "E", "middle": [], "last": "Reiss", "suffix": ""}, {"first": "R", "middle": ["D"], "last": "Vincent", "suffix": ""}, {"first": "R", "middle": [], "last": "Goewert", "suffix": ""}, {"first": "W", "middle": ["E"], "last": "Goldman", "suffix": ""}, {"first": "G", "middle": ["S"], "last": "Kobayashi", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Lambowitz", "suffix": ""}], "year": 1977, "venue": "Infect Immun", "link": null}, "BIBREF1": {"title": "Classification of Histoplasma capsulatum isolates by restricwalled form quickly enough. 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C. de Alencar", "authors": [{"first": "Crispim", "middle": [], "last": "Cerutti", "suffix": ""}], "year": "", "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "We examined the ultrastructure of yeasts ingested by macro- inherent limitations of the two methodologies: Entire yeasts phages by seeding 2.8 1 10 5 P388D1.D2 cells in 16-mm wells and are seen by light microscopy, whereas only ultrathin cross- then inoculating them the following day with 6 1 10 5 yeasts in 1 sections of yeasts are examined via electron microscopy. mL of HMM-M medium [16] completed as for F-12 above. The To determine whether variants actively altered their walls next day, they were washed three times in PBS before in situ fixation inside macrophages, we used glutaraldehyde pretreated yeasts in 2% glutaraldehyde at 4\u040aC. After postfixing with osmium tetroxide and dehydrating as above, embedding medium was poured into the as an inoculum. Glutaraldehyde treatment prevented allomorph wells and the samples were processed in a manner identical to the formation as assessed by fluorescence microscopy. However, yeast pellets. In some experiments, yeasts were glutaraldehyde-fixed this treatment did not prevent changes in the ultrastructure of as described above, washed twice in modified Tyrode's buffer, and the walls of variants within macrophages: They still acquired stored overnight in HMM [4] at 4\u040aC prior to addition to macrophages a thin, wavy appearance (not shown). at 37\u040aC in completed HMM-M. Glutaraldehyde-treated fungi were Yeasts infecting HTE cells. Variant yeasts do not form allo- unable to form colonies on solid HMM. morphs in HTE cells [5] but nonetheless had thin, wavy walls To examine yeasts inside HTE cells, we plated 5 1 10 4 cells/ inside them (figure 2A). Unexpectedly, the parental strains were 16-mm well and infected them the following day with 1-5 1 10 7 found in two different states within these cells. About half the yeasts in 1 mL of completed F-12 medium. After 20-24 h, the yeasts had thick, electron-lucent walls (figure 2B) but often wells were washed 10 times with completed medium, twice with seemed irregular in shape or had profoundly disarrayed cyto- PBS, and then fixed with glutaraldehyde, as described earlier for macrophages. Samples were treated as above to detect a-(1,3)- plasms, as though the fungi were dead or dying. Organisms glucan by electron microscopy. Approximately 50 yeast cells were cohabiting a single phagosome were sometimes at different examined to evaluate the cell wall architecture. stages of deterioration. The other half of the population had Fluorescence microscopy. For comparative purposes, com- thin, sinuous walls and an intact cytoplasm and were ultrastruc- panion monolayers on coverslips were infected and stained as turally indistinguishable from variants inside HTE cells (figure previously described [4] with Fungiqual (provided by J. R. Little, 2C). In additional experiments (data not shown), we determined Washington University School of Medicine, St. Louis) to detect that the thick-walled organisms possessed a-(1,3)-glucan, chitin and monitor for the presence of allomorphic yeasts [5].", "type": "figure"}, "FIGREF1": {"text": "Figure 1. Ultrastructure of H. capsulatum yeasts in suspension and in macrophages. A, Ruthenium red staining was used on broth-grown yeasts to demonstrate presence of carbohydrate-rich cell wall (thick gray layer, arrow) surrounding yeasts (shown here: UCLA 531-R; UCLA 531-S, UCLA 531-HTE; corresponding set of G186A strains were identical). B-D, Immunogold staining to detect a-(1,3)-glucan (MOPC 104E was primary antibody). B, In broth-grown parental strains (representative strain G186A-R is shown), a-(1,3)-glucan was localized in electron-lucent cell wall layer (arrow). C, One day after inoculation of macrophages, parental Histoplasma strains (G186A-R is shown) had thick, uniform cell walls (arrow) in which a-(1,3)-glucan was localized. Arrowhead: phagosomal membrane. D, Avirulent variants (e.g., UCLA 531-S shown here) have thin, wavy wall (arrows) in macrophages. No a-(1,3)-glucan was detected. Arrowhead: phagosomal membrane. Bar \u00c5 500 nm.", "type": "figure"}, "FIGREF2": {"text": "Figure 2. Ultrastructure of H. capsulatum yeasts inside HTE cells. A, One day after inoculation, thin, sinuous walls (arrow) were again seen on variants (UCLA 531S is shown). B, At same time point in samples inoculated with parental yeasts, electron-lucent wall (arrow) was present on some yeasts (representative strain, UCLA 531R). Cytoplasm of a few remained intact but in many it was in great disarray (*). As seen here, both degrading and apparently intact yeast can occupy same host vesicle. C, Remainder of ingested yeasts (UCLA 531R) had lost thick, electron-lucent wall and acquired wavy, thin one (arrow). Arrowhead: phagosomal membrane. Bar \u00c5 500 nm.", "type": "figure"}, "TABREF0": {"text": "tained as previously described [4]. The suffix ''R'' refers to the Both parental and variant yeasts survive in macrophages; rough colony phenotype of the parental strain. These parent strains however, only the former kills these phagocytes [4]. The vari- are representative of two separate evolutionary classes [10] within ants can persist within macrophages for at least 3 months in chemotype II. Broth cultures of any strain are routinely \u00fa95% viable, as assessed by staining with fluorescein-diacetate and ethid- ium bromide [11].Tyrode's buffer, rinsed in buffer, and dehydrated with ethanol and morphs, previous work indicates that all chemotype II strains propylene oxide prior to embedding (Poly/Bed 812; Polysciences). behave identically inside cells [4, 5]. Consequently, the two Thin sections were cut with a glass knife, mounted on copper sets of strains were used interchangeably in the remainder of grids, and stained with lead and uranyl acetate. Grids were exam- this study. ined using a Phillips 201 electron microscope, and representative Yeasts infecting macrophages. Inside P388D1.D2 cells, the fields were photographed.was left out of the fixation and postfixation steps. Thin sections ure 1C). For variants, the thick carbohydrate layer visible in were washed in PBS containing 0.5%-1% bovine serum albumin broth-grown organisms was no longer apparent inside these before monoclonal antibody MOPC 104E (Sigma, St. Louis) was cells. Instead, the cytoplasmic membrane of the yeasts was applied as a primary antibody for 1 h. This antibody is specific for a-(1,3)-linked oligosaccharides [14] and binds to rough strains", "type": "table"}}}
{"paper_id": "17781707", "_pdf_hash": "bd69e42cb7d014bfef003c5443f508b8f10c1669", "abstract": [{"section": "Abstract", "text": ". Metabolic effects of induced alkalosis during progressive forearm exercise to fatigue. J Appl Physiol 96: 2050-2056, 2004. First published February 6, 2004 10.1152/ japplphysiol.01261.2003.-Metabolic alkalosis induced by sodium bicarbonate (NaHCO 3) ingestion has been shown to enhance performance during brief high-intensity exercise. The mechanisms associated with this increase in performance may include increased muscle phosphocreatine (PCr) breakdown, muscle glycogen utilization, and plasma lactate (Lac \u03ea pl) accumulation. Together, these changes would imply a shift toward a greater contribution of anaerobic energy production, but this statement has been subject to debate. In the present study, subjects (n \u03ed 6) performed a progressive wrist flexion exercise to volitional fatigue (0.5 Hz, 14-21 min) in a control condition (Con) and after an oral dose of NaHCO 3 (Alk: 0.3 g/kg; 1.5 h before testing) to evaluate muscle metabolism over a complete range of exercise intensities. Phosphorus-31 magnetic resonance spectroscopy was used to continuously monitor intracellular pH, [PCr] ]pl accumulation were detected. In conclusion, NaHCO 3 ingestion was shown to increase plasma pH at rest, which resulted in a delayed onset of intracellular acidification during incremental exercise. Conversely, NaHCO 3 was not associated with increased [Lac \u03ea ]pl accumulation or PCr breakdown. sodium bicarbonate; intracellular pH; lactate; phosphorus-31 magnetic resonance spectroscopy; skeletal muscle; ergogenic aid METABOLIC ALKALOSIS INDUCED by sodium bicarbonate (NaHCO 3 ) ingestion has been shown to enhance intense exercise lasting \u03f31-7 min (1, 3, 22, 25, 32) . Several explanations for this effect have been proposed, but the mechanism has not yet been clearly elucidated. A common explanation is that induced alkalosis leads to an enhanced muscle glycolytic ATP production and consequently a greater capacity for high-intensity exercise. Studies that have reported NaHCO 3 ingestion increases the blood plasma lactate concentration ([Lac \u03ea ] pl ) during exercise would be consistent with this explanation (2, 11, 25, 29) . Furthermore, it has been reported by Hollidge-Horvat et al. (9) that induced alkalosis may increase muscle glycogen utilization, phosphocreatine breakdown, and inorganic phosphate (P i ) accumulation during 15 min of cycling at 75% maximal O 2 uptake. In summary, these findings would tend to suggest that NaHCO 3 ingestion results in a shift toward a greater contribution of anaerobic energy production during exercise.", "cite_spans": [{"start": 1647, "end": 1650, "text": "(1,", "ref_id": "BIBREF0"}, {"start": 1651, "end": 1653, "text": "3,", "ref_id": "BIBREF2"}, {"start": 1654, "end": 1657, "text": "22,", "ref_id": "BIBREF21"}, {"start": 1658, "end": 1661, "text": "25,", "ref_id": "BIBREF24"}, {"start": 1662, "end": 1665, "text": "32)", "ref_id": "BIBREF31"}, {"start": 2113, "end": 2116, "text": "(2,", "ref_id": "BIBREF1"}, {"start": 2117, "end": 2120, "text": "11,", "ref_id": "BIBREF10"}, {"start": 2121, "end": 2124, "text": "25,", "ref_id": "BIBREF24"}, {"start": 2125, "end": 2128, "text": "29)", "ref_id": "BIBREF28"}], "ref_spans": []}, {"section": "Abstract", "text": "During single-and repeated-bout sprint exercise, it is plausible that an increase in nonoxidative ATP production would be beneficial to performance. However, NaHCO 3 ingestion has also been shown to improve endurance activity lasting 30-60 min (5, 23, 26) . Fatigue in exercise lasting longer than 15 min has been associated with glycogen depletion and lactate accumulation, in which case a shift toward anaerobic energy production is expected to inhibit, rather than improve, muscle function. Recently, Stephens et al. (30) examined the effects of NaHCO 3 ingestion on \u03f360 min of exhaustive endurance exercise and reported a decrease in muscle [H \u03e9 ] (brackets denote concentration) but no changes in phosphocreatine or glycogen utilization. These findings appear to contradict those of Hollidge-Horvat et al. (9) for 15 min of cycling at a similar intensity. Although differences in the amount of exercise time may account for the conflicting results, a possible explanation for these differences was the use of only a small number (\u03fd5) of muscle biopsies for in vivo monitoring of intracellular metabolism during continuous exercise. Consequently, the inherent limitations of infrequent sampling and poor time resolution associated with muscle biopsy analysis may have prevented a clear understanding of the data.", "cite_spans": [{"start": 244, "end": 247, "text": "(5,", "ref_id": "BIBREF4"}, {"start": 248, "end": 251, "text": "23,", "ref_id": "BIBREF22"}, {"start": 252, "end": 255, "text": "26)", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "Abstract", "text": "The present study, therefore, is the first to use phosphorus-31 magnetic resonance spectroscopy ( 31 P-MRS) to study the effects of NaHCO 3 ingestion on muscle metabolism during continuous exercise.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "31 P-MRS is ideally suited for this type of experiment because it allows for continuous, noninvasive measurement of the kinetics of high-energy phosphate metabolites associated with muscle energy production and utilization. Unlike muscle biopsy analysis, in which intracellular metabolism is inferred from only a small number of discrete data points, 31 P-MRS allows for rapid and continuous measurement of intracellular parameters. Previously, it has been shown with 31 P-MRS that, during incremental exercise to fatigue, the kinetics of intracellular metabolism are not linear but that a power output or inflection point can be identified above which the rate of decline in the ratio of [PCr] to [P i ] and in intracel-", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "METABOLIC ALKALOSIS INDUCED by sodium bicarbonate (NaHCO 3 ) ingestion has been shown to enhance intense exercise lasting \u03f31-7 min (1, 3, 22, 25, 32) . Several explanations for this effect have been proposed, but the mechanism has not yet been clearly elucidated. A common explanation is that induced alkalosis leads to an enhanced muscle glycolytic ATP production and consequently a greater capacity for high-intensity exercise. Studies that have reported NaHCO 3 ", "cite_spans": [{"start": 57, "end": 58, "text": "3", "ref_id": "BIBREF2"}, {"start": 131, "end": 134, "text": "(1,", "ref_id": "BIBREF0"}, {"start": 135, "end": 137, "text": "3,", "ref_id": "BIBREF2"}, {"start": 138, "end": 141, "text": "22,", "ref_id": "BIBREF21"}, {"start": 142, "end": 145, "text": "25,", "ref_id": "BIBREF24"}, {"start": 146, "end": 149, "text": "32)", "ref_id": "BIBREF31"}, {"start": 463, "end": 464, "text": "3", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "ingestion increases the blood plasma lactate concentration ([Lac", "text": "] pl ) during exercise would be consistent with this explanation (2, 11, 25, 29) . Furthermore, it has been reported by Hollidge-Horvat et al. (9) that induced alkalosis may increase muscle glycogen utilization, phosphocreatine breakdown, and inorganic phosphate (P i ) accumulation during 15 min of cycling at 75% maximal O 2 uptake. In summary, these findings would tend to suggest that NaHCO 3 ingestion results in a shift toward a greater contribution of anaerobic energy production during exercise.", "cite_spans": [{"start": 65, "end": 68, "text": "(2,", "ref_id": "BIBREF1"}, {"start": 69, "end": 72, "text": "11,", "ref_id": "BIBREF10"}, {"start": 73, "end": 76, "text": "25,", "ref_id": "BIBREF24"}, {"start": 77, "end": 80, "text": "29)", "ref_id": "BIBREF28"}, {"start": 143, "end": 146, "text": "(9)", "ref_id": "BIBREF8"}, {"start": 395, "end": 396, "text": "3", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "ingestion increases the blood plasma lactate concentration ([Lac", "text": "During single-and repeated-bout sprint exercise, it is plausible that an increase in nonoxidative ATP production would be beneficial to performance. However, NaHCO 3 ingestion has also been shown to improve endurance activity lasting 30-60 min (5, 23, 26) . Fatigue in exercise lasting longer than 15 min has been associated with glycogen depletion and lactate accumulation, in which case a shift toward anaerobic energy production is expected to inhibit, rather than improve, muscle function. Recently, Stephens et al. (30) examined the effects of NaHCO 3 ingestion on \u03f360 min of exhaustive endurance exercise and reported a decrease in muscle [H \u03e9 ] (brackets denote concentration) but no changes in phosphocreatine or glycogen utilization. These findings appear to contradict those of Hollidge-Horvat et al. (9) for 15 min of cycling at a similar intensity. Although differences in the amount of exercise time may account for the conflicting results, a possible explanation for these differences was the use of only a small number (\u03fd5) of muscle biopsies for in vivo monitoring of intracellular metabolism during continuous exercise. Consequently, the inherent limitations of infrequent sampling and poor time resolution associated with muscle biopsy analysis may have prevented a clear understanding of the data.", "cite_spans": [{"start": 244, "end": 247, "text": "(5,", "ref_id": "BIBREF4"}, {"start": 248, "end": 251, "text": "23,", "ref_id": "BIBREF22"}, {"start": 252, "end": 255, "text": "26)", "ref_id": "BIBREF25"}, {"start": 520, "end": 524, "text": "(30)", "ref_id": "BIBREF29"}, {"start": 811, "end": 814, "text": "(9)", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "ingestion increases the blood plasma lactate concentration ([Lac", "text": "The present study, therefore, is the first to use phosphorus-31 magnetic resonance spectroscopy ( 31 P-MRS) to study the effects of NaHCO 3 ingestion on muscle metabolism during continuous exercise. 31 P-MRS is ideally suited for this type of experiment because it allows for continuous, noninvasive measurement of the kinetics of high-energy phosphate metabolites associated with muscle energy production and utilization. Unlike muscle biopsy analysis, in which intracellular metabolism is inferred from only a small number of discrete data points, 31 P-MRS allows for rapid and continuous measurement of intracellular parameters. Previously, it has been shown with 31 P-MRS that, during incremental exercise to fatigue, the kinetics of intracellular metabolism are not linear but that a power output or inflection point can be identified above which the rate of decline in the ratio of [PCr] to [P i ] and in intracel-lular pH (pH i ) is greater relative to that seen at lower power outputs (19) . The slope, or rate of change in these variables, can thus be a useful parameter in describing the status of cellular metabolism. In the present study, therefore, an incremental exercise protocol was employed to examine the metabolic response to NaHCO 3 ingestion over the entire range of power output capable by the muscle [i.e., rest to peak power output (PO peak )]. It is hoped that, with the improved time resolution of 31 P-MRS, our study will help to clarify the changes occurring in intracellular metabolism with exercise during induced alkalosis.", "cite_spans": [{"start": 199, "end": 201, "text": "31", "ref_id": "BIBREF30"}, {"start": 550, "end": 552, "text": "31", "ref_id": "BIBREF30"}, {"start": 667, "end": 669, "text": "31", "ref_id": "BIBREF30"}, {"start": 993, "end": 997, "text": "(19)", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "ingestion increases the blood plasma lactate concentration ([Lac", "text": "In summary, the purpose of the present study was to use 31 P-MRS and venous blood sampling to study the effects of NaHCO 3 ingestion on the metabolic and acid-base responses to incremental forearm wrist flexion exercise in humans. In contrast to previous muscle-biopsy studies that have reported either significant (9) or negligible (30) metabolic effects of induced alkalosis, we have utilized to our advantage the continuous in vivo measurement of intracellular metabolism to elucidate the metabolic effects that have been speculated to occur with NaHCO 3 ingestion. Specifically, it was hypothesized in our study that 1) an oral dose of 0.3 g/kg body wt NaHCO 3 ", "cite_spans": [{"start": 315, "end": 318, "text": "(9)", "ref_id": "BIBREF8"}, {"start": 663, "end": 664, "text": "3", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "METHODS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Subjects.", "text": "Six male volunteers participated in the study [age 27 \u03ee 3 (SD) yr; height 1.80 \u03ee 0.07 m; weight 80.2 \u03ee 8.1 kg]. All subjects were healthy and moderately active, but none was trained specifically in sports that involved extensive use of the forearm musculature, such as squash or tennis. Before the experiment, all procedures and any potential risks were explained to each subject, and an informed consent document was signed previous to participation. The study was approved by The University of Western Ontario Review Board for Health Sciences Research Involving Human Subjects.", "cite_spans": [], "ref_spans": []}, {"section": "Subjects.", "text": "Experimental protocol. Subjects were studied twice during each of two conditions, control (Con) and after NaHCO 3 ingestion (Alk). Two exercise tests were performed during each condition to evaluate 1) muscle metabolism and acid-base status using 31 P-MRS and 2) [Lac \u03ea ]pl and acid-base status in venous blood draining the active forearm muscle via standard blood sampling techniques (Bld).", "cite_spans": [], "ref_spans": []}, {"section": "Subjects.", "text": "Subjects reported to the laboratory at least 2-3 h after a light meal and after abstaining from caffeine-containing foods and beverages; exercise tests were performed at the same time of day for each subject and were separated by at least 48 h. Before the Alk trial, each subject was given an oral dose of NaHCO3 (0.3 g/kg body wt), which has been demonstrated consistently to elicit a state of metabolic alkalosis (16, 20) . To achieve peak venous [HCO 3 \u03ea ], the oral dose of NaHCO3 was administered 1.5 h before the start of the exercise (17) . The oral dose of NaHCO3 was contained within gel capsules and administered with \u03f3500 ml of water because it was found from earlier testing in our laboratory that this mode of administration was easier for the subjects to ingest than when mixed with a sports drink. In both Con and Alk, subjects rested comfortably during the period of time before exercise and were permitted to drink water ad libitum to minimize the potential gastrointestinal effects that are common with NaHCO3 ingestion.", "cite_spans": [{"start": 415, "end": 419, "text": "(16,", "ref_id": "BIBREF15"}, {"start": 420, "end": 423, "text": "20)", "ref_id": "BIBREF19"}, {"start": 454, "end": 455, "text": "3", "ref_id": "BIBREF2"}, {"start": 541, "end": 545, "text": "(17)", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Subjects.", "text": "The exercise protocol was identical for each of the four tests and consisted of progressive wrist-flexion exercise to volitional fatigue performed on a custom-built wrist ergometer. Previous to the start of exercise, subjects lay supine on a table positioned next to the ergometer. The dominant arm of each subject was then placed inside the ergometer by placing the arm in full extension and then abducting to 90\u00b0. The forearm was placed in the pronated position so that subjects were able to grasp the lever of the ergometer, which was aligned such that the pivot of the lever centered on the axis of the wrist joint. With the arm in this position, the contracting forearm musculature was positioned at heart level, thus ensuring adequate perfusion during the relaxation phase of each contraction-relaxation cycle. The subjects remained supine throughout the protocol.", "cite_spans": [], "ref_spans": []}, {"section": "Subjects.", "text": "The exercise consisted of repeatedly depressing the lever at a frequency of 0.5 Hz (1-s contraction/1-s relaxation) through a range of motion of \u03f370\u00b0. This action raised and lowered a water reservoir through the use of a cable-and-pulley system. The resistance was increased in a ramplike fashion by pumping water by means of a roller pump (Cole-Parmer Instruments, Chicago, IL) into the reservoir at a constant rate (0.22 l/min). A metronome set at 0.5 Hz was used to keep subjects on pace, and the experimenters monitored the movement of the water reservoir to ensure that subjects exercised within the full range of motion through to the completion of exercise.", "cite_spans": [], "ref_spans": []}, {"section": "Subjects.", "text": "After a 5-min period during which resting measurements were taken, subjects accommodated to the exercise protocol with 3 min of wrist flexion against low resistance (1.0 kg). After this initial accommodation period, subjects continued to exercise while water was continuously added to the reservoir at a rate of 0.22 kg/min. Subjects exercised to volitional fatigue, which was defined as the point at which subjects failed on repeated attempts to raise the reservoir through the full range of motion. The work done by the subject was calculated by using the known repetition rate (0.5 Hz), the arc distance of the lever (0.10 m), and the weight of the reservoir and water [1.08 kg \u03e9 (flow rate\u2150exercise time)] using standard physical relationships. This produced a ramp slope of \u03f30.11 W/min from an initial load of 0.53 W (accommodation period). The actual flow rate of water into the reservoir was calculated as the total volume of water added during the exercise test divided by the time to fatigue.", "cite_spans": [], "ref_spans": []}, {"section": "Subjects.", "text": "31P-MRS. Forearm muscle metabolism was studied by using 31 P-MRS with the wrist flexion ergometer positioned within the bore of the magnet. Data were obtained using a 30-cm-bore 1.89-Tesla superconducting magnet interfaced with a SMIS/IMRIS console (Surrey Medical Imaging Systems, Guilford, UK; Innovative Magnetic Resonance Imaging Systems, Winnipeg, MB, Canada). When the subject's arm was placed in the ergometer within the bore of the magnet, the belly of the forearm was situated over a 4-cm dual-tuned 1 H-31 P surface coil, \u03f37-9 cm distal to the medial epicondyle of the humerus. In this position, the nuclear magnetic resonance signal was obtained primarily from the flexor digitorum superficialis muscle. All spectra were acquired with a 3-ms 90\u00b0adiabatic radio-frequency pulse, a 3.3 kHz receiver bandwidth, 8-s delay time, and 2,048 complex data points with a 300-s dwell time. Each spectrum was produced from an average of six free induction decay signals with a repetition time of 6 s (total acquisition time of 36 s).", "cite_spans": [], "ref_spans": []}, {"section": "Subjects.", "text": "Quantification of the 31 P-MRS metabolite data was performed in the time (acquisition) domain by fitting each 31 P free induction decay to a sum of damped sinusoids, which could be varied in terms of amplitude, phase, delay time, damping constant, and frequency. This method utilized a priori knowledge and a nonlinear least squares algorithm to iteratively reduced the difference between the data and the experimental model. The concentrations of the phosphate metabolites PCr and Pi were determined from the amplitude of the exponential model function at time equal zero.", "cite_spans": [{"start": 110, "end": 112, "text": "31", "ref_id": "BIBREF30"}], "ref_spans": []}, {"section": "Subjects.", "text": "[ATP] was calculated from the average concentration of the three phosphate resonances: \u2423-ATP, \u2424-ATP, and \u2425-ATP. For each parameter, metabolite concentration was expressed relative to total phosphate signal, and, because only ratios of metabolites were used, correction factors were not applied. Intra-cellular [H \u03e9 ] and pHi were determined from the chemical shift of Pi with respect to PCr.", "cite_spans": [], "ref_spans": []}, {"section": "Subjects.", "text": "Blood sampling. During Bld trials, blood was drawn from a deep arm vein at the following times: 3 min and 1 min before the beginning of exercise; at the end of the 3-min accommodation period; and at 1-min intervals during the ramp protocol (including the point of fatigue). Blood was drawn into syringes containing lithium heparin, mixed, placed in ice water, and analyzed after a short delay. Whole blood samples (200 l) were analyzed at 37\u00b0C for plasma pH, PCO 2,", "cite_spans": [], "ref_spans": []}, {"section": "Subjects.", "text": ", and [Lac \u03ea ]pl by using selective electrodes (StatProfile 9 Plus blood gas-electrolyte analyzer, Nova Biomedical Canada, Mississauga, ON, Canada). The electrodes were calibrated before each test and at regular intervals during analysis. Plasma [H \u03e9 ] was calculated from the measured pH, and plasma [HCO 3 \u03ea ] was calculated from pH and PCO2.", "cite_spans": [{"start": 306, "end": 307, "text": "3", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Subjects.", "text": "Analyses. Because exercise time to fatigue (TTF) and POpeak varied among individuals, group mean comparisons were facilitated by plotting the data as a percentage of PO peak. To perform this normalization, metabolite data during the exercise protocol were plotted vs. power output for each subject, and a nonlinear regression algorithm was used to fit a series of 10 points (deciles) to the experimental data. Data in their final form were thus characterized by 12 data points, which included rest, warm-up, and 10 percentiles of PO peak. In the case of resting metabolite data, values were was taken as the average metabolite concentration recorded over the 5-min rest period and were plotted as 0% PO peak. Data recorded during the accommodation period were also averaged and plotted as the mean percentage of the mean PO peak. The remaining 10 data points comprised the relative power outputs for 10 equally spaced percentiles during exercise.", "cite_spans": [], "ref_spans": []}, {"section": "Subjects.", "text": "The above normalization allowed for comparison between individuals with varying TTF or PO peak; however, to compare between trials (i.e., Con vs. Alk), the data also required an additional control. It was expected that, because of a training effect or an ergogenic benefit of NaHCO 3, subjects in one trial might exercise to a greater TTF and/or POpeak than another. To allow for this variation, the normalization algorithm during the Alk trial was constrained to fit 10 points in the exercise data, which occurred at identical absolute power output values to the 10 percentiles in Con. Thus Alk data are expressed relative to %PO peak in the Con condition (noted as %ConPOpeak). In a situation in which a subject experienced an increased TTF and/or PO peak with Alk, an eleventh point was included (noted as \u03fe100% ConPOpeak) to represent the point of fatigue. Similarly, if a subject experienced a decreased TTF and/or POpeak, one (or more) of the final deciles was excluded from the regression model until it was contained within the experimental data.", "cite_spans": [], "ref_spans": []}, {"section": "Subjects.", "text": "To Piecewise linear regression analysis was applied to these plots by use of an algorithm that estimated the slope and intercept parameters of two regression functions and determined an inflection at which the slope of the two lines diverged. An F test (P \u03fd 0.05) was used to evaluate whether a single or multiple regression provided the optimal fit of the data.", "cite_spans": [], "ref_spans": []}, {"section": "Subjects.", "text": "Statistical analysis. Statistical analyses were performed using SPSS v10.0.7 statistical program for the personal computer (SPSS, Chicago, IL). Muscle and plasma metabolic data were analyzed for main Con, Alk, time, and interaction effects by two-way repeated-measures ANOVA. A significant F ratio was further analyzed via StudentNewman-Keuls post hoc analysis. In addition, metabolite inflections, TTF, and PO peak values were analyzed via a dependent-samples paired Student's t-test. In all cases, statistical significance was considered at P \u03fd 0.05. Data presented in the text and tables are given as means \u03ee SD, and figures are represented by means \u03ee SE.", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "Exercise performance. Two series of exercise tests were performed to allow separate collection of muscle and blood metabolite data. The protocol for each series was identical in every respect except for the use of 31 P-MRS to collect muscle metabolic and acid-base data and venous catheterization for blood sampling and collection of blood metabolite and acidbase data. Resistance increased in a ramplike fashion, with no difference in the rate of ramp increase (\u03f30.11 W/min; \u03f30.225 l/min H 2 O) between 31 P-MRS and Bld or Con and Alk. However, TTF and PO peak were \u03f312% greater (P \u03fd 0.05) during the ramp tests performed after NaHCO 3 ingestion (Table 1). There was no difference between 31 P-MRS and Bld in either instance.", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "Intramuscular metabolic and acid-base status. The effect of NaHCO 3 ingestion on pH i during the forearm exercise protocol is presented in Fig. 1 ] accumulation was biphasic (P \u03fd 0.05), Fig. 1 . Effect of NaHCO3 ingestion (Alk) on forearm muscle intracellular pH during incremental wrist flexion exercise to fatigue. In both control (Con) and Alk, muscle pH during exercise is expressed relative to a percentage of the peak power output in Con (%ConPOpeak). Dotted lines indicate power outputs corresponding to the delayed (P \u03fd 0.05) onset of intracellular acidosis (pH threshold) in Con (pHTCon) and Alk (pHTAlk). Values are means \u03ee SE. *Alk significantly different from Con (P \u03fd 0.05). displaying an initial slow and later fast component separated by a distinct point of inflection (pHT). The slope of the pH-power output relationship was less (P \u03fd 0.05) below the pHT than above, but in neither instance was there any difference between conditions (Table 2) . However, the onset of intracellular acidosis was delayed (P \u03fd 0.05) in Alk (Table 3) . Compared with Con, the pHT in Alk was right-shifted and occurred at a higher power output during exercise (Con: 1.17 \u03ee 0.26 W; Alk: 1.28 \u03ee 0.22 W). These changes corresponded to a higher (P \u03fd 0.05) pH i in Alk than in Con at any relative power output beyond the pHT (Fig. 1) .", "cite_spans": [], "ref_spans": [{"start": 951, "end": 960, "text": "(Table 2)", "ref_id": "TABREF5"}, {"start": 1038, "end": 1047, "text": "(Table 3)", "ref_id": "TABREF6"}]}, {"section": "RESULTS", "text": "The effects of NaHCO 3 ingestion on the high-energy phosphates PCr, P i , and ATP are presented in Fig. 2 The effect of NaHCO 3 on the equilibrated forearm venous plasma pH during the forearm exercise protocol is presented in Fig. 4 Fig. 5 . At rest, the [H \u03e9 ] gradient was similar in both conditions (Con: 45 \u03ee 7 nmol/l; Alk: 51 \u03ee 2 nmol/l). The [H \u03e9 ] gradient remained at resting levels until the power output reached \u03f360% Con PO peak , at which point it abruptly rose (P \u03fd 0.05) in both Con and Alk. The [H \u03e9 ] gradient was higher (P \u03fd 0.05) in Con compared with Alk at power outputs \u03fe60% Con PO peak . At the end of exercise, the [H \u03e9 ] gradient remained higher in Con compared with Alk (Con: 391 \u03ee 52 nmol/l; Alk: 330 \u03ee 79 nmol/l).", "cite_spans": [], "ref_spans": [{"start": 233, "end": 239, "text": "Fig. 5", "ref_id": "FIGREF1"}]}, {"section": "DISCUSSION", "text": "In the present study, we examined the effects of induced alkalosis on the metabolic and acid-base responses to progressive forearm wrist flexion exercise to fatigue using a combination of 31 P-MRS and blood sampling techniques. The major findings of this study were 1) Alk resulted in an increased TTF and PO peak ; 2) the pH i -power output relationship was shifted rightward in Alk, such that, although the rate of intracellular acidification was similar in both conditions, the onset of this acidification was delayed in Alk; 3) the [P i ]/[PCr]-power output relationship was also shifted rightward in Alk such that the onset of rapid increases in this ratio was delayed in Alk; and 4) no differences in venous [Lac \u03ea ] pl were found between conditions.", "cite_spans": [{"start": 188, "end": 190, "text": "31", "ref_id": "BIBREF30"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "The NaHCO 3 protocol (1.5 h before exercise) and dose (0.3 g/kg body wt) used in the present study significantly elevated plasma [HCO 3 \u03ea ] and lowered plasma [H \u03e9 ] by amounts similar to those reported in previous studies (3, 6, 9, 17, 23, 24, 30) . Our observation that, before exercise, muscle intracellular [H \u03e9 ] (or pH i ) was unaffected by NaHCO 3 ingestion has also been reported previously (3, 9, 11) and is consistent with the hypothesis that the muscle membrane is relatively impermeable to HCO 3 \u03ea . In the present study, the effects of induced alkalosis on pH i were not evident until \u03f360% Con PO peak , which corresponded approximately to the onset of intracellular acidosis. Examination of the time-dependent pH relationship reveals that, whereas the onset of intracellular acidification was delayed in Alk, the rate (or slope) of this acidification did not differ between conditions. This would suggest that although the initial accumulation of H \u03e9 is delayed in Alk, the metabolic processes involved in the production and removal of H \u03e9 remain in a similar state of balance in both conditions. These processes may include an increased glycolytic flux and/or increased lactate efflux.", "cite_spans": [{"start": 134, "end": 135, "text": "3", "ref_id": "BIBREF2"}, {"start": 223, "end": 226, "text": "(3,", "ref_id": "BIBREF2"}, {"start": 227, "end": 229, "text": "6,", "ref_id": "BIBREF5"}, {"start": 230, "end": 232, "text": "9,", "ref_id": "BIBREF8"}, {"start": 233, "end": 236, "text": "17,", "ref_id": "BIBREF16"}, {"start": 237, "end": 240, "text": "23,", "ref_id": "BIBREF22"}, {"start": 241, "end": 244, "text": "24,", "ref_id": "BIBREF23"}, {"start": 245, "end": 248, "text": "30)", "ref_id": "BIBREF29"}, {"start": 399, "end": 402, "text": "(3,", "ref_id": "BIBREF2"}, {"start": 403, "end": 405, "text": "9,", "ref_id": "BIBREF8"}, {"start": 406, "end": 409, "text": "11)", "ref_id": "BIBREF10"}, {"start": 506, "end": 507, "text": "3", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "Lactate efflux across the sarcolemma occurs via a monocarboxylate cotransporter (MCT1) (21, 27, 28) . The MCT1 transporter displays concentration dependence, saturation, stereospecificity, and temperature sensitivity and is stimulated by H \u03e9 and Lac \u03ea gradients (13) . However, in the present study increased Lac \u03ea efflux seems unlikely because the [H \u03e9 ] gradient was observed to be lower in Alk during exercise above 70% Con \u03ea uptake by inactive tissue. This suggestion is supported by the study of Granier et al. (7), who observed a lower arteriovenous Lac \u03ea difference across the inactive forearm during repeated sprint cycling after NaHCO 3 infusion. In Fig. 4 . Effect of NaHCO3 ingestion (Alk) on forearm venous plasma pH during incremental wrist flexion exercise to fatigue. In both Con and Alk, muscle pH during exercise is expressed relative to %ConPOpeak. Values are means \u03ee SE. *Alk significantly different from Con (P \u03fd 0.05). (3, 10, 12, 15, 23, 31) . Although the present study cannot reconcile these apparent contradictory findings, it is possible that differences in the types of exercise protocols and muscle groups used in these studies may be an important and often overlooked factor.", "cite_spans": [{"start": 87, "end": 91, "text": "(21,", "ref_id": "BIBREF20"}, {"start": 92, "end": 95, "text": "27,", "ref_id": "BIBREF26"}, {"start": 96, "end": 99, "text": "28)", "ref_id": "BIBREF27"}, {"start": 262, "end": 266, "text": "(13)", "ref_id": "BIBREF12"}, {"start": 940, "end": 943, "text": "(3,", "ref_id": "BIBREF2"}, {"start": 944, "end": 947, "text": "10,", "ref_id": "BIBREF9"}, {"start": 948, "end": 951, "text": "12,", "ref_id": "BIBREF11"}, {"start": 952, "end": 955, "text": "15,", "ref_id": "BIBREF14"}, {"start": 956, "end": 959, "text": "23,", "ref_id": "BIBREF22"}, {"start": 960, "end": 963, "text": "31)", "ref_id": "BIBREF30"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "The results of the present study do not agree with those of Hollidge-Horvat et al. (9), who observed that increased Lac \u03ea production and efflux caused by 15 min of cycling exercise at 75% maximal O 2 uptake with NaHCO 3 lead to increased glycogen utilization, increased PCr utilization, and increased ADP, AMP, and P i accumulation. Furthermore, these perturbations were associated with a greater pyruvate dehydrogenase activation, which presumably allowed for increased glycogenolytic flux in the face of rising [H \u03e9 ]. Although glycogen and pyruvate dehydrogenase activity were not assessed in the present study, we believe that none of these effects would be present in our study because there did not appear to be an enhanced rate of high-energy phosphate metabolism as seen in the Hollidge-Horvat et al. study. Rather, our results indicate that, for the contracting forearm, no significant differences in ATP breakdown, PCr utilization, or P i accumulation were detected between Con and Alk (Table 1) . Furthermore, when the ratio [PCr]/[P i ] (or log[P i ]/[PCr]) was plotted against power output for each subject, the transition from slow-to-rapid increases in this ratio was delayed (P \u03fd 0.05) with Alk. Presumably, these intracellular concentrations of PCr and P i reflect the metabolic activity of the muscle and as such have often been used as an in vivo estimate of the phosphorylation potential or [ATP]-to-[ADP] ratio. Stable values of this ratio indicate an adequate energy status, whereas rapid increases in this ratio reflect an inability of the cell to meet ATP demands. Therefore, it is our conclusion that the delay before the rapid increases in [P i ]/[PCr] with Alk was associated with the delayed accumulation of intracellular [H \u03e9 ]. In other words, the enhanced exercise performance with induced alkalosis is related to the ability of NaHCO 3 to maintain a more optimum pH i in the face of increasing metabolic demand.", "cite_spans": [], "ref_spans": [{"start": 996, "end": 1005, "text": "(Table 1)", "ref_id": "TABREF3"}]}, {"section": "DISCUSSION", "text": "In this respect, we may consider that the fatiguing effects of a declining pH i during exercise include allosteric inhibition of the rate-limiting enzymes phosphofructokinase and glycogen phosphorylase, decreased release of Ca 2\u03e9 from the sarcoplasmic reticulum, and a reduction in the number and force of muscle cross-bridge activations. Hence, it may be possible that the maintenance of a more favorable pH i during exercise may enhance performance; however, the mechanisms responsible Values are means \u03ee SD. Concentration expressed in mmol/l. %ConPOpeak, percent peak power output in Con. *Significant difference (P \u03fd 0.05) between Con and Alk; \u2020Significant difference from rest (P \u03fd 0.05). for the reduced muscle [H \u03e9 ] in Alk are unclear. In the present study, we believe that a more prolonged maintenance of normal pH i was achieved by either increased Na \u03e9 /H \u03e9 transport and/or an increased intracellular strong ion difference (SID). Because blood plasma [Na \u03e9 ] was significantly elevated in Alk throughout the entire exercise protocol (Table 4) , a similar increase in muscle [Na \u03e9 ] may also have occurred. As a result, an increased H \u03e9 efflux via the skeletal muscle Na \u03e9 -H \u03e9 transporter (14) and/or an increased intracellular SID may have occurred. Although the measurement of muscle [Na \u03e9 ] was not possible with the techniques used in the present study, it has been shown previously that metabolic alkalosis increased muscle [Na \u03e9 ] during exercise in a perfused rat hindlimb model (18) .", "cite_spans": [{"start": 1201, "end": 1205, "text": "(14)", "ref_id": "BIBREF13"}, {"start": 1498, "end": 1502, "text": "(18)", "ref_id": "BIBREF17"}], "ref_spans": [{"start": 1045, "end": 1054, "text": "(Table 4)", "ref_id": "TABREF9"}]}, {"section": "DISCUSSION", "text": "An intracellular alkalosis may also have resulted from disruptions in the balance of strong cations and anions within the muscle. The increase in plasma [Na \u03e9 ] and decrease in plasma [Cl \u03ea ] (Table 4 ) in the present study would have the combined effect of increasing the plasma SID, which has been shown to be the major contributor to plasma alkalosis with NaHCO 3 ingestion (17) . If a similar increase in the SID in the intracellular compartment was present before exercise, then it is expected that the elevated SID would partially counteract the acidifying effect (through a fall in SID) of the rise in muscle [Lac \u03ea ], attenuating the acidification of both the intracellular and extracellular compartments.", "cite_spans": [{"start": 377, "end": 381, "text": "(17)", "ref_id": "BIBREF16"}], "ref_spans": [{"start": 192, "end": 200, "text": "(Table 4", "ref_id": "TABREF9"}]}, {"section": "DISCUSSION", "text": "In summary, the metabolic effects of induced alkalosis were shown to include an increased plasma pH at rest that led to a delayed onset of intracellular acidification during incremental exercise. 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"middle": [], "last": "Gledhill", "suffix": ""}, {"first": "R", "middle": [], "last": "Smyth", "suffix": ""}], "year": 1983, "venue": "Med Sci Sports Exerc", "link": "8096118"}}, "ref_entries": {"FIGREF0": {"text": "Fig. 3. Effect of NaHCO3 ingestion (Alk) on forearm venous plasma lactate concentration ([Lac \u03ea ]pl) during incremental wrist flexion exercise to fatigue. In both Con and Alk, venous [Lac \u03ea ]pl during exercise is expressed relative to %ConPOpeak. Dotted lines indicate power outputs corresponding to the onset of [Lac \u03ea ]pl accumulation (lactate threshold) in Con (LTCon) and Alk (LTAlk). Values are means \u03ee SE. No significant differences between Con and Alk for [Lac \u03ea ]pl or LT (P \u03ed 0.255, 0.241)", "type": "figure"}, "FIGREF1": {"text": "Fig. 5. Effect of NaHCO3 ingestion (Alk) on forearm muscle-to-venous H \u03e9 gradient during incremental wrist flexion exercise to fatigue. In both Con and Alk, the H \u03e9 gradient during exercise is expressed relative to %ConPOpeak. Values are means \u03ee SE. *Alk significantly different from Con (P \u03fd 0.05).", "type": "figure"}, "TABREF0": {"text": "delivered 1.5 h before exercise would significantly elevate plasma [HCO 3 \u03ea ] and lower plasma [H \u03e9 ] at rest; 2) before exercise, this induced plasma alkalosis would not be associated with a decrease in intracellular [H \u03e9 ]; 3) during progressive exercise, the onset of intracellular acidosis would be delayed after NaHCO 3 ingestion; and 4) an oral dose of NaHCO 3 would be associated with increased accumulation of [Lac \u03ea ] pl and increased breakdown of PCr.", "type": "table"}, "TABREF1": {"text": "determine the onset of intracellular [H \u03e9 ] accumulation, the onset of [Lac \u03ea ]pl accumulation, and the onset of rapid increases in the phosphorylation potential ([Pi]-to-[PCr] ratio; [Pi]/[PCr]), these pa- rameters were plotted as a function of power output for each subject. Intracellular [H \u03e9 ] data were expressed in pH units, and the [Pi]/[PCr] data were expressed as the logarithm (log[Pi]/[PCr]) to facilitate detection of a biphasic response.", "type": "table"}, "TABREF2": {"text": ". In both Con and Alk, pH i and [H", "type": "table"}, "TABREF3": {"text": "Time to fatigue and peak power output during ramp exercise to fatigue in the 31 P-MRS and blood sampling exercise series during control and induced alkalosisValues are means \u03ee SD. Bld, blood sampling; TTF, time to fatigue; POpeak, peak power output; Con, control; Alk, alkalosis. *Significant difference (P \u03fd 0.05) between Con and Alk.", "type": "table"}, "TABREF4": {"text": ". With increas- ing power output, [PCr] decreased (P \u03fd 0.05), [P i ] increased (P \u03fd 0.05), and [ATP] remained similar to resting levels. No differences were observed between Con and Alk in either case. From these data, log[P i ]/[PCr] was also calculated, and the rate of change of log[P i ]/[PCr] was found to be biphasic (P \u03fd 0.05), displaying an initial slow and later fast component separated by a distinct point of inflection (PT) (Table 2). The slope of the log[P i ]/[PCr]-power output relationship was less (P \u03fd 0.05) below the PT than above, but in neither instance was there any difference between conditions. However, the onset of rapid changes in log[P i ]/[PCr] (Table 3) was delayed (P \u03fd 0.05) in Alk (Con: 1.21 \u03ee 0.30 W; Alk: 1.30 \u03ee 0.30 W). Plasma lactate and acid-base status. The effect of NaHCO 3 ingestion on the equilibrated forearm venous [Lac \u03ea ] pl during progressive forearm exercise is presented in Fig. 3. Venous [Lac \u03ea ] pl increased (P \u03fd 0.05) with increasing power output, reaching similar end-exercise values in Con and Alk (Con: 7.1 \u03ee 2.5 mmol/l; Alk: 7.5 \u03ee 2.4 mmol/l). In both conditions, the rate of [Lac \u03ea ] pl accumulation was biphasic (P \u03fd 0.05), displaying an initial slow and later fast component separated by a distinct point of inflection (LT). The slope of the [Lac \u03ea ] pl - power output relationship was less (P \u03fd 0.05) below the LT than above, but in neither instance was there any difference between conditions (Table 2). The onset of [Lac \u03ea ] pl accumu- lation (Table 3) was similar (P \u03ed 0.241) between conditions (Con: 1.17 \u03ee 0.19 W; Alk: 1.30 \u03ee 0.21 W).", "type": "table"}, "TABREF5": {"text": ". Plasma pH was higher (P \u03fd 0.05) at rest (Con: 7.43 \u03ee 0.01 pH, 37 \u03ee 1 nmol/l [H \u03e9 ]; Alk: 7.48 \u03ee 0.01 pH, 33 \u03ee 1 nmol/l [H \u03e9 ]). Plasma pH decreased (P \u03fd 0.05) with increasing power output and was higher (P \u03fd 0.05) during the entire exercise protocol in Alk compared with Con. At the end of exercise in Con (100% Con PO peak ) and Alk (112% Con PO peak ), plasma pH and [H] during Alk was also observed throughout the entire exercise protocol. Plasma [Na \u03e9 ] was not different at restBiphasic parameters of intracellular pH, log [P i ]/[PCr], and blood plasma lactate occurring during progressive exercise in Con and AlkValues are means \u03ee SD. Slope and intercept parameters are given for the piecewise linear regression function: y \u03ed m1x \u03e9 b1 (x \u03fd threshold); y \u03ed m2x \u03e9 b2 (x \u0546 threshold). pHT, intracellular pH threshold; PT, log[Pt]/[PCr] thresh- old; LT, plasma lactate threshold. *Significant difference (P \u03fd 0.05) between Con and Alk.", "type": "table"}, "TABREF6": {"text": "Piecewise linear regression analysis for the determination of an onset (or threshold) of a rapid decrease in intracellular pH and the rapid increases in log [P i ]/[PCr] and blood plasma lactate during Con and Alk] with increasing power output was greater (P \u03fd 0.05) in Alk compared with Con from warm-up to \u03f370% Con PO peak .", "type": "table"}, "TABREF7": {"text": "PO peak . In fact, a decrease in the muscle-to-blood [H", "type": "table"}, "TABREF9": {"text": "Venous plasma concentrations of HCO 34\u03ee2.0* 32.5\u03ee2.4* 32.8\u03ee2.5* 32.5\u03ee2.7* 32.4\u03ee3.1* 32.4\u03ee2.8* 32.8\u03ee3.1* 32.8\u03ee3.3* 32.2\u03ee3.2\u03ee1.1 135.8\u03ee3.5* \u2020 137.5\u03ee1.3* \u2020 139.2\u03ee1.3* \u2020 139.7\u03ee1.8* \u2020 139.3\u03ee0.8* \u2020 139.7\u03ee1.5* \u2020 140.2\u03ee1.2* \u2020 140.8\u03ee1.5 \u2020 141.6\u03ee2.1 \u2020 141.7\u03ee1.7 \u2020 141.6\u03ee2.4 \u2020 Alk 133.3\u03ee3.0 139.9\u03ee4.5* \u2020 141.0\u03ee4.7* \u2020 143.2\u03ee3.9* \u2020 144.2\u03ee3.3* \u2020 144.4\u03ee3.4* \u2020 144.2\u03ee3.0* \u2020 144.7\u03ee1.8* \u2020 142.9\u03ee2.1 \u2020 143.1\u03ee2.4 \u2020 142.1\u03ee1.9 \u2020 142.1\u03ee2.3 \u2020 140.1\u03ee6.2\u03ee0.2* \u2020 4.2\u03ee0.2* \u2020 4.3\u03ee0.2* \u2020 4.4\u03ee0.2* \u2020 4.4\u03ee0.3* \u2020 4.5\u03ee0.3* \u2020 4.4\u03ee0.3* \u2020 4.6\u03ee0.3* \u2020 4.7\u03ee0.3* \u2020 4.7\u03ee0.5* \u2020 [Cl \u03ea ] Con 104.1\u03ee3.3* 101.2\u03ee4.5* \u2020 100.8\u03ee4.4* \u2020 100.8\u03ee4.0* \u2020 101.1\u03ee4.1* 101.2\u03ee4.8* 101.6\u03ee5.4* 101.5\u03ee5.5* 101.3\u03ee4.7* 101.4\u03ee4.8* 102.0\u03ee4.7* 102.5\u03ee4.2* Alk 99.4\u03ee1.6* 94.9\u03ee2.6* \u2020 94.0\u03ee1.9* \u2020 94.2\u03ee2.0* \u2020 94.5\u03ee1.9* \u2020 94.6\u03ee2.1* \u2020 94.8\u03ee2.0* \u2020 95.5\u03ee2.0* \u2020 97.5\u03ee4.3* 98.6\u03ee4.1* 98.2\u03ee4.3* 98.7\u03ee3.3* 100.7\u03ee3.1", "type": "table"}, "TABREF10": {"text": "was not associated with increased [Lac \u03ea ] pl accumulation or increased PCr breakdown. We have concluded therefore that the oral ingestion of NaHCO 3 appears to effect intracellular metabolism primarily by inducing a small but measurable decrease in [H \u03e9 ] that is not evident until \u03f360% PO peak . It is believed that this effect may have been consequence of increased skeletal muscle Na \u03e9 -Hexchange and/or an increased intracellular SID. Furthermore, we suggest that previous reports in the literature of increased blood [Lac \u03ea ] during Alk are not due to increases in muscle Lac \u03ea production but instead may be due to decreased Lacuptake by inactive tissues.", "type": "table"}}}
{"paper_id": "17781830", "_pdf_hash": "affae73fbe07e794e7047396e4ce298f55659765", "abstract": [{"section": "Abstract", "text": "Aldehyde dehydrogenases (Aldhs) are a group of NAD(P)+-dependent enzymes that catalyze the oxidation of a wide spectrum of aldehydes to carboxylic acids. Tissue distribution and developmental changes in the expression of the mRNA of 15 Aldh enzymes were quantified in male and female mice tissues using the branched DNA signal amplification assay (bDNA). Furthermore, the regulation of the mRNA expression of Aldhs by 15 typical microsomal enzyme inducers was studied. Aldh1a1 mRNA expression was highest in ovary; 1a2 in testis; 1a3 in placenta; 1a7 in lung; 1b1 in small intestine; 2 in liver; 3a1 in stomach; 3a2 and 3b1 expression was ubiquitous; 4a1, 6a1, 7a1, and 8a1 in liver and kidney; 9a1 in liver, kidney and small intestine; and 18a1 in ovary and small intestine. mRNA of different Aldh enzymes were detected at lower levels in fetuses than adult mice and gradually increased after birth to reach adult levels between 15-45 days of age, when the gender difference in began to appear. AhR ligands induced the liver mRNA expression of Aldh1a7, 1b1, and 3a1, CAR activators induced Aldh1a1 and 1a7, whereas PXR ligands and Nrf2 activators induced Aldh1a1, 1a7, and 1b1. PPAR ligands induced the mRNA expression in liver of almost all Aldhs. The Aldh organ-specific distribution may be important in elucidating their role in metabolism, elimination, and organ-specific toxicity of xenobiotics. Finally, in contrast to other phase I metabolic enzymes such as CYP450 enzymes, Aldh mRNA expression seems to be generally insensitive to typical microsomal inducers except PPAR ligands.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "1", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Aldehyde dehydrogenases (Aldhs) are a group of NAD(P) + -dependent enzymes that catalyze the irreversible oxidation of a wide spectrum of endogenous and exogenous aldehydes to their corresponding carboxylic acids. Most Aldh isozymes prefer NAD + over NADP + as a co-factor . Aldhs exhibit broad substrate specificity and many of them can oxidize aliphatic and aromatic aldehydes. Endogenous aldehydes are formed during metabolism of various alcohols, amino acids, biogenic amines, vitamins, steroids and lipids. Aldehydes formed during oxidative stress are longlived molecules and potent electrophiles that interact with cellular constituents, including proteins and nucleic acids (Esterbauer et al. 1991) . Therefore, Aldhs are considered to be detoxifying enzymes. In some cases, Aldhs serve structural rather than enzymatic roles as major components of lens and corneal proteins (Lee et al. 1993 ).", "cite_spans": [{"start": 681, "end": 705, "text": "(Esterbauer et al. 1991)", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Introduction", "text": "The Aldh gene superfamily members share at least 15% amino acid similarity.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "ALDH isozymes that share more than 40% amino acid identity are grouped in one family. One exception to this nomenclature rule is Aldh2, which preserved its old nomenclature due to the very extensive clinical work on correlations of this gene with alcohol toxicity and addiction. Aldh1a1 and 2 are 68% similar and should be members of the same family (Vasiliou et al. 1999 ).", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The cytosolic class-1 Aldhs have been thoroughly studied because of their role in retinoic acid (RA) biosynthesis. RA is a potent modulator of gene expression and tissue differentiation during development and postnatally, by serving as a ligand for several nuclear RA receptors and retinoid X receptors (Molotkov and Duester 2003 ). Yet, excessive RA causes toxicity, both to the embryo and postnatally. RA is produced in a 3 two-step reaction starting with the oxidation of retinol (vitamin A) by alcohol dehydrogenases, followed by the irreversible conversion of retinal to RA by different retinal dehydrogenases (RALDHs) (Duester 2001 ).", "cite_spans": [{"start": 303, "end": 329, "text": "(Molotkov and Duester 2003", "ref_id": "BIBREF67"}, {"start": 624, "end": 637, "text": "(Duester 2001", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Introduction", "text": "Aldh1a1 (RALDH1) has a substrate preference for the aldehyde products of lipid peroxidation, such as the medium chain aliphatic aldehydes, and malondialdehyde, as well as retinaldehyde. This enzyme also detoxifies cyclophosphamide, which belongs to the widely used oxazaphosphorine family of anticancer drugs (Manthey et al. 1990 ). Cancer cells acquire resistance to these drugs due to the upregulation of Aldh1a1 as well as Aldh3a1 expression in tumors (Sreerama and Sladek 1997; Tsukamoto et al. 1998 ). Aldh1a1 is a major soluble constituent of the eye lens and may play a role in detoxification of peroxidic aldehydes produced by ultraviolet light absorption (King and Holmes 1997) .", "cite_spans": [{"start": 309, "end": 329, "text": "(Manthey et al. 1990", "ref_id": "BIBREF61"}, {"start": 455, "end": 481, "text": "(Sreerama and Sladek 1997;", "ref_id": "BIBREF80"}, {"start": 664, "end": 686, "text": "(King and Holmes 1997)", "ref_id": "BIBREF46"}], "ref_spans": []}, {"section": "Introduction", "text": "Aldh1a2 (RALDH2) exhibits the highest substrate specificity and catalytic efficiency for retinal oxidation to RA (Duester 2001; Maly et al. 2003) . Aldh2a1-null mice exhibit a lethal phenotype with embryos dying and failing to produce RA at E7.5-8.5. Embryos can be partially rescued by maternal RA administration (Niederreither et al. 1999) . Therefore, it was suggested that Aldh1a2 is the predominant regulator of RA synthesis in mouse embryos of the midgestational stages, whereas Aldh1a1 and 1a3 isozymes dominate in late stage embryonic development (Hsu et al. 2000) .", "cite_spans": [{"start": 113, "end": 127, "text": "(Duester 2001;", "ref_id": "BIBREF16"}, {"start": 128, "end": 145, "text": "Maly et al. 2003)", "ref_id": "BIBREF60"}, {"start": 314, "end": 341, "text": "(Niederreither et al. 1999)", "ref_id": "BIBREF69"}, {"start": 555, "end": 572, "text": "(Hsu et al. 2000)", "ref_id": "BIBREF35"}], "ref_spans": []}, {"section": "Introduction", "text": "Both Aldh1a2 and 1a3 (RALDH3) are more effective and selective in retinaldehyde oxidation than Aldh1a1 (Niederreither et al. 1997) . Aldh1a3-null mice die within 10 hrs of birth due to defects in nasal development (Dupe et al. 2003) . All defects can be reversed by RA administration (Dupe et al. 2003) .", "cite_spans": [{"start": 103, "end": 130, "text": "(Niederreither et al. 1997)", "ref_id": "BIBREF68"}, {"start": 214, "end": 232, "text": "(Dupe et al. 2003)", "ref_id": "BIBREF19"}, {"start": 284, "end": 302, "text": "(Dupe et al. 2003)", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "4", "text": "RA exhibits a concentration gradient in embryonic tissues with some tissues containing more RA than others, which is necessary for the overall control of embryonic development by retinoids. Raldhs have different activities in RA synthesis, therefore their age-and tissue-specific distribution is responsible for establishing the aforementioned RA gradient in embryonic tissues (Haselbeck et al. 1999) . In this respect, Aldh1a2 might be the major RA-synthesizing isozyme involved in early embryogenesis, whereas Aldh1a1 and 1a3 isozymes are more important in late stage embryonic development (Dupe et al. 2003) .", "cite_spans": [{"start": 377, "end": 400, "text": "(Haselbeck et al. 1999)", "ref_id": "BIBREF29"}, {"start": 592, "end": 610, "text": "(Dupe et al. 2003)", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "4", "text": "Aldh1a7 is induced by phenobarbital (PB) treatment in rats, resulting in up to a 10-fold increase in liver supernatant Aldh activity (Deitrich 1971) , and therefore is referred to as Aldh-PB or PB-inducible Aldh. Aldh1a7 amino acid sequence is highly identical to Aldh1a1 and its identity is commonly interchanged with 1a1 (Kathmann and Lipsky 1997; Kathmann et al. 2000; Marselos et al. 1987) . They differ in expression patterns, substrate preferences, and sensitivities to disulfiram inhibition. Most importantly, Aldh1a7 can not catalyze the oxidation of retinal to RA, and therefore does not belong to the RALDHs isozymes (Hsu et al. 1999; Marselos et al. 1987) .", "cite_spans": [{"start": 133, "end": 148, "text": "(Deitrich 1971)", "ref_id": "BIBREF13"}, {"start": 323, "end": 349, "text": "(Kathmann and Lipsky 1997;", "ref_id": "BIBREF41"}, {"start": 350, "end": 371, "text": "Kathmann et al. 2000;", "ref_id": "BIBREF42"}, {"start": 372, "end": 393, "text": "Marselos et al. 1987)", "ref_id": "BIBREF64"}, {"start": 627, "end": 644, "text": "(Hsu et al. 1999;", "ref_id": "BIBREF31"}, {"start": 645, "end": 666, "text": "Marselos et al. 1987)", "ref_id": "BIBREF64"}], "ref_spans": []}, {"section": "4", "text": "Aldh2 is a mitochondrial enzyme of special clinical importance because of its major role in alcohol metabolism. Aldh2 is the major enzyme for the disposal of acetaldehyde generated during metabolism of ethanol (Thomasson et al. 1991) . A point mutation in Aldh2 is responsible for the alcohol flushing syndrome in orientals caused by elevated blood levels of acetaldehyde (Thomasson et al. 1991) . . Aldh3a1 is constitutively expressed at low or undetectable levels in the normal liver, whereas it is highly expressed in hepatoma and other cancerous cells, with its expression in direct correlation with the degree of tumor deviation (Canuto et al. 1994) . The increase in Aldh3a1 activity is evident in approximately 50% of liver carcinoma patients . Aldhs, especially Aldh3a1, defend the cell against the cytotoxic and cytostatic aldehyde products of lipid peroxidation, such as 4-hydroxynonenal (4HNE) . Therefore, the increased Aldh3a1 expression of the carcinoma cells are critical for their growth (Canuto et al. 1999) . Furthermore, the increase of Aldh1a1 and 3a1 expression are potentially responsible for the acquired tumor cells resistance to some anticancer drugs (Rekha et al. 1994 ).", "cite_spans": [{"start": 210, "end": 233, "text": "(Thomasson et al. 1991)", "ref_id": "BIBREF85"}, {"start": 372, "end": 395, "text": "(Thomasson et al. 1991)", "ref_id": "BIBREF85"}, {"start": 634, "end": 654, "text": "(Canuto et al. 1994)", "ref_id": "BIBREF3"}, {"start": 1004, "end": 1024, "text": "(Canuto et al. 1999)", "ref_id": "BIBREF4"}, {"start": 1176, "end": 1194, "text": "(Rekha et al. 1994", "ref_id": "BIBREF75"}], "ref_spans": []}, {"section": "4", "text": "Aldh3a2 is a microsomal enzyme with high activity for oxidation of mediumchain aliphatic aldehydes (fatty aldehydes derived from several 16-18 carbon lipids (Rizzo et al. 2001) . Therefore, Aldh3a2 is referred to as fatty aldehyde Aldh (FALDH).", "cite_spans": [{"start": 157, "end": 176, "text": "(Rizzo et al. 2001)", "ref_id": "BIBREF76"}], "ref_spans": []}, {"section": "4", "text": "Various mutations in Aldh3a2 cause an inherited disease called Sj\u00f6gren-Larsson syndrome (SLS). SLS is characterized by ichthyosis, spasticity, preterm birth, and various neurological problems (De Laurenzi et al. 1996) . Aldh4a1, also known as pyrroline-5-carboxylate (P5C) dehydrogenase, is a mitochondrial enzyme that catalyzes the conversion of P5C, derived either from proline or ornithine, to glutamate (Hu et al. 1996) . The preferred substrates of Aldh4a1 are glutamic -semialdehydes, succinic, glutaric, and adipic semialdehydes (Forte-McRobbie and Pietruszko 1986) . Aldh4a1 deficiency causes type II-hyperprolinemia, an autosomal 6 recessive disorder associated with neurological manifestations, including seizures and mental retardation (Valle et al. 1974; Yoshida et al. 1998) .", "cite_spans": [{"start": 192, "end": 217, "text": "(De Laurenzi et al. 1996)", "ref_id": "BIBREF12"}, {"start": 407, "end": 423, "text": "(Hu et al. 1996)", "ref_id": "BIBREF37"}, {"start": 536, "end": 572, "text": "(Forte-McRobbie and Pietruszko 1986)", "ref_id": "BIBREF22"}, {"start": 767, "end": 787, "text": "Yoshida et al. 1998)", "ref_id": "BIBREF88"}], "ref_spans": []}, {"section": "4", "text": "The mitochondrial Aldh6a1 is the only CoA-dependent Aldh. Aldh6a1 is involved in the catabolic pathways of valine and pyrimidine by catalyzing the oxidative decarboxylation of malonate and methylmalonate semialdehydes to acetyl and propionylCoA, respectively (Kedishvili et al. 2000; Kedishvili et al. 1992 ). Therefore Aldh6a1 is also known as methylmalonate semialdehyde dehydrogenase (MMSDH). Aldh6a1 deficiency causes defects in valine catabolism and also is associated with developmental delays (Chambliss et al. 1995) .", "cite_spans": [{"start": 259, "end": 283, "text": "(Kedishvili et al. 2000;", "ref_id": "BIBREF43"}, {"start": 284, "end": 306, "text": "Kedishvili et al. 1992", "ref_id": "BIBREF44"}, {"start": 500, "end": 523, "text": "(Chambliss et al. 1995)", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "4", "text": "The cytosolic Aldh7a1 was found in rats and humans because of the high homology to the protein antiquetin (ATQ1) in the green garden pea (Lee et al. 1994; Skvorak et al. 1997) , which is up regulated when the plant is dehydrated. Aldh7a1 is thought to contribute in balancing the hydrostatic pressure inside the ear. A mutation in Aldh7a1 has been suggested to contribute in the Meniere disease (MD), an inner ear disorder characterized by tinnitus, vertigo, and hearing loss (Lynch et al. 2002) .", "cite_spans": [{"start": 137, "end": 154, "text": "(Lee et al. 1994;", "ref_id": "BIBREF50"}, {"start": 155, "end": 175, "text": "Skvorak et al. 1997)", "ref_id": "BIBREF79"}, {"start": 476, "end": 495, "text": "(Lynch et al. 2002)", "ref_id": "BIBREF58"}], "ref_spans": []}, {"section": "4", "text": "Aldh8a1 is the 4 th member in the RAldh isozymes, therefore it is also known as Raldh4 (O5TD). Compared to other Raldhs, Aldh8a1 is the only isozyme to show preference for 9-cis-retinal vs. all-trans-retinal (Lin et al. 2003) .", "cite_spans": [{"start": 208, "end": 225, "text": "(Lin et al. 2003)", "ref_id": "BIBREF53"}], "ref_spans": []}, {"section": "4", "text": "Aldh9a1 is a cytosolic enzyme with a high activity for oxidation of 4-aminobutyraldehyde to the inhibitory neurotransmitter -aminobutyric acid (GABA) (GABA) (Kikonyogo and Pietruszko 1996) , betaine aldehyde to betaine, which can serve as a methyl donor for biosynthesis of methionine, and has also been proposed to be involved in the regulation of the osmolarity in the kidney (Grunewald and Eckstein 7 1995) . Aldh9a1 also has been identified as -trimethylaminobutyraldehyde dehydrogenase involved in carnitine biosynthesis (Vaz et al. 2000) .", "cite_spans": [{"start": 157, "end": 188, "text": "(Kikonyogo and Pietruszko 1996)", "ref_id": "BIBREF45"}], "ref_spans": []}, {"section": "4", "text": "The mitochondrial Aldh18a1, also known as pyrroline-5-carboxylate synthase (P5CS), is one of 7 enzymes that operate synchronously in arginine and proline synthesis from their endogenous precursor glutamate (Hu et al. 1999) . Aldh18a1 catalyzes the conversion of L-glutamate to glutamic -semialdehyde (Hu et al. 1999) . A human genetic disease caused by a deficient P5CS is associated with skin hyperelasticity, cataracts, and mental retardation (Aral et al. 1996) .", "cite_spans": [{"start": 206, "end": 222, "text": "(Hu et al. 1999)", "ref_id": "BIBREF36"}, {"start": 300, "end": 316, "text": "(Hu et al. 1999)", "ref_id": "BIBREF36"}, {"start": 445, "end": 463, "text": "(Aral et al. 1996)", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "4", "text": "Early studies addressed tissue distribution, ontogenic expression, and induction of Aldh isozymes by a wide variety of chemical inducers. Many of these studies reported different results due to the various methodologies used, ranging from mRNA and protein expression to enzymatic activity measurement. Furthermore, many studies have reported significant induction of ALDHs by chemical inducers in vitro, which were absent in vivo.", "cite_spans": [], "ref_spans": []}, {"section": "4", "text": "In the present study, the tissue distribution, gender differences, and ontogenic expression of 15 Aldh isozymes in mice were determined. Most studies in the literature concerning the tissue distribution of Aldhs have been limited to a few tissues, and were not quantitative. The Aldh organ-specific distribution may be important in elucidating their role in metabolism, elimination, and organ-specific toxicity of xenobiotics. Furthermore, the present study addresses the regulation of Aldh isozymes by 5 groups of prototypical microsomal enzyme inducers (MEIs) in male mice. These 5 groups represent common ligand-activated transcription factors pathways known to be involved in the induction of phase-I and -II enzymes, and comprise AhR, PXR, CAR, PPAR and Nrf2 ligands or activators. Animals. Eight-week-old male and female C57BL/6 mice were purchased from Charles River Laboratories Inc (Wilmington, MA). Animals were housed in a temperature-, light-, and humidity-controlled environment. Mice were fed Laboratory Rodent Chow W (Harlan Teklad, Madison, WI) ad libitum. Tissues were removed from five mice of each gender, frozen in liquid nitrogen, and stored at -80\u00baC until mRNA isolation. For the ontogeny study, livers and kidneys from male and female mice were collected at -2, 0, 5, 10, 15, 22, 30, and 45 days of age (n= 5/gender/age). Male and female pups were pooled at age -2, because it was difficult to determine their gender.", "cite_spans": [], "ref_spans": []}, {"section": "8", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Materials and Methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Chemicals", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Treatment with MEIs.", "text": "Approximately eight-week-old male C57BL/6 mice were purchased from Charles River Laboratories Inc (Wilmington, MA) and were dosed with microsomal enzyme inducers (n=5/treatment). The chemicals, route of administration, dosing regimen, and vehicles are indicated in Table 1 . After dosing each day for 4 days Aldh1a1 mRNA was expressed in all tissues examined except kidney. Highest mRNA expression was detected in ovary followed by lung, testis, and liver. Aldh1a1 mRNA was also expressed at lower levels in stomach, as well as small and large intestine ( Fig. 1 ). Aldh1a2 mRNA was primarily expressed in gonads followed by uterus; it was also detected at low levels in all other tissues except liver ( Fig. 1 ). Aldh1a3 was highly expressed in placenta, followed by small intestine, brain, gonads, and uterus. Aldh1a3 mRNA was expressed at low levels in kidney, lung, stomach and large intestine, and was not expressed in liver and heart ( Fig. 1 ).", "cite_spans": [], "ref_spans": [{"start": 265, "end": 272, "text": "Table 1", "ref_id": "TABREF13"}]}, {"section": "Treatment with MEIs.", "text": "Aldh1a7 mRNA expression pattern was similar to Aldh1a1, that is Aldh1a7 mRNA was mainly expressed in lung, liver, gonads, and stomach, followed by duodenum, ovary, and placenta ( Fig. 2 ). Aldh1b1 mRNA was primarily expressed in small and large intestine, however it was present at low levels in all other tissues (Fig. 2 ).", "cite_spans": [], "ref_spans": []}, {"section": "Treatment with MEIs.", "text": "Aldh2 mRNA was ubiquitously expressed in all tissues examined, with higher expression in liver, lung, large intestine, and ovary ( Fig. 2 ). 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60 12 Aldh3a1 mRNA expression was highest in stomach followed by lung. It was expressed at much lower levels in gonads, uterus, and placenta (Fig. 3 ). Aldh3a2 mRNA was expressed at similar levels in all tissues (Fig. 3 ). Aldh3b1 mRNA expression was highest in lung, followed by ovary and small intestine, and was detected at lower levels in all other tissues (Fig. 3 ).", "cite_spans": [], "ref_spans": [{"start": 141, "end": 370, "text": "1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60", "ref_id": "TABREF11"}, {"start": 509, "end": 516, "text": "(Fig. 3", "ref_id": "FIGREF3"}, {"start": 580, "end": 587, "text": "(Fig. 3", "ref_id": "FIGREF3"}, {"start": 729, "end": 736, "text": "(Fig. 3", "ref_id": "FIGREF3"}]}, {"section": "Page 12 of 48 Toxicological Sciences", "text": "Aldh4a1 mRNA was expressed at high levels in all tissues examined with the highest expression in kidney, liver, ovary, and placenta (Fig. 4) . Aldh6a1 was primarily expressed in kidney followed by heart and gonads. Aldh6a1 was also expressed at lower levels in other tissues with minimum levels in small and large intestine (Fig. 4) . The highest expression of Aldh7a1 was in kidney followed by liver, brain, ovary, uterus, and placenta. Aldh7a1 mRNA expression was also lowest in small and large intestine ( Aldh8a1 was primarily expressed in kidney and liver, followed by placenta, brain, and gonads (Fig. 5 ). Aldh9a1 mRNA expression was detected in all tissues, but with highest expression in small intestine, kidney, and liver (Fig. 5 ). Aldh18a1 was highly expressed in ovary, placenta, uterus, and small intestine, followed by brain, stomach, and testes. Liver and kidney however, exhibited no Ald18a1 mRNA expression (Fig. 5 ).", "cite_spans": [], "ref_spans": [{"start": 132, "end": 140, "text": "(Fig. 4)", "ref_id": "FIGREF9"}, {"start": 324, "end": 332, "text": "(Fig. 4)", "ref_id": "FIGREF9"}, {"start": 602, "end": 609, "text": "(Fig. 5", "ref_id": "FIGREF10"}, {"start": 732, "end": 739, "text": "(Fig. 5", "ref_id": "FIGREF10"}, {"start": 925, "end": 932, "text": "(Fig. 5", "ref_id": "FIGREF10"}]}, {"section": "Page 12 of 48 Toxicological Sciences", "text": "Some Aldh isozymes exhibited gender differences in their mRNA tissue distribution. Most Aldh isozymes were expressed at slightly higher levels in female hearts than in male hearts, namely Aldh1a1, 1b1, 2, 3a1, 4a1, 6a1, 7a1, and 9a1 (Fig 1, 2, 3, 4, 5). In liver, Aldh3a2 ( 13 mRNA expression was also higher in males, whereas Aldh7a1 (Fig. 4 ) was higher in females.", "cite_spans": [], "ref_spans": [{"start": 335, "end": 342, "text": "(Fig. 4", "ref_id": "FIGREF9"}]}, {"section": "Page 12 of 48 Toxicological Sciences", "text": "Ontogeny of Aldhs. Liver was selected to study the developmental changes in the mRNA expression of Aldhs because a number of Aldh isozymes are highly expressed there. mRNA levels were quantified in tissues from 5 male and 5 female mice at ages of -2, 0, 5, 10, 15, 22, 30 and 45 days. The developmental changes in the mRNA expression of Aldh 1a2, 1a3, 3a1, 3b1, and 18a1 isozymes, which are minimally expressed in liver was determined in pooled samples (five animals per sample) to screen for any unique trends. These Aldh isozymes were all expressed at undetectable or very low levels in the liver before birth and throughout their postnatal development (data not shown). Figure 6 demonstrates the ontogenic expression pattern of Aldhs in mouse livers.", "cite_spans": [], "ref_spans": []}, {"section": "Page 12 of 48 Toxicological Sciences", "text": "Aldh1a1, and 1a7 mRNA expression was low 2 days before birth and gradually increased until 45 days of age without reaching a plateau. Aldh1b1, 6a1, and 7a1 exhibited a similar trend in their ontogenic pattern, where mRNA expression is low at 2 days before birth, but gradually increases reaching a plateau before 45 days of age. Aldh2 mRNA was detected at a relatively high level before birth (one third of that in adults), remained constant until 5 days of age and then gradually increased to reach adult levels at 30 days of age. Aldh3a2 mRNA expression increased immediately after birth to levels close to that in adults. The mRNA remained constant in males, but continued to increase in females causing a gender difference in mRNA expression at 45 days of age. Aldh4a1 ontogenic pattern was also different between male and female mice. In male mice, mRNA expression reached a maximum at day 22 and gradually decreased afterward, whereas in females, mRNA levels reached a maximum at day 15 and remained constant. 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59 Previous studies in rats demonstrated that Aldh1a1 mRNA is highly expressed in lung, kidney, liver, skeletal muscle, and testis, and to a lesser extent in heart and brain (Kathmann and Lipsky 1997; Kathmann et al. 2000) . In mice, Aldh1a1 mRNA expression was reported in lung, liver, and testis, and to a lesser extent in small intestine (Hsu et al. 1999) . Aldh1a1 protein expression in mice was found to be highest in testis, lung and stomach, followed by small and large intestine, eye, and ovary, but not detected in brain, heart, kidney, and skin (Haselbeck et al. 1999) . Aldh1a1 enzymatic activity was also only found in mouse liver, lung, testes, and ovary (Rout and Holmes 1996) . In humans, Aldh1a1 mRNA expression is highest in liver, kidney, skeletal muscle, pancreas, testis, ovary, lung and small intestine. Heart, placenta, colon, and brain had undetectable levels (Stewart et al. 1996) . In this current report, Aldh1a1 mRNA expression was highest in mouse ovary followed by liver, lung, stomach, and testis. Aldh1a1 mRNA was also detected at low levels at all tissues examined except kidney (Fig. 1 ). There is a marked difference in Aldh1a1 expression between rats and mice, as kidney is the organ with the highest Aldh1a1 expression in rats, whereas in mice Aldh1a1 is not expressed in kidney. This difference may result from documented differences in the 5'-flanking promoter region of Aldh1a1 gene between mice and rats (Kathmann et al. 2000) .", "cite_spans": [{"start": 1639, "end": 1665, "text": "(Kathmann and Lipsky 1997;", "ref_id": "BIBREF41"}, {"start": 1666, "end": 1687, "text": "Kathmann et al. 2000)", "ref_id": "BIBREF42"}, {"start": 1806, "end": 1823, "text": "(Hsu et al. 1999)", "ref_id": "BIBREF31"}, {"start": 2020, "end": 2043, "text": "(Haselbeck et al. 1999)", "ref_id": "BIBREF29"}, {"start": 2133, "end": 2155, "text": "(Rout and Holmes 1996)", "ref_id": "BIBREF77"}, {"start": 2348, "end": 2369, "text": "(Stewart et al. 1996)", "ref_id": "BIBREF81"}, {"start": 2909, "end": 2931, "text": "(Kathmann et al. 2000)", "ref_id": "BIBREF42"}], "ref_spans": [{"start": 1016, "end": 1241, "text": "1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59", "ref_id": "TABREF11"}, {"start": 1242, "end": 1467, "text": "1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59", "ref_id": "TABREF11"}]}, {"section": "Page 14 of 48 Toxicological Sciences", "text": "In mice, Aldh1a2 mRNA has been reported to only be expressed in testis, uterus, and ovary, and not detected in kidney, stomach, small and large intestine, lung, liver, skeletal muscle, spleen, brain, or heart (Haselbeck et al. 1999; Hsu et al. 2000; Zhao et al. 1996) . Aldh1a2 enzyme activity in mice was also mainly detected in uterus and testis (Mather and Holmes 1984; Rout and Holmes 1996; Wang et al. 1996; Zhao et al. 1996) .", "cite_spans": [{"start": 209, "end": 232, "text": "(Haselbeck et al. 1999;", "ref_id": "BIBREF29"}, {"start": 233, "end": 249, "text": "Hsu et al. 2000;", "ref_id": "BIBREF35"}, {"start": 250, "end": 267, "text": "Zhao et al. 1996)", "ref_id": "BIBREF89"}, {"start": 348, "end": 372, "text": "(Mather and Holmes 1984;", "ref_id": "BIBREF66"}, {"start": 373, "end": 394, "text": "Rout and Holmes 1996;", "ref_id": "BIBREF77"}, {"start": 413, "end": 430, "text": "Zhao et al. 1996)", "ref_id": "BIBREF89"}], "ref_spans": []}, {"section": "Page 14 of 48 Toxicological Sciences", "text": "In rats, Aldh1a2 mRNA was only detected in testes, but female sex organs were not examined (Wang et al. 1996) . In agreement with the previous data, this current report also demonstrates that the highest mRNA expression of Aldh1a2 is in testes, followed by ovary and uterus. Aldh1a2 was also expressed at a low level in all tissues examined except liver (Fig 1) .", "cite_spans": [], "ref_spans": []}, {"section": "Page 14 of 48 Toxicological Sciences", "text": "Aldh1a3 mRNA has been detected in various parts of the eye, and in the nasal epithelium (Dupe et al. 2003; Marlier and Gilbert 2004) in both rats and mice. Aldh1a3-null mice results in lethal defects in nasal development. Tissue distribution of Aldh1a3", "cite_spans": [{"start": 88, "end": 106, "text": "(Dupe et al. 2003;", "ref_id": "BIBREF19"}, {"start": 107, "end": 132, "text": "Marlier and Gilbert 2004)", "ref_id": "BIBREF63"}], "ref_spans": []}, {"section": "Page 14 of 48 Toxicological Sciences", "text": "has not been reported in rodents or humans. This manuscript is the first to report detailed tissue distribution of Aldh1a3 in mice. Aldh1a3 mRNA expression was highest in placenta, and was detected in most tissues except liver and heart (Fig 1) .", "cite_spans": [], "ref_spans": []}, {"section": "Page 14 of 48 Toxicological Sciences", "text": "In rats, Aldh1a7 mRNA expression is high in liver, kidney, and lung, followed by colon, brain, and heart, but was not detected in small intestine (Dunn et al. 1989) . 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60 18 However, in another rat study, Aldh1a7 mRNA was very weakly expressed in lung and liver, and was not detected in kidney, testis, heart, brain, spleen, or skeletal muscle (Kathmann et al. 2000) . In mice, Aldh1a7 mRNA expression has been reported to be highest in liver and lung, followed by kidney and testis, and was not detected in heart, brain, spleen, or skeletal muscle (Hsu et al. 1999) . In this current report, however, Aldh1a7 mRNA expression was not detected in kidney. mRNA expression of Aldh1a7 was highest in lung followed by liver, then testes and stomach (Fig 2) . Similar to Aldh1a1, Aldh1a7 is expressed at high levels in kidney in rats, whereas not detected in mouse kidney.", "cite_spans": [{"start": 146, "end": 164, "text": "(Dunn et al. 1989)", "ref_id": "BIBREF17"}, {"start": 570, "end": 592, "text": "(Kathmann et al. 2000)", "ref_id": "BIBREF42"}, {"start": 775, "end": 792, "text": "(Hsu et al. 1999)", "ref_id": "BIBREF31"}], "ref_spans": [{"start": 167, "end": 396, "text": "1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60", "ref_id": "TABREF11"}]}, {"section": "Page 18 of 48 Toxicological Sciences", "text": "In humans, Aldh1b1 mRNA is detected in liver and to a lesser extent in testis, but not in brain (Hsu and Chang 1991) . Another human study also reported the highest mRNA expression in liver, kidney, skeletal muscle, and to a lesser extent in brain, placenta, sex organs, small intestine, and pancreas (Stewart et al. 1996) . However in rats, Aldh1b1 mRNA expression was not detected in liver, testis, or eye (the only tissues examined) (Boesch et al. 1996 ). This current study shows different Aldh1b1 mRNA tissue distribution pattern in mice compared to humans. Aldh1b1 mRNA was primarily expressed in small and large intestine in mice, however it was present at low levels in other tissues (Fig 2) .", "cite_spans": [{"start": 96, "end": 116, "text": "(Hsu and Chang 1991)", "ref_id": "BIBREF30"}, {"start": 301, "end": 322, "text": "(Stewart et al. 1996)", "ref_id": "BIBREF81"}, {"start": 436, "end": 455, "text": "(Boesch et al. 1996", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Page 18 of 48 Toxicological Sciences", "text": "In a previous study in mice, Aldh2 mRNA was detected in liver, followed by kidney, whereas no signal was detected in stomach, brain, spleen, or skeletal muscle . However Aldh2 enzyme activity is widely distributed throughout several mouse tissues, exhibiting highest levels in liver, stomach, pancreas, and adrenal gland, followed by ovary, heart, spleen, and to a lesser extent in testes and 19 urinary bladder (Rout and Holmes 1996) . In humans, Aldh2 activity was detected in 16", "cite_spans": [{"start": 412, "end": 434, "text": "(Rout and Holmes 1996)", "ref_id": "BIBREF77"}], "ref_spans": []}, {"section": "Page 18 of 48 Toxicological Sciences", "text": "tissues, but not in placenta. The same study reported highest activity in liver, lung, kidney, skeletal, and cardiac muscles (Stewart et al. 1996 ). In the current study, Aldh2 mRNA was also ubiquitously expressed in all tissues examined except placenta. mRNA levels were highest in liver, lung, large intestine, ovary, and kidney (Fig 2) .", "cite_spans": [{"start": 125, "end": 145, "text": "(Stewart et al. 1996", "ref_id": "BIBREF81"}], "ref_spans": []}, {"section": "Page 18 of 48 Toxicological Sciences", "text": "Aldh3a1 is known to have undetectable constitutive expression in livers of rats, mice, and humans (Boesch et al. 1996) . However, Aldh3a1 expression is up-regulated during carcinogenesis, and also highly expressed in many carcinoma cell lines. Aldh3a1 expression is also markedly induced after high doses of TCDD in rats and in many cancer cell lines, therefore, Aldh3a1 is historically known as the TCDD-inducible Aldh.", "cite_spans": [{"start": 98, "end": 118, "text": "(Boesch et al. 1996)", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Page 18 of 48 Toxicological Sciences", "text": "Aldh3a1 is also known as stomach-specific Aldh because of its high expression in stomach. In rats, Aldh3a1 mRNA is highest in stomach, followed by heart and lung, but not detected in small intestine, liver, kidney, colon, testes, brain, adrenal, bladder or skeletal muscle (Dunn et al. 1988) . In mice, Aldh3a1 activity was also mainly detected in stomach (Mather and Holmes 1984; Rout and Holmes 1996) . In humans, Aldh3a1 mRNA has been detected in stomach, but not in liver (Hsu et al. 1992) . In this study, Aldh3a1 mRNA expression was also found highest in stomach followed by kidney (Fig.   3 ).", "cite_spans": [{"start": 273, "end": 291, "text": "(Dunn et al. 1988)", "ref_id": "BIBREF18"}, {"start": 356, "end": 380, "text": "(Mather and Holmes 1984;", "ref_id": "BIBREF66"}, {"start": 381, "end": 402, "text": "Rout and Holmes 1996)", "ref_id": "BIBREF77"}, {"start": 476, "end": 493, "text": "(Hsu et al. 1992)", "ref_id": "BIBREF33"}], "ref_spans": [{"start": 588, "end": 597, "text": "(Fig.   3", "ref_id": "FIGREF3"}]}, {"section": "Page 18 of 48 Toxicological Sciences", "text": "Aldh3a2 is considered a housekeeping gene because of its wide tissue distribution. In mice, Aldh3a2 mRNA expression was reported to be highest in liver and kidney; followed by stomach, testes, small intestine, and brain; and lowest in heart, skeletal muscle, skin, and thymus . Ald3a2 mRNA expression is also widely distributed in many human (Chang and Yoshida 1997) and rat tissues (Demozay 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60 et al. 2004), with highest expression found in liver. Data from this current report also demonstrates the expression of Aldh3a2 mRNA in all tissues examined, with highest expression in kidney and ovary, and lowest expression in heart (Fig. 3) .", "cite_spans": [{"start": 342, "end": 366, "text": "(Chang and Yoshida 1997)", "ref_id": "BIBREF9"}], "ref_spans": [{"start": 392, "end": 621, "text": "1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60", "ref_id": "TABREF11"}, {"start": 856, "end": 864, "text": "(Fig. 3)", "ref_id": "FIGREF3"}]}, {"section": "Page 18 of 48 Toxicological Sciences", "text": "In humans, Aldh3b1 mRNA has its highest abundance in lung followed by kidney and placenta, but not detected in heart, brain, liver, or skeletal muscle (Hsu et al. 1995; Hsu et al. 1994) . The data in this manuscript, indicates that mouse Aldh3b1 mRNA expression is also highest in lung, followed by ovary and small intestine, and present at detectable levels in all other tissues (Fig 3) .", "cite_spans": [{"start": 151, "end": 168, "text": "(Hsu et al. 1995;", "ref_id": "BIBREF32"}, {"start": 169, "end": 185, "text": "Hsu et al. 1994)", "ref_id": "BIBREF34"}], "ref_spans": [{"start": 380, "end": 387, "text": "(Fig 3)", "ref_id": "FIGREF3"}]}, {"section": "Page 18 of 48 Toxicological Sciences", "text": "In humans, Aldh4a1 mRNA expression is highest in liver, kidney, and skeletal muscle; followed by heart, brain, and placenta; and very low in lung and pancreas (Hu et al. 1996 ). In the current study, we report ubiquitous Aldh4a1 mRNA expression in all tissues examined with highest expression in kidney and liver, followed by ovary and placenta (Fig 4) .", "cite_spans": [{"start": 159, "end": 174, "text": "(Hu et al. 1996", "ref_id": "BIBREF37"}], "ref_spans": [{"start": 345, "end": 352, "text": "(Fig 4)", "ref_id": "FIGREF9"}]}, {"section": "Page 18 of 48 Toxicological Sciences", "text": "In rats, Aldh6a1 mRNA and protein is highest in kidney, followed by liver and heart, and undetected in brain (Kedishvili et al. 1992) . In humans, Aldh6a1 mRNA is expressed at low levels in many tissues and at higher levels in kidney (Hsu et al. 1995) .", "cite_spans": [{"start": 109, "end": 133, "text": "(Kedishvili et al. 1992)", "ref_id": "BIBREF44"}, {"start": 234, "end": 251, "text": "(Hsu et al. 1995)", "ref_id": "BIBREF32"}], "ref_spans": []}, {"section": "Page 18 of 48 Toxicological Sciences", "text": "Data from the present study shows highest Aldh6a1 mRNA expression in mouse kidney; followed by liver, stomach, heart, and ovary; and lower expression in lung, brain, placenta and uterus (Fig 4) .", "cite_spans": [], "ref_spans": [{"start": 186, "end": 193, "text": "(Fig 4)", "ref_id": "FIGREF9"}]}, {"section": "Page 18 of 48 Toxicological Sciences", "text": "In the human fetus, Aldh7a1 mRNA was highest in kidney, ovary, eye, heart, and cochlea; followed by liver, adrenal, lung, skeletal muscle and spleen; and no signal in brain (Skvorak et al. 1997) . In rats, Aldh7a1 mRNA expression was highest in heart, liver, and kidney, with minimal expression in lung, brain, intestine, pancreas, and brain 21 (Lee et al. 1994) . The data in this manuscript indicate that in mice, Aldh7a1 mRNA expression is highest in mice kidney and liver, followed by brain, gonads, placenta, and uterus; and to a lesser extent in all other tissues examined (Fig 4) . Therefore, tissue distribution of Aldh7a1 is conserved between rodents and humans.", "cite_spans": [{"start": 173, "end": 194, "text": "(Skvorak et al. 1997)", "ref_id": "BIBREF79"}, {"start": 345, "end": 362, "text": "(Lee et al. 1994)", "ref_id": "BIBREF50"}], "ref_spans": [{"start": 579, "end": 586, "text": "(Fig 4)", "ref_id": "FIGREF9"}]}, {"section": "Page 18 of 48 Toxicological Sciences", "text": "Aldh8a1 mRNA has been reported to be expressed in only kidney and liver in mice (Lin et al. 2003) and humans (Lin and Napoli 2000) . In the current study, we report similar results in mice. Aldh8a1 mRNA expression was highest in kidney followed by liver, and lower expression in placenta, gonads, and brain (Fig 5) .", "cite_spans": [{"start": 80, "end": 97, "text": "(Lin et al. 2003)", "ref_id": "BIBREF53"}, {"start": 109, "end": 130, "text": "(Lin and Napoli 2000)", "ref_id": "BIBREF52"}], "ref_spans": [{"start": 307, "end": 314, "text": "(Fig 5)", "ref_id": "FIGREF10"}]}, {"section": "Page 18 of 48 Toxicological Sciences", "text": "In humans, Aldh9a1 mRNA is highly expressed in kidney, liver, and skeletal muscle, followed by pancreas, heart, placenta, and lung . In a previous study with human tissues, Aldh9a1 mRNA was also found to be highest in kidney, liver, skeletal muscle, and heart (Hsu et al. 1995) . Western blotting showed the highest protein expression in human liver, adrenal gland, and kidney; followed by brain and skeletal muscle; with lowest expression in heart, brain, lung, and placenta (Izaguirre et al. 1997 ).", "cite_spans": [{"start": 260, "end": 277, "text": "(Hsu et al. 1995)", "ref_id": "BIBREF32"}, {"start": 476, "end": 498, "text": "(Izaguirre et al. 1997", "ref_id": "BIBREF39"}], "ref_spans": []}, {"section": "Page 18 of 48 Toxicological Sciences", "text": "In rats, highest Aldh9a1-enzyme activity was detected in small intestine (Rebouche and Engel 1980) . Tissue distribution of Aldh9a1 mRNA in mice in this current report is similar to the previous human and rat data. Aldh9a1 mRNA was expressed in all mice tissue examined, with highest expression in kidney, small intestine, and liver (Fig 5) .", "cite_spans": [{"start": 73, "end": 98, "text": "(Rebouche and Engel 1980)", "ref_id": "BIBREF74"}], "ref_spans": [{"start": 333, "end": 340, "text": "(Fig 5)", "ref_id": "FIGREF10"}]}, {"section": "Page 18 of 48 Toxicological Sciences", "text": "In humans, Aldh18a1 mRNA has been detected in heart, testis, spleen, skeletal muscle, ovary, prostate, small intestine, and colon, but not in kidney, liver, lung, brain, or placenta (Aral et al. 1996) . However, another study reported highest mRNA expression in human ovary, testis, pancreas, and kidney; followed by colon, small intestine, placenta, and heart; and minimum levels in brain, liver, and skeletal muscle (Hu et al. 1999) . In 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60 22 rats, the highest Aldh18a1 enzyme activity was found in small intestine (Wakabayashi et al. 1991) . The data in this manuscript indicate that Aldh18a1 mRNA expression is highest in ovary, followed by placenta, uterus, and small intestine, and to a lesser extent in stomach and brain. Liver and kidney however, exhibited no Ald18a1 mRNA expression (Fig. 5) . Therefore, it can be concluded that the highest expression of Aldh18a1 is in small intestine and in female sex organs in both rodents and humans.", "cite_spans": [{"start": 182, "end": 200, "text": "(Aral et al. 1996)", "ref_id": "BIBREF1"}, {"start": 418, "end": 434, "text": "(Hu et al. 1999)", "ref_id": "BIBREF36"}], "ref_spans": [{"start": 440, "end": 669, "text": "1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60", "ref_id": "TABREF11"}, {"start": 1020, "end": 1028, "text": "(Fig. 5)", "ref_id": "FIGREF10"}]}, {"section": "Page 22 of 48 Toxicological Sciences", "text": "Ontogeny. Ontogenic pattern of cytosolic, mitochondrial, and microsomal Aldh enzymatic activity was previously studied in mouse livers. Regardless of their subcellular localization, Aldh activity was very low in fetal liver and could be only detected a few days before birth. Mitochondrial and microsomal Aldh activities increased steadily after birth to reach adult levels by 6 weeks of age. However, cytosolic Aldh activity increased dramatically during the period of 3-6 weeks after birth (Timms and Holmes 1981). The current data show similar ontogenic pattern of Aldh mRNA compared with the previous enzymatic activity data. The cytosolic Aldh1a1 and 1a7 mRNA levels were very low 2 days before birth, increased after birth and started to increase rapidly 22 days after birth (Fig 6) . However, Aldh3a2 mRNA expression increased immediately after birth to levels close to that in adults. The mRNA remained constant in males, but continued to increase in females causing a gender difference in mRNA expression at 45 days of age. (Fig 6) .", "cite_spans": [], "ref_spans": []}, {"section": "Page 22 of 48 Toxicological Sciences", "text": "In guinea pigs, low K m Aldh activity (mainly Aldh2) gradually increased in fetal livers during gestation, and reached similar adult levels only 2 days after birth. High K m Aldh activity (mainly Aldh1a1) in fetal livers, also gradually increased during gestation, but was only half adult levels 2 days after birth (Card et al. 1989) . However, in rats, (Sjoblom et al. 1978) . The current report in mice, demonstrates that Aldh1a1 mRNA levels are less than 10% of adult levels 2 days before birth, and gradually increase until 45 days of age. Aldh2 mRNA levels were about one third of that in adult mice 2 days before birth and gradually increased until 30 days of age.", "cite_spans": [{"start": 315, "end": 333, "text": "(Card et al. 1989)", "ref_id": "BIBREF5"}, {"start": 354, "end": 375, "text": "(Sjoblom et al. 1978)", "ref_id": "BIBREF78"}], "ref_spans": []}, {"section": "Page 22 of 48 Toxicological Sciences", "text": "It has previously been shown that total Aldh activity is undetectable in rat livers 10 days before birth, and gradually increases until 49 days of age (Lindahl 1977) . The current data in mice also illustrates that the mRNA of various Aldh isozymes are lower in mice fetuses than adult mice, and gradually increase after birth to reach adult levels at 15-45 days of age. 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60 24 (B/NADP + activity) (Lindahl and Evces 1984) . This isozyme is also induced in normal rat liver by high doses of TCDD (higher than 100 \u00b5g/kg) (Deitrich et al. 1977; Lindahl and Evces 1984) . Furthermore, this isozyme is very similar to the normal dominant Aldh found in lung and stomach, known as stomach-specific Aldh (Yin et al. 1989 ). This isozyme was later cloned, found to be responsible for the hepatoma cells B/NADP + activity, identical to the stomach-specific Aldh, and has been referred to as TCDDinducible or Tumor-Associated Aldh Hsu et al. 1992 ). This isozyme is currently known as Aldh3a1 (Vasiliou et al. 1999) .", "cite_spans": [{"start": 151, "end": 165, "text": "(Lindahl 1977)", "ref_id": "BIBREF56"}, {"start": 624, "end": 648, "text": "(Lindahl and Evces 1984)", "ref_id": "BIBREF57"}, {"start": 746, "end": 768, "text": "(Deitrich et al. 1977;", "ref_id": "BIBREF14"}, {"start": 769, "end": 792, "text": "Lindahl and Evces 1984)", "ref_id": "BIBREF57"}, {"start": 923, "end": 939, "text": "(Yin et al. 1989", "ref_id": "BIBREF87"}, {"start": 1147, "end": 1162, "text": "Hsu et al. 1992", "ref_id": "BIBREF33"}], "ref_spans": [{"start": 371, "end": 600, "text": "1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60", "ref_id": "TABREF11"}]}, {"section": "Induction. Induction of phase-I drug metabolizing enzymes, especially", "text": "AhR was suggested to mediate, at least in part, the TCDD-mediated induction of Aldh3a1 in rats and hepatoma cell lines (Dunn et al. 1988) , but not the constitutive tissue-specific expression of Aldh3a1, as shown in AhR-null mice (Korkalainen et al. 1995) . Aldh3A1 expression is induced to different extents by TCDD and other AhR ligands in various rat hepatoma cell lines (Huang and Lindahl 1990; Lin et al. 1984; Takimoto et al. 1991 Takimoto et al. , 1992 . In rats, in vivo, Aldh3a1 is relatively refractory to induction by TCDD, as a relatively high dose is required (Deitrich et al. 1977; Germolec et al. 1996; Tank et al. 1986 ). At least a 10-fold higher dose of TCDD is needed for half maximal induction of Aldh3a1, compared to the typical AhR target gene, Cyp1a1 (Dunn et al. 1988; Germolec et al. 1996; Takimoto et al. 1992) . Aldh3a1 expression was induced in mouse hepatoma cell lines (Marks-Hull et al. 1997; Torronen et al. 1992; Vasiliou et al. 1993) , however, in vivo, doses up to 100 \u00b5g/kg (Marks-Hull et al. 1997) or 200 \u00b5g/kg (Vasiliou et al. 1993 ) of TCDD did not increase Aldh3a1 mRNA expression. In contrast, these high doses of TCDD induce Aldh3a1 in both culture cells and intact rats (Vasiliou et al. 1996; Vasiliou et al. 1993) . A similar phenomenon was 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60 25 also observed with another AhR ligand, 3-methylcolanthrene (3MC), where Aldh3a1 activity was markedly induced in rat but not in mice (Vasiliou et al. 1989) . In agreement, with previous in vivo studies, this current data shows the lack of induction of Aldh3a1 by TCDD in mouse livers (Fig. 7) .", "cite_spans": [{"start": 119, "end": 137, "text": "(Dunn et al. 1988)", "ref_id": "BIBREF18"}, {"start": 230, "end": 255, "text": "(Korkalainen et al. 1995)", "ref_id": "BIBREF47"}, {"start": 374, "end": 398, "text": "(Huang and Lindahl 1990;", "ref_id": "BIBREF38"}, {"start": 399, "end": 415, "text": "Lin et al. 1984;", "ref_id": "BIBREF51"}, {"start": 416, "end": 436, "text": "Takimoto et al. 1991", "ref_id": "BIBREF82"}, {"start": 437, "end": 459, "text": "Takimoto et al. , 1992", "ref_id": "BIBREF83"}, {"start": 573, "end": 595, "text": "(Deitrich et al. 1977;", "ref_id": "BIBREF14"}, {"start": 618, "end": 634, "text": "Tank et al. 1986", "ref_id": "BIBREF84"}, {"start": 774, "end": 792, "text": "(Dunn et al. 1988;", "ref_id": "BIBREF18"}, {"start": 815, "end": 836, "text": "Takimoto et al. 1992)", "ref_id": "BIBREF83"}, {"start": 899, "end": 923, "text": "(Marks-Hull et al. 1997;", "ref_id": "BIBREF62"}, {"start": 1010, "end": 1034, "text": "(Marks-Hull et al. 1997)", "ref_id": "BIBREF62"}], "ref_spans": [{"start": 1285, "end": 1514, "text": "1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60", "ref_id": "TABREF11"}, {"start": 1802, "end": 1810, "text": "(Fig. 7)", "ref_id": "FIGREF5"}]}, {"section": "Induction. Induction of phase-I drug metabolizing enzymes, especially", "text": "AhR ligands, including 3-methylcolanthrine (3MC), benzo[a]pyrene, and other polyaromatic hydrocarbon compounds, have been reported to minimally induce cytosolic Aldh NAD + -dependent activity (Marselos et al. 1987; Marselos and Vasiliou 1991; Pappas et al. 2003; Vasiliou and Marselos 1989a, b; Vasiliou et al. 1989 ). This might result from Aldh1a7 induction, because the present data illustrates mild induction of cytosolic Aldh1a7 by TCDD in mice. TCDD and 3MC did not induce Aldh3a2 (Vasiliou et al. 1996) , Aldh1a1, nor Aldh2 in rats (Boesch et al. 1996) . In rats, TCDD treatment results in a small increase in mitochondrial and microsomal Aldh activity, however this increase was explained by contamination from cytosolic fractions (Tank et al. 1986 ). In agreement with these reports, in this current study, AhR ligands did not increase the expression of the microsomal (Aldh3a2), or the mitochondrial (Aldh2, 4a1, and 6a1) Aldhs (Fig 7) in mice.", "cite_spans": [{"start": 192, "end": 214, "text": "(Marselos et al. 1987;", "ref_id": "BIBREF64"}, {"start": 215, "end": 242, "text": "Marselos and Vasiliou 1991;", "ref_id": "BIBREF65"}, {"start": 243, "end": 262, "text": "Pappas et al. 2003;", "ref_id": "BIBREF71"}, {"start": 539, "end": 559, "text": "(Boesch et al. 1996)", "ref_id": "BIBREF2"}, {"start": 739, "end": 756, "text": "(Tank et al. 1986", "ref_id": "BIBREF84"}], "ref_spans": [{"start": 938, "end": 945, "text": "(Fig 7)", "ref_id": "FIGREF5"}]}, {"section": "Induction. Induction of phase-I drug metabolizing enzymes, especially", "text": "Cytosolic NAD + -dependent Aldh activity in rats was previously shown to be induced by PB to various degrees, ranging from no induction to 20-fold induction, depending on the rat strain, dose, and dosing regimen (Ganem and Jefcoate 1998; Jones and Lubet 1992; Pappas et al. 2003; Pappas et al. 2001; Vasiliou and Marselos 1989a, b; Vasiliou et al. 1989) . Induction by PB was also reported in mice, but to a lower magnitude (Timms and Holmes 1981; Vasiliou et al. 1989 ). This enzymatic induction was attributed to the up-regulation of PB-inducible Aldh isozyme. The identity of PB- 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60 26 inducible Aldh was commonly interchanged between Aldh1a1 and Aldh1a7 (Dunn et al. 1989; Kathmann et al. 2000) . PB-inducible Aldh was then cloned and referred to as Aldh1a7 (Dunn et al. 1989; Hsu et al. 1999; Kathmann et al. 2000; Vasiliou et al. 1999) .", "cite_spans": [{"start": 212, "end": 237, "text": "(Ganem and Jefcoate 1998;", "ref_id": "BIBREF23"}, {"start": 238, "end": 259, "text": "Jones and Lubet 1992;", "ref_id": "BIBREF40"}, {"start": 260, "end": 279, "text": "Pappas et al. 2003;", "ref_id": "BIBREF71"}, {"start": 280, "end": 299, "text": "Pappas et al. 2001;", "ref_id": "BIBREF72"}, {"start": 885, "end": 903, "text": "(Dunn et al. 1989;", "ref_id": "BIBREF17"}, {"start": 904, "end": 925, "text": "Kathmann et al. 2000)", "ref_id": "BIBREF42"}, {"start": 989, "end": 1007, "text": "(Dunn et al. 1989;", "ref_id": "BIBREF17"}, {"start": 1008, "end": 1024, "text": "Hsu et al. 1999;", "ref_id": "BIBREF31"}, {"start": 1025, "end": 1046, "text": "Kathmann et al. 2000;", "ref_id": "BIBREF42"}], "ref_spans": [{"start": 583, "end": 815, "text": "1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60 26", "ref_id": "TABREF11"}]}, {"section": "Induction. Induction of phase-I drug metabolizing enzymes, especially", "text": "The current data demonstrate the induction of both Aldh1a1 and Aldh1a7 in mouse livers by PB (Fig. 7) . Furthermore, other CAR activators (TCPOBOP, DAS) also induced both isozymes to a similar extent.", "cite_spans": [], "ref_spans": [{"start": 93, "end": 101, "text": "(Fig. 7)", "ref_id": "FIGREF5"}]}, {"section": "Induction. Induction of phase-I drug metabolizing enzymes, especially", "text": "It was previously reported that mitochondrial and microsomal Aldh (Timms and Holmes 1981) activities as well as the B/NADP + are not affected by PB treatment in humans, rats, and mice (Lin et al. 1984; Marselos et al. 1987; Tank et al. 1986; Vasiliou and Marselos 1989a; Vasiliou et al. 1989 ). The present data in mice also demonstrate that PB does not affect the mRNA expression of the mitochondrial (Aldh2, 4a1, 6a1, and 9a1), the microsomal (Aldh3a2), and the B/NADP + -specific (Aldh3a1) Aldhs in mice (Fig. 7) .", "cite_spans": [{"start": 184, "end": 201, "text": "(Lin et al. 1984;", "ref_id": "BIBREF51"}, {"start": 202, "end": 223, "text": "Marselos et al. 1987;", "ref_id": "BIBREF64"}, {"start": 224, "end": 241, "text": "Tank et al. 1986;", "ref_id": "BIBREF84"}], "ref_spans": [{"start": 507, "end": 515, "text": "(Fig. 7)", "ref_id": "FIGREF5"}]}, {"section": "Induction. Induction of phase-I drug metabolizing enzymes, especially", "text": "The PPAR ligand (clofibrate) has been previously shown to induce rat Aldh enzyme activity in rat liver microsomal and mitochondrial (except mitochondrial Aldh2) fractions, but not the cytosolic fraction Panchenko et al. 1985) .", "cite_spans": [{"start": 203, "end": 225, "text": "Panchenko et al. 1985)", "ref_id": "BIBREF70"}], "ref_spans": []}, {"section": "Induction. Induction of phase-I drug metabolizing enzymes, especially", "text": "Clofibrate did not affect Aldh2 mRNA expression in rats. Furthermore, Aldh2 mRNA expression was not different in PPAR -null mice (Crabb et al. 2001) . In mice, clofibrate was shown to induce Aldh3a2 and failed to affect Aldh3a1 mRNA expression (Vasiliou et al. 1996) . DEHP (another PPAR ligand) was also shown to induce Aldh3a2 mRNA expression in mice (Wong and Gill 2002) . In agreement with the previous reports, the current results demonstrate induction of the microsomal (Aldh3a2), and the Page 27 of 48 Toxicological Sciences   1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60 27 mitochondrial (4a1, 6a1, and 9a1) Aldhs, and there was no induction of Aldh2 and Aldh3a1 by CLOF nor by other PPAR ligands in mice (Fig 7) .", "cite_spans": [{"start": 129, "end": 148, "text": "(Crabb et al. 2001)", "ref_id": "BIBREF10"}, {"start": 353, "end": 373, "text": "(Wong and Gill 2002)", "ref_id": "BIBREF86"}], "ref_spans": [{"start": 523, "end": 763, "text": "Sciences   1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60", "ref_id": "TABREF11"}, {"start": 898, "end": 905, "text": "(Fig 7)", "ref_id": "FIGREF5"}]}, {"section": "Induction. Induction of phase-I drug metabolizing enzymes, especially", "text": "The effect of dexamethasone (a PXR ligand) on the expression of Aldhs was examined previously. Dexamethasone did not affect Aldh2 and Aldh3a1 mRNA expression in rat and human cell cultures (Crabb et al. 1995; Falkner et al. 1999; Prough et al. 1997) . Aldh1a3 expression was also not up-regulated by transfecting carcinoma cell lines with RXR, VDR, GR, or PPAR constructs (Grun et al. 2000) . The current data also demonstrates the lack of induction of Aldh1a3 (data not shown), Aldh2, and", "cite_spans": [{"start": 189, "end": 208, "text": "(Crabb et al. 1995;", "ref_id": "BIBREF11"}, {"start": 209, "end": 229, "text": "Falkner et al. 1999;", "ref_id": "BIBREF21"}, {"start": 230, "end": 249, "text": "Prough et al. 1997)", "ref_id": "BIBREF73"}, {"start": 372, "end": 390, "text": "(Grun et al. 2000)", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "Induction. Induction of phase-I drug metabolizing enzymes, especially", "text": "Aldh3a1 by any of the PXR ligands in livers of mice. In contrast, Aldh1a1, Aldh1a7, and Aldh1b1 mRNA expression was induced by all 3 PXR ligands ( PCN, SPR, and DEX) in mice livers (Fig. 7) .", "cite_spans": [], "ref_spans": [{"start": 181, "end": 189, "text": "(Fig. 7)", "ref_id": "FIGREF5"}]}, {"section": "Induction. Induction of phase-I drug metabolizing enzymes, especially", "text": "The role of Nrf2 in the transcriptional regulation of Aldhs has not been previously studied in any species. Nrf2 activators, especially BHA, increased the mRNA expression of many Aldhs. Aldh1a1 and 1a7 mRNA expression was induced by all Nrf2 activators (OPZ, EXQ, and BHA). Aldh1b1 was induced by 2 Nrf2 activators (EXQ and BHA), whereas, Aldh3a1, Aldh4a1, Aldh7a1, and Aldh8a1 (Fig. 12) were induced by BHA only.", "cite_spans": [], "ref_spans": []}, {"section": "Induction. Induction of phase-I drug metabolizing enzymes, especially", "text": "In summary, the present data demonstrate the relative tissue distribution of 15", "cite_spans": [], "ref_spans": []}, {"section": "Induction. Induction of phase-I drug metabolizing enzymes, especially", "text": "Aldh isozymes mRNA in 14 tissues of mice, hepatic ontogenic pattern, and induction of the most abundant isozymes in mice livers. Aldh1a1 mRNA expression was highest in ovary; 1a2 in testis; 1a3 in placenta; 1a7 in lung; 1b1 in small intestine; 2 in liver; 3a1 in stomach; 3a2 and 3b1 expression was ubiquitous; 4a1, 6a1, 7a1, and 8a1 in liver and kidney; 9a1 in liver, kidney, and small intestine; and 18a1 in ovary and small intestine.", "cite_spans": [], "ref_spans": []}, {"section": "Induction. Induction of phase-I drug metabolizing enzymes, especially", "text": "mRNA expression of Aldh isozymes was lower in pups than in adults in mice, and 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60 39   Table 1 : List of chemicals, dosing regimen and known target transcription factors Figure 1 : Total RNA was isolated from approximately 8-weeks-old male and female mice and analyzed by the bDNA signal amplification assay for Aldh1a1, 1a2, and 1a3 mRNA expression. The data are presented as mean RLU \u00b1 SEM (n=5). * represents a statistically significant difference (p 0.05) between males and females.", "cite_spans": [], "ref_spans": [{"start": 79, "end": 551, "text": "1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60 39   Table 1", "ref_id": "TABREF11"}]}, {"section": "Induction. Induction of phase-I drug metabolizing enzymes, especially", "text": "Figure 2: Total RNA was isolated from approximately 8-weeks-old male and female mice and analyzed by the bDNA signal amplification assay for Aldh1a7, 1b1, and 2 mRNA expression. The data are presented as mean RLU \u00b1 SEM (n=5). * represents a statistically significant difference (p 0.05) between males and females. Figure 6: Total RNA was isolated from livers of -2, 0, 5, 10, 25, 30, and 45 day-old mice, and analyzed by bDNA signal amplification assay for Aldh1a1, 1a7, 1b1, 2, 3a2, 4a1, 6a1, and 7a1 mRNA expression. The data are presented as mean RLU \u00b1 SEM (n=5). * represents a statistically significant difference (p 0.05) between males and females. Figure 7 : Expression of Aldh1a1, 1a7, 1b1, 2, 3a1, 3a2, 4a1, 6a1, 7a1, 8a1 and 9a1 in liver after treatment with 15 prototypical drug-metabolizing enzyme inducers. Total RNA from liver of treated male mice (n=5/treatment) was analyzed by the bDNA signal amplification assay. The data are presented as mean RLU \u00b1 SEM (n=5). * represents a statistically significant difference (p 0.05) between treated and control mice.", "cite_spans": [], "ref_spans": [{"start": 655, "end": 663, "text": "Figure 7", "ref_id": "FIGREF5"}]}, {"section": "Induction. Induction of phase-I drug metabolizing enzymes, especially", "text": "Supplementary Data: Table 2 : Oligonucleotide probes generated for analysis of Aldh expression by bDNA signal amplification. Target sequence refers to the sequence of mRNA transcript as enumerated in the GenBank file. Function refers to the utility of the oligonucleotide probe in the bDNA assay. Ce, capture extender, LE, label extender, BL, blocker probe 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60 40 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47 Aldh mRNA (RLU/10 g total RNA)", "cite_spans": [], "ref_spans": [{"start": 20, "end": 27, "text": "Table 2", "ref_id": "TABREF11"}, {"start": 357, "end": 586, "text": "1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60", "ref_id": "TABREF11"}, {"start": 590, "end": 815, "text": "1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59", "ref_id": "TABREF11"}, {"start": 816, "end": 993, "text": "1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47", "ref_id": "TABREF11"}, {"start": 994, "end": 1171, "text": "1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47", "ref_id": "TABREF11"}, {"start": 1172, "end": 1345, "text": "1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46", "ref_id": "TABREF11"}, {"start": 1346, "end": 1523, "text": "1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47", "ref_id": "TABREF11"}]}, {"section": "Induction. 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The cytosolic Aldh3A1 isozyme oxidizes medium-chain lipid and", "type": "figure"}, "FIGREF1": {"text": "of Kansas Medical Center, KS). Oltipraz (OPZ) was a gift from Dr. R. Lubet (National Cancer Institute, Bethesda, MD). Polychlorinated biphenyl 126 (PCB126) was obtained from AccuStandard (New Haven, CT). -Naphthoflavone (BNF), diallyl sulfide (DAS), clofibric acid (CLOF), di-(2-ethylhexyl) phthalate (DEHP), ethoxyquin (EXQ), dexamethasone (DEX), pregnenolone-16I-carbonitrile (PCN), ciprofibrate (CIPRO), butylated hydroxyanisole (BHA), spironolactone (SPR), phenobarbital (PB) and 1,4-bis[2-(3,5-dichloropuridyloxy)]benzene (TCPOBOP) were purchased from Sigma-Aldrich Co. (St. Louis, MO). RNA Bee was obtained from TelTest Inc. (Friendswood, TX).", "type": "figure"}, "FIGREF3": {"text": "and Aldh4a1 (Fig. 4) mRNA expression were higher in females, whereas Aldh3b1 (Fig. 3) was higher in males. In kidney, Aldh3b1 (Fig. 3)", "type": "figure"}, "FIGREF4": {"text": "60 Induction of Aldhs by MEIs. Male C57BL/6 mice were dosed with five groups of prototypical microsomal enzymes inducers. These inducers include AhR ligands: TCDD, PCB126, and BNF; CAR activators: TCPOBOP, DAS, and PB; PXR ligands: PCN, SPR, and DEX; PPAR ligands: CLOF, CIPRO, and DEHP; and Nrf2 activators: OPZ, EXQ, and BHA. The effect of these inducers on the expression of the Aldh 1a2, 1a3, 3b1, and 18a1 isozymes, which are lowly expressed in liver was determined in pooled samples (five animals per sample) to examine for induction. None of these Aldh isozymes were induced by any of the studied inducers (data not shown). The induction of Aldh3a1 mRNA was fully investigated despite its low expression in liver because of the large amount of literature addressing its induction by various inducers.", "type": "figure"}, "FIGREF5": {"text": "Figure 7 demonstrates the effect of the various MEIs on the hepatic expression of Aldhs. AhR ligands, TCDD and BNF, moderately induced the mRNA expression of Aldh1a7, Aldh1b1 and Aldh3a1. The AhR ligand PCB126 had no effect on the expression of any of the Aldh isozymes. The 3 CAR activators, TCPOBOP, DAS, and PB induced the mRNA expression of Aldh1a1 about 100%, and Aldh1a7 by approximately 200%. However, the hepatic expression of Aldh6a1 and Aldh7a1 were suppressed by TCPOBOP, whereas Aldh8a1 expression was suppressed by PB and DAS Aldh8a1. Aldh1a7, and Aldh1b1 mRNA expression was induced by all 3 PXR ligands, PCN, SPR, and DEX; Aldh1a1 was induced by PCN and SPR; whereas Aldh4a1 was", "type": "figure"}, "FIGREF6": {"text": ". Aldehyde dehydrogenases catalyze a major pathway of phase-I biotransformation of numerous endo-and xenobiotics. Understanding the tissue distribution of Aldh isozymes may help determine their impact on the pharmacokinetics as well as the pharmacological and toxicological profiles of numerous substrates. Most studies in the literature concerning the tissue distribution of Aldhs have been limited to a few tissues, and were not quantitative. These previous studies have primarily been performed in rat and human tissues, with limited data available for mice. The mouse is becoming a more common laboratory species because of the availability of transgenic and gene-knockout mice. Therefore, in the present study we evaluated the relative distribution of Aldh isoform mRNA in 14 tissues in mice.", "type": "figure"}, "FIGREF7": {"text": "CYPs, and the resulting metabolic activation/deactivation is well characterized. Chemicals that induce the gene expression of Cyps might similarly affect the expression of Aldhs. Therefore, we studied the effect of 15 prototypical microsomal metabolizing enzyme inducers, which are known to induce Cyp enzymes by activating 5 distinct transcription factors (3 inducers in each group), on the hepatic mRNA expression of individual Aldhs in male mice. The role of AhR in the transcriptional regulation of Aldh3a1 in hepatocarcinogenesis has been studied thoroughly. In normal rat liver, the major Aldh activity prefers aliphatic aldehyde substrates, such as propanyldehyde with. In hepatoma cells, a new activity appears due to the appearance of an Aldh isoenzyme that is not present in normal livers, which prefers aromatic aldehyde substrates, such as benzaldehyde and NADP + as a co-factor", "type": "figure"}, "FIGREF8": {"text": "Figure 3: Total RNA was isolated from approximately 8-weeks-old male and female mice and analyzed by the bDNA signal amplification assay for Aldh3a1, 3a2, and 3b1 mRNA expression. The data are presented as mean RLU \u00b1 SEM (n=5). * represents a statistically significant difference (p 0.05) between males and females.", "type": "figure"}, "FIGREF9": {"text": "Figure 4: Total RNA was isolated from approximately 8-weeks-old male and female mice and analyzed by the bDNA signal amplification assay for Aldh4a1, 6a1 and 7a1mRNA expression. The data are presented as mean RLU \u00b1 SEM (n=5). * represents a statistically significant difference (p 0.05) between males and females.", "type": "figure"}, "FIGREF10": {"text": "Figure 5: Total RNA was isolated from approximately 8-weeks-old male and female mice and analyzed by the bDNA signal amplification assay for Aldh8a1, 9a1, and 18a1 mRNA expression. The data are presented as mean RLU \u00b1 SEM (n=5). * represents a statistically significant difference (p 0.05) between males and females.", "type": "figure"}, "FIGREF11": {"text": "Figure 1", "type": "figure"}, "FIGREF12": {"text": "Figure 2", "type": "figure"}, "FIGREF13": {"text": "Figure 3", "type": "figure"}, "FIGREF15": {"text": "Figure 4", "type": "figure"}, "FIGREF16": {"text": "Figure 5", "type": "figure"}, "FIGREF18": {"text": "Figure 7", "type": "figure"}, "TABREF0": {"text": "10 mouse gene transcripts were eliminated from the design. The sequences and functions of the probe sets are listed in Table 2 as a supplementary material. Total RNA (1 \u00b5g/\u00b5l; 10 \u00b5l/well) was added to each well of a 96-well plate containing 50 \u00b5l of each diluted probe set. RNA was allowed to hybridize with the probe sets overnight at 53 \u00baC. Subsequent hybridization steps were carried out according to the manufacturer's protocol, and luminescence was quantified with a Quantiplex 320 bDNA luminometer interfaced with Quantiplex Data Management software v5.02. Data are presented as relative light units (RLU) per 10 \u00b5g of total RNA. Statistical Analysis. Statistical differences were determined using student's t test with significance set at p 0.05. Bars represent mean \u00b1 SEM.", "type": "table"}, "TABREF2": {"text": "PPAR activators (CLOF and DEHP), whereas Aldh7a1, and 8a1 were induced by clofibrate only. Nrf2 activators, especially BHA also induced the mRNA expression of many Aldhs. Aldh1a1 and 1a7 mRNA expression was induced by all Nrf2 activators (OPZ, EXQ, and BHA). Aldh1b1 was induced by 2 Nrf2 activators (EXQ and BHA), whereas, Aldh3a1, 4a1, 7a1, and 8a1 were induced by BHA only.", "type": "table"}, "TABREF10": {"text": "gradually increased after birth to reach adult levels between 15-45 days of age. AhR ligands induced the liver mRNA expression of Aldh1a7, 1b1, and 3a1. CAR activators induced the liver mRNA expression of Aldh1a1 and 1a7. PXR ligands and Nrf2 activators induced the liver mRNA expression of Aldh1a1, 1a7, and 1b1. PPAR ligands specialy CLOF induced the mRNA expression of almost all Aldhs.", "type": "table"}, "TABREF11": {"text": "Oligonucleotide probes generated for analysis of Aldh expression by bDNA signal amplification. Target sequence refers to the sequence of mRNA transcript as enumerated in the GenBank file. Function refers to the utility of the oligonucleotide probe in the bDNA assay. 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J Biol Chem 271, 16288-93.", "type": "table"}, "TABREF13": {"text": "List of chemicals, dosing regimen and known target transcription factorsNrf2 activators Oltipraz (OPZ) 150 mg/kg CORN OIL PO Ethoxyquin (ETHOXY) 250 mg/kg CORN OIL PO Butylated Hydroxyanisole (BHA) 350 mg/kg CORN OIL IP", "type": "table"}}}
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{"paper_id": "17782314", "_pdf_hash": "30f4a6913db5868f0a5d0d91443c286312ebaec6", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "The gyrator, a new electric network element", "authors": [{"first": "B", "middle": ["D H"], "last": "Tellegen", "suffix": ""}], "year": 1948, "venue": "Philips Res. Rep", "link": null}, "BIBREF1": {"title": "Low-voltage low-power high-Q CMOS RF bandpass filter", "authors": [{"first": "A", "middle": [], "last": "Thanachayanont", "suffix": ""}], "year": 2002, "venue": "Electronics Letters", "link": "109528496"}, "BIBREF2": {"title": "A single VHF and UHF Receiver for Radio Paging", "authors": [{"first": "J", "middle": ["F"], "last": "Wilson", "suffix": ""}, {"first": "R", "middle": [], "last": "Youell", "suffix": ""}, {"first": "T", "middle": ["H"], "last": "Richards", "suffix": ""}, {"first": "G", "middle": [], "last": "Luff", "suffix": ""}, {"first": "R", "middle": [], "last": "Pilaski", "suffix": ""}], "year": 1991, "venue": "IEE Journal of Solid State Circuits", "link": null}, "BIBREF3": {"title": "NMOS transistors based Karsilayan & Schaumann gyrator : lowpass and bandpass filter applications", "authors": [{"first": "H", "middle": [], "last": "Barth\u00e9lemy", "suffix": ""}, {"first": "W", "middle": [], "last": "Rahajandraibe", "suffix": ""}], "year": "", "venue": "MWSCAS 2004. Proceedings of the 46th IEEE 2003 Midwest Symposium on Circuits and Systems", "link": "29097069"}, "BIBREF4": {"title": "A highfrequency high-Q CMOS active inductor with DC bias control", "authors": [{"first": "A", "middle": ["I"], "last": "Karsilayan", "suffix": ""}, {"first": "R", "middle": [], "last": "Schaumann", "suffix": ""}], "year": 2000, "venue": "Proceedings of the 43rd IEEE Midwest Symposium", "link": null}, "BIBREF5": {"title": "Austria Mikro Syteme International A : Schlo\u03b2 Premst\u00e4tten A-8141 Unterpremst\u00e4tten Austria: electronic file available at", "authors": [], "year": "", "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "17782618", "_pdf_hash": "771cfadb0bb20f99811d387b3cd767592bfaba1c", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Asset Pricing and the Bid-Ask Spread", "authors": [{"first": "Yakov", "middle": [], "last": "Amihud", "suffix": ""}, {"first": "Haim", "middle": [], "last": "Mendelson", "suffix": ""}], "year": 1986, "venue": "Journal of Financial economics", "link": "154543937"}, "BIBREF1": {"title": "Inflation Illusion and Stock Prices", "authors": [{"first": "John", "middle": ["Y"], "last": "Campbell", "suffix": ""}, {"first": "Tuomo", "middle": [], "last": "Vuolteenaho", "suffix": ""}], "year": 2004, "venue": "Papers and Proceedings of the One Hundred Sixteenth Annual Meeting of the American Economic Association", "link": null}, "BIBREF2": {"title": "Federal reserve Bank of Cleveland, economic Commentary", "authors": [{"first": "Charles", "middle": ["T"], "last": "Carlstrom", "suffix": ""}, {"first": "Timothy", "middle": ["S"], "last": "Fuerst", "suffix": ""}], "year": 2004, "venue": "", "link": null}, "BIBREF3": {"title": "inflation-indexed Securities: Bonds, Swaps and other derivatives", "authors": [{"first": "Mark", "middle": [], "last": "Deacon", "suffix": ""}, {"first": "Andrew", "middle": [], "last": "Derry", "suffix": ""}, {"first": "Dariush", "middle": [], "last": "Mirfendereski", "suffix": ""}], "year": 2004, "venue": "", "link": "151277471"}, "BIBREF4": {"title": "Board of Governors of the Federal reserve System", "authors": [{"first": "Refet", "middle": ["S"], "last": "Gurkaynak", "suffix": ""}, {"first": "P", "middle": [], "last": "Brian", "suffix": ""}, {"first": "Jonathan", "middle": ["H"], "last": "Sack", "suffix": ""}, {"first": "", "middle": [], "last": "Wright", "suffix": ""}], "year": 2008, "venue": "FEDS Working Paper", "link": "197767422"}, "BIBREF5": {"title": "International Evidence on real Estate Securities as an Inflation Hedge", "authors": [{"first": "D", "middle": ["J"], "last": "Hartzell", "suffix": ""}, {"first": "C", "middle": ["H"], "last": "Liu", "suffix": ""}, {"first": "Martin", "middle": [], "last": "Hoesli", "suffix": ""}], "year": 1997, "venue": "Real estate economics", "link": "54913804"}, "BIBREF6": {"title": "Australia's Experience with Indexed Bonds", "authors": [{"first": "Peter", "middle": [], "last": "Mccray", "suffix": ""}], "year": 1997, "venue": "Presentation to a BZW Investor Forum", "link": null}, "BIBREF7": {"title": "Hearing before the U.S. Congress Subcommittee on Trade, Productivity, and Economic Growth of the Joint Economic Committee", "authors": [{"first": "Robert", "middle": ["A"], "last": "Monks", "suffix": ""}], "year": 1985, "venue": "", "link": null}, "BIBREF8": {"title": "The Case for TIPS: An Examination of the Costs and Benefits", "authors": [{"first": "Jennifer", "middle": [], "last": "Roush", "suffix": ""}, {"first": "William", "middle": [], "last": "Dudley", "suffix": ""}, {"first": "Michelle", "middle": ["Steinberg"], "last": "Ezer", "suffix": ""}], "year": 2008, "venue": "Staff reports", "link": null}, "BIBREF9": {"title": "Liquidity risk Premia and Breakeven Inflation rates", "authors": [{"first": "Pu", "middle": [], "last": "Shen", "suffix": ""}], "year": 2006, "venue": "Federal reserve Bank of Kansas City, economic Review", "link": "153836294"}, "BIBREF10": {"title": "Federal reserve Bank of Kansas City, economic Review", "authors": [{"first": "", "middle": [], "last": "__________", "suffix": ""}], "year": 1998, "venue": "", "link": null}, "BIBREF11": {"title": "Can TIPS Help Identify Long-Term Inflation Expectations?", "authors": [{"first": "Jonathan", "middle": [], "last": "__________", "suffix": ""}, {"first": "", "middle": [], "last": "Corning", "suffix": ""}], "year": 2001, "venue": "", "link": "12281761"}, "BIBREF12": {"title": "Liquidity of the Treasury Bill Market and the Term Structure of Interest rates", "authors": [{"first": "Pu", "middle": [], "last": "Shen", "suffix": ""}, {"first": "Ross", "middle": ["M"], "last": "Starr", "suffix": ""}], "year": 1998, "venue": "Journal of economics and Business", "link": "154118774"}}, "ref_entries": {}}
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{"paper_id": "17783244", "_pdf_hash": "6504758422c27a925ed86e1ef69381c62eeba646", "abstract": [{"section": "Abstract", "text": "Visual feedback and non-visual information play different roles in tracking of an external target. This study explored the respective roles of the visual and non-visual information in eleven healthy volunteers who coupled the manual cursor to a rhythmically moving target of 0.5 Hz under three sensorimotor conditions: eye-alone tracking (EA), eye-hand tracking with visual feedback of manual outputs (EH tracking), and the same tracking without such feedback (EHM tracking). Tracking error, kinematic variables, and movement intermittency (saccade and speed pulse) were contrasted among tracking conditions. The results showed that EHM tracking exhibited larger pursuit gain, less tracking error, and less movement intermittency for the ocular plant than EA tracking. With the vision of manual cursor, EH tracking achieved superior tracking congruency of the ocular and manual effectors with smaller movement intermittency than EHM tracking, except that the rate precision of manual action was similar for both types of tracking. The present study demonstrated that visibility of manual consequences altered mutual relationships between movement intermittency and tracking error. The speed pulse metrics of manual output were linked to ocular tracking error, and saccade events were time-locked to the positional error of manual tracking during EH tracking. In conclusion, peripheral non-visual information is critical to smooth pursuit characteristics and rate control of rhythmic manual tracking. Visual information adds to eye-hand synchrony, underlying improved amplitude control and elaborate error interpretation during oculo-manual tracking.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Oculo-manual tracking relies on multimodal sensory streams to achieve target goals and coordinate ocular and manual effectors [1] [2] [3] . Non-visual information from efferent copy and proprioceptive inputs is crucial for the oculo-manual plant to calibrate movement consequences in a conjugate manner [2, 4, 5] . Using a self-moved target design (SMT), the respective roles of non-visual inputs from manual effectors have been explored by contrasting behavioral consequences of simultaneous eye and manual tracking with those of eye-alone (EA) tracking in healthy and deafferented subjects [5] [6] [7] . SMT tracking exhibits a smoother ocular pursuit, higher pursuit velocity, and less pursuit delay than EA tracking [6, 8, 9] , due to predictive estimates of pursuit through integration of arm kinesthetic information with ocular commands in the cerebellum [3, [10] [11] [12] . In addition, arm motor command (efferent copy) is keyed to synchronize ocular motion onset, as latency for ocular tracking of the passively-moved arm is similar to that for EA tracking [7] . Subserving to visual guidance of manual tracking, target spatial representation is registered with composite eye movements [13, 14] and then transformed into oculo-manual synergy in target tracking [1, 14] . Although much literature is available on visual and non-visual roles in oculo-manual tracking, little attention has been paid to the following issues of interests. First, the respective role of the non-visual inputs could be different for tracking of an externally-driven target. The reason is that expected sensory consequences during tracking of a bodily target take precedence over feedback processes [5, 9] , which external tracking of low frequency relies on in order to remedy tracking deviations [2, 15] . Next, direct comparison of behavioral consequences between SMT and EA tracking [6, 7] may overstate the proprioceptive contribution to eye-hand synergy during oculomanual tracking, for improvement of manual action during tracking is partially attributed to visual perception of mismatch between target trajectory and manual consequence. The cognitive effects of visual feedback of manual consequences on tracking improvement should be specified separately.", "cite_spans": [{"start": 126, "end": 129, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 130, "end": 133, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 134, "end": 137, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 303, "end": 306, "text": "[2,", "ref_id": "BIBREF1"}, {"start": 307, "end": 309, "text": "4,", "ref_id": "BIBREF3"}, {"start": 310, "end": 312, "text": "5]", "ref_id": "BIBREF4"}, {"start": 592, "end": 595, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 596, "end": 599, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 600, "end": 603, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 720, "end": 723, "text": "[6,", "ref_id": "BIBREF5"}, {"start": 724, "end": 726, "text": "8,", "ref_id": "BIBREF7"}, {"start": 727, "end": 729, "text": "9]", "ref_id": "BIBREF8"}, {"start": 861, "end": 864, "text": "[3,", "ref_id": "BIBREF2"}, {"start": 865, "end": 869, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 870, "end": 874, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 875, "end": 879, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 1067, "end": 1070, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 1196, "end": 1200, "text": "[13,", "ref_id": "BIBREF12"}, {"start": 1201, "end": 1204, "text": "14]", "ref_id": "BIBREF13"}, {"start": 1271, "end": 1274, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 1275, "end": 1278, "text": "14]", "ref_id": "BIBREF13"}, {"start": 1685, "end": 1688, "text": "[5,", "ref_id": "BIBREF4"}, {"start": 1689, "end": 1691, "text": "9]", "ref_id": "BIBREF8"}, {"start": 1784, "end": 1787, "text": "[2,", "ref_id": "BIBREF1"}, {"start": 1788, "end": 1791, "text": "15]", "ref_id": "BIBREF14"}, {"start": 1873, "end": 1876, "text": "[6,", "ref_id": "BIBREF5"}, {"start": 1877, "end": 1879, "text": "7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Introduction", "text": "Movement intermittency is inherent in human oculo-manual tracking [16, 17] . Discontinuity of ocular tracking (or corrective saccade) is an online corrective process for bringing the deviated gaze quickly into the vicinity of the target [13, 18, 19] . As retinal gaze errors of velocity or position can be coded separately in saccade generating networks, saccade genesis seemingly pertains to task condition and spatial uncertainty for the behavior goal [18, 20, 21] . Manual intermittent behaviors (or submovements) are manifested with the velocity profiles of goal-directed aiming [22, 23] and rhythmic tracking [24] [25] [26] . The submovement superimposes kinematical irregularity on the prototype movement with speed pulses of different scales. Akin to corrective saccades, speed pulses rely heavily on visual feedback for fine-tuning the manual trajectory in accordance with accuracy demands [15, 24, 26] . Intriguingly, the movement intermittency of ocular and manual effectors is cross-modulated by feedback information of their counterpart. Proprioceptive inputs from manual effectors suppress saccadic eye movements [27] , and on-line visual feedback enhances discontinuities of the manual output during tracking [15] . Cross modulation of movement intermittency supports the reciprocal transfer of sensory and motor information between ocular and manual subsystems [8] , subservient to a fundamental element of eye-hand synergy in the execution of oculo-manual tracking. Despite these facts, no previous studies have specified reciprocity of movement intermittency and error correction processes of the counterpart during rhythmic oculo-manual tracking. It still remains unclear how submovement metrics are adjusted to ocular tracking error and whether saccade events are a cross function of manual tracking error. To gain insight into the relative contributions of non-visual and visual information to achieve a target goal, it is valuable to clarify the intermittencyerror reciprocity of the oculo-manual plant, since the central nervous system could weigh different feedback sources to regulate intermittent behaviors under different sensorimotor conditions.", "cite_spans": [{"start": 66, "end": 70, "text": "[16,", "ref_id": "BIBREF15"}, {"start": 71, "end": 74, "text": "17]", "ref_id": "BIBREF16"}, {"start": 237, "end": 241, "text": "[13,", "ref_id": "BIBREF12"}, {"start": 242, "end": 245, "text": "18,", "ref_id": "BIBREF17"}, {"start": 246, "end": 249, "text": "19]", "ref_id": "BIBREF18"}, {"start": 454, "end": 458, "text": "[18,", "ref_id": "BIBREF17"}, {"start": 459, "end": 462, "text": "20,", "ref_id": "BIBREF19"}, {"start": 463, "end": 466, "text": "21]", "ref_id": "BIBREF20"}, {"start": 583, "end": 587, "text": "[22,", "ref_id": "BIBREF21"}, {"start": 588, "end": 591, "text": "23]", "ref_id": "BIBREF22"}, {"start": 614, "end": 618, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 619, "end": 623, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 624, "end": 628, "text": "[26]", "ref_id": "BIBREF25"}, {"start": 898, "end": 902, "text": "[15,", "ref_id": "BIBREF14"}, {"start": 903, "end": 906, "text": "24,", "ref_id": "BIBREF23"}, {"start": 907, "end": 910, "text": "26]", "ref_id": "BIBREF25"}, {"start": 1126, "end": 1130, "text": "[27]", "ref_id": "BIBREF26"}, {"start": 1223, "end": 1227, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 1376, "end": 1379, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Introduction", "text": "The present work was undertaken to re-examine the respective roles of visual and non-visual information on eye-hand synergy for tracking of an externally-driven target. Our specific foci were 1) the relative contributions of non-visual information to ocular tracking, and 2) the effect of the visibility of manual consequences on scaling of movement intermittency and intermittency-error reciprocity. It was hypothesized that non-visual input during oculo-manual tracking was specified for rate control of manual tracking and enhancement of pursuit characteristics (increments of pursuit incidence and velocity gain). Visual feedback of manual consequences improved the amplitude control of manual tracking with unit displacement gain, accompanied by rescaling of speed pulse metrics (amplitude, duration, and frequency). For the visibility of manual consequence, manual movement intermittency was causally linked to ocular tracking error. Ocular movement intermittency was hypothesized to be triggered by different aspects of manual tracking error, since tracking with and without vision of the manual cursor relies preferentially on visual [2, 28] and proprioceptive feedback [2, 29] , respectively.", "cite_spans": [{"start": 1142, "end": 1145, "text": "[2,", "ref_id": "BIBREF1"}, {"start": 1146, "end": 1149, "text": "28]", "ref_id": "BIBREF27"}, {"start": 1178, "end": 1181, "text": "[2,", "ref_id": "BIBREF1"}, {"start": 1182, "end": 1185, "text": "29]", "ref_id": "BIBREF28"}], "ref_spans": []}, {"section": "Materials and Methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Ethics Statement", "text": "The experiment was approved by the local human experiment and ethics committee (National Cheng Kung University Hospital Institutional Review Board, NCKUH IRB), and written informed consent was obtained from all the participants, conforming to the Declaration of Helsinki.", "cite_spans": [], "ref_spans": []}, {"section": "Participants", "text": "Eleven right-handed young adults (6 females and 5 males, mean age: 25.562.0 years) with normal-to-corrected visual acuity participated in this study. None of them had any known neurological disorders that could affect eye-hand coordination. Figure 1A illustrates the experimental setup of this study. The subjects were seated 60 cm from a 190 PC screen (resolution set at 10246768 pixels) that displayed the target signal at eye level. The head was immobilized on a chin rest and the forehead restraint of an eye-tracking column. The forearm was pronated on the table of the tracking column, and the index finger was pointed forward and hidden from view by the tracking column. The subjects performed a force tracking task by isometrically pressing a multi-function push/pull force gauge (Model: 9810P, AIKOH, Taito-ku, Japan, Capacity: 6100 Nt, Resolution: 0.01 Nt, Accuracy: 60.2% Full Scale) on the table with the index fingers. A thirteen-point calibration procedure for eye movement was performed before the experiment, according to user guidelines provided by the manufacturer. Vertical eye movements were registered with an infrared illumination video-based eye tracker (iView X Hi-speed 1250, SensoMotoric Instruments GmbH, Germany), and then converted into analog voltage values using a built-in 14-bit D/A board (voltage range: 610V, Model: PIO-DA4, Taiwan). The eye movement, finger exertion, and target signal were synchronized and digitized at 1.25 kHz using a 16-bit A/D converter (DAQ Card-6036E, National Instruments, Austin, TX, USA) on a LabVIEW platform (National Instruments, Austin, TX, USA).", "cite_spans": [], "ref_spans": [{"start": 241, "end": 250, "text": "Figure 1A", "ref_id": "FIGREF0"}]}, {"section": "Experimental Setup and Procedures", "text": "All the subjects completed tracking tasks under three different conditions in a random order, by visually and/or manually tracking a sinusoidally moving target of 0.5 Hz. The target signal moved vertically in a range of 7.2u of visual angle (i.e., 3.6u above and 3.6u below the eye level on the screen). The maximal velocity was about 11.31 degree/s. In the eye-alone (EA) condition, the subjects visually tracked the moving target without any finger action (Fig. 1B) . Eye-hand tracking (EH) required the subjects to track with the ocular and manual effectors when the visual target and manual cursor were simultaneously displayed on the screen. During EH tracking, the subjects coupled the position of the manual cursor to that of the visual target on the screen by scaling the exertion level of the index finger on the force gauge. The minimum and maximum positions of the target trajectory (23.6u,3.6u of visual angle) represented force applications of 25 grams and 250 grams, respectively. This resulted in a forceposition conversion ratio equal to 0.3125 Nt/degree. The minimal force output during force-tracking was zero gram (24.4u of visual angle), when the subjects completely released from the force gauge without any force exertion. There would be no negative force output under the current force-tracking setting (i.e., pushing force). Known as kinesthetic tracking, eye-hand masked tracking (EHM) was identical to EH tracking except that the force output of the index finger (i.e., manual cursor) was not shown on the screen. Practice trials were allowed for each participant to get familiar with the tracking paradigms. All participants were soon able to track the target after 3-5 practice trials, given a vertical display of the level of force exertion on the screen during load-varying isometric abduction of the index finger. In the experiment, each tracking protocol consisted of six trials of 30 seconds with a between-trial interval of 1 minute.", "cite_spans": [], "ref_spans": [{"start": 458, "end": 467, "text": "(Fig. 1B)", "ref_id": "FIGREF0"}]}, {"section": "Data Processing and Statistical Analyses", "text": "Eye blinks in the ocular trajectory were detected and replaced with a cubic spline function [30] . If a trial contained more than five eye-blinks (less than 3% of total trials), it was automatically excluded from the subsequent analysis. Vertical eye movements were conditioned with a low-pass filter (cut-off frequency: 20 Hz). The spatial relations among vertical eye movement, finger exertion profile, and target signal were reconstructed in a standardized form of visual angles (u). Subsequent analyses of the rescaled signals included estimations of the following:", "cite_spans": [{"start": 92, "end": 96, "text": "[30]", "ref_id": "BIBREF29"}], "ref_spans": []}, {"section": "Data Processing and Statistical Analyses", "text": "Tracking performance variables. Ocular and manual tracking errors were defined as root mean square (RMS) values of the mismatch between positional eye movements and finger exertion with respect to the target signal, respectively. Eye-hand trajectory mismatch was the RMS value of the mismatch between positional eye movements and finger exertion. A cross-correlation algorithm was applied to obtain lag-times for ocular and manual tracking with respect to the target signal and lag-time for manual tracking in reference to ocular tracking.", "cite_spans": [], "ref_spans": []}, {"section": "Data Processing and Statistical Analyses", "text": "Incidences and kinematic properties for composite eye movements. The eye movements during EHM and EH tracking were principally composed of saccadic and pursuit components. The first and second derivatives of positional eye movements were calculated to obtain velocity and acceleration traces. Saccade was empirically determined by a 750u/s 2 acceleration threshold and a 15u/s velocity threshold with a minimum dispersion of 0.8u [19, 31] . Maximal velocity values of saccade segments were averaged across trials to obtain the mean peak saccade velocity for each subject. Saccade incidences were obtained by dividing the saccade component duration with the overall duration of a tracking trial, and the remaining portion of eye movements was considered as pursuit incidences. Saccadic variables defined the patterns of ocular movement intermittency. After saccade components were replaced with a cubic spline function [30] , pursuit velocity gain was defined as the ratio of RMS velocity of eye movement to that of target velocity signal.", "cite_spans": [{"start": 430, "end": 434, "text": "[19,", "ref_id": "BIBREF18"}, {"start": 435, "end": 438, "text": "31]", "ref_id": "BIBREF30"}, {"start": 918, "end": 922, "text": "[30]", "ref_id": "BIBREF29"}], "ref_spans": []}, {"section": "Data Processing and Statistical Analyses", "text": "Displacement gain, peak frequency, and submovement metrics of finger movements. The displacement gain of finger exertion reflected the amplitude control of manual tracking. It was computed as the ratio of RMS amplitude of finger exertion to that of the target displacement signal. The peak frequency of finger action was derived via a fast Fourier transform to represent the spectral acuity of manual tracking. Greater deviation of the peak frequency from the target rate indicated poorer rate control of the manual tracking. The substructure of the velocity profile of finger action was characterized with speed pulse analysis for continuous rhythmic tracking [24] [25] [26] . The velocity profile of finger action was obtained by differentiation of displacement trajectory, following 6 Hz low-pass filtering and the removal of the primary movement of the target rate at 0.5 Hz [26] . Duration of speed pulse was the time interval between two successive local minima, and speed pulse amplitude was the difference between the averaged speed value of the two successive local minima and the speed value of an in-between local maximum [24] [25] [26] . Speed pulse frequency was the number of pulses per second in a tracking trial. All speed pulse variables representing a pattern of manual movement intermittency were determined in the EH and EHM tracking conditions. Ocular tracking error-finger intermittency relationship. The quantitative analysis was designed to characterize the impact of manual consequences upon adjustments of ocular movement. Linear regression analysis was applied to model the relationships between the scaling properties of speed pulse (amplitude, duration, and frequency) and the amount of ocular positional error for EH and EHM tracking. A significant regression slope indicated functional linkage between ocular tracking error and speed pulse scaling. Manual tracking error-ocular intermittency relationship. The analysis was designed to evaluate the impact of saccadic response on manual tracking error during EH and EHM tracking. The mismatches between the finger channel and the target signal in the position profile (positional error) and in the velocity profile (velocity error) were calculated within a set of time window, 200 ms before saccade onset (2200,0 ms) and 200 ms after the end of the saccade event (0,200 ms). Regression slopes of the best-fit line for absolute values of manual tracking error before and after saccade were determined. Significant regression coefficients indicated saccade-related adjustments for manual tracking errors. All data analyses were performed off-line using custom-made Matlab scripts (The Mathworks Inc., Natick, MA, USA). One-way repeated-measures ANOVA and post-hoc paired ttest were used to examine the differences in ocular movement variables (ocular tracking error, ocular tracking delay, and incidences and kinematic properties of composite eye movements) among the three tracking conditions (i.e., EA, EHM, and EH). Paired-t test was used to contrast the manual movement variables (manual tracking error, manual tracking delay, displacement gain, and all speed pulse metrics) between the EHM and EH conditions. All statistical analyses were completed using the SPSS 17.0 statistical package (SPSS Inc. Armonk, NY, USA) with the significance level set at P = 0.05.", "cite_spans": [{"start": 661, "end": 665, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 666, "end": 670, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 671, "end": 675, "text": "[26]", "ref_id": "BIBREF25"}, {"start": 879, "end": 883, "text": "[26]", "ref_id": "BIBREF25"}, {"start": 1133, "end": 1137, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 1138, "end": 1142, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 1143, "end": 1147, "text": "[26]", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Tracking Error and Tracking Delay", "text": "Figures 2A and 2B show typical examples of the position and velocity profiles for eye movement, manual output, and target signal for all tracking conditions. Figure 3 shows mean ocular tracking error, manual tracking error, and eye-hand trajectory mismatch in the different tracking conditions. Ocular tracking error varied significantly with tracking conditions (F 2, 20 = 9.44, P = 0.001). Post-hoc analysis suggested that ocular tracking error was larger in the EA tracking condition than in the EHM and EH conditions (P,0.01), but that it was the same in the EHM and EH conditions (P = 0.719), when manual tracking was a factor. In EH tracking, manual tracking error (t 10 = 3.62, P = 0.005) and eyehand trajectory mismatch (t 10 = 3.65, P = 0.004) were smaller than in EHM tracking. Table 1 summarizes the lag-times for given pairs of eye movement, finger action, and target signal for different tracking conditions. All lag-time variables differed significantly with tracking paradigm (Eye-Target: F 2,20 = 49.54, P = 0.000; Finger-Target: t 10 = 4.29, P = 0.002; Eye-Finger: t 10 = 22.52, P = 0.030). Post-hoc analysis indicated that concurrent finger action and visual knowledge of manual consequence significantly reduced lag-times for ocular (P,0.01) and manual tracking (P,0.01). Figure 4A contrasts the mean incidences of saccadic and pursuit movements under the three tracking conditions. ANOVA statistics revealed that incidences of saccadic (F 2, 20 = 54.20, P = 0.000) and pursuit components (F 2, 20 = 54.20, P = 0.000) differed among tracking paradigms. Concurrent finger action and visual feedback of manual action suppressed saccade occurrence (EA.EHM. EH, P,0.05), but conversely added to pursuit incidence (EH .EHM. EA, P,0.05). Figures 4B and 4C contrast kinematical properties of saccadic and pursuit movements among different tracking conditions. Peak saccade velocity differed with tracking condition (Fig. 4B, F 2 , 20 = 9.26, P = 0.002), and EA and EH tracking respectively exhibited the highest and lowest peak saccade velocities among all tracking conditions (EA .EHM .EH, P,0.05). Pursuit velocity gain was also a function of shift in tracking paradigms (Fig. 4C, F 2 , 20 = 19.10, P = 0.000). Contrary to a decreasing trend of peak saccade velocity, pursuit velocity gain increased for tracking with concurrent finger action and visual feedback of the finger action (EA ,EHM ,EH, P,0.05).", "cite_spans": [], "ref_spans": [{"start": 158, "end": 166, "text": "Figure 3", "ref_id": "FIGREF2"}, {"start": 788, "end": 795, "text": "Table 1", "ref_id": "TABREF0"}, {"start": 1291, "end": 1300, "text": "Figure 4A", "ref_id": "FIGREF3"}, {"start": 1751, "end": 1768, "text": "Figures 4B and 4C", "ref_id": "FIGREF3"}, {"start": 1927, "end": 1940, "text": "(Fig. 4B, F 2", "ref_id": "FIGREF1"}, {"start": 2185, "end": 2198, "text": "(Fig. 4C, F 2", "ref_id": "FIGREF1"}]}, {"section": "Incidences and Kinematic Properties of Composite Eye Movements", "text": "Displacement Gain, Peak Frequency, and Submovement Metrics of Finger Movement Figure 5A compares the finger displacement gains of EHM and EH tracking. EHM tracking exhibited a greater displacement gain (1.5560.51) than EH tracking (0.9760.10) (t 10 = 3.95, P = 0.003). With visual feedback, amplitude of finger movement was almost identical to target amplitude, for the displacement gain during EH tracking did not differ from unity (t 10 = 21.13, P = 0.283 by onesample t test). Figure 5B shows a spectrum plot of finger movement during EHM and EH tracking; the inset is an enlargement of the spectral peak and a bar chart comparing the average peak frequencies of the two tracking paradigms. All the subjects exhibited similar rate control of the manual tracking, as the spectrum profile peaked consistently at 0.5 Hz for EHM and EH tracking (Fig. 5) . Figure 6A displays representative speed pulse traces of finger movements after removal of a sinusoidal trend from the velocity profiles during EH and EHM tracking. In EH tracking, speed pulses were more frequent (Fig. 6D, t 10 = 5.01, P = 0.001), of smaller amplitude (Fig. 6B, t 10 = 4.80, P = 0.001), and of shorter duration (Fig. 6C , t 10 = 5.05, P = 0.001) than in EHM tracking.", "cite_spans": [], "ref_spans": [{"start": 78, "end": 87, "text": "Figure 5A", "ref_id": "FIGREF4"}, {"start": 480, "end": 489, "text": "Figure 5B", "ref_id": "FIGREF4"}, {"start": 844, "end": 852, "text": "(Fig. 5)", "ref_id": "FIGREF4"}, {"start": 855, "end": 864, "text": "Figure 6A", "ref_id": "FIGREF5"}, {"start": 1067, "end": 1081, "text": "(Fig. 6D, t 10", "ref_id": "FIGREF0"}, {"start": 1123, "end": 1137, "text": "(Fig. 6B, t 10", "ref_id": "FIGREF0"}, {"start": 1182, "end": 1190, "text": "(Fig. 6C", "ref_id": "FIGREF5"}]}, {"section": "Ocular Tracking Error-finger Intermittency Relationship", "text": "Figure 7 displays scatter plots and regression lines of ocular tracking error and speed pulse metrics for EHM and EH tracking. Ocular tracking error was linearly correlated to speed pulse amplitude during EH tracking (r = 0.698, P = 0.017), but not to speed pulse amplitude during EHM tracking (r = 0.185, P = 0.587) (Fig. 7A) . Similarly, ocular tracking error increased in proportion to speed pulse duration during EH tracking (r = 0.745, P = 0.008), but it was independent of speed pulse duration during EHM tracking (r = 0.045, P = 0.896) (Fig. 7B) . During EH tracking, greater ocular tracking error was associated with less frequent speed pulses (r = 0.793, P = 0.004), but ocular tracking error was not related to speed pulse frequency during EHM tracking (r = 0.006, P = 0.987) (Fig. 7C) . Figure 8 contrasts the position/velocity errors of manual tracking within the window (200 ms before and after a saccade event) of EHM and EH tracking. For EHM tracking, the regression slope of positional error of manual tracking before a saccade event (0.7561.72u/s) was not different from zero (P = 0.175), though the regression slope after a saccade event (1.4561.95u/s) was slightly positive (P = 0.034) (Fig. 8A) . In contrast, the velocity error of manual tracking for EHM tracking was a bell-shaped distribution peaking around the saccade onset (Fig. 8B) , with the positive regression slope before saccade (19.70616.23u/s 2 , P = 0.002) and the negative regression slope after saccade (220.47613.52u/s 2 , P = 0.001). For EH tracking, positional error of manual tracking also exhibited a bell-shaped distribution (Fig. 8C) . The regression slopes of positional error before (0.6560.53u/s, P = 0.002) and after (20.9860.71u/s, P = 0.001) saccade were of opposite signs and significantly different from zero. However, the distribution of velocity error was temporally invariant within the defined window (P.0.05) (Fig. 8D) .", "cite_spans": [], "ref_spans": [{"start": 317, "end": 326, "text": "(Fig. 7A)", "ref_id": "FIGREF6"}, {"start": 543, "end": 552, "text": "(Fig. 7B)", "ref_id": "FIGREF6"}, {"start": 786, "end": 795, "text": "(Fig. 7C)", "ref_id": "FIGREF6"}, {"start": 798, "end": 806, "text": "Figure 8", "ref_id": "FIGREF7"}, {"start": 1205, "end": 1214, "text": "(Fig. 8A)", "ref_id": "FIGREF7"}, {"start": 1349, "end": 1358, "text": "(Fig. 8B)", "ref_id": "FIGREF7"}, {"start": 1618, "end": 1627, "text": "(Fig. 8C)", "ref_id": "FIGREF7"}, {"start": 1916, "end": 1925, "text": "(Fig. 8D)", "ref_id": "FIGREF7"}]}, {"section": "Manual Tracing Error-ocular Intermittency Relationship", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Concomitant Finger Action and Changes in Ocular Behavior", "text": "With an external target design, we noted that mismatch error (Fig. 3) and temporal delay of ocular pursuit were smaller (roughly 50 ms less phase lag) ( Table 1) for EHM tracking than for EA tracking. Non-visual information during EHM tracking both increased the pursuit component and suppressed saccadic responses (Figs. 4) .", "cite_spans": [], "ref_spans": [{"start": 61, "end": 69, "text": "(Fig. 3)", "ref_id": "FIGREF2"}, {"start": 153, "end": 161, "text": "Table 1)", "ref_id": "TABREF0"}, {"start": 315, "end": 324, "text": "(Figs. 4)", "ref_id": "FIGREF3"}]}, {"section": "Concomitant Finger Action and Changes in Ocular Behavior", "text": "Elaboration of the changes in ocular behaviors is efferent copy for concurrent eye-hand movements and proprioceptive inputs that convey phase information from manual effectors. Primate studies have shown overlapped neural activities of saccadic and manual actions in the frontal eye field, superior colliculus, and cerebellum [11, [32] [33] [34] . During tracking with non-visual information, proprioceptive inputs could accentuate the phase information transfer in the cerebellum, reinforcing the internal representation of target motion [35] and predictive mode of tracking response [36] . Hence, ocular tracking in the EHM condition could be better synchronized with the target signal, leading to infrequent, smaller corrective saccades (Figs. 4A and 4B ) and more stable pursuit with a greater velocity gain than in EA tracking (Fig. 4C) . The alternating modulation of pursuit and saccadic synergies is potentially related to gating mechanisms of omnipause neurons in the brain stem [34, 37] . Considering smooth pursuit with small saccade, EHM tracking may involve graded disinhibition of omnipause neurons that suppress the saccade-related ocular motor neurons, accompanied by cooperative tuning of neurons of the rostral superior colliculus [38] and pursuit drive through the cortico-ponto-cerebellar route [34, 37] .", "cite_spans": [{"start": 326, "end": 330, "text": "[11,", "ref_id": "BIBREF10"}, {"start": 331, "end": 335, "text": "[32]", "ref_id": "BIBREF31"}, {"start": 336, "end": 340, "text": "[33]", "ref_id": "BIBREF32"}, {"start": 341, "end": 345, "text": "[34]", "ref_id": "BIBREF33"}, {"start": 539, "end": 543, "text": "[35]", "ref_id": "BIBREF34"}, {"start": 585, "end": 589, "text": "[36]", "ref_id": "BIBREF35"}, {"start": 988, "end": 992, "text": "[34,", "ref_id": "BIBREF33"}, {"start": 993, "end": 996, "text": "37]", "ref_id": "BIBREF36"}, {"start": 1249, "end": 1253, "text": "[38]", "ref_id": "BIBREF37"}, {"start": 1315, "end": 1319, "text": "[34,", "ref_id": "BIBREF33"}, {"start": 1320, "end": 1323, "text": "37]", "ref_id": "BIBREF36"}], "ref_spans": [{"start": 740, "end": 756, "text": "(Figs. 4A and 4B", "ref_id": "FIGREF3"}, {"start": 832, "end": 841, "text": "(Fig. 4C)", "ref_id": "FIGREF3"}]}, {"section": "Concomitant Finger Action and Changes in Ocular Behavior", "text": "Despite the reduction in phase lag of ocular tracking with the aid of manual action, ocular tracking using the external target design exhibited greater phase lag (44 ms in the EHM condition) than in previous studies that used a bodily target (5 ms-30 ms) [7] [8] [9] . The longer phase lag in this study was due to the lower predictability of the external target motion. Koken and Erkelens [27] reported that the complexity of target motion determines the impact of hand movements on ocular tracking. If an unpredictable target is tracked, concurrent manual action has little effect on ocular movement. Hence, a comparably shorter lag time in a bodily target experiment could be explained by proprioceptive inputs [39] and efferent copy signals [40, 41] , which enable the subjects to better predict target motion with conscious awareness of action. Another methodological factor that may affect eye-hand synergy, visibility of manual consequence, is discussed in the following section.", "cite_spans": [{"start": 255, "end": 258, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 259, "end": 262, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 263, "end": 266, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 390, "end": 394, "text": "[27]", "ref_id": "BIBREF26"}, {"start": 714, "end": 718, "text": "[39]", "ref_id": "BIBREF38"}, {"start": 745, "end": 749, "text": "[40,", "ref_id": "BIBREF39"}, {"start": 750, "end": 753, "text": "41]", "ref_id": "BIBREF40"}], "ref_spans": []}, {"section": "Visibility of Manual Consequence and Changes in Ocular and Manual Behaviors", "text": "The contrast in EHM and EH tracking illustrates the effect of visual feedback of manual consequences upon eye-hand synergy during tracking. It was evident that visibility of manual consequences during EH tracking increased the incidence and gain of pursuit movement, but it also further suppressed saccadic responses (Figs. 4A, B, C) . In EH tracking, manual performance was better than in EHM tracking, with less tracking error, smaller phase lag (Fig. 3, Table 1 ), and better eye-hand synchronization (Table 1) . Support for the merits of using visual feedback of manual consequences is that sensory streams are reweighted onto the visual channel [28] so as to alter strategies of visual scanning and error-correction processes during tracking. During EH tracking, increases in pursuit gain approaching unity minimized visual tracking error and the need for rapid realignment of the target image on the fovea with corrective saccades. In addition, the visibility of manual consequence enhanced the perception of target motion, which involved intricate oculomotor and attentional networks. The functioning of the inferior parietal lobule is important in establishing maps of extrapersonal space for manual action and target movement [42, 43] through multiple aspects of sensory processing (visual and non-visual) and sensorimotor integration.", "cite_spans": [{"start": 650, "end": 654, "text": "[28]", "ref_id": "BIBREF27"}, {"start": 1235, "end": 1239, "text": "[42,", "ref_id": "BIBREF41"}, {"start": 1240, "end": 1243, "text": "43]", "ref_id": "BIBREF42"}], "ref_spans": [{"start": 317, "end": 333, "text": "(Figs. 4A, B, C)", "ref_id": "FIGREF3"}, {"start": 448, "end": 464, "text": "(Fig. 3, Table 1", "ref_id": "FIGREF0"}, {"start": 504, "end": 513, "text": "(Table 1)", "ref_id": "TABREF0"}]}, {"section": "Visibility of Manual Consequence and Changes in Ocular and Manual Behaviors", "text": "Visibility of manual consequences during EH tracking modified manual action by rescaling inappropriate gain potentiation in the non-visual condition to a normal unity (Fig. 5A) . Without visual feedback of manual consequences, the subjects uniformly perceived generated amplitudes smaller than the actual values during EHM tracking because the spatial sensitivity of proprioception was naturally degraded as compared to vision [29] . Strikingly, in pursuit of the sinusoidal target, both EH and EHM tracking demonstrated manual action with excellent spectral precision (Fig. 5B) . This fact implies that the rate of rhythmic oculo-manual tracking could be controlled by non-visual information, despite that amplitude control of manual tracking still remained inadequate. Manual movement intermittency changed with visual feedback of manual consequences, and speed pulses in EH tracking were smaller and greater in number than those in EHM tracking (Figs. 6B, 6C, and 6D ). This observation suggests that visual feedback of manual consequences could modify speed pulse metrics to control the amplitude of manual tracking, as previously reported for continuous tracking tasks [24] [25] [26] and goal-directed movements [44, 45] . The intermittent servomechanism [15, 16] considers speed pulses as elementary units of an additive accuracy control mechanism, and the limb speed profile is the progressive overlapping and blending of the speed pulses according to accuracy constraints [25, 26, 46] . A smoother movement with a high accuracy demand could allow for more frequent and smaller speed pulses for fine-tuning the movement trajectory. With changes in submovement dynamics, we may well reason that visual feedback of manual consequences improves movement smoothness and spatial accuracy with a reiterated internal feedback process [2, 15, [24] [25] [26] , supplementary to proprioceptive inputs that serve to stabilize temporal acuity and rhythmic control (Fig. 5B) [29, 47] . The present study first reported that the availability of visual feedback of manual consequences alters the interrelationship between the accuracy of visual guidance and manual movement intermittency (i.e., speed pulse) (Figs. 7A, B, C) . Since ocular tracking error is independent of speed pulse metrics during EHM tracking, manual adjustments rely little on the accuracy of visual guidance, for EHM tracking makes use of efferent copy and/or proprioceptive inputs as internal cues for manual tracking [31, 48] . In contrast, visually-guided tracking, like EH tracking, relies on accurate visual information of target movements to adjust manual outputs with scaled speed pulses. Thus, speed pulse metrics were correlated to ocular tracking error in this study. Poorer ocular tracking congruency demands greater speed pulses for drastic corrections of manual action. When ocular movement was coupled well with the visual target, manual movement was finetuned with smaller speed pulses in a more frequent manner. Our observations are in good agreement with the study of Selen et al. [26] , who reported that faster visuomotor tracking with greater tracking deviation was associated with a larger speed pulse gain to remedy tracking error quickly.", "cite_spans": [{"start": 427, "end": 431, "text": "[29]", "ref_id": "BIBREF28"}, {"start": 1174, "end": 1178, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 1179, "end": 1183, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 1184, "end": 1188, "text": "[26]", "ref_id": "BIBREF25"}, {"start": 1217, "end": 1221, "text": "[44,", "ref_id": "BIBREF43"}, {"start": 1222, "end": 1225, "text": "45]", "ref_id": "BIBREF44"}, {"start": 1260, "end": 1264, "text": "[15,", "ref_id": "BIBREF14"}, {"start": 1265, "end": 1268, "text": "16]", "ref_id": "BIBREF15"}, {"start": 1480, "end": 1484, "text": "[25,", "ref_id": "BIBREF24"}, {"start": 1485, "end": 1488, "text": "26,", "ref_id": "BIBREF25"}, {"start": 1489, "end": 1492, "text": "46]", "ref_id": "BIBREF45"}, {"start": 1834, "end": 1837, "text": "[2,", "ref_id": "BIBREF1"}, {"start": 1838, "end": 1841, "text": "15,", "ref_id": "BIBREF14"}, {"start": 1842, "end": 1846, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 1847, "end": 1851, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 1852, "end": 1856, "text": "[26]", "ref_id": "BIBREF25"}, {"start": 1969, "end": 1973, "text": "[29,", "ref_id": "BIBREF28"}, {"start": 1974, "end": 1977, "text": "47]", "ref_id": "BIBREF46"}, {"start": 2483, "end": 2487, "text": "[31,", "ref_id": "BIBREF30"}, {"start": 2488, "end": 2491, "text": "48]", "ref_id": "BIBREF47"}, {"start": 3062, "end": 3066, "text": "[26]", "ref_id": "BIBREF25"}], "ref_spans": [{"start": 167, "end": 176, "text": "(Fig. 5A)", "ref_id": "FIGREF4"}, {"start": 569, "end": 578, "text": "(Fig. 5B)", "ref_id": "FIGREF4"}, {"start": 948, "end": 969, "text": "(Figs. 6B, 6C, and 6D", "ref_id": "FIGREF5"}, {"start": 1959, "end": 1968, "text": "(Fig. 5B)", "ref_id": "FIGREF4"}, {"start": 2200, "end": 2216, "text": "(Figs. 7A, B, C)", "ref_id": "FIGREF6"}]}, {"section": "Visibility of Manual Consequence and Changes in Ocular and Manual Behaviors", "text": "On the other hand, visibility of manual consequences also affected the reciprocity of manual tracking error and visual movement intermittency (saccadic responses). In the absence of visual feedback of manual consequences, saccadic events during EHM tracking responded to the accumulated velocity error of manual tracking, but were insensitive to positional error (Figs. 8A and 8B). During EH tracking, the genesis of saccade was conversely a function of positional error, rather than of velocity error of manual action (Figs. 8C and 8D ). Our data tended to confirm a switching mechanism for two distributed streams of saccadic control signals (positional error and velocity error) with respect to sensory contexts. Miall et al. [49] showed that monkeys, while tracking a sinusoidal target, can make use of observed positional error and estimated target velocity (efferent copy) to scale the final movement amplitude for each correction attempt. If the positional error of manual tracking exceeds a certain level, a saccadic response is triggered to recalibrate localization information from vision to guide manual action. However, during EHM tracking, velocity errors of manual movement triggered saccadic responses (Fig. 8B) , probably due to direct use of kinematic information from the manual effectors in the oculomotor vermis and fastigial oculomotor region [11, 50] . These cerebral structures are known to receive Ia excitatory feedback encoding the phase information of manual movement and contraction-induced changes in muscle length during EHM tracking [51] . Prsa et al. [50] reported that mossy fiber in the cerebellum discharges coherently with saccade timing for precise directional tuning of ongoing manual movement. In fact, anatomical evidence also supports the operation of two different modes of saccade genesis in position and velocity channels. The middle temporal area appears to process velocity information [52, 53] , and the superior colliculus may be responsible for processing position information [20, 21, 54] . Also, parietal-cerebellar circuits are organized to deal with differing error properties before they are transformed into commands for saccade generation during tracking [55] .", "cite_spans": [{"start": 729, "end": 733, "text": "[49]", "ref_id": "BIBREF48"}, {"start": 1364, "end": 1368, "text": "[11,", "ref_id": "BIBREF10"}, {"start": 1369, "end": 1372, "text": "50]", "ref_id": "BIBREF49"}, {"start": 1564, "end": 1568, "text": "[51]", "ref_id": "BIBREF50"}, {"start": 1583, "end": 1587, "text": "[50]", "ref_id": "BIBREF49"}, {"start": 1932, "end": 1936, "text": "[52,", "ref_id": "BIBREF51"}, {"start": 1937, "end": 1940, "text": "53]", "ref_id": "BIBREF52"}, {"start": 2026, "end": 2030, "text": "[20,", "ref_id": "BIBREF19"}, {"start": 2031, "end": 2034, "text": "21,", "ref_id": "BIBREF20"}, {"start": 2035, "end": 2038, "text": "54]", "ref_id": "BIBREF53"}, {"start": 2211, "end": 2215, "text": "[55]", "ref_id": "BIBREF54"}], "ref_spans": [{"start": 519, "end": 535, "text": "(Figs. 8C and 8D", "ref_id": "FIGREF7"}, {"start": 1217, "end": 1226, "text": "(Fig. 8B)", "ref_id": "FIGREF7"}]}, {"section": "Methodological Considerations", "text": "The present study investigated eye-hand synergy with vertical target presentation, contrary to most previous studies which examined synchronous ocular-manual behaviors with horizontal Eye-Hand Synergy in Pursuit of an External Target PLOS ONE | www.plosone.orgtarget presentation. Although horizontal eye movement is typically greater than vertical eye movement [56, 57] , we found that the non-visual effect on ocular movement was largely consistent with previous studies [6, 8, 9, 27] . It was probably because directional asymmetry in ocular behaviors depends on the target kinematics [57] , and we used a slow visual target with an acceleration of 50u/ s 2 , which could be reliably featured in the normal visual field in both directions [57] . However, the effect of visibility of manual consequences on intermittency-error reciprocity should be generalized to horizontal target presentation with prudence. One potential confounding factor is the different thresholds for perceiving retinal velocity error between vertical and horizontal pursuits [57] .", "cite_spans": [{"start": 362, "end": 366, "text": "[56,", "ref_id": "BIBREF55"}, {"start": 367, "end": 370, "text": "57]", "ref_id": "BIBREF56"}, {"start": 473, "end": 476, "text": "[6,", "ref_id": "BIBREF5"}, {"start": 477, "end": 479, "text": "8,", "ref_id": "BIBREF7"}, {"start": 480, "end": 482, "text": "9,", "ref_id": "BIBREF8"}, {"start": 483, "end": 486, "text": "27]", "ref_id": "BIBREF26"}, {"start": 588, "end": 592, "text": "[57]", "ref_id": "BIBREF56"}, {"start": 742, "end": 746, "text": "[57]", "ref_id": "BIBREF56"}, {"start": 1052, "end": 1056, "text": "[57]", "ref_id": "BIBREF56"}], "ref_spans": []}, {"section": "Methodological Considerations", "text": "Next, the present study adopted a force-tracking paradigm to investigate eye-hand synergy during oculo-manual tracking. Force tracking differs from positional tracking, as it calls for forceposition transformation (0.3125 N/degree) to scale force exertion in terms of visual angles on the screen. Although our subjects could learn to conduct force-tracking after only a few practices, the effects of cognitive effort due to force-position transformation on eye-hand synergy could be further investigated.", "cite_spans": [], "ref_spans": []}, {"section": "Methodological Considerations", "text": "Finally, sinusoidal force-tracking in this study often led to a more positional error on manual response in the upward direction, especially around the local maxima of target trajectory during EHM tracking. It was not surprising because force-tracking in the upward direction progressively recruited motor units with larger twitch force, known as the size principle [58, 59] . In the absence of visual feedback, force scaling around the local maxima of target trajectory was less accurate but more variable than that around the local minima of target trajectory [60, 61] . Also, the subjects Eye-Hand Synergy in Pursuit of an External Target realized a minimal force exertion was necessary in the whole forcetracking process, and they did not allow excessive undershoot around the local minima of target trajectory for releasing from the force gauge without any voluntary effort. Hence, positional error in the upward direction (overshoot) appeared to be more influential to eye-hand synergy than that in the downward direction during the force-tracking maneuver.", "cite_spans": [{"start": 366, "end": 370, "text": "[58,", "ref_id": "BIBREF57"}, {"start": 371, "end": 374, "text": "59]", "ref_id": "BIBREF58"}, {"start": 562, "end": 566, "text": "[60,", "ref_id": "BIBREF59"}, {"start": 567, "end": 570, "text": "61]", "ref_id": "BIBREF60"}], "ref_spans": []}, {"section": "Conclusions", "text": "The present study reexamined the respective roles of visual and non-visual inputs during oculo-manual tracking of an externallydriven target. In line with previous studies using a self-moved target design, we found that non-visual inputs and visual guidance contribute to eye-hand synchronization and smoothness of ocular tracking. Non-visual information secures the rate control rather than the amplitude control of manual action which is mainly achieved by scaling of speed pulse variables for visibility of manual consequences. Visual feedback of manual consequences also changes the intermittency-error relationship. Speed pulse variables are correlated to ocular tracking error with the vision of manual cursor, which also switches operation of the visual detection of manual error from the velocity channel during EHM tracking to the position channel during EH tracking. The present study highlights the fact that movement intermittency is differently scaled with non-visual or visual information, underlying strategic changes in detection and correction of tracking errors.", "cite_spans": [], "ref_spans": []}, {"section": "Author Contributions", "text": "Conceived and designed the experiments: CTH ISH. Performed the experiments: CTH. Analyzed the data: CTH. Contributed reagents/ materials/analysis tools: CTH ISH. Wrote the paper: CTH ISH. 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(A) A schematic drawing of the experimental setup and the equipment. (B) Diagrammatic representations of the experimental conditions: EA, EHM, and EH tracking. Subjects tracked the target signal (black solid line) visually and/or manually (see the text for details). Timely visual feedback of the manual force output (blue solid line) was available during EH tracking, but was masked during EHM tracking. doi:10.1371/journal.pone.0051417.g001", "type": "figure"}, "FIGREF1": {"text": "Figure 2. Raw data plots. Central 10 seconds of data of finger action and eye movement from a typical subject under the three tracking conditions. (A) Displacement traces, (B) velocity traces. doi:10.1371/journal.pone.0051417.g002", "type": "figure"}, "FIGREF2": {"text": "Figure 3. Ocular and manual tracking errors and eye-hand trajectory mismatches for three tracking conditions. (Significant difference, ** : P,0.01). doi:10.1371/journal.pone.0051417.g003", "type": "figure"}, "FIGREF3": {"text": "Figure 4. Contrasts of characteristics for composite eye movements under the three tracking conditions. (A) Incidences of saccade and pursuit movements (*: P,0.05; + : P,0.05), (B) peak saccade velocity, and (C) pursuit velocity gain. (Significant difference, * : P,0.05; ** : P,0.01; *** : P,0.001). doi:10.1371/journal.pone.0051417.g004", "type": "figure"}, "FIGREF4": {"text": "Figure 5. Comparison of manual tracking variables between EH and EHM tracking. (A) Displacement gain; (B) peak frequency, together with a representative amplitude spectrum. (Significant difference, *** : P,0.001). doi:10.1371/journal.pone.0051417.g005", "type": "figure"}, "FIGREF5": {"text": "Figure 6. Contrasts of submovement characteristics between EH and EHM tracking. (A) Representative examples of speed pulse traces, with a box showing the measures of pulse amplitude and duration; (B) amplitude, (C) duration, (D) frequency of speed pulses (Significant difference, *** : P,0.001). doi:10.1371/journal.pone.0051417.g006", "type": "figure"}, "FIGREF6": {"text": "Figure 7. Scatter plots and regression lines of ocular tracking error versus speed pulse metrics. (A) amplitude, (B) duration, and (C) frequency of speed pulses under the EHM ( N ) and EH (#) conditions. The symbol x in the equations represents ocular tracking error, and the symbol y represents speed pulse metrics in each plot of (A)-(C). (Significant regression slope: * : P,0.05, ** : P,0.01). doi:10.1371/journal.pone.0051417.g007", "type": "figure"}, "FIGREF7": {"text": "Figure 8. Temporal dispersion and regressive slope for manual positional and velocity errors in the defined window. (A) Positional errors, and (B) velocity errors in the EHM condition; (C) positional errors, and (D) velocity errors in the EH condition. For each plot of (A)-(D), individual (thin line) and mean (thick line) temporal error dispersions are displayed in the left panel. The shadowed area (from time point Ta to Tb) represents an occurrence of a saccade event. The box-plots in the right panel of (A)-(D) show the median (central line), lower and upper quartile (lower and upper lines), and the mean value (circle) for regressive slope of manual tracking errors before and after the saccade event. The lines extending from each end of the box represent the minimum and maximum observations. Asterisks in the box-plots denote significant differences of the regression slope from zero. ( * : P,0.05; ** : P,0.01; ** : P,0.01). doi:10.1371/journal.pone.0051417.g008", "type": "figure"}, "TABREF0": {"text": "Lag-times between Eye and Target, Finger and Target, Eye and Finger under different tracking conditions.Values were presented as mean 6 sd. and all were significantly different from zero (P,0.01). Positive values in Eye-Target and Finger-Target mean that eye movement and finger exertion lag behind the target signal, respectively. Negative values in Eye-Finger mean that eye movement leads finger action.", "type": "table"}}}
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{"paper_id": "17783421", "_pdf_hash": "be9a0e2f1b44ca1e3085e7f0324a6228514f4f34", "abstract": [], "body_text": [{"section": "Introduction", "text": "Let G be a compact Lie group. Let X be a Hausdorff compact G-space which is a cohomology sphere over a ring R (cf. Def. 1.1).", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "In Section 1 we define the Euler class of a locally trivial bundle with X as fiber. Using this definition we show that the main result of [7] still holds if the sphere of an orthogonal representation is replaced by a G-space which is a cohomology sphere over R (Ths. 1.8, 1.9).", "cite_spans": [{"start": 138, "end": 141, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Introduction", "text": "In the second section we consider actions of a finite cyclic group G = C k . For this group, and X as above, an index of X has been defined in [1] and [2] . First, with the use of the Euler class we define an index of X (cf. [7] for the case where X is the sphere of an orthogonal representation; see Def. 2.2). Next we prove that this index is equal to that introduced by Borisovich and Izrailevich (Th. 2.3), and consequently we obtain a simple geometrical interpretation of the index defined in [1] . Finally, using our definition of the index (via the Euler class) we compute its value for X = S(V ), the sphere of an orthogonal representation V of G = C k (Th. 3.3) . This allows us to find for which V this index is different from 0. From the results of [7] and those quoted above we derive a formula on the degree (modulo k) of a G-equivariant map f : S(W ) \u2192 S(V ) between the spheres of representations W and V of G = C k (Prop. 3.11) (cf. [3] , [8] ).", "cite_spans": [{"start": 143, "end": 146, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 151, "end": 154, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 225, "end": 228, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 498, "end": 501, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 760, "end": 763, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 949, "end": 952, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 955, "end": 958, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Introduction", "text": "The presented material is a part of the authors' preprint [5] . In [6] it is shown that the vanishing of the Euler class of V is the only obstruction to the existence of an equivariant map from the sphere of another representation W of dimension greater than the dimension of V. This is connected with the problem of estimating the G-category of X ( [6] ) and consequently can be applied to invariant variational problems.", "cite_spans": [{"start": 58, "end": 61, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 67, "end": 70, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 350, "end": 353, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "The Euler class of a cohomology sphere", "text": "Assume that X is a compact Hausdorff G-space with finitely generated\u010cech cohomology with coefficients in a ring R.", "cite_spans": [], "ref_spans": []}, {"section": "The Euler class of a cohomology sphere", "text": "We denote by CX the cone over X, CX = X \u00d7 I/X \u00d7 {0}, with the natural action of G. Note that (CX)", "cite_spans": [], "ref_spans": []}, {"section": "The Euler class of a cohomology sphere", "text": "where EG is the universal space of G. X G , (CX) G and ((CX) G , X G ) are the total spaces of fibrations over the classifying space BG with fibers X, CX and (CX, X) respectively. Since the fibration EG \u2192 BG = EG/G is locally trivial, all the above fibrations are locally trivial. We denote (CX) G by CX G . We shall use the same letter p to denote the projections of all the above fibrations. Let f : X \u2192 Y be a G-equivariant map between two G-spaces X and Y . Clearly, f induces the map", "cite_spans": [], "ref_spans": []}, {"section": "The Euler class of a cohomology sphere", "text": ", is a G-map which maps (CX, X) into (CY, Y ), and consequently induces a map", "cite_spans": [], "ref_spans": []}, {"section": "The Euler class of a cohomology sphere", "text": "Moreover, the restrictions of f G and Cf G to the fibers X b and (CX, X) b , b \u2208 BG, are equal to f and Cf , respectively.", "cite_spans": [], "ref_spans": []}, {"section": "The Euler class of a cohomology sphere", "text": "We shall denote by j the inclusion of CX G = (CX G , \u2205) into the pair (CX G , X G ) and by s 0 : BG \u2192 CX G the map s 0 = [b, * ]. We use the same letters for restrictions of these maps.", "cite_spans": [], "ref_spans": []}, {"section": "The Euler class of a cohomology sphere", "text": "A G-space X is called a cohomology sphere of dimension n over R if X is path-connected and H * (X; R) = H * (S n ; R), H * (X; R) = H * (S n ; R).", "cite_spans": [], "ref_spans": []}, {"section": "Definition.", "text": "Assume that a G-space X is an R-cohomology sphere of dimension n. A fibration X G is said to be R-orientable if there exists a cohomology class U \u2208 H n+1 (CX G , X G ; R), called the Thom class, such that for every b \u2208 BG the restriction U |b of U to H n+1 (CX, X; R) is a fixed generator of the module H n+1 (CX, X; R) R. We say that X is orientable if the fibration X G is orientable (cf. [9] , [10] ).", "cite_spans": [{"start": 391, "end": 394, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 397, "end": 401, "text": "[10]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Definition.", "text": "This means that X is always orientable if G acts trivially on H n (X; Z) and is also orientable if G acts nontrivially on Z = H n (X; Z) but the characteristic of R equals 2.", "cite_spans": [], "ref_spans": []}, {"section": "Definition.", "text": "1.4. Corollary. Let G = C k be the cyclic group of order k. If k is odd then every cohomology sphere over Z, or Z k , is Z-orientable, respectively Z korientable. Every cohomology sphere is Z 2 -orientable.", "cite_spans": [], "ref_spans": []}, {"section": "Definition.", "text": "One can prove Proposition 1.3 by adapting the standard proof for the vector bundle ( [9] ) and using the following lemma.", "cite_spans": [{"start": 85, "end": 88, "text": "[9]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Definition.", "text": "1.6. Definition. Suppose that a G-space X is an R-orientable cohomology sphere of dimension n over R. The class", "cite_spans": [], "ref_spans": []}, {"section": "Definition.", "text": "is called the Euler class of X in R. If V is an orthogonal representation of dimension n then we denote by e(V ) \u2208 H * (BG; R) the Euler class of its sphere S(V ).", "cite_spans": [], "ref_spans": []}, {"section": "Definition.", "text": "1.7. Remark. Since ps 0 : BG \u2192 BG is the identity on BG, the homo-", "cite_spans": [], "ref_spans": []}, {"section": "Definition.", "text": "which shows that X G = \u2205 implies e(X) = 0 for any coefficient ring R.", "cite_spans": [], "ref_spans": []}, {"section": "Definition.", "text": "The following theorems can be shown by the same arguments as for the analogous statements of [7] .", "cite_spans": [{"start": 93, "end": 96, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Definition.", "text": "1.8. Theorem. Let Y be a G-space which is an R-orientable cohomology sphere of dimension n. Assume that e(Y ) = 0. Suppose that X is a G-space which is l-acyclic over R. If l \u2265 n then there is no G-equivariant map f : X \u2192 Y.", "cite_spans": [], "ref_spans": []}, {"section": "Definition.", "text": "Suppose that f : X \u2192 Y is a G-map between two cohomology spheres of dimension n over R. The degree of f in the ring R, denoted by deg R f, is defined to be the remainder of deg f modulo char R. For example, if R = Z k then deg R is the remainder of deg f modulo k.", "cite_spans": [], "ref_spans": []}, {"section": "Theorem. Suppose that G-spaces X and Y with", "text": "1.10. Remark. One can get rid of the R-orientability assumption but then we have to work with a local coefficient system on BG given by the action of", "cite_spans": [], "ref_spans": []}, {"section": "Equality of indices for the cyclic group", "text": "From now on we assume that G = C k is a cyclic group of order k > 1, and all representations considered are Z k -orientable.", "cite_spans": [], "ref_spans": []}, {"section": "Equality of indices for the cyclic group", "text": "Using the Euler class and periodicity of cohomology of C k we define a numerical index (in Z k ) of a cohomology sphere. Next we show that this index is equal to another one defined earlier by Borisovich and Izrailevich. As a matter of fact this is a simple exercise in algebraic topology, but requires a little background on the cohomology of cyclic groups, which we include for the convenience of the reader. On the other hand, this fact gives a geometric interpretation of the index, allows us to derive an explicit formula for it in the case when X is the sphere of an orthogonal representation, and allows extending the definition of the index to the case of a finite group with periodic cohomology.", "cite_spans": [], "ref_spans": []}, {"section": "Equality of indices for the cyclic group", "text": "First we recall some facts on the cohomology groups of C k with coefficients in Z k (cf. [4] ). It is known that", "cite_spans": [{"start": 89, "end": 92, "text": "[4]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Equality of indices for the cyclic group", "text": "given by multiplication by an element", "cite_spans": [], "ref_spans": []}, {"section": "Equality of indices for the cyclic group", "text": "The element u is defined as follows. Let V 1 be the one-", "cite_spans": [], "ref_spans": []}, {"section": "Equality of indices for the cyclic group", "text": "Note that e((V 1 ) k ) = k \u00b7 e(V ) = 0, and m \u00b7 e(V 1 ) = 0 if 0 < m < k, which means that u is a generator of", "cite_spans": [], "ref_spans": []}, {"section": "Equality of indices for the cyclic group", "text": "Let X be a G-space which is a Z k -orientable cohomology sphere of dimension n over Z k . We make the following choice of generators. Let \u03b4 0 \u2208 H 0 (X; Z k ) be the generator given by \u03b4 0 = c * (1), where c : X \u2192 * is the map to the point. Denote by \u03b4 0 the corresponding generator of", "cite_spans": [], "ref_spans": []}, {"section": "Equality of indices for the cyclic group", "text": "We denote by \u00b5 the corresponding generator of", "cite_spans": [], "ref_spans": []}, {"section": "Equality of indices for the cyclic group", "text": "We can assume that \u03b4 0 = \u00b5.", "cite_spans": [], "ref_spans": []}, {"section": "Equality of indices for the cyclic group", "text": "Next, let \u03bd \u2208 H 1 (BG; Z k ) be an element such that u\u03b4 0 = \u03b2(\u03bd), where \u03b2 : ", "cite_spans": [], "ref_spans": []}, {"section": "Equality of indices for the cyclic group", "text": "We can now formulate the definitions of both the indices mentioned above. First note that the Borel-Serre spectral sequence of X G with coefficients in Z k exists and converges to H * (X G ; Z k ) since X is orientable. We have E p,q", "cite_spans": [], "ref_spans": []}, {"section": "Equality of indices for the cyclic group", "text": "and therefore", "cite_spans": [], "ref_spans": []}, {"section": "Equality of indices for the cyclic group", "text": "Consequently, d n+1 is the only nontrivial differential of this sequence. Let \u03b1 : H n (X; Z k ) \u2192 H 0 (X; Z k ) be the composition of the following functorial homomorphisms:", "cite_spans": [], "ref_spans": []}, {"section": "Equality of indices for the cyclic group", "text": "where the first (resp. last) homomorphism is given by \u00b5 \u2192 \u03bd (resp. \u03be n+1 \u2192 \u03b4 0 ). The following definition is a simplified version of that of [1] since we assume X G = \u2205. If X G = \u2205 one has to use the relative cohomology of the pair (X, X G ).", "cite_spans": [{"start": 142, "end": 145, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Equality of indices for the cyclic group", "text": "2.1. Definition. Let G = C k be a cyclic group. Let X be a G-space which is a Z k -orientable cohomology sphere of dimension n over Z k . The number (modulo k) ind(X) \u2208 Z k is defined by", "cite_spans": [], "ref_spans": []}, {"section": "Equality of indices for the cyclic group", "text": "where \u03b1, \u03bd, \u03b4 0 are as above.", "cite_spans": [], "ref_spans": []}, {"section": "Definition.", "text": "Let G = C k be a cyclic group. Let X be a G-space which is a Z k -orientable cohomology sphere of dimension n over Z k . The number (modulo k) Ind(X) \u2208 Z k is defined by", "cite_spans": [], "ref_spans": []}, {"section": "Definition.", "text": "Our aim is to show the following theorem:", "cite_spans": [], "ref_spans": []}, {"section": "Definition.", "text": "2.3. Theorem. Suppose that X is a cohomology sphere of dimension n over Z k equipped with an orientation preserving action of the cyclic group C k . Assume that X G = \u2205. Then both Ind(X) and ind(X) are well defined and are equal.", "cite_spans": [], "ref_spans": []}, {"section": "Definition.", "text": "Proof. We refer the reader to Switzer's book ( [10] ). First note that the isomorphism H n (X; Z k ) \u2192 H 0 (BG; H n (X; Z k )) maps \u00b5 onto \u00b5, by its definition.", "cite_spans": [{"start": 47, "end": 51, "text": "[10]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Definition.", "text": "Set e(X) = d n+1 ( \u00b5). We have e(X) = ind(X) \u00b7 \u03be n+1 , since the homomorphism H n+1 (BG; H 0 (X; Z k )) \u2192 H 0 (BG; H 0 (X; Z k )) maps \u03be n+1 onto \u03b4 0 by its definition. On the other hand, d n+1 = \u03a8, where \u03a8 = (p * ) \u22121 j * \u03a6, and \u03a6(z) = p * (z) \u222a U is the Thom isomorphism (see [10] , Ex. 15.31). This gives The problem of equality of the two indices was posed to the authors by H. Steinlein.", "cite_spans": [{"start": 278, "end": 282, "text": "[10]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Computations of the Euler class and degree of C k -equivariant maps", "text": "First we will derive the Euler class of any orthogonal Z k -orientable representation of C k .", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Euler class and degree of C k -equivariant maps", "text": "Note that V 1 can be considered as a 2-dimensional real orthogonal repre- ", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Euler class and degree of C k -equivariant maps", "text": "Since a representation (V, : G \u2192 GL(V )) is Z k -orientable iff the map sgn det : G \u2192 {\u22121, 1} is trivial modulo k, we have the following 3.1. Fact. Every real orthogonal representation of C k is of the form", "cite_spans": [], "ref_spans": []}, {"section": "Computations of the Euler class and degree of C k -equivariant maps", "text": "As a consequence we get", "cite_spans": [], "ref_spans": []}, {"section": "Corollary. Every orientable orthogonal representation", "text": "In particular, if V G = {0} then dim R V is even and V admits a complex structure.", "cite_spans": [], "ref_spans": []}, {"section": "Corollary. Every orientable orthogonal representation", "text": "Using the facts that e(V \u2295 W ) = e(V ) \u00b7 e(W ) (cf. [3] ) and e(V i ) = i \u00b7 e(V ) = i \u00b7 u \u2208 H 2 (C k ; Z k ) (cf. e.g. [7] ), we get the following theorem:", "cite_spans": [{"start": 52, "end": 55, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 119, "end": 122, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Corollary. Every orientable orthogonal representation", "text": "The last means that e(V ) = 0 iff the integer h(V ) = i mi is not divisible by k (with the convention that 0 0 = 1 and 0 r = 0 for r > 0). In particular, e(V ) = 0 if m 0 = 0.", "cite_spans": [], "ref_spans": []}, {"section": "Now we turn to the derivation of deg", "text": "The following relative analogue of Theorem 1.9 holds for equivariant maps of spheres of orthogonal representations of G.", "cite_spans": [], "ref_spans": []}, {"section": "Now we turn to the derivation of deg", "text": ".28, for G = Z p , p prime, and [7] for any compact Lie group). Theorem 3.3 and (3.4) lead to the following theorem.", "cite_spans": [{"start": 32, "end": 35, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Now we turn to the derivation of deg", "text": "In particular, if", "cite_spans": [], "ref_spans": []}, {"section": "Now we turn to the derivation of deg", "text": "and thus depends on W and V only.", "cite_spans": [], "ref_spans": []}, {"section": "Now we turn to the derivation of deg", "text": "Note that in the special case", "cite_spans": [], "ref_spans": []}, {"section": "Now we turn to the derivation of deg", "text": "3.7. Problem. Theorem 3.5 and Corollary 3.6 give some necessary condition on W and V for the existence of a G-equivariant map f : S(W ) \u2192 S(V ) (cf. [7] for such a condition for", "cite_spans": [{"start": 149, "end": 152, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Now we turn to the derivation of deg", "text": "It is natural to ask whether it is also a sufficient condition.", "cite_spans": [], "ref_spans": []}, {"section": "Now we turn to the derivation of deg", "text": "To end this section we describe e(V ) and deg Z k f of a representation of C k and a C k -map respectively.", "cite_spans": [], "ref_spans": []}, {"section": "Now we turn to the derivation of deg", "text": "First we recall the description of the cohomology groups of C k , k = p r , with coefficients in the ring Z p l . It is known that (cf. [12] , 15.7)", "cite_spans": [{"start": 136, "end": 140, "text": "[12]", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "Now we turn to the derivation of deg", "text": "if |G| = k and A is a trivial G-module. Since G = C p r is cyclic, it is 2-periodic. Altogether, the above gives", "cite_spans": [], "ref_spans": []}, {"section": "Now we turn to the derivation of deg", "text": "and consequently, for n \u2265 0,", "cite_spans": [], "ref_spans": []}, {"section": "Now we turn to the derivation of deg", "text": "For l \u2264 r, let C p l \u2282 C p r be the canonical embedding. Then the restriction homomorphism", "cite_spans": [], "ref_spans": []}, {"section": "Now we turn to the derivation of deg", "text": ", thus its p-torsion, for p \u2208 {p 1 , . . . , p N }, is equal to", "cite_spans": [], "ref_spans": []}, {"section": "Now we turn to the derivation of deg", "text": "The functoriality of the Euler class and the above yield 3.8. Proposition. Let V be an orthogonal representation of a cyclic group", "cite_spans": [], "ref_spans": []}, {"section": "Now we turn to the derivation of deg", "text": "Then res * H (e(V )) = e(res H V ), and consequently e(V ) = 0 iff there exists p | k such that e(res H V ) = 0 in H * (BH; Z p r ).", "cite_spans": [], "ref_spans": []}, {"section": "Now we turn to the derivation of deg", "text": "Let V be an orthogonal representation of C k and p a prime dividing k. Assume that p is odd. For simplicity we use the same symbol V for the restriction of V to H = C p r \u2282 C k . Expanding V into irreducible factors with respect to H,", "cite_spans": [], "ref_spans": []}, {"section": "Now we turn to the derivation of deg", "text": "From Theorem 3.3 we have", "cite_spans": [], "ref_spans": []}, {"section": "Now we turn to the derivation of deg", "text": "(mod p r )}, and A 0 = {0}, A = {i \u2208 Z p r : (p, i) = 1}. Note also that i\u2208A i li is an invertible element of Z p r . Writing h(V ) as the product", "cite_spans": [], "ref_spans": []}, {"section": "Now we turn to the derivation of deg", "text": "and observing that for i \u2208 A \u03b1 we have i li = p \u03b1li c, where c \u2208 Z * p r , we get the following proposition.", "cite_spans": [], "ref_spans": []}, {"section": "Now we turn to the derivation of deg", "text": "We are left with the case k = 2. Every orthogonal representation of C 2 is isomorphic to", "cite_spans": [], "ref_spans": []}, {"section": "Now we turn to the derivation of deg", "text": ". Also h(V ) = 1 iff m 0 = 0. Note also that the statement of Proposition 3.9 still holds if p = 2 but V is orientable over Z p r (or equivalently over Z if r > 1). Obviously, l 0 = 0 yields e(V ) = 0. From Proposition 3.9 it follows that the Euler class e(V ) (or equivalently h(V ), cf. Theorem 3.3) is uniquely determined by all its p-torsions. Moreover, we can write down a more explicit formula for the modulo k number h(V ). As follows from the Chinese remainder theorem, h(V ) \u2208 Z k is uniquely given by {h(V ) (p) }, p | k, as the solution of the system of congruences ( * )", "cite_spans": [], "ref_spans": []}, {"section": "Now we turn to the derivation of deg", "text": "x \u2261 h(V ) (p) (mod p r ) (cf. [11] , IV, 3a). For p j | k, 1 \u2264 j \u2264 N , let q j = k/p rj j , and {q j } \u22121 be the inverse of q j in Z p r j j \u2282 Z k . Then the unique (modulo k) solution x 0 = h(V ) of ( * ) is given by the formula (3.10)", "cite_spans": [{"start": 30, "end": 34, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Now we turn to the derivation of deg", "text": "Analogously, we can describe deg Z k f by its p-torsions, ", "cite_spans": [], "ref_spans": []}, {"section": "Now we turn to the derivation of deg", "text": "(pj ) .", "cite_spans": [], "ref_spans": []}, {"section": "Now we turn to the derivation of deg", "text": "3.12. Remark. Using the relative Euler class of a pair (X, Y ) of Z kcohomology spheres one can extend our results to the relative case. In particular, if W V is a pair of orthogonal, Z k -orientable representations of C k then Ind(S(V ), S(W )) = ind(S(V ), S(W )) = e(S(V ), S(W )) is equal to e(S(W G \u22a5 )) \u2208 H * (C k ; Z k ).", "cite_spans": [], "ref_spans": []}, {"section": "Now we turn to the derivation of deg", "text": "3.13. Remark. The formula of Proposition 3.11 has been shown by Shchelokova [8] for G-equivariant maps of Z k -cohomology spheres. In her formulas the index ind(X) appears instead of the Euler classes. We wish to emphasize that in all our formulas the coefficients h(V ) are explicitly given by the representations, which is not the case in [8] .", "cite_spans": [{"start": 76, "end": 79, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 341, "end": 344, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Computation of the degree of equivariant mappings of spheres by the spectral sequence method", "authors": [{"first": "Yu", "middle": ["A"], "last": "Borisovich", "suffix": ""}, {"first": "Ya", "middle": ["A"], "last": "Izrailevich", "suffix": ""}], "year": 1973, "venue": "Voronezh. Gos. Univ. Trudy Mat. Fak", "link": null}, "BIBREF1": {"title": "On the method of A. Borel spectral sequence in the theory of equivariant mappings, Uspekhi Mat", "authors": [{"first": "Yu", "middle": ["G"], "last": "Borisovich", "suffix": ""}, {"first": "Ya", "middle": ["A"], "last": "Izrailevich", "suffix": ""}, {"first": "E", "middle": [], "last": "Shchelokova", "suffix": ""}], "year": 1977, "venue": "Nauk", "link": null}, "BIBREF2": {"title": "Transformation Groups, de Gruyter Stud", "authors": [{"first": "T", "middle": [], "last": "Tom Dieck", "suffix": ""}], "year": 1987, "venue": "", "link": null}, "BIBREF3": {"title": "A Course in Homological Algebra", "authors": [{"first": "P", "middle": [], "last": "Hilton", "suffix": ""}, {"first": "S", "middle": [], "last": "Stammbach", "suffix": ""}], "year": 1971, "venue": "Graduate Texts in Math", "link": "122854219"}, "BIBREF4": {"title": "Equivariant maps between cohomology spheres, preprint, Forschungsschwerpunkt Geometrie, Univ. 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Zh", "link": null}, "BIBREF8": {"title": "Algebraic Topology", "authors": [{"first": "E", "middle": [], "last": "Spanier", "suffix": ""}], "year": 1966, "venue": "", "link": null}, "BIBREF9": {"title": "Algebraic Topology-Homotopy and Homology", "authors": [{"first": "R", "middle": [], "last": "Switzer", "suffix": ""}], "year": 1975, "venue": "Grundlehren Math. Wiss", "link": "118158692"}, "BIBREF10": {"title": "Elements of Number Theory", "authors": [{"first": "I", "middle": [], "last": "Vinogradov", "suffix": ""}], "year": 1954, "venue": "", "link": "117851553"}, "BIBREF11": {"title": "Cohomology of Groups", "authors": [{"first": "E", "middle": [], "last": "Weiss", "suffix": ""}], "year": 1969, "venue": "", "link": "117938133"}, "BIBREF12": {"title": "Marek Izydorek", "authors": [], "year": "", "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "= \u00b5 and this is a ring generator of H 0 (BG; Z k ) Z kBG; Z k ). This proves the theorem.", "type": "figure"}, "FIGREF1": {"text": "its ith tensor power (over C) and by V 0 the 1-dimensional (real) trivial representation of G. If k = 2m, then for", "type": "figure"}, "FIGREF2": {"text": ", let J 1 = {1 \u2264 j \u2264 N : e(W G \u22a5 ) (pj ) = 0} and J 2 = {1 \u2264 j \u2264 N : e(W G \u22a5 ) (pj ) = 0}. Combining 3.3, 3.5 and 3.9 we get the following statement.", "type": "figure"}, "FIGREF3": {"text": "Proposition. Let W and V be Z k -orientable orthogonal representa- tions of a cyclic group G = C k , where k =. Assume that dim W = dim V and dim W G = dim V G . Then for any G-equivariant map f : S(W ) \u2192 S(V ), deg Z k f is uniquely determined by deg Z k f G , up to the ideal I", "type": "figure"}, "TABREF0": {"text": "the Bockstein homomorphism. Since \u03b2 is an isomorphism, \u03bd is a generator. Finally, let \u03be i be a generator of H i (BG; Z k )", "type": "table"}}}
{"paper_id": "17784201", "_pdf_hash": "2a03301dcd8f51cd2887068ebf60cf45dbe94d73", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Object Oriented Analysis and Design with Applications", "authors": [], "year": 1994, "venue": "", "link": "60541485"}}, "ref_entries": {}}
{"paper_id": "17784225", "_pdf_hash": "a2410a95f905dfbd05c8a4873012e9cd0942c76e", "abstract": [], "body_text": [{"section": "Introduction", "text": "Hemangiopericytoma is a highly vascular tumor arising from pericytes. This tumor occasionally shows malignant behaviors such as local recurrence or distant metastasis [1] . Brain tumor manifesting as intracranial hemorrhage is a wellknown phenomenon [2] , but hemangiopericytoma is rarely associated with hemorrhage in either central nervous system or extracranial sites [3] [4] [5] . We encountered an extremely rare case with recurrent infratentorial hemangiopericytoma presenting as life-threatening massive intracranial hemorrhage.", "cite_spans": [{"start": 167, "end": 170, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 250, "end": 253, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 371, "end": 374, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 375, "end": 378, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 379, "end": 382, "text": "[5]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Case Report", "text": "A 42-year-old man presented with morning headache. Magnetic resonance imaging (MRI) showed the mass as hypointense on T1-weighted imaging and hyperintense on T2-weighted imaging, with homogenous enhancement on gadolinium-enhanced imaging ( Figure 1) . Cerebral angiography demonstrated that the tumor was fed by the ascending pharyngeal and occipital arteries (Figures 2(a)-2(c) ). Surgery was performed via a retrosigmoid lateral suboccipital approach. Gross total removal of the tumor was performed and the dural attachment was cauterized. The tumor was highly vascular, with elastic, hard, and soft reddish components. Histological examination showed that the tumor was densely cellular and was composed of oval-shaped cells with vascular spaces (Figure 3(a) ). A rich network of reticulin fibers was seen between the tumor cells and vascular spaces (Figure 3(b) ). MIB-1 index was 3%. The postoperative course was uneventful. Postoperative MRI showed total removal of the tumor, and the patient was discharged 1 week postoperatively. Eight months later, follow-up MRI demonstrated that no recurrence was apparent except enhancing lesion on the convexity dura at the previous excision site that is retrospectively considered to be suspicious of a recurrence ( Figure 4 ). Although the neurological status of the patient had been intact at that time, nine months after the final follow-up MRI, the patient presented with sudden onset of headache and generalized convulsions, followed by cardiorespiratory arrest. Computed tomography (CT) revealed a huge hematoma in the resected tumor cavity that resulted in cerebellar tonsillar herniation ( Figure 5 ); therefore, emergent craniotomy was performed. The hematoma was located in the subdural space and contained soft, reddish extra-axial tumor tissue with abundant vasculature. Histological examination showed a highly cellular tumor composed of spindle cells surrounding elongated blood vessels with a \"staghorn\" appearance ( Figure 6 ). MIB-1 index was 5%. Postoperatively, the clinical course was dismal, and two weeks postoperatively, a clinical diagnosis of brain death was confirmed. Autopsy was not performed.", "cite_spans": [], "ref_spans": [{"start": 1979, "end": 1987, "text": "Figure 6", "ref_id": "FIGREF2"}]}, {"section": "Discussion", "text": "Sudden death from intracranial tumors is often associated with subarachnoid and/or cerebral hemorrhage from the tumor or intratumoral hemorrhage. Wakai et al. reported that hemorrhage from brain tumors was confirmed either clinically, surgically, or at autopsy in 45 of 1550 cases of brain tumors (2.9%) other than pituitary adenoma [2] . Hemangiopericytoma was not included in that series. According to the literature, among cases of sudden unexpected death arising from primary brain tumor, colloid cysts of the third ventricle are the most frequent, followed by gliomas, ependymomas, and meningiomas [6] [7] [8] [9] [10] . However, only three cases of sudden unexpected death arising from intracranial hemangiopericytoma have been reported, including the present case (Table 1 ) [4, 6, 11] . Brain tumor hemorrhage is caused by endothelial proliferation, which leads to vascular obliteration, vessel compression, and/or distortion as a result of rapid tumor growth resulting in distal necrosis and an increased venous pressure associated with increased intracranial pressure. In hemangiopericytoma, dilated vessels with thin walls including erosion, distortion, and/or distension of the blood vessels caused by tumor growth, in addition to intense vascularity of the tumor and changes in the structure of the vessel walls, are considered to be possible sources of hemorrhage. Bleeding might occur from the dilated tumor vessels near the dural attachment. In addition, coagulatory changes or fragile malformed tumor microvessels induced by radiotherapy may represent a cause of bleeding in some cases [12] . Weakening or malformation of tumor vessels may also be induced by radiotherapy, resulting in bleeding. Mena et al. reported that 22 of 94 intracranial hemangiopericytoma cases (23.4%) exhibited intratumoral hemorrhage [13] . Cervoni et al. summarized and reviewed nine cases of meningeal hemangiopericytoma associated with subarachnoid [5] , subdural [3, 14] , intratumoral [12] , and intracerebral hemorrhage [11, 15, 16] . All cases involved supratentorial lesions. According to the report from Maruya et al. [11] , most patients with meningeal hemangiopericytoma associated with intracranial hemorrhage were men under 60 years old. Massive intracranial hemorrhage, especially from infratentorial lesions, resulted in rapid neurological deterioration and the need for emergent surgery. In the present case, the patient had already undergone craniotomy for total resection of an infratentorial hemangiopericytoma without adjuvant therapy such as radiation, differing from previously reported cases. Surprisingly, the tumor recurred at the same site with life-threatening massive intratumoral hemorrhage only 17 months postoperatively, representing a first report according to the literature. The cause of such rapid progression of recurrent hemangiopericytoma remains unclear. We speculated the pathogenesis as follows. Dilated tumor vessels at the dural attachment were only cauterized in the first operation, and residual tumor cells may have remained. Residual tumor cells at the dural attachment would then have rapidly progressed, and the tumor vessels were involved, resulting in fragile vessels.", "cite_spans": [{"start": 333, "end": 336, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 603, "end": 606, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 607, "end": 610, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 611, "end": 614, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 615, "end": 618, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 619, "end": 623, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 782, "end": 785, "text": "[4,", "ref_id": "BIBREF3"}, {"start": 786, "end": 788, "text": "6,", "ref_id": "BIBREF5"}, {"start": 789, "end": 792, "text": "11]", "ref_id": "BIBREF10"}, {"start": 1603, "end": 1607, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 1828, "end": 1832, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 1946, "end": 1949, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 1961, "end": 1964, "text": "[3,", "ref_id": "BIBREF2"}, {"start": 1965, "end": 1968, "text": "14]", "ref_id": "BIBREF13"}, {"start": 1984, "end": 1988, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 2020, "end": 2024, "text": "[11,", "ref_id": "BIBREF10"}, {"start": 2025, "end": 2028, "text": "15,", "ref_id": "BIBREF14"}, {"start": 2029, "end": 2032, "text": "16]", "ref_id": "BIBREF15"}, {"start": 2121, "end": 2125, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": [{"start": 771, "end": 779, "text": "(Table 1", "ref_id": "TABREF0"}]}, {"section": "Discussion", "text": "Postoperative radiotherapy is generally recommended for hemangiopericytoma, particularly if the tumor is not removed completely. Several retrospective studies have demonstrated that radiotherapy after surgery is beneficial for patients with hemangiopericytomas [17] [18] [19] [20] . In those studies, the mean local recurrence rate of patients with postoperative adjuvant radiotherapy was less than those without radiotherapy, suggesting that surgical removal followed by external radiotherapy reduced the risk of local recurrence. However, it was not demonstrated that postoperative radiotherapy protected against neuroaxis metastasis or peripheral metastasis [18] . Ghia et al. described that the extent of surgery and the use of adjuvant radiotherapy did not have statistically significant effects on overall survival [19, 20] .", "cite_spans": [{"start": 261, "end": 265, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 266, "end": 270, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 271, "end": 275, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 276, "end": 280, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 661, "end": 665, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 821, "end": 825, "text": "[19,", "ref_id": "BIBREF18"}, {"start": 826, "end": 829, "text": "20]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "Discussion", "text": "In the present case, we thought that gross total removal of the tumor had been successfully achieved; therefore, postoperative radiotherapy was not performed. However, the growth of the recurrent tumor in the present case might be generated from the enhancing lesion on the convexity dura at excision site, which grew more rapid than we had been afraid. Previous reports have described that mean time to local recurrence of hemangiopericytomas after initial surgery was between 40.5 to 104 months [20] [21] [22] [23] . J\u00e4\u00e4skel\u00e4inen et al. described hemangiopericytomas attached to sinuses, occipitally located, and that bled profusely at operation had a higher risk of recurrence and metastasis [23] .", "cite_spans": [{"start": 497, "end": 501, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 502, "end": 506, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 507, "end": 511, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 512, "end": 516, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 695, "end": 699, "text": "[23]", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "Discussion", "text": "In the present case, MIB-1 index in both initial and recurrent hemangiopericytomas was 3% and 5%, respectively, suggesting growth potential and suspicious recurrence of the tumor. In addition, regardless the extent of resection, patients with hemangiopericytomas have a high risk of developing tumor recurrence; thus, we should have considered postoperative radiotherapy for suspicious residual tumor on the convexity dura following the initial operation.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Sudden death from an intracranial tumor is often associated with a rapid increase in intracranial pressure as a result of hemorrhage from the tumor or acute obstructive hydrocephalus caused by obstruction of the flow of cerebrospinal fluid. In infratentorial tumors, direct involvement of the respiratory and cardiac centers is also postulated to be a further cause of sudden death [7] . Postoperative radiotherapy might be necessary, even if total removal of the tumor appears to have been achieved.", "cite_spans": [{"start": 382, "end": 385, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Discussion", "text": "In conclusion, recurrent infratentorial hemangiopericytoma manifesting as intracranial hemorrhage is quite rare but carries a risk of life-threatening massive bleeding. 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Case report and review of literature", "authors": [{"first": "Z", "middle": ["T"], "last": "Feldman", "suffix": ""}, {"first": "E", "middle": [], "last": "Reichenthal", "suffix": ""}, {"first": "G", "middle": [], "last": "Zucker", "suffix": ""}, {"first": "M", "middle": [], "last": "Greiff", "suffix": ""}], "year": 1991, "venue": "Acta Neurochirurgica", "link": "22879623"}, "BIBREF15": {"title": "Subarachnoid hemorrhage in infancy due to brain tumor", "authors": [{"first": "A", "middle": ["R"], "last": "Wyler", "suffix": ""}, {"first": "J", "middle": [], "last": "Hered", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Smith", "suffix": ""}, {"first": "J", "middle": ["D"], "last": "Loeser", "suffix": ""}], "year": 1973, "venue": "Archives of Neurology", "link": "34468521"}, "BIBREF16": {"title": "Meningeal hemangiopericytoma: defining the role for radiation therapy", "authors": [{"first": "K", "middle": ["T"], "last": "Bastin", "suffix": ""}, {"first": "M", "middle": ["P"], "last": "Mehta", "suffix": ""}], "year": 1992, "venue": "Journal of NeuroOncology", "link": "24360061"}, "BIBREF17": {"title": "Meningeal hemangiopericytoma: a retrospective study of 21 patients with special review of postoperative external radiotherapy", "authors": [{"first": "H", "middle": [], "last": "Dufour", "suffix": ""}, {"first": "P", "middle": [], "last": "M\u00e9tellus", "suffix": ""}, {"first": "S", "middle": [], "last": "Fuentes", "suffix": ""}], "year": 2001, "venue": "Neurosurgery", "link": "11791226"}, "BIBREF18": {"title": "Intracranial hemangiopericytoma: patterns of failure and the role of radiation therapy", "authors": [{"first": "A", "middle": ["J"], "last": "Ghia", "suffix": ""}, {"first": "E", "middle": ["L"], "last": "Chang", "suffix": ""}, {"first": "P", "middle": ["K"], "last": "Allen", "suffix": ""}], "year": 2013, "venue": "Neurosurgery", "link": null}, "BIBREF19": {"title": "Intracranial meningeal hemangiopericytoma: the role of radiotherapy: report of 29 cases and review of the literature", "authors": [{"first": "S", "middle": [], "last": "Soyuer", "suffix": ""}, {"first": "E", "middle": ["L"], "last": "Chang", "suffix": ""}, {"first": "U", "middle": [], "last": "Selek", "suffix": ""}, {"first": "I", "middle": ["E"], "last": "Mccutcheon", "suffix": ""}, {"first": "M", "middle": ["H"], "last": "Maor", "suffix": ""}], "year": 2004, "venue": "Cancer", "link": "27398358"}, "BIBREF20": {"title": "Meningeal hemangiopericytoma: histopathological features, treatment, and long-term follow-up of 44 cases", "authors": [{"first": "B", "middle": ["L"], "last": "Guthrie", "suffix": ""}, {"first": "M", "middle": ["J"], "last": "Ebersold", "suffix": ""}, {"first": "B", "middle": ["W"], "last": "Scheithauer", "suffix": ""}, {"first": "E", "middle": ["G"], "last": "Shaw", "suffix": ""}], "year": 1989, "venue": "Neurosurgery", "link": "29292137"}, "BIBREF21": {"title": "Meningeal hemangiopericytomas: long-term outcome and biological behavior", "authors": [{"first": "J", "middle": ["H"], "last": "Kim", "suffix": ""}, {"first": "H.-W", "middle": [], "last": "Jung", "suffix": ""}, {"first": "Y.-S", "middle": [], "last": "Kim", "suffix": ""}], "year": 2003, "venue": "Surgical Neurology", "link": "7196546"}, "BIBREF22": {"title": "Intracranial hemangiopericytoma: radiology, surgery, radiotherapy, and outcome in 21 patients", "authors": [{"first": "J", "middle": [], "last": "J\u00e4\u00e4skel\u00e4inen", "suffix": ""}, {"first": "A", "middle": [], "last": "Servo", "suffix": ""}, {"first": "M", "middle": [], "last": "Haltia", "suffix": ""}, {"first": "T", "middle": [], "last": "Wahlstr\u00f6m", "suffix": ""}, {"first": "S", "middle": [], "last": "Valtonen", "suffix": ""}], "year": 1985, "venue": "Surgical Neurology", "link": "2348472"}}, "ref_entries": {"FIGREF0": {"text": "Figure 1: Preoperative T1-weighted plain (a), gadolinium-enhanced (b), and T2-weighted (c) magnetic resonance imaging showing the infratentorial extra-axial tumor with perifocal edema. Note that the tumor shows strong, homogeneous enhancement.", "type": "figure"}, "FIGREF1": {"text": "Figure 4: Postoperative T1-weighted plain (a), gadolinium-enhanced (b), and T2-weighted (c) MRI with contrast medium suggesting complete removal of the tumor without recurrence at 9 months postoperatively.", "type": "figure"}, "FIGREF2": {"text": "Figure 6: Photomicrographs revealing a highly cellular tumor consisting of spindle cells surrounding elongated blood vessels with a \"staghorn\" appearance ((a): \u00d7200). A rich network of reticulin fibers is present among the tumor cells ((b): \u00d7200).", "type": "figure"}, "TABREF0": {"text": "Age", "type": "table"}}}
{"paper_id": "17784284", "_pdf_hash": "0b171bd076e25545f8cb54f282305aeb9821e254", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Code division multiple access techniques in optical fiber networks-Part I: Fundamental principles", "authors": [{"first": "J", "middle": ["A"], "last": "Salehi", "suffix": ""}], "year": 1989, "venue": "IEEE Trans. Commun", "link": "42957579"}, "BIBREF1": {"title": "Spread Spectrum Fiber-optic Local Area Network Using Optical Processing", "authors": [{"first": "P", "middle": ["R"], "last": "Prucnal", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Santoro", "suffix": ""}, {"first": "T", "middle": ["R"], "last": "Fan", "suffix": ""}], "year": 1986, "venue": "J. Lightwave Technol", "link": "110304544"}, "BIBREF2": {"title": "Optical code-division-multiplexed systems based on spectral encoding of noncoherent sources", "authors": [{"first": "M", "middle": [], "last": "Kavehrad", "suffix": ""}, {"first": "M", "middle": [], "last": "Zaccarin", "suffix": ""}], "year": 1995, "venue": "J. Lightwave Technol", "link": "18694927"}, "BIBREF3": {"title": "Experimental comparison of coherent versus incoherent sources in a four-user \u03bb-t OCDMA system at 1.25Gb/s, IEEE Photon", "authors": [{"first": "S", "middle": [], "last": "Ayotte", "suffix": ""}, {"first": "L", "middle": ["A"], "last": "Rusch", "suffix": ""}], "year": 2005, "venue": "Tech. Lett", "link": null}, "BIBREF4": {"title": "Spectral efficiency analysis of OCDMA systems", "authors": [{"first": "H", "middle": [], "last": "Yan", "suffix": ""}, {"first": "K", "middle": [], "last": "Qiu", "suffix": ""}, {"first": "Y", "middle": [], "last": "Ling", "suffix": ""}], "year": 2009, "venue": "Chin. Opt. Lett", "link": "62188738"}, "BIBREF5": {"title": "Spectral Efficiency of OCDMA Systems with Coherent Pulsed Sources", "authors": [{"first": "M", "middle": [], "last": "Rochette", "suffix": ""}, {"first": "L", "middle": ["A"], "last": "Rusch", "suffix": ""}], "year": 2005, "venue": "J. Lightwave Technol", "link": "22299454"}, "BIBREF6": {"title": "Analysis of the spectral efficiency of frequency encoded OCDMA systems with incoherent sources", "authors": [{"first": "M", "middle": [], "last": "Rochette", "suffix": ""}, {"first": "S", "middle": [], "last": "Ayotte", "suffix": ""}, {"first": "L", "middle": ["A"], "last": "Rusch", "suffix": ""}], "year": 2005, "venue": "J. Lightwave Technol", "link": "15501896"}}, "ref_entries": {}}
{"paper_id": "17784377", "_pdf_hash": "4ff0cd1a51d926f99ab291f9a90fe03280afdb61", "abstract": [{"section": "Abstract", "text": "In previous articles, a magnetic pseudodifferential calculus and a family of C * -algebras associated with twisted dynamical systems were introduced and the connections between them have been established. We extend this formalism to symbol classes of H\u00f6rmander type with an x-behavior modelized by an abelian C * -algebra. Some of these classes generate C * -algebras associated with the twisted dynamical system. We show the relevance of these classes to the spectral analysis of pseudodifferential operators with anisotropic symbols and magnetic fields.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "In previous works [25, 27, 13] a twisted form of the usual Weyl calculus and of the corresponding crossed product C * -algebras has been introduced. We refer to [23, 29, 15, 16, 22] for related works. The twisting is defined by a 2-cocycle on the group R n with values in the unitary group of a function algebra. The calculus is meant to model the family of observables of a physical system consisting in a spin-less particle moving in the euclidean space R n under the influence of a variable magnetic field B. It goes without saying that the standard theory is recovered for B = 0. The 2-cocycle is defined by fluxes of the magnetic field through simplexes and it corresponds to a modification of the canonical symplectic structure of the phase space R 2n by a magnetic contribution. Actually the modified symplectic form defines a new Poisson algebra structure on the smooth classical observables on R 2n and it was shown in [26] that the twisted form of the Weyl calculus constitutes a strict deformation quantization in the sense of Rieffel [17, 35] of the usual Poisson algebra.", "cite_spans": [{"start": 18, "end": 22, "text": "[25,", "ref_id": "BIBREF24"}, {"start": 23, "end": 26, "text": "27,", "ref_id": "BIBREF26"}, {"start": 27, "end": 30, "text": "13]", "ref_id": "BIBREF12"}, {"start": 161, "end": 165, "text": "[23,", "ref_id": "BIBREF22"}, {"start": 166, "end": 169, "text": "29,", "ref_id": "BIBREF28"}, {"start": 170, "end": 173, "text": "15,", "ref_id": "BIBREF14"}, {"start": 174, "end": 177, "text": "16,", "ref_id": "BIBREF15"}, {"start": 178, "end": 181, "text": "22]", "ref_id": "BIBREF21"}, {"start": 928, "end": 932, "text": "[26]", "ref_id": "BIBREF25"}, {"start": 1046, "end": 1050, "text": "[17,", "ref_id": "BIBREF16"}, {"start": 1051, "end": 1054, "text": "35]", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "Introduction", "text": "A basic requirement for a magnetic pseudodifferential theory is gauge covariance. A magnetic field B being a closed 2-form in R n , it can be generated in many equivalent ways by derivatives of 1-forms, traditionally named vector potentials. These vector potentials are involved in the process of prescribing operators (intended to represent quantum observables) to classical functions defined on the phase space. Different equivalent choices should lead to unitarily equivalent operators, and this is indeed the case for our formalism, see Section 2.2, in contrast to previous wrong attempts.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Most often the usual pseudodifferential calculus is studied in the framework of the H\u00f6rmander symbol classes S m \u03c1,\u03b4 (R 2n ). The necessary magnetic adaptations, nontrivial because of the bad behavior of the derivatives of the magnetic flux, were performed in [13] . Among others, the following results were obtained: good composition properties, asymptotic developments, an extension of the Calderon-Vaillancourt result on L 2 -boundedness, selfadjointness of elliptic operators on magnetic Sobolev spaces and positivity properties. A short recall of the magnetic pseudodifferential theory may be found in Sections 2.1 and 2.2.", "cite_spans": [{"start": 260, "end": 264, "text": "[13]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Introduction", "text": "Beside the order of a pseudodifferential operator defined by a symbol f , another useful information is the properties of the coefficients, i.e. the behavior of the function x \u2192 f (x, \u03be) at fixed \u03be. One possible way to take them into account is to confine them to some abelian C * -algebra A of functions on R n . In the framework of the standard calculus this was performed in a variety of situations, with a special emphasis on almost periodic functions, and with various purposes. We cite for example [3, 4, 5, 6, 36] . In Section 2 we are going to investigate the corresponding magnetic case, insisting on composition properties. We also use this occasion to improve previous results on asymptotic developments.", "cite_spans": [{"start": 504, "end": 507, "text": "[3,", "ref_id": "BIBREF2"}, {"start": 508, "end": 510, "text": "4,", "ref_id": "BIBREF3"}, {"start": 511, "end": 513, "text": "5,", "ref_id": "BIBREF4"}, {"start": 517, "end": 520, "text": "36]", "ref_id": "BIBREF35"}], "ref_spans": []}, {"section": "Introduction", "text": "As soon as the symbol spaces with coefficients in A are shown to possess good properties, they can be used to define non-commutative C * -algebras composed of distributions in phase-space. Such algebras are investigated in Section 3.1. Then, a partial Fourier transformation makes the connection with the approach of [27] recalled in Section 3.2. In that reference, relying on general constructions of [31, 32] , magnetic C * -algebras were introduced in relation with twisted C * -dynamical systems. These C * -algebras are called twisted crossed products and can be defined by a universal property with respect to covariant representations. And once again the 2-cocycle obtained by the flux of the magnetic field is the main relevant object, defining both the twisted action and the algebraico-topological structure of the non-commutative C * -algebras. Through various representations, these algebras will become concrete C * -algebras of magnetic pseudodifferential operators in natural Hilbert spaces.", "cite_spans": [{"start": 317, "end": 321, "text": "[27]", "ref_id": "BIBREF26"}, {"start": 402, "end": 406, "text": "[31,", "ref_id": "BIBREF30"}, {"start": 407, "end": 410, "text": "32]", "ref_id": "BIBREF31"}], "ref_spans": []}, {"section": "Introduction", "text": "The non-commutative C * -algebras composed of distributions in phase-space can be generated by Avalued symbols of strictly negative orders, as shown in Section 3.1. But having in mind applications to the spectral analysis of unbounded operators, we undertake in Section 3.4 the task to relate positive order symbols to these algebras. The key ingredient for that purpose is to understand inversion with respect to the magnetic composition law, or equivalently, to understand inversion of magnetic pseudodifferential operators. This is the subject of Section 3.3. Among others we show that the inverse of a real elliptic symbol of order m > 0 with coefficients in A is a symbol of order \u2212m, also with coefficients in A. Combined with results of the previous section, this implies that such a symbol defines an affiliated observable, meaning that its C 0 -functional calculus is contained in the twisted crossed product C * -algebra. We also obtain that the A-valued symbols of order 0 form a \u03a8 * -algebra, and in particular that this algebra is spectrally invariant. These results on inversion rely at a crucial step on a theorem from [14] . This theorem, which characterizes magnetic pseudodifferential operators of suitable classes by their behaviors under successive commutators, is an extension of classical results of Beals and Bony. Since [14] is not yet published and since the main result on inversion will be used in the following section, we give an independent proof for the affiliation in an Appendix, extending the approach of [28] .", "cite_spans": [{"start": 1134, "end": 1138, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 1344, "end": 1348, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 1539, "end": 1543, "text": "[28]", "ref_id": "BIBREF27"}], "ref_spans": []}, {"section": "Introduction", "text": "Our main motivation was spectral analysis, and the last section is devoted to this subject. Even for the simplest magnetic differential operators the determination of its spectrum involves a rather high degree of complexity. The main reason is that even though the magnetic field is the relevant physical object, the operators are defined by a vector potential. Such vector potentials are not unique and one problem is to show the independence of the result of a particular choice. Another difficulty is that usually any vector potential defining a magnetic field will be ill-behaved compared to the magnetic field itself. For example, bounded magnetic fields might not admit any bounded vector potential, certain periodic magnetic fields are only defined by non-periodic vector potentials, etc. And on the top of all that, general pseudodifferential operators with magnetic fields were even not correctly defined a couple of years ago.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "So Section 4 is devoted to spectral theory. We investigate the essential spectrum of magnetic pseudodifferential operators affiliated to the non-commutative algebras mentioned before. The key of this approach is the use of the structure of the twisted crossed products; see [7, 8, 9, 24, 34] for related approaches in the absence of magnetic field, and also [12, 18] for a description of the essential spectrum for certain classes of magnetic fields. We will show how to find information on the essential spectrum in the quasi-orbit structure of the Gelfand spectrum of the C * -algebra A. In particular, this allows us to express in Section 4.2 the essential spectrum of any elliptic magnetic pseudodifferential operators defined by a symbol of positive order and with coefficient in A in terms of simpler operators that are defined on the quasi-orbits at infinity. For example, our approach covers generalized Schr\u00f6dinger operators of the form h(\u2212i\u2202 \u2212 A) + V , with h a real elliptic symbol of positive order, and with V and the components of the magnetic field B in some smooth subalgebra of A. But more generally, our approach works for any operator of the form f (\u2212i\u2202 \u2212 A, X), once suitably defined, for f a real and elliptic symbol of positive order with coefficients in A. We stress that there is no condition on A, only the components of the magnetic fields have to satisfy some smoothness conditions and have to belong to A. We also emphasize that even in the degenerate case B = 0, we have not been able to locate in the literature a procedure for the calculation of the essential spectrum of such general pseudodifferential operators with coefficients in some abelian C * -algebra A. It is rather obvious that the formalism and techniques of this article can be further developed and extended. More general twisted actions can be taken into account, cf. [35] for the untwisted case. This would open the way towards applications to random magnetic operators, which is the topic of a forthcoming article. Our approach might also be relevant for index theory. On the other hand, the groupoid setting has shown its role in pseudodifferential theory, in C * -algebraic spectral analysis and in quantization; we cite for example [17, 20, 21, 30] . Groupoids with 2-cocycles and associated C * -algebras are available [33] , but they are still largely ignored in connection with applications. Extending the pseudodifferential calculus and the spectral theory to such a framework would be an interesting topic.", "cite_spans": [{"start": 274, "end": 277, "text": "[7,", "ref_id": "BIBREF6"}, {"start": 278, "end": 280, "text": "8,", "ref_id": "BIBREF7"}, {"start": 281, "end": 283, "text": "9,", "ref_id": "BIBREF8"}, {"start": 284, "end": 287, "text": "24,", "ref_id": "BIBREF23"}, {"start": 288, "end": 291, "text": "34]", "ref_id": "BIBREF33"}, {"start": 358, "end": 362, "text": "[12,", "ref_id": "BIBREF11"}, {"start": 363, "end": 366, "text": "18]", "ref_id": "BIBREF17"}, {"start": 1865, "end": 1869, "text": "[35]", "ref_id": "BIBREF34"}, {"start": 2234, "end": 2238, "text": "[17,", "ref_id": "BIBREF16"}, {"start": 2239, "end": 2242, "text": "20,", "ref_id": "BIBREF19"}, {"start": 2243, "end": 2246, "text": "21,", "ref_id": "BIBREF20"}, {"start": 2322, "end": 2326, "text": "[33]", "ref_id": "BIBREF32"}], "ref_spans": []}, {"section": "Introduction", "text": "Acknowledgements: M. M\u0203ntoiu is partially supported by N\u00facleo Cient\u00edfico ICM P07-027-F \"Mathematical Theory of Quantum and Classical Magnetic Systems\" and by the Chilean Science Fundation Fondecyt under the Grant 1085162. S. Richard is supported by the Swiss National Science Foundation. Discussions with V. Iftimie and R. Purice were one of our sources of inspiration.", "cite_spans": [], "ref_spans": []}, {"section": "Pseudodifferential theory 2.1 The magnetic Moyal algebra", "text": "We recall the structure and the basic properties of the magnetic Weyl calculus in a variable magnetic field. The main references are [25] and [13] , which contain further details and technical developments.", "cite_spans": [{"start": 133, "end": 137, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 142, "end": 146, "text": "[13]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Pseudodifferential theory 2.1 The magnetic Moyal algebra", "text": "Let X := R n and let us denote by X * the dual space of X ; the duality is given by X \u00d7 X * \u220b (x, \u03be) \u2192 x \u00b7 \u03be. The Lebesgue measures on X and X * are normalized in such a way that the Fourier transform (F f )(\u03be) =", "cite_spans": [], "ref_spans": []}, {"section": "Pseudodifferential theory 2.1 The magnetic Moyal algebra", "text": "The phase space is \u039e := T * X \u2261 X \u00d7 X * and the notations X = (x, \u03be), Y = (y, \u03b7) and Z = (z, \u03b6) will be systematically used for its points. If no magnetic field is present, the standard symplectic form on \u039e is given by", "cite_spans": [], "ref_spans": []}, {"section": "Pseudodifferential theory 2.1 The magnetic Moyal algebra", "text": "The magnetic field is described by a closed 2-form B on X . In the standard coordinates system on X it is represented by a function taking real and antisymmetric matrix values {B jk }, with j, k \u2208 {1, . . . , n}, and verifying the relation \u2202 j B kl + \u2202 k B lj + \u2202 l B jk = 0. We shall always assume that the components of the magnetic fields are smooth functions, and additional requirements will be imposed when needed.", "cite_spans": [], "ref_spans": []}, {"section": "Pseudodifferential theory 2.1 The magnetic Moyal algebra", "text": "Classically, the effect of B is to change the geometry of phase space, by adding an extra term to (2.1):", "cite_spans": [], "ref_spans": []}, {"section": "Pseudodifferential theory 2.1 The magnetic Moyal algebra", "text": ", where \u03c0 * is the pull-back associated to the cotangent bundle projection \u03c0 : \u039e \u2192 X . In coordinates one has", "cite_spans": [], "ref_spans": []}, {"section": "Pseudodifferential theory 2.1 The magnetic Moyal algebra", "text": "Associated with this new symplectic form, one assigns the Poisson bracket acting on elements f, g \u2208 C \u221e (\u039e):", "cite_spans": [], "ref_spans": []}, {"section": "Pseudodifferential theory 2.1 The magnetic Moyal algebra", "text": "It is a standard fact that C \u221e (\u039e; R) endowed with {\u00b7, \u00b7} B and with the pointwise multiplication is a Poisson algebra, i.e. C \u221e (\u039e; R) is a real abelian algebra and {\u00b7, \u00b7} B :", "cite_spans": [], "ref_spans": []}, {"section": "Pseudodifferential theory 2.1 The magnetic Moyal algebra", "text": "an antisymmetric bilinear composition law that satisfies the Jacobi identity and is a derivation with respect to the usual product. In the quantum picture, the magnetic field B comes into play in defining a new composition law in terms of its fluxes through triangles. For x, y, z \u2208 X , let x, y, z denote the triangle in X of vertices x, y and z and let us set \u0393 B ( x, y, z ) :=", "cite_spans": [], "ref_spans": []}, {"section": "Pseudodifferential theory 2.1 The magnetic Moyal algebra", "text": "x,y,z B for the flux of B through this triangle (integration of a 2-form through a 2-simplex). With this notation, one defines the Moyal product by the formula", "cite_spans": [], "ref_spans": []}, {"section": "Pseudodifferential theory 2.1 The magnetic Moyal algebra", "text": "for f, g : \u039e \u2192 C. For B = 0 it coincides with the Weyl composition of symbols in pseudodifferential theory. The composition law \u266f B provides an intrinsic algebraic structure underlying the multiplication of the magnetic pseudodifferential operators that are going to be defined below.", "cite_spans": [], "ref_spans": []}, {"section": "Pseudodifferential theory 2.1 The magnetic Moyal algebra", "text": "The integrals defining f \u266f B g are absolutely convergent only for a restricted class of symbols. In order to deal with more general distributions, an extension by duality was proposed in [26] under an additional condition on the magnetic field. So let us assume that the components of the magnetic field are C \u221e pol (X )-functions, i.e. they are indefinitely derivable and each derivative is polynomially bounded, and let S(\u039e) denote the Schwartz space on \u039e. Its dual is denoted by S \u2032 (\u039e). Then S(\u039e) is stable under \u266f B , and the product can be extended to maps ", "cite_spans": [{"start": 187, "end": 191, "text": "[26]", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "Pseudodifferential theory 2.1 The magnetic Moyal algebra", "text": "It is well known that S ", "cite_spans": [], "ref_spans": []}, {"section": "Pseudodifferential theory 2.1 The magnetic Moyal algebra", "text": "Remark 2.2. The product formula (2.3) has been proved in [13, Thm. 2.2] under the assumption 0 \u2264 \u03b4 < \u03c1 \u2264 1. But the special case \u03c1 = \u03b4 = 0 is a consequence of the statement contained in [14] .", "cite_spans": [{"start": 57, "end": 61, "text": "[13,", "ref_id": "BIBREF12"}, {"start": 186, "end": 190, "text": "[14]", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Magnetic pseudodifferential operators", "text": "Being a closed 2-form in X , the magnetic field can be written as B = dA for some 1-form A called vector potential. Any equivalent choice A \u2032 = A + d\u03c8, with \u03c8 : X \u2192 R of suitable smoothness, will give the same magnetic field. It is easy to see that if B is of class C \u221e pol (X ), then A can be chosen in the same class, which is tacitly assumed in the sequel. For example, the vector potential in the so-called \"transversal gauge\" satisfies this property.", "cite_spans": [], "ref_spans": []}, {"section": "Magnetic pseudodifferential operators", "text": "For any vector potential A defining the magnetic field B, and for x, y \u2208 X let us set", "cite_spans": [], "ref_spans": []}, {"section": "Magnetic pseudodifferential operators", "text": "A for the circulation of A along the linear segment [x, y] (integration of a 1-form through a 1-simplex). We can then define for u : X \u2192 C the map:", "cite_spans": [], "ref_spans": []}, {"section": "Magnetic pseudodifferential operators", "text": "For A = 0 one recognizes the Weyl quantization, associating to functions or distributions on \u039e linear operators acting on function spaces on X . Suitably interpreted and by using rather simple duality arguments, Op A defines a representation of the * -algebra M B (\u039e) by linear continuous operators :", "cite_spans": [], "ref_spans": []}, {"section": "Magnetic pseudodifferential operators", "text": "restricts to an isomorphism from S(\u039e) to B S \u2032 (X ), S(X ) and extends to an isomorphism from S \u2032 (\u039e) to B S(X ), S \u2032 (X ) , where B(R, T ) is the family of all linear and continuous operators between the topological vector spaces R and T .", "cite_spans": [], "ref_spans": []}, {"section": "Magnetic pseudodifferential operators", "text": "An important property of (2.4) is gauge covariance: if A \u2032 = A + d\u03c8 defines the same magnetic field as", "cite_spans": [], "ref_spans": []}, {"section": "Magnetic pseudodifferential operators", "text": "Such a property would not hold for the wrong quantization, appearing in the literature", "cite_spans": [], "ref_spans": []}, {"section": "Magnetic pseudodifferential operators", "text": "Another important result is a magnetic version of the Calderon-Vaillancourt theorem:", "cite_spans": [], "ref_spans": []}, {"section": "Magnetic pseudodifferential operators", "text": "Assume that the components of the magnetic field belong to BC \u221e (X ), and let", "cite_spans": [], "ref_spans": []}, {"section": "Magnetic pseudodifferential operators", "text": "and we have the inequality", "cite_spans": [], "ref_spans": []}, {"section": "Magnetic pseudodifferential operators", "text": "where c(n) and p(n) are constants depending only on the dimension of the configuration space.", "cite_spans": [], "ref_spans": []}, {"section": "Symbol spaces with coefficients in A", "text": "We first introduce the coefficients C * -algebra A, which can be thought of as a way to encode the behavior of the magnetic fields and of the configurational part of the symbols.", "cite_spans": [], "ref_spans": []}, {"section": "Symbol spaces with coefficients in A", "text": "Let A be a unital C * -subalgebra of BC u (X ), the set of bounded and uniformly continuous functions on X . Depending on the context, the L \u221e -norm of this algebra will be denoted either by \u00b7 A or by \u00b7 \u221e . We shall always assume that A is stable by translations, i.e. \u03b8 x (\u03d5) := \u03d5(\u00b7 + x) \u2208 A for all \u03d5 \u2208 A and x \u2208 X , and sometimes we ask that C 0 (X ) is contained in A. Here, C 0 (X ) denotes the algebra of continuous functions on X that vanish at infinity.", "cite_spans": [], "ref_spans": []}, {"section": "Symbol spaces with coefficients in A", "text": "The following definition is general and applies to any C * -algebra A endowed with an action of X .", "cite_spans": [], "ref_spans": []}, {"section": "Definition 2.4. Let us define", "text": "It is known that A \u221e is a dense * -subalgebra of A, as well as a Fr\u00e9chet * -algebra with the family of seminorms {s a | a \u2208 N n }. But our setting is quite special: A is an abelian C * -algebra composed of bounded and uniformly continuous complex functions defined on the group X itself. The easy proof of the next result is left to the reader.", "cite_spans": [], "ref_spans": []}, {"section": "Definition 2.4. Let us define", "text": "Furthermore, for any a \u2208 N n and \u03d5 \u2208 A \u221e , one has \u03b4 a (\u03d5) = \u2202 a x \u03d5. We now introduce the anisotropic version of the H\u00f6rmander classes of symbols, cf. also [3, 4, 5, 6, 36] . For any f : \u039e \u2192 C and (x, \u03be) \u2208 \u039e, we will often write f (\u03be) for f (\u00b7, \u03be) and [f (\u03be)](x) for f (x, \u03be). In that situation, f will be seen as a function on X * taking values in some space of functions defined on X .", "cite_spans": [{"start": 157, "end": 160, "text": "[3,", "ref_id": "BIBREF2"}, {"start": 161, "end": 163, "text": "4,", "ref_id": "BIBREF3"}, {"start": 164, "end": 166, "text": "5,", "ref_id": "BIBREF4"}, {"start": 170, "end": 173, "text": "36]", "ref_id": "BIBREF35"}], "ref_spans": []}, {"section": "Definition 2.4. Let us define", "text": "Definition 2.6. The space S m \u03c1,\u03b4 (X * ; A \u221e ) of A-anisotropic symbols of order m and type (\u03c1, \u03b4) is", "cite_spans": [], "ref_spans": []}, {"section": "Definition 2.4. Let us define", "text": "Due to the very specific nature of the C * -algebra A, we have again some simplifications:", "cite_spans": [], "ref_spans": []}, {"section": "Definition 2.4. Let us define", "text": "Lemma 2.7. The following equality holds:", "cite_spans": [], "ref_spans": []}, {"section": "Definition 2.4. Let us define", "text": "Proof. First we notice that the conditions", "cite_spans": [], "ref_spans": []}, {"section": "Definition 2.4. Let us define", "text": "are identical. On the other hand, by Lemma 2.5,", "cite_spans": [], "ref_spans": []}, {"section": "Definition 2.4. Let us define", "text": "It thus follows that S m \u03c1,\u03b4 (X * ; A \u221e ) is included in the r.h.s. of (2.5), and we are then left with proving that if", "cite_spans": [], "ref_spans": []}, {"section": "Definition 2.4. Let us define", "text": "where e 1 , . . . , e n is the canonical base in X * \u223c = R n . Indeed, we have for t > 0:", "cite_spans": [], "ref_spans": []}, {"section": "Definition 2.4. Let us define", "text": "and similarly for t < 0. We can continue to apply this procedure to the resulting derivative \u2202 \u03bej f \u2208 S m\u2212\u03c1 \u03c1,\u03b4 (\u039e) and finish the proof by recurrence.", "cite_spans": [], "ref_spans": []}, {"section": "Definition 2.4. Let us define", "text": "In particular, for A = BC u (X ), it is easy to see that", "cite_spans": [], "ref_spans": []}, {"section": "Definition 2.4. Let us define", "text": "Then it follows from the previous lemma that", "cite_spans": [], "ref_spans": []}, {"section": "Definition 2.4. Let us define", "text": "But since A is closed, it is enough to show that for any a, \u03b1 \u2208 N n , the following statement holds: if g n \u2208 S m \u03c1,\u03b4 (\u039e) and \u03c3", "cite_spans": [], "ref_spans": []}, {"section": "Definition 2.4. Let us define", "text": "This follows from the definition of \u03c3 \u03b1a m . Statement (b) follows by applying Lemma 2.7, Leibnitz's rule and the fact that A is an algebra. Statement (c) is a direct consequence of Lemma 2.7.", "cite_spans": [], "ref_spans": []}, {"section": "Symbol composition", "text": "In this section we study the product of two symbols by the composition law \u266f B defined in (2.2). For simplicity, we introduce \u03c9 B and \u0393 B (low indices) by the relations", "cite_spans": [], "ref_spans": []}, {"section": "Symbol composition", "text": "One has explicitly", "cite_spans": [], "ref_spans": []}, {"section": "Symbol composition", "text": "We state the main result of this section :", "cite_spans": [], "ref_spans": []}, {"section": "Symbol composition", "text": "Theorem 2.9. Assume that the each component B jk belongs to A \u221e . Then, for any m 1 , m 2 \u2208 R and 0 \u2264 \u03b4 < \u03c1 \u2264 1 or \u03c1 = \u03b4 = 0, one has", "cite_spans": [], "ref_spans": []}, {"section": "Symbol composition", "text": "Before proving this theorem, we need a technical lemma.", "cite_spans": [], "ref_spans": []}, {"section": "Symbol composition", "text": "Lemma 2.10. Assume that the each component B jk belongs to A \u221e . Then, for all a, b, c \u2208 N n and all x, y, z \u2208 X , one has:", "cite_spans": [], "ref_spans": []}, {"section": "Symbol composition", "text": "can be explicitly calculated by using (2.6), (a) follows from the completeness of A and (b) easily follows from (a). Statement (c) is borrowed from [13] .", "cite_spans": [{"start": 148, "end": 152, "text": "[13]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Symbol composition", "text": "Proof of Theorem 2.9. Since the components of the magnetic field belong to BC \u221e (X ) \u2282 C \u221e pol (X ), it follows from Lemma 2.7 and [13, Lem. ", "cite_spans": [], "ref_spans": []}, {"section": "Symbol composition", "text": "For that purpose, let", "cite_spans": [], "ref_spans": []}, {"section": "Symbol composition", "text": "satisfies the properties of Lemma 2.10. We have to study the x-behavior of the expression", "cite_spans": [], "ref_spans": []}, {"section": "Symbol composition", "text": "The precise definition of these integrals involves rewriting the factors e \u22122iz\u00b7\u03b7 e 2iy\u00b7\u03b6 as", "cite_spans": [], "ref_spans": []}, {"section": "Symbol composition", "text": "where D := 1 2i \u2202 and p, q \u2208 N, and integrating by parts. So the r.h.s. of (2.9) contains the integrals", "cite_spans": [], "ref_spans": []}, {"section": "Symbol composition", "text": "which will be proved now to be absolutely convergent for p, q large enough. For this, one has to estimate , and the a priori estimates on F \u03b1 1 a 1 and G \u03b1 2 a 2 , the absolute value of (2.11) is dominated by", "cite_spans": [], "ref_spans": []}, {"section": "Symbol composition", "text": "Since (1 \u2212 \u03b4) > 0, the factors involving \u03b7 and \u03b6 will be integrable for p large enough. Fixing a suitable p, for an even larger q we also ensure integrability in y and z.", "cite_spans": [], "ref_spans": []}, {"section": "Symbol composition", "text": "is given by an absolutely convergent integral, the integrand being a function of x which belongs to A for all values of \u03be, y, \u03b7, z, \u03b6. It is easy to conclude, by the Dominated Convergence Theorem, that the map", "cite_spans": [], "ref_spans": []}, {"section": "Symbol composition", "text": ") (x, \u03be) also belongs to A, and this finishes the proof.", "cite_spans": [], "ref_spans": []}, {"section": "Asymptotic developments", "text": "In this section we simplify and generalize to A-valued symbols the asymptotic expansion of the magnetic product of two symbols already derived in [13] . We refer to [22] for parameter-dependent developments.", "cite_spans": [{"start": 146, "end": 150, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 165, "end": 169, "text": "[22]", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Asymptotic developments", "text": "For any multi-index \u03b1 \u2208 N m , we use the notation \u03b1! = \u03b1 1 ! . . . \u03b1 m !. For shortness we shall also write a := (a, \u03b1) and b := (b, \u03b2), with a, b \u2208 N 2n . ", "cite_spans": [], "ref_spans": []}, {"section": "Asymptotic developments", "text": ", and the constants are given by", "cite_spans": [], "ref_spans": []}, {"section": "Asymptotic developments", "text": "The remainder term R N belongs to S m1+m2\u2212\u03c1N \u03c1,0", "cite_spans": [], "ref_spans": []}, {"section": "Asymptotic developments", "text": "Remark 2.12. If B = 0, which implies that \u03c9 B = 1, one has h a,b = 0 only if a = \u03b2 and b = \u03b1; by setting\u00e2", "cite_spans": [], "ref_spans": []}, {"section": "Asymptotic developments", "text": "Before proving the theorem, we list the first two terms in the development:", "cite_spans": [], "ref_spans": []}, {"section": "Asymptotic developments", "text": "Proof of Theorem 2.11. In the formula (2.7) we shall use the Taylor series", "cite_spans": [], "ref_spans": []}, {"section": "Asymptotic developments", "text": "where the remainder r f,g will be specified later. It follows that", "cite_spans": [], "ref_spans": []}, {"section": "Asymptotic developments", "text": "In other words, one has", "cite_spans": [], "ref_spans": []}, {"section": "Asymptotic developments", "text": "with \u2126 a,b (x) given by", "cite_spans": [], "ref_spans": []}, {"section": "Asymptotic developments", "text": "The following factor vanishes unless b \u2264 \u03b1 and a \u2264 \u03b2:", "cite_spans": [], "ref_spans": []}, {"section": "Asymptotic developments", "text": "So, restricting to the case b \u2264 \u03b1 and a \u2264 \u03b2, we can write:", "cite_spans": [], "ref_spans": []}, {"section": "Asymptotic developments", "text": "By Proposition 2.8 and Lemma 2.10, one finally obtains that h a,b \u2208 S m1+m2\u2212\u03c1(|\u03b1|+|\u03b2|) \u03c1,0 (X * ; A \u221e ). We now treat the remainder R N (X) given by", "cite_spans": [], "ref_spans": []}, {"section": "Asymptotic developments", "text": "In order to show that this term belongs to S m1+m2\u2212\u03c1N \u03c1,0", "cite_spans": [], "ref_spans": []}, {"section": "Asymptotic developments", "text": "(X * ; A \u221e ), we take into account", "cite_spans": [], "ref_spans": []}, {"section": "Asymptotic developments", "text": "and introduce it into R N (X) which can then be rewritten as", "cite_spans": [], "ref_spans": []}, {"section": "Asymptotic developments", "text": "So we have ", "cite_spans": [], "ref_spans": []}, {"section": "Asymptotic developments", "text": "Retaining only its essential features, we shall rewrite this last expression as", "cite_spans": [], "ref_spans": []}, {"section": "Asymptotic developments", "text": "In order to show that R N belongs to S ", "cite_spans": [], "ref_spans": []}, {"section": "Asymptotic developments", "text": "where, for suitable integers p, q, the expression L", "cite_spans": [], "ref_spans": []}, {"section": "Asymptotic developments", "text": "where \u03d5 qc 1 and \u03c8 qb 1 are bounded functions produced by derivating the factors z \u22122q and y \u22122q , respectively. By taking the explicit form of \u03a3 B , F, G and Lemma 2.10 into account, one has", "cite_spans": [], "ref_spans": []}, {"section": "Asymptotic developments", "text": "Then, it only remains to insert this estimate into the expression of R N given in (2.12), and to observe that by choosing p large enough, one gets absolute integrability in \u03b7 and \u03b6. A subsequent choice of q also ensures integrability in y and z. The behavior in \u03be is finally the one expected for \u2202 (\u039e). By taking then Theorem 2.9 and the properties of h l into account, one has", "cite_spans": [], "ref_spans": []}, {"section": "Asymptotic developments", "text": "for any \u03be \u2208 X * . It finally follows from Lemma 2.7 that R N belongs to S m1+m2\u2212\u03c1N \u03c1,0 (X * ; A \u221e ).", "cite_spans": [], "ref_spans": []}, {"section": "Asymptotic developments", "text": "3 C * -algebras 3.1 C * -algebras generated by symbols", "cite_spans": [], "ref_spans": []}, {"section": "Asymptotic developments", "text": "We continue to assume that all components of the magnetic field belong to A \u221e and let H := L 2 (X ). As already mentioned, we choose a vector potential A that belongs to C \u221e pol (X ) and thus the map Op A extends to a linear topological isomorphism S \u2032 (\u039e) \u2192 B S(X ), S \u2032 (X ) . Since B(H) is continuously imbedded in B S(X ), S \u2032 (X ) , one can define", "cite_spans": [], "ref_spans": []}, {"section": "Asymptotic developments", "text": "It is obviously a vector subspace of S \u2032 (\u039e) which only depends on the magnetic field (by gauge covariance). On convenient subsets, for example on A B (\u039e) \u2229 M B (\u039e), the transported product from B(H) coincides with \u266f B , and the adjoint in B(H) corresponds to the involution \u266f B . Endowed with the transported norm", "cite_spans": [], "ref_spans": []}, {"section": "Asymptotic developments", "text": "is a C * -algebra. With these notations and due to the inclusion S We shall now define two A-depending C * -subalgebras of A B (\u039e).", "cite_spans": [], "ref_spans": []}, {"section": "Definition 3.2. We set (a) B B", "text": "A for the C * -subalgebra of", "cite_spans": [], "ref_spans": []}, {"section": "Definition 3.2. We set (a) B B", "text": "It is easily observed that S(X * ; A \u221e ) is really independent of \u03c1 and \u03b4. Part of our interest in the algebra B B A is due to the following proposition and its corollary. We first recall that", "cite_spans": [], "ref_spans": []}, {"section": "Definition 3.2. We set (a) B B", "text": "Proof. We adapt the proof of Proposition 1.1.11 in [11] to show that any f \u2208 S \u22120 \u03c1,\u03b4 (X * ; A \u221e ) is the limit of a sequence f \u01eb 0\u2264\u01eb\u22641 \u2208 S(X * ; A \u221e ) in the topology of S Let f \u2208 S m \u03c1,\u03b4 (X * ; A \u221e ) for some m < 0, 0 \u2264 \u03b4 \u2264 \u03c1 \u2264 1, \u03b4 = 1, and let \u03c7 \u2208 S(X * ) with \u03c7(0) = 1. We set f \u01eb (x, \u03be) := \u03c7(\u01eb\u03be) f (x, \u03be) for 0 \u2264 \u01eb \u2264 1. By using Proposition 2.8 (b), one has f \u01eb \u2208 S(X * ; A \u221e ) for all \u01eb > 0, and f \u01eb 0\u2264\u01eb\u22641 is a bounded subset of S ", "cite_spans": [{"start": 51, "end": 55, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Magnetic twisted crossed products", "text": "In the previous section we introduced some C * -algebras through a representation that was constructed with a vector potential A. However, all these algebras did not depend on the choice of a particular A. Starting from a magnetic twisted C * -dynamical system, we shall now recall the constructions of magnetic twisted C * -algebras [27] and relate them to the previous algebras. These are particular instances of twisted C * -algebras extensively studied in [31] and [32] (see also references therein). We recall that Gelfand theory describes completely the structure of abelian C * -algebras. The Gelfand spectrum S A of A is the family of all characters of A (a character is just a morphism \u03ba : A \u2192 C). With the topology of simple convergence S A is a locally compact space, which is compact exactly when A is unital.", "cite_spans": [{"start": 334, "end": 338, "text": "[27]", "ref_id": "BIBREF26"}, {"start": 460, "end": 464, "text": "[31]", "ref_id": "BIBREF30"}, {"start": 469, "end": 473, "text": "[32]", "ref_id": "BIBREF31"}], "ref_spans": []}, {"section": "Magnetic twisted crossed products", "text": "Since A \u2282 BC(X ), there exists a continuous surjection \u03b9 A : \u03b2(X ) \u2192 S A , where \u03b2(X ) is the Stone-\u010cech compactification of the locally compact space X . By restriction, we get a continuous mapping with dense image (also denoted by \u03b9 A : X \u2192 S A ). This one is injective exactly when C 0 (X ) \u2282 A, case in which S A is a compactification of X . The isomorphism between A and C(S A ) can be precisely expressed as follows: \u03d5 : X \u2192 C belongs to A if and only if there is a (necessarily unique)\u03c6 \u2208 C(S A ) such that \u03d5 =\u03c6 \u2022 \u03b9 A . We shall extend the notation to functions depending on extra variables. For example, if f : \u039e = X \u00d7 X * \u2192 C is some convenient function, we define f : S A \u00d7 X * \u2192 C by the property f (x, \u03be) = f (\u03b9 A (x), \u03be) for all (x, \u03be) \u2208 \u039e. Let us finally mention that the map \u03b8 : X \u00d7 X \u2192 X , \u03b8(x, y) := x + y extends to a continuous map \u03b8 : S A \u00d7 X \u2192 S A , because A was assumed to be stable under translations. We also use the notations \u03b8(\u03ba, y) = \u03b8 y (\u03ba) = \u03b8 \u03ba (y) for (\u03ba, y) \u2208 S A \u00d7 X and get a topological dynamical system (S A , \u03b8, X ) with compact space S A . Obviously one has \u03b9 A \u2022 \u03b8 y = \u03b8 y \u2022 \u03b9 A for any y \u2208 X . Now assume that the components B jk of the magnetic field belong to A. We define for each x, y, z \u2208 X the expression \u03c9 B (x; y, z) := e \u2212i\u0393 B ( x,x+y,x+y+z ) .", "cite_spans": [], "ref_spans": []}, {"section": "Magnetic twisted crossed products", "text": "For fixed x and y, the function \u03c9 B (\u00b7; x, y) \u2261 \u03c9 B (x, y) belongs to the unitary group U(A) of A. Moreover, the mapping X \u00d7 X \u220b (x, y) \u2192 \u03c9 B (x, y) \u2208 U(A) is a strictly continuous and normalized 2-cocycle on X , i.e. for all x, y, z \u2208 X the following relations hold:", "cite_spans": [], "ref_spans": []}, {"section": "Magnetic twisted crossed products", "text": "The quadruplet (A, \u03b8, \u03c9 B , X ) is a particular case of a twisted C * -dynamical system (A, \u03b8, \u03c9, X ). In the general case X is a locally compact group, A is a C * -algebra, \u03b8 is a continuous morphism from X to the group of automorphisms of A, and \u03c9 is a strictly continuous 2-cocycle with values in the unitary group of the multiplier algebra of A. We refer to [27, Def. 2.1] for more explanations.", "cite_spans": [], "ref_spans": []}, {"section": "Magnetic twisted crossed products", "text": "Let L 1 (X ; A) be the set of Bochner integrable functions on X with values in A, with the L 1 -norm", "cite_spans": [], "ref_spans": []}, {"section": "Magnetic twisted crossed products", "text": "1 (X ; A) and x \u2208 X , we define the product", "cite_spans": [], "ref_spans": []}, {"section": "Magnetic twisted crossed products", "text": "and the involution F Theorem 3.7. The partial Fourier transform F :", "cite_spans": [], "ref_spans": []}, {"section": "Magnetic twisted crossed products", "text": "Proof. The partial Fourier transform F is an isomorphism from S(X ; A \u221e ) to S(X * ; A \u221e ) which intertwines the products and the involutions:", "cite_spans": [], "ref_spans": []}, {"section": "Magnetic twisted crossed products", "text": "The statement follows then from the density of S(X * ; A \u221e ) in B B A , and from the density of S(X ; A \u221e ) in L 1 (X ; A), and hence also in C B A . Remark 3.8. In Definition 3.2, the algebra B B A was introduced as a closure of a set of smooth elements, but it can easily be guessed that non-smooth elements also belong to B B A . Indeed, by [28, Lemma A.4] one has that for any m < 0 the set", "cite_spans": [{"start": 344, "end": 348, "text": "[28,", "ref_id": "BIBREF27"}], "ref_spans": []}, {"section": "Magnetic twisted crossed products", "text": "A . Here we have used the notation S m 1 (X * ; A) for the set of all functions f : \u039e \u2192 C that satisfy: (i) f (\u00b7, \u03be) \u2208 A for all \u03be \u2208 X * , (ii) f (x, \u00b7) \u2208 C \u221e (X * ) \u2200x \u2208 X , and (iii) for each \u03b1 \u2208 N n one has \u03c3 \u03b10 m (f ) < \u221e. Even more simply, one can also observe that the partial Fourier transform of the elements in L 1 (X ; A) belong to B B A , and that these elements do not necessarily possess any smoothness except continuity. Remark 3.9. In the same vein, let us also mention that a trivial extension of the same lemma [28, Lem. A.4 ] to arbitrary \u03b4 imply that", "cite_spans": [{"start": 528, "end": 532, "text": "[28,", "ref_id": "BIBREF27"}], "ref_spans": []}, {"section": "Magnetic twisted crossed products", "text": "But by a remark in [1, p. 17 ] such an inclusion is no longer true for \u03c1 = 1. It follows that for 0 \u2264 \u03b4 \u2264 \u03c1 < 1 many elements of", "cite_spans": [], "ref_spans": []}, {"section": "Magnetic twisted crossed products", "text": "We finally state a result about how the algebra B", "cite_spans": [], "ref_spans": []}, {"section": "B", "text": "A can be generated from a simpler set of its elements. It is an adaptation of [27, Prop. 2.6]. We recall now the definition of a covariant representation of a magnetic C * -dynamical system. We denote by U(H) the group of unitary operators in the Hilbert space H. ", "cite_spans": [], "ref_spans": []}, {"section": "B", "text": "extends to a representation of", "cite_spans": [], "ref_spans": []}, {"section": "B", "text": "One can recover the covariant representation from Rep T r . Actually, there is a one-to-one correspondence between covariant representations of a twisted C * -dynamical system and non-degenerate representations of the twisted crossed product, which preserves unitary equivalence, irreducibility and direct sums.", "cite_spans": [], "ref_spans": []}, {"section": "B", "text": "By composing with the partial Fourier transformation, one gets the most general representations of the pseudodifferential C * -algebra B ", "cite_spans": [], "ref_spans": []}, {"section": "Inversion", "text": "The following approach is mainly inspired by a similar construction in [14, Sec. 7.1]. It also relies on some basic results on \u03a8 * -algebras that we borrow from [19, Sec. 2] , see also [20] and references therein. Let C be a C * -algebra with unit 1, and let S be a * -subalgebra of C with 1 \u2208 S. S is called spectrally invariant if S \u2229 C \u22121 = S \u22121 , where S \u22121 , resp. C \u22121 , denotes the set of invertible elements in S, resp. C. Furthermore, S is called a \u03a8 * -algebra if it is spectrally invariant and endowed with a Fr\u00e9chet topology such that the embedding S \u0592\u2192 C is continuous. It is shown in [19, Cor. 2.5 ] that a closed * -subalgebra of a \u03a8 * -algebra (also containing 1), endowed with the restricted topology, is also a \u03a8 * -algebra. It has been proved in [14] ", "cite_spans": [{"start": 161, "end": 165, "text": "[19,", "ref_id": "BIBREF18"}, {"start": 185, "end": 189, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 598, "end": 602, "text": "[19,", "ref_id": "BIBREF18"}, {"start": 765, "end": 769, "text": "[14]", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Inversion", "text": "In order to state the next lemma some notations are needed. For m > 0, \u03bb > 0 and \u03be \u2208 X * , set", "cite_spans": [], "ref_spans": []}, {"section": "Inversion", "text": "The map p m,\u03bb is clearly an element of S Proof. For m \u2265 0, the statement is trivial from the definition of r m . But for m < 0 the function r m will also depend on the variable x, so one has to take the proof of [28, Thm. 1.8] into account. Indeed, it has been shown in that reference that for \u03bb large enough, p := p |m|,\u03bb(|m|) is invertible with respect to the composition law \u266f B , and that its inverse is given by the formula", "cite_spans": [], "ref_spans": []}, {"section": "Inversion", "text": "where p \u22121 is the the inverse of p with respect to pointwise multiplication, and \u03bb has been chosen such that (p \u266f B p \u22121 ) (\u22121)B is well defined and belongs to A B (\u039e). Furthermore, since p", "cite_spans": [], "ref_spans": []}, {"section": "Inversion", "text": "It then follows that the inverse of p \u266f B p \u22121 also belongs to S ", "cite_spans": [], "ref_spans": []}, {"section": "Inversion", "text": "Proof. Let us first observe that ", "cite_spans": [], "ref_spans": []}, {"section": "Inversion", "text": "In order to verify the hypotheses of the above proposition, a condition of ellipticity is usually needed.", "cite_spans": [], "ref_spans": []}, {"section": "Inversion", "text": "for all x \u2208 X and |\u03be| > R.", "cite_spans": [], "ref_spans": []}, {"section": "Inversion", "text": "We are now in a position to state and prove our main theorem on inversion (see also the Appendix):", "cite_spans": [], "ref_spans": []}, {"section": "Inversion", "text": "Proof. It has been proved in [13, Thm. 4.1] that Op A (f ) defines a self-adjoint operator in H := L 2 (X ) for any vector potential A whose components belong to C \u221e pol (X ). In particular, z does not belong to the spectrum of Op A (f ), which is independent of A by gauge covariance, and ", "cite_spans": [{"start": 29, "end": 33, "text": "[13,", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Affiliation", "text": "We start by recalling the meaning of affiliation, borrowed from [1] . We shall then prove that some of the classes of symbols introduced in Section 2 define observables affiliated to B B A . Definition 3.18. An observable affiliated to a C * -algebra C is a morphism \u03a6 : C 0 (R) \u2192 C.", "cite_spans": [{"start": 64, "end": 67, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Affiliation", "text": "For example, if H is a Hilbert space and C is a C * -subalgebra of B(H), then a self-adjoint operator H in H defines an observable \u03a6 H affiliated to C if and only if \u03a6 H (\u03b7) := \u03b7(H) belongs to C for all \u03b7 \u2208 C 0 (R). A sufficient condition is that (H \u2212 z) \u22121 \u2208 C for some z \u2208 C with Im z = 0. Thus an observable affiliated to a C * -algebra is the abstract version of the functional calculus of a self-adjoint operator. The next result is a rather simple corollary of our previous results. We call it Theorem to stress its importance in our subsequent spectral results. A . Proof. For z \u2208 C \\ R, let us set r z := (f \u2212 z) \u22121 . We also define \u03a6(r z ) := (f \u2212 z) (\u22121)B . We first prove that the family {\u03a6(r z ) | z \u2208 C \\ R} satisfies the resolvent equation. Indeed, for any two complex numbers", "cite_spans": [], "ref_spans": []}, {"section": "Affiliation", "text": "By multiplication to the left with \u03a6(r z ) and using the associativity, one then gets the resolvent equation", "cite_spans": [], "ref_spans": []}, {"section": "Affiliation", "text": "We has thus obtained a map ", "cite_spans": [], "ref_spans": []}, {"section": "Spectral analysis 4.1 Preliminaries", "text": "Recall that A is a C * -subalgebra of BC u (X ) which is invariant under translations. Such an algebra is called admissible. It is also unital, but most of the constructions do not require this. For any \u03d5 \u2208 A we systematically denote by\u03c6 the unique element of C(S A ) satisfying \u03d5 =\u03c6 \u2022 \u03b9 A . In fact,\u03c6 corresponds to the image of \u03d5 through the Gelfand isomorphism G A : A \u2192 C(S A ).", "cite_spans": [], "ref_spans": []}, {"section": "Spectral analysis 4.1 Preliminaries", "text": "A basic fact is that A comes together with a family of short exact sequences", "cite_spans": [], "ref_spans": []}, {"section": "Spectral analysis 4.1 Preliminaries", "text": "indexed by Q A , the set of all quasi-orbits of the topological dynamical space (S A , \u03b8, X ). We recall that a quasi-orbit is the closure of an orbit, and let us now explain the meaning of (4.1).", "cite_spans": [], "ref_spans": []}, {"section": "Spectral analysis 4.1 Preliminaries", "text": "For Q \u2208 Q A we say that the element \u03ba \u2208 S A generates Q if the orbit of \u03ba is dense in Q. In general not all the elements of Q generates it. There is a canonical epimorphism p Q : C(S A ) \u2192 C(Q), coming from the inclusion of the closed set Q in S A . On the other hand, if \u03ba generates Q, we set A \u03ba := {\u03d5 \u03ba :=\u03c6 \u2022 \u03b8 \u03ba | \u03d5 \u2208 C(Q)}. It is clear that A \u03ba is an admissible C * -algebra isomorphic to C(Q). Indeed, by taking into account the surjectivity of the morphism p Q and the continuity of translations in A \u2282 BC u (X ), one easily sees that \u03d5 \u03ba : X \u2192 C belongs to BC u (X ). Furthermore, the induced action of X on \u03d5 \u03ba coincides with the natural action of X on BC u (X ). Thus, we get an epimorphism \u03c0 \u03ba : A \u2192 A \u03ba by \u03c0 \u03ba := \u03b8 \u03ba \u2022 p Q \u2022 G A . We note that in general A \u03ba has no reason to be contained in A.", "cite_spans": [], "ref_spans": []}, {"section": "Spectral analysis 4.1 Preliminaries", "text": "It is clear that the kernel of this epimorphism is A Q = {\u03d5 \u2208 A |\u03c6| Q = 0}. Furthermore, if \u03ba and \u03ba \u2032 generate the same quasi-orbit Q, the algebras A \u03ba and A \u03ba \u2032 are isomorphic. So by a slight abuse of notation, we call them generically A Q , and corresponding morphism by \u03c0 Q . This finishes to explain (4.1). We now recall some more definitions in relation with spectral analysis in a C * -algebraic framework, cf. [1] . Let \u03a6 be an observable affiliated to a C * -algebra C and let K be an ideal of C. Then, the K-essential spectrum of \u03a6 is", "cite_spans": [{"start": 417, "end": 420, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Spectral analysis 4.1 Preliminaries", "text": "is an observable affiliated to the quotient algebra, and one has", "cite_spans": [], "ref_spans": []}, {"section": "Spectral analysis 4.1 Preliminaries", "text": ". Assume now that C is a C * -subalgebra of B(H) for some Hilbert space H and that C contains the ideal K(H) of compact operators on H. Furthermore, let H be a self-adjoint operator in H affiliated to C. Then \u03c3 K(H) (\u03a6 H ) is equal to the essential spectrum \u03c3 ess (H) of H. Here we shall be mainly interested in the usual spectrum and in the essential spectrum. The need for the K-essential spectrum with K different from {0} or K(H) is relevant in the context of Remark 4.5.", "cite_spans": [], "ref_spans": []}, {"section": "The essential spectrum of anisotropic magnetic operators", "text": "We consider again the magnetic twisted C * -dynamical system (A, \u03b8, \u03c9 B , X ) and explain how to calculate the essential spectrum of any observable affiliated to the twisted crossed product algebra C B A . Then, by using the results of the previous sections, we particularize to the case of magnetic pseudodifferential operators and prove our main result concerning their essential spectrum. For simplicity, we omit in this section the subscript B to the 2-cocycle \u03c9 B . We follow now the strategy of [24, 28] (see also references therein). We are going to assume that A contains C 0 (X ), so S A is a compact space and X can be identified with a dense open subset of S A . Since the group law \u03b8 : X \u00d7 X \u2192 X extends to a continuous map \u03b8 : X \u00d7 S A \u2192 S A , the complement F A of X in S A is closed and invariant; it is the space of a compact topological dynamical system. For any quasi-orbit Q, the algebra A Q is clearly an invariant ideal of A. The abelian twisted dynamical system (A Q , \u03b8, \u03c9, X ) obtained by replacing A with A Q and performing suitable restrictions is well defined. Furthermore, the twisted crossed product A In order to have an explicit description of the quotient, let us first note that A/A Q is canonically isomorphic to the unital C * -algebra C(Q) of all continuous functions on Q. The natural action of X on \u03c6 \u2208 C(Q) is given by (\u03b8 x\u03c6 )(\u03ba) =\u03c6 (\u03b8 x [\u03ba]) for each x \u2208 X and \u03ba \u2208 Q. Now, the restriction of \u03c9 to Q gives rise to a 2-cocycle \u03c9 Q : X \u00d7 X \u2192 U C(Q) precisely defined by \u03c9 Q (x, y) := p Q G A \u03c9(x, y) for each x, y \u2208 X . Thus C(Q), \u03b8, \u03c9 Q , X is a well-defined abelian twisted C * -dynamical system. Moreover, the quotient A\u22ca ", "cite_spans": [{"start": 501, "end": 505, "text": "[24,", "ref_id": "BIBREF23"}, {"start": 506, "end": 509, "text": "28]", "ref_id": "BIBREF27"}], "ref_spans": []}, {"section": "The essential spectrum of anisotropic magnetic operators", "text": "for all x \u2208 X . Let us now consider Q \u2282 Q A such that the elements Q of Q define a covering of F A . At the algebraic level, the covering requirement reads \u2229 Q\u2208Q A Q = C 0 (X ). This implies immediately the equality", "cite_spans": [], "ref_spans": []}, {"section": "The essential spectrum of anisotropic magnetic operators", "text": "By putting all these together one obtains, cf. also [24, Prop. 1.5]:", "cite_spans": [], "ref_spans": []}, {"section": "The essential spectrum of anisotropic magnetic operators", "text": "(a) There exists an injective morphism:", "cite_spans": [], "ref_spans": []}, {"section": "The essential spectrum of anisotropic magnetic operators", "text": "We now introduce a represented version of this proposition in the Hilbert space H := L 2 (X ). We recall that for any continuous vector potential A, a representation Rep A of A\u22ca ", "cite_spans": [], "ref_spans": []}, {"section": "The essential spectrum of anisotropic magnetic operators", "text": "where A and A Q are continuous vector potentials for B and B Q , and", "cite_spans": [], "ref_spans": []}, {"section": "The essential spectrum of anisotropic magnetic operators", "text": "Proof. Let us first observe that the morphism", "cite_spans": [], "ref_spans": []}, {"section": "The essential spectrum of anisotropic magnetic operators", "text": "extends to a surjective morphism\u03a0 Q : B ", "cite_spans": [], "ref_spans": []}, {"section": "The essential spectrum of anisotropic magnetic operators", "text": "where K is now the ideal of B Remark 4.3. Combining our approach with techniques from [1, 7, 8] , one could extend the result above to more singular symbols f . We shall not do this; our main goal was to cover functions f which have no specific dependence of the variable in \u039e (as f (x, \u03be) = h(\u03be) + V (x) for instance) in a pseudodifferential setting.", "cite_spans": [{"start": 86, "end": 89, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 90, "end": 92, "text": "7,", "ref_id": "BIBREF6"}, {"start": 93, "end": 95, "text": "8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "The essential spectrum of anisotropic magnetic operators", "text": "Remark 4.4. To have a good understanding of (4.2), one needs admissible algebras A for which the space Q A is explicit enough. Many examples are scattered through [1, 2, 7, 9, 8, 24, 28 , 34] and we will not reconsider this topic here.", "cite_spans": [{"start": 163, "end": 166, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 167, "end": 169, "text": "2,", "ref_id": "BIBREF1"}, {"start": 170, "end": 172, "text": "7,", "ref_id": "BIBREF6"}, {"start": 173, "end": 175, "text": "9,", "ref_id": "BIBREF8"}, {"start": 176, "end": 178, "text": "8,", "ref_id": "BIBREF7"}, {"start": 179, "end": 182, "text": "24,", "ref_id": "BIBREF23"}, {"start": 183, "end": 185, "text": "28", "ref_id": "BIBREF27"}], "ref_spans": []}, {"section": "The essential spectrum of anisotropic magnetic operators", "text": "Remark 4.5. Non-propagation results easily follow from this algebraic framework. They have been explicitly exhibited in the non-magnetic case in [2] and in the magnetic case in [28] . In these references, the authors were mainly concerned with generalized Schr\u00f6dinger operators and their results were stated for these operators. But the proof relies only on the C * -algebraic framework, and the results extend mutatis mutandis to the classes of symbols introduced in the present paper. For shortness, we do not present these propagation estimates here, but statements and proofs can easily be mimicked from these references.", "cite_spans": [{"start": 145, "end": 148, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 177, "end": 181, "text": "[28]", "ref_id": "BIBREF27"}], "ref_spans": []}, {"section": "Appendix: An independent proof for the affiliation", "text": "In this Appendix, we give a second proof of Theorem 3.19 which is independent of the results contained in [14] , which is not yet published.", "cite_spans": [{"start": 106, "end": 110, "text": "[14]", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Appendix: An independent proof for the affiliation", "text": "Let m > 0, \u03c1 \u2208 (0, 1] and f be a real-valued elliptic element of S for a finite number of multi-indices \u03b4, d \u2208 N n , see Theorem 2.3 for the precise statement. Thus it remains to study the dependence on z of (4.3). Fortunately, a similar expression has already been studied in the proof of the asymptotic development and we shall rely on some of the expressions derived in the proof of Theorem 2.11.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix: An independent proof for the affiliation", "text": "Since f is an elliptic symbol of strictly positive order we can fix z \u2208 R \u2212 with z \u2264 inf f \u2212 1. The pointwise inverse of f \u2212 z is thus well defined, and is denoted by (f \u2212 z) \u22121 . We recall from the proof of Theorem 2.11 that Retaining only its essential features, we shall rewrite this last expression as Then, it only remains to insert these estimates for L \u03c4,z,\u03b4 1 ,\u03b4 2 p,q,d 0 ,d 1 ,d 2 into the expression of R z , and to observe that by choosing p large enough, one gets absolute integrability in \u03b7 and \u03b6. A subsequent choice of q also ensures integrability in y and z.", "cite_spans": [], "ref_spans": []}, {"section": "Appendix: An independent proof for the affiliation", "text": "We are now in a position to obtain estimates for (4.3). By summing the contributions in the critical case and in the regular one, we obtain:", "cite_spans": [], "ref_spans": []}, {"section": "Appendix: An independent proof for the affiliation", "text": "with c independent of z, x and \u03be. Then, by choosing \u03bd close enough to 1 such that m(1 \u2212 1/\u03bd) \u2212 \u03c1 < 0, the expression decrease as |z| increases. Thus, for |z| big enough, R z B is strictly less than 1 and the Neumann series in then convergent. It follows that (f \u2212 z) (\u22121)B belongs to B B A for any z \u2208 R \u2212 with |z| large enough. Finally, by an argument similar to the one proposed in the proof of Theorem 1.8 of [28] , one can extend this result to any z \u2208 C \\ R and show that the resolvent equation is satisfied. 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Surreys", "link": "120729280"}}, "ref_entries": {"FIGREF0": {"text": "quite a large class of distributions, containing the Fourier transform of all bounded measures on \u039e as well as the class C \u221e pol,u (\u039e) of all smooth functions on \u039e having polynomial growth at infinity uniformly in all the derivatives. In addition, if we assume that all the derivatives of the functions B jk are bounded, the H\u00f6rmander classes of symbols S m \u03c1,\u03b4 (\u039e) belong to M B (\u039e) and compose in the usual way under \u266f1 , m 2 \u2208 R and 0 \u2264 \u03b4 < \u03c1 \u2264 1 or \u03c1 = \u03b4 = 0. Here we have used the following standard definition: Definition 2.1. The space S m \u03c1,\u03b4 (\u039e) of symbols of order m and of type (\u03c1, \u03b4) is", "type": "figure"}, "FIGREF1": {"text": "(\u039e) is a Fr\u00e9chet space under the family of semi-norms {\u03c3 \u03b1a m } \u03b1,a\u2208N n", "type": "figure"}, "FIGREF3": {"text": "\u03c4 . Actually, by using (2.10), the oscillatory integral definition of \u2202", "type": "figure"}, "FIGREF4": {"text": "N . Thus, we have obtained so far that R N belongs to S m1+m2\u2212\u03c1N \u03c1,0", "type": "figure"}, "FIGREF5": {"text": "\u03b4 (\u039e) for \u03b4 < \u03c1, Theorem 2.3 can be rephrased: Proposition 3.1. For any 0 \u2264 \u03b4 \u2264 \u03c1 \u2264 1 with \u03b4 = 1, the following continuous embedding holds: S 0 \u03c1,\u03b4 (\u039e) \u0592\u2192 A B (\u039e).", "type": "figure"}, "FIGREF6": {"text": "A \u221e ), see also [10, Sec. 1] for more details. This and Proposition 3.1 will imply the result.", "type": "figure"}, "FIGREF7": {"text": "A \u221e ). Finally, one easily obtains that f \u01eb converges to f as \u01eb \u2192 0 in the topology of S 0 \u03c1,\u03b4 (X * ; A \u221e ).", "type": "figure"}, "FIGREF8": {"text": "The same proof shows the density of S(X * ; A \u221e ) in SThe C * -algebra M B A is contained in the multiplier algebra M(B B A ) of B B A . Proof. This follows from the fact that S(X * ; A \u221e ) is a two-sided ideal in S= BC u (X * ), while M(B B C ) = BC(X * ); so, in the Corollary, the inclusion could be strict.", "type": "figure"}, "FIGREF9": {"text": "(x) := F (\u2212x). Definition 3.6. The enveloping C * -algebra of L 1 (X ; A) is called the twisted crossed product and is denoted by A\u22ca \u03c9 B \u03b8 X , or simply by C B A . The C * -algebras C B A and B B A are simply related by a partial Fourier transform [F(F )](\u03be, x) := X dy e iy\u00b7\u03be F (y, x).", "type": "figure"}, "FIGREF10": {"text": "The norm closure in A B (\u039e) of the subspaces generated either by {a \u266f B b | a \u2208 A, b \u2208 S(X * )} or by {b \u266f B a | b \u2208 A, b \u2208 S(X * )} are equal and coincide with the C * -algebra B B A .", "type": "figure"}, "FIGREF11": {"text": "Given a magnetic C * -dynamical system (A, \u03b8, \u03c9 B , X ), we call covariant representation (H, r, T ) a Hilbert space H together with two maps r : A \u2192 B(H) and T : X \u2192 U(H) satisfying (a) r is a non-degenerate representation, (b) T is strongly continuous and T", "type": "figure"}, "FIGREF12": {"text": "continuous vector potential A we construct a representation of C B A in H = L 2 (X ). For any u \u2208 H and x, y \u2208 X , we define the magnetic translations [T A (y)u](x) := \u03bb A (x; y) u(x + y) = e \u2212i\u0393 A ([x,x+y]) u(x + y). Let us also set r(\u03d5) := \u03d5(Q) for any \u03d5 \u2208 A, where \u03d5(Q) denotes an operator of multiplication in H. Then the triple (H, r, T A ) is a covariant representation of the magnetic C * -dynamical system, see [27, sec. 4] for details. The corresponding representation Rep T A r of the algebra C B A , denoted by Rep A , is explicitly given for any F \u2208 L 1 (X ; A) and any u \u2208 H byis called the Schr\u00f6dinger representation of C B A associated with the vector potential A. It is proved in [27, Prop. 2.17] that this representation is faithful. We recall that the choice of another vector potential generating the same magnetic field would lead to a unitarily equivalent representation of C B A in B(H). By comparing (2.4) and (3.1), one sees that Op A \u2261 Op T A r and Rep A are connected by the partial Fourier transform:", "type": "figure"}, "FIGREF13": {"text": "A \u221e ) is a \u03a8 * -algebra, it is stable under the holomorphic functional calculus,", "type": "figure"}, "FIGREF14": {"text": "A \u221e ). It has been proved in [28, Thm. 1.8] that for \u03bb large enough, p m,\u03bb is invertible with respect to the composition law \u266f B and that its inverse p. So for any m > 0 we can fix \u03bb = \u03bb(m) such that p m,\u03bb(m) is invertible. Then, for arbitrary m \u2208 R,\u2212m clearly holds for all m \u2208 R. Let us still show an important property of r m . Lemma 3.14. For any m \u2208 R, one has r m \u2208 S m 1,0 (X * ; A \u221e ).", "type": "figure"}, "FIGREF15": {"text": "A \u221e ), and corresponds to r m for m < 0. Proposition 3.15. Let m > 0, \u03c1 \u2208 [0, 1] and f \u2208 S", "type": "figure"}, "FIGREF17": {"text": "invertible. Its inverse belongs to B(H), which means that (f \u2212 z) (\u22121)B exists in M B (\u039e) and belongs to A B (\u039e). Furthermore, Theorem 4.1 of [13] also implies that Op A (f \u2212 z)B \u2208 A B (\u039e). One finally concludes by taking Proposition 3.15 into account.", "type": "figure"}, "FIGREF18": {"text": "For m > 0 and \u03c1 \u2208 [0, 1], any real-valued elliptic element f \u2208 S m \u03c1,0 (X * ; A \u221e ) defines an observable affiliated to the C * -algebra B B", "type": "figure"}, "FIGREF19": {"text": ", where Theorem 3.17 and Proposition 3.3 have been taken into account. Furthermore, the relation \u03a6(r z ) \u266f B = \u03a6(r z ) clearly holds. A general argument presented in [1, p. 364] allows now to extend in a unique way the map \u03a6 to a C * -algebra morphism C 0 (R) \u2192 B B A .", "type": "figure"}, "FIGREF20": {"text": "may be identified with an ideal of A\u22ca \u03c9 \u03b8 X [32, Prop. 2.2].", "type": "figure"}, "FIGREF21": {"text": "may be identified with the corresponding twisted crossed product C(Q)\u22ca \u03c9Q \u03b8 X . This follows from [32, Prop. 2.2] if A is separable. For the non-separable case, just perform obvious modifications in the proof of [8, Th. 2.10] to accommodate the 2-cocycle. Finally, by taking the isomorphisms \u03c0 Q introduced in Section 4.1 into account, the algebra C(Q)\u22ca \u03c9Q \u03b8 X is isomorphic to A Q \u22ca \u03c9Q \u03b8 X , and the canonical morphism \u03a0 Q : A\u22ca \u03c9 \u03b8", "type": "figure"}, "FIGREF22": {"text": "has been introduced in (3.1), and that this representation is irreducible and faithful [27, Prop. 2.17]. Furthermore, it is proved in the same reference that Rep A C 0 (X )\u22ca \u03c9 \u03b8 X is equal to K(H). If \u03a6 is an observable affiliated to A\u22ca \u03c9 \u03b8 X, then the l.h.s. term of (4.2) is equal to \u03c3 ess Rep A (\u03a6) , and it does not depend on a choice of A. We are now in a position to prove a concrete result for the calculation of the essential spectrum of any magnetic pseudodifferential operator. It consists essentially in an application of Proposition 4.1 together with a partial Fourier transformation. It also relies on the affiliation result obtained in Theorem 3.19. The components of the magnetic field B Q are defined by \u03c0 Q (B jk ).", "type": "figure"}, "FIGREF23": {"text": "Let m > 0, \u03c1 \u2208 [0, 1] and let Q \u2282 Q A define a covering of F A . Then, for any real-valued elliptic element f of S m \u03c1,0 (X * ; A \u221e ) one has", "type": "figure"}, "FIGREF24": {"text": ". The equality (4.2) can then be rewritten in this framework and for any observable f affiliated to B B A :", "type": "figure"}, "FIGREF25": {"text": "A given by the image of C 0 (X )\u22ca \u03c9 \u03b8 X through the map F. The result follows now from the central observation that\u03a0 Q [f ] is equal to f Q and by considering faithful representations of B B A through Op A and of B BQ AQ through Op AQ .", "type": "figure"}, "FIGREF26": {"text": "A \u221e ). For some z \u2208 C, we are first going to show that (f \u2212 z) (\u22121)B belongs to B B A by writing down a series for the inverse (f \u2212 z)f \u2212 z) \u22121 the pointwise inverse of f \u2212 z. Notice that (f \u2212 z)the k'th power of g with respect to \u266f B . By the asymptotic development, one knows that the reminder R z := (f \u2212 z) \u266f B (f \u2212 z). However, an additional argument is needed to show that the \u00b7 B -norm of R z is subunitary for suitable z, insuring the convergence of the Neumann series. For that purpose, we recall from Section 3 that R z B \u2261 R z A B (\u039e) := Op A (R z ) B(H) . Furthermore, from the magnetic Calderon-Vaillancourt theorem this norm can be estimated from above with expressions of the form sup", "type": "figure"}, "FIGREF27": {"text": "\u2212 z)](x \u2212 \u03c4 y, \u03be \u2212 \u03c4 \u03b7) [\u2202 b+\u03b1 \u2032 x \u2202 a+\u03b2 \u03be (f \u2212 z) \u22121 ](x \u2212 \u03c4 z, \u03be \u2212 \u03c4 \u03b6).", "type": "figure"}, "FIGREF28": {"text": "us first consider the simple situation, i.e. at least one of the multi-indices a-null. Then, by taking into account the above estimates, the explicit form of \u03a3 B and Lemma 2.10, one obtains that for any \u03c4 \u2208 [trivial inequality mentioned above has been used once for the first inequality. In the critical case, i.e. a = \u03b2 \u2032 = \u03b1 = b = d 1 = b 3 = \u03b4 1 = q 1 = 0, one has |\u03b2| = 1 because of the definition of R z given in (4.4). Thus, we are not in the exceptional case for G z and (4.5) always holds. So, let us consider the following inequalities: f (x \u2212 \u03c4 y, \u03be \u2212 \u03c4 \u03b7) \u2212 z f (x \u2212 \u03c4 z, \u03be \u2212 \u03c4 \u03b6)\u2202 xj f ] x \u2212 \u03c4 z + s\u03c4 (z \u2212 y), \u03be \u2212 \u03c4 \u03b6 + s\u03c4 (\u03b6 \u2212 \u03b7) f (x \u2212 \u03c4 z, \u03be \u2212 \u03c4 \u03b6)[\u2202 \u03bej f ] x \u2212 \u03c4 z + s\u03c4 (z \u2212 y), \u03be \u2212 \u03c4 \u03b6 + s\u03c4 (\u03b6 \u2212 \u03b7) f (x \u2212 \u03c4 z, \u03be \u2212 \u03c4 \u03b6) \u2212 z \u2264 1 + c f (x \u2212 \u03c4 z, \u03be \u2212 \u03c4 \u03b6)c, d independent of all variables and of z. By using these inequalities one obtains in the critical case:(x \u2212 \u03c4 y, \u03be \u2212 \u03c4 \u03b7) \u2212 z f (x \u2212 \u03c4 z, \u03be \u2212 \u03c4 \u03b6) \u2212 z |f (x \u2212 \u03c4 z, \u03be \u2212 \u03c4 \u03b6) \u2212 z| \u22121 \u03be \u2212 \u03c4 \u03b6", "type": "figure"}, "TABREF1": {"text": "2}, and thus the \u266f B -product in (2.8) is well defined in M B (\u039e), as explained in Section 2.1. Under the additional hypothesis that B jk \u2208 BC \u221e (X ), it has even been proved in [13, Thm. 2.2] (see also Remark 2.2) that the product belongs to S(\u039e) and can also be defined by the usual oscillatory integral techniques. Thus, thanks to Lemma 2.7, it only remains to show that for any", "type": "table"}, "TABREF2": {"text": "and \u03d5 qc 1 and \u03c8 qb 1 are bounded functions produced by derivating the factors z \u22122q and y \u22122q , respectively. By using the estimates obtained in Lemma 2.10 for \u2126", "type": "table"}, "TABREF3": {"text": "Theorem 2.11. Assume that the each component B jk belongs to A \u221e and let m 1 , m 2 \u2208 R and \u03c1 \u2208 (0, 1].", "type": "table"}}}
{"paper_id": "17784463", "_pdf_hash": "c655b97550afd238f52f307fba7359c2fcffd2a4", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "How does dispositional resiliency affect psychological processes followed by hurtful experience?", "authors": [{"first": "T", "middle": [], "last": "Otabe", "suffix": ""}, {"first": "K", "middle": [], "last": "Kato", "suffix": ""}, {"first": "", "middle": ["S"], "last": "Maruno", "suffix": ""}], "year": 2009, "venue": "Stress management research", "link": null}, "BIBREF1": {"title": "The causes, phenomenology, and consequences of hurt feelings", "authors": [{"first": "M", "middle": ["R"], "last": "Leary", "suffix": ""}, {"first": "C", "middle": [], "last": "Springer", "suffix": ""}, {"first": "L", "middle": [], "last": "Negel", "suffix": ""}, {"first": "E", "middle": [], "last": "Ansell", "suffix": ""}, {"first": "K", "middle": [], "last": "Evans", "suffix": ""}], "year": 1998, "venue": "Journal of personality and social psychology", "link": "144748940"}, "BIBREF2": {"title": "Positive change following trauma and adversity: A review", "authors": [{"first": "P", "middle": ["A"], "last": "Linley", "suffix": ""}, {"first": "S", "middle": [], "last": "Joseph", "suffix": ""}], "year": 2004, "venue": "Journal of traumatic stress", "link": "19585205"}, "BIBREF3": {"title": "The construct of resilience: A critical evaluation and guidelines for future work", "authors": [{"first": "S", "middle": ["S"], "last": "Luthar", "suffix": ""}, {"first": "D", "middle": [], "last": "Cicchetti", "suffix": ""}, {"first": "B", "middle": [], "last": "Becker", "suffix": ""}], "year": 2000, "venue": "Child development", "link": "10438513"}, "BIBREF4": {"title": "Time course changes of brain function related to emotional stress, The journal of electronics, information and communication engineers", "authors": [{"first": "T", "middle": [], "last": "Hayashi", "suffix": ""}, {"first": "Y", "middle": [], "last": "Mizuno", "suffix": ""}, {"first": "E", "middle": [], "last": "Okamoto", "suffix": ""}, {"first": "R", "middle": [], "last": "Ishii", "suffix": ""}, {"first": "S", "middle": [], "last": "Ukai", "suffix": ""}, {"first": "K", "middle": [], "last": "Shinosaki", "suffix": ""}], "year": 2008, "venue": "", "link": null}, "BIBREF5": {"title": "Physiological recovery responses to socially pleasant images in stress", "authors": [{"first": "D", "middle": [], "last": "Dhoi", "suffix": ""}, {"first": "S", "middle": [], "last": "Watanuki", "suffix": ""}], "year": 2012, "venue": "Japanese journal of physiological anthropology", "link": "148210112"}, "BIBREF6": {"title": "The Geneva affective picture database (GAPED): a new 730-picture database focusing on valence and normative significance", "authors": [{"first": "S", "middle": [], "last": "Elise", "suffix": ""}, {"first": "K", "middle": [], "last": "Dan-Glauser", "suffix": ""}, {"first": "R", "middle": [], "last": "Scherer", "suffix": ""}], "year": 2011, "venue": "Behavior research methods", "link": "207655542"}, "BIBREF7": {"title": "Negative appraisal and cognitive avoidance of intrusive memories in depression: A replication and extension", "authors": [{"first": "A", "middle": ["D"], "last": "Williams", "suffix": ""}, {"first": "B", "middle": ["A"], "last": "Hons", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "Moulds", "suffix": ""}], "year": 2008, "venue": "Depression and anxiety", "link": "9257266"}}, "ref_entries": {}}
{"paper_id": "17784949", "_pdf_hash": "3b9211e45e65a414f17adc3775cdc06cbaed6fc6", "abstract": [], "body_text": [], "bib_entries": {"BIBREF8": {"title": "Solid State Technology", "authors": [{"first": "", "middle": ["A C"], "last": "X9", "suffix": ""}, {"first": "", "middle": [], "last": "Adams", "suffix": ""}], "year": 1983, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "17784977", "_pdf_hash": "6b9e104652879b43d132ad9b0b35ff90f021ca0a", "abstract": [{"section": "Abstract", "text": "The present study was conducted to find out the ethambutol resistance pattern of indigenous isolates of Mycobacterium tuberculosis from Tuberculosis diagnosed human patients. A total of 172 specimens were collected from six different sources and comprised of 84.9% sputum, 10.5% pus and 4.7% bronchial washings. There were 70.9% males and 29.1% females with 84.30% pulmonary and 15.69% extrapulmonary tuberculosis. The Mycobacterium tuberculosis isolates collected from primary culture were further studied to determine their pattern and level of resistance. The inoculums were prepared using 0.5 Mac Farland turbidity standards. Five different concentration of ethambutol were used in Lowenstein Jensen (LJ) medium i.e. 2\u00b5g/ml, 4\u00b5g/ml, 6\u00b5g/ml, 8\u00b5g/ml and 10\u00b5g/ml for sensitivity testing. Data showed 10 (5.8%) resistant and 162 (94.2%) sensitive Mycobacterium tuberculosis out of total 172 clinical isolates. The growth was not inhibited at 1 st (2\u00b5g/ml) and 2 nd (4\u00b5g/ml) drug levels, while growth of 50% isolates inhibited at 3 rd level (6\u00b5g/ml), 30% inhibited at 4 th level (8\u00b5g/ml) and 20% at 5 th level (10\u00b5g/ml).", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "The last three levels are above the therapeutic index and not recommended in actual clinical practice. It is thus conceivable to explore some other more effective chemotherapeutic agents, modify combinations or find more effective procedures to stop morbidity and mortality due to ethambutol resistant Mycobacterium tuberculosis.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "isolates. The growth was not inhibited at 1 st (2\u00b5g/ml) and 2 nd (4\u00b5g/ml) drug levels, while growth of 50% isolates inhibited at 3 rd level (6\u00b5g/ml), 30% inhibited at 4 th level (8\u00b5g/ml) and 20% at 5 th level (10\u00b5g/ml).", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "The last three levels are above the therapeutic index and not recommended in actual clinical practice. It is thus conceivable to explore some other more effective chemotherapeutic agents, modify combinations or find more effective procedures to stop morbidity and mortality due to ethambutol resistant Mycobacterium tuberculosis.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Key words: Ethambutol; Mycobacterium tuberculosis; Resistance; Lowenstein Jensen medium; Human patients.", "cite_spans": [], "ref_spans": []}, {"section": "I IN NT TR RO OD DU UC CT TI IO ON N", "text": "Advancements in health care facilities offered a goal to eradicate tuberculosis (TB) by the end of the 20 th century, but it reemerged because of the global resistance against antitubercular drugs. The 95% of TB cases occur in developing countries (9) and the disease remained endemic for many decades (7) . Tuberculosis (TB) is the biggest killer of young adults in their economically most productive age. solution. The supernatant fluids were discarded and sediments were collected. These concentrated residues of sputum, pus and bronchial washings were used for primary culture.", "cite_spans": [{"start": 248, "end": 251, "text": "(9)", "ref_id": "BIBREF11"}, {"start": 302, "end": 305, "text": "(7)", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "MATERIALS AND METHODS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Collection and Processing of Samples", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Preparation and inoculation of Lowenstein Jensen (LJ) Medium", "text": "Lowenstein Jensen medium was prepared by the method described by Nazir et al. ", "cite_spans": [], "ref_spans": []}, {"section": "Preparation of inoculums of Mycobacterium tuberculosis", "text": "The over seeding of a drug containing medium was used in LJ medium i.e. 2\u00b5g/ml, 4\u00b5g/ml, 6\u00b5g/ml, 8\u00b5g/ml and 10\u00b5g/ml. Each LJ medium slant was inoculated by using the above inoculums prepared from primary cultures of Mycobacterium tuberculosis and incubated at 37 o C for 4", "cite_spans": [], "ref_spans": []}, {"section": "Preparation of inoculums of Mycobacterium tuberculosis", "text": "weeks.", "cite_spans": [], "ref_spans": []}, {"section": "Recording and interpretation of results", "text": "The Bijoux bottles were inspected weekly for appearance of growth. When the growth was evident on LJ medium, colony morphology was noted. One culture bottle was exposed to day light for one hour and re-incubated to be examined for were found resistant at 1 st (2\u00b5g/ml) and 2 nd (4\u00b5g/ml) levels.", "cite_spans": [], "ref_spans": []}, {"section": "Recording and interpretation of results", "text": "The 5 (50%) isolates were resistant up to 3 rd level (6\u00b5g/ml), 3(30%) up to 4 th level (8\u00b5g/ml), and 2 (20%) at higher than 5", "cite_spans": [], "ref_spans": []}, {"section": "Recording and interpretation of results", "text": "th Ethambutol resistance of M. tuberculosis level (>10\u00b5g/ml) ( Table 1) . These concentrations incorporated in LJ medium exceed the therapeutic ranges of 3-5\u00b5g/ml (1), 2-5\u00b5g/ml (6) and 4-6\u00b5g/ml (11) . These exceeding than the mentioned plasma concentrations may introduce toxicity in actual clinical practice. The most important adverse effects of ethambutol are optic neuritis (diminished visual acuity and loss of ability to discriminate red and green colors), blurred vision, and decreased urate excretion which may lead to gout (11) .", "cite_spans": [], "ref_spans": [{"start": 63, "end": 71, "text": "Table 1)", "ref_id": "TABREF1"}]}, {"section": "Recording and interpretation of results", "text": "Additionally drug fever, abdominal pain, headache, dizziness and confusion may also occur. Discontinuation of the drug results in reversal of the toxic symptoms (6). ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Basic and Clinical Pharmacology", "authors": [{"first": "G", "middle": ["K"], "last": "Bertram", "suffix": ""}], "year": 2004, "venue": "", "link": null}, "BIBREF2": {"title": "Clustering of multi-drug resistant tuberculosis cases from nine European countries", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF3": {"title": "Sensitivity Pattern of Mycobacterium tuberculosis at Lahore, Pakistan", "authors": [{"first": "M", "middle": ["A"], "last": "Haq", "suffix": ""}, {"first": "S", "middle": ["R"], "last": "Khan", "suffix": ""}, {"first": "S", "middle": ["U"], "last": "Saeed", "suffix": ""}, {"first": "S", "middle": [], "last": "Iqbal", "suffix": ""}, {"first": "R", "middle": [], "last": "Shabbir", "suffix": ""}, {"first": "J", "middle": [], "last": "Magsi", "suffix": ""}], "year": 2002, "venue": "Annals King Edwards Med.Univ", "link": "80606985"}, "BIBREF4": {"title": "Multidrug resistance pulmonary tuberculosis", "authors": [{"first": "T", "middle": [], "last": "Herendra", "suffix": ""}, {"first": "J", "middle": ["R"], "last": "Shah", "suffix": ""}], "year": 1998, "venue": "Ind. J. Tubercul", "link": null}, "BIBREF5": {"title": "Increasing resistance of Mycobacterium tuberculosis to anti-TB drugs in Saudi Arabia", "authors": [{"first": "M", "middle": ["Y"], "last": "Khan", "suffix": ""}, {"first": "A", "middle": ["J"], "last": "Kinsara", "suffix": ""}, {"first": "A", "middle": ["O"], "last": "Osoba", "suffix": ""}], "year": 2001, "venue": "Int. J. Antimicrob", "link": null}, "BIBREF8": {"title": "Antimicrobial susceptibility determined by the E-test, Lowenstein Jensen proportion, and DNA sequencing methods among Mycobacterium tuberculosis isolates -discrepancies", "authors": [{"first": "I", "middle": [], "last": "Maria", "suffix": ""}, {"first": "F", "middle": [], "last": "Moura", "suffix": ""}, {"first": "P", "middle": ["C S"], "last": "Caldas", "suffix": ""}, {"first": "A", "middle": [], "last": "Said", "suffix": ""}, {"first": "F", "middle": [], "last": "Martins", "suffix": ""}, {"first": "C", "middle": ["R"], "last": "Brito", "suffix": ""}], "year": 2004, "venue": "", "link": "12814479"}, "BIBREF10": {"title": "Pyrazinamide resistance of Mycobacterium tuberculosis strains isolated from human patients", "authors": [{"first": "T", "middle": [], "last": "Nazir", "suffix": ""}, {"first": "A", "middle": [], "last": "Hameed", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "Akhtar", "suffix": ""}, {"first": "E", "middle": [], "last": "Shabbir", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Qureshi", "suffix": ""}, {"first": "A", "middle": [], "last": "Malik", "suffix": ""}, {"first": "M", "middle": ["N"], "last": "Qaisar", "suffix": ""}], "year": 2008, "venue": "Pharmacol. Online", "link": null}, "BIBREF11": {"title": "Global surveillance for anti-tuberculosis drug resistance", "authors": [{"first": "M", "middle": ["A"], "last": "Pablos", "suffix": ""}, {"first": "M", "middle": ["C"], "last": "Raviglione", "suffix": ""}, {"first": "A", "middle": [], "last": "Laszlo", "suffix": ""}, {"first": "N", "middle": [], "last": "Binkin", "suffix": ""}, {"first": "H", "middle": ["L"], "last": "Rieder", "suffix": ""}, {"first": "F", "middle": [], "last": "Bustreo", "suffix": ""}, {"first": "D", "middle": ["L"], "last": "Cohn", "suffix": ""}, {"first": "C", "middle": ["S B"], "last": "Lambregts", "suffix": ""}, {"first": "S", "middle": ["J"], "last": "Kim", "suffix": ""}, {"first": "P", "middle": [], "last": "Chaulet", "suffix": ""}, {"first": "P", "middle": [], "last": "Nunn", "suffix": ""}], "year": 1998, "venue": "Engl. J. Med", "link": null}, "BIBREF12": {"title": "Ethambutol resistance of M. tuberculosis", "authors": [{"first": "T", "middle": [], "last": "Nazir", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF14": {"title": "Incidence and drug susceptibility pattern of Mycobacterium tuberculosis in HIV infected patients. Military J. Armed Forces Ind", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF16": {"title": "Lippincott' s Illustrated reviews: Pharmacology", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF17": {"title": "Inhibition of synthesis of arabinogalactan by ethambutol in Mycobacterium smegmatis", "authors": [{"first": "K", "middle": [], "last": "Takayama", "suffix": ""}, {"first": "J", "middle": ["O"], "last": "Kilburn", "suffix": ""}], "year": 1989, "venue": "", "link": "8518079"}, "BIBREF19": {"title": "Attention to gender issues in tuberculosis control", "authors": [{"first": "M", "middle": ["W"], "last": "Uplekar", "suffix": ""}, {"first": "S", "middle": [], "last": "Rangan", "suffix": ""}, {"first": "M", "middle": ["G"], "last": "Weiss", "suffix": ""}, {"first": "J", "middle": [], "last": "Ogden", "suffix": ""}, {"first": "M", "middle": ["W"], "last": "Borgdorff", "suffix": ""}], "year": 2001, "venue": "Int. J. Tubercul. Lung Dis", "link": "32423863"}, "BIBREF20": {"title": "World Heath Organization Surveillance of drug resistant tuberculosis in South East Asia", "authors": [], "year": 2004, "venue": "WHO", "link": null}, "BIBREF21": {"title": "Anti-tuberculosis drug resistance in the world report No. 2, prevalence and trends", "authors": [{"first": "", "middle": [], "last": "Who/Iualtd", "suffix": ""}], "year": 2000, "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "EmbCAB proteins are believed to be integral membrane proteins, consistent with their role in the synthesis of various arabinan-linkage motifs of the arabinogalactan and lipoarabinomannan. Planned and supervised therapy with judicious surgical interference is the only way to ensure cure for the patient and prevention of the spread of drug resistance (4). Ethambutol is a bacteriostatic drug and specific for most strains of Mycobacterium tuberculosis and Mycobacterium kansasi. The objective of this investigation was to study the pattern and level of resistance of indigenous Mycobacterium tuberculosis isolated from tuberculosis diagnosed human patients against ethambutol which is the 1 st line antitubercular drug.", "type": "figure"}, "FIGREF1": {"text": "Pure chemical of ethambutol was obtained from the Schazoo Laboratories (Pvt.), Lahore. A total number of 172 pulmonary and extra-pulmonary tuberculosis diagnosed (AFB positive) patients were selected from six different sources. The patients of all age groups were selected, regardless of their age, gender and previous therapeutic profile. The sputum, pus and bronchial washings were collected, labeled and stored, separately. All the samples were centrifuged at 1500 rpm for 15 minutes and decontaminated with NaOH 40g/ L (4%w/v)", "type": "figure"}, "FIGREF2": {"text": "and used for primary culturing of the processed samples. A 15ml of medium was poured into sterilized 25mL McCartney vials and closed with sterilized silver caps. The medium was autoclaved at 115 o C under 15 lb/inch 2 pressure for 20 minutes. Then it was solidified in slanting position, cooled, labeled and stored at 2-8 o C. The LJ medium slants were inoculated with processed samples in class-II safety cabinet (Telstar, Spain). The inoculated slants were kept in incubator at 37 o C for 4 weeks. The growth of M. tuberculosis thus obtained was identified though Acid Fast staining and further used for sensitivity testing.", "type": "figure"}, "FIGREF3": {"text": "prevented by standardization of inoculums that mitigate the possibility of miss judgment of considering the resistance to a susceptible strain. Approximately 1mg wet weight bacilli/ml was estimated to vary between 10 6 and 10 8 CFU. The representative samples of growth containing minimally 50 colonies were taken from primary culture and placed into McCartney vials containing 1mL of distilled water and 5 glass beads. The mixtures were homogenized by vigorous stirring by Vortex Mixer (Eyela, Japan) for 1-3 minutes and left in class-II safety cabinet (Telstar, Spain). The opacity of the suspensions was adjusted by the addition of sterile distilled water to that of a 0.5 Mac Farland turbidity standard. Four serial 10 fold dilutions of inoculums were prepared i.e. 10 -1 , 10 -2 , 10 -3 and 10 - 4 in sterilized test tubes and labeled as 1, 2, 3 and 4, respectively. The tube No. 3 of dilution inoculums of 10Susceptibility testing of Mycobacterium tuberculosis The drug sensitivity testing was performed within 1-2 weeks after obtaining primary growth of M. tuberculosis. The sensitivity was evaluated against ethambutol by drug proportion method as recommended by WHO and International Union against Tuberculosis and Lung Diseases (15). The patient's samples were processed in batches of 10-15 specimens on drug containing LJ medium and drug free control LJ medium. Five different concentration of ethambutol were", "type": "figure"}, "FIGREF4": {"text": "pigmentation on the following day. The cultures with no growth were discarded after 8 weeks of incubation. The presence and amount of growth in term of number of colonies on control and drug inoculated medium recorded. The results were interpreted for resistance on the basis of percentage of colonies on drug containing media in comparison to the growth on drug free medium. The strains showing susceptibility were again incubated and examined at 6 weeks before declaring as sensitive. The growth pattern, number of colonies and contamination were checked carefully on weekly basis. RESULTS AND DISCUSSION A total number of 172 samples were collected from six different local sources i.e. 41(23.8%) Outdoor, Mayo Hospital, 110(64%) Indoor, Mayo Hospital, 14(8.1%) Jinnah Hospital,15.69%) extra-pulmonary tuberculosis cases. These findings are in conformity with Bitar et al. (2) who also reported that majority of cases 89% (n=607) were of pulmonary, 6%(n=39) presenting extra-pulmonary tuberculosis and 5%(n=37) cases for whom site of disease was unknown. There were 122(70.9%) males and 50 (29.1%) females out of total 172 clinical isolates. Gender comparison depicts greater percentage of tuberculosis in males than females. These findings have been substantiated by Uplekar et al. (13) who reported a seventy percent (70%) excess of males over females globally each year. The reasons for this difference are unclear as yet. The findings of this study are also consistent with the findings of Haq et al. [3] who also reported 68% male and 32% female tuberculosis patients. Our findings are also in conformity with WHO/ IUALTD (15) which reported 67% of male tuberculosis patients. The critical concentration of Ethambutol maintained in LJ media to consider as border line for declaration of resistant was 2\u00b5g/ml. The results of this study showed 10 (5.8%) resistant and 162 (94.2%) sensitive out of total 172 clinical isolates of indigenous Mycobacterium tuberculosis. Quantitatively out of 10 resistant isolates on LJ medium, 1 (10%) had 10 colonies and 9 (90%) had 100 colonies. Our findings are in line with the reports of WHO/ IUALTD, (15) which reported ethambutol resistance as 5.8% in Iran and 4.1% in china. These finding are also in conformity with Bitar et al. (2) who reported 4.4% ethambutol resistance. These results are similar to Khan et al. (5) who reported markedly increased resistance in Saudi Arabia during the last 5 years, except pyrazinamide and ethambutol showing resistance of 8% & 7%, respectively. The indigenous Mycobacterium tuberculosis isolates were also inoculated in the medium containing five different ethambutol concentrations/levels. All of the 10 (100%) isolates", "type": "figure"}, "TABREF0": {"text": "Nine million new cases of TB occur every year. Two million people died annually, that makes it the biggest killer after HIV. Poorly implemented directly observed treatment strategy (DOTS)", "type": "table"}, "TABREF1": {"text": "Level of ethambutol resistance (% age) among indigenous Mycobacterium tuberculosis Ethambutol Concentrations (\u00b5g/ ml)(20%) inhibited at higher than 5 th level (>10\u00b5g/ml). These concentrations can not be maintained without the risk of sever health hazards, therefore not recommended for use in actual chemotherapeutic practice. The findings of this study are in line with the work of WHO/ IUALTD (15) which reportedth level. These finding are also in conformity with the work of Praharaj et al. (10) who reported the resistance of ethambutol above than the critical concentration of 2\u00b5g/ ml. During this study, the most seriously ill tuberculosis patients were generally seen in hospitals, requiring special attention. They might also contribute to the spread of contagious nosocomial tubercular infection in the society. The epidemiological data has pointed out five time higher prevalence of pulmonary tuberculosis than extra-pulmonary tuberculosis. Approximately 1/16 of total Mycobacterium tuberculosis isolates were resistant to ethambutol. Maximum resistance was observed at 1 st & 2 nd drug levels and minimum at above than 5 th level. The final concentrations incorporated in LJ medium have exceeded the therapeutic index, thus not recommended in actual clinical practice. Therefore we have to treat resistant patients by replacing and modifying the existing drugs or by exploring some other novel and more effective methods to stop the morbidity and mortality due to the ethambutol resistant Mycobacterium tuberculosis.", "type": "table"}}}
{"paper_id": "17785044", "_pdf_hash": "3c3f41a3f2d60ae7b0d8a299f4828a5f10b88b3c", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
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{"paper_id": "17785409", "_pdf_hash": "f12862d0408ce899ba60a0c9eba95106ebd2d3cf", "abstract": [{"section": "Abstract", "text": "Different classical theories are commonly applied in various branches of physics to describe the relativistic dynamics of electrons by coupled equations for the orbital motion and spin precession. Exemplarily, we benchmark the Frenkel model and the classical Foldy-Wouthuysen model with spin-dependent forces (Stern-Gerlach forces) to the quantum dynamics as predicted by the Dirac equation. Both classical theories can lead to different or even contradicting predictions how the Stern-Gerlach forces modify the electron's orbital motion, when the electron moves in strong electromagnetic field configurations of emerging high-intensity laser facilities. In this way, one may evaluate the validity and identify the limits of these classical theories via a comparison with possible experiments to provide a proper description of spin-induced dynamics. Our results indicate that the Foldy-Wouthuysen model is qualitatively in better agreement with the Dirac theory than the widely used Frenkel model.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "The electron couples to external electromagnetic fields via its charge as well as via its spin. Gradients of the electromagnetic fields induce a spin-dependent force in addition to the Lorentz force. Spin-dependent motion is implemented in the seminal Stern-Gerlach experiment 1 and variants thereof 2,3 . Effects of spin-dependent forces appear in condensed matter 4 , in astrophysical systems 5 , in quantum plasmas 6, 7 , and at relativistic electrons in strong electromagnetic fields [8] [9] [10] [11] [12] [13] . A consistent theoretical framework for the description of particles with internal angular momentum is provided by the Dirac equation 14 . The application of this quantum-mechanical theory, however, is not always feasible and/or necessary if quantum effects are not important. Classical models of charged point-like particles with spin in electromagnetic fields are appealing because they are usually simpler from a mathematical point of view than the Dirac equation and are easier to interpret. A first covariant theory to describe the dynamics of a charged particle with spin was proposed by Frenkel in 1926 by purely classical considerations 15 . The Frenkel model has been employed in many studies and continues stimulating new research [16] [17] [18] [19] [20] [21] . Considering that the spin was introduced as an intrinsic quantum feature of the electron 22 it may, however, appear appropriate to start from quantum theory to find a classical model for the electron. Such a model can be derived from relativistic quantum theory by applying the correspondence principle to the Heisenberg equation for the time evolution of the position, the kinematic momentum, and the spin in the Foldy-Wouthuysen representations of the Dirac equation 23, 24 . Both kinds of classical models are currently employed in different branches of physics, e. g., the classical Foldy-Wouthuysen model in gravitational fields 25 or in crystals 26 , and the Frenkel model in astrophysics 5 or in plasma fields 27 . Nevertheless, the validity and the limits of those classical models have not been studied, e. g., by a comparison to the Dirac theory. The lack of a widely accepted classical description of the electron is deeply related to interpretation problems regarding kinematic momentum operators in the Dirac theory 28 and identifying an accurate classical model may also facilitate insights into quantum theory and will be valuable for systems where quantum descriptions are too complex such as for many-particle systems in extreme laser pulses.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "The dynamics of a classical particle with rest mass m, charge q, and internal spin degree of freedom are governed by the modified Lorentz equation", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "which incorporates the model-specific spin-dependent force F ", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Here, \u03c4 denotes the proper time of the particle with d\u03c4 = dt/\u03b3, u \u03b1 = dr \u03b1 /d\u03c4 = (\u03b3c, \u2212p/m) T the four-velocity, r \u03b1 = (ct, \u2212r) The classical spin vector in the rest frame s of length /2 is proportional to the particle's polarisation and corresponds to the spin operator in quantum mechanics. The spin-dependent forces may be written for the classical Foldy-Wouthuysen model (FW) and the Frenkel model (F) as 15, 23 ", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "The electron couples to external electromagnetic fields via its charge as well as via its spin. Gradients of the electromagnetic fields induce a spin-dependent force in addition to the Lorentz force. Spin-dependent motion is implemented in the seminal Stern-Gerlach experiment 1 and variants thereof 2, 3 . Effects of spin-dependent forces appear in condensed matter 4 , in astrophysical systems 5 , in quantum plasmas 6, 7 , and at relativistic electrons in strong electromagnetic fields [8] [9] [10] [11] [12] [13] . A consistent theoretical framework for the description of particles with internal angular momentum is provided by the Dirac equation 14 . The application of this quantum-mechanical theory, however, is not always feasible and/or necessary if quantum effects are not important. Classical models of charged point-like particles with spin in electromagnetic fields are appealing because they are usually simpler from a mathematical point of view than the Dirac equation and are easier to interpret. A first covariant theory to describe the dynamics of a charged particle with spin was proposed by Frenkel in 1926 by purely classical considerations 15 . The Frenkel model has been employed in many studies and continues stimulating new research [16] [17] [18] [19] [20] [21] . Considering that the spin was introduced as an intrinsic quantum feature of the electron 22 it may, however, appear appropriate to start from quantum theory to find a classical model for the electron. Such a model can be derived from relativistic quantum theory by applying the correspondence principle to the Heisenberg equation for the time evolution of the position, the kinematic momentum, and the spin in the Foldy-Wouthuysen representations of the Dirac equation 23, 24 . Both kinds of classical models are currently employed in different branches of physics, e. g., the classical Foldy-Wouthuysen model in gravitational fields 25 or in crystals 26 , and the Frenkel model in astrophysics 5 or in plasma fields 27 . Nevertheless, the validity and the limits of those classical models have not been studied, e. g., by a comparison to the Dirac theory. The lack of a widely accepted classical description of the electron is deeply related to interpretation problems regarding kinematic momentum operators in the Dirac theory 28 and identifying an accurate classical model may also facilitate insights into quantum theory and will be valuable for systems where quantum descriptions are too complex such as for many-particle systems in extreme laser pulses.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "The dynamics of a classical particle with rest mass m, charge q, and internal spin degree of freedom are governed by the modified Lorentz equation", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "which incorporates the model-specific spin-dependent force", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "T , and the Thomas-Bargmann-Michel-Telegdi equation 29, 30 ", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "Here, \u03c4 denotes the proper time of the particle with d\u03c4 = dt/\u03b3,", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "T the time-space coordinate, \u03b3 = 1 + p 2 /(mc) 2 the relativistic Lorentz factor, c the speed of light, F \u03b1\u03b2 the electrodynamic field tensor, p the kinematic momentum, M the effective mass, S \u03b1 = (S 0 , S) T the spin's four-vector in the laboratory frame with", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "The classical spin vector in the rest frame s of length /2 is proportional to the particle's polarisation and corresponds to the spin operator in quantum mechanics. The spin-dependent forces may be written for the classical Foldy-Wouthuysen model (FW) and the Frenkel model (F) as 15, 23 with the scalars U FW and U F defined as", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "The effective masses in these two models are M FW = m and", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": ", respectively. The forces (3a) and (3b) become equal in the limit of low electron energies. The classical Foldy-Wouthuysen and the Frenkel models differ mainly in the large-kinematic-momentum limit.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "The spin-dependent forces (3a) and (3b) are gradient forces, which become large in systems of ultra strong laser fields in the short-wavelength limit. In the following, we consider the interaction of relativistic electrons with strong electromagnetic fields in the X-ray regime. The electron moves initially in x direction opposite to the plane-wave laser pulse, which is assumed to have linear polarisation in y direction and to be modulated by a sin 2 -shaped envelope. At time zero, the front of the laser pulse reaches the origin of the coordinate system, where the electron is initially located. The electron's initial spin orientation is parallel or anti-parallel to the direction of the magnetic field (z direction), representing spin up (indicated by \u2191) or down (indicated by \u2193) states. Note that as a consequence of equation (1b) the spin remains in its initial state for all times for the considered setup.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "Due to the spin-dependent forces, the electron's trajectory depends on the spin orientation. Although the influence of the spin on the shape of the trajectory is very small, the spindependent force may be used to compare the three models. In the classical models the total force can be split directly into a Lorentz force part and a spin force part (see equation (1a)), which is not possible in the framework of the Dirac equation. Therefore, the magnitude of the spin-dependent force is evaluated by calculating the difference of the total forces F \u2191 and F \u2193 for the trajectories of electrons with initial spin parallel and anti-parallel to the z direction. For symmetry reasons the net effect of the plane-wave pulse on the electron momentum vanishes in the Frenkel model as well as the classical Foldy-Wouthuysen model, although both models predict different forces acting on the electron during its interaction with the laser pulse. Therefore, a plane-wave ", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "2 \u03b3 2 \u2212 1/(|q|\u03bb), which causes a strong acceleration of the electron opposite to its initial velocity but without reflecting it. Other parameters are the wavelength \u03bb = 800 nm, the duration (number of cycles) n = 20, and focus radius w 0 = 2\u03bb.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "setup is not suitable to test the classical models experimentally. However, considering focused infrared laser pulses of upcoming high-power laser facilities the discrepancy in the predicted electron dynamics by the classical Foldy-Wouthuysen and the Frenkel models becomes large enough to distinguish between them experimentally.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "An electron, which is initially directed towards the focus of a counter-propagating high-intensity laser pulse with linear polarisation, is displaced transversely due to the transverse electric field. When the oscillating field changes its sign, the force drives the electron back to its initial transverse position. However, this force is smaller than the expelling force due to the focusing inhomogeneity. As a result, the oscillation centre of a spinless charged particle drifts radially from the spot centre, which is called ponderomotive scattering 31 . Beside the deflection of a charged particle in the ponderomotive potential of the laser fields, the spin may induce a further deflection via the spin-dependent forces (3a) and (3b), in particular, if the electron is polarised parallel or anti-parallel to the direction of the magnetic field. As the spin is (anti-)parallel to the magnetic field direction it follows from equation (1) that the electron remains in the plane perpendicular to the magnetic field direction and the electron's spin is frozen to its initial state. The deflection of a particle in the ponderomotive potential of the focused laser pulse is defined by the angle \u03b8 between its initial momentum and its final momentum after the particle is separated from the laser fields. It is dominated by the ponderomotive scattering due to the dominant Lorentz force, which increases with increasing field strength.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "Besides the deflection due to the charge, the electron's spin state leads to a modification of the deflection angle \u03b8, which depends on the spin orientation. In this way, one can define the aberration angle \u2206\u03b8 = \u03b8 \u2191 \u2212 \u03b8 \u2193 , where \u03b8 \u2191 and \u03b8 \u2193 denote the deflection angles for the spin-up and spin-down cases, see also Methods section. The Frenkel and the classical FoldyWouthuysen models lead to different aberrations \u2206\u03b8, as shown in figure 2 for varying electron energies. As indicated in the inset, the two models share the same non-relativistic limit. In the relativistic regime, the angle \u2206\u03b8 as predicted by the classical Foldy-Wouthuysen model does not vary with the electron's initial energy monotonically and it may even change its sign. Furthermore, the absolute value of the spin-induced additional deflection angle \u2206\u03b8 FW from the classical Foldy-Wouthuysen model remains under the magnitude of 10 \u22126 rad and decreases with the electron's initial energy in the relativistic parameter regime. In contrast to the classical Foldy-Wouthuysen model, the aberration angle of the Frenkel model \u2206\u03b8 F increases to about 0.05 rad with the electron's energy for relativistic electrons in high-intensity laser fields of the applied parameters.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "We have investigated the dynamics of electrons in various setups by applying two different classical models, the classical Foldy-Wouthuysen and the Frenkel models. The predictions of these classical models were compared to each other and to predictions by the Dirac equation, when a numerical solution of the Dirac equation was feasible. In specific parameter regimes, these classical models can lead to conflicting predictions. The Frenkel model may be of timely interest 5, 27, 32 and prominent 33, 34 for its much longer history and its wide application 35, 36 . The classical Foldy-Wouthuysen model, however, may be superior as it is qualitatively in better agreement with the quantum mechanical Dirac equation.", "cite_spans": [{"start": 497, "end": 500, "text": "33,", "ref_id": "BIBREF32"}], "ref_spans": []}, {"section": "Discussion", "text": "The discrepancies in the predictions of the two classical models may become experimentally detectable in light-matter interaction in strong highly focused beams. As electron bunches with the emittance as low as 10 \u22123 rad have been prepared 37 , the spin-induced aberration angle of the order of 10 \u22122 rad from the Frenkel model is potentially measurable, if an electron beam with an energy of tens of MeV and an infrared laser of the intensity \u223c 10 22 W/cm 2 are applied as discussed above. The spin-induced contribution to the deflection as predicted by the classical Foldy-Wouthuysen model, which is for the applied parameters of the order of 10 \u22126 rad, is too small to be demonstrated. However, a differentiation among both predictions appears feasible. In current head-on experiments 38, 39 with focused fields of high inhomogeneities and energetic electrons no significant spin effect in orbital motion was observed. The lack of experimental evidence for a non-negligible spin-induced deflection may be seen as a superiority of the classical FoldyWouthuysen model again regarding spin modified dynamics.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "For the plane-wave setup, the laser pulse is assumed to have linear polarisation in the y direction and is modulated by a sin 2 -shaped envelope", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "where \u03b8(\u03b7) denotes the Heaviside step function. Introducing the wavelength \u03bb, the peak amplitude\u00ca, and the pulse width n measured in laser cycles, the electric field component of the laser pulse is given by", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "and the magnetic field component follows via B(r, t) = e x \u00d7 E(r, t)/c. At time zero the front of the laser pulse reaches the origin of the coordinate system, where the electron is initially located. The electron's initial spin orientation is parallel or anti-parallel to the direction of the magnetic field (z direction). We solved the equations of motion of the classical Foldy-Wouthuysen model and the Frenkel model for the planewave setup numerically via the Boris algorithm 40 . The timedependent Dirac equation for a two-dimensional wavepacket in the same setup was propagated numerically employing a Fourier split operator method [41] [42] [43] [44] . In order not to violate the quantum-classical correspondence between classical operators and quantum mechanical operators, the Dirac wavepacket was prepared to have a small width compared to the wavelength of the applied electromagnetic field 45 . The force, which acts on the electron during its interaction with the plane-wave electromagnetic field and which enters in figure 1 , is given by equations (3a) and (3b). In the case of the Dirac equation, the force was determined as the time derivative of the quantum mechanical expectation value of the electron's kinematic momentum \u03a8(r, t)| \u2212 i \u2207 \u2212 q A(r, t)|\u03a8(r, t) , where \u03a8(r, t) is the electron's four-component wave function and A(r, t) the vector potential of the electromagnetic fields.", "cite_spans": [], "ref_spans": [{"start": 1030, "end": 1038, "text": "figure 1", "ref_id": "FIGREF0"}]}, {"section": "Methods", "text": "For the setup with a focused infrared laser pulse, numerical solutions of the Dirac equation are not feasible due to the long time scale of infrared laser pulses. A longer pulse length in combination with wavepacket spreading leads to a \u03bb 3 -or \u03bb 4 -scaling of the computational demand to solve the Dirac equation in two or respectively three dimensions. Thus numerical simulations were limited to the two classical models.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "The polarisation and the longitudinal (in propagation direction) profile of the focused laser pulse are as in the plane-wave case. The transverse profile and the phase are modelled as a Gaussian beam with the transversal focus radius w 0 , e. g. with terms up to the 5th order of the small diffraction angle = w 0 /x r as in Ref. 46 , where x r = \u03c0w 2 0 /\u03bb is the Rayleigh length. The phase of the focused pulse depends not only on the longitudinal coordinate but also on the transverse coordinate. The deflection of an electron in a head-on collision with a focused laser pulse is defined by the angle between the final transverse and the longitudinal momentum components after the particle is separated from the laser fields. Due to spin-dependent forces the deflection depends on the electron's initial spin orientation (relative to the magnetic field direction). In this way, the aberration angle \u2206\u03b8 is defined as the angle between the final momenta for electrons with initial spin-up and spin-down orientation, see figure 3 .", "cite_spans": [], "ref_spans": [{"start": 1020, "end": 1028, "text": "figure 3", "ref_id": "FIGREF3"}]}, {"section": "Methods", "text": "The considered setup with the employed parameters is also sensitive to radiative reaction forces. Our calculations involving both spin and radiative reaction forces (via the LandauLifshitz equation 47 ) have, however, confirmed that the key deviations displayed in figure 2 are not essentially modified such as especially the strong rise of the aberration angle \u2206\u03b8 for the Frenkel model as compared to the Foldy-Wouthuysen model in the highly relativistic regime. Because of this and since the Landau-Lifshitz equation has not been confirmed experimentally as well, we decided here to present comparisons not including the radiative reaction forces.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF25": {"title": "Journal of Surface Investigation. X-ray, Synchrotron and Neutron Techniques", "authors": [{"first": "A", "middle": ["J"], "last": "Silenko", "suffix": ""}], "year": 2015, "venue": "", "link": null}, "BIBREF32": {"title": "Electrodynamics and Classical Theory of Fields and Particles", "authors": [{"first": "A", "middle": ["O"], "last": "Barut", "suffix": ""}], "year": 1980, "venue": "", "link": "117443371"}, "BIBREF33": {"title": "Classical and quantum theories of spinning particles", "authors": [{"first": "H", "middle": ["C"], "last": "Corben", "suffix": ""}], "year": 1968, "venue": "", "link": "123146785"}, "BIBREF39": {"title": "Plasma Physics via Computer Simulation, Series in Plasma Physics", "authors": [{"first": "C", "middle": ["K B"], "last": "Birdsall &amp; A", "suffix": ""}, {"first": "", "middle": [], "last": "Langdon", "suffix": ""}], "year": 2005, "venue": "", "link": null}, "BIBREF46": {"title": "The Classical Theory of Fields", "authors": [{"first": "L", "middle": ["D M"], "last": "Landau &amp; E", "suffix": ""}, {"first": "", "middle": [], "last": "Lifshitz", "suffix": ""}], "year": 1980, "venue": "", "link": "125206824"}}, "ref_entries": {"FIGREF0": {"text": "Figure 1: Difference between the force components in laser propagation direction for electrons in a strong plane-wave laser pulse with initial spin orientation parallel or anti-parallel to the magnetic field direction as predicted by the various considered models. The four sub-figures correspond to different initial electron momenta opposite to the propagation direction of the laser pulse. (a): p = (0, 0, 0) T ; (b): p = (\u2212mc, 0, 0) T ; (c) and (d): p = (\u22122mc, 0, 0) T . Sub-figures (c) and (d) show the same data but on different scales. Laser parameters are peak electric field strength\u00ca = 2.57 \u00d7 10 15 V/m, wavelengths \u03bb = 1.06 nm, the pulse length equals n = 6 cycles. In case of the Dirac equation the wavepacket had an initial width of 0.026 nm.", "type": "figure"}, "FIGREF1": {"text": "shows the x compo- nent of F \u2191 \u2212 F \u2193 as a function of time t as determined from the Dirac equation, the classical Foldy-Wouthuysen model, and the Frenkel model. For zero initial momentum, the three models yield very similar results, as shown in figure 1(a). In partic- ular, the predictions of the Dirac equation and the classical Foldy-Wouthuysen model for the force difference F \u2191,x \u2212 F \u2193,x match very well and the prediction of the Frenkel model shows only small deviations from the other two models. The quali- tative predictions of the various models diverge with growing initial electron momentum, see figure 1(b)-(d). The Frenkel model predicts that the force difference becomes larger for relativistic electrons, while the Dirac equation and the classi- cal Foldy-Wouthuysen model yield smaller force differences. The qualitatively different behaviour of the Frenkel model and the classical Foldy-Wouthuysen model is a consequence of a different dependence on \u03b3 of the spin-dependent forces (3a) and (3b).", "type": "figure"}, "FIGREF3": {"text": "Figure 3: Definition of the aberration angle \u2206\u03b8. Lines represent trajectories of a highly energetic electron with initial \u03b3 = 100 in a focused laser pulse with the wavelength \u03bb = 800 nm, the amplitude of strength\u00ca = 8.03 \u00d7 10 14 V/m, the duration (number of cycles) n = 20, and focus radius w 0 = 2\u03bb. The solid and dashed curves correspond to those of electrons with the spin parallel to the z axis and anti-parallel to the z axis (magnetic field direction), respectively, as described by the Frenkel model. The deflection angle for the Frenkel model is indicated by \u2206\u03b8 F .", "type": "figure"}}}
{"paper_id": "17785718", "_pdf_hash": "fd8ef7098cbc17b1b39431598250a10490a172aa", "abstract": [{"section": "Abstract", "text": "Water decontamination and oil/water separation are principal motives in the surge to develop novel means for sustainability. In this prospect, supplying clean water for the ecosystems is as important as the recovery of the oil spills since the supplies are scarce. Inspired to design an engineering material which not only serves this purpose, but can also be altered for other applications to preserve natural resources, a facile template-free process is suggested to fabricate a superporous, superhydrophobic ultra-thin graphite sponge. Moreover, the process is designed to be inexpensive and scalable. The fabricated sponge can be used to clean up different types of oil, organic solvents, toxic and corrosive contaminants. This versatile microstructure can retain its functionality even when pulverized. The sponge is applicable for targeted sorption and collection due to its ferromagnetic properties. We hope that such a cost-effective process can be embraced and implemented widely.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Over the past decades, alarming consumption of earth's resources and subsequent environmental pollution has raised staid concerns. Frequent oil spills and oil tanker incidents which resulted in catastrophic consequences for marine wild life and ecosystems are evident instances and whistleblowers. To prevent further damage to the environment, novel materials and methods for immediate decontamination and purification of water as well as sustaining the scarce natural resources are most favored. Hence, the research has been converged to adopt and develop new and novel oil sorbent materials [1] [2] [3] [4] [5] .", "cite_spans": [{"start": 593, "end": 596, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 597, "end": 600, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 601, "end": 604, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 605, "end": 608, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 609, "end": 612, "text": "[5]", "ref_id": "BIBREF4"}], "ref_spans": []}], "body_text": [{"section": "", "text": "Over the past decades, alarming consumption of earth's resources and subsequent environmental pollution has raised staid concerns. Frequent oil spills and oil tanker incidents which resulted in catastrophic consequences for marine wild life and ecosystems are evident instances and whistleblowers. To prevent further damage to the environment, novel materials and methods for immediate decontamination and purification of water as well as sustaining the scarce natural resources are most favored. Hence, the research has been converged to adopt and develop new and novel oil sorbent materials [1] [2] [3] [4] [5] . A state of the art material for such purpose should have low affinity to water and high oil absorption capacity 6 . In addition, it is expected to cause the least possible harm to the environment and must be reusable 6 . Nonetheless, the proposed structure must be equally inexpensive and scalable to be adopted widely for sustainability 7, 8 . Different physical and chemical processes have been foreseen and implemented to engineer such materials with enhanced superhydrophobicity and superoleophilicity as well as high surface area in form of a membrane. The hydrophobicity of graphene foams obtained on a sacrificial nickel foam template was reported to increase dramatically by synthesizing Carbon Nanotubes (CNTs) on graphene foam which physically alters the surface 9, 10 . Consequently, the contact angle of water with the structure is changed from 108.5\u00b0 to 152.3\u00b0. However, the porosity of these architectures is limited to macro and hardly ever mesopores. Most recently, promising results have been reported regarding the exceptional oil absorption capacity and recyclability of the CNT and Carbon Nanofiber (CNF) sponges 11, 12 . Though these sponges may only be used for a specific purpose which might result in an expensive and challenging transition to industry. Owing to their high surface to volume ratio, very low density and desirable electrical properties as well as chemical and Scientific RepoRts | 6:21858 | DOI: 10.1038/srep21858 mechanical stability, three dimensional (3-D) graphene-based architectures such as foams, sponges and aerogels have been considered as multifunctional viable candidates for oil absorbing materials 10, 13 . Additionally, such graphene-based structures are found to be significantly favorable materials for gas sensing 14 and adsorption 15 , biological applications 16 , thermal management 17 , radiation protection and shielding 18 , energy conversion and storage 10, 15, 19, 20 and even structural reinforcement 21, 22 . Although total surface area of graphene-based sponges must be improved for some specific applications via chemical activation, capitalizing a multifunctional and scalable paradigm is believed to be more practical. The most widely used fabrication process for graphene-based sponges is reported to be hydrothermal reduction and assembly of graphene oxide nanosheets 10, 23, 24 . Whereas well thought out functionalization of these structures yields tailored assemblies for specific environmental applications 25, 26 , the hydrothermal process is long and preceded by Hummers method 23, 24 . Therefore, characteristics and effectiveness of the sponges strongly depend on a well-established modified Hummers method which is long as well 27 . Herein, to propose a facile, relatively fast and scalable fabrication process, we report the synthesis of a scalable, multifunctional free-standing ultra-thin graphite sponge with superhydrophobic, oleophilic and ferromagnetic properties. The sponge provides an exceptional surface area as well as multimodal porous structure including macro, meso and micropores. In this sense, the structure may be considered as self-activated, and a separate chemical activation to enhance the surface properties is not primarily obligatory. The structure and synthesis process have been thought out to be effortlessly inexpensive and scalable and with minor modifications can be pertinent for different applications.", "cite_spans": [{"start": 593, "end": 596, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 597, "end": 600, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 601, "end": 604, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 605, "end": 608, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 609, "end": 612, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 727, "end": 728, "text": "6", "ref_id": "BIBREF5"}, {"start": 832, "end": 833, "text": "6", "ref_id": "BIBREF5"}, {"start": 953, "end": 955, "text": "7,", "ref_id": "BIBREF6"}, {"start": 956, "end": 957, "text": "8", "ref_id": "BIBREF7"}, {"start": 1388, "end": 1390, "text": "9,", "ref_id": "BIBREF8"}, {"start": 1391, "end": 1393, "text": "10", "ref_id": "BIBREF9"}, {"start": 1748, "end": 1751, "text": "11,", "ref_id": "BIBREF10"}, {"start": 1752, "end": 1754, "text": "12", "ref_id": "BIBREF11"}, {"start": 2266, "end": 2269, "text": "10,", "ref_id": "BIBREF9"}, {"start": 2270, "end": 2272, "text": "13", "ref_id": "BIBREF12"}, {"start": 2386, "end": 2388, "text": "14", "ref_id": "BIBREF13"}, {"start": 2404, "end": 2406, "text": "15", "ref_id": "BIBREF14"}, {"start": 2433, "end": 2435, "text": "16", "ref_id": "BIBREF15"}, {"start": 2457, "end": 2459, "text": "17", "ref_id": "BIBREF16"}, {"start": 2497, "end": 2499, "text": "18", "ref_id": "BIBREF17"}, {"start": 2532, "end": 2535, "text": "10,", "ref_id": "BIBREF9"}, {"start": 2536, "end": 2539, "text": "15,", "ref_id": "BIBREF14"}, {"start": 2540, "end": 2543, "text": "19,", "ref_id": "BIBREF18"}, {"start": 2544, "end": 2546, "text": "20", "ref_id": "BIBREF19"}, {"start": 2581, "end": 2584, "text": "21,", "ref_id": "BIBREF20"}, {"start": 2585, "end": 2587, "text": "22", "ref_id": "BIBREF21"}, {"start": 2955, "end": 2958, "text": "10,", "ref_id": "BIBREF9"}, {"start": 2959, "end": 2962, "text": "23,", "ref_id": "BIBREF22"}, {"start": 2963, "end": 2965, "text": "24", "ref_id": "BIBREF23"}, {"start": 3098, "end": 3101, "text": "25,", "ref_id": "BIBREF24"}, {"start": 3102, "end": 3104, "text": "26", "ref_id": "BIBREF25"}, {"start": 3171, "end": 3174, "text": "23,", "ref_id": "BIBREF22"}, {"start": 3175, "end": 3177, "text": "24", "ref_id": "BIBREF23"}, {"start": 3324, "end": 3326, "text": "27", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "Synthesis of the Ultra-thin graphite sponge", "text": "The Ultra-thin graphite sponge (referred to as UtGS hereafter) is synthesized via a sol-gel process followed by curing and annealing at high temperatures. The synthesis process is shown schematically in Fig. 1(a) . A clear, homogeneous aqueous solution of the precursors (sol) was prepared, and a few droplets of nitric acid were added to the solution to adjust the pH at 3 and initiate the polymerization. Under constant stirring at 90 \u00b0C, a viscous resin (gel) was formed after a few hours. The viscous resin was spread on a glass substrate and cured in a vacuum oven at 120 \u00b0C to form a spongy mass as an intermediate precursor. The spongy precursor was cut to desired shapes with a blade. The UtGS structure was achieved by heat treating the intermediate precursor at high temperatures (500-1000 \u00b0C) under argon and hydrogen flow in a horizontal tube furnace.", "cite_spans": [], "ref_spans": [{"start": 203, "end": 212, "text": "Fig. 1(a)", "ref_id": "FIGREF0"}]}, {"section": "Characterization of the UtGS sponge", "text": "As in Fig. 1(b-d) , UtGS can be used to remove toluene from water where toluene is dyed with n-blue dye. In this typical experiment, UtGS sample floating on water was first soaked with toluene droplets (Fig. 1(b) ). It appears that toluene is contained within the sponge (Fig. 1(c) ), and the soaked sponge can further absorb toluene ( Fig. 1(d) ). Moreover, supplementary Figure 1 illustrates the separation of chloroform highlighted with 4-(dicyanomethylene)-2-methyl-6-(4-dimethylaminostyryl)-4 H -pyran (DCM), from water. The sequence also exhibits the replacement of air with chloroform within the sponge structure. It appears that UtGS is capable of absorbing organic contaminants with different densities compared to water as well as several dyes and stains from water and also can retain its functionality under water.", "cite_spans": [], "ref_spans": [{"start": 6, "end": 17, "text": "Fig. 1(b-d)", "ref_id": "FIGREF0"}, {"start": 202, "end": 212, "text": "(Fig. 1(b)", "ref_id": "FIGREF0"}, {"start": 271, "end": 281, "text": "(Fig. 1(c)", "ref_id": "FIGREF0"}, {"start": 336, "end": 345, "text": "Fig. 1(d)", "ref_id": "FIGREF0"}, {"start": 373, "end": 381, "text": "Figure 1", "ref_id": "FIGREF0"}]}, {"section": "Characterization of the UtGS sponge", "text": "To put the recyclability of UtGS to test, a sample was soaked with toluene and then subjected to a flame. The sample containing the absorbed toluene was combusted until all of toluene was consumed. The fire was self-extinguished due to the absence of fuel, and the UtGS sample remained intact and could be used again (supplementary Figure 2(a-c) ). Similar studies have been carried out to demonstrate the fire-resistivity and recyclability of graphene-based sponges 28, 29 . However, the recovery of the absorbates such as oil and organic solvents from the sorbent after uptake remains a priority. A simple process can be implemented to heat up the UtGS with the contained absorbate to evaporate the absorbed contaminant. The vapor can then be condensed to liquid form and recycled 30 . To further quantify the cyclic recovery, the weight changes of a UtGS sample has been evaluated (supplementary Figure 3) . In this instance, the sample was saturated with ethanol and the ethanol was evaporated by annealing at 500 \u00b0C for 30 min. UtGS dry weight was accurately consistent within 10 cycles and was measured to be 20.78 mg. UtGS post saturation weight was 469.8 to 471.2 mg and no evident decrease in absorption capacity was observed. Figure 1 (e) reveals the microstructure of the UtGS which appears to be a maze of interconnected macropores. Higher magnification SEM ( Fig. 1(f) ) shows that the surface of the sponge seems to be very porous and may be considered as possible connected mesopores and channels. Also thin stacks of randomly oriented graphene flakes and layers can be identified on the surface. TEM images reveal that UtGS is consisted of wrinkled and convoluted sheets (multilayer graphene layers) as well as dispersed nanoparticles with average diameter of about 20nm ( Fig. 2(a) ). Higher magnification TEM imaging demonstrates that iron nanoparticles are encapsulated within the structure by few layers of graphene ( Fig. 2(b) ). HRTEM images show interplanar distances of 0.34 nm which corresponds to the stacking of sp 2 -hybridized layers of carbon ( Fig. 2 (b) inset). As pointed out in Fig. 2 (c), the structure seems to comprise numerous minuscule graphene domains and randomly oriented flakes which attain a rough microstructure encompassing microchannels. HRTEM image resolved from the surface of the sponge indicates the existence of very small graphene-based domains with random orientation and complex stacking as well as sub-nanometer channels separating them ( Fig. 2(d) ). In this sense, the width of the microchannels separating the graphene domains seems to deviate slightly from the measured interplanar distance of 0.34 nm. HRTEM characterization of UtGS reveals that the interconnected porous structure is supported by graphitic walls consisted of about 10-15 graphene-based layers (supplementary Figure 4) . Moreover, measured interplanar spacing of the stacked layers appeared to conform to that of graphitic structures 17 . Figure 3 (a) represents the contact angle measurement of water on the sponge which was evaluated to be 154.72\u00b0. Such an exceptional hydrophobicity is a result of numerous microscopic and nanoscopic voids of air and surface roughness at the interface with water as well as the possible absence of hydrophilic groups on the surface of the sponge. To investigate the uptake behavior of UtGS structure with time, a sample was exposed to compressor oil, and its weight change was monitored over the course of one minute (Fig. 3(b) ). The oil was absorbed into the sponge upon contact and in about 4 to 6 seconds the maximum absorption was reached. To enumerate the absorption capacity (c = 15.57) of UtGS, the mass change after oil uptake (m f = 327 mg) is divided by the initial mass (m i = 21 mg) of the sponge. As a result, the maximum weight of compressor oil that can be absorbed by UtGS is about 15.57 times of its weight. Meanwhile, UtGS manifested a similar trend for ethanol sorption (supplementary Figure 5(a) ) and the absorption capacity was calculated to be 22.69. Absorption capacities of different organic contaminants are compared in supplementary Figure 5 (b) which signifies the complex effect of density, viscosity and surface tension of the absorbate on sorption phenomenon 9 . Figure 3(c) shows snapshots of spreading and absorption behavior of compressor oil in contact with UtGS surface, acquired at 60 millisecond intervals. It reveals that the sponge is oleophilic since the oil is penetrated into the structure upon contact and completely absorbed by the sponge in about 300 ms. Whilst UtGS oil absorption capacity is higher than modified polyurethane foams (about 13.25 g.g \u22121 ) 3 , it is much lower than sorption capacity of CNF aerogels (about 200 g.g \u22121 ) 12 , CNT aerogels (about 125 g.g \u22121 ) 31 , graphene aerogels (about 85 g.g \u22121 ) 32 , and CVD-graphene/CNT hybrid foams (about 90 g.g \u22121 ) 9 . The porosity of those foams and aerogels is a result of meso-and macro-pores. These 3-D structures also exhibit considerable volume change which contributes to sorption kinetics. UtGS however, offers micro-, meso-and macro-pores at the same time and the high intrinsic surface area of UtGS can be attributed mostly to the meso-and micro-pores. These pores and channels may not contribute to oil absorption due to surface tension restriction of oil which could explain the setback in oil absorption capacity of UtGS compared to CNF, CNT and graphene aerogels. Alternatively, this setback can be compensated by the facile fabrication process, multifunctionality and scalability of UtGS. To characterize the details of the microstructure and overlook the structural changes and phase evolutions, X-ray Diffraction (XRD) and Raman spectroscopy have been carried out on UtGS samples prepared at different temperatures. By means of Fig. 4(a) , XRD patterns of UtGS samples heat treated at 500, 600, 700, 800, 900 and 1000 \u00b0C are demonstrated and compared. According to characteristic diffraction angles, sp 2 -hybridized layers in form of graphene as well as \u03b1 -Fe 33 and Fe 3 O 4 33,34 can be identified at different temperatures ( Fig. 4(a) ). The peak at 24\u00b0 may correspond to (002) reflection and the peak at 43\u00b0 can link to superposition of (101) and (100) reflections in sp 2 -hybridized graphitic lattice structure 35 . It has been reported by other researchers that these two peaks can be related to graphene sheets and flakes [36] [37] [38] [39] . In addition, syntheses at higher temperatures yield to higher crystallinity of the structure since the XRD peaks appear to be sharper with higher relative intensities. As seen in Fig. 2(a,b) , it is most likely that the dispersed nanoparticles in the microstructure are \u03b1 -Fe nanoparticles with diameter of about 20 nm. While some of these nanoparticles are encapsulated with few layers of graphene, some nanoparticles can be found unprotected on the surface of the sponge. It is critical to note that the final heat treatment of the sponge precursor is done under argon and hydrogen atmosphere which prevents the oxidation of Fe nanoparticles. Nevertheless, as soon as the sponge is removed from the reducing environment of the furnace and subjected to air, the nanoparticles are highly prone to surface oxidation. Consequently, trace of Fe 3 O 4 is observed in the XRD pattern from 700 \u00b0C (Fig. 4(a) ). Supplementary Figure 6 (a),(b) represent the Energy Dispersive X-ray Spectroscopy (EDS) spectra of an untreated UtGS sample and a sample treated with hydrochloric acid (HCl), respectively. As a result of acid treatment, the amount of Fe in the structure was decreased from 12.69 to 5.55 wt% by dissolving the unprotected Fe nanoparticles. Therefore, about 5.55 wt% of the structure is believed to be graphene wrapped \u03b1 -Fe nanoparticles. To complement this assessment, the untreated UtGS sample has been subjected to a mixture of C 2 H 4 :H 2 to synthesize carbon nanotubes (CNTs) using the iron nanoparticles as catalysts. Supplementary Figure 6(c) ,(d) demonstrate that multi-walled CNTs of various diameters encompassing iron nanoparticles at their tip can be originated on the surface of the sponge. As an exhibit for its versatility and multifunctionality, UtGS may be used for facile fabrication of free-standing 3-D graphene-CNT hybrid architectures. Figure 4 (b) shows Raman spectra of UtGS heat treated at different temperatures. Three characteristic Raman peaks of graphene, D, G and G' , respectively at 1335, 1580 and 2680 cm \u22121 can be observed in the spectra 40 . Since G' peak of graphite is believed to be asymmetric and splitted into four peaks 41, 42 , the peak centered at about 2680 cm \u22121 can be associated to G' peak of graphene. The broad D peak in the spectra infers the high level of disorder in structure. To investigate the changes in the UtGS structure, D to G (I D /I G ) and G' to G (I G' /I G ) peak intensity ratio at different heat treatment temperatures have been plotted separately in supplementary Figure 7 . As the temperature ramps up, I D /I G which refers to the disorder in graphene layers, follows a general ascending trend except from 600 to 700 \u00b0C, where it plummets. Similarly, I G' /I G as a measure for the number of stacked graphene layers, increases with temperature. It seems that the formation of graphene-based sheets starts at about 700 \u00b0C, since G' peak emerges at this temperature. Evolution of the system from 600 to 700 \u00b0C can be interpreted as incubation for amorphous to crystalline transition. Since the graphene-based sheets are starting to nucleate and grow, the degree of disorder seems to drop temporarily. Afterwards, the formation of the spatially convoluted graphene sheets yields to higher degree of disorder. The ascending trend of I G' /I G implies that the growing graphene layers are not stacking or possibly forming a turbostratic structure, where the stacked layers are slipped sideways relative to one another to create microchannels 43 . The presence of D' peak at 1608 cm \u22121 , accentuates high degree of disorder in graphene domains and also convey that graphene-based sheets may have been doped with nitrogen 44 . In order to investigate the chemical reactions and alterations of the precursors during the synthesis process, Fourier Transform Infrared (FTIR) spectroscopy has been performed on the cured resin. FTIR results (Fig. 5(a) ) display a broad peak at 3398cm \u22121 due to stretching vibrations of O-H bonds 45 . Weak bands appeared at 2920 and 2879 cm \u22121 correspond to the symmetric and asymmetric vibrations of C-H bonds 46 and the bands at 1718 and 1622 cm \u22121 are due to C= O and C= C bonds stretching vibrations respectively 45, 47 . Narrow band at about 1405 cm \u22121 correlates O-H bond bending vibrations 45 , and the peaks at about 1350 cm \u22121 occur as a result of C-OH bond stretching vibrations 48 . C-N bond stretching vibrations as well as breathing vibrations of epoxy groups may be attributed to the peaks at about1200 cm \u22121 49 . Vibrations at about 1050-1070 cm \u22121 can be related to stretching vibrations of C-O bonds 45, 46 . Further trace of C-H bonds can be seen at 932 cm \u22121 as out of plane vibration bands 49 . Bands between 480 to 730 cm \u22121 are suggested to be related to Fe-O stretching vibrations 47, 49 . The chemistry of the sol-gel process is schematically illustrated in Supplementary Figure 8 . It looks as if during the sol-gel process, hydrolysis of sucrose followed by addition of nitric acid results in the formation of saccaric acid 50, 51 . Simultaneous reaction of PVA monomers and iron cations with saccaric acid at 90 \u00b0C first originates long chains of polymeric resin and later yields to cross linking of the chains to convert the sol to a gel 50, 51 . These long chains in the gel have accommodated iron cations, and they seem to contain all of the aforementioned bonds which have been identified in the FTIR measurement. It is likely that heat treatment at high temperatures dissociates the bonds between carbon with hydrogen, oxygen and nitrogen and allows them to leave the structure in form of gas molecules. This may also aid the formation of the microchannels and the possible turbostratic structure of the graphene-based sheet. The heat treatment also results in decomposition of the hydrophilic groups on the surface of the sponge which in its term contributes to hydrophobicity. While the structure is being carbonized at high temperatures in a reducing atmosphere, neighboring iron cations will cluster and form iron nanoparticles. As an example for the adaptability of UtGS, a similar modified sol-gel process has been reported for the synthesis of metal oxides which implies the possibility to incorporate other metallic nanoparticles in the structure upon designated applications 50, 51 . Brunauer-Emmett-Teller (BET) surface area measurements have been carried out to quantify the surface area and porosity of UtGS architecture. Figure 5(b,c) summarize the results of adsorption-desorption isotherms and BET pore size distribution, respectively. It seems that the structure exhibits a combination of type I and type IV N 2 adsorption-desorption isotherms 52, 53 . The adsorption in relative pressures less than about 0.1 implies that micropors or microchannels can be found in the sample, whereas the hysteresis loop from relative pressures of about 0.5 to 1.0 is related to the mesopores 54 . The average pore diameter was calculated using DFT model to be about 1.4 nm. The Langmuir and BET surface area of UtGS sample were measured to be 1356.30 and 823.77 m 2 .g \u22121 , respectively which implies that there will be no predominant concern for chemical activation in order to enhance porosity and surface area. Besides, the density of UtGS was calculated to be 0.017 gr.cm . It may be inferred that the majority of the surface area should be attributed to the micropores and microchannels. Nonetheless, this cannot contradict the actuality and contribution of the mesopores which can be identified in high magnification SEM image (Fig. 1(e) ). While the mesopores may contain a portion of the total volume of the condensate, the amount of micropores and microchannels significantly prevails. Thus mesopores do not contribute to the pore distribution as might be expected 55 . Supplementary Figure 9 (a) through (e) represents the snapshots taken during an experiment designed to qualitatively evaluate the effectiveness of pulverized UtGS. The pulverized sample was poured into a container of water contaminated by ethanol dyed with rhodamine b. A magnet was placed inside the container to collect the sponge powder. The collected sample seems to absorb the contamination effectively, as there was no trace of rhodamine b (pink dye dissolved in ethanol). Supplementary Figure 9(f,g) give an idea about the size of the particles; and show high magnification SEM image of a fractured cross-section to depict the porosity within the bulk of UtGS, respectively. In this sense, the absorption of the contaminants may be attributed to the meso and micropores. Congregated graphene-based layers and exposed iron nanoparticles as well as mesochannels and pores can be envisioned within the cross section of the pulverized sponge particles (Supplementary Figure 9(g) ).", "cite_spans": [{"start": 467, "end": 470, "text": "28,", "ref_id": "BIBREF27"}, {"start": 471, "end": 473, "text": "29", "ref_id": "BIBREF28"}, {"start": 783, "end": 785, "text": "30", "ref_id": "BIBREF29"}, {"start": 2962, "end": 2964, "text": "17", "ref_id": "BIBREF16"}, {"start": 4256, "end": 4257, "text": "9", "ref_id": "BIBREF8"}, {"start": 4786, "end": 4788, "text": "31", "ref_id": "BIBREF30"}, {"start": 4828, "end": 4830, "text": "32", "ref_id": "BIBREF31"}, {"start": 4886, "end": 4887, "text": "9", "ref_id": "BIBREF8"}, {"start": 6049, "end": 6051, "text": "33", "ref_id": "BIBREF32"}, {"start": 6306, "end": 6308, "text": "35", "ref_id": "BIBREF34"}, {"start": 6419, "end": 6423, "text": "[36]", "ref_id": "BIBREF35"}, {"start": 6424, "end": 6428, "text": "[37]", "ref_id": "BIBREF36"}, {"start": 6429, "end": 6433, "text": "[38]", "ref_id": "BIBREF37"}, {"start": 6434, "end": 6438, "text": "[39]", "ref_id": "BIBREF38"}, {"start": 8518, "end": 8520, "text": "40", "ref_id": "BIBREF39"}, {"start": 8607, "end": 8610, "text": "41,", "ref_id": "BIBREF40"}, {"start": 8611, "end": 8613, "text": "42", "ref_id": "BIBREF41"}, {"start": 9953, "end": 9955, "text": "43", "ref_id": "BIBREF43"}, {"start": 10131, "end": 10133, "text": "44", "ref_id": "BIBREF44"}, {"start": 10435, "end": 10437, "text": "45", "ref_id": "BIBREF45"}, {"start": 10550, "end": 10552, "text": "46", "ref_id": "BIBREF46"}, {"start": 10656, "end": 10659, "text": "45,", "ref_id": "BIBREF45"}, {"start": 10660, "end": 10662, "text": "47", "ref_id": "BIBREF47"}, {"start": 10736, "end": 10738, "text": "45", "ref_id": "BIBREF45"}, {"start": 10828, "end": 10830, "text": "48", "ref_id": "BIBREF48"}, {"start": 10962, "end": 10964, "text": "49", "ref_id": "BIBREF49"}, {"start": 11056, "end": 11059, "text": "45,", "ref_id": "BIBREF45"}, {"start": 11060, "end": 11062, "text": "46", "ref_id": "BIBREF46"}, {"start": 11149, "end": 11151, "text": "49", "ref_id": "BIBREF49"}, {"start": 11243, "end": 11246, "text": "47,", "ref_id": "BIBREF47"}, {"start": 11247, "end": 11249, "text": "49", "ref_id": "BIBREF49"}, {"start": 11489, "end": 11492, "text": "50,", "ref_id": "BIBREF50"}, {"start": 11493, "end": 11495, "text": "51", "ref_id": "BIBREF51"}, {"start": 11705, "end": 11708, "text": "50,", "ref_id": "BIBREF50"}, {"start": 11709, "end": 11711, "text": "51", "ref_id": "BIBREF51"}, {"start": 12755, "end": 12758, "text": "50,", "ref_id": "BIBREF50"}, {"start": 12759, "end": 12761, "text": "51", "ref_id": "BIBREF51"}, {"start": 13131, "end": 13134, "text": "52,", "ref_id": "BIBREF52"}, {"start": 13135, "end": 13137, "text": "53", "ref_id": "BIBREF53"}, {"start": 13365, "end": 13367, "text": "54", "ref_id": "BIBREF54"}, {"start": 14247, "end": 14249, "text": "55", "ref_id": "BIBREF55"}], "ref_spans": [{"start": 332, "end": 345, "text": "Figure 2(a-c)", "ref_id": "FIGREF1"}, {"start": 899, "end": 908, "text": "Figure 3)", "ref_id": "FIGREF2"}, {"start": 1236, "end": 1244, "text": "Figure 1", "ref_id": "FIGREF0"}, {"start": 1372, "end": 1381, "text": "Fig. 1(f)", "ref_id": "FIGREF0"}, {"start": 1789, "end": 1798, "text": "Fig. 2(a)", "ref_id": "FIGREF1"}, {"start": 1938, "end": 1947, "text": "Fig. 2(b)", "ref_id": "FIGREF1"}, {"start": 2075, "end": 2081, "text": "Fig. 2", "ref_id": "FIGREF1"}, {"start": 2112, "end": 2118, "text": "Fig. 2", "ref_id": "FIGREF1"}, {"start": 2495, "end": 2504, "text": "Fig. 2(d)", "ref_id": "FIGREF1"}, {"start": 2837, "end": 2846, "text": "Figure 4)", "ref_id": "FIGREF3"}, {"start": 2967, "end": 2975, "text": "Figure 3", "ref_id": "FIGREF2"}, {"start": 3482, "end": 3492, "text": "(Fig. 3(b)", "ref_id": "FIGREF2"}, {"start": 3970, "end": 3981, "text": "Figure 5(a)", "ref_id": "FIGREF5"}, {"start": 4126, "end": 4134, "text": "Figure 5", "ref_id": "FIGREF5"}, {"start": 4260, "end": 4271, "text": "Figure 3(c)", "ref_id": "FIGREF2"}, {"start": 5816, "end": 5825, "text": "Fig. 4(a)", "ref_id": "FIGREF3"}, {"start": 6117, "end": 6126, "text": "Fig. 4(a)", "ref_id": "FIGREF3"}, {"start": 6620, "end": 6631, "text": "Fig. 2(a,b)", "ref_id": "FIGREF1"}, {"start": 7332, "end": 7342, "text": "(Fig. 4(a)", "ref_id": "FIGREF3"}, {"start": 8304, "end": 8312, "text": "Figure 4", "ref_id": "FIGREF3"}, {"start": 10346, "end": 10356, "text": "(Fig. 5(a)", "ref_id": "FIGREF5"}, {"start": 12905, "end": 12918, "text": "Figure 5(b,c)", "ref_id": "FIGREF5"}, {"start": 14006, "end": 14016, "text": "(Fig. 1(e)", "ref_id": "FIGREF0"}]}, {"section": "Characterization of the UtGS sponge", "text": "To further demonstrate the versatility of G-sponge, the viscous resin was cured while a constant flow of nitrogen was used to generate bubbles in the resin, the microstructure was affected as shown with different magnifications in Supplementary Figure 10(a),(b) . It seems that this process prompts macropore formation as opposed to mesopores, since the surface seems to be less porous ( Supplementary Figure 10(b) ). Conversely, when curing was done under nitrogen pressure, a conformal layered structure was formed after annealing at high temperatures (Supplementary Figure 10(c),(d) ) as if the crosslinking of the resin chains was suppressed under pressure.", "cite_spans": [], "ref_spans": [{"start": 231, "end": 261, "text": "Supplementary Figure 10(a),(b)", "ref_id": "FIGREF0"}, {"start": 388, "end": 414, "text": "Supplementary Figure 10(b)", "ref_id": "FIGREF0"}, {"start": 569, "end": 585, "text": "Figure 10(c),(d)", "ref_id": "FIGREF0"}]}, {"section": "Characterization of the UtGS sponge", "text": "The magnetic hysteresis loop of UtGS is demonstrated in Fig. 5(d) and conforms to that of ferromagnetic materials 56 . The saturation magnetism (M S ) and the coercivity (H C ) have been measured to be 8.49 emu.g \u22121 and 336 Oe at room temperature. Hence, \u03b1 -Fe nanoparticles may accommodate single magnetic domains, due to the high measured H C and the average diameter of the particles (20 nm) 56 . The measured M S is relatively small compared to the reported values for \u03b1 -Fe nanoparticles with similar size since it is only 12.69% of the total weight. Relating back to XRD multiplot shown in Fig. 4(a) , at 500 and 600 \u00b0C no or minute traces of \u03b1 -Fe was observed which points out that ferromagnetism may not be observed in the samples heat treated bellow 600 \u00b0C. The ferromagnetic properties can offer selectivity for targeted delivery and collection of the sponge.", "cite_spans": [{"start": 114, "end": 116, "text": "56", "ref_id": "BIBREF56"}, {"start": 395, "end": 397, "text": "56", "ref_id": "BIBREF56"}], "ref_spans": [{"start": 56, "end": 65, "text": "Fig. 5(d)", "ref_id": "FIGREF5"}, {"start": 596, "end": 605, "text": "Fig. 4(a)", "ref_id": "FIGREF3"}]}, {"section": "Conclusions", "text": "In summary, we have successfully demonstrated the synthesis of a scalable, multifunctional ultra-thin graphite sponge with exceptional porosity and surface area as well as superhydrophobic and oleophilic properties via a modified sol-gel assisted process. The structure and synthesis process are designed to be effortlessly inexpensive and highly scalable to be widely adopted and used. The synthesized sponge has ferromagnetic properties as a result of graphene-wrapped \u03b1 -Fe nanoparticles with average diameter of about 20 nm. We have also illustrated the versatility of the architecture enabling the required modifications such as direct CNT growth or incorporation of other metallic nanoparticles within the structure which expands its applicable venues. The obtained sponge has an exceptional contact angle of 154.72\u00b0 with water as well as oleophilic properties. It offers a remarkable surface area of 823.77 m 2 .g \u22121 and an average pore diameter of 1.4 nm without chemical activations. Such surface area is due to the presence of macro, meso and micropores and channels in the structure. The sponge is effectively applicable to be used underwater and even when pulverized. Selective and targeted delivery and collection of the sponge to contaminated coordinates is also possible as a result of embedded ferromagnetic \u03b1 -Fe nanoparticles. The achieved architecture offers a promising ability environmental cleaning applications such as oil-water separation and water decontamination. Owing to its versatile microstructure, it may also be used for gas filtration and sensing as well as energy storage.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "Synthesis of the UtGS. UtGS was prepared by a modified sol-gel process followed by curing in vacuum and annealing at high temperature. Briefly, 2.82 g sucrose (Sigma-Aldrich, > 99.5%), 0.12 g polyvinyl alcohol (SigmaAldrich, 98-99%) and 0.84 g iron nitrate nonahydrate (Sigma-Aldrich, > 98%) were dissolved in 17 ml deionized (DI) water and stirred to form a homogenous solution. 0.1 ml nitric acid (HNO 3 ) was added to the final solution (sol), and the temperature was then raised up to 90 \u00b0C for 1 hour. A viscous dark brown resin (gel) was formed as a result of a series of chemical reactions and polymerization. The resin was cured at 120 \u00b0C under vacuum for 2 hours. Then the cured resin was cut into the desired shapes with a blade and transferred into a horizontal tube furnace. The temperature was ramped up with a rate of 10 \u00b0C.min \u22121 to the final temperature (500, 600, 700, 800, 900 and 1000 \u00b0C). The samples were annealed at 5 torr for 30 minutes in Ar and H 2 atmosphere with the flow rates of 100 and 50 sccm, respectively to form the final sponge structure.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "Absorption capacity measurements of UtGS. To evaluate the kinetic sorption behavior, a 1:1 ratio of deionized (DI) water and contaminant was used. UtGS samples were placed on the surface of water and weighed at different times upon absorption. The measurements continued until a plateau of weight change was achieved. Each set of measurements repeated eight times.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "To measure the absolute absorption capacity, UtGS samples were submerged in a container of contaminant and sonicated for 10 minutes. Each set of measurements repeated 8 times.", "cite_spans": [], "ref_spans": []}, {"section": "Synthesis of CNTs on UtGS.", "text": "The CNTs were grown on UtGS via Chemical Vapor Deposition (CVD) method in a horizontal tube furnace using the Fe nanoparticles on the surface of UtGS as catalyst. A mixture of Ar, H 2 and ethylene (as carbon precursor) were flowed with the rate of 150,100 and 50 sccm, respectively. The temperature was ramped up with a rate of 10 \u00b0C.min \u22121 to 750 \u00b0C and, the growth was done at 700 torr for 30 minutes.", "cite_spans": [], "ref_spans": []}, {"section": "Synthesis of CNTs on UtGS.", "text": "Acid treatment to remove Fe nanoparticles. UtGS samples were sonicated overnight in a mixture of ethanol and HCl with the ratio of 1:1 by volume. The acid treated samples were sonicated and washed several times with absolute ethanol until the neutral pH was achieved and dried overnight under vacuum at 90 \u00b0C.", "cite_spans": [], "ref_spans": []}, {"section": "Materials characterization.", "text": "The morphology investigation and imaging analysis were performed using scanning electron microscope (SEM; FIB NNS450) equipped with X-ray energy dispersive spectroscopy (EDS) Scientific RepoRts | 6:21858 | DOI: 10.1038/srep21858", "cite_spans": [], "ref_spans": []}, {"section": "Materials characterization.", "text": "and transmission electron microscope (TEM; Philips, CM300) with a LaB 6 cathode operated at 300 KV. For TEM imaging, the pulverized sponge was dispersed ultrasonically in ethanol for 1 hour, and a diluted sample was drop casted on the carbon-coated TEM grid. Crystal structure and phase identification was done by X-ray diffraction analysis (XRD, Philips X\u2032 Pert) using Cu K\u03b1 radiation. 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(f) High magnification SEM image acquired from the surface of the sponge roughly where the white arrow is pointing at.", "type": "figure"}, "FIGREF1": {"text": "Figure 2. (a) Low magnification TEM image of UtGS (b) High magnification image of the Fe nanoparticles encapsulated in graphene-based sheets (inset: HRTEM image showing the graphene layers with the interplanar distance highlighted). (c) Low magnification image around the surface of UtGS. (d) HRTEM image showing the microstructure of the surface of UtGS.", "type": "figure"}, "FIGREF2": {"text": "Figure 3. (a) Contact angle measurement of UtGS showing superhydrophobicity. (b) Graph showing the oil uptake of UtGS with time. (c) Snapshots of spreading and absorption of oil by UtGS showing oleophilicity.", "type": "figure"}, "FIGREF3": {"text": "Figure 4. (a) XRD multiplot of UtGS heat treated at different temperatures. (b) Raman spectra multiplot of UtGS heat treated at different temperatures.", "type": "figure"}, "FIGREF5": {"text": "Figure 5. (a) FTIR spectrum of UtGS precursor after curing and before final heat treatment. (b) BET surface area measurement of UtGS with a combination of type I and type IV N 2 sorption. (c) Pore size distribution of UtGS (calculated based on DFT model). (d) Magnetic hysteresis loop curve acquired from UtGS.", "type": "figure"}}}
{"paper_id": "17785750", "_pdf_hash": "1d80429c46c782e7f1b39d51f3192cf279422008", "abstract": [], "body_text": [], "bib_entries": {"BIBREF13": {"title": "Symposium on Magnetoelectric Interaction Phenomena in Crystals", "authors": [{"first": "G", "middle": ["T"], "last": "Rado", "suffix": ""}], "year": 1997, "venue": "Science Publishers Ltd", "link": null}, "BIBREF14": {"title": "Introduction to Solid State Physics", "authors": [{"first": "C", "middle": ["A"], "last": "Kittel", "suffix": ""}], "year": 1996, "venue": "", "link": "121571376"}, "BIBREF15": {"title": "Mechatronics: Dynamics of Electromechanical and Piezoelectric Systems", "authors": [{"first": "A", "middle": [], "last": "Preumont", "suffix": ""}], "year": 2006, "venue": "", "link": "109364115"}, "BIBREF16": {"title": "Introduction to Composite Materials", "authors": [{"first": "S", "middle": ["W"], "last": "Tsai", "suffix": ""}, {"first": "H", "middle": ["T"], "last": "Hahn", "suffix": ""}], "year": 1980, "venue": "", "link": "136983382"}, "BIBREF17": {"title": "Ceramic Materials: Science and Engineering", "authors": [{"first": "C", "middle": ["B"], "last": "Carter", "suffix": ""}, {"first": "G", "middle": ["M"], "last": "Norton", "suffix": ""}], "year": 2007, "venue": "", "link": "137413475"}, "BIBREF18": {"title": "Magnetostrictive Materials Background. UCLA Active Materials Lab", "authors": [{"first": "G", "middle": ["P"], "last": "Mcknight", "suffix": ""}], "year": "", "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "17786445", "_pdf_hash": "d540f1915553d289a056af749ab6cbeb93d9b4c7", "abstract": [{"section": "Abstract", "text": "Structural Health Monitoring (SHM) has become an important research problem which has the potential to monitor and ensure the performance and safety of civil structures. Traditional wire-based SHM systems require significant time and cost for cable installation. With the recent advances in wireless communication technology, wireless SHM systems have emerged as a promising alternative solution for rapid, accurate and low-cost structural monitoring. This paper presents a newly designed integrated wireless monitoring system that supports real-time data acquisition from multiple wireless sensing units. The selected wireless transceiver consumes relatively low power and supports long-distance peer-to-peer communication. In addition to hardware, embedded multithreaded software is also designed as an integral component of the proposed wireless monitoring system. A direct result of the multithreaded software paradigm is a wireless sensing unit capable of simultaneous data collection, data interrogation and wireless transmission. A reliable data communication protocol is designed and implemented, enabling robust real-time and near-synchronized data acquisition from multiple wireless sensing units. An integrated prototype system has been fabricated, assembled, and validated in both laboratory tests and a large-scale field test conducted upon the Geumdang Bridge in Icheon, South Korea.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "the bridges in the United States were built before 1940's, and nearly 42% of them were reported to be structurally deficient and below established safety standards (Stallings et al., 2000) . To protect the public from unsafe bridge structures, current U.S. federal requirements necessitate local transportation authorities to visually inspect the entire inventory of well over 580,000 highway bridges biannually (Chase, 2001 ). An inherent drawback of visual inspections is that they only consider damage that is visible on the surface of the structure; damage located below the surface often remains elusive to the inspectors. Furthermore, bridge inspections can be highly subjective. For example, a recent study by the U.S. Federal Highway Administration (FHWA) quantified the reliability of visual inspections with wide variability discovered in the condition ratings assigned by trained inspectors to a bridge intentionally damaged as part of the study (Moore et al., 2001) . With visual inspections both costly and labor intensive, low cost sensing systems that can quantitatively assess the integrity and remaining life of a structure are needed .", "cite_spans": [{"start": 164, "end": 188, "text": "(Stallings et al., 2000)", "ref_id": "BIBREF31"}, {"start": 957, "end": 977, "text": "(Moore et al., 2001)", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "", "text": "As a complimentary approach and promising alternative to visual structural inspections, structural health monitoring (SHM) systems have been proposed to predict, identify, and locate the onset of structural damage (Sohn et al. 2001 , Chang et al. 2003 , Elgamal et al. 2003 . SHM systems employ smart sensor technologies to assist in identifying subtle structural abnormality based on measured structural response parameters (Farrar et al. 2003 , Spencer et al. 2004 . Various types of structural sensors, including accelerometers, displacement transducers, strain gages, and thermometers, can be deployed to provide valuable real-time information about the behavior of a structure or environmental conditions. A necessary element of a SHM system is the data acquisition (DAQ) system used to collect sensor measurements and to store the data in a centralized location. Current commercial DAQ systems designed for permanent installation or for short-term vibration tests employ cables to directly transmit sensor data to the central data repository. By running cables between sensors and the data server, traditional DAQ systems suffer from high installation costs in terms of both time and money. Installing extensive lengths of cables can consume over 75% of the total SHM system installation time (Straser and Kiremidjian, 1998) . In the U.S., the cost of installing a typical system summarized. Various aspects of the system software design are also described. A state machine design concept is employed in developing a robust communication protocol for the wireless SHM system. The software mechanism that enables near-synchronized real-time data acquisition simultaneously from multiple wireless sensing units is also described herein. Embedded computing algorithms executed by the wireless sensing unit illustrate the potential for local data processing within a wireless sensor network.", "cite_spans": [{"start": 214, "end": 231, "text": "(Sohn et al. 2001", "ref_id": "BIBREF29"}, {"start": 232, "end": 251, "text": ", Chang et al. 2003", "ref_id": "BIBREF0"}, {"start": 252, "end": 273, "text": ", Elgamal et al. 2003", "ref_id": "BIBREF5"}, {"start": 425, "end": 444, "text": "(Farrar et al. 2003", "ref_id": "BIBREF7"}, {"start": 445, "end": 466, "text": ", Spencer et al. 2004", "ref_id": "BIBREF30"}, {"start": 1299, "end": 1330, "text": "(Straser and Kiremidjian, 1998)", "ref_id": "BIBREF32"}], "ref_spans": []}, {"section": "", "text": "Finally, the paper presents both laboratory and field tests intended to accurately assess the performance merits and weaknesses of the integrated hardware and software SHM system proposed.", "cite_spans": [], "ref_spans": []}, {"section": "HARDWARE DESIGN OF A WIRELESS SENSING UNIT", "text": "The prototype SHM system incorporates an integrated hardware and software design to implement a simple star-topology wireless sensor network (Callaway, 2004) . A wireless SHM system with a star-topology includes multiple wireless sensing units assembled in a network with one central server coordinating the activities of the network. In our prototype implementation, the central server can be a laptop or desktop computer connected with a compatible wireless transceiver through a typical RS232 serial communication port. Using the wireless transceiver, the central server can communicate with the wireless sensing units that are dispersed throughout the structure. The wireless sensing units are responsible for acquiring sensor measurements, analyzing data, and transferring data to the central server for permanent storage or further data interrogation. The functional properties of the global SHM system depend on the hardware design of the individual wireless sensing units. As discussed earlier, some of the key issues considered in the hardware design of the wireless sensing units include limited power consumption, long peer-to-peer communication range, and local data processing capability. These issues pose the major challenges addressed in the hardware design of the novel wireless SHM system proposed in this study. A functional diagram of the proposed wireless sensing unit is illustrated in Figure 1 . The design of the wireless sensing unit consists of three functional modules: the sensing interface, the computational core, and the wireless communication channel. The sensing interface converts analog sensor signals into a digital format usable by the computational core. The digitized sensor data is then transferred to the computational core through a high-speed Serial Peripheral Interface (SPI) port. Besides a low-power 8-bit Atmel ATmega128 microcontroller, external Static Random Access Memory (SRAM) is integrated with the computational core to accommodate local data storage and analysis. Through a Universal Asynchronous Receiver and Transmitter (UART) interface, the computational core communicates with the MaxStream 9XCite wireless transceiver, which provides a wireless connection between the unit and other wireless devices or between the unit and the central server. The 9XCite operates on the unlicensed 900MHz radio frequency spectrum and can achieve communication ranges of 300m in open space and 90m in an indoor environment. This section describes in detail the hardware design of each functional module of the wireless sensing unit, and summarizes the corresponding performance properties of the wireless SHM system.", "cite_spans": [], "ref_spans": [{"start": 1408, "end": 1416, "text": "Figure 1", "ref_id": "FIGREF0"}]}, {"section": "Sensing Interface", "text": "Each wireless sensing unit represents an autonomous node within the wireless monitoring system, collecting and analyzing measurements from multiple sensors. In the sensing interface module of each unit, a fourchannel, 16-bit and 100 kHz analog-to-digital (A/D) converter, Texas Instrument ADS8341, is employed for converting analog sensor signals into digital data that can be recognized by the microcontroller. Any analog sensor signal between 0V and 5V can be accepted by the A/D converter, so that the sensing unit is sufficiently generic for accommodating a heterogeneous set of analog sensors. The A/D converter can be interfaced with up to four sensors at the same time with its 16-bit resolution providing adequate accuracy for most applications in structural health monitoring. The upper limit for the sampling rate of this A/D converter is 100kHz, which means each A/D conversion takes a very short period of time (10 \u00b5s). Therefore, each A/D conversion can be finished swiftly through the timer interrupt service of the ATmega128 microcontroller, without disrupting the UART communication between the microcontroller and the wireless transceiver. This means that it is possible for the wireless sensing unit to keep its wireless communication module functioning, even when the unit is sampling data from the sensing interface.", "cite_spans": [], "ref_spans": []}, {"section": "Computational Core", "text": "For the computational core of the wireless sensing unit, a low-power microcontroller is employed to coordinate all of the different parts of the sensing unit hardware, and to provide the capability for local data interrogation. A low-cost 8-bit Atmel AVR microcontroller, ATmega128, is selected in this design. The", "cite_spans": [], "ref_spans": []}, {"section": "Computational Core", "text": "ATmega128 microcontroller provides 128kB of in-system reprogrammable flash memory, which is sufficient for storing embedded programs for many typical computational algorithms, such as fast Fourier transforms (FFT), wavelet transforms, and various other algorithms . When the microcontroller is running at a system clock of 8MHz, it consumes about 15mA of current at a power supply of 5V. The 64-pin ATmega128 provides UART/SPI communication interfaces, timer modules, interrupt modules and multiple input/output ports. Its timer and interrupt modules are used to command the A/D conversion at user-specified sampling rates. The 4kB SRAM integrated in the microcontroller is insufficient for sensor data storage and analysis; therefore, the microcontroller is interfaced with an external 128kB memory chip, Cypress CY62128B. Although there is a limitation of the ATmega128 microcontroller to only allow accessing 64kB of external memory at a time, it is still possible to make full use of the 128kB external memory by controlling a separate line that selects the lower half 64kB or upper half 64kB of the CY62128B chip. The external memory is sufficient for executing many sophisticated damage identification algorithms on a large quantity of sensor data.", "cite_spans": [], "ref_spans": []}, {"section": "Computational Core", "text": "To coordinate the behavior of the wireless sensing unit, embedded system software is written for the ATmega128 microcontroller. The embedded system software encapsulates the lower level details of the unit hardware, so that these modularized functions can be conveniently employed for upper level software development. An attractive feature of the implemented embedded software is that it can execute two tasks in parallel (multithreaded tasking). In particular, the unit is capable of collecting data from the sensing interface and simultaneously performing another operational task, such as transferring data over the wireless transceiver or executing a computational algorithm to interrogate sensor data. The multi-task execution is made possible because of the timer interrupt service provided by the ATmega128 microcontroller and the very short A/D conversion time. The interrupt function is a powerful feature that allows the software to momentarily pause an executing task (such as data processing or wireless communication) when it is the scheduled time to sample data from the sensing interface. After servicing the sensing interface, the paused task is immediately resumed.", "cite_spans": [], "ref_spans": []}, {"section": "Wireless Communication", "text": "Robust data communication between sensors and between sensors and the data repository is important in structural health monitoring applications. For civil structures, the anticipated communication range could be upwards of several hundred meters. However, long communication ranges usually require higher power consumption on the part of the wireless transceiver. In this study, the MaxStream 9XCite wireless transceiver is selected for the wireless sensing unit because of its capability for providing relatively long range communication yet only consuming a modest amount of battery energy. This wireless transceiver offers the trade-off and balance between low power consumption and long communication distance for applications in structural health monitoring.", "cite_spans": [], "ref_spans": []}, {"section": "Wireless Communication", "text": "The key performance characteristics of the 9XCite wireless transceiver are summarized in Table 1 . As specified, the 90m indoor and 300m outdoor communication range of the 9XCite wireless transceiver is sufficient for most small and medium-sized civil structures. Meanwhile, the 9XCite transceiver consumes a current of only about 50mA when transmitting data, or a current of about 30mA when receiving data. A much lower current is consumed when the 9XCite transceiver is set in sleep mode. The raw data transfer rate of the transceiver is 38.4kbps; however, after incorporating a communication protocol, which includes a reliable retry-acknowledgement procedure, the effective data transfer rate is approximately 26kbps. From the effective data transfer rate, it is estimated that if the sampling frequency of each sensor channel is 50Hz, Table 2   Table 1 the central server is able to collect raw data from up to 24 sensing channels sampled continuously in realtime. The peer-to-peer communication capability of the wireless transceiver also makes it possible for the wireless sensing units to communicate with each other, thus supporting collaborative local data analysis.", "cite_spans": [], "ref_spans": [{"start": 840, "end": 857, "text": "Table 2   Table 1", "ref_id": "TABREF2"}]}, {"section": "Power Consumption", "text": "Power consumption is another important issue to consider when selecting the hardware elements of a wireless sensing unit. While power consumption of each hardware component should be minimized, it must not be done at the expense of the functionalities needed by the wireless sensing unit. The power consumed by the wireless sensing unit is a function of the voltage and the amount of electrical current supplied to each component. All of the hardware components are internally referenced at 5V. The active and standby electrical current for each component of the wireless sensing unit is listed in Table 2 . When the wireless sensing unit is active, it is collecting, interrogating or wirelessly transmitting sensor data. In contrast, the wireless sensing unit can be placed in a sleep state from which it can be easily awakened; when in sleep mode, the unit consumes minimal amount of electrical current (denoted as the standby current).", "cite_spans": [], "ref_spans": [{"start": 598, "end": 605, "text": "Table 2", "ref_id": "TABREF2"}]}, {"section": "Power Consumption", "text": "The wireless transceiver consumes the greatest amount of electrical power when active (45mA x 5V = 225mW), which indicates the importance of minimizing the use of the wireless communication channel as a means of preserving battery energy (Lynch et al., 2004a) . The total active current of the wireless sensing unit prototype with the wireless transceiver in operation, I active , as measured by a digital multimeter in the laboratory, is found to be 77mA. The wireless sensing unit can operate on any power source providing at least 5.2V of voltage potential. In the current prototype, five ordinary lithium AA batteries (Energizer L91), providing a total voltage of 7.5V, are used. With the total energy capacity of a single L91 AA battery, E battery , over 2900mAh, the fully-active continuous life expectancy of the wireless sensing unit, T active , is estimated to ", "cite_spans": [], "ref_spans": []}, {"section": "Power Consumption", "text": "In all likelihood, wireless sensing units serving as part of a comprehensive structural health monitoring system would be operated on a duty-cycle schedule. For example, units might be programmed to turn on every day for 10 minutes to measure the ambient response of the instrumented structure. If it is assumed that on each day, the system is fully active for 10 minutes for data collection and transmission, the total operation time of the wireless sensing unit unattended in the field is estimated to be: ", "cite_spans": [], "ref_spans": []}, {"section": "E E E T", "text": "If the unit is only used for 5 minutes every day, then the life expectancy of the unit can last about one year.", "cite_spans": [], "ref_spans": []}, {"section": "The Assembled Prototype Wireless Sensing Unit", "text": "For compact design of the wireless sensing unit, a simple two-layer printed circuit board (PCB) is designed and fabricated. A picture of the completed PCB, with integrated circuit chips attached, is shown in Figure 2 .", "cite_spans": [], "ref_spans": [{"start": 208, "end": 216, "text": "Figure 2", "ref_id": "FIGREF3"}]}, {"section": "The Assembled Prototype Wireless Sensing Unit", "text": "The dimension of the simple two-layer PCB is roughly 9.7cm by 5.8cm, which can further be reduced when using multi-layer PCB manufacturing. To protect the electronics from the harsh weather conditions common to outdoor structural applications, the PCB, wireless transceiver, and batteries are stored within a weatherproof plastic container. Figure 2 also shows a picture of the prototype package that is opened to illustrate the internal components. The visible parts include the battery pack, the weatherproof container, the 9XCite wireless transceiver that is mounted on the PCB board, and the antenna of the wireless transceiver.", "cite_spans": [], "ref_spans": [{"start": 341, "end": 349, "text": "Figure 2", "ref_id": "FIGREF3"}]}, {"section": "The Assembled Prototype Wireless Sensing Unit", "text": "The final dimensions of the wireless sensing unit (i.e. the plastic container) are 10.2cm by 6.5cm by 4.0cm.", "cite_spans": [], "ref_spans": []}, {"section": "SOFTWARE DESIGN FOR THE WIRELESS SHM SYSTEM", "text": "A simple star-topology wireless data acquisition system is designed and implemented in our current prototype SHM system. The system includes one central data server and multiple wireless sensing units.", "cite_spans": [], "ref_spans": []}, {"section": "SOFTWARE DESIGN FOR THE WIRELESS SHM SYSTEM", "text": "The central server is responsible for: 1) commanding all of the wireless sensing units to perform data collection tasks, 2) synchronizing the internal clocks of the wireless sensing units, 3) receiving data from the wireless network, and 4) storing the measurement data in a file server. Any desktop or laptop computer with a MaxStream 9XCite wireless transceiver connected can be used as the central server. Software written for the wireless structural monitoring system is divided into two parts: computer software for the central server and embedded software for the wireless sensing units. Since the central server and the wireless sensing units must communicate frequently with one another, portions of their software are designed to allow seamless integration and coordination. A state diagram is constructed to describe in detail the program flow for both the central server and the wireless sensing unit. The intention of the state diagram is to encode a sequence of actions for both the central server and the wireless sensing units so that all potential problematic scenarios (or states) commonly encountered in an unreliable wireless channel can be efficiently handled. In the prototype system, the central server is assigned the responsibility for ensuring reliable wireless communication. In other words, the central server plays an \"active\" role in the communication channel while the wireless sensing unit plays more of a \"passive\" role. For example, communication is always initiated by the central server. After the central server sends a command to the wireless sensing unit, if the server does not receive an expected response from the unit, the server will resend the last command again until the expected response is received. However, after a wireless sensing unit sends a message to the central server, the unit does not check if the message has arrived at the central server correctly or not, because the communication reliability is always guaranteed by the server. The wireless sensing unit only becomes aware of the lost data when the central server queries the unit for the same data again. This section describes the nature of the communication between the central server and the wireless sensing units, and the memory management mechanism implemented on the wireless sensing units that enables real-time continuous data collection by the central server from multiple wireless sensing units. The implementation of a local data processing algorithm in the current set of prototype wireless sensing units is also described in detail.", "cite_spans": [], "ref_spans": []}, {"section": "Data Synchronization", "text": "For many damage and system identification procedures, measurement data individually collected by the different sensors must be time synchronized. For example, modal analysis and system identification algorithms usually require synchronized acceleration data from different locations of the structure (Ljung 1999 , Ewins 2000 . Figure 3 shows the design of the communication protocol between the central server and the wireless sensing units to accomplish clock synchronization.", "cite_spans": [{"start": 300, "end": 311, "text": "(Ljung 1999", "ref_id": "BIBREF16"}, {"start": 312, "end": 324, "text": ", Ewins 2000", "ref_id": "BIBREF6"}], "ref_spans": [{"start": 327, "end": 335, "text": "Figure 3", "ref_id": "FIGREF4"}]}, {"section": "Data Synchronization", "text": "The synchronization procedure utilizes the 9XCite wireless transceiver's point-to-multipoint communication capability. This feature permits the central data server's wireless transceiver to broadcast a beacon signal to which all wireless sensing units can synchronize. Once the wireless sensing units receive the beacon signal from the central server, each unit starts sampling the data at the requested rate. To account for the scenario where a wireless sensing unit might not receive the beacon signal, it is necessary for all wireless sensing units to confirm with the central server that they have received the beacon signal successfully. As shown in Figure 3 , when the central server inquires with a unit whether the unit has received the beacon signal, the server may be communicating with a unit that is still waiting for the beacon signal it has never received. If this happens, the central server restarts all of the wireless sensing units by asking them to wait for another beacon signal, and then re-broadcasts the beacon signal. The synchronization procedure is iterated until the central server has confirmed that the beacon signal has been received by all of the wireless sensing units in the network.", "cite_spans": [], "ref_spans": [{"start": 655, "end": 663, "text": "Figure 3", "ref_id": "FIGREF4"}]}, {"section": "Data Synchronization", "text": "Although all the units can receive the same beacon signal from the central server, each wireless sensing unit may not receive the beacon at precisely the same time; therefore, some units may start collecting data slightly earlier while others may start slightly later. Because the propagation of the wireless radio-frequency (RF) signal takes only nano-seconds in this application, the synchronization error mainly originates from the difference in the time each wireless sensing unit takes to interpret the broadcasted beacon signal. Using precise timers in the laboratory, the synchronization error between two sensing units is measured to be within 20\u00b5s of one another. This laboratory based timing of the synchronization error is intended to measure the expected error in a single-hop wireless sensor network installed in a civil structure within a short range to the central data repository (within 100m). Because each wireless sensing unit is listening for the single central server beacon signal, time synchronization across the entire wireless sensor network is represented by uncoupled unit-server pairs. With one unit not dependent upon other units for time synchronization, the tests results encountered in the lab using two sensing units represents the synchronization error for an entire wireless SHM system, independent of the number of wireless sensing units installed.", "cite_spans": [], "ref_spans": []}, {"section": "Data Synchronization", "text": "However, it should be noted that although the system synchronization error is around 20\u00b5s at the beginning of the data collection, the synchronization error might increase after long periods of time because of a natural time drift in the crystal clocks integrated with each wireless sensing unit. Current prototype unit employs a low-cost 8MHz crystal to provide system clock for the ATmega128 microcontroller. Laboratory tests show that the synchronization error between two units can accumulate up to 5ms in a 6-minute period. Thus, synchronization error is considered minimal and reasonable within the realistic time period for data collection, and synchronization of the system should be carried out at certain time interval.", "cite_spans": [], "ref_spans": []}, {"section": "Communication Protocol Design and Implementation using State Machine Concept", "text": "A robust data acquisition software system should be sufficiently reliable and able to detect failures in the wireless communication channel and to recover from any communication failures encountered. Due to the system complexity needed to ensure the reliability of the wireless communication channel, the state machine concept (Tweed, 1994) is employed for the software architecture for both the wireless sensing units and the central server. A state machine consists of a set of states and the definition of a set of transitions among these states. At any point in time, the state machine can only be in one of the possible states. In response to different events, the state machine transits between its discrete states. When a wireless sensing unit is powered on, the unit starts from \"State0 Bootup\" in Figure 5 . Under \"no condition\", the unit automatically initializes the memory space, and transits into \"State1 Wait for 00Start\", where the '00Start' is the beacon signal that is broadcasted from the central server to all of the wireless sensing units, requesting all units to start data collection simultaneously. Accordingly, when the data collection program at the central server starts running, as shown in Figure 4 , the server will automatically broadcast the '00Start' beacon signal which all of the wireless sensing units receive. As soon as the wireless sensing unit receives and recognizes the '00Start' beacon, the sensing unit starts collecting data from its associated sensors at a specified sampling rate, and saves the data temporarily into its external SRAM for later acquisition by the central server. If all the wireless sensing units are assumed to take the same amount of time to receive and recognize this '00Start' signal, then all the units start recording data at the same time,", "cite_spans": [{"start": 327, "end": 340, "text": "(Tweed, 1994)", "ref_id": "BIBREF33"}], "ref_spans": [{"start": 806, "end": 814, "text": "Figure 5", "ref_id": "FIGREF7"}, {"start": 1218, "end": 1226, "text": "Figure 4", "ref_id": "FIGREF5"}]}, {"section": "Communication Protocol Design and Implementation using State Machine Concept", "text": "i.e. the data acquisition is synchronized.", "cite_spans": [], "ref_spans": []}, {"section": "Communication Protocol Design and Implementation using State Machine Concept", "text": "As shown in Figure 5 , after the wireless sensing unit receives the '00Start' command, it transits into \"State2", "cite_spans": [], "ref_spans": [{"start": 12, "end": 20, "text": "Figure 5", "ref_id": "FIGREF7"}]}, {"section": "Communication Protocol Design and Implementation using State Machine Concept", "text": "Wait for 07InqStart\". Accordingly, after the central server broadcasts the '00Start' beacon signal, the server sends '07InqStart' to each unit, and waits until '08AckStart' message is returned from the sensing unit to confirm that this unit has received the '00Start' beacon. If any one of the wireless sensing units misses the '00Start' beacon, this unit will receive '07InqStart' command when itself is in \"State1\" (instead of in \"State2\"). In this case, the wireless sensing unit will send '09LostStart' in response to the central server's '07InqStart' inquiry. Knowing that the sensing unit has not properly received the '00Start' beacon, the central server will ask all of the units to restart and run the synchronization procedure again from the beginning, until the central server confirms that all the units have received the broadcasted '00Start' signal correctly.", "cite_spans": [], "ref_spans": []}, {"section": "Communication Protocol Design and Implementation using State Machine Concept", "text": "As mentioned earlier, the central server is assigned the responsibility for ensuring the wireless communication channel is reliable (e.g. no data loss). To illustrate this, assume that in Figure 5 , when the wireless sensing unit transits from \"State2\" to \"State3\", the '08AckStart' message sent from the unit to the central server is lost. The central server is now at its \"State1\" waiting for the '08AckStart', but because the server cannot receive this '08AckStart' message with certain expected time, the server will resend '07InqStart' to the unit. Therefore, in \"State3\" of the wireless sensing unit, although the unit should be waiting for the data acquisition request from the central server, the unit may still receive the '07InqStart' command because the last '08AckStart' was lost. In this case, the wireless sensing unit can handle this situation by simply resending '08AckStart' to the central server. This simple example illustrates the advantages inherent to the state machine concept when visualizing communication procedures. Although not presented here, the development of other facets of the communication protocol have demonstrated that the state machine concept provides the convenience for both designing and implementing program flow between the data server and the wireless sensing units.", "cite_spans": [], "ref_spans": [{"start": 188, "end": 196, "text": "Figure 5", "ref_id": "FIGREF7"}]}, {"section": "Real-time Continuous Data Collection", "text": "After the central server confirms that all of the wireless sensing units have received the latest beacon signal, the server starts inquiring the units one by one for the data they have thus far collected. Before the wireless sensing unit is queried for its data, the data is temporarily stored in the unit's onboard SRAM memory buffer.", "cite_spans": [], "ref_spans": []}, {"section": "Real-time Continuous Data Collection", "text": "With over 128kB of space available in memory, the wireless sensing unit can effectively store up to 64,000 data points (at 16-bit resolution). Once a unit is inquired by the server for measurement data, the wireless sensing unit transmits its most recently collected sensor data. A unique feature of the embedded wireless sensing unit software is that it can continue collecting data from interfaced sensors in real-time as the wireless sensing unit is transmitting data to the central server. The communication between the wireless sensing units and the central server during data transfer is highly reliable because of the network protocol in which the central server continues to request data from a unit until it receives the requested data.", "cite_spans": [], "ref_spans": []}, {"section": "Real-time Continuous Data Collection", "text": "At each instant in time, the central server can only communicate with one wireless sensing unit. In order to achieve real-time continuous data collection from multiple wireless sensing units with each unit having up to four analog sensors attached, a dual stack approach to managing the SRAM memory is taken in the current embedded software design. Essentially, the available memory bank of each unit is divided into four pairs of smaller memory stacks. When a wireless sensing unit starts collecting data, the embedded software establishes two memory stacks dedicated to each sensor channel for storing the sensor data. For each sensing Figure 6 channel, at any point of time, only one of the stacks is used to store the incoming data stream. During the procedure of storing new data into this memory stack, the system is responsible for sending the data in the other stack out to the central server. The role of each channel's two memory stacks alternates as soon as one stack is filled with newly collected data. Figure 6 illustrates the embedded system's management of the external SRAM memory. The two memory stacks, labeled Stacks \"X\"-1 and \"X\"-2 for sensor channel \"X\" (X is 1 or 2 in this example), are shown in Figure 6 . In the diagram, incoming data from each sensor channel is stored in the second stack (denoted as Stacks 1-2 and 2-2) while the system is wirelessly transferring data from the first stack (denoted as Stacks 1-1 and 2-1). Before Stacks \"X\"-2 are full, the wireless communication must be fast enough to transfer all the data from Stacks \"X\"-1. After Stacks \"X\"-2 are filled with new data, the role of each pair of stacks alternates with the radio transmitting entries from Stacks \"X\"-2 and storing sensor data in Stacks \"X\"-1.", "cite_spans": [], "ref_spans": []}, {"section": "Real-time Continuous Data Collection", "text": "The promptness of wireless communication is largely a function of the available wireless data transfer rate.", "cite_spans": [], "ref_spans": []}, {"section": "Real-time Continuous Data Collection", "text": "In the current prototype system using the MaxStream 9XCite transceiver, the central server is able to collect raw data from up to 24 wireless sensors continuously in real-time with a sampling frequency of 50Hz for each sensor, with the complete retry and acknowledgement communication protocol observed. As the sampling rate increases, the number of sensors that can be utilized decreases. For example, if a sampling rate of 100 Hz is desired, then only 12 sensors can be accommodated for real-time data communication with a single data server. If a high sampling rate and a large number of sensors are needed, then the system is not able to simultaneously collect data and wirelessly transmit at the same time. In such circumstances, the wireless sensing unit is first asked to collect a certain amount of data and to store the data temporarily in the local memory buffer. Upon completion, the wireless sensing unit can then send the data or the analysis results to the central server.", "cite_spans": [], "ref_spans": []}, {"section": "Real-time Continuous Data Collection", "text": "It should be noted that when the wireless sensing units are commanded to first store a certain period of data entirely before transmitting, the capacity of the wireless sensor network can be largely increased. Since in this configuration the demand for real-time delivery is not present, any sample rate can now be used. The only limitation encountered in this mode of operation is the available on-board memory which would control the duration of time the wireless sensor can collect data before exceeding its memory capacity.", "cite_spans": [], "ref_spans": []}, {"section": "Fourier Analysis using the Wireless Sensing Unit", "text": "To test the local data processing capability of the wireless sensing unit, a Fast Fourier Transform (FFT) algorithm using Cooley-Turkey method (Press et al., 1992 ) is implemented and embedded in the core of the wireless sensing unit. Upon demand from the central server, the wireless sensing units can be commanded to collect sensor data and perform a floating-point FFT on the sampled data. After the FFT is calculated, the wireless sensing units would then wirelessly transfer either the complex valued FFT spectrum and/or the raw time-history data to the central server. Using the currently selected microcontroller and SRAM, a 4,096-point floating-point Cooley-Turkey FFT method takes about 18 seconds to complete. Within the wireless bandwidth limitation from 9XCite wireless transceiver, if a 50Hz sampling frequency is applied at each sensor, and only the FFT spectrum from 0 to 10Hz is requested to be transferred back to the central server, the system can support real-time non-stopping data collection and FFT results collection from up to 11 wireless sensing units simultaneously. Depending on the application, it may not be necessary to transfer the original time-history data. In that case, the number of units that are supported for simultaneous FFT analysis and results collection can be increased to approximately 25, if a 50Hz sampling frequency is employed and a 0 to 10Hz FFT spectrum is transferred from the wireless sensing units to the data server. In general, if the embedded local data processing algorithm is not computationally expensive and the size of the desired results to be transmitted is small, the number of wireless sensing units that can be supported for real-time data interrogation and simultaneous results transmission can be quite large. ", "cite_spans": [{"start": 143, "end": 162, "text": "(Press et al., 1992", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "VALIDATION TESTS", "text": "To test the performance of the proposed wireless structural monitoring system, various validation tests are performed both in the laboratory and in the field. The results obtained from both sets of tests corroborate that the wireless sensing system is capable of accurately collecting data, performing data interrogation, and achieving reliable wireless communication. The field tests conducted at the Geumdang Bridge in Icheon, South Korea especially demonstrates the capability of the system to be applied to civil structures. This section presents in detail the results from the laboratory and field tests.", "cite_spans": [], "ref_spans": []}, {"section": "Laboratory Tests", "text": "Laboratory tests of the wireless SHM system are devised using a three-story experimental structure. Figure 7 shows the aluminum structure employed in a shake-table test. Each floor of the structure weighs about 7.26kg. The lateral stiffness of the structure is provided by four slender aluminum columns, each of which has a cross section of 0.64cm by 1.27cm. For theoretical computation, the three-story structure is simulated as a lumped-mass shear frame model. In another room about 15 meters away, a 9XCite wireless transceiver is connected with a computer so that it can serve as the central server for data acquisition. Two types of accelerometers are used for the validation test, showing the ability of the system to accommodate different analog sensors. A Crossbow CXL02LF1 accelerometer, which has an RMS (Root-Mean-Square) noise floor of 0.5mg, is placed on the ground, the first, and the third floor, respectively. A Bosch SMB110 accelerometer, which has an RMS noise floor of 6.8mg, is placed on the second floor.", "cite_spans": [], "ref_spans": [{"start": 100, "end": 108, "text": "Figure 7", "ref_id": "FIGREF8"}]}, {"section": "Laboratory Tests", "text": "In the first laboratory test, the structure is excited with a random initial velocity and displacement by the shake-table, then the shake-table stops moving and the structure vibrates freely. The wireless sensing unit associated with an accelerometer mounted on the third floor records the acceleration time history and transfers the data to the central server. Figure 8 shows the discrete Fourier transform (DFT) function corresponding to the measured acceleration time-history of the third-floor when the structure is under free 20 vibration. The three natural frequencies extracted from the three peaks of the DFT plot are 2.07Hz, 5.73Hz, and 8.27Hz, while the three theoretical natural frequencies computed from the simulation model are 2.08Hz, 5.71Hz, and 8.18Hz, respectively. The experimental and theoretical natural frequencies corroborate well, which underscores the accuracy of the acceleration time history collected by the wireless SHM system.", "cite_spans": [], "ref_spans": [{"start": 362, "end": 370, "text": "Figure 8", "ref_id": "FIGREF10"}]}, {"section": "Laboratory Tests", "text": "In the second laboratory test, the acceleration time history of each floor is measured when the structure is excited by a ground motion that is applied along the longitudinal direction of the structure. As shown in The ground excitation for the second laboratory test is a chirping signal that has constant displacement amplitude with a linearly varying frequency. The actual ground acceleration time history is measured by the accelerometer and collected by the central server, as plotted in Figure 9 . The measurement shows that because the table excitation is not ideal, the actual ground acceleration measured at the ground level is noisy compared with an ideal chirping signal. Using the measured ground acceleration as input, the numerical simulation model is again executed to compute the theoretical response of the three floors by employing the average acceleration time integration method. A comparison between the measured and theoretical absolute acceleration time history at the third floor is shown in Figure 10 . The measured and the theoretical time history plots are similar in both shape and magnitude, which demonstrates the high quality of the data collected by the wireless monitoring system. Although the time history data at two other floors are not plotted, the measured and theoretical maximum absolute accelerations at each floor are presented in Table 3 .", "cite_spans": [], "ref_spans": [{"start": 1016, "end": 1025, "text": "Figure 10", "ref_id": "FIGREF0"}, {"start": 1373, "end": 1380, "text": "Table 3", "ref_id": "TABREF3"}]}, {"section": "Laboratory Tests", "text": "The difference between the maximum values at the second floor is slightly larger than the difference at the first and third floor. This is probably the result of differences in the performance of the two types of accelerometers.", "cite_spans": [], "ref_spans": []}, {"section": "Laboratory Tests", "text": "The third laboratory test is intended to measure the steady-state acceleration response of the structure under harmonic loading, and to use the wireless sensing unit to calculate the discrete Fourier transform of the acceleration response using the embedded FFT algorithm. Provided only the steady state behavior of the structure is recorded, the frequency response should contain energy mostly in the harmonic frequency of the shaking table. The shake-table is commanded to apply a harmonic base motion at a frequency of 5.7 Hz, which is close to the second natural frequency of the lumped-mass shear-frame structure. First, the three wireless sensing units installed in the structure at each floor are employed to collect 4,096 data points at a sampling rate of 100Hz after all dynamic response transients have died out. After collecting the acceleration response of the structure, the wireless sensing units then automatically calculate a 4096-point FFT using the acceleration response time-history of the structure. After the FFT computation, both the time history data and FFT results are transferred back to the central server for validation. Figure 11 illustrates the acceleration time history and FFT results computed by the wireless sensing units at the ground and at the third floor.", "cite_spans": [], "ref_spans": [{"start": 1149, "end": 1158, "text": "Figure 11", "ref_id": "FIGREF0"}]}, {"section": "Laboratory Tests", "text": "Based on the FFT results calculated by the wireless sensing units, the frequency responses corresponding to the ground and third floor accelerations both have peak values at the frequency of 5.7Hz, which matches well with the expectation for this experiment.", "cite_spans": [], "ref_spans": []}, {"section": "Geumdang Bridge Tests", "text": "To test the performance of a large-scale wireless sensor network in a civil structure, field tests on the Geumdang Bridge in Icheon, South Korea are conducted. The Geumdang Bridge, a long-span concrete box girder bridge spanning 122m, is instrumented with two sets of accelerometers attached to both a tethered and a wireless monitoring system. The depth of the box girder is 2.6m while the top bridge deck has a total width of 12.6m. The total span is supported along its length by three concrete piers and one concrete abutment.", "cite_spans": [], "ref_spans": []}, {"section": "Geumdang Bridge Tests", "text": "The locations of the piers along the span length are shown in Figure 12 . Table 3 Figure 9 Figure 12 Besides the wireless monitoring system, a wire-based structural monitoring system has also been installed.", "cite_spans": [], "ref_spans": [{"start": 62, "end": 71, "text": "Figure 12", "ref_id": "FIGREF0"}, {"start": 74, "end": 81, "text": "Table 3", "ref_id": "TABREF3"}, {"start": 91, "end": 100, "text": "Figure 12", "ref_id": "FIGREF0"}]}, {"section": "Geumdang Bridge Tests", "text": "The wire-based system employs piezoelectric accelerometers to measure the vertical acceleration response of the bridge at the locations #1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 13, 14, 15 and 16 , as denoted in Figure 12 (a) . The piezoelectric accelerometers used by the wire-based monitoring system are PCB393 accelerometers manufactured by PCB Piezotronics. For direct comparison, the wireless monitoring system also deploys accelerometers at these locations, with one accelerometer installed side-by-side to each PCB393 accelerometer. However, for the wireless monitoring system, lower-cost capacitive Piezotronics PCB3801 accelerometers are attached to the wireless sensing units at the 14 different sensor installation locations. Table 4 provides a performance comparison of the two accelerometers installed on the Geumdang Bridge.", "cite_spans": [], "ref_spans": [{"start": 203, "end": 216, "text": "Figure 12 (a)", "ref_id": "FIGREF0"}, {"start": 728, "end": 735, "text": "Table 4", "ref_id": "TABREF4"}]}, {"section": "Geumdang Bridge Tests", "text": "As illustrated in the table, PCB393 accelerometers used by the wire-based system have higher sensitivity and lower noise floors. Therefore, they are expected to have better performance than the PCB3801 accelerometers used by the wireless system. While the interior of the box girder protects the wireless sensing units from the natural elements, there are a number of vertical stiffener diaphragms within the box girder that attenuate the wireless signal between the wireless sensing units. The central server (laptop) is placed at the vicinity of sensor location #9, with a maximum distance between the central server and the furthest wireless sensing unit of about 60m. As opposed to the wire-based system, installation of the wireless monitoring system takes only about one hour. For subsequent tests, the wireless sensing units are also moved around to different locations inside the box girder, a convenience made possible by using wireless communications.", "cite_spans": [], "ref_spans": []}, {"section": "Geumdang Bridge Tests", "text": "For the wire-based monitoring system, the analog outputs of the PCB393 accelerometers are fed into a 16-channel PCB Piezotronics 481A03 signal conditioning unit. Before being sampled and digitized, the signals are amplified by a factor of 10 using an amplification circuit native to the signal conditioning unit. A National Instruments' 12-bit data acquisition card (model number 6062E) is used by a standard laptop computer to sample and digitize the amplified accelerometer signals. The wire-based monitoring system is configured to sample the 14 sensor channels at 200Hz. For the wireless monitoring system, the PCB3801 Table 4 Figure 13", "cite_spans": [], "ref_spans": [{"start": 623, "end": 630, "text": "Table 4", "ref_id": "TABREF4"}]}, {"section": "Geumdang Bridge Tests", "text": "accelerometers are connected directly to the sensing interface of each wireless sensing unit. Due to the limited wireless communication bandwidth and the large number of wireless sensing units that are streaming data simultaneously, the sampling rate of the wireless monitoring system is selected at 70Hz. Over the course of two full days of testing, the wireless monitoring system never experiences any communication problems including data loses. The designed communication protocol for near-synchronized and non-stop real-time data acquisition proves to be highly reliable for the wireless sensor deployment on the bridge structure.", "cite_spans": [], "ref_spans": []}, {"section": "Geumdang Bridge Tests", "text": "The Geumdang Bridge is kept closed to regular highway traffic while the bridge is excited using trucks of known weight and speed crossing the bridge. Figure 13 illustrates the acceleration response of the bridge at sensor locations #8 and #13, when a 40-ton truck crosses the bridge at 60 km/hr. Sensor #8 is near the central server, while sensor #13 is among the farthest units from the central server. The figure plots the acceleration time histories collected by the two different systems. There exists a strong one-to-one correspondence in the acceleration response time history records collected by the two systems. As expected, the acceleration record measured by the wireless monitoring system appears noisier than that collected by the wire-based monitoring system, due to the difference in the accelerometers being used and the signal conditioning in the tethered system. The wireless sensing units are also commanded to perform a 4096 point FFT using the measured acceleration response. The frequency response as calculated by the wireless sensing unit is shown in Figure 13 . If the frequency response is compared to the frequency response calculated offline using the response data collected by the wire-based monitoring system, again the FFT results from the two systems are very close to each other. The difference in the amplitude of FFT results is mainly caused by the different sampling frequencies used in the two systems.", "cite_spans": [], "ref_spans": [{"start": 150, "end": 159, "text": "Figure 13", "ref_id": "FIGREF0"}, {"start": 1075, "end": 1084, "text": "Figure 13", "ref_id": "FIGREF0"}]}, {"section": "SUMMARY AND DISCUSSION", "text": "This paper presented in great detail, the design of an integrated software and hardware architecture for wireless structural health monitoring systems. Special features of the prototype wireless monitoring system includes: 1) low power consumption without sacrificing long-range communication, 2) rapid system installation and low system costs, 3) reliable communication protocols ensuring lossless wireless communications, 4) a multithreaded embedded software allowing for simultaneous data sampling and wireless communications, 5) high-precision time synchronization, and 6) local data processing capabilities integrated with the wireless sensing units. Both laboratory and field validation tests corroborate the capability and reliability of the prototype system for large-scale deployment in civil structures. It should be noted that the hardware components and the circuit design will likely be changed with new requirements and as microprocessor and wireless technologies advance. Nevertheless, the design and decision process as described in this paper will likely remain valid.", "cite_spans": [], "ref_spans": []}, {"section": "SUMMARY AND DISCUSSION", "text": "The prototype system can further be improved in a number of areas. With respect to the wireless sensing unit hardware design, sensor signal conditioning and anti-noise filters can be designed to improve the measurement fidelity of the wireless sensing units. With the rapid development in wireless communication technologies, wireless transceivers that support longer communication ranges and higher data rates while consuming less power should be pursued. Improvements can also be made with respect to the embedded software. For example, more advanced communication protocols are needed to organize very-large-scale wireless sensor networks with peer-to-peer connections. Local data compression algorithm can be incorporated to reduce wireless communication in the network, thereby improving the scalability of the system. Different decentralized damage detection and system identification algorithms that are suitable for embedment in the computational core of the wireless sensing units can be tested. In terms of application of the system to civil structures, while the Geumdang Bridge tests illustrate the potential and robustness of large-scale wireless structural monitoring systems to replace tethered monitoring systems, additional field studies are needed to further refine the design of the prototype system. ", "cite_spans": [], "ref_spans": []}, {"section": "ACKNOWLEDGEMENT", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Wait for 00Start", "text": "State0 Bootup", "cite_spans": [], "ref_spans": []}, {"section": "State2", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Wait for 07InqStart", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "State3", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Wait for 01Inquiry Data", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Initialize memory", "text": "No condition", "cite_spans": [], "ref_spans": []}, {"section": "Send 09LostStart", "text": "Figure 6 ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Review paper: health monitoring of civil infrastructure, Struct. 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However, duty cycle usage of the battery allows for the internal cell chemistries to attain equilibrium and can thus extend batteries' life expectancies. The standby life-time of the wireless sensing unit, T standby ,", "type": "figure"}, "FIGREF3": {"text": "Figure 2", "type": "figure"}, "FIGREF4": {"text": "Figure 3", "type": "figure"}, "FIGREF5": {"text": "shows the abridged state diagram for the central server software, and Figure 5 shows the abridged state diagram for the wireless sensing unit software. For simplicity, only the part of the communication state diagram for synchronizing wireless sensing units is presented, i.e. these two parts of communication state diagrams describe the program flow to realize the synchronization procedure introduced in Section 3.1. In the state diagrams shown in Figures 4 and 5, each rectangle or circle with bold boundary lines stands for one possible state; lines with arrows represent state transitions. As shown in the legend, for each transition, the normal text above the horizontal line specifies the event/condition upon which the transition should happen, and the italic text below the horizontal line specifies the service/action to be completed during this transition.", "type": "figure"}, "FIGREF6": {"text": "Figure 4", "type": "figure"}, "FIGREF7": {"text": "Figure 5", "type": "figure"}, "FIGREF8": {"text": "Figure 7", "type": "figure"}, "FIGREF9": {"text": "Figure 7, accelerometers are placed on each floor including the ground level. An accelerometer is associated", "type": "figure"}, "FIGREF10": {"text": "Figure 8", "type": "figure"}, "FIGREF11": {"text": "Figure 11", "type": "figure"}, "FIGREF12": {"text": "Figure 10", "type": "figure"}, "FIGREF13": {"text": "Figure 1. Functional diagram detailing the hardware design of the wireless sensing unit", "type": "figure"}, "FIGREF14": {"text": "Figure 3. State diagram detailing the procedure for synchronizing the wireless sensing units", "type": "figure"}, "FIGREF15": {"text": "Figure 4. Abridged communication state diagram for the central server", "type": "figure"}, "FIGREF16": {"text": "Figure 7. Test structure for laboratory validation of the wireless monitoring system", "type": "figure"}, "FIGREF17": {"text": "Figure 10. Comparison of measured and theoretical absolute acceleration at third floor", "type": "figure"}, "FIGREF18": {"text": "Figure 3", "type": "figure"}, "FIGREF20": {"text": "Figure 5", "type": "figure"}, "FIGREF22": {"text": "Figure 7", "type": "figure"}, "FIGREF23": {"text": "Figure 11", "type": "figure"}, "FIGREF25": {"text": "Figure 12", "type": "figure"}, "FIGREF26": {"text": "Plan view showing tethered and wireless accelerometers placed side-by-side for 14 solid-dot locations (b) Outside perspective view of the bridge (c) Interior of the box girder", "type": "figure"}, "FIGREF27": {"text": "Figure 13", "type": "figure"}, "TABREF1": {"text": "Key characteristics of the MaxStream 9XCite wireless transceiver Table 2. Approximate current consumption of the wireless sensing unit Table 3. Comparison of measured and theoretical maximum absolute acceleration Table 4. Performance comparison between accelerometers used by the wire-based and wireless systemsSpecification Transceiver Parameter Communication Range Up to 300' (90m) indoor, 1000' (300m) outdoor", "type": "table"}, "TABREF2": {"text": "Component Active Current Standby Current A/D converter ADS8341 (at 100 Hz) 1mA 1\u00b5A Micro-controller ATmega128 (at 8MHz)", "type": "table"}, "TABREF3": {"text": "Quantity", "type": "table"}, "TABREF4": {"text": "Specification", "type": "table"}}}
{"paper_id": "17787136", "_pdf_hash": "544b8f4fad9e6a3579232aa07cfbf1ea6c0d3671", "abstract": [{"section": "Abstract", "text": "Abbreviations used in this paper: DSB, double-strand break; PCNA, proliferating cell nuclear antigen; PI, propidium iodide; RPA, replication protein A.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "The online version of this article contains supplemental material.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Genetic information in eukaryotes is organized in chromatin, a highly conserved structural polymer that supports and controls crucial functions of the genome. Chromatin undergoes dynamic changes, including massive structural reorganization, during genetic processes such as DNA replication and cell division, transcription, DNA repair, and recombination. Histones and particularly their N-terminal tails are modulated by a large number of posttranslational modifi cations, including lysine methylations that influence these fundamental biological processes (Kouzarides, 2007) .", "cite_spans": [{"start": 557, "end": 575, "text": "(Kouzarides, 2007)", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Introduction", "text": "The contribution from the chromatin environment to DNA replication and DNA damage response processes is only starting to become evident. Recently, a link between histone lysine methylation and the DNA damage responses have been uncovered. The checkpoint mediator 53BP1 is directly recruited to chromatin regions flanking DNA double-strand breaks (DSBs). This occurs via interaction with histone H4 that is specifi cally mono-or dimethylated at Lys20 or with histone H3 dimethylated at Lys79 (Huyen et al., 2004; Botuyan et al., 2006) . 53BP1 plays an important role in the cellular response to DNA damage by acting as an adaptor in the repair of DNA DSBs . Histone H4 Lys20 (H4-K20) can be mono-, di-, or trimethylated, and SET8 (also known as PR-Set7 and SETD8) can catalyze the monomethylation (Fang et al., 2002; Nishioka et al., 2002; Couture et al., 2005; Xiao et al., 2005) . Previously, the expression of SET8 in mammalian cells has been shown to increase during S phase until mitosis ; however, the functional role of SET8 remains poorly understood. Key issues such as the consequences of SET8 depletion have not been reported. The fl y SET8 homologue PR-Set7 has been deleted in Drosophila melanogaster larvae, in which tissues with higher rates of cell divisions were severely affected. In this organism, progression through early mitosis was delayed, and levels of the essential mitotic regulator cyclin B was reduced (Sakaguchi and Steward, 2007) .", "cite_spans": [{"start": 491, "end": 511, "text": "(Huyen et al., 2004;", "ref_id": "BIBREF6"}, {"start": 512, "end": 533, "text": "Botuyan et al., 2006)", "ref_id": "BIBREF1"}, {"start": 796, "end": 815, "text": "(Fang et al., 2002;", "ref_id": "BIBREF3"}, {"start": 816, "end": 838, "text": "Nishioka et al., 2002;", "ref_id": "BIBREF11"}, {"start": 839, "end": 860, "text": "Couture et al., 2005;", "ref_id": "BIBREF2"}, {"start": 861, "end": 879, "text": "Xiao et al., 2005)", "ref_id": "BIBREF23"}, {"start": 1429, "end": 1458, "text": "(Sakaguchi and Steward, 2007)", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Introduction", "text": "In this study, we have analyzed the functional role of human H4-K20 methyltransferase SET8. We establish that it is important for proper progression through the cell cycle. Inhibition of SET8 expression by siRNA results in the massive accumulation of DNA damage that subsequently activates a", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The histone methyltransferase SET8 is required for S-phase progression C hromatin structure and function is infl uenced by histone posttranslational modifi cations. SET8 (also known as PR-Set7 and SETD8) is a histone methyltransferase that monomethylates histonfe H4-K20. However, a function for SET8 in mammalian cell proliferation has not been determined. We show that small interfering RNA inhibition of SET8 expression leads to decreased cell proliferation and accumulation of cells in S phase. This is accompanied by DNA double-strand break (DSB) induction and recruitment of the DNA repair proteins replication protein A, Rad51, and 53BP1 to damaged regions. SET8 depletion causes DNA damage specifi cally during replication, which induces a Chk1-mediated S-phase checkpoint. Furthermore, we fi nd that SET8 interacts with proliferating cell nuclear antigen through a conserved motif, and SET8 is required for DNA replication fork progression. Finally, codepletion of Rad51, an important homologous recombination repair protein, abrogates the DNA damage after SET8 depletion. Overall, we show that SET8 is essential for genomic stability in mammalian cells and that decreased expression of SET8 results in DNA damage and Chk1-dependent S-phase arrest.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Chk1-dependent checkpoint. This leads to slower progression through S phase and decreased proliferation. We also show that SET8 interacts with proliferating cell nuclear antigen (PCNA) through a PCNA interaction motif and that there is a requirement for SET8 during replication fork progression. Collectively, our data suggest that SET8 plays an important role in securing the accurate completion of DNA replication and, for the fi rst time, demonstrates such a role for a histone methyltransferase in protecting against genomic instability.", "cite_spans": [], "ref_spans": []}, {"section": "Results and discussion", "text": "Depletion of SET8 prevents cell proliferation and causes cell cycle delay in", "cite_spans": [], "ref_spans": []}, {"section": "S phase", "text": "To investigate the role of SET8 depletion in cell cycle progression, we transfected U2OS cells with siRNA against SET8. U2OS cells are human osteosarcoma cells that are widely used in cell cycle studies. Cells were counted 48 and 96 h after siRNA treatment, and the SET8-depleted cells proliferated signifi cantly slower than mock-treated cells (Fig. 1 A) . We have not observed marked sub-G1 peaks or accumulating debris indicative of apoptosis/cell death at these time points. Depletion of SET8 also induced morphological alterations of the cells (Fig. 1 B) , as depleted cells increased the size of their cytoplasm.", "cite_spans": [], "ref_spans": [{"start": 345, "end": 355, "text": "(Fig. 1 A)", "ref_id": "FIGREF0"}, {"start": 549, "end": 559, "text": "(Fig. 1 B)", "ref_id": "FIGREF0"}]}, {"section": "S phase", "text": "To explore the nature of the cell cycle delay observed during SET8 depletion, cells were analyzed by fl ow cytometry (FACS). Addition of the mitotic spindle inhibitor nocodazole 16 h before harvesting resulted in the accumulation of cells in M phase in the mock-treated sample (Fig. 2 A) . In contrast, inhibition of SET8 expression led to a signifi cant accumulation of the cells in S phase, a defect that became more visible in the presence of nocodazole (Fig. 2 A) . Western blotting of SET8-depleted cells supported the notion that SET8 is required for normal S-phase progression. These results were reproduced by two different individual siRNA as well as SMARTpool siRNA targeting SET8 (Fig. S1 , A and B; available at http://www.jcb.org/cgi/ content/full/jcb.200706150/DC1). As shown in Fig. 2 B, the levels of histone H3 Ser10 phosphorylation, a marker of mitotic cells, were low in SET8-depleted cells compared with mock cells. Consistently, the levels of cyclin A2, which is known to accumulate from the G1/S transition to G2 phase and is degraded in metaphase cells, were higher in SET8-depleted cells compared with mock cells.", "cite_spans": [], "ref_spans": [{"start": 277, "end": 287, "text": "(Fig. 2 A)", "ref_id": "FIGREF1"}, {"start": 457, "end": 467, "text": "(Fig. 2 A)", "ref_id": "FIGREF1"}, {"start": 691, "end": 699, "text": "(Fig. S1", "ref_id": "FIGREF0"}, {"start": 793, "end": 799, "text": "Fig. 2", "ref_id": "FIGREF1"}]}, {"section": "S phase", "text": "Next, we wanted to determine whether decreasing SET8 levels would affect DNA replication. U2OS cells treated with SET8 or mock siRNA were pulse labeled with BrdU and analyzed by FACS. Remarkably, a significant fraction of cells in S phase were not incorporating BrdU (Fig. 2 C) . Collectively, these data show that DNA replication is impaired in SET8-depleted cells, resulting in S-phase delay and, consequently, decreased cell proliferation.", "cite_spans": [], "ref_spans": [{"start": 267, "end": 277, "text": "(Fig. 2 C)", "ref_id": "FIGREF1"}]}, {"section": "Inhibition of SET8 expression results in DSBs", "text": "Next, we investigated whether the slower progression through S phase might be related to DNA replication-associated lesions. To address this, we stained U2OS cells using an antibody against phosphorylated H2AX (\u03b3-H2AX), a well-established marker for DNA DSBs (Pilch et al., 2003) . As shown in Fig. 3 A, inhibition of SET8 expression led to a dramatic increase in \u03b3-H2AX-positive cells as early as 24 h after siRNA transfection, suggesting that SET8 depletion leads to massive DNA damage. To further corroborate these fi ndings, we analyzed and quantifi ed \u03b3-H2AX levels in a FACS-based assay. Again, SET8 silencing lead to marked DNA damage (Fig. 3 B) . Cells with DNA damage were negative for H4-K20 monomethylation, which is consistent with the concomitant loss of the monomethylase function of SET8 in these cells (Figs. 3 C and S1 C). \u03b3-H2AX foci formation after SET8 depletion was also observed in HeLa cells (Fig. S1 D) as well as by direct analysis of DNA strand breaks using pulsedfi eld gel electrophoresis (Fig. 4 D) . Collectively, our data demonstrate that SET8 has a critical role in maintaining correct genomic structure.", "cite_spans": [{"start": 259, "end": 279, "text": "(Pilch et al., 2003)", "ref_id": "BIBREF13"}], "ref_spans": [{"start": 294, "end": 300, "text": "Fig. 3", "ref_id": "FIGREF2"}, {"start": 642, "end": 652, "text": "(Fig. 3 B)", "ref_id": "FIGREF2"}, {"start": 915, "end": 926, "text": "(Fig. S1 D)", "ref_id": "FIGREF0"}, {"start": 1017, "end": 1027, "text": "(Fig. 4 D)", "ref_id": "FIGREF3"}]}, {"section": "Inhibition of SET8 expression results in DSBs", "text": "We reasoned that massive DNA damage observed after SET8 depletion could result from the inhibition of vital DNA repair processes because SET8 status could affect the recruitment of 53BP1 as well as other proteins to sites of DNA damage. 53BP1 is a checkpoint mediator involved in the initial sensing and signaling of DNA strand breaks . The protein has been suggested to be recruited to DNA DSBs via interaction with dimethylated histone H3-K79 and mono-or dimethylated H4-K20, and this interaction has been suggested to be dependent on SET8 (Botuyan et al., 2006) . To understand whether the inhibition of SET8 expression affected the recruitment of key DNA repair proteins to sites of DNA damage, we investigated the nuclear accumulation of these proteins by confocal microscopy. As demonstrated in Fig. 3 (C and D), decreased SET8 expression lead to 53BP1 recruitment to sites of DNA damage and a marked increase in Rad51 and replication protein A (RPA) foci. Thus, inhibition of SET8 expression and reduction of H4-K20 monomethylation led to an increased recruitment of 53BP1. To test whether SET8 would be required for 53BP1 recruitment after exogenously induced DSB, we also treated SET8-depleted cells with ionizing irradiation. Yet again, 53BP1 readily relocated to radiation-induced DNA damage foci (Fig. S1 D) . This strongly indicates that the presence of SET8 is not essential for the recruitment of 53BP1. 53BP1 was found primarily to bind dimethylated H4-K20, and we noticed that dimethylated H4-K20 persists after SET8 silencing (Fig. S2 A, available at http://www.jcb.org/cgi/content/full/jcb.200706150/DC1). This indicates that 53BP1 is recruited via persisting dimethylated H4-K20 or via interaction with accessible dimethylated H3-K79 or \u03b3-H2AX (Huyen et al., 2004; Ward et al., 2006) .", "cite_spans": [{"start": 542, "end": 564, "text": "(Botuyan et al., 2006)", "ref_id": "BIBREF1"}, {"start": 1764, "end": 1784, "text": "(Huyen et al., 2004;", "ref_id": "BIBREF6"}, {"start": 1785, "end": 1803, "text": "Ward et al., 2006)", "ref_id": "BIBREF22"}], "ref_spans": [{"start": 801, "end": 807, "text": "Fig. 3", "ref_id": "FIGREF2"}, {"start": 1308, "end": 1319, "text": "(Fig. S1 D)", "ref_id": "FIGREF0"}, {"start": 1544, "end": 1552, "text": "(Fig. S2", "ref_id": "FIGREF1"}]}, {"section": "The S-phase delay in SET8-depleted cells is", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Chk1 mediated", "text": "DNA replication can cease for a variety of reasons before scheduled termination, including progression into areas with DNA damage lesions. Chk1 is a key regulator of the cellular response induced by stalled replication forks, a response that leads to the inhibition of DNA replication initiation at origins of replication (Feijoo et al., 2001) . Therefore, we investigated whether Chk1 is activated in SET8-depleted cells. To do this, we transfected cells with SET8 siRNA. Nocodazole was added during the last 16 h, and cells were processed for immunoblotting analysis. The inhibition of SET8 expression led to a dramatic activation of Chk1 as measured by the phosphorylation of Ser317 on Chk1 (Fig. 4 A; Zhao and Piwnica-Worms, 2001 ). Phosphorylation of RPA was also markedly increased when SET8 was depleted. RPA is required for activation of the ataxia telangiectasia related kinase, which activates Chk1 in the presence of DNA damage (Zou et al., 2003) . The activation of Chk1 suggested a role for the checkpoint kinase in mediating the cell cycle delay in SET8-depleted cells. To explore this, Chk1 was specifi cally long-term depleted using siRNA in combination with SET8 depletion. Inhibition of Chk1 prevented the delay in S phase (Fig. 4 B) . Similar data were obtained with the Chk1 inhibitors G\u00f66976 (Fig. 4 C; Kohn et al., 2003) , CEP-3891 (Sorensen et al., 2003) , and UCN-01 (Sarkaria et al., 1999; and unpublished data) . These cells progress through the cell cycle with markedly damaged DNA as judged by quantitative \u03b3-H2AX FACS analysis (Figs. 4 C and S2 B) and pulsed-fi eld gel electrophoresis (Figs. 4 D and S2 C) . This is consistent with a critical role for Chk1 in restraining cell cycle progression after DNA damage. . SET8 depletion leads to replication-dependent DNA damage that activates Chk1. (A) SET8 was depleted in U2OS cells using siRNA for 52 h. Nocodazole was added for the last 16 h as indicated. Cells were collected and processed for immunoblotting. (B) U2OS cells were treated with siRNA against mock, SET8, or Chk1 for 48 h. Nocodazole was added 13 h before harvest. Cells were fi xed, stained with PI, and analyzed by FACS. A graph was generated by overlaying the FACS profi les from SET8-depleted cells and cells codepleted for SET8 and Chk1. (C) SET8 was depleted in U2OS cells using siRNA for 52 h. Nocodazole (16 h) and the Chk1 inhibitor G\u00f66976 (3 h) were added before harvest. Samples were fi xed, stained with PI, and analyzed by FACS. (B and C) A fraction of the cells was collected and processed for immunoblotting. (D) 48 h after SET8 siRNA transfection, cells were treated with 5 \u03bcM aphidicolin and/or the Chk1 inhibitor CEP-3891 for an additional 24 h. Cells were then processed for pulsed-fi eld gel electrophoresis. (E) U2OS cells were treated with siRNA against mock, SET8, Cdc45, or Rad51 for 48 h. Cells were then fi xed and stained for \u03b3-H2AX and PI followed by FACS analysis. We next wanted to address whether the lesions generated by SET8 silencing were dependent on DNA replication. Importantly, as shown in Fig. 4 D, the DNA replication inhibitor aphidicolin abrogated the DNA damage induced by SET8 depletion, suggesting that the lesions depend on ongoing DNA replication (Fig. 4 D) . To corroborate this, we cosilenced several genes with an important role in DNA replication. Rapid accumulation of \u03b3-H2AX foci was not observed by individual depletion of other replication-associated proteins such as Cdc45 and MCM4, which are both essential for the initiation of DNA replication (Fig. 4 E and not depicted; Bell and Dutta, 2002; Pacek and Walter, 2004) . When codepleted with SET8, these proteins all reduced the DNA damage. This confi rmed that DNA replication is necessary for SET8 silencing to cause DNA damage. The homologous recombination repair pathway plays an important role in the repair of DNA damage occurring during DNA replication (Saintigny et al., 2001; Helleday et al., 2007) . Depletion of Rad51, a key component of this repair pathway, did not cause such massive DNA damage at the time points analyzed (Fig. 4 E) . At such early time points, cells depleted for Rad51 were still viable and progressed through S phase like control depleted cells (Fig. S3 C, available at http://www.jcb .org/cgi/content/full/jcb.200706150/DC1). Notably, Rad51 depletion blocked DNA damage after SET8 depletion. We suggest that SET8 in unperturbed cells is involved downstream of Rad51 in resolving recombination structures forming spontaneously in cells during DNA replication. When SET8 is depleted, these structures are collapsed into DSBs.", "cite_spans": [{"start": 322, "end": 343, "text": "(Feijoo et al., 2001)", "ref_id": "BIBREF4"}, {"start": 705, "end": 733, "text": "Zhao and Piwnica-Worms, 2001", "ref_id": "BIBREF24"}, {"start": 939, "end": 957, "text": "(Zou et al., 2003)", "ref_id": "BIBREF25"}, {"start": 1324, "end": 1342, "text": "Kohn et al., 2003)", "ref_id": "BIBREF8"}, {"start": 1354, "end": 1377, "text": "(Sorensen et al., 2003)", "ref_id": "BIBREF18"}, {"start": 1391, "end": 1414, "text": "(Sarkaria et al., 1999;", "ref_id": "BIBREF17"}, {"start": 3573, "end": 3594, "text": "Bell and Dutta, 2002;", "ref_id": "BIBREF0"}, {"start": 3595, "end": 3618, "text": "Pacek and Walter, 2004)", "ref_id": "BIBREF12"}, {"start": 3910, "end": 3934, "text": "(Saintigny et al., 2001;", "ref_id": "BIBREF15"}, {"start": 3935, "end": 3957, "text": "Helleday et al., 2007)", "ref_id": "BIBREF5"}], "ref_spans": [{"start": 694, "end": 701, "text": "(Fig. 4", "ref_id": "FIGREF3"}, {"start": 1241, "end": 1251, "text": "(Fig. 4 B)", "ref_id": "FIGREF3"}, {"start": 1313, "end": 1323, "text": "(Fig. 4 C;", "ref_id": "FIGREF3"}, {"start": 1556, "end": 1576, "text": "(Figs. 4 C and S2 B)", "ref_id": "FIGREF1"}, {"start": 3071, "end": 3077, "text": "Fig. 4", "ref_id": "FIGREF3"}, {"start": 3237, "end": 3247, "text": "(Fig. 4 D)", "ref_id": "FIGREF3"}, {"start": 3545, "end": 3554, "text": "(Fig. 4 E", "ref_id": "FIGREF3"}, {"start": 4086, "end": 4096, "text": "(Fig. 4 E)", "ref_id": "FIGREF3"}, {"start": 4228, "end": 4236, "text": "(Fig. S3", "ref_id": "FIGREF2"}]}, {"section": "Chk1 mediated", "text": "Recent results have suggested that Drosophila PR-Set7 function is required for chromosome condensation and mitosis (Sakaguchi and Steward, 2007) . Thus, to investigate whether the S-phase checkpoint observed in mammalian cells is dependent on progression through mitosis, we arrested cells at the G1/S transition by addition of the DNA replication inhibitor thymidine. At the same time, SET8 was depleted using siRNA, and cells were released 30 h after arrest and analyzed by FACS. As seen in Fig. 5 A, cells released from the thymidine arrest were also affected by the depletion of SET8, as these cells progressed slower through S phase compared with mock-treated cells. Therefore, we conclude that the S-phase delay in response to SET8 silencing can occur independently of progression through mitosis.", "cite_spans": [{"start": 115, "end": 144, "text": "(Sakaguchi and Steward, 2007)", "ref_id": "BIBREF16"}], "ref_spans": [{"start": 493, "end": 499, "text": "Fig. 5", "ref_id": "FIGREF4"}]}, {"section": "Chk1 mediated", "text": "Our results suggest that depletion of SET8 in the Drosophila and mammalian organisms may have different outcomes. This can partly be explained by the fact that Drosophila PR-Set7 and human SET8 only are moderately homologous. However, the different phenotypes could also be a consequence of the experimental approaches used. In the Drosophila study (Sakaguchi and Steward, 2007) , the investigators used cells from PR-Set7 knockout fl ies. The cells originated from third instar larvae fl ies and, thus, had progressed through several cell cycles before analysis. In contrast, we used mammalian cells and investigated the defects of SET8 depletion after cells were released from a G1/S block. We cannot eliminate the possibility that cells depleted for SET8 experience defects in progression through M phase; however, such defects were not detected in our study.", "cite_spans": [{"start": 349, "end": 378, "text": "(Sakaguchi and Steward, 2007)", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "SET8 is required for replication fork progression and interacts with PCNA", "text": "Having established that DNA damage after SET8 depletion is dependent on DNA replication, we further investigated whether SET8 plays a direct role in DNA replication. To achieve this, we monitored replication fork progression using a previously described method in which newly synthesized DNA is labeled with [", "cite_spans": [], "ref_spans": []}, {"section": "SET8 is required for replication fork progression and interacts with PCNA", "text": "3 H]thymidine (Johansson et al., 2004) . The assay is based on the principle that each replication fork consists of a pair of single-stranded ends. These ends become unwound in alkaline solution. If replication elongation is inhibited, the labeled DNA will be present in the single-stranded DNA fraction. On the contrary, replication elongation will lead to the presence of the labeled DNA in the double-stranded DNA fraction. Thus, 100% labeled single-stranded DNA is equivalent to no fork progression (Fig. S3 D) . Using this assay, we found that replication progression was slowed signifi cantly by SET8 depletion (Fig. 5 B) , confi rming that SET8 is required for effi cient DNA replication. Fork progression was not increased by the coinhibition of Chk1; rather, this inhibition lead to further replication inhibition. This indicates that SET8 and Chk1 function on separate pathways to regulate replication fork progression.", "cite_spans": [{"start": 14, "end": 38, "text": "(Johansson et al., 2004)", "ref_id": "BIBREF7"}], "ref_spans": [{"start": 503, "end": 514, "text": "(Fig. S3 D)", "ref_id": "FIGREF2"}, {"start": 617, "end": 627, "text": "(Fig. 5 B)", "ref_id": "FIGREF4"}]}, {"section": "SET8 is required for replication fork progression and interacts with PCNA", "text": "Stimulated by this fi nding, we performed detailed sequence analysis of SET8 in Scan Prosite searching for conserved motifs that could link SET8 with DNA replication. Remarkably, we found a conserved PIP box in SET8, which is a short sequence that mediates binding to PCNA (Warbrick, 1998) . The SET8 PIP-box sequence is N-X-X-L-X-X-F-Y, which is located from amino acid residues 178-185 in human SET8. To investigate the interaction between PCNA and SET8, we fi rst performed immunofl uorescence staining. This indeed revealed colocalization between SET8 and PCNA (Fig. 5 C) . Next, we determined whether the two proteins could interact. As shown in Fig. 5 D,  SET8 and PCNA interact in a manner dependent on a functional PIP box. We also detected an interaction at endogenous protein levels (Fig. 5 E) , which, altogether, links SET8 directly with the replication machinery. Collectively, we propose that SET8 supports the organization and maintenance of chromatin structures to facilitate DNA replication and effi cient DNA repair. SET8 may also play a transcriptional role in regulating the expression of genes critical for S-phase progression; however, we have not observed abnormalities in the expression of the DNA replication-associated proteins analyzed so far. In conclusion, our results demonstrate that SET8 is required for normal S-phase progression. Inhibition of SET8 expression leads to a dramatic increase in Chk1 activity, resulting in Chk1-dependent inhibition of DNA replication.", "cite_spans": [{"start": 273, "end": 289, "text": "(Warbrick, 1998)", "ref_id": "BIBREF21"}], "ref_spans": [{"start": 565, "end": 575, "text": "(Fig. 5 C)", "ref_id": "FIGREF4"}, {"start": 651, "end": 666, "text": "Fig. 5 D,  SET8", "ref_id": "FIGREF4"}, {"start": 793, "end": 803, "text": "(Fig. 5 E)", "ref_id": "FIGREF4"}]}, {"section": "Materials and methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Cell culture and chemicals", "text": "The human U2-OS osteosarcoma cell line was grown in DME medium with 10% FBS. For siRNA-mediated ablation, cells were transfected using OligofectAMINE (Invitrogen) according to the manufacturer's protocol. The following oligonucleotide sequences were used: 5\u2032-P A C U U C A U G G C-G C U C C G U A C U U -3\u2032 and 5\u2032-P G A U U U G U C U C U C U A G U U G C U U -3\u2032 (SET8 siRNA). Chk1 siRNA were purchased from Dharmacon (SMARTpool reagents M-003255-02; four siRNAs combined into a single pool). A control oligonucleotide targeting cyclophilin was also purchased from Dharmacon. Experiments with siRNA-transfected cells were performed as indicated in the fi gure legends. The PCNA construct was a gift from C. Lukas (Danish Cancer Society, Copenhagen, Denmark). Nocodazole (Sigma-Aldrich) was used at 100 ng/ml. Inhibition of Chk1 activity was achieved by the addition of 100 nM G\u00f66976 (Calbiochem). Thymidine and 2-deoxycytidine-HCl were purchased from Sigma-Aldrich and used at 2 mM and 24 \u03bcM, respectively.", "cite_spans": [], "ref_spans": []}, {"section": "FACS", "text": "Cells pulse labeled with 10 \u03bcM BrdU (Roche) for 5 min were analyzed according to standard protocols. In brief, cells were fi xed in 70% ethanol and incubated in 2 M HCl for 30 min. Cells were stained with mouse antibody to BrdU (1:100) for 1 h followed by 1-h incubation with conjugated anti-mouse IgG (AlexaFluor488 at 1:1,000). DNA was then counterstained with 0.1 mg/ml propidium iodide (PI) containing RNase for 30 min at 37\u00b0C. \u03b3-H2AX, Cdc45, and Rad51 were stained as described above for BrdU except for the omission of HCl treatment. Analysis was performed on a FACSCalibur (BD Biosciences) using CellQuest software (Becton Dickinson). Quantifi cations were performed using Modfi t LT software (Verity Software House).", "cite_spans": [], "ref_spans": []}, {"section": "Microscopy and immunofl uorescence", "text": "Cells were grown on coverslips and treated as indicated in the fi gure legends. The coverslips were then washed briefl y in PBS followed by extraction for 10 min on ice with Triton buffer (0.5% Triton X-100 in 20 mM Hepes, pH 7.4, 50 mM NaCl, 3 mM MgCl, and 300 mM sucrose) and fi xation for 10 min with 4% PFA. Samples were incubated with primary antibodies in PBS/1% FCS for 1 h at room temperature, washed in PBS/1% FCS three times for 10 min, and incubated with AlexaFluor488-or 594-conjugated secondary antibodies (1:1,000; Invitrogen) for 1 h at room temperature. Cells were washed in PBS three times for 10 min and mounted using Vectashield mounting medium containing DAPI (Vector Laboratories). Pictures were acquired on a microscope (Axiovert 200M LSM 510; Carl Zeiss, Inc.) using a 40\u00d7 c-Apochromat objective with an NA of 1.2 in H 2 O. Pictures were taken at room temperature using LSM 510 META software and LSM image examiner software (Carl Zeiss, Inc.) . Brightfi eld pictures were taken with a microscope (Axiovert 135; Carl Zeiss, Inc.) using a 10\u00d7 Achroplan objective with an NA of 0.25. Pictures were acquired at room temperature with a camera (CoolSNAP cf 2 ; Photometrics) using MetaMorph software (MDS Analytical Technologies). All pictures were exported in preparation for printing using Photoshop (Adobe).", "cite_spans": [], "ref_spans": []}, {"section": "Immunoprecipitation", "text": "Antibodies for immunoprecipitation were coupled to protein A beads for 1 h at 4\u00b0C. Extracts for immunoprecipitation were prepared using immunoprecipitation buffer (50 mM Hepes, pH 7.5, 150 mM NaCl, 1 mM EDTA, 2.5 mM EGTA, 10% glycerol, 0.1% Tween 20, and protease inhibitors leupeptin, aprotinin, and PMSF). The lysis mixture was incubated on ice for 15 min, sonicated three times with a digital sonifi er for 3 s (20%; S250; Branson), and microfuged for 10 min at 4\u00b0C. Extracts were precleared with 20 \u03bcl of protein A-Sepharose and 2 \u03bcg of normal IgG. After microcentrifugation, 20 \u03bcl of protein A-Sepharose conjugated with 1 \u03bcg of antibody was added and allowed to precipitate for 1.5 h at 4\u00b0C with rotation. The immune complexes were pelleted by gentle centrifugation and washed four times with 1 ml of immunoprecipitation buffer. After a fi nal wash with immunoprecipitation buffer, the buffer was aspirated completely, and beads were resuspended in laemmli buffer. Immunoblotting was performed as indicated in the next section.", "cite_spans": [], "ref_spans": []}, {"section": "Immunoblotting and antibodies", "text": "In brief, cells were lysed on ice in radioimmunoprecipitation assay buffer (50 mM Hepes, pH 7.5, 150 mM NaCl, 1 mM EDTA, 2.5 mM EGTA, 10% glycerol, 1% IgePal630, 1% deoxycholic acid [sodium salt], 0.1% SDS, 1 mM PMSF, 5 \u03bcg/ml leupeptin, 1% vol/vol aprotinin, 50 mM NaF, and 1 mM DTT). Proteins were separated on an SDS-PAGE gel and transferred to a nitrocellulose membrane. The membranes were incubated in primary antibody diluted in 5% milk as indicated in the fi gures followed by incubation with secondary antibody (peroxidase-labeled anti-mouse or -rabbit IgG; 1:10,000; Vector Laboratories). Films were developed using an x-ray machine (Valsoe; Ferrania). Phospho-Chk1 antibody (Chk1-pSer317) was purchased from Cell Signaling Technology. Antibodies to MCM7 (DCS-141) and Chk1 (DCS-310) have been described previously . Cdc25A (F-6), cyclin A1 (H-432), Rad51 (H-92), and 53BP1 (H-300) were obtained from Santa Cruz Biotechnology, Inc. Phosphorylated H2AX (JBW103), monomethylated histone H4 Lys20, and phosphorylated histone H3 Ser10 were purchased from Millipore. SET8 (ab3744) and PCNA (PC10) were purchased from Abcam, and RPA (Ab-3) was purchased from EMD.", "cite_spans": [], "ref_spans": []}, {"section": "Immunoblotting and antibodies", "text": "Pulsed-fi eld gel electrophoresis 48 h after SET8 siRNA transfection, cells were treated with 5 \u03bcM aphidicolin (Fluka) and/or 500 nM CEP-3891 (Cephalon) for an additional 24 h. 10 6 cells were inserted into 10 mg/ml InCert agarose (Cambrex) plugs and incubated for 48 h in 0.5 M EDTA, 1% N-laurylsarcosyl, and 2 mg/ml proteinase K at 20\u00b0C in darkness. After washing of plugs four times in Tris-EDTA buffer, separation was performed for 20 h as described previously ) on a 1% certifi ed megabase agarose (Bio-Rad Laboratories) gel. The gel was then stained overnight with ethidium bromide. Three independent experiments were performed.", "cite_spans": [], "ref_spans": []}, {"section": "Replication fork elongation", "text": "Analysis of replication fork elongation was performed as described previously (Johansson et al., 2004 ). Basically, [ 3 H]thymidine was incorporated in ongoing forks, and, after labeling, the fork progressed from the labeled area. In alkaline solution, unwinding was initiated from the single-stranded ends of the fork; thus, the amount of labeled single-stranded DNA is greater the slower the fork is moving. 24 h after SET8 siRNA transfection, cells were replated in 24-well plates (10 5 cells/well) and allowed to grow for an additional 24 h. Cells were then pulse labeled with 37 kBq/ml [ 3 H]thymidine (GE Healthcare) in DME at 37\u00b0C with 5% CO 2 for 30 min, washed, and incubated with prewarmed media \u00b1500 nM CEP-3891 at 37\u00b0C with 5% CO 2 for the indicated times. After incubation, replication was terminated by rinsing the cells with ice-cold 0.15 M NaCl before the addition of 0.5 ml of ice-cold 0.15 M NaCl and 0.03 M NaOH unwinding solution. After 30-min incubation on ice in darkness, unwinding was terminated by the addition of 1 ml of 0.02-M NaH 2 PO 4 . DNA was fragmented to \u202b3\u0641\u202c kb by sonication (B-12 sonifi er with micro-tip; Branson) for 15 s, and SDS was added to a fi nal concentration of 0.25%. After overnight storage at \u221220\u00b0C, single-and double-stranded DNA was separated on hydroxy apatite columns at 60\u00b0C. Three independent experiments were performed. Fig. S1 shows the specifi city of SET8 removal by RNAi, the inverse relationship between \u03b3-H2AX and H4-K20me1-positive cells, and the recruitment of 53BP1 in \u03b3-irradiated HeLa cells during SET8 depletion. Fig. S2 shows the unchanged level of H4-K20me2 in U2OS cells after the depletion of SET8, a quantifi cation of DNA damage during removal of SET8 combined with the inhibition of Chk1 using CEP-3891, and a quantifi cation of replicationdependent DNA damage after SET8 depletion from Fig. 4 D. Fig. S3 shows the down-regulation of SET8, Rad51, and Cdc45 corresponding to Fig. 4 E, the progression of U2OS cells through the cell cycle after depletion of Rad51 for 48 h, and a schematic presentation of the replication fork progression assay. Online supplemental material is available at http:// www.jcb.org/cgi/content/full/jcb.200706150/DC1.", "cite_spans": [{"start": 78, "end": 101, "text": "(Johansson et al., 2004", "ref_id": "BIBREF7"}], "ref_spans": [{"start": 1377, "end": 1384, "text": "Fig. S1", "ref_id": "FIGREF0"}, {"start": 1582, "end": 1589, "text": "Fig. S2", "ref_id": "FIGREF1"}, {"start": 1863, "end": 1880, "text": "Fig. 4 D. 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Error bars represent SD. Bars: (top) 25 \u03bcm; (bottom) 4 \u03bcm.", "type": "figure"}, "FIGREF1": {"text": "Figure 2. SET8 depletion leads to a delay in S-phase progression. (A) SET8 was depleted in U2OS cells using siRNA for 52 h. Nocodazole was added 16 h before harvest to the indicated samples. The samples were stained with PI and analyzed by fl ow cytometry analysis (FACS). (B) Cells were collected from a similar experiment as in A and were processed for immunoblotting. (C) U2OS cells were treated with siRNA against SET8 or mock for 48 and 72 h. Cells were pulsed with BrdU for 5 min, fi xed, stained for BrdU and PI, and analyzed by FACS. The distribution of cells corresponding to the boxed areas is presented in the table beneath the graph. A fraction of the cells was collected and processed for immunoblotting.", "type": "figure"}, "FIGREF2": {"text": "Figure 3. SET8 depletion leads to DSBs and checkpoint activation in S-phase cells. (A) SET8 was depleted in U2OS cells for 24 and 48 h. Cells were preextracted and fi xed before staining with antibody toward \u03b3-H2AX and Rad51. (B) U2OS cells were treated as in A and were fi xed and stained for \u03b3-H2AX and PI followed by FACS analysis. (C) Cells were treated as in A and stained with antibodies recognizing \u03b3-H2AX and monomethylated H4 Lys20. Cells were also collected and processed for Western blotting with the indicated antibodies. Reduction of H4 Lys20 monomethylation upon SET8 depletion is quantifi ed and indicated below the immunoblot. (D) Cells were treated as in A and were stained with 53BP1 and RPA antibodies. Bars, 10 \u03bcm.", "type": "figure"}, "FIGREF3": {"text": "Figure 4. SET8 depletion leads to replication-dependent DNA damage that activates Chk1. (A) SET8 was depleted in U2OS cells using siRNA for 52 h. Nocodazole was added for the last 16 h as indicated. Cells were collected and processed for immunoblotting. (B) U2OS cells were treated with siRNA against mock, SET8, or Chk1 for 48 h. Nocodazole was added 13 h before harvest. Cells were fi xed, stained with PI, and analyzed by FACS. A graph was generated by overlaying the FACS profi les from SET8-depleted cells and cells codepleted for SET8 and Chk1. (C) SET8 was depleted in U2OS cells using siRNA for 52 h. Nocodazole (16 h) and the Chk1 inhibitor G\u00f66976 (3 h) were added before harvest. Samples were fi xed, stained with PI, and analyzed by FACS. (B and C) A fraction of the cells was collected and processed for immunoblotting. (D) 48 h after SET8 siRNA transfection, cells were treated with 5 \u03bcM aphidicolin and/or the Chk1 inhibitor CEP-3891 for an additional 24 h. Cells were then processed for pulsed-fi eld gel electrophoresis. (E) U2OS cells were treated with siRNA against mock, SET8, Cdc45, or Rad51 for 48 h. Cells were then fi xed and stained for \u03b3-H2AX and PI followed by FACS analysis.", "type": "figure"}, "FIGREF4": {"text": "Figure 5. SET8 interacts with PCNA and is required for replication fork progression. (A) U2OS cells were transfected with siRNA against mock or SET8 and treated with thymidine for 30 h. Cells in the bottom panel were released from G1 arrest by the addition of new media. Nocodazole was added as the cells were released 10 h before harvest. (B) 48 h after SET8 siRNA transfection, cells were pulse labeled with [", "type": "figure"}, "FIGREF5": {"text": "progress with and without Chk1 inhibitor CEP-3891 for the indicated times. Replication fork elongation from the incorporated [ 3 H]thymidine was then measured as described in Fig. S3 D. 100% labeled single-stranded DNA (ssDNA) is equivalent to no fork progression. (C) Colocalization between HA-FLAG-tagged SET8 and YFP-PCNA transfected in U2OS cells. Cells were preextracted before fi xation and processed for immunostaining with HA antibody. (D) Immunoprecipitation of HA-FLAG-tagged SET8 wild type and PIP-box mutant (LTDFY mutated to ATDAA) from HEK293 cells. Cells were transfected with the indicated constructs followed by lysis, immunoprecipitation, and immunoblotting. (E) Endogenous SET8 from HEK293 cells was immunoprecipitated and processed for immunoblotting. Bars, 10 \u03bcm.", "type": "figure"}}}
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{"paper_id": "17787261", "_pdf_hash": "87827a08c5da97bfee86d049a4e6ed18073a71ec", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "17787327", "_pdf_hash": "9c50f8d3e715a7983a7e6e27ee2ffe89c9514c7e", "abstract": [{"section": "Abstract", "text": "A unifying feature of mammalian and insect olfactory systems is that olfactory sensory neurons (OSNs) expressing the same unique odorant-receptor gene converge onto the same glomeruli in the brain [1] [2] [3] [4] [5] [6] [7] . Most odorants activate a combination of receptors and thus distinct patterns of glomeruli, forming a proposed combinatorial spatial code that could support discrimination between a large number of odorants [8] [9] [10] [11] . OSNs also exhibit odor-evoked responses with complex temporal dynamics [11] , but the contribution of this activity to behavioral odor discrimination has received little attention [12] . Here, we investigated the importance of spatial encoding in the relatively simple Drosophila antennal lobe. We show that Drosophila can learn to discriminate between two odorants with one functional class of Or83b-expressing OSNs. Furthermore, these flies encode one odorant from a mixture and cross-adapt to odorants that activate the relevant OSN class, demonstrating that they discriminate odorants by using the same OSNs. Lastly, flies with a single class of Or83b-expressing OSNs recognize a specific odorant across a range of concentration, indicating that they encode odorant identity. Therefore, flies can distinguish odorants without discrete spatial codes in the antennal lobe, implying an important role for odorantevoked temporal dynamics in behavioral odorant discrimination.", "cite_spans": [{"start": 197, "end": 200, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 201, "end": 204, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 205, "end": 208, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 209, "end": 212, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 213, "end": 216, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 217, "end": 220, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 221, "end": 224, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 433, "end": 436, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 437, "end": 440, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 441, "end": 445, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 446, "end": 450, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 524, "end": 528, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 633, "end": 637, "text": "[12]", "ref_id": "BIBREF11"}], "ref_spans": []}], "body_text": [{"section": "", "text": "A unifying feature of mammalian and insect olfactory systems is that olfactory sensory neurons (OSNs) expressing the same unique odorant-receptor gene converge onto the same glomeruli in the brain [1] [2] [3] [4] [5] [6] [7] . Most odorants activate a combination of receptors and thus distinct patterns of glomeruli, forming a proposed combinatorial spatial code that could support discrimination between a large number of odorants [8] [9] [10] [11] . OSNs also exhibit odor-evoked responses with complex temporal dynamics [11] , but the contribution of this activity to behavioral odor discrimination has received little attention [12] . Here, we investigated the importance of spatial encoding in the relatively simple Drosophila antennal lobe. We show that Drosophila can learn to discriminate between two odorants with one functional class of Or83b-expressing OSNs. Furthermore, these flies encode one odorant from a mixture and cross-adapt to odorants that activate the relevant OSN class, demonstrating that they discriminate odorants by using the same OSNs. Lastly, flies with a single class of Or83b-expressing OSNs recognize a specific odorant across a range of concentration, indicating that they encode odorant identity. Therefore, flies can distinguish odorants without discrete spatial codes in the antennal lobe, implying an important role for odorantevoked temporal dynamics in behavioral odorant discrimination.", "cite_spans": [{"start": 197, "end": 200, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 201, "end": 204, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 205, "end": 208, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 209, "end": 212, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 213, "end": 216, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 217, "end": 220, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 221, "end": 224, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 433, "end": 436, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 437, "end": 440, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 441, "end": 445, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 446, "end": 450, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 524, "end": 528, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 633, "end": 637, "text": "[12]", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "Results and Discussion", "text": "In fruit flies, specific odorants interact with unique combinations of olfactory sensory neurons (OSNs), giving rise to a putative topographic odor code of activated glomeruli in the antennal lobe. To test the requirement of differential spatial encoding in odorant discrimination, we reduced olfactory input complexity by using Or83b 2 null mutant flies [13] . OR83b is an essential subunit of odorant receptor (OR) containing odorant-gated cation channels [13] [14] [15] [16] . Most fruit fly OSNs coexpress Or83b with a single unique OR gene and all those housed in basiconic and trichoid sensillae, with the exception of a highly specialized class that detects CO 2 , require Or83b for function [13, [16] [17] [18] . Or83b is also coexpressed with Or35a in a broadly tuned class of coeloconic OSNs, but the remaining OSNs in coeloconic sensillae, specialized to select volatiles including small amines, have not been reported to express Or83b, Or, or Gr genes [6, 7, 19] . Therefore, Or83b 2 mutant flies are anosmic to odorants sensed by basiconic and trichoid sensillae. Importantly, OSNs wire to the appropriate glomeruli in Or83b mutant flies, and one can restore function to a single OSN class by expressing a uas-Or83b transgene with Or-specific GAL4 control [20, 21] . Using this technique, others demonstrated that larvae with a single OSN chemotax toward odorants that attract wild-type larvae [20, 21] . Although they clearly established a role for single OSNs, these studies did not investigate whether odorant-evoked activity through a single class of OSN can be decoded as a discrete odor percept. One way to do this is to assign value to an arbitrary odorant with associative conditioning and demonstrate that flies choose appropriately between odorants. If discrete spatial patterns of glomerular activation are essential for encoding odorant identity, flies with one OSN class will fail to discriminate odorants, because the glomerulus activated by all odorants is the same in these flies. Odorant discrimination with one class of OSNs would challenge a purely spatial encoding model.", "cite_spans": [{"start": 355, "end": 359, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 458, "end": 462, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 463, "end": 467, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 468, "end": 472, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 473, "end": 477, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 699, "end": 703, "text": "[13,", "ref_id": "BIBREF12"}, {"start": 704, "end": 708, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 709, "end": 713, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 714, "end": 718, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 964, "end": 967, "text": "[6,", "ref_id": "BIBREF5"}, {"start": 968, "end": 970, "text": "7,", "ref_id": "BIBREF6"}, {"start": 971, "end": 974, "text": "19]", "ref_id": "BIBREF18"}, {"start": 1269, "end": 1273, "text": "[20,", "ref_id": "BIBREF19"}, {"start": 1274, "end": 1277, "text": "21]", "ref_id": "BIBREF20"}, {"start": 1407, "end": 1411, "text": "[20,", "ref_id": "BIBREF19"}, {"start": 1412, "end": 1415, "text": "21]", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Results and Discussion", "text": "We used an olfactory-conditioning paradigm where flies associate one of two odorants with electric-shock punishment and then choose between the two odorants [22] . Trained flies preferentially avoid the T maze arm with the conditioned odorant. A different population of the same genotype of flies is subsequently taught to associate the other odorant with punishment, and a single learning score represents the average of the two reciprocal experiments. This design provides a rigorous test of odorant discrimination and controls against innate odorant bias.", "cite_spans": [{"start": 157, "end": 161, "text": "[22]", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Results and Discussion", "text": "The electrophysiological response to a large panel of odorants has been reported for most Drosophila ORs [11] , allowing us to select and test OSNs and their cognate odorants. We first determined whether Or83b 2 mutant flies can learn to discriminate between six pairs of odorants (6-methyl-5-hepten-2-one versus pentyl acetate, methyl salicylate versus methyl benzoate, isoamyl acetate versus methyl benzoate, methyl hexanoate versus diethyl succinate, methyl salicylate versus 4-methyl phenol, and geranyl acetate versus ethyl acetate) selected because they activate defined ORs ( Figure 1A ). As expected, wild-type flies showed robust learned discrimination with all six odorant pairs, whereas Or83b 2 mutant flies did not. Therefore, Or83b-expressing OSNs are required to learn to discriminate between the chosen odorants, and residual responses in Or83b 2 mutant flies are not sufficient to support learned odorant discrimination.", "cite_spans": [{"start": 105, "end": 109, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": [{"start": 583, "end": 592, "text": "Figure 1A", "ref_id": "FIGREF0"}]}, {"section": "Results and Discussion", "text": "We next tested flies in which the function of Or46a-, Or67a-, or Or98a-expressing OSNs were restored individually. These OSNs are housed in different sensory sensilla (pb2, ab10, and ab7a) in the maxillary palp or antenna; project their axons to the spatially discrete VA7l, DM6, and VM5 glomeruli ( Figure 1B) ; and respond to a subset of the odorant pairs used in Figure 1A [6, 7, 11, 23] . Furthermore, these receptors are not coexpressed with other functional ORs [6, 7, 24] . We first used Or46a-GAL4 to express uas-Or83b in an otherwise Or83b 2 mutant fly and tested whether these flies could discriminate between two odorants reported to activate OR46a: 4-methyl phenol and methyl salicylate [23] . Re-establishing OR46a OSN function in this way faithfully restored odorevoked responses to those approximating wild-type OR46a *Correspondence: scott.waddell@umassmed.edu neurons [23] . We assayed wild-type, Or83b 2 mutant, Or46a-GAL4; Or83b 2 , and uas-Or83b; Or83b 2 mutant flies in parallel for comparison ( Figure 1C ). All flies without functional Or83b-expressing OSNs did not learn, whereas flies with restored OR46a neurons learned to discriminate between 4-methyl phenol and methyl salicylate. As an indicator of specificity, we tested flies with restored OR67a neurons. OR67a is broadly tuned but apparently does not respond to 4-methyl phenol and methyl salicylate [11, 23] . Consistent with this, OR67a-restored flies did not learn with these odorants ( Figure 1C) . Therefore, flies with a single class of functional Or83b-expressing OSNs can discriminate between two odorants if they activate the relevant OR.", "cite_spans": [{"start": 376, "end": 379, "text": "[6,", "ref_id": "BIBREF5"}, {"start": 380, "end": 382, "text": "7,", "ref_id": "BIBREF6"}, {"start": 383, "end": 386, "text": "11,", "ref_id": "BIBREF10"}, {"start": 387, "end": 390, "text": "23]", "ref_id": "BIBREF22"}, {"start": 468, "end": 471, "text": "[6,", "ref_id": "BIBREF5"}, {"start": 472, "end": 474, "text": "7,", "ref_id": "BIBREF6"}, {"start": 475, "end": 478, "text": "24]", "ref_id": "BIBREF23"}, {"start": 699, "end": 703, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 885, "end": 889, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 1382, "end": 1386, "text": "[11,", "ref_id": "BIBREF10"}, {"start": 1387, "end": 1390, "text": "23]", "ref_id": "BIBREF22"}], "ref_spans": [{"start": 300, "end": 310, "text": "Figure 1B)", "ref_id": "FIGREF0"}, {"start": 366, "end": 375, "text": "Figure 1A", "ref_id": "FIGREF0"}, {"start": 1017, "end": 1026, "text": "Figure 1C", "ref_id": "FIGREF0"}, {"start": 1472, "end": 1482, "text": "Figure 1C)", "ref_id": "FIGREF0"}]}, {"section": "Results and Discussion", "text": "The odor-tuning curve of OR67a partially overlaps with that of OR98a [11] . We therefore tested flies with restored OR67a or OR98a neurons for learned discrimination between methyl benzoate and isoamyl acetate ( Figure 1D ). As in the previous experiments, all flies without functional Or83b-expressing OSNs did not learn, but robust learning was evident in flies with restored OR67a or OR98a neurons. Therefore, Or83b 2 mutant flies can use either OR67a-or OR98a-restored OSNs to discriminate between methyl benzoate and isoamyl acetate.", "cite_spans": [{"start": 69, "end": 73, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": [{"start": 212, "end": 221, "text": "Figure 1D", "ref_id": "FIGREF0"}]}, {"section": "Results and Discussion", "text": "OR67a also responds to pentyl acetate and 6-methyl-5-hepten-2-one [11] . We therefore tested whether flies with restored OR67a neurons could learn to discriminate between these two odorants ( Figure 1E ). Flies without functional Or83b-expressing OSNs did not exhibit learning, whereas flies with restored OR67a OSNs learned. Therefore, OR67a-restored flies can learn to discriminate between at least two pairs of different odorants that activate OR67a. The preceding experiments demonstrate that flies can employ a single class of Or83b-expressing OSNs to learn to discriminate between two odorants that activate that OSN class, consistent with the notion that they can use neural activity in the same class of OSNs to differentially represent odorants.", "cite_spans": [{"start": 66, "end": 70, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": [{"start": 192, "end": 201, "text": "Figure 1E", "ref_id": "FIGREF0"}]}, {"section": "Results and Discussion", "text": "Our findings with Or83b 2 mutant flies suggest that Or83b-independent OSNs are not sufficient for learned discrimination with multiple odorant combinations (Figure 1) . Nevertheless, we further tested whether flies with restored OR67a neurons had other relevant OSNs by testing whether flies could simultaneously encode multiple odorant components, like wild-type flies. We combined the four odorants that flies with restored OR67a neurons can discriminate between-methyl benzoate, isoamyl acetate, pentyl acetate, and 6-methyl-5-hepten-2-one-into two binary mixtures, trained the flies with these mixtures (Figures 2A and 2B) , and tested for discrimination between the component odorants. Whereas wild-type flies exhibited learned discrimination for all four component odorants, regardless of the mixture combination used during training, learned discrimination was only observed for the 6-methyl-5-hepten-2-one and pentyl acetate components in OR67a-restored flies. These data suggest that OR67a-restored flies encode one odor component at a time, consistent with the notion that these odorants activate the same OSNs.", "cite_spans": [], "ref_spans": [{"start": 156, "end": 166, "text": "(Figure 1)", "ref_id": "FIGREF0"}, {"start": 607, "end": 626, "text": "(Figures 2A and 2B)", "ref_id": "FIGREF1"}]}, {"section": "Results and Discussion", "text": "To further test the model that odorants compete for ORs in OR67a-restored flies, we trained flies with single odorants and tested discrimination with binary mixtures (Figures 2C and  2D) . We reasoned that a competing odorant in a mixture during testing would mask learned behavior for the other odorant. Training wild-type flies with either 6-methyl-5-hepten-2-one versus pentyl acetate or isoamyl acetate versus methyl benzoate and testing with 6-methyl-5-hepten-2-one + isoamyl acetate versus pentyl acetate + methyl benzoate revealed learned discrimination in both cases ( Figure 2C ). However, in flies with OR67a-restored neurons, robust learned discrimination was only observed after training with 6-methyl-5-hepten-2-one (Figures 2A and 2B ). Asterisks denote no significant difference to zero (all p > 0.5, Mann Whitney U test).", "cite_spans": [], "ref_spans": [{"start": 166, "end": 186, "text": "(Figures 2C and  2D)", "ref_id": "FIGREF1"}, {"start": 577, "end": 586, "text": "Figure 2C", "ref_id": "FIGREF1"}, {"start": 729, "end": 747, "text": "(Figures 2A and 2B", "ref_id": "FIGREF1"}]}, {"section": "Results and Discussion", "text": "versus pentyl acetate and not with isoamyl acetate versus methyl benzoate. We also tested learned discrimination with a different odorant combination: 6-methyl-5-hepten-2-one + methyl benzoate versus pentyl acetate + isoamyl acetate ( Figure 2D ). Wild-type flies showed learned discrimination in both cases, whereas OR67a-restored flies only showed learned discrimination when trained with 6-methyl-5-hepten-2-one versus pentyl acetate. Therefore, these data are consistent with the notion that odorants compete at the OSN level in OR67a-restored flies, providing further support that these flies have a single relevant OSN class ( Figures S1 and S2, available  online) .", "cite_spans": [], "ref_spans": [{"start": 235, "end": 244, "text": "Figure 2D", "ref_id": "FIGREF1"}, {"start": 633, "end": 670, "text": "Figures S1 and S2, available  online)", "ref_id": "FIGREF0"}]}, {"section": "Results and Discussion", "text": "We further tested the contribution of Or83b-independent OSNs by using a cross-adaptation assay that does not require learning. We predicted that OR67a-restored flies would cross-adapt to odorants that activate OR67a OSNs if these odorants activated the same OSNs. We first used methyl benzoate and pentyl acetate because odorant-mixture experiments suggested that these odorants compete for OR67a neurons (Figures 2A and 2C ). Wild-type and OR67a-restored flies were adapted by pre-exposure to methyl benzoate for 30 min and tested for methyl benzoate or pentyl acetate avoidance behavior. Naive wild-type and OR67a-restored flies avoided methyl benzoate, but avoidance was abolished in both genotypes after adaptation ( Figure 3A) , demonstrating the efficacy of the adaptation protocol. For cross-adaptation, we tested separate groups of methyl benzoate-adapted flies for pentyl acetate avoidance ( Figure 3A) . Wild-type flies adapted with methyl benzoate avoided pentyl acetate, indicating that pentyl acetate activates additional OSNs in wildtype flies that do not respond to methyl benzoate. However, OR67a-restored flies adapted with methyl benzoate also adapted their behavioral response to pentyl acetate, suggesting that pentyl acetate activates the same OSNs in these flies that respond to methyl benzoate. We also performed reciprocal cross-adaptation experiments where flies were adapted to pentyl acetate and tested for pentyl acetate or methyl benzoate avoidance behavior ( Figure 3B ). OR67a-restored flies adapted to pentyl acetate also lost their response to methyl benzoate. In contrast, the same pentyl acetate preexposure partially altered the pentyl acetate and methyl benzoate response in wild-type flies. Therefore, methyl benzoate and pentyl acetate activate overlapping OSNs in OR67a-restored flies, again supporting the notion that odorants compete for a single relevant class of functional OSNs in OR67a-restored flies.", "cite_spans": [], "ref_spans": [{"start": 405, "end": 423, "text": "(Figures 2A and 2C", "ref_id": "FIGREF1"}, {"start": 721, "end": 731, "text": "Figure 3A)", "ref_id": "FIGREF2"}, {"start": 901, "end": 911, "text": "Figure 3A)", "ref_id": "FIGREF2"}, {"start": 1489, "end": 1498, "text": "Figure 3B", "ref_id": "FIGREF2"}]}, {"section": "Results and Discussion", "text": "Lastly, we used cross-adaptation to test whether odorants that can be discriminated by OR67a-restored flies activate overlapping OSNs. Indeed, Or67a-restored flies displayed reciprocal cross-adaptation to methyl benzoate and isoamyl acetate ( Figures 3A and 3C ) and to pentyl acetate and 6-methyl-5-hepten-2-one ( Figures 3B and 3D) . In addition, we demonstrated that OR67a-restored flies discriminate between methyl benzoate and pentyl acetate ( Figure S3 ), two other odorants that they cross-adapt to. These data present further evidence that flies can discriminate between odorants by using the same, and very likely a single class of, OSNs. Importantly, a purely spatial model for odorant encoding cannot account for discrimination between two odorants that activate the same class(es) of OSNs.", "cite_spans": [], "ref_spans": [{"start": 243, "end": 260, "text": "Figures 3A and 3C", "ref_id": "FIGREF2"}, {"start": 315, "end": 333, "text": "Figures 3B and 3D)", "ref_id": "FIGREF2"}, {"start": 449, "end": 458, "text": "Figure S3", "ref_id": "FIGREF2"}]}, {"section": "Results and Discussion", "text": "Flies with a single class of functional Or83b-expressing OSNs could discriminate between odorants by using odorant intensity (relative concentration) and/or identity (chemical structure) information. We therefore tested whether OR67a-restored flies only coded odorant intensity by altering the concentration of one of the two odorants between training and testing discrimination. These manipulations simultaneously changed absolute concentration of one of the odorants and the relationship between odorants. We used pentyl acetate and 6-methyl-5-hepten-2-one because the odor-evoked firing rate of Or67a-expressing OSNs to these odorants has been reported to vary between 10 22 and 10 24 dilutions [11] . We first trained flies with 10 22 , 10 23 , or 10 24 dilutions of 6-methyl-5-hepten-2-one versus a constant 10 23 dilution of pentyl acetate and tested all groups for discrimination between 10 23 6-methyl-5-hepten-2-one versus 10 23 pentyl acetate ( Figure 4A ). Learned discrimination scores varied little for wild-type and OR67a-rescued flies with changing 6-methyl-5-hepten-2-one concentration demonstrating that both wild-type and OR67a-rescued flies identify 6-methyl-5-hepten-2-one, despite a change in absolute and relative odorant intensity. We similarly manipulated pentyl acetate concentration between training and testing. In this case, learned discrimination in wild-type and OR67a-restored flies was robust when training concentration was lower than, or the same as, that at test ( Figure 4B ). Both wild-type and OR67a-restored flies performed most poorly when training concentration was higher than that at test. Because flies with restored OR67a neurons distinguish the appropriate odorant across changing concentration, they cannot be only coding absolute odorant intensity. Furthermore, because our experimental design also changed relative odorant intensity between training and testing, the flies do not utilize this parameter to discriminate odorants. Instead, these data suggest that flies with restored OR67a neurons encode odorant identity.", "cite_spans": [{"start": 698, "end": 702, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": [{"start": 955, "end": 964, "text": "Figure 4A", "ref_id": "FIGREF3"}, {"start": 1500, "end": 1509, "text": "Figure 4B", "ref_id": "FIGREF3"}]}, {"section": "Results and Discussion", "text": "In conclusion, multiple classes of OSNs are not required for flies to discriminate odorants. Although flies without functional Or83b-expressing neurons cannot learn to discriminate between a number of chemically distinct odorants, providing a single class of Or83b-expressing OSNs restores learned discrimination between two odorants that activate that particular OSN class. These flies cross-adapt to odorants that activate the restored OSNs, demonstrating that the relevant OSNs are the same, thus challenging a requirement for discrete spatial codes for odorants in the antennal lobe. As expected, flies with one class of Or83b-expressing OSNs have limitations and can apparently only encode one odorant that activates the appropriate receptor at a time. These data suggest that a benefit of having multiple classes of OSNs is the ability to identify certain odorants present within a more complex milieu. Importantly, Or83b 2 mutant flies with one functional class of Or83b-expressing OSNs choose appropriately between two odorants even though the absolute and relative concentration was changed between training and testing, implying that they encode odorant identity and do not only rely on encoding odorant intensity.", "cite_spans": [], "ref_spans": []}, {"section": "Results and Discussion", "text": "Finding that distinct combinatorial spatial patterns of OSN activation in the antennal lobe are not essential to represent odorant information implies an important role for odorantevoked temporal dynamics. Previous studies in insects and vertebrates have documented considerable temporal complexity in odor-evoked activity at successive layers of the olfactory system [12, [25] [26] [27] [28] [29] [30] [31] [32] , but few have investigated the behavioral relevance [12] . Recent work has shown that excitatory and inhibitory lateral connectivity in the Drosophila antennal lobe can shape projection neuron responses [21, [33] [34] [35] [36] [37] ; therefore, we expect different temporal signals in the same OSNs to generate distinct temporal, and perhaps spatial, patterns of projection neuron activity. However, because flies with a single functional class of Or83b-expressing OSNs lack the lateral input driven by additional classes of OSN, it will be important to determine how lateral connectivity within the antennal lobe contributes to odorant discrimination in Drosophila.", "cite_spans": [{"start": 368, "end": 372, "text": "[12,", "ref_id": "BIBREF11"}, {"start": 373, "end": 377, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 378, "end": 382, "text": "[26]", "ref_id": "BIBREF25"}, {"start": 383, "end": 387, "text": "[27]", "ref_id": "BIBREF26"}, {"start": 388, "end": 392, "text": "[28]", "ref_id": "BIBREF27"}, {"start": 393, "end": 397, "text": "[29]", "ref_id": "BIBREF28"}, {"start": 398, "end": 402, "text": "[30]", "ref_id": "BIBREF29"}, {"start": 403, "end": 407, "text": "[31]", "ref_id": "BIBREF30"}, {"start": 408, "end": 412, "text": "[32]", "ref_id": "BIBREF31"}, {"start": 466, "end": 470, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 617, "end": 621, "text": "[21,", "ref_id": "BIBREF20"}, {"start": 622, "end": 626, "text": "[33]", "ref_id": "BIBREF32"}, {"start": 627, "end": 631, "text": "[34]", "ref_id": "BIBREF33"}, {"start": 632, "end": 636, "text": "[35]", "ref_id": "BIBREF34"}, {"start": 637, "end": 641, "text": "[36]", "ref_id": "BIBREF35"}, {"start": 642, "end": 646, "text": "[37]", "ref_id": "BIBREF36"}], "ref_spans": []}, {"section": "Supplemental Data", "text": "Supplemental Data include Supplemental Experimental Procedures and three figures and can be found with this article online at http://www. current-biology.com/supplemental/S0960-9822(08)01257-8. (A) Wild-type flies and OR67a-restored flies were trained with 6-methyl-5-hepten-2-one concentrations that were 103 less than, the same as, or 103 more than they were tested with while pentyl acetate concentrations were kept constant. (B) Wild-type flies and those with restored OR67a neurons were trained with pentyl acetate concentrations that were 103 less than, the same as, or 103 more than they were tested with while 6-methyl-5-hepten-2-one concentrations were kept constant. Asterisks indicate significant difference (all p < 0.01, ANOVA). 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Or83b 2 Flies with Functional Or46a, Or67a or Or98a-Expressing Neurons Learn to Discriminate between Odorants that Activate These Receptors (A) Or83b 2 mutant flies cannot learn to discriminate between odors. Wild-type flies can learn to discriminate between six pairs of odorants, whereas Or83b 2 mutant flies cannot. Asterisks indicate no significant difference from zero (all p > 0.1, Mann Whitney U test). (B) Upper panel, volume rendering of the fly antennal lobes highlighting the relative position of the VA7l (orange), DM6 (green), and VM5 (yellow) glomeruli innervated by Or46a-, Or67a-, and Or98a-expressing OSNs. Lower panels show corresponding confocal-stack projections through the antennal lobes of flies expressing uas-n-syb::GFP driven by Or46a-GAL4, Or67a-GAL4, or Or98a-GAL4. N-syb::GFP is stained with anti-GFP (green), and neuropil is visualized with nc82 antibody (magenta) staining. The scale bar represents 20 mm and refers to all micrographs. (C) Flies with only functional OR46a neurons can learn to discriminate between 4-methyl phenol and methyl salicylate, but flies with only OR67a neurons cannot. Asterisks indicate significant difference (all p < 0.04, ANOVA) between the marked groups and all others. (D) Flies with only functional OR67a or OR98a neurons can learn to discriminate between methyl benzoate and isoamyl acetate. Asterisks indicate significant difference (all p < 0.005, ANOVA) between the marked groups and all others. (E) Flies with only functional OR67a neurons can learn to discriminate between pentyl acetate and 6-methyl-5-hepten-2-one. Asterisks indicate significant difference (all p < 0.005, ANOVA) between the marked groups and all others. Data are mean 6 standard error of the mean (SEM).", "type": "figure"}, "FIGREF1": {"text": "Figure 2. Limitations in Learned Behavior in Or83b 2 Flies with Functional Or67a-Expressing Neurons (A) Flies with only functional OR67a neurons learn one component of a binary blend. Flies were trained with 6-methyl-5-hepten-2-one + isoamyl acetate versus methyl benzoate + pentyl acetate mixtures. Wild-type flies show learning when tested with all components alone, whereas flies with only functional OR67a neurons exclusively show learned discrimination for the 6-methyl-5-hepten-2-one and pentyl acetate components. (B) Wild-type flies learn both components of a different binary blend, but OR67a-restored flies only learn one. Flies were trained with 6-methyl-5-hepten-2-one + methyl benzoate versus pentyl acetate + isoamyl acetate mixtures. Wild-type flies learn all components, whereas flies with restored OR67a neurons again only show learned discrimination for the 6-methyl-5-hepten-2-one and pentyl acetate components. (C) Flies with restored OR67a neurons do not show learned discrimination of isoamyl acetate and methyl benzoate when 6-methyl-5-hepten-2-one and pentyl acetate are also present during test. Wild-type flies trained with either set of single components show learned discrimination when tested with the additional complexity of binary mixtures, but flies with OR67a neurons only show robust performance if trained with 6-methyl-5-hepten-2-one versus pentyl acetate. (D) Flies with functional OR67a neurons do not show learned discrimination of isoamyl acetate and methyl benzoate when tested with a different composition of odorant mixtures. Wild-type flies trained with either set of single components, 6-methyl-5-hepten-2-one versus pentyl acetate or isoamyl acetate versus methyl benzoate show learned discrimination when tested with binary mixtures, but flies with OR67a neurons only show robust performance if trained with 6-methyl-5-hepten-2-one versus pentyl acetate. Individual odor concentrations in the blends were the same as those used separately in Figures 1D and 1E and when tested for component learning (Figures 2A and 2B). Asterisks denote no significant difference to zero (all p > 0.5, Mann Whitney U test).", "type": "figure"}, "FIGREF2": {"text": "Figure 3. OR67a-Restored Flies Cross-Adapt to Odorants that Activate OR67a Neurons (A) Adaptation of innate odor-avoidance behavior in wild-type and OR67a-restored flies. Pre-exposing wild-type flies and those with restored OR67a neurons to methyl benzoate adapts methyl benzoate avoidance behavior. Flies with OR67a-restored neurons, but not wild-type flies, cross-adapt to methyl benzoate, pentyl acetate, and isoamyl acetate. Asterisk indicates significant difference (p < 0.003, ANOVA). (B) Pre-exposure to pentyl acetate significantly adapts pentyl acetate avoidance behavior of flies with restored OR67a neurons (p < 0.002, ANOVA) but does not significantly adapt wild-type flies (p > 0.1, ANOVA). Pre-exposure to pentyl acetate cross-adapts methyl benzoate and 6-methyl-5-hepten-2-one avoidance in flies with OR67a-restored neurons (both p < 0.001, ANOVA) but not in wild-type flies (p > 0.2, ANOVA). (C) Pre-exposure to isoamyl acetate crossadapts the methyl benzoate avoidance behavior of flies with restored OR67a neurons (p < 0.01, ANOVA) but does not significantly adapt wildtype flies (p > 0.6, ANOVA). (D) Pre-exposure to 6-methyl-5-hepten-2-one cross-adapts pentyl acetate avoidance behavior of flies with restored OR67a neurons (p < 0.0004, ANOVA) but does not significantly adapt wild-type flies (p > 0.6, ANOVA). Data are mean 6 SEM.", "type": "figure"}, "FIGREF3": {"text": "Figure 4. Or83b 2 Flies with Functional OR67a Neurons Discriminate Odorants across Changing Concentration", "type": "figure"}}}
{"paper_id": "17787358", "_pdf_hash": "81ca33074c76527bdba38fe24e0d445202313939", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
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{"paper_id": "17787631", "_pdf_hash": "87ea74e7c96bd464b442eb00e11a3e34d95e0c20", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Development and calibration of an automated mueller matrix polarization imaging system", "authors": [{"first": "Justin", "middle": ["S"], "last": "Baba", "suffix": ""}, {"first": "Jung-Rae", "middle": [], "last": "Chung", "suffix": ""}, {"first": "Aimee", "middle": ["H"], "last": "Delaughter", "suffix": ""}, {"first": "Brent", "middle": ["D"], "last": "Cameron", "suffix": ""}, {"first": "Gerard", "middle": ["L"], "last": "Cot\u00e9", "suffix": ""}], "year": 2002, "venue": "Journal of Biomedical Optics", "link": null}, "BIBREF1": {"title": "Polarization-sensitive optical coherence tomography of invasive basal cell carcinoma", "authors": [{"first": "John", "middle": [], "last": "Strasswimmer", "suffix": ""}, {"first": "Mark", "middle": ["C"], "last": "Pierce", "suffix": ""}, {"first": "B", "middle": [], "last": "Park", "suffix": ""}, {"first": "Victor", "middle": [], "last": "Neel", "suffix": ""}, {"first": "Johannes", "middle": ["F"], "last": "De Boer", "suffix": ""}], "year": 2004, "venue": "Journal of Biomedical Optics", "link": "15260968"}, "BIBREF2": {"title": "Two-dimensional brdf estimation from polarisation", "authors": [{"first": "G", "middle": [], "last": "Atkinson", "suffix": ""}, {"first": "E", "middle": ["R"], "last": "Hancock", "suffix": ""}], "year": 2008, "venue": "Computer Vision and Image Understanding", "link": "19579537"}, "BIBREF3": {"title": "Normalized cuts and image segmentation", "authors": [{"first": "Jianbo", "middle": [], "last": "Shi", "suffix": ""}, {"first": "Jitendra", "middle": [], "last": "Malik", "suffix": ""}], "year": 2000, "venue": "IEEE Transactions on Pattern Analysis and Machine Intelligence", "link": "177653"}, "BIBREF4": {"title": "Constraining object features using a polarisation reflectance model", "authors": [{"first": "B", "middle": [], "last": "Lawrence", "suffix": ""}, {"first": "Terrance", "middle": ["E"], "last": "Wolff", "suffix": ""}, {"first": "", "middle": [], "last": "Boult", "suffix": ""}], "year": 1991, "venue": "IEEE Transactions on Pattern Analysis and Machine Intelligence", "link": null}, "BIBREF5": {"title": "A surface-based approach for classification of 3d neuroanatomic structures", "authors": [{"first": "Li", "middle": [], "last": "Shen", "suffix": ""}, {"first": "James", "middle": [], "last": "Ford", "suffix": ""}, {"first": "Fillia", "middle": [], "last": "Makedon", "suffix": ""}, {"first": "Andrew", "middle": [], "last": "Saykin", "suffix": ""}], "year": 2004, "venue": "Intelligent Data Analysis", "link": "6802677"}, "BIBREF6": {"title": "Tensorbased cortical surface morphometry via weighted spherical harmonic representation", "authors": [{"first": "M", "middle": ["K"], "last": "Chung", "suffix": ""}, {"first": "K", "middle": ["M"], "last": "Dalton", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Davidson", "suffix": ""}], "year": 2008, "venue": "IEEE Transactions on Medical Imaging", "link": "11310818"}, "BIBREF7": {"title": "3-d model retrieval with spherical harmonics and moments", "authors": [{"first": "D", "middle": [], "last": "Saupe", "suffix": ""}, {"first": "D", "middle": ["V"], "last": "Vrani\u0107", "suffix": ""}], "year": 2001, "venue": "Proceedings of the 23rd DAGM-Symposium on Pattern Recognition", "link": "5563857"}}, "ref_entries": {}}
{"paper_id": "17787859", "_pdf_hash": "3fb9ac07cf632401ed377aa3c28d41f8bf3d3618", "abstract": [], "body_text": [], "bib_entries": {"BIBREF1": {"title": "Piecewise linear optimal controllers for hybrid systems", "authors": [{"first": "A", "middle": [], "last": "Bemporad", "suffix": ""}, {"first": "F", "middle": [], "last": "Borrelli", "suffix": ""}, {"first": "M", "middle": [], "last": "Morari", "suffix": ""}], "year": "", "venue": "Proc", "link": "121593783"}, "BIBREF3": {"title": "On the optimal control law for linear discrete time hybrid systems", "authors": [{"first": "A", "middle": [], "last": "Bemporad", "suffix": ""}, {"first": "F", "middle": [], "last": "Borrelli", "suffix": ""}, {"first": "M", "middle": [], "last": "Morari", "suffix": ""}], "year": "", "venue": "", "link": "17221611"}, "BIBREF4": {"title": "Hybrid Systems: Computation and Control", "authors": [], "year": 2002, "venue": "", "link": null}, "BIBREF5": {"title": "Observability and controllability of piecewise affine and hybrid systems", "authors": [{"first": "A", "middle": [], "last": "Bemporad", "suffix": ""}, {"first": "G", "middle": [], "last": "Ferrari-Ttecate", "suffix": ""}, {"first": "M", "middle": [], "last": "Morari", "suffix": ""}], "year": 2000, "venue": "IEEE Trans. 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{"paper_id": "17788213", "_pdf_hash": "29bc144f531cbb7dd22fbf82128d0241c5893178", "abstract": [{"section": "Abstract", "text": "The Solar Tower Atmospheric Cherenkov Effect Experiment (STACEE) is designed to explore the gamma-ray sky between 20 and 250 GeV using the atmospheric Cherenkov technique. STACEE will use large solar heliostat mirrors to reflect Cherenkov light created in gamma-ray air showers to secondary mirrors on a central tower. The secondary mirrors image this light onto photomultiplier tube cameras that are read out by fast electronics. Here we outline the important features of the STACEE design. We present an overview of the experimental site, describe the method of heliostat selection and control, and discuss the current designs for the detector components, including the secondary mirror structures, cameras, and electronics.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "There is a window in the gamma-ray spectrum which has yet to be systematically explored by any telescope. Current state-of-the-art atmospheric Cherenkov telescopes have energy thresholds of 250 GeV or greater. Conversely, the EGRET experiment on the Compton Gamma Ray Observatory detects few astrophysical photons above 20 GeV. Exploring the gamma-ray window between 20 and 250 GeV is a primary goal of STACEE. A more complete discussion of the scientific motivation for exploring this window can be found elsewhere (Ong 1997) .", "cite_spans": [{"start": 516, "end": 526, "text": "(Ong 1997)", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Introduction", "text": "To first order, the energy threshold of an atmospheric Cherenkov telescope is limited by night sky fluctuations and scales inversely with the square root of the telescope mirror collection area. The most straightforward way to achieve a low gamma-ray energy threshold is to use a very large mirror area. Two approaches to significantly increasing mirror area have been considered. The first is to build large (e.g. 10 m diameter) mirrors from scratch. In this way the mirrors can be custom-built for Cherenkov astronomy but the costs will be relatively high. A second approach is to make use of large mirror facilities that already exist. More than a decade ago, it was pointed out that large solar mirrors (heliostats) could be used as the primary collector in an atmospheric Cherenkov telescope (Danaher et al. 1982) . Later, a design incorporating a secondary optic was suggested by members of our group (T\u00fcmer et al. 1990 ). In the past three years, the CELESTE (Par\u00e9 1997 and Qu\u00e9bert 1997) and STACEE (Chantell et al. 1997 , Covault et al. 1997 groups have carried out tests at solar mirror facilities to demonstrate that low energy Cherenkov telescopes can in fact be constructed at these locations. Both experiments have been funded and are now under construction. A third experiment called GRAAL (Plaga 1997 ) is under development. The designs of CELESTE and STACEE are similar in many respects, but here we concentrate on the issues relevant for STACEE.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The STACEE collaboration explored the possibility of using the heliostat mirrors of the Solar Two power plant near Barstow CA, USA. Initial prototype work at the Solar Two site led to the first detection of atmospheric Cherenkov radiation at such a facility (Ong et al. 1996) . Solar Two is currently an operating power plant, and a more favorable U.S. location is the research heliostat field of the National Solar Thermal Test Facility (NSTTF) at Sandia National Laboratories in Albuquerque NM.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The overall design of STACEE is shown in Figure 1 . Cherenkov light created in gammaray air showers reaches the ground with a broad lateral extent \u223c 250 m across. The NSTTF consists of 220 heliostat mirrors (each 37.2 m 2 in area). STACEE uses 48 heliostats for a total reflector surface of 1785 m 2 . The heliostats reflect the Cherenkov light onto secondary mirrors on a central tower. Three 2 m diameter secondary mirrors viewing different parts of the heliostat field are used. Light reflected from each secondary mirror is imaged onto a photomultiplier tube (PMT) camera. Each heliostat is viewed by a single PMT.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "In this paper, we describe the essential features of the STACEE design. We first discuss the NSTTF site itself. We then outline the essential hardware components of STACEE, including the:", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "1. heliostats, 2. secondary mirror structures, 3. cameras, and 4. electronics.", "cite_spans": [], "ref_spans": []}, {"section": "The Site", "text": "The NSTTF is located approximately 15 km southeast of Albuquerque at an altitude of 1700 m above sea level. The site is dry and has excellent sky clarity. Weather patterns accumulated over the last thirty years predict an average precipitation of 13.4 cm per year and a yearly average of 170 fully clear days and 111 mostly clear days (NOAA 1997) . We have measured the intensity of night sky background light at the site and have found an average value of (4.3 \u00b1 0.9) \u00d7 10 12 photons m \u22122 sec \u22121 sr \u22121 over the wavelength range spanned by a typical bi-alkali PMT (300-600 nm).", "cite_spans": [], "ref_spans": []}, {"section": "The Site", "text": "The NSTTF is located at Sandia National Laboratories on Kirtland Air Force Base. The facility is fully supported and operated by the U.S. Department of Energy (DOE). As such, the DOE maintains the heliostat field, heliostat control tower, and solar tower. Heliostat repair is done as a matter of course. Since the NSTTF is a research facility and not an operating power plant, there is little potential for interference between STACEE work and solar energy research.", "cite_spans": [], "ref_spans": []}, {"section": "Fig. 1: Plan view of the STACEE telescope. STACEE uses 48 heliostat mirrors of the National Solar Thermal Test Facility near Albuquerque NM, USA (upper drawing). Each heliostat has an area of 37 m 2 and the distance between heliostat centers is \u223c 12.5 m. The heliostats reflect Cherenkov radiation onto three secondary mirrors located on a central tower (lower drawing). The secondary mirrors image the light onto photomultiplier tube cameras.", "text": "We are able to schedule our observations well in advance with minimal interruption from other activities at the site. ", "cite_spans": [], "ref_spans": []}, {"section": "Heliostats", "text": "Heliostat mirrors at the NSTTF consist of 25 square facets made of rear-surfaced glass. Facets for selected heliostats are aligned and focused using a television camera mounted at the top of the central tower. Each heliostat mirror can be positioned in azimuth and elevation with 13-bit precision (0.05", "cite_spans": [], "ref_spans": []}, {"section": "Heliostats", "text": "\u2022 ). The optical and pointing performance of the heliostats is found to be satisfactory for atmospheric Cherenkov astronomy and has been described elsewhere (Covault et al. 1997 , Chantell et al. 1997 .", "cite_spans": [], "ref_spans": []}, {"section": "Heliostat Selection", "text": "Of the 220 heliostats at the NSTTF site, we have selected 48 heliostats to be used for STACEE (16 heliostats for each of three secondary mirrors). Ideally, heliostats are selected so as to provide uniform coverage over the entire area of the field. However, selected heliostats must also not crowd each other in the focal plane of the secondary mirror. We also select heliostats to minimize off-axis aberrations. Finally, field-of-view requirements prevent consideration of heliostats that are too close to the central tower. Figure 2 shows the view from the tower into the northeastern corner of the heliostat array corresponding to one of the three secondary mirrors. This view is imaged onto the focal plane of the mirror. The rectangular border indicates the boundary of the camera. Thick circles indicate the position of each PMT can entrance aperture for the 16 selected heliostats in this part of the array. Note that in actual operation, non-selected heliostats will be turned edge-on and thus will not reflect light up to the secondary mirror.", "cite_spans": [], "ref_spans": [{"start": 526, "end": 534, "text": "Figure 2", "ref_id": "FIGREF0"}]}, {"section": "Heliostat Control", "text": "All heliostats at the NSTTF are operated using a single Master Control System (MCS) based on an HP-1000 mini-computer. Software to control heliostats and to track the sun onto various targets has been previously developed by the NSTTF staff. The STACEE group has modified this software to track astrophysical sources, accounting for the fact that air showers originate near the top of the atmosphere and not at infinity. The MCS is operated directly by STACEE scientists during observations", "cite_spans": [], "ref_spans": []}, {"section": "Heliostat Control", "text": "The MCS communicates with individual heliostats over a network of serial lines. Heliostat pointing coordinates are updated at least once every 1.2 sec. Several video displays provide real-time information on every aspect of the heliostat field and warn the operator if there is a malfunction. Status and pointing information for every heliostat is logged to a file every 5 seconds.", "cite_spans": [], "ref_spans": []}, {"section": "Secondary Mirror Structure", "text": "A schematic view of one of the three secondary mirror structures is shown in Figure 3 . The structure consists of a commercial pallet stacker which is secured to a steel base plate, or skid. The stacker raises and lowers the mirror assembly consisting of a jib-crane and spider, both made of aluminum. The jib-crane allows for azimuthal control by means of a linear actuator. The spider holds the mirror and is attached to the jib-crane by a ball joint and two actuators for elevation control. The actuators are used only for alignment and the mirror is not moved during observations. The 2 m diameter mirror is spherical in shape and consists of seven approximately hexagonal segments, as shown in Figure 4 . Each segment is a single piece of lime float glass that has been slumped, ground, polished from a 0.5\" thick blank to a 2 m focal length. The glass is coated by evaporation of aluminum onto its front surface and by a protective layer of AlSiO. Each mirror segment is attached to the spider by means of a triangular aluminum base-plate which is glued to the mirror and is attached by bolts to the spider frame. Mirror adjustments are made by a three-point mounting system on each facet. The overall mirror size is set by the focal properties of the heliostats themselves. Solar images have been measured for fifteen individual heliostats and their sizes are reported in Covault et al. 1997 . The maximum image size at the tower is 1.7 m (FWHM) and the image sizes scale as expected with the distance from the tower.", "cite_spans": [], "ref_spans": [{"start": 699, "end": 707, "text": "Figure 4", "ref_id": "FIGREF1"}]}, {"section": "Fig. 3: Schematic diagram of the STACEE secondary mirror structure (one of three). The structure supports a 2.0 m diameter spherical mirror with a 2.0 m focal length. The mirror is positioned to reflect Cherenkov light from the heliostat field into the PMT camera. A full description of the various structure components is given in the text.", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Camera", "text": "The camera consists of two principal components: an adjustable stand, and PMT can assemblies mounted on a slotted plate, as shown in Figure 5 . The stand is a rigid structure made of aluminum bolted to a movable carriage. The carriage allows the entire camera to slide away from the tower edge to the proper focal point of the secondary mirror. The slotted plate is tilted in elevation to allow for correct focusing of the heliostat images in the center of the field-of-view of the mirror onto the entrance apertures of their respective can elements.", "cite_spans": [], "ref_spans": []}, {"section": "Camera", "text": "Each PMT can element holds an assembly which comprises an acrylic light concentrator followed by a photomultiplier tube. The PMT and concentrator are held together in a hollow metal cylinder which has an edge ring at one end and a threaded disk at the other. The disk pushes the concentrator and PMT together; they are separated by a silicone rubber cookie which provides good optical and mechanical coupling. This assembly is approximately 13 cm in diameter and 40 cm long. The concentrators are dielectric total internal reflecting concentrators (DTIRCs) (Ning et al. 1987) .", "cite_spans": [], "ref_spans": []}, {"section": "Camera", "text": "The can elements are mounted in a sleeve arrangement. The sleeves are secured to the slotted plate with a system that allows for continuous x-y adjustment as well as canting so that PMTs away from the optical axis can be pointed towards the center of the mirror. For cans furthest from the optic axis of the mirror the canting angle is 17", "cite_spans": [], "ref_spans": []}, {"section": "Camera", "text": "\u2022 . Operationally, one positions and cants the sleeves before sliding in the heavy PMT can elements.", "cite_spans": [], "ref_spans": []}, {"section": "Camera", "text": "The DTIRC is approximated by a converging cylinder of length between 10.6 cm and 13.2 cm. The cylinder is made of a single piece of UV transparent acrylic that has been machined on a numerically controlled mill to the proper dimensions. The front surface of the DTIRC is a sphere and the rear surface is a circular aperture. The DTIRC is designed so the field-of-view", "cite_spans": [], "ref_spans": []}, {"section": "Fig. 5: Schematic diagram of a STACEE camera (one of three). The camera consists of a slotted aluminum backplane into which PMT can assemblies are mounted. Only one assembly (of sixteen) is shown for reasons of clarity. A full description of the camera is given in the text.", "text": "of each PMT is restricted. Three different types of DTIRCs are used corresponding to PMTs that view different parts of the heliostat field. PMTs viewing heliostats closest to the tower are matched with DTIRCs that have a field-of-view of 16", "cite_spans": [], "ref_spans": []}, {"section": "Fig. 5: Schematic diagram of a STACEE camera (one of three). The camera consists of a slotted aluminum backplane into which PMT can assemblies are mounted. Only one assembly (of sixteen) is shown for reasons of clarity. A full description of the camera is given in the text.", "text": "\u2022 (half-angle), whereas PMTs viewing heliostats farthest from the tower are matched with DTIRCs having a field-of-view of 26", "cite_spans": [], "ref_spans": []}, {"section": "Fig. 5: Schematic diagram of a STACEE camera (one of three). The camera consists of a slotted aluminum backplane into which PMT can assemblies are mounted. Only one assembly (of sixteen) is shown for reasons of clarity. A full description of the camera is given in the text.", "text": "\u2022 . The photomultiplier tubes are chosen for high speed and moderate gain. Speed is important to minimize the level of pile-up from pulses created by night sky photons. A moderate gain is needed so that a sufficient amount of charge is generated, but at the same time the total current draw of the tube must be kept to an acceptable level (< 100\u00b5A). The PMTs (Philips XP2282) have eight dynode stages and a typical gain of \u223c 3 \u00d7 10 5 at a high voltage value of -1500 V. Each tube has a transistorized base (Philips VD 182K/C) that has been optimized for good linearity and speed. The pulse width of a single photoelectron signal at the output of the base is \u223c 1.8 nsec (FWHM) and the time transit spread of the pulse is \u223c 0.45 nsec. The tube has a 2\" diameter bi-alkalai photocathode and a front window made of borosilicate glass.", "cite_spans": [], "ref_spans": []}, {"section": "X10", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "PMT", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Electronics", "text": "The electronics serve two major purposes. First, the PMT signals must be combined together in a coincidence circuit to form the experiment trigger. The trigger detects the occurrence of a Cherenkov air shower amidst the fluctuations of the night sky background light. Second, electronics are needed to measure the arrival time and pulse-height of the Cherenkov signal reaching each of the PMTs. The shower direction is reconstructed from the arrival time information and the pulse-height information is used to estimate the shower energy.", "cite_spans": [], "ref_spans": []}, {"section": "Electronics", "text": "A block diagram of the electronics is shown in Figure 6 . Commercial components are used wherever possible. The PMTs are powered by a high voltage mainframe (Lecroy 4032).", "cite_spans": [], "ref_spans": [{"start": 47, "end": 55, "text": "Figure 6", "ref_id": "FIGREF2"}]}, {"section": "Electronics", "text": "The PMT signals are capacitively coupled (time constant = 75 nsec), amplified (Phillips 776), and discriminated (Lecroy 4413). Copies of the PMT signals are generated by a linear fan-out (Phillips 748) and these copies are sampled by waveform digitizers. The waveform information is read out via Ethernet by the data acquisition (DAQ) computer.", "cite_spans": [], "ref_spans": []}, {"section": "Electronics", "text": "The trigger is formed by a coincidence of the discriminated PMT signals that are delayed appropriately to bring the signals into time. The delays account for the fact that the Cherenkov light reaches different PMTs at different times because of variations in the times of flight from individual heliostats to the secondary mirror. In addition, delays are needed to account for time of flight differences due to the orientation of the shower wavefront. The trigger is composed of two distinct parts: Level 1 (L1) and Level 2 (L2)", "cite_spans": [], "ref_spans": []}, {"section": "Electronics", "text": "The discriminated signals are delayed by programmable delay units (Lecroy 4518) and fixed length time of flight cables (RG 58U) and combined to form the L1 trigger. The L1 trigger consists of multiplicity logic acting on parallel groups of four PMTs (i.e. N of 4 logic). The PMTs are grouped to form L1 triggers based on the proximity of their respective heliostats. The L1 trigger signals are passed through additional programmable delay (CAEN 469) to the L2 multiplicity logic, which makes a majority decision based on the number of in-time L1 signals (i.e. N of 12 logic). The L2 trigger signifies an event trigger which stops the waveform digitizers and initiates an event read-out.", "cite_spans": [], "ref_spans": []}, {"section": "Electronics", "text": "The waveform digitizers are 1 GHz sampling units with 8-bit resolution. Two commercially available products are being considered. One is a digitizer made in the VXI standard (Tektronix TVS641) and the other is a flash ADC in the VME standard (ETEP 301).", "cite_spans": [], "ref_spans": []}, {"section": "Electronics", "text": "The DAQ computer will be a Silicon Graphics Workstation (Indy R4400 or equivalent). The workstation will control the CAMAC components via an Ethernet crate controller (Hytec 1365). Universal time will be recorded via a CAMAC-based Global Positioning System (GPS) clock (Hytec GPS92).", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "STACEE is an experiment designed to carry out gamma-ray observations in the unopened window between 20 and 250 GeV using the atmospheric Cherenkov technique. The experiment uses large heliostat mirrors of the National Solar Thermal Test Facility to achieve a very large Cherenkov photon collection area. Additional components of STACEE include secondary mirrors and structures, cameras, and electronics. The baseline design for STACEE has been finalized and the full experiment is now under construction. Qu\u00e9bert, and D.A. Smith for many useful discussions. This work is supported in part by the National Science Foundation, the Institute of Particle Physics of Canada, the Natural Sciences and Engineering Research Council, and the California Space Institute. RAO acknowledges the support of the Grainger Foundation and the University of Chicago. CEC is a Cottrell Scholar of the Research Corporation.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF5": {"title": "Very High Energy Gamma-Ray Astronomy, EFI 97-41", "authors": [{"first": "Rene", "middle": ["A"], "last": "Ong", "suffix": ""}], "year": 1997, "venue": "Physics Reports, submitted", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Fig. 2: View of northeastern corner of NSTTF heliostat field as seen from the position of the secondary mirror. Camera outline (rectangle) and position of PMT entrance apertures (circles) at focal plane are indicated.", "type": "figure"}, "FIGREF1": {"text": "Fig. 4: Schematic diagram of a STACEE secondary mirror (one of three). The mirror has an overall width of 2 m and a 2 m focal length. It consists of seven hexagonal segments of ground, polished glass. The segments are front-surfaced with aluminum and are mounted to a rigid aluminum support structure known as the spider. Alignment of each segment is accomplished by means of a three point adjustment system, as shown.", "type": "figure"}, "FIGREF2": {"text": "Fig. 6: Block diagram of the STACEE electronics. The PMT signals are amplified and discriminated. The discriminated signals are delayed to form a two-level (L1,L2) experiment trigger. The trigger is used to gate fast digitizers which record the PMT waveforms.", "type": "figure"}}}
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{"paper_id": "17788331", "_pdf_hash": "1910f4bd43ecf4b257b20bfc7279d6908788369d", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "17788388", "_pdf_hash": "f8d87f9db2d73e4b9cca9c9a84d6bcfc27eff128", "abstract": [{"section": "Abstract", "text": "This paper describes the three phases of the Durkheim Project. For this project we developed a clinician's dashboard that displays output of models predicting suicide risk of veterans and active duty military personnel. During phase one, we built the clinician's dashboard and completed a Veterans Affairs (VA) predictive risk medical records study, based on an analysis of the narrative, or free text, portions of VA medical records, In phase two, we will predict suicide risk based on opt-in social media postings by patients using social media websites, e.g., Facebook. We describe the software infrastructure that we have completed for this phase two system. During phase three we will provide a three layer intervention strategy. We discuss our methodology for the three phases, including IRBapproved protocols for the first two phases and a soon-to-be approved IRB protocol for phase three.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Diagnosis of psychological health and the prediction of negative events, such as suicide, or suicide ideation, is limited by: a) a lack of understanding of the true differentiating risks of suicidality (Health Promotion, 2010; Treating Soldiers, 2010 ) and b) a lack of near real-time reaction capability to large volumes of data. There is a need for broader coverage suicide risk detection and a better understanding of the expression of suicide ideation through data mining of text and images. The Durkheim Project's proposed solution is to provide continuous monitoring of text based information, such as found in social network user behavioral intent enabling intervention; facilitated by social / online data sources, powered by a medically-validated suicide risk classifier.", "cite_spans": [], "ref_spans": []}, {"section": "Suicide risk and military culture", "text": "The suicide rate among members of the United States Armed Forces has continued to rise for the past decade, beginning soon after the onset of military operations in Iraq and Afghanistan. Suicide is now the second-leading cause of death among military personnel, with more service members dying by suicide in 2012 than by combat-related causes (Zoroya, 2012) . In response to steadily rising suicide rates among military personnel and veterans, researchers, clinicians, policy-makers, and military leaders have responded with an overwhelming and concerted effort to reverse these trends. Despite these considerable efforts, however, no evidence of effectiveness has been observed to date, resulting in considerable frustration for all involved. Although specific reasons explaining the lack of success to date are not yet known, it has been noted that most suicide prevention efforts used with military and veteran populations lack cultural relevance and do not incorporate several critical characteristics of the military culture that can create unique challenges from a suicide prevention perspective (Bryan et al., 2012) . For instance, mental toughness and suppressive coping, fearlessness of death, and self-sacrifice are qualities that are valued in the military, but can serve as barriers to traditional prevention efforts.", "cite_spans": [{"start": 343, "end": 357, "text": "(Zoroya, 2012)", "ref_id": "BIBREF16"}, {"start": 1102, "end": 1122, "text": "(Bryan et al., 2012)", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Suicide risk and military culture", "text": "The military culture values strength, resilience, courage, and personal sacrifice when faced with adversity. Weakness is not tolerated, and service members are expected to \"shake it off\" or \"suck it up\" when experiencing problems or illness.", "cite_spans": [], "ref_spans": []}, {"section": "Suicide risk and military culture", "text": "Suppression and avoidance have long been linked to mental health problems and emotional distress (Hayes et al., 1996) , including suicidal ideation and suicide attempts (Najmi et al., 2007) . Yet despite this \"common sense\" piece of knowledge, suppression and avoidance are nonetheless taught and reinforced within the military culture as a coping strategy because, in the short term after a stressful or traumatic event, suppression can actually reduce emotional distress and foster adaptation to extreme adversity (Beck et al., 2006; Bonanno 2004) . This is especially relevant in combat situations, when natural grief responses may need to be suppressed to sustain adequate performance and achieve mission objectives. For example, crying in the midst of a fire fight is not adaptive or conducive to survival, and therefore must be stifled. Suppression and avoidance therefore presents the first paradox for understanding military and veteran suicide: a skill that is adaptive and useful in the short-term following a traumatic event can be detrimental and impair adaptive functioning in the long-term.", "cite_spans": [{"start": 97, "end": 117, "text": "(Hayes et al., 1996)", "ref_id": "BIBREF26"}, {"start": 169, "end": 189, "text": "(Najmi et al., 2007)", "ref_id": "BIBREF24"}, {"start": 516, "end": 535, "text": "(Beck et al., 2006;", "ref_id": "BIBREF18"}, {"start": 536, "end": 549, "text": "Bonanno 2004)", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "Suicide risk and military culture", "text": "Military personnel are also explicitly trained to overcome their fear of injury and death, typically through repeated exposure to scenarios and environments that increasingly mimic actual combat situations, which habituates them to fear and eventually replaces this fear with exhilaration and/or other positive emotions (i.e., the opponent-process). Indeed, greater exposure to combat, especially combat marked by higher levels of violence and injury, are associated with less fear of death among military personnel (Bryan and Cukrowicz, 2011; Bryan et al. 2011) . Fearlessness is an essential quality of a service member; retreating from danger and life-threatening situations are generally not conducive to an effective fighting force. Yet at the same time, fear of death is a well-known protective factor for suicide, given that individuals who are afraid to die are unlikely to attempt suicide, and fearlessness is associated with more severe levels of suicide risk among military personnel relative to civilian samples, and is associated with increased severity of suicide risk among military personnel . Consequently, fearlessness about death paradoxically serves both as a necessary strength and asset for military personnel, yet also serves as a risk factor for suicide.", "cite_spans": [{"start": 516, "end": 543, "text": "(Bryan and Cukrowicz, 2011;", "ref_id": "BIBREF5"}, {"start": 544, "end": 562, "text": "Bryan et al. 2011)", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Suicide risk and military culture", "text": "The military culture also places a premium on selflessness in the service of a higher good, and does not necessarily view life as the highest good in every situation. In the military, one's life might actually be viewed as subordinate to other, higher \"goods\" such as the well-being of others or ideals and principles such as freedom and justice. Laying down one's life for a greater good is widely considered to be one of the highest honors a service member can achieve. A considerable amount of research has converged on a very suicide-specific and dangerous thought process for suicidal behavior: perceived burdensomeness. Perceived burdensomeness entails the mistaken perception that \"others would be better off without me\" or that one's death is of greater value than one's life. Perceived burdensomeness and self-sacrifice are in many ways opposite sides of the same coin, and it is not yet clear how or when perceived burdensomeness (\"taking\" one's life) becomes mistaken for self-sacrifice (\"giving\" one's life) among military personnel and veterans.", "cite_spans": [], "ref_spans": []}, {"section": "Suicide risk and military culture", "text": "These characteristics simultaneously function as an asset (in terms of military performance) and as a liability (in terms of suicide prevention) for military personnel and veterans, thereby creating a paradox for suicide prevention in military and veteran populations, and contributing directly to mental health stigma. Furthermore, the values of the military culture are generally at odds with the values and ideals of mental health systems, which value emotional vulnerability and helpseeking, and focus on deficiencies and clinical disorders, thereby reinforcing stigma even more. In essence, traditional prevention approaches have conceptualized suicide in a way that conflicts with the core identity and values of military personnel and veterans. To be effective, suicide prevention efforts must be culturally-relevant and integrate these values and ideals of military personnel and veterans.", "cite_spans": [], "ref_spans": []}, {"section": "Related work", "text": "In addition to the work related to military culture issues discussed in section 2, there are many linguistic approaches to analyzing suicide risk (Barak and Miron, 2005; Jones and Bennell, 2007; Lester, 2008a; Lester, 2008b; Lester, 2010a; Lester, 2010b; Lester and McSwain, 2010; Stirman and Pennebaker, 2001) . In 2011, one of the Informatics for Integrating Biology & the Bedside (i2b2) shared tasks was a sentiment analysis task to identify emotion in suicide notes (Combined Objective, 2011) . Of this literature only Barak and Miron (2005) considers online text. Most other text analysis suicide research concerns analysis of suicide notes. There are studies of the writings of suicidal poets (Lester and McSwain, 2010; Stirman and Pennebaker, 2001 ) and studies involving distinguishing genuine and simulated suicide notes (Jones and Bennell, 2007; Lester, 2010a) .", "cite_spans": [{"start": 146, "end": 169, "text": "(Barak and Miron, 2005;", "ref_id": "BIBREF1"}, {"start": 170, "end": 194, "text": "Jones and Bennell, 2007;", "ref_id": "BIBREF22"}, {"start": 195, "end": 209, "text": "Lester, 2008a;", "ref_id": "BIBREF9"}, {"start": 210, "end": 224, "text": "Lester, 2008b;", "ref_id": "BIBREF10"}, {"start": 225, "end": 239, "text": "Lester, 2010a;", "ref_id": "BIBREF11"}, {"start": 240, "end": 254, "text": "Lester, 2010b;", "ref_id": "BIBREF12"}, {"start": 255, "end": 280, "text": "Lester and McSwain, 2010;", "ref_id": "BIBREF14"}, {"start": 281, "end": 310, "text": "Stirman and Pennebaker, 2001)", "ref_id": "BIBREF25"}, {"start": 523, "end": 545, "text": "Barak and Miron (2005)", "ref_id": "BIBREF1"}, {"start": 699, "end": 725, "text": "(Lester and McSwain, 2010;", "ref_id": "BIBREF14"}, {"start": 726, "end": 754, "text": "Stirman and Pennebaker, 2001", "ref_id": "BIBREF25"}, {"start": 830, "end": 855, "text": "(Jones and Bennell, 2007;", "ref_id": "BIBREF22"}, {"start": 856, "end": 870, "text": "Lester, 2010a)", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "The Durkheim Project", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Overview", "text": "The Durkheim Project consists of three phases. During the first phase, described in section 4.2, a clinician's dashboard was built and a Veterans Affairs (VA) predictive risk medical records study was completed, based on an analysis of the narrative, or free text, portions of VA medical records. Also during the first phase, the initial software infrastructure to collect and analyze the social media data for phase two, was designed and implemented. During the second phase, section 4.3, now underway, opt-in social media postings are being collected and will be analyzed. During the third phase, section 4.4, a pilot program will isolate serious suicide risk for individuals in real-time, and develop a prediction triage model for improved suicide intervention", "cite_spans": [], "ref_spans": []}, {"section": "Phase 1: Veteran Affairs medical records study", "text": "During phase 1 linguistics-driven prediction models were developed to estimate the risk of suicide. These models were generated from unstructured clinical notes taken from a national sample of United States VA medical records. The protocol for this study was approved by the Institutional Review Board (IRB) of the VA Medical Center, where the study was conducted. We created three matched cohorts: veterans who completed suicide, veterans who used mental health services and did not complete suicide, and veterans who did not use mental health services and did not complete suicide during the observation period (n = 70 in each group). From the clinical notes, we generated datasets of single keywords and multi-word phrases, and constructed prediction models using a supervised machinelearning algorithm based on a genetic programming framework, MOSES (Looks, 2006 (Looks, , 2007 Goertzel et al., 2013) . MOSES can be described as a variant of a decision-tree forest, with certain genetic and maximum entropy techniques mixed in: maximum entropy to apply pressure to minimize tree size and genetic to ensure tree species diversity. In our prior research we have found that MOSES consistently outperforms standard text classification approaches, such as Support Vector Machines (SVMs). The primary hyperparameter that we used was the dynamic feature size. The resulting inference accuracy was at first 65% and then consistently 67% or more. This was the prediction accuracy for assigning a patient to the correct cohort. These data suggest that computerized text analytics can be applied to unstructured sections of medical records to estimate the risk of suicide (Poulin et al. 2014 ). The resulting system could potentially allow clinicians to screen seemingly healthy patients at the primary care level, and to continuously evaluate suicide risk among psychiatric patients.", "cite_spans": [{"start": 854, "end": 866, "text": "(Looks, 2006", "ref_id": "BIBREF20"}, {"start": 867, "end": 881, "text": "(Looks, , 2007", "ref_id": "BIBREF21"}, {"start": 882, "end": 904, "text": "Goertzel et al., 2013)", "ref_id": "BIBREF2"}, {"start": 1665, "end": 1684, "text": "(Poulin et al. 2014", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Phase 2: Predicting risk with opt-in social media postings", "text": "Although data collection and analysis for phase 2 is just beginning, the software development required for this data collection and analysis was completed during phase 1. A phase 2 protocol for collecting and analyzing opt-in social media postings and presenting predictions to clinicians via the Durkheim Project's Clinicians' dashboard has also been approved by our IRB. When the system is fully operational, a clinician will see predictive models of suicide risk for a patient constructed from the patient's medical records and the patient's opt-in social media postings. Subjects are being recruited via targeted efforts. Subjects will be recruited through our collaboration with Facebook (PR Newswire 2013). A Facebook pop-up window will be used to recruit people that Facebook has identified as being military personnel or veterans.", "cite_spans": [], "ref_spans": []}, {"section": "Phase 3: Intervention", "text": "For phase 3, a protocol has been completed, which will soon be submitted to a final IRB. This protocol includes an unblinded, 3-cohort design, for a pilot program, which proposes to isolate serious suicide risks for individuals in real-time and to develop a prediction triage model for improved suicide intervention. Plans are to use and improve upon the linguistically-based prediction capabilities of the model developed during phase 1. The phase 1 retrospective study was able to predict with limited accuracy before suicides occurred. The theoretic assumption is that wording chosen by those at risk will vary at different stages of risk. By building from ongoing observations from the phase 2 study and feedback obtained during the conduct of the phase 3 study, the aim is to adjust the linguisticsdriven model to predict suicide risk within the critical period for interventions of various levels of severity.", "cite_spans": [], "ref_spans": []}, {"section": "Phase 3: Intervention", "text": "In this protocol, ongoing monitoring of the network will allow continuous updating and change in value of risk alert levels among the green-tored color coding. When the predictive system detects postings that indicate a certain threshold level of potential suicide risk, risk alerts are triggered in real-time and sent to either a monitoring clinician or a pre-identified buddy monitor, or to an automated system, which will generate supportive messages that are sent to the at-risk individual.", "cite_spans": [], "ref_spans": []}, {"section": "Phase 3: Intervention", "text": "To better characterize the risk for the population of active-duty military and veterans, the analysis for this study will be limited to the primary participants. These primary participants may be newly recruited via the dedicated Facebook and mobile applications or, through that same dedicated application, from among those already participating in the phase 2 study. In either case, all primary participants must provide informed consent for this specific study. That is, those already involved in the phase 2 study must provide separate consent to participate in the phase 3 study. However, outside of the context of this study, the computerized intervention will be open to members of the general public who might wish to take advantage of the program's intervention potential. Primary participants are active duty U.S. military or veterans with English as a primary or secondary language, who agree to post to social media using English. The age limit for primary participants in the phase 3 study, as with phase 2 study, targets the age group most likely to actively use social media, i.e., those between the ages of 18 and 45.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "So far results are only available for the phase 1 study. For single-word models, the predictive accuracy was approximately 59% (the average for 100 models), and scores for individual candidate models ranged from 46-67%. Because our training sets are balanced, we have used accuracy as a surrogate for precision and recall. Accuracy was computed using five-way cross-validation. Models that used certain word pairs had significantly better scores than single-word models, though they are far less human readable. The phrases \"negative assessment for PTSD\" and \"positive assessment for PTSD\" carry different meanings. This phrase-based approach was more accurate than a single-word approach. For pre-selected word pairs, the individual model scores ranged from 52-69%, with an average of 64% (for 100 models). In the final experiments, the combined Cohorts '1v2v3 classifier' had a peak performance of 70%, and an average performance of 67%.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Our analyses were successful at determining useful text-based signals of suicide risk. We obtained accuracies of greater than 60% for ensemble averages of 100 models, and our individual model accuracies reached 67-69%. Given the small size of the dataset and the fragmentary nature of the clinical notes, this performance level represents a significant achievement. For a classifier, these results represent a statistically significant 'signal'. Meanwhile, we showed that, methodologically, word pairs are more useful than single words for model construction on electronic medical record (EMR) data.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Furthermore, the predictive feature words that distinguished each group were highly revealing, especially for the suicidal cohort, and were consistent with the existing medical literature on suicide. Many medical conditions have been associated with an increased risk for suicide, but these conditions have generally not been included in suicide risk assessment tools. These conditions include gastrointestinal conditions, cardiopulmonary conditions, oncologic conditions, and pain conditions. Also, some research has emerged that links care processes to suicide risk. The word \"integrated\" emerged as a key term in our study and is also reflected in the integrated care literature (Bauer et al., 2013) .", "cite_spans": [{"start": 682, "end": 702, "text": "(Bauer et al., 2013)", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Discussion", "text": "Although the text on which our predictive model was based for the phase 1 medical records study was text written by a physician or other healthcare provider, our hypothesis is that some of the highly predictive features learned during phase 1 will carry over to the predictive modeling of opt-in social media postings during phase 2. This text is written by the patient. However, we expect that some of the features, or concepts, will be the same due to the ability to do software based synonym matches Additionally, a physician or other healthcare worker may sometimes quote or paraphrase what a patient said when adding a note to the clinical record. A key predictive feature, such as the word \"anxiety,\" may be used either by a clinician or a patient. We believe that the use of specialized text-analytic resources such as linguistic inquiry and word count (LIWC) would also help improve our results. Some preliminary results have been obtained using LIWC on our dataset.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "In future research we plan to scale up the phase 1 medical records study from our current study where each cohort had 70 subjects to a study, using the same protocol, with at least 1000 subjects in each cohort. We also plan to transfer the predictive model built from the phase 1 study to the analysis of phase 2 opt-in social media postings. Once our phase 3 protocol has IRB approval, we plan to begin the phase 3 of the Durkheim Project, informed by the results, and ongoing follow-on research, of our phase 1 and 2 studies. In our future research we plan to use additional features from the structured portions of the medical record, as well as to use LIWC. In both our medical records and social media research we plan to use temporal analysis.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "Although the phase 1 study was successful in distinguishing the cohort of completed suicides both from the control group cohort and the psychiatric cohort, it was difficult to distinguish text based noise from signal with high accuracy in our initial results. We expect that our planned follow-on study with 1000 subjects in each cohort will have much less problem in distinguishing signal from noise. Suicide risk prediction is a very difficult problem. We believe that studies such as our phases 1 and 2 studies, which use supervised machine learning techniques, can uncover predictive risk factors that are not clearly understood by the medical community. At the same time, we also believe that more effective suicide risk prediction systems can be built based on the integration of machine learning methods and the expertise of suicidologists. 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{"paper_id": "17788845", "_pdf_hash": "da318a198533ccbe7366b41bf163a1ce41e4bc8e", "abstract": [{"section": "Abstract", "text": "The synthesis of mRNA by Pol II involves cotranscriptional premRNA processing including 5\u2032 capping, splicing and 3\u2032-end processing. Pol II recruits pre-mRNA-processing factors via its CTD throughout transcription [1] [2] [3] , and this process is regulated by changes in CTD phosphorylation 4 . The CTD forms a flexible extension of Pol II consisting of 26 (yeast) or 52 (human) heptapeptide repeats of the consensus sequence Tyr1-Ser2-Pro3-Thr4-Ser5-Pro6-Ser7. When Pol II is recruited to promoters, the CTD is not phosphorylated 4 . As transcription proceeds, Ser5 phosphorylation recruits the mRNA 5\u2032-capping machinery near the promoter 5, 6 , whereas Ser2 phosphorylation recruits 3\u2032-processing and termination factors near the polyadenylation (pA) site 7 . Tyr1 phosphorylation prevents premature recruitment of termination factors within gene bodies 8 . At the pA site, Tyr1 phosphorylation levels drop, whereas Ser2 phosphorylation remains, apparently enabling termination-factor recruitment 8 . Thus, CTD kinases and phosphatases have key roles in mRNA synthesis 4 .", "cite_spans": [{"start": 213, "end": 216, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 217, "end": 220, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 221, "end": 224, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 291, "end": 292, "text": "4", "ref_id": "BIBREF3"}, {"start": 640, "end": 642, "text": "5,", "ref_id": "BIBREF4"}, {"start": 643, "end": 644, "text": "6", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Abstract", "text": "Addition of a 3\u2032 poly(A) tail to mRNA facilitates nuclear export, regulates the stability of mRNAs and enhances translation 9-11 . 3\u2032-end processing is performed by a large number of proteins including the ~1-MDa CPF complex (CPSF in mammals), which cleaves pre-mRNA with its endonuclease subunit (Ysh1 (CPSF73)) and then polyadenylates the new 3\u2032 end with its poly(A) polymerase (Pap1 (PAP)) 12,13 . Accessory proteins, such as CF IA (comprising Pcf11, Clp1, Rna14 and Rna15) and CF IB in yeast, contribute to the specificity and efficiency of 3\u2032-end-processing reactions.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "The cleavage-and-polyadenylation machinery is recruited to nascent transcripts early in the transcription cycle. CPF associates with the Pol II CTD and TFIID at promoters and is presumed to travel with the transcription complex until it reaches the pA site 12 . Interestingly, the Pol II CTD itself is proposed to have a role in 3\u2032-end processing because it is required for efficient pre-mRNA processing in vivo 14, 15 and stimulates the cleavage event in vitro 16 . Disruption of 3\u2032-end processing can lead to defects in transcription termination, thus suggesting an intimate link between these two processes 17 . For example, temperaturesensitive mutations in CF IA subunits result in defective transcription termination 18 . Pcf11 contains a CTD-interacting domain (CID) that binds Ser2-phosphorylated CTD and has a role in transcription termination that is separable from its role in 3\u2032-end processing 15, [19] [20] [21] .", "cite_spans": [{"start": 412, "end": 415, "text": "14,", "ref_id": "BIBREF13"}, {"start": 416, "end": 418, "text": "15", "ref_id": "BIBREF14"}, {"start": 462, "end": 464, "text": "16", "ref_id": "BIBREF15"}, {"start": 906, "end": 909, "text": "15,", "ref_id": "BIBREF14"}, {"start": 910, "end": 914, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 915, "end": 919, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 920, "end": 924, "text": "[21]", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Abstract", "text": "The transition from transcription elongation to termination involves CTD Tyr1 dephosphorylation by an unknown phosphatase. We reasoned that the Tyr1 phosphatase might be part of the mRNA 3\u2032-endprocessing and termination machinery. In particular, CPF contains two candidate phosphatases, Ssu72 (refs. 22,23) and Glc7 (ref. 24). Ssu72 can dephosphorylate CTD residue Ser5 during transcription elongation 22, 25, 26 . Glc7 is implicated in transcription termination on genes encoding small nucleolar RNAs 27 , in mRNA export 28 and in the polyadenylation activity of CPF 29 but has no known CTD-related activity. We therefore set out to investigate the role of CPF in CTD phosphorylation. Here, we show that Glc7 is a Tyr1 phosphatase both in vitro and in vivo. We further show that Glc7 is required for normal recruitment of termination factors and for Pol II termination in vivo.", "cite_spans": [{"start": 402, "end": 405, "text": "22,", "ref_id": "BIBREF21"}, {"start": 406, "end": 409, "text": "25,", "ref_id": "BIBREF24"}, {"start": 410, "end": 412, "text": "26", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "Abstract", "text": "RESULTS", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "To investigate whether Ssu72 or Glc7 has CTD Tyr1-phosphatase activity, we purified endogenous CPF from yeast. Analysis of the At the 3\u2032 ends of protein-coding genes, RNA polymerase (Pol) II is dephosphorylated at tyrosine residues (Tyr1) of its C-terminal domain (CTD). In addition, the associated cleavage-and-polyadenylation factor (CPF) cleaves the transcript and adds a poly(A) tail. Whether these events are coordinated and how they lead to transcription termination remains poorly understood. Here we show that CPF from Saccharomyces cerevisiae is a Pol II-CTD phosphatase and that the CPF subunit Glc7 dephosphorylates Tyr1 in vitro. In vivo, the activity of Glc7 is required for normal Tyr1 dephosphorylation at the polyadenylation site, for recruitment of termination factors Pcf11 and Rtt103 and for normal Pol II termination. These results show that transcription termination involves Tyr1 dephosphorylation of the CTD and indicate that pre-mRNA processing by CPF and transcription termination are coupled via Glc7-dependent Pol II-Tyr1 dephosphorylation.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "npg", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "7 6", "text": "VOLUME 21 NUMBER 2 FEBRUARY 2014 nature structural & molecular biology a r t i c l e s entire CPF complex was necessary because isolated phosphatases generally have little specificity, and target-specific dephosphorylation often relies on cofactors 30 . The resulting preparations contained all CPF subunits, including Ssu72 and Glc7 (Fig. 1a) . To test CPF preparations for CTD-phosphatase activity, we used a substrate of purified yeast Pol II that had been prephosphorylated with MAP kinase, at residues including Tyr1, Ser2 and Ser5 (Online Methods; Fig. 1b) . In these assays, we used a molar ratio of CPF to Pol II of 1:4, i.e., 1:104 of CPF to each Pol II-CTD heptad. Incubation with CPF led to almost complete dephosphorylation of Tyr1, Ser2 and Ser5, as revealed by western blotting (Fig. 1b) .", "cite_spans": [{"start": 249, "end": 251, "text": "30", "ref_id": "BIBREF29"}], "ref_spans": [{"start": 334, "end": 343, "text": "(Fig. 1a)", "ref_id": "FIGREF0"}, {"start": 554, "end": 562, "text": "Fig. 1b)", "ref_id": "FIGREF0"}, {"start": 792, "end": 801, "text": "(Fig. 1b)", "ref_id": "FIGREF0"}]}, {"section": "7 6", "text": "To identify which of the two CPF phosphatases was responsible for Tyr1 dephosphorylation, we specifically inhibited Glc7 with EDTA or microcystin. EDTA chelates metal ions and abolishes activity of the metal ion-dependent phosphatase Glc7 (refs. 31,32) but does not affect Ssu72 activity, which is metal-ion independent 23 . Microcystin is a bacterial toxin that specifically inhibits PP1-and PP2A-type phosphatases 30 including Glc7 but not Ssu72. Addition of 10 mM EDTA or 200 nM microcystin to the reaction selectively inhibited Tyr1 and Ser2 dephosphorylation, whereas Ser5 dephosphorylation was still present (Fig. 1b) . These results show that the Glc7 subunit of CPF functions as a CTD phosphatase for Tyr1 and Ser2 in vitro.", "cite_spans": [{"start": 320, "end": 322, "text": "23", "ref_id": "BIBREF22"}, {"start": 416, "end": 418, "text": "30", "ref_id": "BIBREF29"}], "ref_spans": [{"start": 614, "end": 623, "text": "(Fig. 1b)", "ref_id": "FIGREF0"}]}, {"section": "Glc7 is required for Tyr1 dephosphorylation in vivo", "text": "To investigate whether Glc7 acts as a CTD phosphatase in vivo, we depleted Glc7 from the nucleus, using the anchor-away method 33 ( Supplementary Fig. 1a ) and monitored changes in genome-wide occupancy of Tyr1-and Ser2-phosphorylated Pol II by chromatin immunoprecipitation (ChIP) profiling 34 . For metagene analysis of ChIP-chip data, we aligned genes at their pA sites and excluded genes flanked by a neighboring gene within 400 nucleotides downstream of the pA site. This showed that nuclear depletion of Glc7 with rapamycin led to a defect in Tyr1 dephosphorylation at the pA sites (Fig. 2a) . In addition, the levels of Tyr1 phosphorylation increased around the transcription start sites (TSSs, Supplementary Fig. 2 ). The defect in Tyr1 dephosphorylation was also present on individual genes (Fig. 2b) and was not due to treatment with rapamycin ( Supplementary Fig. 3 ).", "cite_spans": [{"start": 127, "end": 129, "text": "33", "ref_id": "BIBREF32"}, {"start": 292, "end": 294, "text": "34", "ref_id": "BIBREF33"}], "ref_spans": [{"start": 132, "end": 153, "text": "Supplementary Fig. 1a", "ref_id": "FIGREF0"}, {"start": 588, "end": 597, "text": "(Fig. 2a)", "ref_id": "FIGREF1"}, {"start": 702, "end": 722, "text": "Supplementary Fig. 2", "ref_id": "FIGREF1"}, {"start": 800, "end": 809, "text": "(Fig. 2b)", "ref_id": "FIGREF1"}]}, {"section": "Glc7 is required for Tyr1 dephosphorylation in vivo", "text": "Nuclear depletion of Glc7 specifically affected Tyr1 dephosphor ylation and not Ser2 dephosphorylation. ChIP occupancy of Ser2-phosphorylated Pol II normalized against total Pol II occupancy revealed no changes around the pA site, whereas occupancy with Tyr1-phosphorylated Pol II increased (Fig. 2c,d ). Thus the Glc7-dependent Ser2 dephosphorylation observed in vitro (Fig. 1b) is probably nonspecific and not used in vivo, consistently with the previously observed Ser2 dephosphorylation by Fcp1 in vivo 25, 35 .", "cite_spans": [{"start": 507, "end": 510, "text": "25,", "ref_id": "BIBREF24"}, {"start": 511, "end": 513, "text": "35", "ref_id": "BIBREF34"}], "ref_spans": [{"start": 291, "end": 301, "text": "(Fig. 2c,d", "ref_id": "FIGREF1"}, {"start": 370, "end": 379, "text": "(Fig. 1b)", "ref_id": "FIGREF0"}]}, {"section": "Glc7 is required for Tyr1 dephosphorylation in vivo", "text": "Although the mammalian homolog of Glc7, protein phosphatase 1 (PP1), acts primarily on phosphorylated serine and threonine residues 30, 36 , the recombinant enzyme is active on phosphorylated tyrosine residues 37 . Tyrosine dephosphorylation can also be performed by the related Arabidopsis PPP-Kelch phosphatase BSU1 (refs. 38,39) and the serine/threonine protein phosphatase 2A (PP2A) if activated by the correct binding partner 40 .", "cite_spans": [{"start": 132, "end": 135, "text": "30,", "ref_id": "BIBREF29"}, {"start": 136, "end": 138, "text": "36", "ref_id": "BIBREF35"}, {"start": 210, "end": 212, "text": "37", "ref_id": "BIBREF36"}, {"start": 431, "end": 433, "text": "40", "ref_id": "BIBREF39"}], "ref_spans": []}, {"section": "Glc7 is required for Tyr1 dephosphorylation in vivo", "text": "Our results for Glc7 demonstrate that a PP1 enzyme can act on a natural phosphorylated tyrosine substrate when present in the context of the correct multiprotein complex, in this case CPF.", "cite_spans": [], "ref_spans": []}, {"section": "Ssu72 does not dephosphorylate Tyr1", "text": "As previously predicted 22, 23 , Ssu72 was recently shown to contain a protein-tyrosine-phosphatase fold 26 , but it apparently acts as a serine-specific phosphatase. Indeed, we found that recombinant human Ssu72 (hSsu72) was able to dephosphorylate Ser5 but neither Tyr1 nor Ser2 in vitro, with up to 1.4 molar excess hSsu72 for each ChIP-chip occupancy profiling of tandem affinity purification-tagged Pcf11 (top) and Rtt103 (bottom) in the Glc7 anchor-away strain, after treatment with rapamycin (+rapa) or no treatment (\u2212rapa). The profiles show ChIP-chip signals averaged by taking the median signal (log 2 (IP/input)) at each genomic position over a set of representative medium-length genes (1,238 \u00b1 300 bp, n = 339, Online Methods). TSS, transcription start site. Experiments in a and b were performed in biological duplicates. (c) Model for the Pol II elongation-termination transition. Dark blue, DNA; red, RNA; black, Pol II and its CTD; light blue, Ser2-P; purple, Tyr1-P. Details are in main text. (Fig. 3a) . This is consistent with previous reports that Ssu72 is a CTD-Ser5 phosphatase 22, 25, 26 .", "cite_spans": [{"start": 24, "end": 27, "text": "22,", "ref_id": "BIBREF21"}, {"start": 28, "end": 30, "text": "23", "ref_id": "BIBREF22"}, {"start": 105, "end": 107, "text": "26", "ref_id": "BIBREF25"}, {"start": 1101, "end": 1104, "text": "22,", "ref_id": "BIBREF21"}, {"start": 1105, "end": 1108, "text": "25,", "ref_id": "BIBREF24"}, {"start": 1109, "end": 1111, "text": "26", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "Ssu72 does not dephosphorylate Tyr1", "text": "To investigate whether Ssu72 indeed does not dephosphorylate Tyr1 in vivo, we prepared a Ssu72 anchor-away yeast strain and depleted Ssu72 from the nucleus by rapamycin addition. ChIP-chip experiments after Ssu72 nuclear depletion showed that Tyr1 dephosphorylation at the pA site was not influenced (Fig. 3b) , thus suggesting that Glc7 remained in the nucleus and dephosphorylated Tyr1 normally. To show this, we tagged Glc7 with mCherry in the Ssu72 anchor-away strain and found that the localization of Glc7 was not influenced by rapamycin addition (Supplementary Fig. 1) . These results are consistent with a previous report that a point mutation in the CPF subunit Ref2 leads to Glc7 dissociation but has no impact on the integrity of the remaining complex 27 . Taken together, these results indicate that Glc7 or Ssu72 can be depleted from CPF without destabilizing the complex and that Glc7 catalyzes Tyr1 dephosphorylation, whereas Ssu72 does not.", "cite_spans": [{"start": 763, "end": 765, "text": "27", "ref_id": "BIBREF26"}], "ref_spans": [{"start": 553, "end": 575, "text": "(Supplementary Fig. 1)", "ref_id": "FIGREF0"}]}, {"section": "Glc7 is involved in transcription termination", "text": "Additional ChIP data indicated that Glc7 is required for transcription termination. The ChIP signal for total Pol II (Rpb3 subunit) normally decreases about 200 nucleotides downstream of the pA site, owing to transcription termination and Pol II release from DNA (Fig. 4a) . Upon nuclear depletion of Glc7, however, strong Pol II ChIP signals remained further downstream (Fig. 4a) . These data suggest that Glc7 acts globally and may be required for normal transcription termination in vivo.", "cite_spans": [], "ref_spans": []}, {"section": "Glc7 is involved in transcription termination", "text": "To investigate whether Tyr1 dephosphorylation is required for normal termination-factor recruitment, we determined Pcf11 and Rtt103 ChIP-chip occupancy after Glc7 nuclear depletion (Fig. 4b) . These experiments revealed a strong decrease in termination-factor occupancy. Both Pcf11 and Rtt103 showed much lower occupancies downstream of the pA site after rapamycin addition, thus indicating that the defect in Pol II termination (Fig. 4a) results from a defect in termination-factor recruitment.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "Whereas previous work showed that the Pol II CTD is phosphorylated at Tyr1, and that Tyr1 phosphorylation impairs binding of transcription-termination factors 8 , it remained unknown whether Tyr1 dephosphorylation is required for termination in vivo and which enzyme dephosphorylates Tyr1. Here we establish yeast CPF subunit Glc7 as a CTD-Tyr1 phosphatase and show that Tyr1 dephosphorylation is required for normal recruitment of termination factors and transcription termination. These results support the previously proposed 'extended CTD code' for the coordination of factor recruitment during the transcription cycle 8 and indicate a crucial role for Tyr1 dephosphorylation in the elongation-termination transition.", "cite_spans": [{"start": 159, "end": 160, "text": "8", "ref_id": "BIBREF7"}, {"start": 623, "end": 624, "text": "8", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "The data presented here and previously 8 lead to the following model for the elongation-termination transition of Pol II at the 3\u2032 ends of protein-coding genes (Fig. 4c) . Elongating Pol II is phosphorylated mainly at Tyr1 (Y1P) and Ser2 (S2P), and this facilitates elongationfactor binding. Tyr1 phosphorylation impairs premature recruitment of termination factors. When Pol II reaches the pA site, the Glc7 subunit of CPF dephosphorylates Tyr1 (\u2212Y1P), whereas Ser2 phosphorylation levels remain high. This allows for the binding of Pcf11 and Rtt103, termination factors that are not part of CPF and show peak occupancy ~100 nucleotides downstream of the pA site 8 . Both Pcf11 and Rtt103 contain CIDs that interact with Ser2-phosphorylated CTD 19, 41 . Further downstream, transcription terminates, and Pol II is released from genes. When Glc7 is depleted from the nucleus (in the presence of rapamycin), Tyr1 phosphorylation levels remain high downstream of the pA site, thus impairing termination and Pol II release and causing read-through. In addition, we observed an influence of Glc7 depletion on Tyr1 phosphorylation levels near the TSS (Supplementary Fig. 2 ). This may be explained by initiation with polymerases that remained partially phosphorylated on Tyr1 residues, by termination defects at upstream genes 24 or by a possible role of Glc7 in transcription attenuation, which would be consistent with the role of Glc7 in Nrd1-dependent termination of genes encoding small nucleolar RNAs 27 .", "cite_spans": [{"start": 39, "end": 40, "text": "8", "ref_id": "BIBREF7"}, {"start": 664, "end": 665, "text": "8", "ref_id": "BIBREF7"}, {"start": 746, "end": 749, "text": "19,", "ref_id": "BIBREF18"}, {"start": 750, "end": 752, "text": "41", "ref_id": "BIBREF40"}, {"start": 1322, "end": 1324, "text": "24", "ref_id": "BIBREF23"}, {"start": 1502, "end": 1504, "text": "27", "ref_id": "BIBREF26"}], "ref_spans": [{"start": 1146, "end": 1167, "text": "(Supplementary Fig. 2", "ref_id": "FIGREF1"}]}, {"section": "DISCUSSION", "text": "Our results also provide evidence that pA-dependent 3\u2032 pre-mRNA processing is coupled to transcription termination via CPF-triggered Pol II dephosphorylation. A link between the pA site and transcription termination was established over 25 years ago 42 . In the 'antiterminator' model, transcription of the pA site triggers a change in the Pol II machinery that allows for termination 1, 2, 43 . In the 'torpedo' model, CPF-dependent RNA cleavage at the pA site results in a new RNA 5\u2032 end that is recognized by the Rat1-Rai1-Rtt103 exonuclease complex, which degrades nascent RNA and triggers termination 1, 2, 43 . Our data are consistent with a combination of both models; Tyr1 phosphorylation would serve as an antiterminator that is removed at the pA site by Glc7, thus allowing for recruitment of termination factors, including the torpedo nuclease complex that contains Rtt103.", "cite_spans": [{"start": 250, "end": 252, "text": "42", "ref_id": "BIBREF41"}, {"start": 385, "end": 387, "text": "1,", "ref_id": "BIBREF0"}, {"start": 388, "end": 390, "text": "2,", "ref_id": "BIBREF1"}, {"start": 391, "end": 393, "text": "43", "ref_id": "BIBREF42"}, {"start": 606, "end": 608, "text": "1,", "ref_id": "BIBREF0"}, {"start": 609, "end": 611, "text": "2,", "ref_id": "BIBREF1"}, {"start": 612, "end": 614, "text": "43", "ref_id": "BIBREF42"}], "ref_spans": []}, {"section": "METHODS", "text": "Methods and any associated references are available in the online version of the paper.", "cite_spans": [], "ref_spans": []}, {"section": "Accession codes. Raw and normalized ChIP-chip data are available at ArrayExpress under accession number E-MTAB-1528.", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "ONLINE METHODS", "text": "CPF purification and analysis. Primers specific to 40 bp of the C terminus and 3\u2032 UTR of REF2 were used to PCR-amplify the TAP-tag cassette from a modified pFA6a-TAP-kanMX6 vector 44 , where a strepII tag replaces the calmodulinbinding peptide. The PCR product was transformed into S. cerevisiae strain JWY104 (MAT\u03b1 pra1-1 prb1-1 prc1-1 cps1-3 ura3\u22065 leu2-3 his -, obtained from S. Munro, MRC-LMB) via homologous recombination. Cells were grown at 30 \u00b0C in YPD to an OD 600 nm of 5.0-5.5, pelleted at 6,700g, washed once with cold water, pelleted at 3,200g, snap-frozen in liquid N 2 and stored at \u221280 \u00b0C. Cells were mixed 1:1 (v/v) with lysis buffer (100 mM HEPES, pH 7.9, 200 mM KCl, 0.5 mM MgCl 2 , 0.5 mM Mg(OAc) 2 , 10% glycerol, 1.6 \u00b5g/mL DNase I and EDTAfree protease-inhibitor-cocktail tablets (Roche)) and lysed at 35,000 p.s.i. via cell disruption (Constant Systems). Lysate was clarified at 25,000g for 25 min, bound to IgG Sepharose (GE Healthcare) for 1 h and washed with buffer A (20 mM HEPES, pH 7.9, 150 mM KCl, 3 mM DTT, 0.5 mM MgCl 2 , 0.5 mM Mg(OAc) 2 , 0.2 mM PMSF and 0.2 mM benzamidine-HCl). CPF was eluted from the IgG resin with TEV protease at 16 \u00b0C for 1.5 h, and the supernatant was applied to StrepTactin Sepharose (GE Healthcare) for 1 h. StrepTactin resin was washed three times with buffer B (buffer A with 400 mM KCl) and three times with buffer C (buffer A without PMSF and benzamidine) and then eluted with 5 mM desthiobiotin in buffer C. Concentration was determined via absorbance at 280 nm with a calculated extinction coefficient. Bands were excised from Coomassie blue-stained SDS-PAGE gels (Fig. 1a) and identified via tryptic-digest MS.", "cite_spans": [{"start": 180, "end": 182, "text": "44", "ref_id": "BIBREF43"}], "ref_spans": [{"start": 310, "end": 357, "text": "(MAT\u03b1 pra1-1 prb1-1 prc1-1 cps1-3 ura3\u22065 leu2-3", "ref_id": "FIGREF0"}, {"start": 1630, "end": 1639, "text": "(Fig. 1a)", "ref_id": "FIGREF0"}]}, {"section": "ONLINE METHODS", "text": "Dephosphorylation assay. After prephosphorylation of RNA Pol II (ref. 45 ) with MAP kinase (P6080S; NEB) for 60 min at 30 \u00b0C, the kinase was inactivated for 20 min at 65 \u00b0C, and then 234 nM RNA Pol II was incubated with 59 nM CPF at 30 \u00b0C for the indicated periods in buffer C. For Glc7 inhibition, 10 mM EDTA or 200 nM microcystin-LR (Sigma) was added. Samples were dissolved in 3\u00d7 SDS-PAGE buffer (250 mM Tris-HCl, pH 6.8, 100 mM DTT, 7.5% SDS, 50% glycerol and 0.03% bromophenol blue) and boiled at 95 \u00b0C for 90 s. After SDS-PAGE (0.5 \u00b5g of Pol II per lane), samples were blotted onto a polyvinylidene difluoride (PVDF) membrane (Millipore), and the membranes were probed with primary antibodies anti-Tyr1-P (3D12, dilution 1:7) 8 , anti-Ser5-P (3E8, dilution 1:4) 46 and antiSer2-P (3E10, dilution 1:14) 46 , kindly provided by D. Eick (Helmholtz-Zentrum M\u00fcnchen), and anti-Rpb3 (1Y26, cat. no. W0012, NeoClone, dilution 1:1,000; ref. 8) . Secondary antibodies anti-rat IgG HRP (A9037, Sigma, dilution 1:5,000) and anti-mouse IgG HRP (170-6516, Bio-Rad, dilution 1:3,000) were used. Antibody detection was performed with Pierce enhanced chemiluminescence (ECL) western blotting substrate (Thermo Scientific) and Amersham Hyperfilm ECL (GE Healthcare) or LAS-3000 camera (FUJIFILM).", "cite_spans": [{"start": 70, "end": 72, "text": "45", "ref_id": "BIBREF44"}, {"start": 768, "end": 770, "text": "46", "ref_id": "BIBREF45"}, {"start": 808, "end": 810, "text": "46", "ref_id": "BIBREF45"}, {"start": 939, "end": 941, "text": "8)", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "ONLINE METHODS", "text": "For Pol II dephosphorylation with hSsu72, the protein was expressed and purified as described 23 . 3 \u00b5g of Pol II was incubated with 1, 3 or 5 \u00b5g purified recombinant hSsu72 in Ssu72 buffer (50 mM Tris-HCl, pH 8.0, 10 mM MgCl 2 , 20 mM KCl, 2% glycerol, 5 mM DTT, 0.1 mM EDTA and 0.025% Tween 20) for 2 h at 30 \u00b0C. Samples were dissolved in 3\u00d7 SDS-PAGE buffer and processed as described above.", "cite_spans": [{"start": 94, "end": 96, "text": "23", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "ONLINE METHODS", "text": "Original images of blots used in this study can be found in Supplementary  Figure 4 .", "cite_spans": [], "ref_spans": []}, {"section": "ONLINE METHODS", "text": "Yeast strains and methods. Yeast strains Glc7-FRB-KanMX6 and Ssu72-FRBKanMX6 were constructed by amplification of the cassette from vector pFA6a-FRBKanMX6 (P30578, Euroscarf) with suggested primer pairs and transformation of the parental strain HHY168 (Y40343, Euroscarf, MAT\u03b1 ade2-1 trp1-1 can1-100 leu2-3,112 his3-11,15 ura3 GAL psi + tor1-1 fpr1\u00f8NAT RPL13A-2 \u00d7 FKBP12\u00f8TRP1) by homologous recombination. The mCherry-tag on Glc7 in the Ssu72-FRB-KanMX6 strain and the TAP tags on Pcf11 and Rtt103 in the Glc7-FRB-KanMX6 strain were inserted by homologous recombination of PCR products amplified from the pFA6a-mCherry-His3MX6 and pYM-TAP-HIS3MX6 plasmids, respectively.", "cite_spans": [], "ref_spans": []}, {"section": "ONLINE METHODS", "text": "For serial-dilution growth assays, cells were grown in YPD at 30 \u00b0C to stationary phase and resuspended to an OD 600 nm of 1.0 in water. 3 \u00b5L of cells were spotted onto YPD, with or without 1 \u00b5g/mL rapamycin (Cayman Chemical) in ten-fold serial dilutions. Plates were incubated at 30 \u00b0C and inspected daily.", "cite_spans": [], "ref_spans": []}, {"section": "ONLINE METHODS", "text": "For fluorescence microscopy, cells were grown in 1 mL YPD + 40 \u00b5g/mL adenine hemisulfate (Sigma) to OD 600 nm ~0.8 and 0.5 mL of paraformaldehyde solution (10% paraformaldehyde (Sigma), 13 mM NaOH and 150 mM PBS) was added and incubated for 10 min. Cells were washed with PBS once, resuspended in 50 \u00b5L PBS and applied to a poly-l-lysine-coated glass slide (Sigma, Roth).", "cite_spans": [], "ref_spans": []}, {"section": "ONLINE METHODS", "text": "Remaining liquid was removed, and 1.0 ng/\u00b5L DAPI (Sigma) in PBS was applied for 1 min. Fixed cells on glass slides were washed twice with PBS and covered with a cover slip. DAPI and mCherry fluorescence was analyzed under the microscope (Leica DM2500, EL 6000). Camera DFC365FX and Software LAS AF 6000 Modular Systems Version 2.6.0.7266 (Leica) were used for image analysis.", "cite_spans": [], "ref_spans": []}, {"section": "ONLINE METHODS", "text": "Chromatin immunoprecipitation. Experiments were performed in duplicate as described elsewhere 47 with the following modifications. Yeast cultures were grown in 400 mL YPD to OD 600 nm of ~0.65, split and incubated with equal volumes of either rapamycin (1 \u00b5g/mL f.c. in DMSO) or DMSO at 30 \u00b0C for another 60 min before formaldehyde cross-linking. Precooled lysis buffer additionally contained a phosphatase-inhibitor cocktail (PhosSTOP, Roche) when Tyr1-P, Ser2-P or Ser5-P were immunoprecipitated. Cell disruption by bead-beating was performed for 2 h. For immunoprecipitation, 700 \u00b5L of chromatin sample was incubated with 16.5 \u00b5L antibody-coated and prewashed magnetic Protein G beads (Dynabeads Protein G, Life Technologies) at 4 \u00b0C overnight or for 3 h when TAP tags were immunoprecipitated. Beads were prewashed four times with BSA-PBS (5 mg/mL bovine serum albumin in 137 mM NaCl, 2.7 mM KCl, 8.1 mM Na 2 HPO 4 \u20222H 2 O and 1.4 mM KH 2 PO 4 , pH 7.4, with protease inhibitors), coated with the respective antibody for 30 min at 4 \u00b0C (100 \u00b5L anti-Tyr1-P (3D12), 25 \u00b5L anti-Ser2-P or 5 \u00b5L anti-Rpb3 (1Y26, cat. no. W0012, NeoClone) or 13.6 \u00b5g rabbit IgG (Sigma) for TAP tags per chromatin sample) and washed again three times. After immunoprecipitation, beads were washed five times with wash buffer (100 mM Tris-HCl, pH 7.5, 500 mM LiCl, 1% NP-40, 1% sodium deoxycholate) and once with TE buffer (10 mM Tris-HCl, pH 7.4, 1 mM EDTA). Immunoprecipitated chromatin was eluted for 5 min at 95 \u00b0C with ChIP elution buffer (0.1 M NaHCO 3, 1% SDS). Eluted chromatin was digested with Proteinase K (Sigma) at 37 \u00b0C for 2 h, and the reversal of cross-links was performed at 65 \u00b0C overnight. DNA was purified with the QIAquick PCR Purification Kit (Qiagen) according to the manufacturer's instructions. DNA amplification and labeling as well as microarray handling were performed as described 34 .", "cite_spans": [{"start": 94, "end": 96, "text": "47", "ref_id": "BIBREF46"}, {"start": 1888, "end": 1890, "text": "34", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "ONLINE METHODS", "text": "ChIP-chip occupancy profiling. ChIP-chip data analysis was performed as described 34 with some modifications. Briefly, first we performed quantile normalization between replicate measurements and averaged the signal for each probe over the replicate intensities for the Glc7-FRB strain. For Supplementary  Figure 3 , one replicate was analyzed. ChIP enrichments were obtained by division of ChIP intensities by the corresponding input intensities. The normalized ChIP signal at each nucleotide was calculated as the median signal for all probes overlapping this position. Profiles were smoothed by running median smoothing with a window half size of 75 bp. To average profiles over genes, yeast genes were filtered: of 4,366 yeast genes with annotated TSS and pA sites 48 , we excluded genes shorter than 800 bp or with a neighboring gene within 400 bp downstream of the pA site. The resulting 619 genes were aligned at their pA sites and the ChIP signals averaged in a region from 400 bp upstream to 400 bp downstream. Averaging was performed by calculation of the median over genes at each genomic position. Because CPF acts around the pA site, we were especially interested in whether the profile changed around the pA site relative to the region upstream of the pA site. To better visualize these relative differences, we further normalized the data to have approximately equal occupancy levels upstream (around \u2212400 bp) of the pA site for the profiles with and without rapamycin treatment. Corresponding non-normalized data averaged over the entire gene length (250 bp upstream of TSS to 400 bp downstream of pA site) are shown in Supplementary Figure 2 .", "cite_spans": [{"start": 82, "end": 84, "text": "34", "ref_id": "BIBREF33"}, {"start": 769, "end": 771, "text": "48", "ref_id": "BIBREF47"}], "ref_spans": [{"start": 1636, "end": 1658, "text": "Supplementary Figure 2", "ref_id": "FIGREF1"}]}, {"section": "ONLINE METHODS", "text": "Changes in termination-factor occupancy were visualized over the entire gene length. 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Identities of bands confirmed by MS are labeled. (b) In vitro dephosphorylation assay measuring CPF activity toward phosphorylated Pol II CTD, as shown by western blotting with antibodies against Pol II subunit Rpb3 and Tyr1-, Ser2-or Ser5-phosphorylated (-P) CTD residues (1Y26, 3D12, 3E10 and 3E8 antibodies, respectively). For lanes 6-13, 10 mM EDTA or 200 nM microcystin were included in the reactions. Uncropped versions of blots can be found in Supplementary Figure 4a.", "type": "figure"}, "FIGREF1": {"text": "Figure 2 Glc7 is required for dephosphorylation of Tyr1 but not Ser2 in vivo. (a) Metagene analysis for genome-wide ChIP occupancy of Tyr1-phosphorylated Pol II around polyadenylation (pA) sites (dashed black line) in the Glc7 anchor-away strain treated with rapamycin to deplete Glc7 from the nucleus (+rapa) or untreated (\u2212rapa). Averaged ChIP-chip signals are plotted as the median signal (log 2 (immunoprecipitation (IP)/input)) at each genomic position over a set of 619 representative genes (Online Methods) and are normalized to have approximately equal occupancy levels upstream (around \u2212400 bp) of the pA site. The profiles are shown from 400 nucleotides upstream to 400 nucleotides downstream of the pA site. Non-normalized data averaged over the entire gene length are shown in Supplementary Figure 2. Experiments were performed in biological duplicates. (b) Profiles of Tyr1-P levels normalized to total Pol II (Fig. 4a) on selected genes, smoothed by a 150-nt-window running median, are shown in purple. Below, gray boxes indicate transcripts on the Watson (top) and Crick (bottom) strands. Chr, chromosome. (c,d) ChIP-chip occupancy profiles of Tyr1-phosphorylated (c) and Ser2-phosphorylated (d) Pol II over 619 genes aligned at the pA site (dashed line) and normalized against the corresponding Rpb3 profile (Fig. 4a) without and with rapamycin. Experiments were performed in biological duplicates.", "type": "figure"}, "FIGREF3": {"text": "Figure 3 Ssu72 does not change Tyr1 phosphorylation levels in vitro and in vivo. (a) In vitro dephosphorylation assay of Pol II CTD with recombinant hSsu72, monitored by western blotting with antibodies against Pol II subunit Rpb3 and Tyr1-, Ser2-and Ser5-phosphorylated (-P) CTD residues (1Y26, 3D12, 3E10 and 3E8 antibodies, respectively). Uncropped versions of blots can be found in Supplementary Figure 4b. (b) ChIP-chip occupancy profiling of Tyr1-phosphorylated Pol II over 619 genes aligned at the pA site (dashed line) and normalized against the corresponding Rpb3 profile without and with rapamycin treatment in a Ssu72 anchor-away strain. Profiles in a region from 400 nucleotides upstream to 400 nucleotides downstream of the pA site are shown. This experiment was performed in biological duplicates.", "type": "figure"}}}
{"paper_id": "17788931", "_pdf_hash": "ec3aee94649ee2adffe54dfd3c3e886ab950491c", "abstract": [{"section": "Abstract", "text": "Abstract. The paper considers semi-global stereo matching in the context of vision-based driver assistance systems. The need for real-time performance in this field requires a design change of the originally proposed method to run on current hardware. This paper proposes such a new design; the novel strategy first generates a disparity map from halfresolution input images. The result is then used as prior to restrict the disparity search space for full-resolution computation. This approach is compared to an SGM strategy as employed currently in a state-of-theart real-time FPGA solution. Furthermore, trinocular stereo evaluation is performed on ten real-world traffic sequences with a total of 4,000 trinocular frames. An extension to the original evaluation methodology is proposed to resolve ambiguities and to incorporate disparity density in a statistically meaningful way. Evaluation results indicate that the novel SGM method is up to 40% faster when compared to the previous strategy. It returns denser disparity maps, and is also more accurate on evaluated traffic scenes.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Stereo correspondence analysis by semi-global stereo matching (SGM), as proposed by Heiko Hirschm\u00fcller [7] , is a popular choice for real-time applications that require dense disparity maps at high frame rates. For example, vision-based driver assistance systems (DAS) favour the SGM strategy; see Rabe et al. [11] . A major constraint for real-time SGM implementation is the available memory throughput in current hardware. Because SGM integrates along multiple 1-dimensional (1D) energy paths, a large memory block needs to be updated in off-chip memory.", "cite_spans": [{"start": 103, "end": 106, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 310, "end": 314, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Introduction", "text": "Current literature on real-time SGM proposes to alter the design to the original method for ensuring high frame rates for image resolutions equivalent to the VGA norm (i.e. 640\u00d7480). For example, Hirschm\u00fcller [7] recommends to integrate at least along eight directions to obtain satisfactory results. But Nedevschi et al. [5] propose to integrate only along horizontal and vertical directions, leaving out diagonal energy paths. They justify their approach with the argument that objects recorded from a moving vehicle are usually aligned along the main axis, such that diagonal directions do not contribute as much to the final solution. But by omitting 50% of the accumulation procedure, the requirements on data processing are eased and real-time performance is achieved.", "cite_spans": [{"start": 209, "end": 212, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 322, "end": 325, "text": "[5]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Introduction", "text": "A research group at Daimler A.G. uses another design concept for their FPGA implementation that was proposed by Gehrig et al. [4] . They keep the recommended eight accumulation paths, but calculate a disparity image on a downscaled image pair first. The result is then scaled-up to full resolution and serves as a disparity prior. In a consecutive step they calculate a disparity map for a specified region-of-interest with SGM on full resolution images, but using only half of the disparity search space. They generate the final result by replacing disparities in the prior image with disparities from the full resolution map, if the prior suggests that a disparity lies inside the reduced search space. Otherwise the prior disparity is taken as the final result. This is based on the argument that sufficient disparity accuracy for close objects can be obtained when computing half-resolution disparity images only. But, as the re-projection error increases quadratically when disparities get smaller and boundaries of objects further away may become vague due to downscaling, it is required to calculate disparities at full resolution to minimize distance uncertainties for those objects.", "cite_spans": [{"start": 126, "end": 129, "text": "[4]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Introduction", "text": "The SGM design as proposed in this paper follows the Daimler approach and calculates a disparity prior on half-resolution images. However, in contrast we use the prior to actively determine the search space for the full-resolution SGM, instead of having an indication how to merge independently calculated disparity maps. Our approach therefore follows the standard coarse-to-fine concept, where results from lower-resolution images are used to initialize the same algorithm operating on the next higher resolution level. Such coarse-to-fine approaches are nowadays standard in variational motion estimation algorithms to achieve faster convergence; see, for example, the work by Brox et al. [1] or Zach et al. [18] . To the best of our knowledge, no coarse-to-fine concept as described in the previous paragraph has been proposed so far in combination with SGM, and therefore has not been evaluated either. For the evaluation we propose an extension to an existing methodology [9] that can be used for stereo performance evaluation in the absence of ground truth and employ it on a reasonably large database of real-world traffic sequences. Of course, coarse-to-fine strategies are already employed to improve the performance of stereo matching algorithms in general. For example, a recent publication by Sizintsev and Wildes [14] employs a coarse-to-fine strategy to a block-matching algorithm. Also, in the original SGM design by Hirschm\u00fcller [7] , a coarse-to-fine strategy is used, but only to support the mutual information (MI) cost function. The author recommends to calculate the disparities with SGM at each pyramid level from scratch. So, the prior information is just used to improve the quality of the MI cost function and not to improve the run-time performance of SGM. This defines the place where this paper is positioned, namely somewhere between the original SGM [7] and the SGM design proposed by Gehrig et al. [4] . We use design considerations from the latter work to select a method to be compared with our novel strategy, because of the shared goal to improve the run-time performance of SGM while maintaining stereo accuracy on real-world traffic scenes.", "cite_spans": [{"start": 692, "end": 695, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 711, "end": 715, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 978, "end": 981, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 1327, "end": 1331, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 1446, "end": 1449, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 1881, "end": 1884, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 1930, "end": 1933, "text": "[4]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Introduction", "text": "The rest of this paper is organized as follows. In Section 2, relevant details of the SGM algorithm are recalled and parameter settings of the used implementation are given. We present the design consideration as proposed by Gehrig et al., followed by our proposed coarse-to-fine approach. We also provide a discussion about run-time performance. The trinocular evaluation concept as proposed by Morales and Klette [9] is outlined in Section 3; we propose alterations and further extensions to the original method. In Section 4 we present ten real-world sequences, each of 400 trinocular frames, and outline the methodology of our experiments using trinocular evaluation. The results of this study are discussed in detail in Section 5. The paper concludes with a summary in Section 6.", "cite_spans": [{"start": 415, "end": 418, "text": "[9]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Semi-Global Matching", "text": "We first recall the SGM algorithm and explain our alterations to the original configuration as reported in [7] . We then compare two SGM design consideration of this reference implementation. The first, called SGM G , is our implementation following the design concept as proposed by Gehrig et al. [4] , and this serves as the method of comparison. The second implements our coarse-to-fine approach. We discuss the run-time and disparity analysis performance of both methods.", "cite_spans": [{"start": 107, "end": 110, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 298, "end": 301, "text": "[4]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Semi-Global Matching", "text": "Cost Accumulation and Cost Function. We introduce the notation for defining the cost accumulation procedure. For a cost accumulation path L a with direction a, processed between image border and pixel p, we consider the segment p 0 , p 1 , . . . , p n of that path, with p 0 on the image border, and p n = p. The cost at pixel position p for a disparity d \u2208 {0, . . . , D} \u2282 N on the path L a is recursively defined as follows,", "cite_spans": [], "ref_spans": []}, {"section": "Semi-Global Matching", "text": "with", "cite_spans": [], "ref_spans": []}, {"section": "Semi-Global Matching", "text": "where C(p, d) is the similarity cost of pixel p for disparity d, and c 1 and c 2 are the penalties of the smoothness term. The second penalty c 2 is individually adjusted at each pixel p i to c 2 (p i ). The magnitude of the forward difference in direction a scales the penalty for each p i with", "cite_spans": [], "ref_spans": []}, {"section": "Semi-Global Matching", "text": "where I(\u00b7) refers to the intensity at a pixel. For disparities", "cite_spans": [], "ref_spans": []}, {"section": "Semi-Global Matching", "text": "The standard SGM algorithm uses eight paths for accumulation (up, down, left, right, and the four in-between angles). To enforce uniqueness, two disparity maps are calculated to perform a left-right consistency check. A disparity passes this test if corresponding disparities do not deviate by more than one disparity level. To identify an occlusion or mismatch, a unique invalid label is assigned to pixels whose disparities failed this test. Disparities are calculated with sub-pixel accuracy using the equiangular interpolation method proposed by Shimizu and Okutomi [13] . The penalties are set to c 1 = 30 and c 2 = 150 for an intensity domain of [0, 255] . The input images are smoothed with a small 3 \u00d7 3 mean kernel. As similarity cost, we employ the census cost function which is based on the census transform. Several studies [8, 6] found that this function is very 'descriptive' and robust, even under strong illumination variations, which is crucial for real-world applications.", "cite_spans": [{"start": 570, "end": 574, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 836, "end": 839, "text": "[8,", "ref_id": "BIBREF7"}, {"start": 840, "end": 842, "text": "6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Semi-Global Matching", "text": "The census transform [16] assigns to each pixel in the left and right image a signature vector, which is stored as a bit string (i.e. as an integer). This transformation is performed once prior to cost calculation, and signatures are stored in an integer matrix of the dimension of the image. The signature sequence is generated as follows:", "cite_spans": [{"start": 21, "end": 25, "text": "[16]", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "Semi-Global Matching", "text": "where \u03a8 (\u00b7) returns 1 if true, and 0 otherwise. N denotes a neighbourhood (e.g. 8-neighbourhood) centred at the origin.", "cite_spans": [], "ref_spans": []}, {"section": "Semi-Global Matching", "text": "The census cost is the Hamming distance of two signature vectors and can be calculated very efficiently [15] . In fact, the cost of calculating the Hamming distance is proportional to the actual Hamming distance and not to the length of the signature string. This is useful in GPU implementations: calculating the cost from scratch is here cheaper than accessing the global memory [3] .", "cite_spans": [{"start": 104, "end": 108, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 381, "end": 384, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Semi-Global Matching", "text": "Design Considerations. First we introduce some terminology. A standard SGM implementation was described in the previous subsection. We now describe the design consideration reported by Gehrig et al. [4] , denoted by SGM G . Our new approach is denoted by SGM F , where subscript F stands for \"fast\".", "cite_spans": [{"start": 199, "end": 202, "text": "[4]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Semi-Global Matching", "text": "Both programs, SGM G and SGM F , calculate a dense disparity map applying standard SGM on half-resolution input images. The images were scaled down using a 5 \u00d7 5 Gauss kernel with \u03c3 = 1. The half-resolution disparity maps are scaled up; in-between pixels are linearly interpolated if both neighbours have a valid disparity assigned to them. When identifying (by the left-right consistency check) a case of occlusion or mismatch, we assign an invalid label to the corresponding 3 \u00d7 3 neighbourhood. This calculated half-resolution disparity map P serves in both methods as prior for subsequent calculations.", "cite_spans": [], "ref_spans": []}, {"section": "Semi-Global Matching", "text": "In case of SGM G , a second disparity map F is calculated on full-resolution input images. However, the maximum disparity D is reduced to D/2 to reduce the memory to be processed. The final disparity map R is created as follows", "cite_spans": [], "ref_spans": []}, {"section": "Semi-Global Matching", "text": "In case of SGM F , the prior P is used to define the search space for every individual pixel. For a valid disparity \u03b4 in P, we process Equation (1) ", "cite_spans": [], "ref_spans": []}, {"section": "Semi-Global Matching", "text": "In other words we restrict the disparity search space to nine pixels around the prior. In case of disparities close to 0 or D, we do not reduce the search space but shift it accordingly. In case of invalid pixels we simply assign the default search space which would be d \u2208 {0, . . . , D} \u2282 N, to allow for all possible disparities.", "cite_spans": [], "ref_spans": []}, {"section": "Semi-Global Matching", "text": "Run-Time Performance. We analyse the approximate run-time performance on images with resolution W\u00d7H. We assume that the maximum possible disparity is D. This means that a memory block of W\u00d7H\u00d7D has to be processed, which resides in off-chip memory. Because one individual integration step consists of a constant number of operations [see Equation (1) ], the run-time performance can be related to the size of the memory that needs to be processed. The advantage of this model is its independence from any hardware consideration or implementation.", "cite_spans": [{"start": 346, "end": 349, "text": "(1)", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Semi-Global Matching", "text": "The memory block used in standard SGM serves as reference to define a coefficient X that indicates the ratio of memory needed in SGM X . Without alterations, we have S = 1 in standard SGM.", "cite_spans": [], "ref_spans": []}, {"section": "Semi-Global Matching", "text": "In case of SGM G , we have to process a memory block of size W/2\u00d7H/2\u00d7D/2 for the half resolution image, and W\u00d7H\u00d7D/2 for the full resolution image. Adding those two quantities results in ", "cite_spans": [], "ref_spans": []}, {"section": "Semi-Global Matching", "text": "In case of SGM F , the individual run-time depends on the density of the halfresolution disparity map, because the whole search space is considered at occlusions in the full-resolution run. We denote the density of this map by \u03d5. The total memory to be processed equals", "cite_spans": [], "ref_spans": []}, {"section": "Semi-Global Matching", "text": "A few algebraic operations lead to", "cite_spans": [], "ref_spans": []}, {"section": "Semi-Global Matching", "text": "The gain compared to SGM G equals", "cite_spans": [], "ref_spans": []}, {"section": "Semi-Global Matching", "text": "We see that in case of the new design, the run-time performance can actually be worse compared to the standard SGM in cases where the prior disparity map is very sparse. However, in practice this is almost never the case; if it occurs then full-resolution SGM is well justified (i.e. the stereo data is 'challenging'). Consider on the other hand a perfectly dense prior map (i.e. \u03d5 = 1). To obtain the same run time as with SGM G , the minimum disparity range has to be at least D = 18. As \u03d5 = 1 is also unlikely, the performance advantage only occurs for larger values of D. For example, a common value such as D = 128 defines a possible run-time gain of up to 68%. We measure performance advantages in our experiments by applying Equation (9) . Results below show an expected performance gain of about 40%.", "cite_spans": [{"start": 741, "end": 744, "text": "(9)", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Trinocular Stereo Evaluation", "text": "A predicted-error technique was first employed by Morales and Klette [9] for evaluating stereo analysis on long real-world stereo sequences. It requires at least stereo triples of the same scene, recorded at the same time instance by three calibrated cameras. Two of the three images (i.e reference and match image) are used to calculate a disparity map by the stereo matching algorithm of choice. Each pixel of the reference image is then projected into the position in which it would be located in the third (i.e. control) image C. This virtual image V is then compared to the control image C by calculating the normalized cross-correlation (NCC) index as follows:", "cite_spans": [{"start": 69, "end": 72, "text": "[9]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Trinocular Stereo Evaluation", "text": "where \u03bc V and \u03bc C denote the means, and \u03c3 V and \u03c3 C the standard deviations of the control and virtual images, respectively. The domain \u03a9 contains only nonoccluded pixels (i.e. pixels which are successfully mapped from the reference image to the virtual image domain).", "cite_spans": [], "ref_spans": []}, {"section": "Trinocular Stereo Evaluation", "text": "Generating the Virtual Image. In the original work by Morales and Klette [9] it is proposed to use a forward mapping to generate the virtual image. In other words, intensities of the reference image are mapped to positions in the control image and assigned to the closest pixel position. The problem here is that during the mapping process more than one intensity value may be mapped to the same pixel location. Discarding any of these mappings would cause a bias in the evaluation, as the final index is affected by removing potentially wrong or correct disparities. To avoid this bias we do not calculate a virtual image but rather calculate a control intensity by means of bilinear lookup from the calculated position in the control image that is compared with the intensity of the reference image.", "cite_spans": [{"start": 73, "end": 76, "text": "[9]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Trinocular Stereo Evaluation", "text": "To make this process as easy as possible and to avoid any bias from an otherwise required de-rectification step, we recorded with a horizontally aligned trinocular camera system and rectified the images with respect to the left-most camera. This way we obtain three rectified images where corresponding epipolar lines in all three images are running along the same image row. Thus, a pixel position in the control image has the same y-coordinate as the corresponding pixel in the reference image. The x-coordinate is then calculated as the current location in the reference image plus an offset, which is the product of the current disparity and the ratio of the baselines from the reference image to the control and to the match image. Figure 2 shows the setup in our experiments. The stereo camera has a 30 cm baseline and a disparity map is calculated with the centre image as reference. Then the virtual image is generated and compared with the control image. The scale factor to multiply the disparities with is here 50 30 . Remember that in practice we warp the control image to the image plane of the reference camera as discussed before, but we will stick with the previous terminology as it makes it easier when proposing the following alteration to the original index.", "cite_spans": [], "ref_spans": [{"start": 737, "end": 745, "text": "Figure 2", "ref_id": "FIGREF2"}]}, {"section": "Trinocular Stereo Evaluation", "text": "Comparing Two Stereo Algorithms. The basic idea of trinocular stereo evaluation is, of course, to have a quality measure to compare the performance of different stereo algorithms in the absence of ground truth. Following the original approach, the difference of the NCC index at each frame for each stereo algorithm is evaluated. In case of only two stereo algorithms, we introduce a measure \u0394NCC that calculates the signed difference of two indices. This makes it easy to compare very similar results as the sign already gives an indication which algorithm performs better.", "cite_spans": [], "ref_spans": []}, {"section": "Trinocular Stereo Evaluation", "text": "However, there is a bias in this evaluation. The density of a disparity map is not reflected. Therefore, a sparse stereo algorithm that calculates disparities only at pixels that respond to a robust feature detector would very likely perform much better in this index than a dense algorithm which also assigns disparities in case of weak confidence. The question is how to incorporate the density in the index in a meaningful way. For that, we first introduce some further notation.", "cite_spans": [], "ref_spans": []}, {"section": "Trinocular Stereo Evaluation", "text": "We think of images as being random variables X and Y that take intensity values as events. The NCC value can be interpreted as the correlation coefficient", "cite_spans": [], "ref_spans": []}, {"section": "Trinocular Stereo Evaluation", "text": "So the index reflects a mean of some distribution, and it is possible to calculate the standard deviation of it, referred to by Cov \u03c3 (X, Y ). We consider two disparity images D 1 and D 2 that generate two virtual images V 1 and V 2 , respectively, both to be compared with a control image C. For the evaluation we consider all pixels of the domain \u03a9 1 \u222a \u03a9 2 . The total number of this domain is n = |\u03a9 1 \u222a \u03a9 2 |. We determine for each disparity image the number of invalid pixels as", "cite_spans": [], "ref_spans": []}, {"section": "Trinocular Stereo Evaluation", "text": "We propose for l = {1, 2} the following index for the comparison of two stereo algorithms:", "cite_spans": [], "ref_spans": []}, {"section": "Trinocular Stereo Evaluation", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "Trinocular Stereo Evaluation", "text": "We omit the arguments (V i , C) in N CC \u03c3 , N CC, and Cov \u03c3 for better readability. The index works as follows. Consider \u03a9 1 = \u03a9 2 , which results in k 1 = k 2 = 0. In this case this index will be identical to the original NCC index as proposed in Equation (10) . Now consider the symmetric case that k 1 > k 2 and Cov \u03c3 (V 1 , C) = Cov \u03c3 (V 2 , C) = \u03c5. Again, the index will be identical, because we only add terms that correspond to the pre-calculated mean. However, since we can assume that \u03c5 > 0, we add terms such that the final index decreases. If the first term is identical for both images, the index that corresponds to the denser disparity map increases. If, on the other hand, \u03c5 1 > \u03c5 2 , k 1 = k 2 and the first term is again identical in both cases, then the index that corresponds to the smaller standard deviation wins. This is reasonable, as we can assume that a smaller standard deviation refers to a 'more consistent' disparity result.", "cite_spans": [{"start": 257, "end": 261, "text": "(10)", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Trinocular Stereo Evaluation", "text": "To summarize, with Equation (12) we proposed an alteration to the original evaluation index. It slightly adjusts the original index such that a higher disparity density has a positive impact on the index. We propose to use the standard deviation of the covariance for the index adjustment. This is useful because it relates to the underlying data and therefore gives also an additional quality measure (see evaluation below). But, the main motivation is that it can annihilate the benefit of a higher disparity density in case that ''additional' disparity values, which do not positively contribute to the index, increase the standard deviation and therefore have a negative affect on the final result. Thus, we regulate the NCC adjustment by two parameters, which can have a compensating or amplifying effect.", "cite_spans": [], "ref_spans": []}, {"section": "Evaluation Methodology and Datasets", "text": "We evaluate on ten trinocular sequences that show urban and rural environments. Each sequence consists of 400 frames. Figure 3 shows some frame samples. We refer to them by numbers only as we do not discuss them in the context of the scene they are showing, but the sample frames may help to 'read' Table 1 . We evaluated SGM F and SGM G on each frame of all sequences using the trinocular evaluation as proposed in Section 3. We calculated the signed difference of several values except the performance where values relating to SGM F constitute the first summand. This list describes the results provided in Tab. 1:", "cite_spans": [], "ref_spans": [{"start": 118, "end": 126, "text": "Figure 3", "ref_id": "FIGREF3"}, {"start": 299, "end": 306, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Evaluation Methodology and Datasets", "text": "-\u0394NCC: difference of the original index.", "cite_spans": [], "ref_spans": []}, {"section": "Evaluation Methodology and Datasets", "text": "-\u0394NCC \u03c3 : difference of the adjusted index.", "cite_spans": [], "ref_spans": []}, {"section": "Evaluation Methodology and Datasets", "text": "-\u0394\u03c3: difference of calculated Cov \u03c3 -\u0394density: difference of the disparity density over the whole image. -perf. gain: the run-time gain of SGM F compared to SGM G . The left entry for each item is the mean over the whole image sequence; the right entry is the standard deviation. At the bottom of the table, mean standard deviation and median are given for each item. A positive value favours SGM F except for \u0394\u03c3 where a negative \u0394 \u03c3 defines 'better'. Highlighted entries show relatively better performances for SGM G (red / sequence 6), and for SGM F (green / sequence 10). For a more detailed illustration of one sequence, see frame-by-frame results for Sequence 8 in Fig. 4 ; values for this sequence are close to medians and thus 'kind of representative' Disparities of these images increase to up to 84, but we decided to run the algorithms on D = 128, for two reasons: First, this disparity limit is the current standard for real-time DAS stereo systems; second, the fact that this way most of the disparity map is taken from the full resolution disparity image in case of SGM G is considered beneficial according to Gehrig et al. (page 136, [4] ) who state that \"Ideally, SGM would be computed everywhere at full resolution\".", "cite_spans": [{"start": 1148, "end": 1151, "text": "[4]", "ref_id": "BIBREF3"}], "ref_spans": [{"start": 670, "end": 676, "text": "Fig. 4", "ref_id": "FIGREF4"}]}, {"section": "Results", "text": "Looking at performance indices \u0394NCC and \u0394NCC \u03c3 at Tab. 1 a clear tendency in favour for SGM F is obvious. All index differences are positive with one exception in Sequence 6. However, since these values refer to percentage point differences, the performance quality of both methods is very similar. But this result comes with a mean run-time improvement of 40% over all sequences for SGM F . Along with that the new design return 5% to 6% denser disparity maps than SGM G .", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "To summarize, our compressed results over 4000 real-world traffic stereo frames suggest that we get slightly denser disparity maps and a positive tendency in stereo performance with a run time improvement of 40% over the method of comparison, which already has a run-time advantage of 37.5% to the standard SGM design. As we already mentioned, we defined the disparity range D = 128 but find actual disparities only up to 84. Therefore, the major part of the disparity map generated by SGM G consists of the full resolution SGM. Thus, qualitative conclusion most likely hold against the standard SGM design. Different configurations and designs will be evaluated in the future, the scope of this paper only allows to introduce the new design and compare it with one design that follows a similar approach and is state-of-the-art.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "We can also use the table to check the new evaluation index for consistency. See Sequence 6, where SGM G performs best w.r.t. the new index. In this sequence we also have a low density advantage for SGM F which is well below the mean and we have a very high Cov \u03c3 . These three values are consistent with our motivation for this index. Also, Sequence 10 where SGM F performs best has a very low Cov \u03c3 and a high disparity density compared to SGM G . This also supports our argument.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "For further analysis and to give an example, we picked sequence 8. for frameby-frame analysis. We choose this sequence as it is close to the median performance (compare with final row of Tab. 1). The graphs for the first four evaluation differences of Tab. 1 can be seen in Fig. 1 .", "cite_spans": [], "ref_spans": [{"start": 274, "end": 280, "text": "Fig. 1", "ref_id": "FIGREF0"}]}, {"section": "Results", "text": "Consider the part from Frame 1-150. The old and the new index follow the same pattern, but the new index pushes SGM F on a higher index level. Looking at \u0394\u03c3 and \u0394density we get the explanation. We have a much higher density and lower Cov \u03c3 than SGM G . Here both factors work in combination. Between Frames 150 and 250 the original index stays constant and even increases a little. The new index however, slightly decreases. Looking again to the right side of the figure we see that also the density decreases and the Cov \u03c3 increases. Again, this effect is visible in the new index. Between Frame 250 and 350 we have a positive impact for the method of comparison. The \u0394\u03c3 is here in favour for SGM G . There is a slightly higher disparity density for SGM F that has a small compensation affect. However, this again shows, that the new index works as intended and that results are conform with the expectations. We could not find an example in our results that has a contradicting tendency.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "We proposed a new design for SGM that employs a coarse-to-fine strategy to reduce computational complexity. We compared this new method to a design that follows a similar approach but with a very different implementation. The common goal of both designs is to reduce the run-time of the algorithm while keeping the quality of results of the original algorithm. We evaluated both designs on 4,000 real-world traffic sequences. For the evaluation we extended an existing trinocular evaluation approach. Our experiments support that the proposed design results in a slightly higher density, has an overall tendency to more accurate results and also has an average run-time advantage of 40% over the other method. Furthermore, we evaluated a novel evaluation index and found that results are conform with out motivation for defining this index. 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Disparity results from the new SGM design (left) and the standard SGM design (right). The new design is 60% faster and is much denser especially inside the challenging road area.", "type": "figure"}, "FIGREF1": {"text": "We can now measure the performance gain of SGM G compared to standard SGM, taking into", "type": "figure"}, "FIGREF2": {"text": "Fig. 2. Setup for the trinocular stereo experiment in this paper, showing one example frame from the experimental database", "type": "figure"}, "FIGREF3": {"text": "Fig. 3. From left to right: Example frames of sequence, 3, 5, 9, 10, 6", "type": "figure"}, "FIGREF4": {"text": "Fig. 4. Results of Sequence 8. Top: \u0394NCC and \u0394\u03c3. Bottom: \u0394NCC\u03c3 and \u0394density.", "type": "figure"}, "TABREF0": {"text": "Table of evaluation results", "type": "table"}}}
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{"paper_id": "17789530", "_pdf_hash": "7fe221dccdb1bafd0ffe4a90a64cf590d0318a81", "abstract": [{"section": "Abstract", "text": "Abstract. We proposed a pivot algorithm using the affine-scaling technique. It produces a sequence of interior points as well as a sequence of vertices, until reaching an optimal vertex. We report preliminary but favorable computational results obtained with a dense implementation of it on a set of standard Netlib test problems.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "where c \u2208 R n , b \u2208 R m , A \u2208 R m\u00d7n (m < n). Assume that rank(A) = m and c \u2208 range(A T ). So the trivial case is eliminated where the objective value c T x is constant over the feasible region of (1.1). The assumption rank(A) = m is not substantial either to the proposed algorithm,and will be dropped later.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "As a LP problem solver, the simplex algorithm might be one of the most famous and widely used mathematical tools in the world. Its philosophy is to move on the underlying polyhedron, from a vertex to adjacent vertex, along edges until an optimal vertex is reached. Since it was founded by G.B.Dantzig [8] in 1947, the simplex algorithm has been very successful in practice, and occupied a dominate position in this area, despite its infiniteness in case of degeneracy. However, it turned out that the simplex algorithm may require an exponential amount of time to solve LP problems in the worst-case [29] .", "cite_spans": [{"start": 301, "end": 304, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 600, "end": 604, "text": "[29]", "ref_id": "BIBREF28"}], "ref_spans": []}, {"section": "", "text": "Basically, there have been two trends of developments of the simplex algorithm. On one side, various pivot rules have been suggested (e.g., [5, 6, 10, 15, 18, 21, 24, 25, 31] . On the other side, much effort has also been made to reduce computational work involved in each iteration (e.g., [4, 9, 14, 17] .", "cite_spans": [{"start": 140, "end": 143, "text": "[5,", "ref_id": "BIBREF4"}, {"start": 144, "end": 146, "text": "6,", "ref_id": "BIBREF5"}, {"start": 147, "end": 150, "text": "10,", "ref_id": "BIBREF9"}, {"start": 151, "end": 154, "text": "15,", "ref_id": "BIBREF14"}, {"start": 155, "end": 158, "text": "18,", "ref_id": "BIBREF17"}, {"start": 159, "end": 162, "text": "21,", "ref_id": "BIBREF20"}, {"start": 163, "end": 166, "text": "24,", "ref_id": "BIBREF23"}, {"start": 167, "end": 170, "text": "25,", "ref_id": "BIBREF24"}, {"start": 171, "end": 174, "text": "31]", "ref_id": "BIBREF30"}, {"start": 290, "end": 293, "text": "[4,", "ref_id": "BIBREF3"}, {"start": 294, "end": 296, "text": "9,", "ref_id": "BIBREF8"}, {"start": 297, "end": 300, "text": "14,", "ref_id": "BIBREF13"}, {"start": 301, "end": 304, "text": "17]", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "", "text": "Khachiyan [28] proposed the first polynomial-time algorithm for LP, the ellipsoid algorithm. Unfortunately, it soon became clear that in spite of its theoretical superiority, this algorithm was not a competitor of the simplex algorithm in practice. Later, Karmarkar [26] proposed his algorithm that has better polynomial-time complexity than the ellipsoid algorithm, and initiates an upsurge of interior point algorithms. Approaching an optimal solution by traveling across the interior of the polyhedron, some implementations of them are very efficient for solving large sparse LP problems. However, interior point algorithms are not suitable for cases when a vertex solution is required.", "cite_spans": [{"start": 10, "end": 14, "text": "[28]", "ref_id": "BIBREF27"}, {"start": 266, "end": 270, "text": "[26]", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "", "text": "Algorithms proposed by Pan [32] [33] [34] [35] can be viewed as variants of the simplex algorithm. Nevertheless, some of the proposed pivot rules lead to non-monotone changes of the objective value in solution process, and produce iterates that are no longer necessarily vertices. Such algorithms might better be classified into the category of pivot algorithms, like criss-cross algorithms by Zionts [52] and Terlaky et al [44, 50] . Recent algorithms [36] [37] [38] [39] [40] allow a deficient basis, characterized as a submatrix from A that has fewer columns than rows and whose range space includes b. An interesting relation is found between one of them [36, 41] and the LPDASA algorithm [22, 23] -both involve a common least squares subproblem, which is unconstrained for the former while bound-constrained for the latter.", "cite_spans": [{"start": 27, "end": 31, "text": "[32]", "ref_id": "BIBREF31"}, {"start": 32, "end": 36, "text": "[33]", "ref_id": "BIBREF32"}, {"start": 37, "end": 41, "text": "[34]", "ref_id": "BIBREF33"}, {"start": 42, "end": 46, "text": "[35]", "ref_id": "BIBREF34"}, {"start": 401, "end": 405, "text": "[52]", "ref_id": "BIBREF51"}, {"start": 424, "end": 428, "text": "[44,", "ref_id": "BIBREF43"}, {"start": 429, "end": 432, "text": "50]", "ref_id": "BIBREF49"}, {"start": 453, "end": 457, "text": "[36]", "ref_id": "BIBREF35"}, {"start": 458, "end": 462, "text": "[37]", "ref_id": "BIBREF36"}, {"start": 463, "end": 467, "text": "[38]", "ref_id": "BIBREF37"}, {"start": 468, "end": 472, "text": "[39]", "ref_id": "BIBREF38"}, {"start": 473, "end": 477, "text": "[40]", "ref_id": "BIBREF39"}, {"start": 659, "end": 663, "text": "[36,", "ref_id": "BIBREF35"}, {"start": 664, "end": 667, "text": "41]", "ref_id": "BIBREF40"}, {"start": 693, "end": 697, "text": "[22,", "ref_id": "BIBREF21"}, {"start": 698, "end": 701, "text": "23]", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "", "text": "Simplex algorithms and interior point algorithms have their own advantages and disadvantages. In this paper, a step is taken toward developing algorithms having advantages of both types. Combining the affine-scaling tactic and Pan's pivotal approach, the proposed algorithm produces a sequence of interior points as well as a sequence of vertices, until reaching an optimal vertex. Computational results with a dense implementation of it on a set of Netlib test problems are preliminary but favorable, compared with the affine-scaling (interior) algorithm.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "The paper is organized as follows. In the remaining part of this section, we introduce notation used in this paper, describe the affine-scaling algorithm and a Phase-1 procedure briefly, and transform program (1.1) to a special form. In section 2, we describe a variant of the affine-scaling algorithm. Section 3 describes a pivotal subalgorithm. Section 4 establish the affine-scaling pivot algorithm supported by the subalgorithm. Section 5 reports computational results with a dense implementation of the algorithm on a set of Netlib test problems against the affine-scaling algorithm.", "cite_spans": [], "ref_spans": []}, {"section": "Notation.", "text": "The following conventions will be used in this paper: e: the vector of all ones. e i : the unit vector with the ith component 1. \u2022 : the 2-norm of a vector \u2022.", "cite_spans": [], "ref_spans": []}, {"section": "Notation.", "text": "\u2022 J : the subvector (or submatrix) of a vector (or matrix) \u2022 composed of the components (or columns) associated with an ordered index set J.", "cite_spans": [], "ref_spans": []}, {"section": "Notation.", "text": "X: the diagonal matrix whose diagonals are the components of a vectorx.", "cite_spans": [], "ref_spans": []}, {"section": "Notation.", "text": "1.2. The affine-scaling algorithm. It should be noted that the first interior point algorithm, affine-scaling algorithm for LP was proposed by Dikin [12] earlier in 1967. This algorithm is rediscovered as a variation of Karmarkar's algorithm (e.g., [3, 7, 27, 47, 30] . It is also efficient, and known as the first interior point algorithm which suggested that such type of algorithms may outperform simplex algorithms for large LP problems [1, 2] , although the polynomiality of it is still open.", "cite_spans": [{"start": 149, "end": 153, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 249, "end": 252, "text": "[3,", "ref_id": "BIBREF2"}, {"start": 253, "end": 255, "text": "7,", "ref_id": "BIBREF6"}, {"start": 256, "end": 259, "text": "27,", "ref_id": "BIBREF26"}, {"start": 260, "end": 263, "text": "47,", "ref_id": "BIBREF46"}, {"start": 264, "end": 267, "text": "30]", "ref_id": "BIBREF29"}, {"start": 441, "end": 444, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 445, "end": 447, "text": "2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Notation.", "text": "For self-contained, we present the affine-scaling algorithm briefly in this section. For more details, the reader is referred to, e.g., [46, 43, 51] .", "cite_spans": [{"start": 136, "end": 140, "text": "[46,", "ref_id": "BIBREF45"}, {"start": 141, "end": 144, "text": "43,", "ref_id": "BIBREF42"}, {"start": 145, "end": 148, "text": "51]", "ref_id": "BIBREF50"}], "ref_spans": []}, {"section": "Notation.", "text": "Letx be the current interior point of (1.1). Using x =Xu ,we transform (1.1) to min c TX u", "cite_spans": [], "ref_spans": []}, {"section": "Notation.", "text": "Corresponding tox, vector e is the interior point of (1.2). The orthogonal projection of the gradient of the objective onto the null space of AX is", "cite_spans": [], "ref_spans": []}, {"section": "Notation.", "text": "3)", "cite_spans": [], "ref_spans": []}, {"section": "Notation.", "text": "The associated long-step line search in u-space is u = e \u2212 \u03bb\u2206u/ max(\u2206u), (1.4) mapping which back to the original x-space leads t\u00f5 T . Dikin [13] showed that, if (1.1) has an optimal solution, the sequence of iterates produced by the long-step affine-scaling algorithm with \u03bb \u2208 (0, 1) converge to a relative interior point of the optimal face under the nondegeneracy assumption (also see [47, 20] ). Furthermore, the convergence of the algorithm was proved with \u03bb \u2208 (0, 2/3] without the nondegeneracy assumption [45] . The convergence with \u03bb > 2/3 is not guaranteed for general problems. In fact, there is an example for which the algorithm fails by converging to a nonoptimal solution ( for this example, the failure occurs for all \u03bb > 0.995). In practice, however, the affine-scaling algorithm with a large \u03bb \u2208 (0, 1) is reliable and fast. It would be well accepted that \u03bb = 0.9 0.99 is suitable for Phase-2.", "cite_spans": [{"start": 141, "end": 145, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 388, "end": 392, "text": "[47,", "ref_id": "BIBREF46"}, {"start": 393, "end": 396, "text": "20]", "ref_id": "BIBREF19"}, {"start": 512, "end": 516, "text": "[45]", "ref_id": "BIBREF44"}], "ref_spans": []}, {"section": "Notation.", "text": "Therefore, we state the following. ", "cite_spans": [], "ref_spans": []}, {"section": "Notation.", "text": "The preceding has an optimal solution since it has an obvious interior point (x 0 , 1)", "cite_spans": [], "ref_spans": []}, {"section": "Notation.", "text": "T and its objective is bounded below. Moreover, the original program (1.1) has no feasible solution if the optimal value of (1.6) is strictly positive. Suppose that (1.6) was solved by Algorithm 1 with \u03bb \u2208 (0, 2/3] , and that the limiting point of the iterates is x \u221e with objective value zero. Then it is a relative interior point of the feasible region of (1.1). Therefore, using N and B to denote the index sets such that x Consequently, x \u221e B > 0 is ready as an initial interior point of (1.7) to get the affinescaling algorithm started. ", "cite_spans": [], "ref_spans": []}, {"section": "Notation.", "text": "Then problem (1.1) can be transformed to the following simpler form:", "cite_spans": [], "ref_spans": []}, {"section": "Notation.", "text": "It is clear that", "cite_spans": [], "ref_spans": []}, {"section": "Notation.", "text": "n+1 ) is available as an initial interior point of (1.9). Program (1.9) is equivalent to (1.1) in the sense that there is 1-to-1 correspondence between their feasible (or interior or optimal) solutions, infeasibility and unboundedness. The bottom equality constraint of the former is x n+1 + c T x =b m+1 . So their corresponding feasible objective values differ only by the constantb m+1 . It is also clear that e n+1 is included in the range of\u00c2 T if and only if c is included in the range of A T and that rank(\u00c2) = m + 1 if and only if rank(A) = m. Therefore, hereafter we will not hanlde program (1.1) itself directly but its special form below:", "cite_spans": [], "ref_spans": []}, {"section": "Notation.", "text": ", and Ae n = e m . Usually, program (1.10) is solved toghther with its dual, i.e.,", "cite_spans": [], "ref_spans": []}, {"section": "Notation.", "text": "2. Variation of the affine-scaling algorithm. We will apply the affine-scaling technique to (1.10), but with an alternative approach to computing the search direction.", "cite_spans": [], "ref_spans": []}, {"section": "Notation.", "text": "Letx be the current interior point of (1.10). As in the affine-scaling algorithm, we use transformation x =Xw to recast (1.10) to", "cite_spans": [], "ref_spans": []}, {"section": "Notation.", "text": "where the positive factorx n has been dropped from the objective function. The orthogonal projection of the gradient e n of the objective onto the null space of AX is", "cite_spans": [], "ref_spans": []}, {"section": "Notation.", "text": "Assume that the QR factorization ofXA T is available, i.e. ", "cite_spans": [], "ref_spans": []}, {"section": "Notation.", "text": "Base on the preceding, the following is clear. ", "cite_spans": [], "ref_spans": []}, {"section": "Notation.", "text": "where I n\u2212m is the last n \u2212 m columns of the unit n \u00d7 n matrix.", "cite_spans": [], "ref_spans": []}, {"section": "Notation.", "text": "As for a complexity comparison between Algorithms 1 and 2, it is only needed to compare the computations of the \u2206u. If the Householder transformation is utilized in both, then additional O(2(n \u2212 m)(n 2 \u2212 mn + m 2 /3)) multiplications are required by the latter due to the accumulation (2.5) (also see [19] ). Therefore, Algorithm 2 is not a challenging competitor of Algorithm 1, especially when n \u2212 m large relative to m. However, the situation shifts to the opposite side if the affine-scaling tactic is combined with the following pivoting subprocedure.", "cite_spans": [], "ref_spans": []}, {"section": "Notation.", "text": "3. Pivoting subprocedure. As well known, the long-step affine-scaling algorithm is more efficient than the short-step one, practically. This suggests achieving as great reduction of the objective value as possible at each iteration. In fact, it can go even further cheaply based on a pivotal frame similar to that used in [38] to develop a pivot algorithm using the affine-scaling technique. To this end, we describe a subprocedure in this section.", "cite_spans": [{"start": 322, "end": 326, "text": "[38]", "ref_id": "BIBREF37"}], "ref_spans": []}, {"section": "Notation.", "text": "At the beginning of the subprocedure, we are faced with an interior pointx and the associated scaled program (2.1).", "cite_spans": [], "ref_spans": []}, {"section": "Substeps. For the kth", "text": ". . , n}, where |N k | equals k and B k includes index n as its end element. For simplicity of exposition, assume that", "cite_spans": [], "ref_spans": []}, {"section": "Substeps. For the kth", "text": "Hereinafter, we will denote by I N k the n \u00d7 k matrix consisting of k columns of the identity matrix, indexed by N k , and by I B k that consisting of the n \u2212 k remaining columns, indexed by B k .", "cite_spans": [], "ref_spans": []}, {"section": "Substeps. For the kth", "text": "Assume that\u016b ( k) is the current feasible solution to (2.1) such that", "cite_spans": [], "ref_spans": []}, {"section": "Substeps. For the kth", "text": "= e. Correspondingly, introduce the following program:", "cite_spans": [], "ref_spans": []}, {"section": "Substeps. For the kth", "text": "where I k is the k \u00d7 k identity matrix. Note that the constraint matrix is of full row rank m + k. Assume that the following QR factorization is available:", "cite_spans": [], "ref_spans": []}, {"section": "Substeps. For the kth", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "Substeps. For the kth", "text": "is an nonsingular upper-triangular matrix. Consequently, the orthogonal projection of the objective gradient of (3.3) onto the null space of the constraint matrix is", "cite_spans": [], "ref_spans": []}, {"section": "Substeps. For the kth", "text": "or partitioned", "cite_spans": [], "ref_spans": []}, {"section": "Substeps. For the kth", "text": "where e n\u2212k the identity (n \u2212 k)-vector with its last component 1. Thereby, we have", "cite_spans": [], "ref_spans": []}, {"section": "Substeps. For the kth", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "Substeps. For the kth", "text": "if the latter is available. Of course, there is no need for such doing whenever v (k) = 0:", "cite_spans": [], "ref_spans": []}, {"section": "Substeps. For the kth", "text": "Taking \u2212\u2206u B k as a search vector, we compute the next point as follows:\u016b", "cite_spans": [], "ref_spans": []}, {"section": "Substeps. For the kth", "text": "where \u03b1 =\u016b", "cite_spans": [], "ref_spans": []}, {"section": "Substeps. For the kth", "text": "Note that\u016b (k+1) q = 0. Then, move q from B k to the end of N k to form (N k+1 , B k+1 ), and go on the (k + 1)th substep.", "cite_spans": [], "ref_spans": [{"start": 72, "end": 86, "text": "(N k+1 , B k+1", "ref_id": "FIGREF0"}]}, {"section": "Substeps. For the kth", "text": "is degenerate, then \u03b1 defined by (3.10) could vanish, and hence the resulting point is just the same as the old.", "cite_spans": [], "ref_spans": []}, {"section": "Substeps. For the kth", "text": "We state the following theorem, the proof of which is omitted. (3.3) .", "cite_spans": [], "ref_spans": []}, {"section": "Substeps. For the kth", "text": "ii) If \u2206u", "cite_spans": [], "ref_spans": []}, {"section": "Substeps. For the kth", "text": "defined by (3.7)-(3.10) is a feasible point to (2.1), with an objective value less than that for\u016b (k) . If program (1.10) is not unbounded below and v (k) = 0; \u2200k = 0, . . . , n \u2212 m \u2212 1, the substeps can be carried out until the (n \u2212 m \u2212 1)th substep finished. Consequently, v (n\u2212m) vanishes, and the subprocedure ends with the product\u016b (n\u2212m) as an vertex solution to (2.1) (which has at least n \u2212 m zero components). Generally, however, v (k) could vanish for k < n \u2212 m, as will be discussed later in section 3.3.", "cite_spans": [], "ref_spans": []}, {"section": "Canonical tableaus. It is seen that (Q", "text": "needed for the computation of \u2206u", "cite_spans": [], "ref_spans": []}, {"section": "Canonical tableaus. It is seen that (Q", "text": ". If such a vector were computed from scratch by the orthogonalization at every substep, nevertheless, the amount of computational work of the whole subprocedure would be unacceptably large. Fortunately, a nice implementation of it can be made based on a frame similar to that used in [38] . In this subsection, we introduce the so-called canonical tableaus, and show that the substeps can be carried out with the aid of them cheaply.", "cite_spans": [{"start": 285, "end": 289, "text": "[38]", "ref_id": "BIBREF37"}], "ref_spans": []}, {"section": "Canonical tableaus. It is seen that (Q", "text": "Letx be an interior point of (1.10). Consider the dual program of (2. ", "cite_spans": [], "ref_spans": []}, {"section": "Canonical tableaus. It is seen that (Q", "text": "where R", "cite_spans": [], "ref_spans": []}, {"section": "Canonical tableaus. It is seen that (Q", "text": "11 \u2208 R m\u00d7m and R", "cite_spans": [], "ref_spans": []}, {"section": "Canonical tableaus. It is seen that (Q", "text": "22 \u2208 R k\u00d7k are nonsingular upper-triangular matrices. Definition 3.4. Tableau (3.13) is termed the kth canonical tableau. The canonical tableau plays a central rule, including enough information for proceeding the kth substep, described in section 3.1. Specifically, its south-east (n \u2212 m \u2212 k) \u00d7 (n \u2212 k) submatrix is readily available for computing \u2206u (k) (see (3.7)). Also, it will be clear that one can obtain an associated dual solution and do optimality test, using the end canonical tableau.", "cite_spans": [], "ref_spans": []}, {"section": "Canonical tableaus. It is seen that (Q", "text": "The (k + 1)th canonical tableau is updated from (3.13) as follows. Assume that index q \u2208 B k is chosen to enter N k , as yields the (k + 1)th index sets:", "cite_spans": [], "ref_spans": []}, {"section": "Canonical tableaus. It is seen that (Q", "text": "Then, it holds that (3.15) where the first m", "cite_spans": [], "ref_spans": []}, {"section": "Canonical tableaus. It is seen that (Q", "text": "are upper-triangular (see (3.13)). If k = n \u2212 m \u2212 1, therefore, the first m + k + 1 = n columns of the preceding are already upper-triangular, and there is no need for the next substep. The process is terminated in this case.", "cite_spans": [], "ref_spans": []}, {"section": "Canonical tableaus. It is seen that (Q", "text": "Assume now that 0 \u2264 k < n \u2212 m \u2212 1. Determine an Householder H K \u2208 R (n\u2212m)\u00d7(n\u2212m) , partitioned as", "cite_spans": [], "ref_spans": []}, {"section": "Canonical tableaus. It is seen that (Q", "text": "such that", "cite_spans": [], "ref_spans": []}, {"section": "Canonical tableaus. It is seen that (Q", "text": "We premultiply the two sides of (3.15) by P m+k+1 = diag(I m+k , H k ), deducing the (k + 1)th canonical tableau:", "cite_spans": [], "ref_spans": []}, {"section": "Canonical tableaus. It is seen that (Q", "text": "the first m + k + 1 columns of which is upper-triangular. Noted that the first m + k rows of (3.19) are actually the same as those in tableau (3.13), except for the q-indexed column being moved to the (m+k+1)th column position. If H k is available, therefore, the updating involves only 2(n \u2212 k)(n \u2212 m \u2212 k) multiplications. It is such a trick that makes the subprocedure efficient (see the last paragraph of section 2).", "cite_spans": [], "ref_spans": []}, {"section": "Formulation of the subalgorithm.", "text": "Before describing the subalgorithm formally, let us consider more general cases by dropping assumption rank(A) = m. In fact, the substeps can be carried out without difficulty in any case. If rank(A) = r < m, then there are Householders P 1 , . . . , P r such that 20) where R \u2208 R r\u00d7r is a nonsingular upper-triangular matrix. Correspondingly, the first m columns of the canonical tableaus should be the upper-trapezoid above. This has no sbstantial effects on the subsequent substeps, which are carried out until v (k) vanishes for some k \u2208 {1, . . . , n \u2212 m}, with the end product\u016b (k) as a feasible vertex solution to (2.1).", "cite_spans": [], "ref_spans": []}, {"section": "Formulation of the subalgorithm.", "text": "The overall process is summarized as follows. Subalgorithm 1. Given an interior pointx to (1.10) and tolerance 1 > 0.", "cite_spans": [], "ref_spans": []}, {"section": "Construct the 0th canonical tableau (3.13). 3. Compute v", "text": "(k) = ((Q (k) 3 ) T I B k )e n\u2212k (3.8). 4. Go to step 12 if v (k) = 0. 5. Determine \u2206u (k) B k = (I T B k Q (k) 3 )v (k) (3.7). 6. Stop if \u2206u (k) B k \u2264 0.", "cite_spans": [], "ref_spans": []}, {"section": "Compute\u016b", "text": ", where [24] . While it is a good choice for simplex algorithms, however, Harris' tactic seems to be unnecessary in the current context, according to our computational experience. (see section 5).", "cite_spans": [{"start": 8, "end": 12, "text": "[24]", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Compute\u016b", "text": "4. The affine-scaling pivot algorithm. Now it is ready to describe the affinescaling pivot algorithm as a whole.", "cite_spans": [], "ref_spans": []}, {"section": "Compute\u016b", "text": "Beginning with an interior pointx of (1.10), we call Subalgorithm 1. It is clear that (1.10) is unbounded blow if the termination occurs at step 6. Assume that the termination occurs at step 12. Then the following optimality test is relevant. T (with some column exchanges), it represents a system equivalent to the equality constraint of (3.11)", "cite_spans": [], "ref_spans": []}, {"section": "Compute\u016b", "text": "1 . Setting z B k = 0, thereby, this system becomes \uf8ee \uf8ef \uf8f0", "cite_spans": [], "ref_spans": []}, {"section": "Compute\u016b", "text": "which is equivalent to", "cite_spans": [], "ref_spans": []}, {"section": "Compute\u016b", "text": "Assume that (\u1ef9,z N k ) is the solution to (4.2). Corresponding to the end feasible solution\u016b (k) of (2.1), on the other hand, the solution in x-space is", "cite_spans": [], "ref_spans": []}, {"section": "Compute\u016b", "text": "Using the preceding notation, we have the following. Theorem 4.1. Ifz N k \u2265 0, thenx and (\u1ef9,z N k ) are a pair of primal and dual optimal vertex solutions to (1.10) ) and (1.11) , respectively.z Proof. By Theorem 3.5, it is clear that thex is a feasible (vertex) solution to (1.10) and that (\u1ef9,z N k ) together with z B k = 0 is a solution to (3.11). Hence, it holds thatXA T\u1ef9 +z = \u2212e n , or equivalently,", "cite_spans": [], "ref_spans": []}, {"section": "Compute\u016b", "text": ") is a feasible solution to the dual of (1.10) with the positive factor difference 1/x n in the objective coefficient. Moreover,x and (\u1ef9,X \u22121z ) exhibit complementarity. Therefore, the two are a pair of primal and dual optimal solutions.", "cite_spans": [], "ref_spans": []}, {"section": "Compute\u016b", "text": "Assume thatz N k 0 . It is then clear thatx \u2212x is a down-hill with respect to c T x. Thereby, we can retract back to the interior of the feasible region by updatin\u1e21 x as follows:x", "cite_spans": [], "ref_spans": []}, {"section": "Compute\u016b", "text": "where \u03bb \u2208 (0, 1).", "cite_spans": [], "ref_spans": []}, {"section": "Compute\u016b", "text": "It is easy to show that the resultingx is another interior point of (1.10), with a less objective value than the old. Using thex as input, we execute Subalgorithm 1 again. We summarizes the overall process as follows. Algorithm 3 (ASP). Letx be an initial interior point to (1.10) . Given stepsize \u03bb \u2208 (0, 1) and tolerance 1 > 0. This algorithm solves (1.10 Proof. It is deduced from Theorems 3.5 and 4.1. It is seen that Algorithm 3 produces a sequence of interior points as well as a sequence of vertices, until reaching an optimal vertex. It appears to be attractive for having advantages of both pivotal and interior point algorithms. The three codes were coded in FORTRAN 77 models without exploiting sparsity. Compiled using the Visual FORTRAN 5.0, they were run under WINDOWS 98 system on a PENTIUN III 550E microcomputer with 128 Mbytes. The CPU time was measured in seconds with utility routine CP U \u2212 T IM E. The machine precision used was about 16 decimal digits.", "cite_spans": [], "ref_spans": []}, {"section": "Compute\u016b", "text": "The test problems were a set of 26 standard LP problems from Netlib 2 . In Tables  5.1 and 5 .2, columns labeled M and N give the number of rows and columns of the constraint matrix. In the order of increasing sum M + N , these are the first 26 Compared to the optimal objective values reported in [16] , the values reported in Tables 5.1 and 5.2 for AS and VAS are accurate within about 6 to 8 digits overall (where no accurate digit is reached for two problems marked by * ). In contrast, the values reported in Table 5 .3 for ASP are clearly more accurate. We also stress that no degeneracy or stalling was observed during the execution of ASP. Table 5 .4 compares the performance of the three codes against one another by giving count ratios of AS to VAS and of AS to ASP. The bottom line labeled Total indicates that the total iteration ratio of AS to VAS is 0:95 while the total time ratio is as low as 0:26. As expected the affine-scaling slgorithm is superior to the variant of it, as the computation of the projection by the latter is more expensive than that by the former (see the last paragraph of section 2). As for what we are really concerned, the total iteration and time ratio of AS to ASP is 4:56 and 1:52, respectively. Moreover, a closer look at Table 5 .4 reveals that the time ratio is greater than one with all the 16 test problems, except for one (E226). Therefore, the proposed affine-scaling pivot slgorithm outperformed the affine-scaling (interior point) algorithm significantly. This outcome is quite impressive and encouraging. 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Consider the linear programming (LP) problem in the stan- dard form min c T x subject to Ax = b, x \u2265 0, (1.1)", "type": "figure"}, "FIGREF1": {"text": "\u2022 j : the jth component of a vector \u2022. max(\u2022): the largest component of a vector \u2022.", "type": "figure"}, "FIGREF2": {"text": "B s.t. A B x B = b, x B \u2265 0. (1.7)", "type": "figure"}, "FIGREF4": {"text": ". . .I N k ] to upper-triangular. Note that (QT since premulti- plying any matrix by P m+1 through P m+k does not change the first m rows. Thus, premultiplying [XA T . . .I] by the same leads to", "type": "figure"}, "FIGREF5": {"text": "Optimality test. Let (3.13) be the end canonical tableau, where vT I B k )e n\u2212k = 0. Differing from the initial tableau [XA T . . .I] by the orthogonal matrix factor (Q (k) )", "type": "figure"}, "FIGREF6": {"text": "Computational results. Preliminary computational experiments have been performed to gain an insight into the behavior of Algorithm 3. We report numerical results in this section. Implemented, and compared are the following three codes: \u2022 Code AS (Affine-scaling algorithm): Algorithm 1 ( = 10 \u221210 ). \u2022 Code VAS (Variation of affine-scaling algorithm): Algorithm 2 ( = 10 \u221210 ). \u2022 Code ASP (Affine-scaling pivot algorithm): Algorithm 3, supported by Subal- gorithm 1 ( 1 = 10 \u22128 ). Note: For each of the preceding codes, a modification of the associated algorithm is furnished as its Phase-1, as was described in section 1.3. All the codes use \u03bb = 0.66 for Phase-1 and \u03bb = 0.95 for Phase-2.", "type": "figure"}, "TABREF5": {"text": "Note that the end column e n of the constraint matrix [XA", "type": "table"}, "TABREF6": {"text": "B k+1 = B k \\q and adjust the columns of the canonical tableau conformably. 9. If k < n \u2212 m \u2212 1, update the canonical tableau by premultiplying it by a", "type": "table"}, "TABREF7": {"text": "In regarding to exits of the preceding algorithm, we have the following.", "type": "table"}, "TABREF8": {"text": "problems that do not have BOUNDS and RANGES sections in their MPS files, since the current version of our codes cannot handle such problems implicitly. The test problems are categorized into two groups: Group 1 includes the first 16 problems (from AFIRO to SCAGR7), and Group 2 the rest 10 larger problems( from AGG to DEGEN). Numerical results obtained with Codes AS, VAS and ASP are displayed in Tables 5.1, 5.2 and 5.3, respectively. In each of the tables, total iterations and time, required for solving each problem, are listed in the two columns labeled Itn and Time under Total and Ph.1. In Table 5.3, columns labelled Stn offer subiteration counts required by Subalgorithm 1. The bottom lines of tables give total counts for Groups 1 and 2 together. Objective values reached are reported in columns labeled Objective.", "type": "table"}, "TABREF9": {"text": "Code VAS statistics", "type": "table"}, "TABREF10": {"text": "Code ASP statistics", "type": "table"}, "TABREF11": {"text": "", "type": "table"}}}
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{"paper_id": "42950139", "_pdf_hash": "668365a8d9d822874ac31cc8bb736fb588d9e9bc", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Low temperature poly-Si TFT technology for AMLCD application", "authors": [{"first": "I.-W", "middle": [], "last": "Wu", "suffix": ""}], "year": 1995, "venue": "Proc. AM-LCD 95", "link": null}, "BIBREF1": {"title": "Hot carrier analysis in low-temperature poly-Si TFTs using picosecond emission microscope", "authors": [{"first": "Y", "middle": [], "last": "Uraoka", "suffix": ""}, {"first": "N", "middle": [], "last": "Hirai", "suffix": ""}, {"first": "H", "middle": [], "last": "Yano", "suffix": ""}, {"first": "T", "middle": [], "last": "Hatayama", "suffix": ""}, {"first": "T", "middle": [], "last": "Fuyuki", "suffix": ""}], "year": 2004, "venue": "IEEE Trans. Electron Devices", "link": "43998578"}, "BIBREF3": {"title": "Analysis of poly-Si TFT degradation under gate pulse stress using the slicing model", "authors": [{"first": "", "middle": [], "last": "Chien-Kwen Chen", "suffix": ""}], "year": 2006, "venue": "IEEE Electron Device Letters", "link": null}, "BIBREF4": {"title": "Hot Carrier Effects in Low-Temperature Polysilicon Thin-Film Transistors", "authors": [{"first": "Y", "middle": [], "last": "Uraoka", "suffix": ""}, {"first": "T", "middle": [], "last": "Hatayama", "suffix": ""}, {"first": "T", "middle": [], "last": "Fuyuki", "suffix": ""}, {"first": "T", "middle": [], "last": "Kawamura", "suffix": ""}, {"first": "Y", "middle": [], "last": "Tsuchihashi", "suffix": ""}], "year": 2001, "venue": "Jpn. J. Appl. Phys", "link": "123715794"}, "BIBREF5": {"title": "FIGURE 3.THE MOBILITY DEGRADATION FOR THE POLY-SI TFTS UNDER THE DC STRESS CONDITION WITH THE FIXED DRAIN VOLTAGE 15V AND VARIOUS GATE VOLTAGES", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF6": {"title": "THE MOBILITY DEGRADATION FOR THE POLY-SI TFTS WITH VARIOUS STRESS CONDITIONS AND THE DRAIN VOLTAGE IS KEPT AT 15 V", "authors": [], "year": "", "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "42950311", "_pdf_hash": "af45d5d78b4f1602a404739cd447186620cdf2b6", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
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{"paper_id": "42950630", "_pdf_hash": "9fc892ef879f6ec6fa9bd0f6d480f4b93caeac6f", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "A Low-Power UpConversion CMOS Mixer for 22-29-GHz Ultra-Wideband Applications", "authors": [{"first": "Ashok", "middle": [], "last": "Verma", "suffix": ""}, {"first": "Kenneth", "middle": ["K O"], "last": "", "suffix": ""}, {"first": "Jenshan", "middle": [], "last": "Lin", "suffix": ""}], "year": 2006, "venue": "IEEE Transaction on Microwave Theory and Techniques", "link": null}, "BIBREF1": {"title": "A Low Voltage Mixer With Improved Noise Figure", "authors": [{"first": "Chih-Hao", "middle": [], "last": "Chen", "suffix": ""}, {"first": "Pei-Yuan", "middle": [], "last": "Chiang", "suffix": ""}, {"first": "Christina", "middle": ["F"], "last": "Jou", "suffix": ""}], "year": 2009, "venue": "IEEE Microwave and Wireless Components Letters", "link": "38880470"}, "BIBREF2": {"title": "A 5 GHz Differential Colpitts CMOS VCO Using the Bottom PMOS Cross-Coupled Current Source", "authors": [{"first": "Jian-An", "middle": [], "last": "Hou", "suffix": ""}, {"first": "Yeong-Her", "middle": [], "last": "Wang", "suffix": ""}], "year": 2009, "venue": "IEEE Microwave and Wireless Components Letters", "link": "44942905"}, "BIBREF3": {"title": "A Wide-Band CMOS LC VCO With Linearized Coarse Tuning Characteristics", "authors": [{"first": "Jongsik", "middle": [], "last": "Kim", "suffix": ""}, {"first": "Jaewook", "middle": [], "last": "Shin", "suffix": ""}, {"first": "Seungsoo", "middle": [], "last": "Kim", "suffix": ""}, {"first": "Hyunchol", "middle": [], "last": "Shin", "suffix": ""}], "year": 2008, "venue": "IEEE Transactions on Circuits and Systems-II: Express Briefs", "link": "10395136"}, "BIBREF4": {"title": "Design of Analog CMOS Integrated Circuits", "authors": [{"first": "Behzad", "middle": [], "last": "Razavi", "suffix": ""}], "year": 1998, "venue": "", "link": "89615067"}, "BIBREF5": {"title": "The Design of CMOS Radio-Frequency Integrated Circuits", "authors": [{"first": "Thomas", "middle": ["H"], "last": "Lee", "suffix": ""}], "year": 2004, "venue": "", "link": null}, "BIBREF6": {"title": "Power Optimized LC VCO & Mixer Co-design", "authors": [{"first": "Byunghoo", "middle": [], "last": "Jung", "suffix": ""}, {"first": "Shubha", "middle": [], "last": "Bommalingaiahnapallya", "suffix": ""}, {"first": "Ramesh", "middle": [], "last": "Harjani", "suffix": ""}], "year": 2005, "venue": "", "link": null}, "BIBREF7": {"title": "Ultra-LowVoltage Mixer and VCO in 0.18um CMOS", "authors": [{"first": "Hsieh-Hung", "middle": [], "last": "Hsieh", "suffix": ""}, {"first": "Kuo-Sheng", "middle": [], "last": "Chung", "suffix": ""}, {"first": "Liang-Hung", "middle": [], "last": "Lu", "suffix": ""}], "year": 2005, "venue": "IEEE Radio Frequency Integrated Circuits Symposium", "link": null}}, "ref_entries": {}}
{"paper_id": "42950752", "_pdf_hash": "3d15006f3044924e629bfe89e197d8b2a32945e7", "abstract": [{"section": "Abstract", "text": "The BH3-only apoptosis agonists BAD and NOXA target BCL-2 and MCL-1 respectively and co-operate to induce apoptosis. On this basis, therapeutic drugs targeting BCL-2 and MCL-1 might have enhanced activity if used in combination. We identified anti-leukaemic drugs sensitising to BCL-2 antagonism and drugs sensitising to MCL-1 antagonism using the technique of dynamic BH3 profiling, whereby cells were primed with drugs to discover whether this would elicit mitochondrial outer membrane permeabilisation in response to BCL-2-targeting BAD-BH3 peptide or MCL-1-targeting MS1-BH3 peptide. We found that a broad range of anti-leukaemic agents-notably MCL-1 inhibitors, DNA damaging agents and FLT3 inhibitors-sensitise leukaemia cells to BAD-BH3. We further analysed the BCL-2 inhibitors ABT-199 and JQ1, the MCL-1 inhibitors pladienolide B and torin1, the FLT3 inhibitor AC220 and the DNA double-strand break inducer etoposide to correlate priming responses with co-operative induction of apoptosis. ABT-199 in combination with pladienolide B, torin1, etoposide or AC220 strongly induced apoptosis within 4 hours, but the MCL-1 inhibitors did not co-operate with etoposide or AC220. In keeping with the long half-life of BCL-2, the BET domain inhibitor JQ1 was found to downregulate BCL-2 and to prime cells to respond to MS1-BH3 at 48, but not at 4 hours: prolonged priming with JQ1 was then shown to induce rapid cytochrome C release when pladienolide B, torin1, etoposide or AC220 were added. In conclusion, dynamic BH3 profiling is a useful mechanism-based tool for understanding and predicting co-operative lethality between drugs sensitising to BCL-2 antagonism and drugs sensitising to MCL-1 antagonism. A plethora of agents sensitised cells to BAD-BH3-mediated mitochondrial outer membrane permeabilisation in the dynamic BH3 profiling assay and this was associated with effective co-operation with the BCL-2 inhibitory compounds ABT-199 or JQ1.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "a1111111111 a1111111111 a1111111111 a1111111111 a1111111111", "cite_spans": [], "ref_spans": []}, {"section": "Background", "text": "The modes of action of diverse cytotoxic agents generally converge on mitochondrial apoptotic pathways [1] . To allow apoptosis to occur, effector molecules BAX and BAK must oligomerise to form pores that cause mitochondrial outer membrane permeabilisation (MOMP). BAX and BAK activation can be triggered by BH3-only proapoptotic BCL-2 family members such as BID and BIM, PUMA, BAD and NOXA. These are opposed by BCL-2 family prosurvival members, such as MCL-1 and BCL-2 itself, that sequester pro-apoptotic family members to hold apoptosis in check. Effective pro-apoptotic drugs alter the equilibrium of the system, both by altering relative levels of the pro-and anti-apoptotic BCL-2 family members and triggering changes of phosphorylation, conformation and location [1, 2] .", "cite_spans": [{"start": 103, "end": 106, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 771, "end": 774, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 775, "end": 777, "text": "2]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Background", "text": "Monotherapies are not successful at inducing remissions in patients with acute myeloid leukaemia. With many new drugs on the market or in the pipeline [3, 4] , there is a need to establish rational principles for predicting suitable drug combinations. One such principle is cooperation between agents that activate complementary components of pro-apoptotic pathways. For example, the sensitiser molecule BAD is ineffective against MCL-1, and NOXA is ineffective against BCL-2, but there is direct co-operation between BAD and NOXA in mediating apoptosis [5] , suggesting that therapeutic agents that inhibit BCL-2 may complement agents that inhibit MCL-1. Indeed, several studies have now shown synergy between specific BCL-2 and MCL-1 antagonists [6] [7] [8] [9] [10] . Mechanistically, when BCL-2 is inhibited, e.g. by the binding agents ABT-737 or ABT-199, the apoptosis activator BIM is released [7, [10] [11] [12] [13] , but the released BIM can then be taken up by MCL-1, so protection from apoptosis is maintained unless MCL-1 is also antagonised [10, [14] [15] [16] .", "cite_spans": [{"start": 151, "end": 154, "text": "[3,", "ref_id": "BIBREF3"}, {"start": 155, "end": 157, "text": "4]", "ref_id": "BIBREF4"}, {"start": 554, "end": 557, "text": "[5]", "ref_id": "BIBREF5"}, {"start": 748, "end": 751, "text": "[6]", "ref_id": "BIBREF6"}, {"start": 752, "end": 755, "text": "[7]", "ref_id": "BIBREF7"}, {"start": 756, "end": 759, "text": "[8]", "ref_id": "BIBREF8"}, {"start": 760, "end": 763, "text": "[9]", "ref_id": "BIBREF9"}, {"start": 764, "end": 768, "text": "[10]", "ref_id": "BIBREF10"}, {"start": 900, "end": 903, "text": "[7,", "ref_id": "BIBREF7"}, {"start": 904, "end": 908, "text": "[10]", "ref_id": "BIBREF10"}, {"start": 909, "end": 913, "text": "[11]", "ref_id": "BIBREF11"}, {"start": 914, "end": 918, "text": "[12]", "ref_id": "BIBREF12"}, {"start": 919, "end": 923, "text": "[13]", "ref_id": "BIBREF13"}, {"start": 1054, "end": 1058, "text": "[10,", "ref_id": "BIBREF10"}, {"start": 1059, "end": 1063, "text": "[14]", "ref_id": "BIBREF14"}, {"start": 1064, "end": 1068, "text": "[15]", "ref_id": "BIBREF15"}, {"start": 1069, "end": 1073, "text": "[16]", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Background", "text": "There is currently great interest in discovering the ability of different classes of therapeutic agents to synergise with BCL-2 or MCL-1 antagonists [8, 10, [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] . As MCL-1 has a short halflife (approximately 1 hour) [24] it can be rapidly downregulated, as reported after treatment with ultraviolet radiation [25] or sorafenib [26] for 3 hours or less. It is unclear whether this is crucial for induction of apoptosis, since other factors, such as induction of BIM, NOXA or PUMA are also reported. BCL-2 is a much more stable protein than MCL-1, with a protein halflife of approximately 14 hours [27, 28] . BCL-2 downregulation can be effected by BET domain inhibitors, but whereas message downregulation occurs rapidly in sensitive cells, protein loss takes place over a much longer time period [29] . In contrast, BCL-2 binding antagonists such as ABT-737 or [30, 31] can act rapidly to induce apoptosis in sensitive cells.", "cite_spans": [{"start": 149, "end": 152, "text": "[8,", "ref_id": "BIBREF8"}, {"start": 153, "end": 156, "text": "10,", "ref_id": "BIBREF10"}, {"start": 157, "end": 161, "text": "[14]", "ref_id": "BIBREF14"}, {"start": 162, "end": 166, "text": "[15]", "ref_id": "BIBREF15"}, {"start": 167, "end": 171, "text": "[16]", "ref_id": "BIBREF16"}, {"start": 172, "end": 176, "text": "[17]", "ref_id": "BIBREF17"}, {"start": 177, "end": 181, "text": "[18]", "ref_id": "BIBREF18"}, {"start": 182, "end": 186, "text": "[19]", "ref_id": "BIBREF19"}, {"start": 187, "end": 191, "text": "[20]", "ref_id": "BIBREF21"}, {"start": 192, "end": 196, "text": "[21]", "ref_id": "BIBREF22"}, {"start": 197, "end": 201, "text": "[22]", "ref_id": "BIBREF23"}, {"start": 202, "end": 206, "text": "[23]", "ref_id": "BIBREF24"}, {"start": 262, "end": 266, "text": "[24]", "ref_id": "BIBREF25"}, {"start": 355, "end": 359, "text": "[25]", "ref_id": "BIBREF26"}, {"start": 373, "end": 377, "text": "[26]", "ref_id": "BIBREF27"}, {"start": 642, "end": 646, "text": "[27,", "ref_id": "BIBREF28"}, {"start": 647, "end": 650, "text": "28]", "ref_id": "BIBREF29"}, {"start": 842, "end": 846, "text": "[29]", "ref_id": "BIBREF30"}, {"start": 907, "end": 911, "text": "[30,", "ref_id": "BIBREF31"}, {"start": 912, "end": 915, "text": "31]", "ref_id": "BIBREF32"}], "ref_spans": []}, {"section": "Background", "text": "Whilst several authors have documented the efficacy of the BCL-2 antagonists ABT-199 and ABT-737 at co-operating with agents that downregulate or bind MCL-1 [6, 8, 10, 16-19, 21, 22] , the literature is focused on individual drug combinations. In the current study we use a variety of drugs and chemical inhibitors to systematically identify agents sensitising to BCL-2 antagonism and agents sensitising to MCL-1 antagonism. Dynamic BH3 profiling [32] is a novel methodology that measures the capacity of drugs to prime mitochondria for apoptosis, and involves the addition of permeable pro-apoptotic BCL-2 family BH3 peptides to drug primed cells to induce speedy mitochondrial outer membrane permeabilisation (MOMP). In this study we measure MOMP after applying BAD (BCL-2 targeting) or MS1 (MCL-1 targeting) BH3 peptides to the drug-primed cells. Induction of MOMP is measured here with a cytochrome C release assay [33] . Applying this technique previously, we had shown that the MCL1 downregulator TG02 sensitises to the BCL-2-inhibitory BAD-BH3 peptide, whereas the BCL-2 antagonist ABT-199 sensitises to MCL-1 inhibitory NOXA-BH3 peptide, and the two agents synergise in dual-sensitive cells to induce apoptosis [18] . We dichotomise drugs as either agents sensitising to BCL-2 antagonism or agents sensitising to MCL-1 antagonism, and we demonstrate the efficacy of combining an agent from each category in apoptosis assays.", "cite_spans": [{"start": 447, "end": 451, "text": "[32]", "ref_id": "BIBREF33"}, {"start": 919, "end": 923, "text": "[33]", "ref_id": "BIBREF34"}, {"start": 1219, "end": 1223, "text": "[18]", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Materials and methods Materials", "text": "Drugs and suppliers used in the study were as follows: 17-AAG, rapamycin, sorafenib and torin1 from LC labs (www.lclabs.com); AC220, JQ1, selinexor, tosedostat, TW-37 and vosaroxin from Selleck (supplied by Stratech UK); ABT-199 from Adooq, www.adooq.com; ABT-737 from Sequoia, Pangbourne, UK; A-1210477 from Chemie Tek, www.chemietek.com; etoposide from Tocris, Bristol, UK; Mylotarg from Wyeth, Pearl River USA; Pladienolide B from Santa Cruz, supplied by Insight, Wembley, UK; TG02 was from Tragara, San Diego, USA. Other drugs and reagents were from Sigma (Poole, Dorset, UK) unless specified.", "cite_spans": [], "ref_spans": []}, {"section": "Cells", "text": "The MV4.11 cell line was from the American Tissue Culture Collection (Manassas, USA) and was maintained in RPMI 1640 medium with 10% foetal calf serum (FCS; First Link, Birmingham, UK), and 2mM L-glutamine. All cultures were kept at 37\u02daC in 5% CO 2 and all experiments were performed with cell lines in log phase. Continued testing to authenticate these cell lines was performed using multiplex short tandem repeat analysis (Powerplex 16, Promega, Southampton, UK). Mycoplasma testing was carried out routinely using the Mycoalert mycoplasma detection kit (Lonza, Rockland, USA) and following the manufacturer's instructions.", "cite_spans": [], "ref_spans": []}, {"section": "Dynamic BH3 profiling", "text": "MV4.11 cells were incubated (5 X 10 5 /ml) in RPMI with 10% FCS for four hours with the indicated drugs. Cytochrome C release (using Alexa-647-conjugated cytochrome C antibody, BD #558709) was measured by flow cytometry after a further 60 minute incubation of digitonin-permeabilised cells with BH3 peptides as described [18, 33] . Adjustments for peptide induced cytochrome C release in untreated cells were made in order to establish agent-specific release (delta priming), using the formula (percent release with agent and peptide-percent release with peptide)/ (100 -percent release with peptide). A mutated PUMA-BH3 peptide (PUMA2A) [33] was used at 100 \u03bcM as control in all experiments.", "cite_spans": [{"start": 321, "end": 325, "text": "[18,", "ref_id": "BIBREF18"}, {"start": 326, "end": 329, "text": "33]", "ref_id": "BIBREF34"}, {"start": 638, "end": 642, "text": "[33]", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "Determination of apoptosis", "text": "Cytochrome C release, loss of mitochondrial membrane potential (#\u0394\u03c8 m ) and uptake of 7-amino-actinomycin D were measured by flow cytometry.", "cite_spans": [], "ref_spans": []}, {"section": "Determination of apoptosis", "text": "To measure the percentage of cells with loss of Cytochrome C, cells were fixed in 2% paraformaldehyde directly after a 4 hour drug incubation. Fixed and rinsed cells were permeabilised with saponin and incubated overnight with Alexa-647-conjugated cytochrome C antibody and analysed by flow cytometry.", "cite_spans": [], "ref_spans": []}, {"section": "Determination of apoptosis", "text": "The percentage of cells with loss of mitochondrial membrane potential (#\u0394\u03c8 m ) was determined following incubation of cells as previously reported [34] with the fluorescent dye 3,3'-dihexyloxacarbocyanine iodide (DiOC 6 , 40 nM, Molecular Probes, Oregon) for the final 75 minutes of a 5 \u00bc hour drug incubation, with 0.5 \u03bcg/ml 7-aminoactinomycin D (7-AAD) also added for the final 30 minutes to measure a later stage of apoptosis [35] .", "cite_spans": [{"start": 147, "end": 151, "text": "[34]", "ref_id": "BIBREF35"}, {"start": 429, "end": 433, "text": "[35]", "ref_id": "BIBREF36"}], "ref_spans": []}, {"section": "MCL1 mRNA short and long form measurement", "text": "Expression levels of Mcl-1L and Mcl-1S using cDNA from AML cell lines were determined quantitatively by qRT-PCR on an ABI Prism 7500 (Applied Biosystems) using SYBR Green Master Mix (Applied Biosystems). Specific amplification of the isoforms was achieved using primers with previously reported sequences [36] . Gene expression levels were normalized to beta-2-microglobulin (\u03b22m) housekeeping gene expression [37] . Negative controls (no template) were included in all the experiments and the reactions were run in triplicate.", "cite_spans": [{"start": 305, "end": 309, "text": "[36]", "ref_id": "BIBREF37"}, {"start": 410, "end": 414, "text": "[37]", "ref_id": "BIBREF38"}], "ref_spans": []}, {"section": "Calculations and statistics", "text": "Fold excess addititivism was calculated as a ratio of observed to expected values for drug combinations, where the expected value C is calculated from the Bliss algorithm for response to two compounds with effects A and B i.e. C = A + B-A \u00c3 B [38, 39] . This method allows for potentiation and augmentation as well as synergism. Statistics were carried out using SPSS version 22 software (Chicago, IL, USA). P values <0.05 were considered statistically significant.", "cite_spans": [{"start": 243, "end": 247, "text": "[38,", "ref_id": "BIBREF39"}, {"start": 248, "end": 251, "text": "39]", "ref_id": "BIBREF40"}], "ref_spans": []}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Methodology", "text": "MV4-11 cells were used for screening drugs, as these cells were highly sensitive to apoptosis induced by either BCL-2 or MCL-1 targeting (S1 Fig) . These cells do not over-express BCL-X L [18] . Montero and colleagues [32] have described the technique of dynamic BH3 profiling, which involves using short drug exposures to prime mitochondria for BH3 peptide-induced Cytochrome C release, and these authors demonstrated that the assay could predict cytotoxicity. Dynamic BH3 profiling relies on the ability of a drug and a BH3-only pro-apoptotic peptide to induce MOMP in cells when used in combination: sensitivity is compromised if the agent or peptide induce too much apoptosis individually, so it is crucial to establish suitable drug concentrations for the assay. To allow drugs to prime cells as single agents, but not to kill them outright during the course of the assay, we established a suitable incubation time and drug concentrations by screening with a PUMA-BH3 peptide which can sensitise all the antiapoptotic BCL-2 family proteins [28] . We defined appropriate priming concentrations of agents as those that induced >75% Cytochrome C release in the presence of PUMA-BH3 but less than 10% when incubated with a control peptide, i.e. a >65% change in priming (\"\u0394 priming\", Fig 1) . The data show that a variety of agents prime to PUMA-BH3 after as little as four hours. Agents used in the study along with their proposed mechanism of sensitising to apoptosis are delineated in Table 1 . We grouped agents into four main categories. The first category comprised agents expected to strongly inhibit MCL-1. The second category of agents comprised BCL-2 antagonists. Agents which induce double strand breaks (etoposide, mylotarg, and vosaroxin-category 3) and FLT3 inhibitors (AC220, sorafenib-category 4) were also studied. All the agents studied primed to PUMA-BH3 after a four-hour incubation with the exception of JQ1. Rationales and results for priming to PUMA-BH3 for several additional agents (miscellaneous, category 5) are shown in S2 Fig. We previously showed that the MCL-1 reducing agent TG02 primes AML cells to respond to BCL2 antagonism and that ABT-199 primes cells to respond to MCL-1 antagonism [18] . In that assay a NOXA-BH3 peptide was used to antagonise MCL-1. However we refined the methodology for the current study following reports that the MS1 peptide binds to MCL-1 with higher affinity than NOXA-BH3 [52] . In MV4.11 cells the concentration of MS-1 required to complement ABT-199 was 10-100-fold less than that of NOXA-BH3 (S3 Fig). On the basis of this data we selected 3 \u03bcM BAD-BH3 and 3 \u03bcM MS1-BH3 for the complementary profiling assay.", "cite_spans": [{"start": 188, "end": 192, "text": "[18]", "ref_id": "BIBREF18"}, {"start": 218, "end": 222, "text": "[32]", "ref_id": "BIBREF33"}, {"start": 1045, "end": 1049, "text": "[28]", "ref_id": "BIBREF29"}, {"start": 2221, "end": 2225, "text": "[18]", "ref_id": "BIBREF18"}, {"start": 2437, "end": 2441, "text": "[52]", "ref_id": "BIBREF54"}], "ref_spans": [{"start": 1285, "end": 1291, "text": "Fig 1)", "ref_id": "FIGREF0"}, {"start": 1489, "end": 1496, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Co-operative dynamic BH3 profiling", "text": "Cells were incubated for four hours with agents of interest followed by dynamic BH3 profiling. Diverse agents sensitised cells to BAD-BH3, indicating that the four hour drug incubation had increased the BCL-2 dependence of the cells and thus enabled the cells to cross the threshold for apoptosis once the BCL-2 antagonist peptide was added (Fig 2A and S4 Fig) . In contrast, only the highly specific BCL-2 antagonist ABT-199 and the BCL-2/BCL-XL antagonist ABT-737 primed to equimolar (3 \u03bcM) MS1: i.e. after priming with a variety of drugs, MCL-1 antagonism with MS1-BH3 did not generally enable the cells to cross the threshold for apoptosis (Fig 2B and S4 Fig). ", "cite_spans": [], "ref_spans": [{"start": 341, "end": 360, "text": "(Fig 2A and S4 Fig)", "ref_id": "FIGREF1"}, {"start": 644, "end": 664, "text": "(Fig 2B and S4 Fig).", "ref_id": "FIGREF1"}]}, {"section": "Co-operative induction of apoptosis", "text": "On the basis of the BAD-BH3 and MS1-BH3 profiling, we investigated whether the cells would be sensitive to a combination of BCL-2 and MCL-1 antagonists. ABT-199 is well described as a powerful BCL-2 antagonist at nanomolar concentrations in AML cells [53] . From the data illustrated in Fig 2A, we selected two MCL-1 antagonists: pladienolide B and torin1. The spliceosome inhibitor pladienolide B is reported to rapidly induce alternative splicing of MCL-1 from the anti-apoptotic long form to the pro-apoptotic short form [40] . At 10 nM, pladienolide had primed for >99% sensitisation to BAD-BH3 (Fig 2A) . We confirmed the reported alternative splicing mechanism in our system and the rapid loss of MCL1 protein (Fig 3A) . We also used the powerful chemical mTORC1 antagonist torin1 [42] to inhibit translation, because translational activation by oncogenic kinases is a widespread phenomenon in AML, via STAT5, PIM, ERK and PI3K pathways, which all act on translation initiation factors. Inhibition of translation depletes MCL-1 protein [54] . We confirmed that torin1 dephosphorylates the translational activator 4E-BP1 and depletes MCL-1 in the MV4.11 cells (Fig 3B) . A supraadditive effect of combining ABT-199 with either pladienolide B or torin1 to induce cytochrome C release was documented, but no complementary MOMP or apoptosis was detected when MCL-1 targeting agents were used with each other (Fig 3C and 3D) .", "cite_spans": [{"start": 251, "end": 255, "text": "[53]", "ref_id": "BIBREF55"}, {"start": 524, "end": 528, "text": "[40]", "ref_id": "BIBREF41"}, {"start": 787, "end": 791, "text": "[42]", "ref_id": "BIBREF43"}, {"start": 1042, "end": 1046, "text": "[54]", "ref_id": "BIBREF56"}], "ref_spans": [{"start": 287, "end": 294, "text": "Fig 2A,", "ref_id": "FIGREF1"}, {"start": 599, "end": 607, "text": "(Fig 2A)", "ref_id": "FIGREF1"}, {"start": 716, "end": 724, "text": "(Fig 3A)", "ref_id": "FIGREF2"}, {"start": 1165, "end": 1173, "text": "(Fig 3B)", "ref_id": "FIGREF2"}, {"start": 1410, "end": 1425, "text": "(Fig 3C and 3D)", "ref_id": "FIGREF2"}]}, {"section": "Co-operative induction of apoptosis", "text": "We expanded the study to include a DNA damage-inducing agent and a FLT3 inhibitor, since these categories of agent are of particular clinical interest in AML and had sensitised to BAD-BH3 in the dynamic BH3 profiling assay. Combining the double strand break-inducing agent etoposide or the FLT3 inhibitor AC220 with ABT-199 led to early MOMP and apoptosis (Fig 4) , whereas combining the agents with pladienolide B or torin1 did not have significant pro-apoptotic effects. Flow cytometric illustrations of apoptosis in treated cells are shown in S5 Fig. ", "cite_spans": [], "ref_spans": [{"start": 356, "end": 363, "text": "(Fig 4)", "ref_id": "FIGREF3"}]}, {"section": "Delayed co-operative induction of apoptosis: JQ1 as a BCL-2 antagonist", "text": "The pattern observed thus far of common MCL-1 antagonism and rare BCL-2 antagonism is likely, at least in part, to be predicated on differences in the stability of the two proteins. MCL-1 has a very short half-life (approximately one hour) [24] which makes it extremely susceptible Co-operative dynamic BH3 profiling to rapid downregulation when protein synthesis is decreased or degradation pathways are activated [28, 54] . BCL-2 however, has a much longer half-life (10-14 hours) [27] , such that where an agent downregulates BCL-2 at the message level, it may take several hours for functional consequences to be observed. The BET domain inhibitor JQ1 is documented to downregulate BCL-2 [29] and therefore might acquire the capacity to prime for an MS1 (MCL1-antagonist) response. In MV4-11 cells BCL-2 protein downregulation was noted which plateaued at approximately 48 hours, and JQ1 was able to prime to MS-1 BH3 after 48 hours of incubation (Fig 5A and 5B ). Cells were therefore incubated with JQ1 for 48 hours with addition of additional agents for the final four hours. JQ1 was found to prime cells to pladienolide, torin1, etoposide and AC220 (Fig 5C) . No significant interaction was observed between JQ1 and ABT-199.", "cite_spans": [{"start": 240, "end": 244, "text": "[24]", "ref_id": "BIBREF25"}, {"start": 415, "end": 419, "text": "[28,", "ref_id": "BIBREF29"}, {"start": 420, "end": 423, "text": "54]", "ref_id": "BIBREF56"}, {"start": 483, "end": 487, "text": "[27]", "ref_id": "BIBREF28"}, {"start": 692, "end": 696, "text": "[29]", "ref_id": "BIBREF30"}], "ref_spans": []}, {"section": "Scheduling-specific dependence of co-operation between ABT-199 and the MCL-1 antagonist A-1210477", "text": "The specific MCL1 binding inhibitor A-1210477 is an in vitro chemical tool that had not been used in our earlier panel as it induced apoptosis in its own right at high concentrations (> 3\u03bcM) but failed to prime to BAD-BH3 at sub-micromolar concentrations (S6 Fig). We nevertheless decided to investigate it further because of its specificity for MCL-1 [6] . A supra-additive effect of combining ABT-199 or JQ1 with 1 \u03bcM A-1210477 to induce cytochrome C release was documented, but no enhancement of cytochrome C release was detected when A-1210477 was used with the MCL-1 downregulating agents pladienolide B or torin1 or with etoposide or AC220 (Fig 6A) , thus providing further evidence of the particular efficacy of combining BCL-2 antagonists with MCL-1 antagonists. As the BH3 profiling assay had not predicted the co-operative potential of 1 \u03bcM A-1210477 with BCL-2 antagonists, we investigated this anomaly. A possible explanation is predicated on the fact that, in the BH3 profiling assay, the MCL-1 antagonist A-1210477 and the BCL-2 antagonist (BAD-BH3 peptide) are added to cells sequentially, possibly allowing pro-apoptotic activators such as BIM and PUMA to return to an undepleted pool of MCL-1 when the cells are washed in preparation for addition of peptide in permeabilisation buffer, whereas in the apoptosis experiments A-120477 and ABT-199 are incubated with cells simultaneously. An assay in which we compared sequential with concurrent use of ABT-199 and A-1210477 showed that A-1210477 was indeed ineffective when incubated with cells for four hours and washed off before a two hour incubation with ABT-199 (Fig 6B) . However the reverse sequence, i.e. applying ABT-199 before A-1210477, was as effective as using the two agents concurrently.", "cite_spans": [{"start": 352, "end": 355, "text": "[6]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Discussion", "text": "The technique of co-operative dynamic BH3 profiling has shown that a range of anti-AML drugs and chemical inhibitors sensitise to BCL-2 antagonism and a much smaller number of agents (ABT-199, ABT-737 and JQ1) sensitise to MCL-1 antagonism. MCL-1 and BCL-2 are both guardians of mitochondrial integrity, protecting the healthy cell by sequestering pro-apoptotic BCL-2 family members but allowing controlled release of the pro-apoptotic molecules in response to appropriate stresses. The technique provided evidence that many drugs cause early (within 4 hours) pro-apoptotic changes in cells. Dynamic BH3 profiling does not specify exactly which molecules are effecting these pro-apoptotic changes, but it does show whether these changes can be complemented by specifically antagonising BCL-2 or MCL-1. We add https://doi.org/10.1371/journal.pone.0190682.g004", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Co-operative dynamic BH3 profiling (Mean+/-SD for n = 3). B. Cells were incubated with 1 \u03bcM A-1210477 for four hours and 10 nM ABT-199 was added either before, after or concurrently (final 2 hours). In the two-step conditions, cells were pelleted and rinsed twice in RPMI at 4\u02daC in between agents. R10 = medium without drug.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "https://doi.org/10.1371/journal.pone.0190682.g006", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Co-operative dynamic BH3 profiling the caveat that A-1210477, and likely other transient binding agents, do not work well in this assay. Although often described together, there are important functional differences between MCL-1 and BCL-2 which bear upon the findings of the current study. MCL-1 is an unstable protein with a very short half-life [24, 28, 54] . Its rapid destruction may be a common factor in cellular responses to stresses, such that the propensity of major drug types to downregulate MCL-1 may be a dominant cause of sensitising cells to BCL-2 antagonism. Brunelle and colleagues documented that BCL-2 overexpression conferred resistance to a range of chemotherapeutic agents, but the same agents were effective in MCL-1 over-expressing cells. Moreover MCL-1 protein was depleted in sensitive, drug-treated cells [47] . Priming to BCL-2 inhibitors is not exclusively through MCL-1 downregulation: alternative pathways have been documented [55, 56] , but a lot of evidence points to MCL-1 downregulation being a very common feature of chemo responsiveness (see Introduction, Table 1 and Fig 3) . An inference here might be that MCL-1 binding antagonists become redundant where the drug has caused protein depletion. This could account for the lack of interaction between the antagonist A-1210477 and the spliceosome inhibitor pladienolide or the mTOR inhibitor torin1 in our study, both of which ablated MCL-1. From a different angle, MCL-1 binding antagonists may be useful to supplement the MCL-1 depleting effects of less efficient agents, particularly in vivo. Also, the apparent lack of avidity of A-1210477 binding (Fig 6) , draws attention to the complication that, whereas transient MCL-1-binding agents may have an advantage in reducing toxicity in a clinical setting, their efficacy in combination with BCL-2 inhibitors may require co-administration.", "cite_spans": [{"start": 347, "end": 351, "text": "[24,", "ref_id": "BIBREF25"}, {"start": 352, "end": 355, "text": "28,", "ref_id": "BIBREF29"}, {"start": 356, "end": 359, "text": "54]", "ref_id": "BIBREF56"}, {"start": 832, "end": 836, "text": "[47]", "ref_id": "BIBREF49"}, {"start": 958, "end": 962, "text": "[55,", "ref_id": "BIBREF57"}, {"start": 963, "end": 966, "text": "56]", "ref_id": "BIBREF58"}], "ref_spans": [{"start": 1093, "end": 1100, "text": "Table 1", "ref_id": "TABREF0"}, {"start": 1105, "end": 1111, "text": "Fig 3)", "ref_id": "FIGREF2"}]}, {"section": "Discussion", "text": "In contrast to the MCL-1 depleting abilities of many drugs, agents that inhibit BCL-2 are uncommon. ABT-199 has been well characterised in the literature and is being used (as venetoclax) in the clinic. BET domain inhibitors and their interactions with other drugs are less well characterised, but there is currently huge interest in their development [57] . Although BCL-2 downregulation by JQ1 and associated sensitisation to MS1-BH3 were documented in our study, we add the caveat that BET domain inhibitors are highly non-specific and have numerous additional targets [29] .", "cite_spans": [{"start": 352, "end": 356, "text": "[57]", "ref_id": "BIBREF59"}, {"start": 572, "end": 576, "text": "[29]", "ref_id": "BIBREF30"}], "ref_spans": []}, {"section": "Discussion", "text": "The current set of experiments is applicable to agents that elicit rapid pro-apoptotic changes, which could be a useful strategy to pre-empt protective stress responses. Agents as diverse as etoposide and AC220 sensitised powerfully to BAD-BH3 after just 4 hours (Fig 2) . We did not find complementary dynamic BH3 profiling to be useful in the context of nucleoside analogues ara-C or 5-azacytidine, which elicited only weak priming to BAD-BH3 (S4 Fig) or with ABT-199 in 4 hour apoptosis experiments (data not shown). We also did not find the dynamic profiling assay to be useful for predicting synergy in 48 hour dose response assays (data not shown), so the current findings are likely confined to early interactions. The original dynamic BH3 profiling work found correlations between 16-hour drug priming to BIM-BH3 and 72 hour apoptosis [32] , so our much shorter, four-hour, culture is likely to be particularly relevant to agents with early pro-apoptotic effects.", "cite_spans": [{"start": 843, "end": 847, "text": "[32]", "ref_id": "BIBREF33"}], "ref_spans": [{"start": 263, "end": 270, "text": "(Fig 2)", "ref_id": "FIGREF1"}]}, {"section": "Discussion", "text": "In a clinical setting, the combination of an agent sensitising to BCL-2 antagonism and one sensitising to MCL-1 antagonism could be useful in a synthetic lethal combination, such as the combination of ABT-199 or a BET domain inhibitor with the FLT3 inhibitor AC220 documented in Figs 4 and 5. FLT3 internal tandem duplications affect 30% of AML patients [58] . The decision to use FLT3 inhibitors in this study was based on work showing the downregulation of MCL-1 to be a consequence of inhibition of translation initiation by sorafenib [26] . FLT3 internal tandem duplications drive constitutive activation of STAT5 and PI3K, both of which can drive MCL-1 overexpression through the translation initiation complex [59] , such that MCL-1 downregulation is likely to be a common effect of diverse FLT3 inhibitors. Synergy between JQ1 and AC-220 has been reported [60] . The spliceosome inhibitor pladienolide B was also highly effective in combination with or JQ1 in the current study. Early evidence suggests that targeting of the spliceosome in cases of MDS or AML with spliceosome mutations could be effective [61] .", "cite_spans": [{"start": 354, "end": 358, "text": "[58]", "ref_id": "BIBREF60"}, {"start": 538, "end": 542, "text": "[26]", "ref_id": "BIBREF27"}, {"start": 716, "end": 720, "text": "[59]", "ref_id": "BIBREF61"}, {"start": 863, "end": 867, "text": "[60]", "ref_id": "BIBREF62"}, {"start": 1113, "end": 1117, "text": "[61]", "ref_id": "BIBREF63"}], "ref_spans": []}, {"section": "Discussion", "text": "The MV4-11 cells used in this study were sensitive to either BCL-2 or MCL-1 inhibition, and were used in order to focus on differences between drugs, rather than differences between cells. Cellular dependence on different members of the BCL-2 family is highly heterogeneous, even within a single disease such as AML, and possibly even within different clones from a single patient. Considerable further work will be needed to document the efficacy of co-operative drug combinations in cells with different BCl-2 family dependencies. In a previous report we showed that the complementarity between ABT-199 and TG02 was synergistic in some cases of AML, whereas in other cases we showed the combination to be effective when one or other of the agents alone was ineffective [18] .", "cite_spans": [{"start": 771, "end": 775, "text": "[18]", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Discussion", "text": "In conclusion we have used dynamic BH3 profiling to demonstrate that drugs sensitising to BCL-2 antagonism and drugs sensitising to MCL-1 antagonism can be systematically identified and to determine that dynamic co-operative BH3 profiling can predict drug combinations that induce rapid apoptosis. . Suitable priming concentrations (>65% specificity) were established for the hsp90 inhibitor 17-AAG and the CRM1 inhibitor selinexor, but other agents were less effective. Hsp90 inhibitors [62] and selinexor [63] are reported to downregulate MCL-1. Tosedostat is reported to induce NOXA [64] . The contrast in priming abilities between rapamycin and torin1 (Fig 1) merits comment: this may be explicable in terms of the rapamycin insensitive effects of mTORC1 on 4E-BP1 [42] . 5-azacytidine (5-aza) and cytosine arabinoside (ara-C) were included for general interest. 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Dynamic BH3 profiling assay: delta priming to PUMA-BH3. The increase in cells primed to undergo mitochondrial outer membrane depolarisation (\u0394 priming) is measured by Cytochrome C release after 4 hour drug treatment. PUMA-BH3 was used at 3 \u03bcM. Values are corrected for Cytochrome C release with peptide only as described in the methods. (Mean+/-SD for n = 3). https://doi.org/10.1371/journal.pone.0190682.g001", "type": "figure"}, "FIGREF1": {"text": "Fig 2. Dynamic BH3 profiling assay: delta priming to (A) BAD-BH3 and (B) MS1-BH3 peptides. Delta priming is measured by cytochrome C release after 4 hour drug treatment and additional incubation with the indicated BH3 peptides (BAD-BH3 at 3 \u03bcM, MS1-BH3 at 3 \u03bcM, PUMA2A control at 100 \u03bcM). Values are corrected for cytochrome C release with peptide only as described in the methods. (Mean+/-SD for n = 3). https://doi.org/10.1371/journal.pone.0190682.g002", "type": "figure"}, "FIGREF2": {"text": "Fig 3. Co-operative induction of apoptosis by ABT-199 with pladienolide B or torin1. (A) MCL-1 long form (L) and short form (S) transcripts (i) and protein (ii) were quantified in untreated cells and cells treated with 10 nM pladienolide B (PLB) for 4 hours. (B) 4E-BP1 phosphorylation (i) and MCL-1 protein (ii) were quantified in untreated cells and cells treated with 1\u03bcM torin1 for 4 hours. (C, D) Cells were incubated with 10 nM ABT-199 (199, turquoise), 10 nM pladienolide B (PLB, red), 1 \u03bcM torin1 (green) or the indicated combinations (bright blue bar, height = effect with both agents in combination-sum of effects with agents individually). (C) After 4 hours cells were fixed and processed for Cytochrome C release. (D) After 4 hours DiOC6 was added for a further 75 minutes and 7-amino actinomycin D for the last 30 minutes. (Mean+/-SD for n = 3). Fold excess additivism (FEA) is shown on the figures and was calculated as a ratio of observed to expected values after corrections according to the Bliss algorithm (see methods). Asterisks indicate observed values significantly higher than expected values (P<0.05).", "type": "figure"}, "FIGREF3": {"text": "Fig 4. Co-operative induction of apoptosis by ABT-199 with etoposide and AC220. Cells were incubated with 10 nM ABT-199 (199, turquoise), 10 nM pladienolide B (PLB, red), 1 \u03bcM torin1 (green), 1 \u03bcM", "type": "figure"}, "FIGREF4": {"text": "etoposide (orange) and 10 nM AC220 (mauve) or the indicated combinations (bright blue bar, height = effect with both agents in combination-sum of effects with agents individually). (A) After 4 hours cells were fixed and processed for Cytochrome C release. (B) After 4 hours DiOC6 was added for a further 75 minutes and 7-amino actinomycin D for the last 30 minutes. (Mean+/-SD for n = 3). Fold excess additivism (FEA) is shown on the figures and was calculated as a ratio of observed to expected values after corrections according to the Bliss algorithm (see methods). Asterisks indicate observed values significantly higher than expected values (P<0.05).", "type": "figure"}, "FIGREF5": {"text": "Fig 5. Co-operative induction of apoptosis by pladienolide, torin1, etoposide or AC220 with JQ1. (A) Time course of bcl-2 protein downregulation in response to JQ1 measured by flow cytometry. MFI = mean fluorescence intensity, corrected for isotype control. (B) Time course of delta priming to BAD-BH3 and MS1-BH3 measured by cytochrome C release after drug treatment and additional incubation with the indicated BH3 peptides. Values are corrected for Cytochrome C release with peptide only as described in the methods. (C) Cells were incubated with 250 nM JQ1 for 2 days. 10nM pladienolide B (PLB), 1 \u03bcM torin1, 10nM ABT-199 (199), 1 \u03bcM etoposide (ETO) or 10 nM AC220 were added for the final 4 hours. Cells were then fixed and processed for Cytochrome C release. Bright blue bar height = cytochrome C release with both agents in combination-", "type": "figure"}, "FIGREF6": {"text": "Fig. Sensitivity to ABT-199 and TW-37 in AML cell lines. We antagonised BCL-2 with ABT-199 [31] and MCL-1 with TW-37 [44]. The IC 50 s shown were obtained from alamar blue assays after treating 11 AML cell lines at a starting cell concentration of 2.5x10 5 /ml for 48 hours. Each cell line thawed is tested around the time of its final passage to authenticate its provenance using the Powerplex 16 kit (Promega, Southampton, UK) to amplify short tandem repeats. The reactions are run on a 3130 Genetic Analyser and data analysed using Genemap- per. Mycoplasma testing was carried out routinely using the Mycoalert mycoplasma detection kit (Lonza, Rockland, USA) and following the manufacturer's instructions. (TIF) S2 Fig. Dynamic BH3 profiling assay: Delta priming to PUMA-BH3 with additional anti- AML drugs. Delta priming is measured by cytochrome C release after 4 hour drug treatment and additional incubation with 3 \u03bcM PUMA-BH3. Values are corrected for Cytochrome C release with peptide only as described in the methods). (Mean+/-SD for n = 3)", "type": "figure"}, "FIGREF7": {"text": "Fig. Dynamic BH3 profiling assay: Delta priming with TG02 and ABT-199 to BAD-BH3 and MS1-BH3 peptides. Delta priming is measured by cytochrome C release after TG02 (50 nM) and ABT-199 (50 nM) treatment and additional incubation with the indicated BH3 peptides. Values are corrected for Cytochrome C release with peptide only as described in the methods). (Mean+/-SD for n = 3). (TIF) S4 Fig. Dynamic BH3 profiling assay: Delta priming with additional anti-AML drugs to BAD-BH3 and MS1-BH3 peptides. Delta priming is measured by cytochrome C release after drug treatment and additional incubation with the indicated BH3 peptides (BAD-BH3 at 3 \u03bcM, MS1-BH3 at 3 \u03bcM, PUMA2A control at 100 \u03bcM). Values are corrected for Cytochrome C release with peptide only as described in the methods). (Mean+/-SD for n = 3). (TIF) S5 Fig. Additional indicators of co-operative induction of apoptosis by ABT-199 with pla- dienolide B, torin1, etoposide and AC220: FACS plots. Cells were incubated with the indi- cated combinations of 10 nM ABT-199, 10 nM pladienolide B, 1 \u03bcM torin1, 1 \u03bcM etoposide or 10 nM AC220. After 4 hours cells were incubated for a further 75 minutes with DiOC 6 to measure #\u0394\u03c8m. 7-AAD was added to the cells for the final 30 minutes of the incubation. The FACS plots illustrate that the treated cells stained by 7-AAD (indicating cell membrane perme- ability at a final stage of apoptosis) tend to lag very slightly behind cells with #\u0394\u03c8m, indicating rapid transition from #\u0394\u03c8m to irreversible apoptosis. (TIF) S6 Fig. Dynamic BH3 profiling assay: A-1210477. Delta priming is measured by cytochrome C release after A-1210477 treatment and additional incubation with the indicated BH3 pep- tides. Values are corrected for cytochrome C release with peptide only as described in the methods. Results from priming with 10nm pladienolide are illustrated as positive control (<10% priming without peptide, strong priming with peptide) (Mean+/-SD for n = 3). (TIF)", "type": "figure"}, "TABREF0": {"text": "Agents expected to antagonise or downregulate BCL-2 or MCL-1.", "type": "table"}}}
{"paper_id": "42951584", "_pdf_hash": "d9781b670b0f7889f3ad95c0bc16e90c89b4b746", "abstract": [{"section": "Abstract", "text": "Abstract-Ground-based GNSS reflectometry (GNSS-R) systems can be realized by different means. The concept of correlation between direct and reflected GNSS signals is basically possible with all GNSS systems. However, using signals from the Russian GLONASS system simplifies the signal processing so that software-defined radio (SDR) components can be used at replace expensive hardware solutions. This paper discusses how such a solution, called GLONASS-R, can be realized using entirely off-the-shelf components. Field tests with such a system demonstrate the capability to monitor sea surface heights with a precision of 3 cm or better even with a sampling rate of 1.5 Hz. The flexibility of a SDR and the simple concept of GLONASS-R allow build such a system with low costs and adapt it to the needs of any ground-based GNSS-R problem.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "I. INTRODUCTION", "text": "I N ORDER to monitor sea-level changes, it is not only necessary that precise measurements are carried out over long time, but it is also crucial that these measurements are georeferenced in an absolute global reference frame [1] . In particular, when data collected with coastal sea-level sensors (hereafter called \"tide gauges\") are interpreted, it is important to know the movements of the continental crust at the sites where these sensors are deployed. Under this aspect, ground-based GNSS reflectometry (GNSS-R) appears to be an attractive application for monitoring long-term sea-level changes since GNSS-R relates directly to a global reference frame.", "cite_spans": [{"start": 226, "end": 229, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "As for ground-based GNSS-R, one can distinguish between two different concepts. First, there are systems which receive direct and reflected signals via one single antenna and require the extraction of reflector heights from the interpretation of signal-to-noise ratio (SNR) data (see e.g., [2] - [6] ). In these cases, usually commercial geodetic GNSS equipment is used to obtain information about reflector heights. As a second method of retrieving ground-based sea-level measurements, one can utilize two antennas, one uplooking antenna for receiving the direct signal from the satellites, and one downlooking antenna which is dedicated to receiving reflected signals from the water surface (see [7] - [10] ). Also for this method, commercial GNSS equipment is used; however, sea-level heights are obtained from analyzing carrier-phase observations of the direct and reflected signals. In general, it can be stated that single (uplooking) antenna studies are usually carried out when existing groundbased GNSS infrastructure has already been deployed and its data can be easily accessed. Concepts with two antennas are usually developed when reflected signals need to be processed by dedicated algorithms and/or when the scattered power is low and only high-gain downward looking antennas can help to detect ground reflections.", "cite_spans": [{"start": 290, "end": 293, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 296, "end": 299, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 698, "end": 701, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 704, "end": 708, "text": "[10]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "In the following, the dual-antenna concept will be chosen and a simple direct correlation reflectometry system by means of GLONASS and software-defined radio (SDR) will be presented.", "cite_spans": [], "ref_spans": []}, {"section": "II. GLONASS-R", "text": "In its most simple form, GNSS-R operates like a passive bistatic radar [11] , i.e., processing reflections from objects or surfaces by taking advantage of natural or artificial signal transmitters. Such a concept is realized by comparing direct and reflected signals concerning delay and signal strength. In doing so, one can derive properties of the reflector and its location w.r.t. the receiving antennas [12] . Since most GNSS signals are based on a code division multiple access (CDMA) scheme, correlation of direct and reflected signals requires complicated signal processing methods as signals from several satellites appear in the same frequency band. Among those approaches, satellite selection via antenna directivity [13] is the most frequently used method to enable direct correlation of the signals. However, this requires that the beam of at least one antenna is steerable and/or limited in its spatial extent in order to suppress signals from other GNSS satellites.", "cite_spans": [{"start": 71, "end": 75, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 408, "end": 412, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 728, "end": 732, "text": "[13]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "II. GLONASS-R", "text": "An alternative solution that enables direct correlation has been presented by [14] where the authors utilized the frequency division multiple access (FDMA) encoding scheme of the Russian Global Navigation Satellite System (GLONASS) space segment. Results from this first study indicate that sea surface height can be monitored in real time with cm-level precision from ground-based GNSS-R installations. However, the need for complex and expensive RF front ends, downconversion stages, and A/D converters made the so-called GLONASS-R system rather unattractive for being duplicated at other coastal sites. This problem is thought to be overcome by replacing those unflexible components with off-the-shelf SDR equipment. This not only does lead to a drastic price Fig. 1 . Overview of the GLONASS-R concept. Direct and reflected signals are received via dedicated RHCP and LHCP antennas and digitized by two URSP devices which are synchronized with each other. The sampled data are sent to a commodity PC over a 1 GbE connection and stored in two circular buffers. A thread which controls the processing on the GPU fetches data from those buffers, copies them to the GPU and computes interferometric delays, phases and amplitudes for all visible GLONASS satellites. Once the processing of a data batch has been completed, results are copied back to the CPU and the next sampling data are copied to the GPU. reduction but also increases the flexibility of the GLONASS-R concept. Furthermore, advances in graphics processing unit (GPU) architecture enable us now to change the signal processing chain in a way which handles the data more efficiently, thus leading to a higher throughput while still preserving the real-time capability of the original concept.", "cite_spans": [{"start": 78, "end": 82, "text": "[14]", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "A. SDR Integration", "text": "SDR [15] is a very powerful and flexible concept for prototyping and quick realization of projects without the need of application-specific integrated circuit (ASIC) boards. Thus, SDR is a very appealing solution which helps to implement a novel GNSS-R concept with much lower prototyping and development cost. As signal processing can be carried out on a PC, such a GNSS-R solution can be built with off-the-shelf components and adapted in a very flexible way before or during any development phase. Therefore, also [14] have chosen SDR in order to implement their concept of GLONASS-R. However, their first implementation was limited in flexibility due to the fixed frequency setting of the RF front ends and the choice of the analog-digital (A/D) converters. In order to overcome these limitations, the Ettus URSP N210 has been selected to increase the flexibility of the receiver. It was demonstrated in [16] that the USRP N210, which covers all GNSS frequencies, can be used to realize a GNSS software receiver. Thus, this technology was chosen to develop a new version of the GLONASS-R system. Fig. 1 depicts how two USRPs are used to acquire continuous data streams of digitized GLONASS signals.", "cite_spans": [{"start": 4, "end": 8, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 517, "end": 521, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 908, "end": 912, "text": "[16]", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "A. SDR Integration", "text": "In order to make sure that direct, i.e., right-hand circular polarized (RHCP), and reflected, i.e., left-hand circular polarized (LHCP), signals are received coherently, a so-called MIMO cable is applied between the two USRPs. Although only coherence between the two units is required for an interferometric system, external 10 MHz and 1 pulse-persecond (PPS) signals are fed to the \"master\" device. In doing so, one can, at any stage, independently process either RHCP or LHCP data streams and is not affected by drifts of the USRP onboard oscillators. The MIMO cable simplifies also data transfer as samples taken from the \"slave\" device are sent to the \"master\" unit from where the data are time stamped, packetized, and transmitted over a standard 1 Gigabit Ethernet (GbE) connection. The latter feature allows to put the GLONASS-R system at remote places or harsh environment, given that a stable GbE connection between the \"master\" USRP and the PC, which carries out the signal processing, is provided. As the sampling rate of the IQ digital down-converter (DDC) equals the receiver's bandwidth, 12.5 Mega samples per second (Msps) are sufficient to cover the whole GLONASS L1 band in case the center frequency is set to 1602 MHz. Given that the real and imaginary parts of a sample are represented as 8-bit words each, one gets a total data rate of 2 \u00d7 2 \u00d7 8 bit \u00d7 12.5 \u00b7 10 6 = 400 Mbps that contains both RHCP and LHCP data streams. Such a data rate is well below the GbE limit, though it poses the risk of back logging when the signal processing chain cannot keep the pace with the incoming amount of data. In order to avoid bottlenecks and ensure real-time processing of the incoming data stream, data buffering and signal processing have been split between the PC's central processing unit (CPU) and the GPU which does the heavy signal processing. As already discussed in [14] , data parallelism and the use of high-performance signal processing algorithms on the GPU ensure that even higher data rates can be handled in real time.", "cite_spans": [{"start": 1884, "end": 1888, "text": "[14]", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "B. GLONASS-R Receiver on the GPU", "text": "A continuously running process on the CPU receives data packages from the USRPs and stores them in circular buffers.", "cite_spans": [], "ref_spans": []}, {"section": "B. GLONASS-R Receiver on the GPU", "text": "A second process runs a program on the GPU which picks data from these buffers, and computes interferometric information between the direct and reflected signals. Other than GPS or similar CDMA-based satellite systems, GLONASS signals enable direct correlation since the individual satellite signals are clearly distinguishable in the frequency domain. Thus, at its first stage, the GPU-based receiver performs Fourier transforms on the RHCP and LHCP signals. In the original concept presented in [14] data lengths of one millisecond were handled in this way. However, at a later stage, coherent integration was required to achieve sufficient SNR and extract meaningful interferometric phases. This drawback has now been avoided by Fourier transforming 8 388 608 samples, which equals data from about 0.67 s, and making use of high-performance inplace fast-Fourier transformations (FFTs). NVIDIA's compute unified device architecture (CUDA) provides a library which also supports such long FFT transformation while still fulfilling the requirements for real-time processing of the incoming data streams.", "cite_spans": [{"start": 497, "end": 501, "text": "[14]", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "B. GLONASS-R Receiver on the GPU", "text": "After RHCP and LHCP data streams have been Fourier transformed (see Fig. 1 ) and the complex cross spectrum has been obtained, simple orbital information in the form of two-line element [17] strings and a rough estimate of the receiver location are sufficient to determine which satellites are above the local horizon and need to be considered further in the signal processing chain. Based on the knowledge of which GLONASS satellite is visible at the site, a bandpass filter with a width of 562.5 kHz and a center frequency corresponding to the carrier frequency of that satellite can be applied to avoid that the interferometer phase contains information other than those from the selected satellite. As depicted in Fig. 1 , an inverse Fourier transformation immediately provides the interferometric delay between the direct and reflected signal. By using this coarse delay information, one can rotate the cross-spectral phases across the whole bandpass, provide a delay corrected complex cross spectrum, and obtain interferometric phase and amplitude for a particular satellite. This approach needs only 2 FFTs and S inverse FFTs to obtain the interferometric information for all S satellites for a given data batch. Memory restrictions on the GPU make it necessary that satellites are dealt with serially. In addition to the high-performance FFTs provided via CUDA, also fast algorithms for detection of the correlation peak, i.e., extraction of the interferometric delay, and the summation of the corrected cross spectra are necessary. Both reduction tasks can be realized by taking advantage of the concept of parallel prefix computation [18] which maps perfectly to GPU architectures. In doing so, peak search and summation algorithms follow only O(log 2 (N )) which makes the choice of large FFTs (of size N ) even more attractive.", "cite_spans": [{"start": 186, "end": 190, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 1644, "end": 1648, "text": "[18]", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "B. GLONASS-R Receiver on the GPU", "text": "Performance tests with a NVIDIA Tesla K40 have shown that it is possible to run a complete GLONASS-R receiver with up to 12 satellites in real time while maintaining data rates of 12.5 Msps from RHCP and LHCP channels. After all visible satellites are processed, the GPU process transfers interferometric delays \u03c4 i,t , phases \u03c6 i,t , and correlation amplitudes \u03c1 i,t back to the CPU where this information is stored in text files. Indices i and t denote the satellite number and the discrete sampling epoch, respectively. The GPU thread will then fetch the next batch of data from the ring buffer and continue with the next data batch. This process is running continuously until the user stops either the CPU thread which controls the ring buffering or the thread which runs the GPU kernels. Based on this concept, successful and uninterrupted real-time operation of the GLONASS-R was confirmed over a period of several weeks (see Section III).", "cite_spans": [], "ref_spans": []}, {"section": "C. Postprocessing", "text": "From the three observables, \u03c4 i,t , \u03c1 i,t , and \u03c6 i,t , the latter one, i.e., interferometric phase, is providing the most precise measurements which contain information about the geometric relation between the height h(t) of the LHCP antenna above the reflector and the elevation angle \u03b5 i,t under which the ith satellite is seen. As the vertical distance \u03b4 between the two antenna phase centers is known with mm-accuracy, one can express the observed phase as", "cite_spans": [], "ref_spans": []}, {"section": "C. Postprocessing", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "C. Postprocessing", "text": "has been introduced as the virtual height above the reflector. In (1), mod 2\u03c0 denotes the modulo 2\u03c0 operator. The unknown phase bias \u0394\u03c6 i is caused by different electrical path lengths of the RHCP and LHCP signals, which have been confirmed to be constant over the duration of a satellite passage. Given that usually several GLONASS satellites are visible at the same time, (1) portrays an over-determined problem in the case that the functional model of the reflector height h (t) is not expressed by more parameters than the total number of phase observations. Phases from several satellites are obtained every 0.67 s, and it is obvious that even a moderate choice for the temporal resolution of the reflector height leads to a strong over-determined problem. However, the inversion, i.e., the estimation of such a functional model in dependence of the observations, is not a trivial task due to the presence of the modulo operator. Classical least-squares approaches [19] cannot handle this problem due to the discontinuity caused by the modulo operator. Nonlinear minimization algorithms could be applicable; however, a priori values for the unknown model parameters need to be chosen carefully to make sure that such an algorithm converges toward a global minimum. On the other side, if phases would be connected or unwrapped before (1) is inverted, the modulo operator disappears and the unknown number of integer phase cycles gets absorbed into the phase offset \u0394\u03c6 i . This leads to the idea of stepwise inversion of phase data.", "cite_spans": [{"start": 970, "end": 974, "text": "[19]", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "C. Postprocessing", "text": "1) Phase Unwrapping: Connection of phases, hereafter called \"phase unwrapping\" requires that the interferometer phase is not varying by more than a half-cycle between two consecutive epochs. Assuming that the reflector height is not changing during one satellite passage, phase changes for low elevation angles can be approximated to first order by h", "cite_spans": [], "ref_spans": []}, {"section": "C. Postprocessing", "text": "Given that the GNSS-R system is located only a few tens of meters above the reflecting surface and considering that interferometric data are taken with sampling rates of about than 1.5 Hz, it is obvious that phase connection should be feasible for all GNSS wavelengths. Knowing that ( Results from the unwrapping of these phases with the help of the Octave \"unwrap\" function are shown in the middle. It is clearly visible that phase noise at two or more consecutive epochs leads to discontinuities in the time series. The lower plot depicts the phase unwrapping results when a boot strapping method with a background model for the reflector height is applied (see Section II-C1). Using this approach, all discontinuities are removed and the unwrapped phase time series can be used for reflector height retrievals (see Section II-C2 and II-C3).", "cite_spans": [], "ref_spans": []}, {"section": "\u00b7 10", "text": "\u22124 rad/s and considering an extreme height of 100 m, interferometer phases should not change by more about 2 cm (or a tenth of a GNSS wavelength) over 0.67 s, i.e., using a sampling rate of 1.5 Hz. However, this does not consider the fact that individual interferometric phases have an uncertainty that is inverse proportional to the SNR of the cross-correlated signals. This means that phase connection algorithms should not only consider rapid changes of the geometric delay but also deal with the problem that phase observations are noisier at lower elevation angles. Many mathematical software packages provide functions that connect phases, though all implementations tested in this study did not consider the global smoothness of the resulting unwrapped phase time series. On the other side, if one has a good enough functional model that explains the relation between the observed phases and the physical source, simple boot strapping, i.e., empirical minimization of residuals, can be used to unwrap the phases. In order to apply this idea to the interferometric phases from the GLONASS-R system, one needs to assume that the reflector height is not changing during the data period which is considered for phase connection. Following (1), we can define the cost function", "cite_spans": [], "ref_spans": []}, {"section": "\u00b7 10", "text": "and search for a global optimal set of parameters (p 1 , p 2 ) which minimize the sum of the squared residuals over one satellite passage, i.e.,", "cite_spans": [], "ref_spans": []}, {"section": "\u00b7 10", "text": "Based on the set of parameters (p 1 , p 2 ), one can then unwrap the raw interferometer phases by adding/subtracting integer numbers of cycles M i for each observation so that Fig. 2 depicts the robustness of this phase unwrapping concept.", "cite_spans": [], "ref_spans": [{"start": 176, "end": 182, "text": "Fig. 2", "ref_id": "FIGREF0"}]}, {"section": "\u00b7 10", "text": "Unwrapping the raw interferometer phases with a standard function of Octave [20] fails when two or more consecutive epochs contain noisy data, causing the unwrapped phase to jump by more than one cycle. As Octave's algorithm does only connect phases based on the differences between consecutive data points, any wrong unwrapping at an epoch of high phase noise will lead to steps (see Fig. 2 , middle plot) which can be later misinterpreted as sea surface changes. The bootstrapping algorithm, however, produces a smooth time series of unwrapped interferometer phases as shown in the lower plot of Fig. 2 . Periods of low SNR, i.e., high phase noise, do not affect the overall shape of the unwrapped phase time series and thus will not influence the inversion of sea surface height. If the sea surface changes by more than a phase cycle, i.e., roughly 20 cm, the cost function (2) needs to be extended by a time variational term that considers temporal variations of the reflector height during one satellite passage. Another way of dealing with such a situation would be the splitting of satellite passage in subarcs, e.g., a rising and a setting part, in order to stay within the validity range of a constant height model during each arc period.", "cite_spans": [{"start": 76, "end": 80, "text": "[20]", "ref_id": "BIBREF19"}], "ref_spans": [{"start": 385, "end": 391, "text": "Fig. 2", "ref_id": "FIGREF0"}, {"start": 598, "end": 604, "text": "Fig. 2", "ref_id": "FIGREF0"}]}, {"section": "\u00b7 10", "text": "2) Fitting a Model for the Reflector Height Changes: A comparison of (1) and (2) reveals that p 1 = 2h which means that one could obtain sea-level heights directly from the phase unwrapping process described in the prior section. However, this goes along with the crude assumption that the reflector height does not change during the passage of one satellite. Valuable information concerning temporal changes of the reflector height is lost when using a constant height for each arc. This should be therefore avoided. Given that the unwrapped phase \u03c6 * i,t has already be obtained, one can reformulate (1) to", "cite_spans": [], "ref_spans": []}, {"section": "\u00b7 10", "text": "where the temporal variation of the reflector height is approximated by an analytical function H with N parameters x j . As described in [14] , a quadratic B-spline B 2 j (t) function is a suitable functional representation for temporal reflector height variations. The spacing of the knots relates to the temporal resolution of the model and determines the total number of unknowns which need to be estimated. This means that (4) can be expressed as a linear model in the form", "cite_spans": [{"start": 137, "end": 141, "text": "[14]", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "\u00b7 10", "text": "where x j are the so-called scaling coefficients for the corresponding quadratic B-spline functions with N nodes. Given the high sampling rate of the raw data and the fact that always several satellites are tracked in parallel, one can determine the unknown coefficients x j by a simple weighted least-squares approach. In doing so, the interferometric correlation amplitudes \u03c1 i can be taken as weights to avoid that phase data with low SNR contribute too much to the estimated model [14] . Phase offsets \u0394\u03c6 i are estimated as an additional parameter for each arc and can be used for obtaining sea-level heights with a temporal resolution equal to one of the raw interferometer phases.", "cite_spans": [{"start": 485, "end": 489, "text": "[14]", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "3) High-Rate Sea Surface Heights:", "text": "Given that phases are unwrapped and phase offsets \u0394\u03c6 i have been estimated from the prior steps, one can easily invert (1) and obtains", "cite_spans": [], "ref_spans": []}, {"section": "3) High-Rate Sea Surface Heights:", "text": "This means that reflector heights are available with the same temporal resolution as the interferometer phases are output from the software receiver. However, as stated before, usually more than one satellite is tracked per epoch. Thus, it appears to be logical to average all the data at a given epoch to obtain the most robust estimate of reflector height at a particular point in time. It was suggested in [14] to compute a weighted average over all satellites at each epoch, i.e.,", "cite_spans": [{"start": 409, "end": 413, "text": "[14]", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "3) High-Rate Sea Surface Heights:", "text": "In conclusion, it can be stated that different \"sampling rates\" are involved. These rates are summarized below in the order how data pass through the different signal and postprocessing blocks.", "cite_spans": [], "ref_spans": []}, {"section": "3) High-Rate Sea Surface Heights:", "text": "1) A sampling rate of 12.5 Msps is used to cover the whole GLONASS L1 in the RF. 2) Raw data streams with a length of 0.67 s are cross correlated to provide interferometer phases, delays, and amplitudes. Thus, a frequency of 1.5 Hz corresponds to the temporal spacing of these observations. 3) In the height estimation process, B-spline functions are used. These are continuous functions, but the temporal spacing of the nodes might also be considered as an implicit sampling restriction. In the following sections, a temporal resolution of two hours will be chosen for the B-spline nodes, which implies a low-pass filtering of the 1.5-Hz interferometer observations. In summary, GLONASS-R phase data can be inverted to sealevel height in three steps, where in each step, the temporal resolution of the obtained reflector height increases.", "cite_spans": [], "ref_spans": []}, {"section": "3) High-Rate Sea Surface Heights:", "text": "Step 1) Phase unwrapping algorithm and determination of arcwise constant reflector heights (see Section II-C1).", "cite_spans": [], "ref_spans": []}, {"section": "3) High-Rate Sea Surface Heights:", "text": "Step 2) Low-pass-filtered reflector height variations with a temporal resolution defined by the B-spline nodes (see Section II-C2).", "cite_spans": [], "ref_spans": []}, {"section": "3) High-Rate Sea Surface Heights:", "text": "Step 3) High-rate reflector heights using the arc phase biases from", "cite_spans": [], "ref_spans": []}, {"section": "3) High-Rate Sea Surface Heights:", "text": "Step 2) (see Section II-C3).", "cite_spans": [], "ref_spans": []}, {"section": "III. RESULTS", "text": "In order to test the new GLONASS-R architecture and the postprocessing strategies described above, a long-term test at the Onsala Space Observatory (OSO), Sweden was carried out in 2015. Fig. 3 depicts the location of the GNSS-R antennas as well as the recently build tide gauge that is part of the Swedish network of tide gauges operated by the Swedish Meteorological and Hydrological Institute (SMHI). This test not only did aim at the evaluation of the system by comparison with other colocated sea-level instruments but also demonstrated that the SDR concept can process the data in real-time over weeks without loosing a single epoch. As the GLONASS-R software receiver shares the same antennas with the GNSS-R system [10] , a direct comparison between the different systems is possible. The latter system is based on commercial GNSS receivers and can provide single-difference solutions [10] when using observations of the up-and downward looking antenna/receiver pair. As both commercial receivers are tracking GPS and GLONASS on L1 and L2 each, four individual single-difference phase solutions can be obtained. Moreover, SNR data from the upward looking antenna/receiver can be inverted to obtain four additional independent solutions. Measurements from the SMHI tide gauge can be utilized to evaluate how well the independent GNSS-R solutions agree with this reference. Over a period of three weeks in 2015, all systems were operated in parallel, and sealevel height was measured with the individual instruments (see Fig. 4) .", "cite_spans": [{"start": 723, "end": 727, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 893, "end": 897, "text": "[10]", "ref_id": "BIBREF9"}], "ref_spans": [{"start": 187, "end": 193, "text": "Fig. 3", "ref_id": "FIGREF1"}, {"start": 1527, "end": 1534, "text": "Fig. 4)", "ref_id": "FIGREF2"}]}, {"section": "A. Time Series Comparison", "text": "Although all sensors were operated during the whole test period, clear gaps can be seen in some of the time series. First, the SMHI tide gauge underwent final testing before producing official measurements, including adjustment, and calibration of the radar sensor and thus did not record data between June 15 and 19, 2015. The commercial GNSS receivers connected to the RHCP and LHCP antennas were recording during the whole period, but strong winds which lead to a rougher sea surface caused the receiver connected to the LHCP antenna to loose lock and thus made it impossible to apply the single-difference postprocessing scheme during these periods. Therefore, four large gaps in the GNSS phase solutions can be found (see Fig. 4 ), leaving the SNR solutions as the only continuous time series over the whole period. However, the irregular and rather sparse temporal spacing of these time-series makes it impossible to deduce spectral characteristics from the SNR method.", "cite_spans": [], "ref_spans": [{"start": 727, "end": 733, "text": "Fig. 4", "ref_id": "FIGREF2"}]}, {"section": "A. Time Series Comparison", "text": "The GLONASS-R system was operating all the time and recorded interferometer phases which were unwrapped with the method described in Section II-C1. The B-spline approach with a temporal resolution of two hour was used to low-pass filter these raw phases and estimate the phase biases for each satellite passage. By back substitution of these biases, one can obtain sea-level measurements with a temporal resolution of about 0.67 s. As shown in Fig. 4 , the SMHI tide gauge data and the GLONASS-R measurements reveal the same pattern of sea level. Also the single difference GNSS phase solutions reveal a very similar pattern, though the large number of gaps make it difficult to judge this by naked eye. As for the SNR solutions, the agreement is less clear as all of the four time series appear to be rather noisy with a scattering that amounts to a significant fraction of the daily variation of sea level. The SMHI tide gauge has a sampling rate of only one minute which means that the two instruments can only be compared at the epoch of the radar tide gauge. As the sampling of the SNR and single difference solution is irregular and larger than those of the GLONASS-R results, tide gauge data were interpolated to match the epochs of the data from the GNSS-R system based on commercial GNSS receivers. Fig. 5 depicts the root-mean-square error (RMSE) of the individual time series w.r.t. the SMHI tide gauge after removing a mean offset from each series. The SNR solutions agree with the official tide gauge measurements with a standard deviation between 8 and 10 cm, and the single difference solutions from GPS and GLONASS phases reveal RMSE values between 5 and 6 cm. These values are slightly larger than those Fig. 5 . RMSE of the individual time series w.r.t. the SMHI tide gauge measurements. Note: As offsets were removed before computing RMSE, the results can also be interpreted as standard deviations of the time series differences.", "cite_spans": [], "ref_spans": [{"start": 444, "end": 450, "text": "Fig. 4", "ref_id": "FIGREF2"}]}, {"section": "A. Time Series Comparison", "text": "reported in [10] , though one has to consider that during the whole period of the experiment, relatively strong winds were present at the OSO. Both GLONASS-R solutions, the lowpass filtered B-spline results and the inverted interferometer phases, show smaller RMSE w.r.t. the SMHI tide gauge. The Bspline results have a RMSE below 2 cm and the high-frequency measurements agree with the tide gauge data with a standard deviation slightly larger than 3 cm. The better agreement of the GLONASS-R results can be attributed to the way how relative phases between direct and reflected signals are obtained. The GNSS-R system based on commercial receivers tracks RHCP and LHCP signals independently, and cycle slips, which are more likely in the weaker and more disturbed LHCP channel, are occurring more often and thus complicate and weaken the single difference solutions. On the other side, the GLONASS-R system which measures the interferometer phase directly might be also affected by weak signals due to rough surface conditions, but both the long integration time of 0.67 s and the model-based phase unwrapping approach avoid that phase data from low SNR trackings impact the inversion process strongly. In order to check whether GLONASS-R measurements vary in dependence of the wind speed, i.e., agree less with tide gauge data when the sea surface roughness increases, standard deviations between the two time series were computed for different wind speed categories.", "cite_spans": [{"start": 12, "end": 16, "text": "[10]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "A. Time Series Comparison", "text": "These results are depicted in Fig. 6 , and it is confirmed that the GLONASS-R system provides data with the same precision independent of the wind speed, respectively, the resulting sea surface roughness. This differs from the findings reported in [14] where it was concluded that higher wind speeds lead to less precise sea-level retrievals from the GLONASS-R system. However, the system discussed in Section II differs from the earlier concept in many aspects, whereas the fact that coherent integration has been replaced by the usage of very large FFTs is expected to be the main contributor in making the system more robust against weak signals corresponding to reflections from rough sea surfaces.", "cite_spans": [{"start": 248, "end": 252, "text": "[14]", "ref_id": "BIBREF13"}], "ref_spans": [{"start": 30, "end": 36, "text": "Fig. 6", "ref_id": "FIGREF3"}]}, {"section": "A. Time Series Comparison", "text": "Having studied how well the individual time series agree w.r.t. the SMHI tide gauge measurements, the question remains whether and to which extent the GLONASS-R is able to sense sea-level signals.", "cite_spans": [], "ref_spans": []}, {"section": "B. Spectral Analysis", "text": "During the whole period of the experiment only, the GLONASS-R time series have a regular sampling and do not contain data gaps. Tide gauge data are available with a regular but coarser temporal resolution, though the data gap around June 15 splits the time series in two parts. In order to avoid bridging a gap of more than two days, only the period between June 19, 2015 , and the end of the experiment, i.e., July 3 is considered in the following. The sampling rates of 0.67 s for the GLONASS-R solution and 60 s for SMHI tide gauge observations define the Nyquist frequency for any spectral analysis. B-spline low-pass-filtered results are available at any arbitrary resolution as the sea surface is described by a continuous function model [see (5)]. However, periods less than the temporal spacing of the B-spline nodes should not be considered due to the strong effect of the low-pass filtering process. In the following, the B-spline solution has been evaluated with a temporal spacing equal to the SMHI tide gauge, i.e., 60 s, but spectral components with periods less than 7200 s were removed to preserve only the meaningful parts of the spectrum. Power spectral density estimates were computed for all three time series using Welch's method [21] . Fig. 7 depicts these spectra in dependency of the signal period. It is clearly visible that both GLONASS-R results and the tide gauge measurement have identical spectral components for periods longer than 3 h (10 800 s). Distinct peaks, in particular those corresponding to daily and half-daily signals can be assigned to ocean and atmosphere tides. The latter one might be unexpected, but given that the half open bay at the OSO is causing sea surface to correlate strongly with air pressure changes, it is not a surprise that not only ocean but also atmospheric tides contribute to the pattern of sea level at various time scales.", "cite_spans": [{"start": 1251, "end": 1255, "text": "[21]", "ref_id": "BIBREF20"}], "ref_spans": [{"start": 1258, "end": 1264, "text": "Fig. 7", "ref_id": "FIGREF4"}]}, {"section": "B. Spectral Analysis", "text": "For periods shorter than 3 h, GLONASS-R and the SMHI tide gauge time series seem to contain no clear peaks. However, one notices that the GLONASS-R spectrum has a slope which is less steep than those of the tide gauge. This might be attributed to the fact that the radar tide gauge is hosted inside a stilling well which is connected to the open water by a couple of underwater pipes. Thus, sea level as sensed by the GLONASS-R system is strictly speaking a snapshot of the sea surface corresponding to the average of the satellite's footprints/Fresnel zone as seen from the LHCP antenna. On the other side, the water level inside the well is determined by the integral pressure of the sea water next to the tide gauge. Thus, the stilling well acts as a low-pass filter; in particular, it does not map outside sea surface conditions as stimulated by wind to the inside where the radar is mounted. Thus, it is obvious that the spectra start to differ for wavelengths which are r elated to winds and local conditions.", "cite_spans": [], "ref_spans": []}, {"section": "B. Spectral Analysis", "text": "In addition, it appears that the GLONASS-R spectrum flattens out for periods shorter than 100 s which indicates that the instruments' noise level starts to dominate the spectral content for such short periods. Thus, one can state that the GLONASS-R system is capable to detect exactly the same tidal periods as measured by the conventional tide gauge. In general, one needs to take into account that for the interpretation of shorter period signals, one should recall that any GNSS-R system represents the average sea surface heights of all satellite foot-prints, whereas an in-situ or stilling well-hosted tide gauges basically monitor an integral of the water level next to the tide gauge.", "cite_spans": [], "ref_spans": []}, {"section": "IV. CONCLUSION AND OUTLOOK", "text": "The GLONASS-R concept, first presented in [14] , has been developed further by making use of SDR off-the-shelf components and optimizing the signal and postprocessing strategies. Several test runs, including a long-term experiment over three weeks (see Section III), confirm the potential of the system. Signal processing on the GPU proves to be a suitable solution to handle the large sampling rates and process up to 12 satellites in real time. Since all components are commercially available at rather moderate prices, GLONASS-R systems can be duplicated fairly easy and tested on other sites. Looking through the list of necessary components, it appears that the high-end geodetic GNSS antennas would amount for the largest fraction of the total cost of a GLONASS-R system. Such antennas were used as they existed already at the OSO GNSS-R site. If one wants to duplicate a complete GLONASS-R system, much cheaper GLONASS capable antennas are available as commercial products, and even dedicated LHCP antennas are sold for prices less than those of standard gaming GPU cards.", "cite_spans": [{"start": 42, "end": 46, "text": "[14]", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "IV. CONCLUSION AND OUTLOOK", "text": "The long-term test, discussed in Section III, has demonstrated that the system can produce interferometric phases continuously with sampling rates of higher than 1 Hz. The updated signal processing concept of using large FFTs instead of coherent integration of shorter pieces of data has proven to be very successful. In particular, during periods of rougher sea surface conditions, the new cross-correlation approach still provides meaningful interferometer phases which do not cause artifacts in the inverted reflector height products. This goes along with the new postprocessing scheme, in which phase unwrapping is carried out by a boot-strapping approach using an empirical model of the reflector during the passage of one satellite. Although the three-step approach described in Section II-C has proven that it is capable of providing precise results with high temporal resolution, a direct inversion of the interferometer phases is expected be even more robust. However, this requires that (1), which contains the discontinuous modulo operator, can be used by a parameter estimation method. First efforts in this direction have been made, e.g., by [22] - [24] . Tests with such proposed algorithms have been carried out, but results indicated that the obtained sea surface height measurements contain more artifacts than those coming from the three-step approach. The main reason for this is found to be in the fact that there is no straightforward solution that allows to fit model parameters according to (1) . More theoretical work in this direction and the usage of mathematical algorithms which have been designed for similar problems are expected to overcome this drawback and improve the GLONASS-R products further.", "cite_spans": [{"start": 1155, "end": 1159, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 1162, "end": 1166, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 1514, "end": 1517, "text": "(1)", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "IV. CONCLUSION AND OUTLOOK", "text": "As shown in Section III, GLONASS-R agrees better with measurements of a colocated conventional tide gauge, than GNSS-R data from commercial GPS receivers do. The SNR method, using only data from the upward looking RHCP antenna, provides results even during period of rough sea surface conditions, but the precision of these temporally sparse sea surface measurements is only slightly better than about 10 cm. On the other side, single-difference phase solutions have the potential to be at least as precise as the GLONASS-R results (see [10] ); however, the fact that commercial GNSS receivers are dealing with reflected signals using standard GNSS tracking algorithms it happens rather often that cycle slips or large data gaps occur during periods when the reflector surface is rough. Thus, the single difference method fails or produces time series with rather low precision during such periods. The GLONASS-R system, which produces interferometer phases for all conditions, allows to deal with the circumstances of the reflector's physical properties, by considering the SNR values obtained from the software receiver. Moreover, as phases are obtained within the range [\u2212\u03c0, \u03c0], raw data are free of cycle slips and the boot-strapping phase unwrapping method described in Section II-C1 avoids that cycle slips are introduced at a later stage. Thus, it is not a surprise that the inverted GLONASS-R results agree with the tide gauge measurements on the level of 2 and 3 cm, for B-spline and high-frequency reflector height measurements, respectively.", "cite_spans": [{"start": 537, "end": 541, "text": "[10]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "IV. CONCLUSION AND OUTLOOK", "text": "Further tests and validation campaign with ground-based GNSS-R systems from different research groups are anticipated for the near future. In addition, tests with the GLONASS-R system on other locations are being considered as well.", "cite_spans": [], "ref_spans": []}, {"section": "IV. CONCLUSION AND OUTLOOK", "text": "In general, the concept presented here has to be seen under the consideration of GLONASS modernization plans which include the possible use of the CDMA technique instead of the current FMDA concept. 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Unwrapping interferometer phases from a test run in March 2015. The upper plot depicts the raw interferometer phases of a GLONASS satellite (Kosmos 2474) during its passage. Results from the unwrapping of these phases with the help of the Octave \"unwrap\" function are shown in the middle. It is clearly visible that phase noise at two or more consecutive epochs leads to discontinuities in the time series. The lower plot depicts the phase unwrapping results when a boot strapping method with a background model for the reflector height is applied (see Section II-C1). Using this approach, all discontinuities are removed and the unwrapped phase time series can be used for reflector height retrievals (see Section II-C2 and II-C3).", "type": "figure"}, "FIGREF1": {"text": "Fig. 3. Aerial image of the coastal area at the Onsala Space Observatory. The location of the GNSS-R system (latitude: 57.3930 \u2022 , longitude: 11.9135 \u2022 ) in the western part is marked with a green bullet, and the location of the newly built SMHI tide gauge (latitude: 57.3920 \u2022 , longitude: 11.9190 \u2022 ) is depicted in cyan.", "type": "figure"}, "FIGREF2": {"text": "Fig. 4. Upper plot: Tide gauge measurements from 2015 are plotted together with GLONASS-R results and data obtained from the geodetic GNSS receivers. The latter include SNR and single difference solutions for GPS and GLONASS on both L1 and L2 frequencies. Mean values w.r.t. the tide gauge series have been removed, and to improve the readability of the figure, the time series were shifted with offsets of 30 cm. Lower plot: Wind speed measurements from the weather station at the Onsala Space Observatory.", "type": "figure"}, "FIGREF3": {"text": "Fig. 6. RMSE of the two GLONASS-R time series w.r.t. the SMHI tide gauge readings, grouped for different wind speeds.", "type": "figure"}, "FIGREF4": {"text": "Fig. 7. Power spectral density (PSD) estimates from the GLONASS-R time series and the tide gauge data for the period June 19-July 3, 2015.", "type": "figure"}}}
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{"paper_id": "42952558", "_pdf_hash": "37631141b1aaea3b8886a2077f8ab7c61be13bee", "abstract": [{"section": "Abstract", "text": "Abstract: The CMS and ATLAS experiments at the LHC have announced the discovery of a Higgs boson with mass at approximately 125 GeV /c 2 in the search for the Standard Model Higgs boson via notably the \u03b3\u03b3 and ZZ to four leptons final states. Considering the recent results on the Higgs boson searches from the LHC, we study the lightest scalar Higgs boson h1 in the Next-to-Minimal Supersymmetric Standard Model by restricting the next-to-lightest scalar Higgs boson h2 to be the observed 125 GeV /c 2 state. We perform a scan over the relevant NMSSM parameter space that is favoured by low fine-tuning considerations. Moreover, we also take the experimental constraints from direct searches, B-physics observables, relic density and anomalous magnetic moment of the muon measurements as well as the theoretical considerations into account in our specific scan. We find that the signal rate in the two-photon final state for the NMSSM Higgs boson h1 with the mass range from approximately 80 GeV /c 2 to 122 GeV /c 2 can be enhanced by a factor up to 3.5, when the Higgs boson h2 is required to be compatible with the excess from latest LHC results. This motivates the extension of the search at the LHC for the Higgs boson h1 in the diphoton final state down to masses of 80 GeV /c 2 or lower, in particular with the upcoming proton-proton collision data to be taken at center-of-mass energies of 13-14 T eV .", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "The Standard Model (SM) of particle physics has been very successful in explaining high-energy experimental results. One of the remaining questions is to find out what is the source of mass. The solution to this question in the SM is given by the mechanism introduced by Higgs, Englert and Brout [1] [2] [3] which introduces an additional scalar field whose quantum, the so-called Higgs boson, should be experimentally observable. In July 2012, a Higgs boson-like particle with mass at approximately 125 GeV /c 2 was announced to be discovered by the two experiments, ATLAS and CMS, independently at the LHC via notably the two most promising channels, H \u2192 \u03b3\u03b3 and H \u2192 ZZ * channel with a four-lepton final state [4] [5] [6] [7] . Meanwhile, the Tevatron collaborations also announced their new Higgs boson search results, based mainly on V H associated production with H \u2192 bb decay channel [8] , which supported the LHC \u223c125 GeV /c 2 Higgs boson-like particle discovery results. More data should be accumulated in order to test, with higher precision, the consistency between the data analysis results and the SM predictions on the signal strength. If a significant offset were to appear with a more precise measurement in the future, it could provide a window to new physics beyond the Standard Model (BSM).", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Supersymmetry (often abbreviated SUSY) [9] [10] [11] [12] is one of the theoretical options for BSM physics. It introduces a new symmetry between fermions and bosons. The most common SUSY framework is the Minimal Supersymmetric Standard Model (MSSM) [13] [14] [15] which keeps the number of new fields and couplings to the minimum. In the MSSM, the Higgs sector contains two Higgs doublets, which leads to a spectrum including two CP-even, one CP-odd and two charged Higgs bosons. The Lagrangian of the MSSM contains a supersymmetric mass term, the \u00b5-term. This mass term is invariant under supersymmetry and therefore it seems unrelated to the electroweak scale, although it is phenomenologically required to be in this scale. This leads to the well known \"\u00b5 problem\" [16, 17] in the MSSM. The simplest solution to this problem is the so-called Next-to-Minimal Supersymmetric Standard Model (NMSSM) [18] by introducing a new gauge singlet superfield which only couples to the Higgs sector in a similar way as the Yukawa coupling and can give rise to an effective \u00b5-term to solve the \"\u00b5 problem\". Meanwhile, this new singlet adds additional degrees of freedom to the NMSSM particle spectrum. In the CP conserving case, which is assumed in this paper, the states in the Higgs sector can be classified as three CP-even Higgs bosons h i (i = 1,2,3), two CP-odd Higgs bosons a j (j = 1,2) and two charged Higgs bosons h \u00b1 , for a total of seven observable states.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The extended parameter space of the NMSSM gives rise to a rich and interesting phenomenology, in particular related to the two lightest CP-even Higgs bosons h i (i = 1,2). Inspired by the discovery of the new particle with mass at approximately 125 GeV /c 2 from the LHC and also the small LEP excess (approximately 2\u03c3) at about 98 GeV /c 2 in e + e \u2212 \u2192 Zh with h \u2192 bb [19] , in this paper we study the lightest CP-even Higgs boson h 1 in the mass range down to approximately 80 GeV /c 2 , by assuming the next-to-lightest CP-even Higgs boson h 2 as the new particle at m \u223c125 GeV /c 2 , along the lines of the studies of Belanger, Ellwanger, Gunion, Jiang, Kraml and Schwarz [20] . The third CP-even Higgs boson is out of reach of current experiments due to its low cross section in our scanned parameter ranges. To distinguish our study from many other NMSSM studies [21] [22] [23] [24] [25] , we mainly focus on the regions of parameter space favoured by low fine-tuning [23, 46] considerations, with tan \u03b2 chosen small, \u00b5 ef f chosen positive with minimal variations and low soft SUSY-breaking masses of the stop sector M Q 3 and M t R . We choose an sbottom mass which is compatible with the SUSY search results at the LHC [26] [27] [28] . Furthermore, we perform our scan over the parameter space which can explain both dark matter [29] , (g \u2212 2) [30] and some other experimental constraints, described in section 3. For completely testing the compatibility of our chosen region of parameter space with the recent LHC results, we interface the package N M SSM T ools(version 4.1.0) [31] [32] [33] [34] [35] [36] [37] [38] with the newly public packages HiggsBounds\u22124 [40] and HiggsSignals\u22121 [41] * Additionally, we show in section 4 that the h 2 \u2192 XX (XX represents \u03b3\u03b3, ZZ, W W , \u03c4 \u03c4 , or bb) signal strengths can be compatible with the current experimental results, that signal strengths for an h1 with a mass below 110 GeV /c 2 having higher values than currently predicted by the Standard Model are possible, and that the current sensitivities of the LHC experiments are such that the Higgs boson h1 could be detected.", "cite_spans": [{"start": 1228, "end": 1232, "text": "[26]", "ref_id": "BIBREF22"}, {"start": 1233, "end": 1237, "text": "[27]", "ref_id": "BIBREF23"}, {"start": 1238, "end": 1242, "text": "[28]", "ref_id": "BIBREF24"}, {"start": 1338, "end": 1342, "text": "[29]", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "Introduction", "text": "The structure of this paper is organized as follows. In section 2, we briefly introduce the Higgs sector of the NMSSM. The details of the parameter ranges we choose for the scan in the NMSSM parameter space are described in section 3. Section 4 shows the results of our numerical study including the Higgs boson h 2 signal strength in each decay mode and the discussion on the lightest scalar Higgs boson h 1 . The summary and outlook are given in section 5. ", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "In the right-hand side of the above formula, the first three terms are the Yukawa couplings of the quark and lepton superfields. The fouth term replaces the \u00b5-term \u00b5\u0124 u\u0124d of the MSSM superpotential. The last term, cubic in the singlet superfield, is introduced to avoid the appearance of a Peccei-Quinn axion, tightly constrained by cosmological observation [18] . The corresponding soft SUSY-breaking masses and couplings are given in the SLHA2 [43] conventions by [18] ", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "In Eq.1 and Eq.2, clearly the non-zero vacuum expectation value s of the singlet\u015c of the order of the weak or SUSY-breaking scale gives rise to an effective \u00b5-term", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "which solves the \"\u00b5 problem\" of the MSSM. Meanwhile, the three SUSY-breaking mass-squared terms for H u , H d and S appearing in L sof t can be expressed in terms of their VEVs (Vacuum Expectation Value) through the three minimization conditions of the scalar potential. Therefore, the Higgs sector of the NMSSM can be described by the following six parameters", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "in which each pair of brackets denotes the VEV of the respective field inside them. In addition to these six parameters of the Higgs sector, during the scan as described below we need to specify the squark and slepton soft SUSY-breaking masses and the trilinear couplings as well as the gaugino soft SUSY-breaking masses to describe the model completely.", "cite_spans": [], "ref_spans": []}, {"section": "Signal strength of Higgs boson", "text": "As in the Standard Model (SM), the main Higgs boson production processes include gluon-gluon fusion, vector boson fusion, Higgs-strahlung and associated production with a vector boson or tt. The most dominant process is gluon-gluon fusion followed by vector boson fusion and the other two associated production modes. In this paper, we will take all four production processes into account.", "cite_spans": [], "ref_spans": []}, {"section": "Signal strength of Higgs boson", "text": "We are interested in the Higgs boson signal strengths \u00b5 h i XX (XX = \u03b3\u03b3, ZZ, W W , bb, \u03c4 \u03c4 ), which are the relative ratios of the cross section times branching ratio (R", "cite_spans": [], "ref_spans": []}, {"section": "Signal strength of Higgs boson", "text": "In the NMSSM framework, the couplings of the Higgs bosons h 1 , h 2 and h 3 depend on their decompositions into the CP-even weak eigenstates H d , H u and S, which are given by [46] ", "cite_spans": [], "ref_spans": []}, {"section": "Signal strength of Higgs boson", "text": "where the coefficients S i,u , S i,d quantify the amount of up-(down-) likeness and S i,s is a measure for the singlet component of a Higgs mass eigenstate. Then the reduced tree-level couplings of h i (i = 1, 2) to b quarks, t quarks and electroweak gauge bosons V relative to the SM value are [47] ", "cite_spans": [], "ref_spans": []}, {"section": "Signal strength of Higgs boson", "text": "In the NMSSM, the coupling of h 1 to photons relative to that in the Standard Model is increased due to contributions from non-SM particles in the inducing loop diagrams. These can be from stop squarks but also to an even larger extent from charged Higgsinos where they are proportional to \u03bb [44, 45] . In addition, the h 1 total width is smaller than that in the Standard Model due to a reduced coupling to b-quarks [47] . Both effects can serve to enhance the rate of the h 1 decay into two photons in some portions of parameter space.", "cite_spans": [], "ref_spans": []}, {"section": "Scans with constrained parameters", "text": "In the following, we will perform a specific scan in the NMSSM parameter space which favours a Higgs boson h2 with a mass close to 125 GeV /c 2 and with coupling strengths compatible with those measured at the LHC, and the Higgs boson h 1 having mass restricted in the range down to \u223c80 GeV /c 2 . The program package N M SSM T ools (version 4.1.0)[31-38] is used to compute the SUSY particle and NMSSM Higgs boson spectrum and branching ratios. N M SSM T ools contains four subpackages: N M HDECAY , N M SDECAY , N M SP EC and N M GM SB. The Fortran code N M HDECAY provides the Higgs boson masses, decay widths and branching ratios which will be used in this paper. Furthermore, the N M SSM T ools package applies the constraints from theory, constraints from direct Higgs boson searches at LEP [19] ", "cite_spans": [], "ref_spans": []}, {"section": "Scans with constrained parameters", "text": ") and the mass mixings \u2206M s , \u2206M d [48] [49] [50] [51] , and anomalous magnetic moment of the muon (g \u2212 2) constraints [30] . All these constraints are used to perform our scan. More details on the implementation of all these constraints in the package can be checked from the webpage of the N M SSM T ools program [31] .", "cite_spans": [], "ref_spans": []}, {"section": "Scans with constrained parameters", "text": "After careful study, we have chosen to use the following parameter ranges motivated by the theoretical and experimental considerations detailed below. We realize that these may not be unique; more general ranges consistent with these considerations could possibly be more efficiently obtained via techniques such as Markov Chain Monte Carlo (MCMC) as described in [39] .", "cite_spans": [], "ref_spans": []}, {"section": "Scans with constrained parameters", "text": "1. To keep large doublet-singlet mixing in the Higgs sector, we are more interested in large values of \u03bb, \u03ba (but small enough to avoid Landau pole below GUT scale), and to keep the fine-tuning as low as possible in a natural way, low values of tan \u03b2 [46] . Considering the anomalous magnetic moment of the muon (g \u2212 2) constraint, we keep \u00b5 ef f positive with minimal variations, in order to avoid finetuning [30] . Hence the 4 parameters are constrained in the following ranges 0.6 < \u03bb < 0.75, 0.2 < \u03ba < 0.3,", "cite_spans": [], "ref_spans": []}, {"section": "Scans with constrained parameters", "text": "2. The soft SUSY-breaking trilinear couplings A \u03bb and A \u03ba are varied in the ranges [18] \u2212100 GeV /c 2 < A \u03ba < \u221250 GeV /c 2 ,", "cite_spans": [], "ref_spans": []}, {"section": "Scans with constrained parameters", "text": "We remark that, constraining the parameters A \u03bb and A \u03ba in these ranges favor h 1 with higher signal strength as well as being in the mass range down to \u223c80 GeV /c 2 .", "cite_spans": [], "ref_spans": []}, {"section": "Scans with constrained parameters", "text": "3. In order to compare with the recent LHC search bounds [26] [27] [28] , we conservatively set the left-handed soft SUSY-breaking masses of the squark sector (M Q 1,2 ) and right-handed soft SUSY-breaking sup masses (M u R and M c R ) to 2500 GeV /c 2 , both of which are in the first two generations. We take low values of soft SUSYbreaking masses of the slepton sector (M L 1,2,3 , M e R , M \u00b5 R and M \u03c4 R ) as 300 GeV /c 2 to follow the (g \u2212 2) constraint [30] . Furthermore, we set the right-handed soft SUSY-breaking masses (M D R ) and the trilinear couplings (A D , A E and A U ) to 2500 GeV /c 2 and 1000 GeV /c 2 respectively. This results in light sbottom mass of approximately 400 GeV /c 2 < M b 1 < 1000 GeV /c 2 which is compatible with the recent LHC SUSY results. Hence we have", "cite_spans": [{"start": 57, "end": 61, "text": "[26]", "ref_id": "BIBREF22"}, {"start": 62, "end": 66, "text": "[27]", "ref_id": "BIBREF23"}, {"start": 67, "end": 71, "text": "[28]", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Scans with constrained parameters", "text": "4. The Higgs sector is strongly influenced by the stop sector via radiative corrections [52] , and also for fine-tuning reasons we further need to specify the soft SUSY-breaking masses of the stop sector [46] . We modify the N M SSM T ools code in order to constrain them to be rather low. After studying the properties of these parameters, we vary them simultaneously within", "cite_spans": [], "ref_spans": []}, {"section": "Scans with constrained parameters", "text": "(Eqs.9 and 10 presuppose a SUSY scale.)", "cite_spans": [], "ref_spans": []}, {"section": "Scans with constrained parameters", "text": "5. Concerning the relic density constraint [29] , the remaining gaugino soft SUSY-breaking masses are set to be within", "cite_spans": [{"start": 43, "end": 47, "text": "[29]", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "Scans with constrained parameters", "text": "180 GeV /c 2 < M 2 < 300 GeV /c 2 ,", "cite_spans": [], "ref_spans": []}, {"section": "Scans with constrained parameters", "text": "Then we perform our scan after the application of the constraints on the parameters as described above.", "cite_spans": [], "ref_spans": []}, {"section": "Numerical study", "text": "In section 2, we introduced the production processes and the signal strengths of the NMSSM Higgs bosons. In this section, we demonstrate that the constraints on the parameters as described in the above section can produce a next-to-lightest NMSSM scalar Higgs boson h 2 compatible with the observed state at the LHC with mass at approximately 125 GeV /c 2 . We concentrate our study on the lightest NMSSM scalar Higgs boson h 1 . Considering the relic density \u2126h 2 , we will focus on two cases, \u2126h 2 < 0.1102 (named case I) and 0.1102 < \u2126h 2 < 0.1272 (the \"WMAP\" window [53] , named case II). In all plots below, points for case I are represented by blue squares and case II by red triangles.", "cite_spans": [], "ref_spans": []}, {"section": "Mass distributions of the NMSSM Higgs bosons", "text": "Based on the constrained parameters, firstly we show the mass distributions of the two lightest NMSSM scalar Higgs bosons h 1 and h 2 in Fig. 1 [19] could still be allowed in the context of the NMSSM for points in the parameter phase space where the production rate of ee \u2192 Z * \u2192 Zh 1 with h 1 decaying into bb or \u03c4 \u03c4 (the channels searched for at LEP) are reduced or suppressed with respect to the SM. ", "cite_spans": [], "ref_spans": [{"start": 137, "end": 143, "text": "Fig. 1", "ref_id": "FIGREF1"}]}, {"section": "Signal strengths of the NMSSM Higgs boson h 2", "text": "In the NMSSM framework, not all the \u00b5", "cite_spans": [], "ref_spans": []}, {"section": "Signal strengths of the NMSSM Higgs boson h 2", "text": "Only the reduced couplings are calculated by NMSSMTools, we use the absolute values in the Standard Model[54] to calculate the total signal strength including four production modes mentioned in section 2.2. We also check that the differences of weights of the production mode are quite negligible between 7 and 8 T eV with repect to experimental uncertainties. In order to further test whether a given point in our scanned parameter space is allowed or excluded by the recent LEP, Tevatron and LHC results at 95% confidence level (CL), two new public tools are utilised.", "cite_spans": [], "ref_spans": []}, {"section": "Signal strengths of the NMSSM Higgs boson h 2", "text": "We use the public tool HiggsBounds\u22124 [40] to further compare Higgs sector predictions with existing exclusion limits of various search channels. The SLHA format files calculated by N M SSM T ools are used as the inputs for HiggsBounds\u22124. The main algorithm of HiggsBounds can be described in two steps. In the first step, HiggsBounds uses the expected experimental limits from LEP, Tevatron and the LHC [8, 19, 55, 56 ] to determine which decay channel has the highest statistical sensitivity. In the second step, only for this particular channel the theory prediction is compared to the observed experimental limits in order to conclude whether this parameter point is allowed or excluded at 95% CL.", "cite_spans": [], "ref_spans": []}, {"section": "Signal strengths of the NMSSM Higgs boson h 2", "text": "Then, compatibility with the measured mass and rates of the observed new state having a mass of \u223c125 GeV /c 2 is imposed, using the public code HiggsSignals\u22121 [41] . HiggsSignals\u22121 takes the predictions of an arbitrary model (here the NMSSM) as an input, providing a quantitative answer to the statistical question of how compatible the model predictions are with the Higgs boson search experimental results, especially signal strengths and the measured mass, by evaluating a \u03c7 2 calculation. The main results from HiggsSignals\u22121, which are used to further constrain our parameter space, are reported in the form of a \u03c7 2 value and the associated p-value. We consider that the given parameter point is compatible with the experimental constraints only if the p-value given by HiggsSignals\u22121 is greater than 0.05. By using these two programs in parallel, we obtain the most complete test for the scanned NMSSM parameter space.", "cite_spans": [], "ref_spans": []}, {"section": "Signal strengths of the NMSSM Higgs boson h 2", "text": "The allowed values for \u00b5 h 2 XX from the scan over the NMSSM parameter space are shown in Fig. 2 , where all the constraints described in section 3 have been applied. The results are shown before and after applying the additional constraints from the above two programs. We first show \u00b5 Table 1 in the Appendix[6, 7, 55, 56]. It is clearly visible that the parameter points compatible with both HiggsBounds\u22124 and HiggsSignals\u22121 provide theory predictions which are consistent with the experimental results. In Fig. 2 , by taking the di-photon final state as an example, we also show the signal strength \u00b5 h 2 \u03b3\u03b3 plotted against its mass in Fig. 2 (d) . From the right-hand plot, the \u00b5 h 2 \u03b3\u03b3 values cover the range 0.5 to 1.8 while the mass is in the range 120 GeV /c 2 to 132 GeV /c 2 , both of which are consistent with the new observed state within errors. It is clearly visible that the NMSSM can produce rates compatible with both the CMS and ATLAS results for both relic density cases. The plots show that the relatively sizable enhancements with respect to the SM rates for the \u03b3\u03b3 and ZZ final states reported by ATLAS are possible in the vicinity of 125 GeV /c 2 in the NMSSM framework and also possible for the relatively suppressed rates reported by CMS. We will now focus our discussion on the lightest NMSSM scalar Higgs boson h 1 by looking at the diphoton final state, and will further restrict ourselves to the case of CMS results only.", "cite_spans": [], "ref_spans": [{"start": 90, "end": 96, "text": "Fig. 2", "ref_id": "FIGREF3"}, {"start": 507, "end": 516, "text": "In Fig. 2", "ref_id": "FIGREF3"}, {"start": 640, "end": 650, "text": "Fig. 2 (d)", "ref_id": "FIGREF3"}]}, {"section": "Signal strengths of the NMSSM Higgs boson h 2", "text": "Over and above the constraints mentioned in previous sections, we now demand in addition that the mass of the NMSSM Higgs boson h 2 be explicitly compatible with that most recently measured by CMS for the newly-discovered boson, and that the h 2 signal strength in the diphoton channel be compatible at a more stringent level with that measured by CMS. In the most recent CMS results [7] , the SM-like Higgs boson mass has been measured to be 125.7\u00b10.3(stat.)\u00b10.3(syst.) GeV /c 2 . Assuming 3\u03c3 error, where \u03c3 is taken as the linear sum of the above statistical and systematic uncertainties, the mass of h 2 is constrained within the range", "cite_spans": [], "ref_spans": []}, {"section": "Signal strengths of the NMSSM Higgs boson h 2", "text": "We also demand that the signal strength \u00b5 ", "cite_spans": [], "ref_spans": []}, {"section": "Signal strengths of the NMSSM Higgs boson h 2", "text": "Based on these additional constraints, Fig. 3 shows the allowed values for the branching ratio of the h 1 \u2192 \u03b3\u03b3 decay mode in the NMSSM. The cyan solid line shows the quantity including error bands evaluated in the SM for the same mass [54] . From the plots, most of the points show that an enhanced branching ratio relative to that in the SM is possible for both relic density cases. The theory explanation for this enhanced two-photons branching ratio has already been introduced in Section 2.2. In Fig. 4 , we display the possible signal strengths \u00b5 h 1 \u03b3\u03b3 plotted against the Higgs boson h 1 mass. As seen from Fig. 4 , the remaining points selected after application of all the conditions discussed in Sections 3 and 4.2 indicate the possibility of the h 1 mass lying in the range between 80 GeV /c 2 to 122 GeV /c 2 for both relic density cases. Turning to the signal strength \u00b5 h 1 \u03b3\u03b3 , the figure shows that a sizable enhancement over the SM rate is possible for the Higgs boson h 1 for both relic density cases, reaching values as high as 3.5, corresponding to an h 1 mass of \u223c 90 GeV /c 2 . We note that, for the mass range between 100 GeV /c 2 and 110 GeV /c 2 , the allowed signal strengths \u00b5 h 1 \u03b3\u03b3 are lower, falling to \u223c0.9. In order to compare with our signal strength \u00b5 h 1 \u03b3\u03b3 , we also superpose the official CMS public exclusion limit plot in Fig. 4 . The yellow and green regions correspond to the uncertainties at 95% and 68% confidence interval respectively and the cyan solid line corresponds to the SM value. It is clearly seen that the NMSSM points above the solid black line (representing the CMS observed exclusion limit) are almost excluded by the CMS result in the mass range 110 GeV /c 2 to 122 GeV /c 2 . We note that there is a small interesting region that is favoured by a cluster of parameter points in the neighborhood of 120 GeV /c 2 . Especially, the points below 120 GeV /c 2 are already excluded by comparing with the solid black line. The remaining points lying between 120 and 122 GeV /c 2 could constitute a case of a so-called \"degenerate Higgs boson\" [57] which is outside the scope of our discussion in this paper. But it would be advisable to test this interesting scenario with the increased quantity of data and improved resolution in the future 13 and 14-T eV collisions at the LHC. To date, the present experimental results from the LHC do not cover the lower Higgs boson mass range between 80-110 GeV /c 2 in the H \u2192 \u03b3\u03b3 decay channel. In order to be able to make a conclusion for the NMSSM points in this mass range, which show the potential for sizeably enhanced signal strengths in the diphoton decay channel with respect to those predicted in the SM, a detailed analysis is needed taking into account especially the Z \u2192 ee background faking the diphoton signals. If the limit curve were to be extrapolated down to a mass of \u223c 80 GeV /c 2 and the measurement on the signal strength improved in the future experimental analysis, most of the NMSSM parameter space shown in Fig. 4 could be probed. Expected and observed exclusion limits on the signal strength from CMS[55] compared with the possible signal strengths of the process pp \u2192 h1 \u2192 \u03b3\u03b3 from the NMSSM parameter scan. Points for case I are represented by blue squares and case II by red triangles.The solid black line together with the black squares corresponds to the ratio of the CMS observed cross sections with respect to the SM predictions, and the dashed line is the expected ratio.", "cite_spans": [], "ref_spans": [{"start": 39, "end": 45, "text": "Fig. 3", "ref_id": "FIGREF6"}, {"start": 500, "end": 506, "text": "Fig. 4", "ref_id": "FIGREF7"}, {"start": 614, "end": 620, "text": "Fig. 4", "ref_id": "FIGREF7"}, {"start": 1361, "end": 1367, "text": "Fig. 4", "ref_id": "FIGREF7"}, {"start": 3024, "end": 3030, "text": "Fig. 4", "ref_id": "FIGREF7"}]}, {"section": "Summary and outlook", "text": "In this paper, we have performed a scan in the NMSSM, focusing on the regions of parameter space favoured by low fine-tuning considerations. We have studied the lightest scalar Higgs boson h 1 including the mass and the relative signal strength to the SM prediction, especially for Higgs bosons decaying into the di-photon final state, by assuming that the secondlightest scalar Higgs boson h 2 corresponds to the observed \u223c125 GeV /c 2 state at the LHC. We find that a significant excess of the signal strength relative to that of the Standard Model in pp \u2192 h 1 \u2192 \u03b3\u03b3 up to a factor \u223c3.5 is possible in the NMSSM, especially for the mass range below the LEP bound of 114.7 GeV /c 2 . We recommend that experiments extend the exclusion limit to this lowmass region in order to investigate the possibilities of the NMSSM in more detail.", "cite_spans": [], "ref_spans": []}, {"section": "Summary and outlook", "text": "With future LHC data, the best fit values of the signal strengths in each channel may evolve and the uncertainties improve, which may result in changes in the experimental results and reduced error bars in our plots. Additionally, the allowed regions in NMSSM parameter space for the interesting Higgs boson h 1 may also change. With the upcoming 13 and 14-T eV collisions at LHC, the signal for the low-mass NMSSM Higgs boson h 1 could still well be detected by the experiments due to the higher collision energy and integrated luminosity.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF22": {"title": "Proceedings of Physics in Collision", "authors": [{"first": "Jong", "middle": [], "last": "Paul De", "suffix": ""}], "year": 2012, "venue": "ATLAS", "link": "118928194"}, "BIBREF23": {"title": "CMS-SUS-13-011", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF24": {"title": "ATLAS-CONF-2013-093, ATLAS-CONF-2013-062", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF25": {"title": "Submitted to Astronomy and Astrophysics", "authors": [], "year": 2013, "venue": "", "link": null}, "BIBREF37": {"title": "DESY 13-110", "authors": [{"first": "P", "middle": [], "last": "Bechtle", "suffix": ""}], "year": "", "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "22 May 2014 * Supported by National Natural Science Foundation of China (No. 10721140381, No. 11061140514), China Ministry of Science and Technology (No. 2013CB838700), China Scholarship Council and partially by the France China Particle Physics Laboratory", "type": "figure"}, "FIGREF1": {"text": "Fig. 1. The NMSSM Higgs boson mass spectrum in the M h 1 vs. M h 2 plane. Points for case I are represented by blue squares and case II by red triangles.", "type": "figure"}, "FIGREF2": {"text": "(XX = ZZ, W W , bb, \u03c4 \u03c4 ). The points including error bars rep- resent the latest LHC public results for the best fit val- ues of the signal strengths \u00b5 h 2 XX with uncertainties in the different final states, reported by the CMS and ATLAS collaborations[55, 56]. The values and errors are listed in", "type": "figure"}, "FIGREF3": {"text": "Fig. 2. The signal strength of the NMSSM Higgs boson h2 in the \u03b3\u03b3 channel versus its signal strengths in the ZZ(W W ) channel in (a), the bb channel in (b), the \u03c4 \u03c4 channel in (c) and its mass in (d). The results shown in the left-hand (right-hand) plots are obtained before (after) applying the constraints from HiggsBounds\u22124 and HiggsSignals\u22121. The magenta solid point for the mean value and line for the uncertainties represent the CMS results while those in green represent the ATLAS results. Points for case I are represented by blue squares and case II by red triangles. In (a), the solid point and line represent the results from ZZ final state while the dashed line corresponds to W W final state.", "type": "figure"}, "FIGREF5": {"text": "be within 1\u03c3 (taking as \u03c3 the uncertainty shown in the Appendix) of the CMS measured value:", "type": "figure"}, "FIGREF6": {"text": "Fig. 3. Results from the NMSSM parameter scan for the branching ratio of h1 \u2192 \u03b3\u03b3. The cyan solid line represents the corresponding SM value for the same mass. Points for case I are represented by blue squares and case II by red triangles.", "type": "figure"}, "FIGREF7": {"text": "Fig. 4. Expected and observed exclusion limits on the signal strength from CMS[55] compared with the possible signal strengths of the process pp \u2192 h1 \u2192 \u03b3\u03b3 from the NMSSM parameter scan. Points for case I are represented by blue squares and case II by red triangles.The solid black line together with the black squares corresponds to the ratio of the CMS observed cross sections with respect to the SM predictions, and the dashed line is the expected ratio.", "type": "figure"}, "TABREF0": {"text": "The general NMSSM includes two Higgs superfield\u015d H u ,\u0124 d and one additional gauge singlet chiral super- field\u015c. To start, we consider the NMSSM with a scale invariant superpotential W NM SSM and the correspond- ing soft SUSY-breaking masses and couplings L sof t , both of which are limited to the R-parity and CP-conserving case. The superpotential W NM SSM depending on the Higgs superfields\u0124 u ,\u0124 d and\u015c is[18]", "type": "table"}, "TABREF1": {"text": ", Tevatron[8] and LHC[55, 56], some bounds from direct searches of SUSY particles in LHC [26-28], relic density \u2126h 2 [29], B-physics observables such as", "type": "table"}, "TABREF2": {"text": ". As can be seen, most of the parameter points cluster around mass values cen- tered around 125 GeV /c 2 for M h 2 in case I and case II. We conclude that the parameter ranges are correctly chosen to give a mass of the Higgs boson h 2 close to 125 GeV /c 2 . Considering the lightest NMSSM scalar Higgs boson h 1 , it is clear that its mass can lie in a wide range,", "type": "table"}}}
{"paper_id": "42952760", "_pdf_hash": "d659255cac672ab970326ba57d36ad39d8120959", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Clinical cases (two) presentation from the ward at CRHSP, Ballabgarh 2. Family presentation from the urban field practice area at Delhi 3", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF1": {"title": "Guidelines for Academic Courses, Awards and Orations at AIIMS. Fourth Edition. All India Institute of Medical Sciences", "authors": [], "year": 2010, "venue": "", "link": null}, "BIBREF2": {"title": "Syllabus of MD/MSc/MDS/MHA/MSc/MBiotech at the AIIMS. All India Institute of Medical Sciences", "authors": [], "year": 2003, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "42953050", "_pdf_hash": "ec5fefcfa57b997460a36638444bec1d35a1b09e", "abstract": [{"section": "Abstract", "text": "A 1340-bp cDNA fragment encoding the lemurian presenilin 2 protein (PS2) was isolated from a Microcebus murinus brain cDNA library by PCR using oligonucleotide primers based on the nucleotide sequence of the human gene. Analysis of five isolated clones showed that the sequence encoded a 448-amino-acid open reading frame, 95.5% identical to the human and 93.5% identical to the mouse presenilin 2 sequences. However, neither the localization of the 2 positions in PS2 nor that of the 43 positions in PS1 associated with early onset Alzheimer's disease were changed. Expression of the presenilin 2 was detected by RT-PCR and compared with that of presenilin 1 and \u2424APP in the brain and in peripheral tissues (liver, kidney, and spleen). Immunohistochemistry with a specific polyclonal antiserum raised against a synthetic peptide from the N-terminal part of the human PS2 showed that the protein is distributed throughout the microcebe brain, in vascular and nerve structures. In cortical and in subcortical areas, PS2 labeling was weak and granular in appearance and was scattered throughout the cytoplasm of many neurones, extending into neurites. The gene expression of PS2 increased with age but was not affected by the presence of numerous amyloid plaques. Double labeling immunocytochemistry detected very few neurones with combined immunoreactivity PS2 and APP, or PS2 and Tau.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION", "text": "Alzheimer's disease (AD) is genetically heterogeneous since at least three genes are responsible for most cases of early onset familial AD (EOFAD). The first one located on chromosome 21, encodes the \u2424-amyloid precursor protein (\u2424APP) which gives rise to the \u2424 amyloid peptides by endoproteolysis.", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "The majority of EOFAD cases arise from missense mutations in two recently identified genes, 43 in the presenilin 1 (PS1) on chromosome 14 and 2 in the presenilin 2 (PS2) on chromosome 1 (for review Cruts & Van Broeckhoven, 1998 ) . PS1 contains 467 amino acids and PS2 contains 448 amino acids. Both resemble integral transmembrane proteins with 67% identity", "cite_spans": [], "ref_spans": []}], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "42953496", "_pdf_hash": "4e61109fc3ea42da92e323def6bcdccc9ee7b950", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "42956035", "_pdf_hash": "4041051de3e41e98fdbe1bb701d1101b039321e7", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "The reverse dorsal metacarpal flap: experience with 153 cases", "authors": [{"first": "L", "middle": ["J"], "last": "Lu", "suffix": ""}, {"first": "X", "middle": [], "last": "Gong", "suffix": ""}], "year": 2006, "venue": "Ann Plast Surg", "link": "58528792"}, "BIBREF1": {"title": "Repair of soft tissue defects of wrist and fingers by antegrade and retrograde dorsal metacarpal flaps with cutaneous branches as pedicles", "authors": [{"first": "L", "middle": ["J"], "last": "Lu", "suffix": ""}, {"first": "X", "middle": [], "last": "Gong", "suffix": ""}, {"first": "Z", "middle": [], "last": "Liu", "suffix": ""}], "year": 2004, "venue": "Chin J Reparat Reconstr Surg", "link": "43371357"}, "BIBREF2": {"title": "The distally-based dorsal hand flap", "authors": [{"first": "A", "middle": ["A"], "last": "Quaba", "suffix": ""}, {"first": "P", "middle": ["M"], "last": "Davison", "suffix": ""}], "year": 1990, "venue": "Br J Plast Surg", "link": "28623796"}, "BIBREF3": {"title": "The reverse dorsal metacarpal flap", "authors": [{"first": "Y", "middle": [], "last": "Maruyama", "suffix": ""}], "year": 1990, "venue": "Br J Plast Surg", "link": "36344195"}}, "ref_entries": {}}
{"paper_id": "42956083", "_pdf_hash": "77f75ed3b9701aab6bf37873aea693a6f73fca6d", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "A Review of work on Indian Medicinal Plants (ICMR) special series report no 30", "authors": [{"first": "I C", "middle": [], "last": "R N Chopra", "suffix": ""}, {"first": "", "middle": [], "last": "Chopra", "suffix": ""}], "year": 1995, "venue": "", "link": null}, "BIBREF1": {"title": "The Indian Pharmaceutical Cod", "authors": [{"first": "B", "middle": [], "last": "Mukerji", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF4": {"title": "Leather Science (Madras)", "authors": [{"first": "A", "middle": [], "last": "Kk Puroshathman", "suffix": ""}, {"first": "V", "middle": [], "last": "Sarda", "suffix": ""}, {"first": "", "middle": [], "last": "Narayan", "suffix": ""}, {"first": "", "middle": [], "last": "Swami", "suffix": ""}], "year": 1920, "venue": "", "link": null}, "BIBREF13": {"title": "WebsteFrancis Spectroscopic Indentification of Organic Compounds Sixth edition Wiley Indian Publicaton pg 12", "authors": [{"first": "X", "middle": [], "last": "Robert M Silverstein", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF18": {"title": "Arzneimittleforschung/Drug Arzein-Forch", "authors": [{"first": "D", "middle": [], "last": "Coward", "suffix": ""}, {"first": "S", "middle": ["N"], "last": "Doggest", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Sayer", "suffix": ""}], "year": 1977, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "42957032", "_pdf_hash": "357b6e62d8f65e440dda2ac7d2b7a44e72466c75", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Herpes simplex ensefaliti: Bir olgu sunumu", "authors": [{"first": "S", "middle": ["S"], "last": "Eren", "suffix": ""}, {"first": "N", "middle": [], "last": "\u00d6ztoprak", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "\u00c7evik", "suffix": ""}], "year": 2005, "venue": "Flora Derg", "link": null}, "BIBREF1": {"title": "\u0130nfeksiyon Hastal\u0131klar\u0131 ve Mikrobiyolojisi", "authors": [{"first": "N", "middle": [], "last": "Mutluer", "suffix": ""}, {"first": "", "middle": [], "last": "Ensefalomyelitler Ve N\u00f6ritler", "suffix": ""}, {"first": "A", "middle": ["W"], "last": "Top\u00e7u", "suffix": ""}, {"first": "G", "middle": [], "last": "S\u00f6yletir", "suffix": ""}], "year": 2002, "venue": "", "link": null}, "BIBREF2": {"title": "Herpes simplex virus type 2 in the United States", "authors": [{"first": "D", "middle": ["T"], "last": "Fleming", "suffix": ""}, {"first": "G", "middle": ["M"], "last": "Mcquillan", "suffix": ""}, {"first": "R", "middle": ["E"], "last": "Johnson", "suffix": ""}], "year": 1976, "venue": "NEJM", "link": null}, "BIBREF3": {"title": "Psychosis and herpes simplex encephalitis", "authors": [{"first": "M", "middle": [], "last": "Schlitt", "suffix": ""}, {"first": "F", "middle": ["D"], "last": "Lakeman", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Whitley", "suffix": ""}], "year": 1985, "venue": "South Med J", "link": "22134991"}, "BIBREF4": {"title": "Herpex simplex encephalitis clinical assessment", "authors": [{"first": "R", "middle": ["J"], "last": "Whitley", "suffix": ""}, {"first": "S", "middle": ["J"], "last": "Soong", "suffix": ""}, {"first": "C", "middle": [], "last": "Linneman", "suffix": ""}, {"first": "", "middle": [], "last": "Jr", "suffix": ""}], "year": 1982, "venue": "JAMA", "link": null}, "BIBREF7": {"title": "Diagnosis of herpes simplex encephalitis: Application of polymerase chain reaction to cerebrospinal fluid from brain-biopsied patients and corelation with disease", "authors": [{"first": "F", "middle": ["D"], "last": "Lakemman", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Whitley", "suffix": ""}], "year": 1995, "venue": "J Infect Dis", "link": null}, "BIBREF9": {"title": "Two cases of herpes encephalitis with normal cerebrospinal fluid findings", "authors": [{"first": "Avkan", "middle": [], "last": "Oguz", "suffix": ""}, {"first": "V", "middle": [], "last": "Yapar", "suffix": ""}, {"first": "N", "middle": [], "last": "Sezak", "suffix": ""}, {"first": "N", "middle": [], "last": "", "suffix": ""}], "year": 2006, "venue": "Mikrobiyol Bul", "link": null}, "BIBREF10": {"title": "Acyclovir versus vidarabine in herpes simplex encephalitis: Randomised multicenter study in consecutive Swedish patients", "authors": [{"first": "B", "middle": [], "last": "Sk\u00f6ldenberg", "suffix": ""}, {"first": "M", "middle": [], "last": "Forsgren", "suffix": ""}, {"first": "K", "middle": [], "last": "Alestig", "suffix": ""}], "year": 1984, "venue": "Lancet", "link": "41882373"}, "BIBREF11": {"title": "Japanese guidelines for the management of herpes simplex encephalitis; 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{"paper_id": "42958421", "_pdf_hash": "821e0ec3be26d061cc29a71d0a244d24a0dbe9cd", "abstract": [{"section": "Abstract", "text": "Ceramic restorations are appealing because of their esthetics, low density, high hardness, wear resistance and high survival rate [1] [2] [3] [4] . Ceramic inlays can be conservative of tooth structure [5] . They can replace a metal-casting or amalgam restoration in patients who require a class II restoration where buccal and lingual walls remain intact, and offer a viable alternative where excessive isthmus width contraindicates the use of a direct posterior composite restoration [6] . Their brittle nature though can be a limitation [7, 8] .", "cite_spans": [{"start": 130, "end": 133, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 134, "end": 137, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 138, "end": 141, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 142, "end": 145, "text": "[4]", "ref_id": "BIBREF7"}, {"start": 202, "end": 205, "text": "[5]", "ref_id": "BIBREF6"}, {"start": 486, "end": 489, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 540, "end": 543, "text": "[7,", "ref_id": "BIBREF4"}, {"start": 544, "end": 546, "text": "8]", "ref_id": "BIBREF3"}], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "The margins of any type of restoration are important not only for the survival of the restoration itself but also for the periodontal health of the soft tissues and for reducing susceptibility to recurrent decay. Smooth and even margins are essential [9] [10] [11] [12] [13] [14] and a fit of 50-100\u00b5m is desirable to avoid excessive exposure of cement [15] . Marginal adaptation is defined as the accuracy of fit between a restoration and tooth at the cavosurface [16] . Accurate fit of a restoration is related to both laboratory and clinical technique [16] . Poor marginal adaptation results in retention sites for microorganisms that can migrate to the bottom of the cavity preparation and release toxins/products that can damage the pulp [17, 18] . The use of dual-cure resin cement is recommended for better margin support and enhanced durability [19] [20] [21] [22] [23] [24] [25] .", "cite_spans": [{"start": 251, "end": 254, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 255, "end": 259, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 260, "end": 264, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 265, "end": 269, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 270, "end": 274, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 275, "end": 279, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 353, "end": 357, "text": "[15]", "ref_id": "BIBREF18"}, {"start": 465, "end": 469, "text": "[16]", "ref_id": "BIBREF17"}, {"start": 555, "end": 559, "text": "[16]", "ref_id": "BIBREF17"}, {"start": 743, "end": 747, "text": "[17,", "ref_id": "BIBREF16"}, {"start": 748, "end": 751, "text": "18]", "ref_id": "BIBREF15"}, {"start": 853, "end": 857, "text": "[19]", "ref_id": "BIBREF14"}, {"start": 858, "end": 862, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 863, "end": 867, "text": "[21]", "ref_id": "BIBREF25"}, {"start": 868, "end": 872, "text": "[22]", "ref_id": "BIBREF20"}, {"start": 873, "end": 877, "text": "[23]", "ref_id": "BIBREF21"}, {"start": 878, "end": 882, "text": "[24]", "ref_id": "BIBREF24"}, {"start": 883, "end": 887, "text": "[25]", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Introduction", "text": "Ceramic restorations are appealing because of their esthetics, high hardness and wear resistance. They can replace a composite or amalgam restoration in teeth where buccal and lingual walls remain intact and where excessive isthmus width contraindicates the use of a direct posterior composite restoration. Recent clinical trials have shown that porcelain restorations with margins on the occlusal surface of a posterior tooth tend to fail due to fracture of the porcelain under biting forces. Small chips initiate stress patterns that can lead to bulk material fracture overtime as the restoration is in function. Previous in vitro studies have tested the fracture resistance by using load perpendicular to the central groove of the inlay restoration. The purpose of this study is to compare the margin fracture strength of MOD inlay restorations with two different occlusal angles and fabricated with IPS Empress TM The occlusal anatomy, margin design and porcelain material are critical factors that significantly affect the margin strength of inlay/onlay ceramic restorations.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Microstructure includes: 1) glass-based systems (mainly silica), 2) glass-based systems with fillers, usually crystalline (feldspathic, leucite reinforced and lithium disilicate), 3) crystalline-based systems with glass fillers (mainly alumina) and 4) polycrystalline solids (alumina and zirconia).", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Dental porcelain materials can be classified based on the microstructure of a ceramic and on processing technique [43] .", "cite_spans": [{"start": 114, "end": 118, "text": "[43]", "ref_id": "BIBREF41"}], "ref_spans": []}, {"section": "Introduction", "text": "Processing includes: 1) powder/liquid, 2) pressable, 3) CAD/CAM and 4) glass-infiltrated. The flexural strength of lithium disilicate is approximately 360MPa or about three times that of Empress TM (160 MPa) [43] [44] [45] [46] [47] .", "cite_spans": [{"start": 208, "end": 212, "text": "[43]", "ref_id": "BIBREF41"}, {"start": 213, "end": 217, "text": "[44]", "ref_id": "BIBREF42"}, {"start": 218, "end": 222, "text": "[45]", "ref_id": "BIBREF45"}, {"start": 223, "end": 227, "text": "[46]", "ref_id": "BIBREF44"}, {"start": 228, "end": 232, "text": "[47]", "ref_id": "BIBREF43"}], "ref_spans": []}, {"section": "Introduction", "text": "Previous studies have tested the fracture resistance by using load perpendicular to the central groove of the inlay restoration where the material is thicker than near the margin [14, [23] [24] [25] . It may be significantly different when the load is applied to the buccal and lingual inclinations at a position near the margin interface.", "cite_spans": [{"start": 179, "end": 183, "text": "[14,", "ref_id": "BIBREF13"}, {"start": 184, "end": 188, "text": "[23]", "ref_id": "BIBREF21"}, {"start": 189, "end": 193, "text": "[24]", "ref_id": "BIBREF24"}, {"start": 194, "end": 198, "text": "[25]", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Introduction", "text": "The purpose of this study was to compare the margin fracture strength of MOD inlay restorations with two different occlusal margin angles fabricated with IPS Empress TM or IPS e.max TM porcelain. The null hypotheses were: (1) there is no difference in occlusal margin fracture strength of inlay restorations between the two different porcelain angles, (2) there is no difference in occlusal margin fracture strength between IPS Empress TM and IPS e.max TM ceramic restorations and (3) the model system developed for this study is a reliable test to evaluate porcelain margin fracture resistance.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "For this in vitro study, a master die with a mesial-occlusal-distal preparation was fabricated in brass ( Figure 1) . A corresponding stainless steel guide with a 45 \u00ba and 60 \u00ba angled surface was also fabricated ( Figure 2 ). The master preparation die was duplicated with a resin (Viade Products, Camarillo, CA, USA) which has a modulus of elasticity (12.9 GPa) similar to tooth dentin. The dimensions of the MOD cavity were: box depth: 4 mm, pulpal floor depth: 2 mm, axial wall height: 2 mm and isthmus width: 5 mm [6] . Figure  3 is a cross-sectional view of the two wax patterns formed with the 45 \u00ba and 60 \u00ba inclination. The restoration fabricated with the 60 \u00ba inclination will have steeper anatomy and be thinner at the occlusal margin than the 45 \u00ba inclination, which will have shallower anatomy and be thicker at the margin. A total of 40 specimens (sample size determined by previous studies [36] [37] [38] [39] [40] [41] were tested. , angles, the stainless steel guide was heated and passed over the wax pattern to produce the desired margin. The wax patterns were sent to a dental laboratory to press the corresponding ceramic monolithic inlays. The dies were selected at random and the wax patterns, dies and ceramic inlays were coded, so that each inlay was placed on the resin die from which the pattern was fabricated. The glazed inlays were seated in the dies and the fit was checked using an explorer under magnifying loopes 2.5x (Orascoptic, Middleton, WI). A resin cement (Nexus Third Generation, NX3 dual-cure, Kerr, Orange, CA) was used according to the manufacturer's instructions to cement all the inlays. The internal surface of the porcelain was etched with Ultraetch (9.6% buffered Hydrofluoric Acid, Ultradent Products, Inc., S. South Jordan, UT) for 1 minute and silane primer was applied (Kerr, Orange, CA) for 1 minute and lightly air-dried. The die was etched with 37% hydrophosphoric acid for 15 seconds, rinsed and air-dried. Optibond Solo (Kerr,Orange, CA) was applied with a microbrush, air-dried for 3 seconds and light-cured for 10 seconds. Nexus 3 was dispensed to the internal surface of the inlay restoration, seated in the die with finger pressure and excess cement was removed with a microbrush. The restoration was placed under a load of 10 gr, and each surface was light cured for 20 seconds. The load was removed from the die and the occlusal surface was light cured for 40 seconds ( Figure 4 ). All light curing was performed using the VALO curing light (Ultradent Products, Inc. S. South Jordan, UT) at a light intensity of 950 mW/cm 2 .", "cite_spans": [{"start": 518, "end": 521, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 903, "end": 907, "text": "[36]", "ref_id": "BIBREF40"}, {"start": 908, "end": 912, "text": "[37]", "ref_id": "BIBREF35"}, {"start": 913, "end": 917, "text": "[38]", "ref_id": "BIBREF36"}, {"start": 918, "end": 922, "text": "[39]", "ref_id": "BIBREF39"}, {"start": 923, "end": 927, "text": "[40]", "ref_id": "BIBREF38"}, {"start": 928, "end": 932, "text": "[41]", "ref_id": "BIBREF37"}], "ref_spans": [{"start": 106, "end": 115, "text": "Figure 1)", "ref_id": "FIGREF0"}, {"start": 214, "end": 222, "text": "Figure 2", "ref_id": "FIGREF1"}, {"start": 524, "end": 533, "text": "Figure  3", "ref_id": "FIGREF2"}]}, {"section": "Introduction", "text": "Light efficacy/power was tested every 10 samples with a visible curing light meter (Cure Rite, Dentsply, Milford, DE). Excess cement was removed with a No 15 Bard Parker blade (Aspen Surgical TM Caledonia, MI) but no finishing was done on the margins. A sharpie marker (Sharpie\u00ae, Downers Grove, IL) was used to indicate the point of loading 1 mm away from the occlusal margin. Two diametrically opposite margin points were marked on each sample and the specimens were stored in a dark humidor for 48 hours before testing. A stainless steel probe with 1 mm diameter (area = 0.7854 mm 2 ) was mounted in an Instron universal testing machine (Instron 5565, Instron Industrial Products, Grove City, PA and software Bluehill 3) and used to apply compressive loads within 1 mm of the interface at a 0.5 mm/min crosshead speed until initial crack formation was visible. The load was applied perpendicular to the inclined surface by holding the die in a custom jig adjusted in a protractor ( Figure 5 ). The load at initial crack formation was determined by the Instron software. Two values were obtained (one at each marked point) and a mean value was derived for each restoration. After loading and margin fracture, 2 dies were selected from each group, one with the highest margin fracture strength and one with the lowest. The selected dies were trimmed and embedded in clear orthodontic acrylic (KoldMount, Nobilium Company, Albany, NY) for sectioning. The embedded dies were sectioned buccal-lingually at the point where the load was applied using a diamond wheel saw (Model 650 Low Speed Diamond Wheel Saw, South Bay Technology Inc., San Clemente, CA). Qualitative fracture pattern evaluation was performed under a microscope (Nikon SMZ1500, Nikon Instruments, Inc., Melville, New York) at 10X magnification with high intensity illumination and photos were taken using the Image ProPlus software and SPOT Advanced camera (SPOT Imaging Solutions, a division of Diagnostic Instruments, Inc. Sterling Heights, Michigan). Means and standard deviations were calculated for each group and statistically analyzed using 2-way ANOVA and an independent t-test, with significance at p<0.05 (XLSTAT software, Statistical Innovations, Belmont, MA).", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "To confirm that the ceramic inlay restorations were properly seated in the dies, 4 samples (one sample for each group) were fabricated following the same procedures. The inlays were tried-in and the fit was checked using an explorer across the occlusal and cervical margins to document clinical integrity. Super glue was used at the cervical margins to stabilize the restoration in place. The samples were embedded and sectioned buccal-lingual in the center of the restoration. The 2-way ANOVA (Table 2) showed that the material and the angle were both significantly different with no interaction. The Ho3 was accepted, since the model system developed for this study was effective at determining significant material and angle differences. The following pictures (Figures 6 and 7) show the occlusal surfaces of ceramic restorations after loading. A mode of fracture was observed for all 4 groups. The initial crack had a ''c'' shaped pattern along the margin. For the e.max TM 45 \u00ba inlays, the initial fracture was limited to the loading area and did not extend into the occlusal surface ( Figure 6 ): whereas the other groups tended to propagate more quickly into a bulk fracture (Figure 7) . In general, the 45 \u00ba groups had less severe fracture on the occlusal surfaces than the 60 \u00ba groups. The qualitative internal fracture pattern evaluation of the sectioned samples showed that there was not a consistent internal fracture pattern. The only common characteristic in these cross-sectional views was that the fracture point started at the loading point and propagated into the bulk of the ceramic restoration. The fracture pattern observed was either fixed (crack is one direction) ( Figure  8 ) or multidirectional (several cracks in different directions) (Figure 9 ). There was no correlation between the internal fracture pattern and margin fracture strength. This behavior was evident for both the Empress TM and e.max TM materials and for both 45 \u00ba and 60 \u00ba occlusal angles. This in vitro study compared and evaluated the margin fracture strength of two different porcelain MOD inlay restorations with two different occlusal angles. In this study, pressable leucite reinforced ceramic (Empress TM ) and pressable lithium disilicate ceramic (e.max TM ) were compared. The rationale for 2 different occlusal surfaces (45 \u00ba -thicker margin and 60 \u00ba -thinner margin) was that clinically the final ceramic thickness may be less if occlusal anatomy is steeper and after occlusal adjustment [28] . It was anticipated that the risk for fracture may be higher in the case of a 60 \u00ba angle of the porcelain at the margin area.", "cite_spans": [{"start": 2494, "end": 2498, "text": "[28]", "ref_id": "BIBREF27"}], "ref_spans": [{"start": 764, "end": 781, "text": "(Figures 6 and 7)", "ref_id": "FIGREF4"}, {"start": 1091, "end": 1099, "text": "Figure 6", "ref_id": "FIGREF4"}, {"start": 1182, "end": 1192, "text": "(Figure 7)", "ref_id": "FIGREF5"}]}, {"section": "Discussion", "text": "Other investigators have performed the evaluation of ceramic fracture strength by applying the load vertical to the center of the restoration (occlusal central fissure of inlay restoration) [19, 28, 44] . In these studies, ceramic restorations were extended to the functional cusp and were cemented to extracted teeth [28] . Using Finite Element Analysis (FEA) models [19, 34, 35] , variables such as width of preparation and volume of ceramic were evaluated. Bar-shaped [38] specimens and disk samples have been used to determine the edge strength of porcelain in which force was applied 0.5-1.0 mm from the edge of the sample (edge strength) [36, 37, 39, 41] . In this in vitro study, samples had an actual inlay restoration shape and load was applied perpendicular to the buccal and lingual inclines of the restoration. One preparation design was used for preparation consistency and to decrease variables. The indenter was placed 1 mm away from the margin to avoid the load being placed on the die-restoration interface. This is the reason why the test is called margin fracture strength and not edge strength.", "cite_spans": [{"start": 190, "end": 194, "text": "[19,", "ref_id": "BIBREF14"}, {"start": 195, "end": 198, "text": "28,", "ref_id": "BIBREF27"}, {"start": 199, "end": 202, "text": "44]", "ref_id": "BIBREF42"}, {"start": 318, "end": 322, "text": "[28]", "ref_id": "BIBREF27"}, {"start": 368, "end": 372, "text": "[19,", "ref_id": "BIBREF14"}, {"start": 373, "end": 376, "text": "34,", "ref_id": "BIBREF29"}, {"start": 377, "end": 380, "text": "35]", "ref_id": "BIBREF34"}, {"start": 471, "end": 475, "text": "[38]", "ref_id": "BIBREF36"}, {"start": 644, "end": 648, "text": "[36,", "ref_id": "BIBREF40"}, {"start": 649, "end": 652, "text": "37,", "ref_id": "BIBREF35"}, {"start": 653, "end": 656, "text": "39,", "ref_id": "BIBREF39"}, {"start": 657, "end": 660, "text": "41]", "ref_id": "BIBREF37"}], "ref_spans": []}, {"section": "Discussion", "text": "The mean margin fracture strength of e.max TM (lithium disilicate) ceramic material was significantly higher than that of the Empress TM (leucite reinforced) ceramic, which is in agreement with other studies [44] [45] [46] [47] . This increased fracture strength can be attributed to the increased percentage of crystallinity (up to 70%) of this porcelain material as well as a more refined crystal size [43, 46] . There was a significant difference in the fracture strength between the two ceramic materials and between the two occlusal angles, indicating that the test design and method were satisfactory to identify significant differences.", "cite_spans": [{"start": 208, "end": 212, "text": "[44]", "ref_id": "BIBREF42"}, {"start": 213, "end": 217, "text": "[45]", "ref_id": "BIBREF45"}, {"start": 218, "end": 222, "text": "[46]", "ref_id": "BIBREF44"}, {"start": 223, "end": 227, "text": "[47]", "ref_id": "BIBREF43"}, {"start": 404, "end": 408, "text": "[43,", "ref_id": "BIBREF41"}, {"start": 409, "end": 412, "text": "46]", "ref_id": "BIBREF44"}], "ref_spans": []}, {"section": "Discussion", "text": "It is difficult to standardize the preparation design for ceramic inlays clinically because of the uniqueness and complexity of each clinical situation. In the literature, there has been a consensus to have 1.5-2.0 mm as ideal thickness for ceramic restorations [6, 13, [28] [29] [30] [31] . The width of the inlay preparation should not exceed 1/3 of the total width of the tooth because the increased inlay width reduces tooth structure and increases the stress on the restoration [19] . The die for this study was constructed within these guidelines, but the restoration fabricated with the 60 \u00ba inclination was thinner at the occlusal margins (steeper anatomy) than the 45 \u00ba inclination (shallower anatomy), as seen in Figure 3 .", "cite_spans": [{"start": 262, "end": 265, "text": "[6,", "ref_id": "BIBREF5"}, {"start": 266, "end": 269, "text": "13,", "ref_id": "BIBREF12"}, {"start": 270, "end": 274, "text": "[28]", "ref_id": "BIBREF27"}, {"start": 275, "end": 279, "text": "[29]", "ref_id": "BIBREF28"}, {"start": 280, "end": 284, "text": "[30]", "ref_id": "BIBREF33"}, {"start": 285, "end": 289, "text": "[31]", "ref_id": "BIBREF32"}, {"start": 483, "end": 487, "text": "[19]", "ref_id": "BIBREF14"}], "ref_spans": [{"start": 723, "end": 731, "text": "Figure 3", "ref_id": "FIGREF2"}]}, {"section": "Discussion", "text": "However, Holberg [34, 35] reported that a reduced thickness (0.7 mm) of lithium disilicate inlays did not increase the fracture risk of the restoration. Kramer also found no correlation between ceramic thickness and ceramic fractures [12, 14, 32] . The properties of the material were more important (Empress TM vs e.max TM ). Several authors suggested 1.5 mm of minimum ceramic thickness for Empress TM inlays because of higher risk of fracture during the cementation procedure [12, 14, 32] .", "cite_spans": [{"start": 17, "end": 21, "text": "[34,", "ref_id": "BIBREF29"}, {"start": 22, "end": 25, "text": "35]", "ref_id": "BIBREF34"}, {"start": 234, "end": 238, "text": "[12,", "ref_id": "BIBREF11"}, {"start": 239, "end": 242, "text": "14,", "ref_id": "BIBREF13"}, {"start": 243, "end": 246, "text": "32]", "ref_id": "BIBREF31"}, {"start": 479, "end": 483, "text": "[12,", "ref_id": "BIBREF11"}, {"start": 484, "end": 487, "text": "14,", "ref_id": "BIBREF13"}, {"start": 488, "end": 491, "text": "32]", "ref_id": "BIBREF31"}], "ref_spans": []}, {"section": "Discussion", "text": "The cementation was performed with dual-cure resin cement (Nexus Third Generation, NX3 dual-cure, Kerr, Orange, CA), as preferred for posterior ceramic cementation in other studies [20] [21] [22] 28] . A total etch resin cement (Variolink II) performed better in the occlusal margin adaptation than a self-adhesive cement (Rely X Unicem) because the increased amount of water sorption of self-adhesive resin leads to a higher amount of wear at the occlusal enamel margins of the restoration [20] [21] [22] 28] . According to Isidor, et al. [23] , leucite reinforced ceramic inlays had more failures with light-cure cement than dual-cure cement. Beier, et al. [24] , recommended a high viscosity dual-cure cement, while Stoll, et al. showed that there was no difference between low and high viscosity dual-cure cements [25] . On the contrary, Federlin, et al. [28] , reported that there was no difference in crack formation between dual-cure and self-adhesive cement and crack formation was influenced by ceramic thickness. Finally, a marginal fit of 50-100 \u00b5m was recommended to avoid excessive marginal wear [22] . The die used in this study had a modulus of elasticity similar to dentin and was prepared by micro-abrasion and acid washing to simulate the roughness of etched tooth structure. The cement was used to enhance retention and reinforce the porcelain during the test.", "cite_spans": [{"start": 181, "end": 185, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 186, "end": 190, "text": "[21]", "ref_id": "BIBREF25"}, {"start": 191, "end": 195, "text": "[22]", "ref_id": "BIBREF20"}, {"start": 196, "end": 199, "text": "28]", "ref_id": "BIBREF27"}, {"start": 491, "end": 495, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 496, "end": 500, "text": "[21]", "ref_id": "BIBREF25"}, {"start": 501, "end": 505, "text": "[22]", "ref_id": "BIBREF20"}, {"start": 506, "end": 509, "text": "28]", "ref_id": "BIBREF27"}, {"start": 540, "end": 544, "text": "[23]", "ref_id": "BIBREF21"}, {"start": 659, "end": 663, "text": "[24]", "ref_id": "BIBREF24"}, {"start": 818, "end": 822, "text": "[25]", "ref_id": "BIBREF23"}, {"start": 859, "end": 863, "text": "[28]", "ref_id": "BIBREF27"}, {"start": 1109, "end": 1113, "text": "[22]", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Discussion", "text": "Occlusal margins were checked clinically with an explorer for seating and a 10g load was applied on the occlusal surface of the restoration after cement placement. However, in the magnified cross-section pictures, occlusal margins were overextended and were lacking ideal adaptation (Figures 8,9 and 10). The overextended occlusal margins could be attributed to the thickness of die spacer or a discrepancy in occlusal margin adaptation between wax pattern and ceramic restoration. Variations in the laboratory procedures were controlled to some extent by using one experienced technician [9] . Ceramic defects can also occur in occlusal margins and a perfect adaptation of the ceramic to the tooth is influenced by the irregular cavity outline [9] . At the microscopic magnification, it was observed that occlusal margins appeared slightly overextended and marginal adaptation was compromised. The fit of the uncemented inlays was similar to that seen in the cemented samples ( Figure 10 ). Occlusal margins were overextended and the adaptation of ceramic restorations at the pulpal floor of the prepared die was not ideal.", "cite_spans": [{"start": 589, "end": 592, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 745, "end": 748, "text": "[9]", "ref_id": "BIBREF8"}], "ref_spans": [{"start": 979, "end": 988, "text": "Figure 10", "ref_id": "FIGREF0"}]}, {"section": "Discussion", "text": "A specific mode of fracture was observed in the occlusal surface of all restorations. The crack initiation had a ''c'' shape translucent pattern along the margin which progressed in some cases to a ''line'' formed along the proximal marginal ridges. ''Half-moon'' fractures also were detected in the studies of Kramer and Frankenberger [12, 14, 32] . This fracture pattern was limited to the area where the load was applied. Hayashi, et al. [33] also noticed cracking or chipping in a mosaic pattern of the ceramic.", "cite_spans": [{"start": 336, "end": 340, "text": "[12,", "ref_id": "BIBREF11"}, {"start": 341, "end": 344, "text": "14,", "ref_id": "BIBREF13"}, {"start": 345, "end": 348, "text": "32]", "ref_id": "BIBREF31"}, {"start": 441, "end": 445, "text": "[33]", "ref_id": "BIBREF30"}], "ref_spans": []}, {"section": "Discussion", "text": "There was not a consistent internal fracture pattern in the cross-sectional views of the tested samples. The only common characteristic was that the fracture line had a start point on the load area and propagated into the bulk of the ceramic restoration. The fracture pattern observed was either multidirectional (several cracks in different directions) or fixed (crack is in a single direction). There was no correlation between fracture pattern and margin fracture strength. This behavior was evident for both the Empress TM and e.max TM materials and is consistent for brittle materials like ceramics. It was also seen that the first loading on a side of each sample did not affect the margin fracture strength of the b side. There were samples that presented higher margin fracture strength values in b side that a side (Figure 6 and 7) .", "cite_spans": [], "ref_spans": [{"start": 824, "end": 840, "text": "(Figure 6 and 7)", "ref_id": "FIGREF4"}]}, {"section": "Discussion", "text": "This study showed that the marginal design should be decided carefully and accurately to avoid excessive loading on a thin margin. Previous studies have recommended that occlusal contact close to the ceramic/tooth interface should be avoided because of the high risk of debonding and fracture [19, 41] and that occlusal force leads to marginal deterioration and growth of microcracks [15] . As a result, shallower occlusal anatomy will develop thicker and more fracture resistant occlusal margins.", "cite_spans": [{"start": 293, "end": 297, "text": "[19,", "ref_id": "BIBREF14"}, {"start": 298, "end": 301, "text": "41]", "ref_id": "BIBREF37"}, {"start": 384, "end": 388, "text": "[15]", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Discussion", "text": "To avoid overloading a thin margin, a ceramic inlay restoration should not be considered as a treatment option in cases of unfavorable occlusion or parafunctional activity (bruxism) [6] . In a clinical study, Beier, et al. [4] did not find greater risk of failure associated with existing bruxism but the occlusal scheme provided was canine guidance, eliminating all balancing contacts. An occlusal bite splint was also provided to the patients to minimize stress concentration. In patients who had severe bruxism, cast gold restorations might be the treatment of choice.", "cite_spans": [{"start": 182, "end": 185, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 223, "end": 226, "text": "[4]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Discussion", "text": "Future studies could include the development of materials with improved properties such as ceramics with a modulus of elasticity close to that of dentin or a more elastic luting agent for stress relief and to provide marginal stability over time. This study design was adequate to show a significant difference between margin angles and porcelain materials, so it could be extended to compare a variety of other porcelain materials. Loading could be applied using a different shape and size of indenter, different load directions or using cyclic loading patterns. It is also important to further evaluate the cement space and the die spacer material in order to improve internal fit and occlusal margin adaptability.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "\u2022 The e.max TM (lithium disilicate) ceramic inlays had significantly higher margin fracture strength than Empress TM (leucite reinforced) at both 45 \u00ba and 60 \u00ba margin angles.", "cite_spans": [], "ref_spans": []}, {"section": "\u2022 The 45", "text": "\u00ba inlays were significantly stronger than the 60 \u00ba inlays for both e.max TM and IPS EmpressTM.", "cite_spans": [], "ref_spans": []}, {"section": "\u2022 The 45", "text": "\u2022 The margin strength test was effective at determining significant material and angle differences.", "cite_spans": [], "ref_spans": []}, {"section": "Clinical Significance", "text": "The occlusal anatomy, margin design and porcelain material are critical factors that significantly affect the margin strength of inlay/ 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"FIGREF1": {"text": "Figure 2: Stainless steel form with a 45 o and 60 o angled surface; A. top view, B. profile view", "type": "figure"}, "FIGREF2": {"text": "Figure 3: Wax pattern design, cross-section view with occlusal margin angles noted", "type": "figure"}, "FIGREF3": {"text": "Figure 4: Cemented restorations with 45 \u00ba (A) and 60 \u00ba (B); proximal views showing occlusal margin profile", "type": "figure"}, "FIGREF4": {"text": "Figure 6: e.max TM inlay (45 \u00ba angle) with the highest value a: 682.5 MPa, b: 762.7 MPa) showing a '' c'' shape fracture pattern", "type": "figure"}, "FIGREF5": {"text": "Figure 7: Empress TM inlay (60 \u00ba angle) with the lowest value (a: 129.9 MPa, b: 255.9 MPa) showing immediate bulk fracture pattern", "type": "figure"}, "FIGREF6": {"text": "Figure 8: Cross-section view of cemented inlay (e.max TM 60 \u00ba ) after fracture. Divisions below model represent 1 mm increments", "type": "figure"}, "FIGREF7": {"text": "Figure 10: Cross-section view of non-cemented and non-loaded inlay (e.max TM 45 \u00ba ). Divisions below model represent 1 mm increments", "type": "figure"}, "TABREF0": {"text": "and IPS e.max TM ceramic inlay restorations. Four groups of 10 samples each were tested: A: 45 \u00ba /e.maxTM . A rod with a 1mm diameter radius, mounted in an Instron testing machine was used to apply compressive loads on the occlusal margins within 1mm of the interface at a crosshead speed of 0.5mm/min until fracture. Mean load values were: A: 592.1 MPa, B: 455.3 MPa, C: 494.5 MPa and D: 274.8 MPa. For both e.max TM and Empress", "type": "table"}, "TABREF1": {"text": "The purpose of this study was to compare the margin fracture strength of MOD inlay restorations with two different occlusal angles fabricated with IPS Empress TM and IPS e.max TM porcelain.Mean values (SD) of margin fracture strength (MPa) A statistically significant difference was found between the 2 materials and the 2 occlusal angled surfaces and Ho1 and Ho2 were rejected. IPS e.max", "type": "table"}}}
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{"paper_id": "42959556", "_pdf_hash": "89d256327eaa5a3db2238127659c9bc0181e3481", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Marine Painting Manual", "authors": [{"first": "A", "middle": ["M"], "last": "Berendsen", "suffix": ""}], "year": 1989, "venue": "", "link": "193322655"}, "BIBREF1": {"title": "Paper No. 40 in Protecting Industrial and Marine Structures with Coatings, proceedings of PCE '97 conference", "authors": [{"first": "", "middle": [], "last": "Ko Keijman", "suffix": ""}], "year": 1997, "venue": "", "link": null}, "BIBREF2": {"title": "Critical Review of Current & Future Marine Antifouling Coatings", "authors": [], "year": 1993, "venue": "", "link": null}, "BIBREF3": {"title": "What's Involved in Selecting the Correct Antifouling?", "authors": [{"first": "Richard", "middle": [], "last": "Chapman", "suffix": ""}], "year": 1998, "venue": "Protective Coatings Europe", "link": null}, "BIBREF4": {"title": "Developments in TBT-Free Antifouling Technology\" Protective Coatings Europe", "authors": [{"first": "Colin", "middle": ["D"], "last": "Anderson", "suffix": ""}], "year": 1998, "venue": "", "link": null}, "BIBREF5": {"title": "Antifouling Coatings and the Global Environmental Debate", "authors": [{"first": "J", "middle": ["E"], "last": "Hunter", "suffix": ""}], "year": 1997, "venue": "Protective Coatings Europe", "link": null}, "BIBREF6": {"title": "Bioactive Materials in Antifouling Coatings", "authors": [{"first": "Kjaer", "middle": [], "last": "Eva Bie", "suffix": ""}], "year": 1992, "venue": "Progress in Organic Coatings", "link": null}, "BIBREF7": {"title": "Biocidal Products Directive May Impact Antifouling Coatings\" Protective Coatings Europe", "authors": [], "year": 1996, "venue": "", "link": null}, "BIBREF8": {"title": "Impact of New Rules on Structural Protection of Ships", "authors": [{"first": "Rodney", "middle": ["H"], "last": "Towers", "suffix": ""}], "year": 1994, "venue": "The Royal Institution of Naval Architects, International Conference on Marine Corrosion Prevention", "link": null}, "BIBREF9": {"title": "Design Life Specifications-Cost Analysis-Cost-Effective Specification: Their Relation\" in Achieving Cost Effectiveness in Coatings Work, proceedings of PCE '98", "authors": [{"first": "J", "middle": [], "last": "Eliasson", "suffix": ""}, {"first": "R", "middle": [], "last": "Malfanti", "suffix": ""}], "year": 1998, "venue": "", "link": null}, "BIBREF10": {"title": "Ballast Tanks and Cargo Holds in DNV's Guidelines for Corrosion Protection of Ships", "authors": [{"first": "Erik", "middle": [], "last": "Arskheim", "suffix": ""}], "year": 1997, "venue": "Protective Coatings Europe", "link": null}, "BIBREF11": {"title": "Guidelines for the Corrosion Protection of Ships", "authors": [{"first": "Jan", "middle": [], "last": "Aubert", "suffix": ""}], "year": 1992, "venue": "Ballast Tank Integrity and the New IMO Coating Rule\" Drydock", "link": null}, "BIBREF12": {"title": "Choosing the Correct Coatings for Cargo Tanks", "authors": [{"first": "Norbert", "middle": [], "last": "Ackermann", "suffix": ""}], "year": 1998, "venue": "Protective Coatings Europe", "link": null}, "BIBREF13": {"title": "The Absorption/Desorption Characteristics of Organic Tank Lining Systems", "authors": [], "year": 1998, "venue": "Achieving Cost Effectiveness in Coatings Work, proceedings of PCE '98", "link": null}}, "ref_entries": {}}
{"paper_id": "42959981", "_pdf_hash": "cfdfddf25e1f1abf6c4f63177970392429a7115c", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "8330072", "_pdf_hash": "d432d9dfb05d2f24002132065746d2cc3192bb12", "abstract": [], "body_text": [{"section": "Collecting Data and Doing Social Scientific", "text": "Research on Race, a statement emphasizing the social foundation of race. The association noted, \"although racial categories are legitimate subjects of empirical sociological investigation, it is important to recognize the danger of contributing to the popular conception of race as biological.\" (ASA 2003) The completion of the Human Genome Project in 2003 opened the door for better understanding of genetic components of disease that will shape the future practice of medicine. The Human Genome Project detailed the map of our DNA sequence allowing researchers to develop tools to further explore genetic variation across the globe (International HapMap Consortium 2003) . Built on the foundation of this knowledge researchers are continuing to uncover how genetic information can be used to screen, diagnose and treat disease. We learned from the Human Genome Project that we are all genetically 99.9 percent alike. However, given that each person's genome contains 6 billion bases of DNA, a 0.1 percent difference represents 6 million locations that differ between two individuals' DNA (International HapMap Consortium 2003) . The vast majority of these differences in sequence are \"neutral,\" they do not change gene function.", "cite_spans": [{"start": 634, "end": 672, "text": "(International HapMap Consortium 2003)", "ref_id": "BIBREF22"}, {"start": 1090, "end": 1128, "text": "(International HapMap Consortium 2003)", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "Collecting Data and Doing Social Scientific", "text": "Our knowledge of human genetic variation and its correlation with race and ethnicity is growing with our knowledge of the human genome. As biomedical and genetic research continues to propel us into the genomic era, in which researchers investigate the functions and interactions of all genes and environmental factors, the debates regarding the utility of racial and ethnic categories in the study and understanding of genetic variation will continue to increase (Bamshad et al. 2004; Cooper et al. 2003; Jackson 2004; Risch et al. 2002; Royal and Dunston 2004) .", "cite_spans": [{"start": 464, "end": 485, "text": "(Bamshad et al. 2004;", "ref_id": "BIBREF4"}, {"start": 486, "end": 505, "text": "Cooper et al. 2003;", "ref_id": "BIBREF12"}, {"start": 506, "end": 519, "text": "Jackson 2004;", "ref_id": "BIBREF23"}, {"start": 520, "end": 538, "text": "Risch et al. 2002;", "ref_id": "BIBREF39"}, {"start": 539, "end": 562, "text": "Royal and Dunston 2004)", "ref_id": "BIBREF42"}], "ref_spans": []}, {"section": "Race and Multiracial Individuals in the United States", "text": "Race is a relatively recent concept in human history (Smedley 2007) . This modern phenomena of classifying people was initially attached to a biological basis. People assumed that race was fixed or \"rooted in nature\" and physical appearances provided clues to qualities within individuals (Omi and Winant 2003) . Conceptualizations of race often conflate biology and culture to place social meaning on ascribed physical characteristics (Holt 2000) . Current social scientists and race theorists consider racial formation to be a \"process by which social, economic and political forces determine the content and importance of racial categories.\" (Omi and Winant 2003) In the United States, categories of race have always been fluid. In 1790, the U.S. Census categorized people in terms of \"Free\" and \"Slave.\" In 1850 categories described people as \"Black,\" \"White\" and \"Mulatto;\" and by 1890 census definitions had changed to \"White, Black, Mulatto, Quadroon, Octoroon, Chinese, Japanese and Indian.\" (Nobles 2000) These changes highlight the struggle to categorize people of mixed racial backgrounds. The influence of the historical \"one-drop rule\" and the antimiscegenation laws that prohibited interracial marriage in several states until 1967 created challenging and unique circumstances for multiracial persons of African decent (Roth 2005) .", "cite_spans": [{"start": 53, "end": 67, "text": "(Smedley 2007)", "ref_id": "BIBREF48"}, {"start": 289, "end": 310, "text": "(Omi and Winant 2003)", "ref_id": "BIBREF37"}, {"start": 436, "end": 447, "text": "(Holt 2000)", "ref_id": "BIBREF21"}, {"start": 645, "end": 666, "text": "(Omi and Winant 2003)", "ref_id": "BIBREF37"}, {"start": 1000, "end": 1013, "text": "(Nobles 2000)", "ref_id": "BIBREF35"}, {"start": 1333, "end": 1344, "text": "(Roth 2005)", "ref_id": "BIBREF41"}], "ref_spans": []}, {"section": "Race and Multiracial Individuals in the United States", "text": "The United States continues to struggle with the use of racial classifications. In March 1994, the Office of Management and Budget established the Interagency Committee for the Review of Racial and Ethnic Standards, composed of representatives from 30 federal agencies. After a series of debates evaluating categories such as \"Other\" and \"Multiracial,\" the OMB settled on the option to allow respondents to choose more than one race (OMB 1997) . This option was available for the first time in American history during the 2000 U.S. Census.", "cite_spans": [], "ref_spans": []}, {"section": "Race and Multiracial Individuals in the United States", "text": "Although the United States experienced a \"biracial baby boom\" during the late 1960s (Root 1992) , multiracial individuals have only recently been given the tools to represent their ancestral heritage. When the U.S. Census Bureau acknowledged the growing population of multiracial individuals and allowed them to choose more than one race, 6.8 million people, or 2.4 percent of the population, indicated that they belonged to more than one racial group in the year 2000 (Grieco and Cassidy 2001) . It is predicted that this number could reach 21 percent by the year 2050 (Lee and Bean 2004) .", "cite_spans": [{"start": 84, "end": 95, "text": "(Root 1992)", "ref_id": "BIBREF40"}, {"start": 469, "end": 494, "text": "(Grieco and Cassidy 2001)", "ref_id": "BIBREF19"}, {"start": 570, "end": 589, "text": "(Lee and Bean 2004)", "ref_id": "BIBREF31"}], "ref_spans": []}, {"section": "Race and Multiracial Individuals in the United States", "text": "Multiracial persons are often confronted with issues surrounding visual ambiguity, identity confusion, rejection from familial or ethnic groups, and inability to identify with every component of a diverse racial background due to societal pressures (Deters 1997; Harris and Sim 2002) . These challenges are often exaggerated in the lives of multiracial persons with some African American background. The views of laypersons with recently mixed ancestry, each with distinct historical, socioeconomic and political backgrounds have several implications on the continued use and interpretation of research using self-identified racial categories to understand genetic variation. This qualitative study of multiracial individuals explores their identity, health care experiences and presents a valuable lens in analyzing the construct of \"race\" and its relationship to human genetic variation.", "cite_spans": [{"start": 249, "end": 262, "text": "(Deters 1997;", "ref_id": "BIBREF13"}, {"start": 263, "end": 283, "text": "Harris and Sim 2002)", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Human Genetic Variation", "text": "The sequencing of the human genome has provided both natural and social scientists the opportunity to gain new knowledge about the complex relationships between our socio-politically constructed definitions of race, human genetic variation and health differences. Both race and ethnicity carry connotations that reflect culture, history, socioeconomic and political status, as well as an important connection to ancestral geographic origins (Collins 2004) . Humans are genetically less diverse than many other mammalian species including chimpanzees (Fischer et al. 2004; Kaessmann et al. 2001) . It is difficult to define human populations of significant genetic variation because of the clinal nature of our diversity (Long and Kittles 2003) . Only 5 percent to 15 percent of genetic variation occurs between continental populations leaving the majority of diversity within these groups (Jorde et al. 2000) . Additionally, the significance of this diversity is blurred by inconsistencies in the definition and inclusion parameters that are used to classify populations (Long and Kittles 2003) . There are no gene variants that are present in all individuals of one population group and not in individuals of another. No sharp genetic boundaries can be drawn between human population groups (Bonham et al. 2005; Race Ethnicity and Genetics Working Group 2005) .", "cite_spans": [{"start": 441, "end": 455, "text": "(Collins 2004)", "ref_id": "BIBREF9"}, {"start": 550, "end": 571, "text": "(Fischer et al. 2004;", "ref_id": "BIBREF15"}, {"start": 572, "end": 594, "text": "Kaessmann et al. 2001)", "ref_id": "BIBREF27"}, {"start": 720, "end": 743, "text": "(Long and Kittles 2003)", "ref_id": "BIBREF33"}, {"start": 889, "end": 908, "text": "(Jorde et al. 2000)", "ref_id": "BIBREF25"}, {"start": 1071, "end": 1094, "text": "(Long and Kittles 2003)", "ref_id": "BIBREF33"}, {"start": 1292, "end": 1312, "text": "(Bonham et al. 2005;", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Human Genetic Variation", "text": "The highest level of genetic diversity exists within African populations, reflecting the original groups of modern humans that migrated out of Africa to inhabit the rest of the world (Gabriel et al. 2002; Tishkoff and Verrelli 2003) . Although genetic diversity within the human genome is small, these differences have some correlation to broad continental geographic groupings (Bamshad and Wooding 2003) . Some researchers argue that these patterns support a biological basis to traditional racial categories that roughly correspond to groups from Africa, Asia, Europe, Oceania and the Americas (Risch et al. 2002) . However, others contest the validity of the study designs, highlight the limitations of the sample selections and reassert that human genetic variation does not cluster into distinct groups (Frank 2007; Serre and Paabo 2004) .", "cite_spans": [{"start": 183, "end": 204, "text": "(Gabriel et al. 2002;", "ref_id": "BIBREF17"}, {"start": 205, "end": 232, "text": "Tishkoff and Verrelli 2003)", "ref_id": "BIBREF56"}, {"start": 378, "end": 404, "text": "(Bamshad and Wooding 2003)", "ref_id": "BIBREF3"}, {"start": 596, "end": 615, "text": "(Risch et al. 2002)", "ref_id": "BIBREF39"}, {"start": 808, "end": 820, "text": "(Frank 2007;", "ref_id": "BIBREF16"}, {"start": 821, "end": 842, "text": "Serre and Paabo 2004)", "ref_id": "BIBREF46"}], "ref_spans": []}, {"section": "Human Genetic Variation", "text": "The concept of human genetic variation is further compounded by our simplistic view of the world in black and white. Genetic variation across the genome correlates to ancestral geographic origins which have often been associated with specific diseases. Self-identified racial and ethnic identity can correlate with ancestral geographic origins, but many individuals do not trace all of their ancestors to one place (Collins 2004) . Self-identified ethnic and racial identity often does not reflect the totality of one's inheritance. Most individuals emphasize selected aspects of their ancestry, have a limited knowledge of their complete ancestral lineage and live within an imposed social and political parameter of race and ethnicity.", "cite_spans": [{"start": 415, "end": 429, "text": "(Collins 2004)", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Role of Race in Genomic Medicine and Health Disparities Research", "text": "The emerging debate in the field of genetics over the use of race vs. ancestral labels highlights the importance of finding the best proxies for describing genetic population groups (Bamshad 2005; Tang 2006 (Bamshad 2005) . Ancestry correspondence with geography is also less apparent in many Latin American countries that have European, African and Native American admixture (Santos and Maio 2004) . Some geneticists therefore argue that ancestry is a much more reliable marker of an individual's genetic makeup than race (Jorde and Wooding 2004) . This debate is influencing the societal use of race as a category to describe differences in efficacy of drug therapies.", "cite_spans": [{"start": 182, "end": 196, "text": "(Bamshad 2005;", "ref_id": "BIBREF2"}, {"start": 197, "end": 206, "text": "Tang 2006", "ref_id": "BIBREF51"}, {"start": 207, "end": 221, "text": "(Bamshad 2005)", "ref_id": "BIBREF2"}, {"start": 376, "end": 398, "text": "(Santos and Maio 2004)", "ref_id": "BIBREF45"}, {"start": 523, "end": 547, "text": "(Jorde and Wooding 2004)", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "Role of Race in Genomic Medicine and Health Disparities Research", "text": "In June 2005, the U.S. Federal Drug Administration approved the first and only race-specific drug, BiDil, for the treatment of congestive heart failure among self-identified blacks (Temple and Stockbridge 2007) . BiDil, a combination of two generic drugs, Isorsorbide Dinitrate and Hydrazaline, was shown to successfully reduce mortality and hospitalization rates and increase quality of life among hypertensive black patients in the AfricanAmerican Heart Failure Trial (Taylor et al. 2004 ). The approval of BiDil solely for \"self-identified Blacks\" has been widely debated. No data on genetic variants responsible for the proposed racial differences in response to the drug have been reported. Duster (2007) and other scholars have argued that BiDil has raised a number of concerns about the future direction of health disparities research and role of race in clinical decision making (Kahn 2004; Sankar 2006) .", "cite_spans": [{"start": 181, "end": 210, "text": "(Temple and Stockbridge 2007)", "ref_id": "BIBREF55"}, {"start": 470, "end": 489, "text": "(Taylor et al. 2004", "ref_id": "BIBREF54"}, {"start": 696, "end": 709, "text": "Duster (2007)", "ref_id": "BIBREF14"}, {"start": 887, "end": 898, "text": "(Kahn 2004;", "ref_id": "BIBREF28"}, {"start": 899, "end": 911, "text": "Sankar 2006)", "ref_id": "BIBREF43"}], "ref_spans": []}, {"section": "Role of Race in Genomic Medicine and Health Disparities Research", "text": "The genomic era will generate questions surrounding race, difference and health that will challenge us to evaluate the best methods for teasing apart the social, environmental, biological and genetic components that affect individual and population health. Genetic factors (Leroi 2005 ) and nongenetic factors such as, socioeconomic privileges and racial discrimination have all been proposed explanations for racial and ethnic health disparities (Krieger 2005) . Growing multiracial populations with unique ancestry and social experiences provide opportunities for new areas of interdisciplinary research on racial and ethnic health disparities. Contact and interaction with multiracial populations contest other individuals' and social institutions' current construction of race (Johnson 1992) .", "cite_spans": [{"start": 273, "end": 284, "text": "(Leroi 2005", "ref_id": "BIBREF32"}, {"start": 447, "end": 461, "text": "(Krieger 2005)", "ref_id": "BIBREF30"}, {"start": 781, "end": 795, "text": "(Johnson 1992)", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Role of Race in Genomic Medicine and Health Disparities Research", "text": "There is very limited research that is focused on the attitudes and opinions of recently mixed populations and their understanding of race, ethnicity, ancestry and health (Snipp 2003; Sondik et al. 2000; Tashiro 2002) . and colleagues' study on the lay public's attitudes on race and genetics messages included several multiracial individuals but did not report their perspectives or concerns. Research on the layperson's perspective on genetics, race and health has shown that people have complex understandings of genetics research that warrants further exploration . Tashiro (2005) highlighted the need for qualitative research that transcends the \"categorization of people into precise racial combinations and thoroughly explores the complexity of the lives and social locations\" of mixed people. The leader of the International Human Genome Project, Francis Collins (2004) , called for more \"anthropological, sociological and psychological research into how individuals and cultures conceive and internalize concepts of race and ethnicity.\" Data from these types of studies can provide valuable information to clinicians and clinical researchers who frequently encounter multiracial and multicultural patients.", "cite_spans": [{"start": 171, "end": 183, "text": "(Snipp 2003;", "ref_id": "BIBREF49"}, {"start": 184, "end": 203, "text": "Sondik et al. 2000;", "ref_id": "BIBREF50"}, {"start": 570, "end": 584, "text": "Tashiro (2005)", "ref_id": "BIBREF52"}, {"start": 863, "end": 877, "text": "Collins (2004)", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Role of Race in Genomic Medicine and Health Disparities Research", "text": "This study explored the views and experiences of individuals whose parents are from different racial backgrounds. The objective of the study was to learn about the participants' perceptions of their identity, their social and clinical experiences as multiracial individuals and their opinions on the debate regarding the importance of human genetic variation in understanding health disparities and use of race-based therapies. We investigated their attitudes towards the future of genomics and personalized medicine and the use of race as a heuristic in clinical decision making. We hope data from this study will challenge race scholars and other social and natural scientists to further investigate how human genetic variation research interacts with the social constructions of race.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "This qualitative research study utilized in-depth, semi-structured oneon-one interviews to gather information about racial and ethnic identity, ancestry, genetics and health care experiences of multiracial individuals. The study population was comprised of adults at least 21 years of age with one parent of African ancestry and the other parent of European ancestry. While there are numerous individuals who identify as multiracial, our participant pool was limited to individuals of African and European backgrounds. These individuals have a parent who identifies as a member of a racial group with well-documented health disparities, and another parent who identifies as a member of a majority racial group with typically better health outcomes. Only one participant from a family was eligible to participate in the study. A total of 22 interviews were conducted in two metropolitan areas: Washington, DC and Atlanta, GA. A pilot interview was performed in each location followed by 10 interviews, each lasting approximately one to two hours.", "cite_spans": [], "ref_spans": []}, {"section": "Recruitment and Interviews", "text": "Several recruitment strategies were implemented to recruit participants for the study. Notice of the study was sent to national and local multiracial identity organizations in each geographic location via electronic mail. The research team also provided recruitment letters, detailing information about the study to colleagues and listserves for distribution. Lastly, a snowball sampling method was used to recruit additional people to participate in the study from individuals who had already been interviewed.", "cite_spans": [], "ref_spans": []}, {"section": "Recruitment and Interviews", "text": "The interviews were held in Atlanta, GA and Bethesda, MD. A trained interviewer with a multiracial background concordant with the participants conducted the one-on-one interviews. The interviews were led in a semi-structured manner to allow for a natural flow of conversation. An interview guide provided the interviewer with a framework for discussion on the domains of identity, family ancestry, physician-patient interaction and understanding of genetics. Each interview was audio recorded and transcribed verbatim. Research protocol was reviewed and approved by the National Human Genome Research Institute's Institutional Review Board for Human Subjects Research.", "cite_spans": [], "ref_spans": []}, {"section": "Data Analysis", "text": "Data analysis proceeded in several stages. First, a coding tree that depicted all codes and their definitions was created to guide data analysis and ensure that codes were appropriate and representative of important and salient ideas, themes and phrases in the transcripts. Second, two members of the research team used the created coding tree to code two selected transcripts independently. Third, to establish inter-coder reliability, they met to review their coding patterns and verify consistency. After coding differences were clarified and the coding tree was revised, the two research team members independently coded the 20 remaining transcripts using the finalized coding scheme. After subsequent meetings by the independent coders, all transcripts were reviewed and differences in coding patterns were reconciled to create a final dataset. Finally, this final dataset was reviewed to identify the most salient concerns, beliefs, and experience relating to the questions. NVivo 7 qualitative research software was used to support the coding and analyses of the data. Sociodemographic information was obtained from each of the participants at two points during the interview.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "Our participant pool was comprised of relatively young individuals from educated backgrounds. The mean age of participants was 29 but ranged from 21 to 51. Of these participants, 82 percent were female and 42 percent had a master's or doctoral degree. Consistent with interracial marriage patterns, 82 percent of the participants had white mothers and black fathers.", "cite_spans": [], "ref_spans": []}, {"section": "Identity", "text": "Interviews began with questions about a participant's family history and personal identity. There were a variety of factors that affected how participants identified themselves. It is important to remain cognizant that our public categorizations have an impact on personal racial identity (Brunsma 2006) . People may change how they report their race and ethnicity over time depending on age, marital status, parental race, geography or perceived benefit of reporting one way over another (Lee and Bean 2004; Roth 2005; Williams and Jackson 2000) . Consistent with other findings, this study found that participants' identity was influenced by a number of personal, social and contextual factors (Harris and Sim 2002) . It was frequently noted that their personal identity was affected by their physical appearance and the racial labels that others placed upon them. A third of the participants identified as black usually in response to how they felt they were perceived by others. Participants were also conscious of the past experiences of multiracial individuals in the United States with specific reference to the one-drop rule. While they recognized the opportunity to acknowledge both sides of their heritage they also understood that socially and historically they are grouped into the \"black\" race. Some participants were very content with this modern hypo-decent while others thought it was important to identify as multiracial. Their diverse ancestry was a source of pride and they did not want to deny either side.", "cite_spans": [{"start": 289, "end": 303, "text": "(Brunsma 2006)", "ref_id": "BIBREF8"}, {"start": 489, "end": 508, "text": "(Lee and Bean 2004;", "ref_id": "BIBREF31"}, {"start": 509, "end": 519, "text": "Roth 2005;", "ref_id": "BIBREF41"}, {"start": 520, "end": 546, "text": "Williams and Jackson 2000)", "ref_id": "BIBREF57"}, {"start": 696, "end": 717, "text": "(Harris and Sim 2002)", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Well", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Racially? I always tell people I'm mixed. You know I don't really, I never say I'm one or the other. 106", "text": "A short pre-interview survey requested that participants report their race using standard OMB categories. At the end of the interview participants were given a second survey that allowed them to report their race using an open-ended question. In general, a third of the participants identified as black and 15 percent of all participants changed how they reported their race when allowed to write in a response.", "cite_spans": [], "ref_spans": []}, {"section": "Health Care Interactions", "text": "Participants were asked how race and ethnicity information was collected in health care environments. While many of them understood that race could be a sensitive topic, they also admitted that personal and uncomfortable information was often discussed in health care settings. The interviewer asked them to remember how many times they had been directly questioned about their racial background or ancestry. Interestingly, the vast majority of participants reported that questions about race were included on in-take forms, but health care providers rarely had conversations about their background or followed up on what was recorded on the forms. Participants were also asked if they thought health care providers assumed their race without asking them. Again, the majority of participants felt that their race was commonly assumed to be black, and they noted that this assumption was often transferred to their medical records.", "cite_spans": [], "ref_spans": []}, {"section": "But I don't feel like they have to ask me my race because they look at me and they automatically make a determination. 202 So my father being black and taking me to the doctor's office and everything, they would always assume that I was black. And I almost remember --I do remember on at least one occasion when, I guess, when you go to the doctor's office and they bring somebody in first before the doctor gets there and asks you a series of questions, that when the doctor came back after they had left the room, my father noticed, I guess, that it was on the form, that it was bold, and that I was black. And he was, like, \"No, that's not right. His mother's white.\" And they had to change it. And I just thought at that time I was, like, wow. 'Cause my dad's here and I'm here, they must think I'm black. And so generally whenever I go into a doctor's office, that's how I'm perceived. 103 Interviewer: And how many times do you think that they just assumed what your race is? Participant: Oh, the majority of the time. 107", "text": "The consequences of race collection became apparent when the participants were then asked if they thought physicians and health care providers used their race when making decisions about their care. Some participants thought that race was completely irrelevant to health which may account for the lack of conversation about their racial background. Others thought that providers could offer more culturally appropriate care based on the patients' race (perceived or confirmed) and agreed that it should be considered when making health care decisions.", "cite_spans": [], "ref_spans": []}, {"section": "No, I don't think, not unless it came to, no I really don't think it would matter, like, for like, health-care wise, like what they would need to treat differently or what they would need to do. I don't think it would be that different if I was another race.-206 I would think that they have to sort of tailor things to the individual and that's, you know, part of, you know, sort of what's culturally appropriate for someone. I mean, people aren't going to adhere to things that contrast with their culture they're comfortable with or things of that nature. And that's sort of a real phenomenon, so I think it does, yeah. 108", "text": "Several of the participants thought that family health history, information that nearly all of them remembered being collected, was far more important and relevant to decisions about their care. They agreed that family health history was a more specific and accurate tool to guide health decisions. Race represented a complex and dynamic construct that did not possess the stability to inform medical decisions.", "cite_spans": [], "ref_spans": []}, {"section": "I would think they would use family health history more than they would race because I think -well, I guess it's just coming from me. Family makes up what you are and it makes up everything about you. Race doesn't tell everything about you. 104 Do you think they're making decisions based on my race? I think that, well would hope that if they were they would be confirming my race before they, you know before they made those decisions. 106", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Race-Based Therapeutics", "text": "Conversations about the collection of race and use of race in health care decision-making led to more broad questions about race-based medicine. Participants were presented the BiDil example and asked to comment on drugs indicated for specific racial groups. While the reaction to racebased care was mildly accepted especially in reference to culturally competent practices, the development of race-based therapeutics provoked a largely negative response. Participants were suspicious of the science behind these types of drugs. They wanted to know exactly how the medication would benefit one race over another and struggled with the suggestion that they could take a pill developed for \"black patients.\" There was a general disconnect with the idea that drugs could treat one group better than another because in the participants' experiences, they could be considered black or mixed in healthcare settings. It made them uncomfortable to think their personal identity decisions could influence how drugs are prescribed. Participants also seemed concerned about the social implications of creating race-based therapeutics. They questioned if these drugs supported the concept of a biological or genetic basis to race. Participants thought that complexities surrounding race and identity made it impossible for drugs to treat groups of people based on race. Discussion about race-based therapeutics stirred new questions about identity and pushed participants to conceptualize how they connect race to genetics and health. It was often mentioned that many people in America have a mixed ancestry, and therefore invalidated the idea that race could be used as a heuristic for treatment decisions. Their personal experiences had illustrated the inconsistencies of racial identity and they therefore concluded that race was not an appropriate tool to guide medical decisions. ", "cite_spans": [], "ref_spans": []}, {"section": "My next question is why is it", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "It", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "I mean, I think especially in this country", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Health Disparities", "text": "Some participants liked the idea of drugs made for specific minority groups because of the history of health disparities in this country. They thought that drugs such as BiDil were a necessary response to the higher prevalence of diseases in minority populations such as African Americans. These participants thought that race provided a useful link to genetics that could help researchers identify treatment options for different groups.", "cite_spans": [], "ref_spans": []}, {"section": "I think they need to do more determination for the African American groups and the Latino groups and the other minority groups. The reason why is because the majority of the medications that they do test on, they've probably done more tests on Caucasian medication or Caucasian descent than anybody else. So they've already got medications that they've decided or worked out that satisfy that particular genetic make up or ancestral make-up. They need to do more on the African American side because hypertension is killing more African Americans than it is whites. 202", "text": "Others commented on the political and social power of the race construct. They mentioned that our current research and medical systems reinforce the use of race.", "cite_spans": [], "ref_spans": []}, {"section": "Well, for one, I mean, if you're not educated then you may not think those things in those terms. So you may think that there are biological or genetic differences between races. Or if you're in a position of power and may have certain political agendas then you may push those factors, such as genetics or something, to very much differentiate the races. 110", "text": "Discussion of race and medicine also prompted numerous comments about social and environmental factors that affect health. Participants acknowledged health disparities as a problem that should be addressed, but contested the idea of improving these disparities through race-based therapeutics. They thought that social factors such as diet, education, income or discrimination were far more pertinent contributors to health disparities. These participants thought that genetics played a minor role in differences in health outcomes by race. ", "cite_spans": [], "ref_spans": []}, {"section": "But I think it's ridiculous really. I mean I don't think,", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Race, Ancestry and Genetics", "text": "When participants were questioned about how they connect race, ancestry and genetics, many of them could construct a correlation among the concepts. However, ancestry was seen to be more closely related to genetics than race and therefore served as a more accurate reflection of their genetic make-up. Race was typically connected to genetics through physical characteristics that serve as important identifiers in racial categorizations. Several participants thought there may be some connection between race and genetics, but they struggled to decipher the strength of the relationship. ", "cite_spans": [], "ref_spans": []}, {"section": "How would I describe the relationship between race", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Vision of Race, Health and Identity in the Genome Era", "text": "After participants were questioned about their personal identity, health care interactions, conceptions of race and race-based therapeutics, they were asked how they envision genetics affecting the use of race as an indicator of genetic difference in the future. There was a wide range of responses; some predicted an increased use of race while others thought genetics might phase out the use of racial categories. Participants' responses were founded on how closely they linked race and genetics. However, many of them anticipated that technological advances and personalized medicine will focus on an individual's genetic make-up rather than his or her racial background. Throughout the interviews, participants offered their thoughts for the future direction of research and medical care. Their comments generally addressed the importance of race in this country and simultaneously suggested the need to control the future use of racial identifiers. As our population continues to diversify, the issues that these multiracial individuals voiced will be relevant to all people. ", "cite_spans": [], "ref_spans": []}, {"section": "Discussion and Conclusions", "text": "The voices of the study participants illustrate diverse perspectives on topics of identity, race, genetics and health. While opinions about personal racial identity were varied, there was a general consensus that individual identity cannot be captured with the limited constructs of race and ethnicity and should therefore not be interpreted as such. Participants' healthcare experiences were also different, but the overwhelming majority noted that they had never been directly asked about their ancestral background in a health care setting. This trend is juxtaposed to the fact that several participants thought that race was used by their provider when making clinical decisions. Although some discontinuity existed within opinions about race-based care, most of the participants objected to the development of race-based therapeutics. Many cited social and environmental factors as sources of health disparities and disliked the idea of creating drugs that would treat social groups of people. The majority of participants struggled to articulate their understanding of race, genetics and health. Most of them could draw strong connections between ancestry and genetics, but admitted weaker links existed between race and genetics. Many participants appreciated the potential for genetics to improve healthcare, but hoped that improved technology would allow health providers to assess them individually and not as part of a racial group.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion and Conclusions", "text": "The results of this study are limited to the sample of 22 individuals from two geographic locations. Our participant pool lacked age, gender and education diversity, and the majority of our participants were healthy individuals who often experienced minimal interaction with the health care system. Their voices cannot be extrapolated to experiences of all biracial people. However, to our knowledge, this is the first qualitative study of a multiracial population to investigate their attitudes regarding race, genetics and health. More empirical data is needed on the lay public's understanding of race and its relationship to human genetic variation. Untangling the web of identity, ancestry and genetics requires that more attention be paid to the diversity that exists not only within the racial spectrum of humankind, but also within the culture, behavior and privileges that define who we are.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion and Conclusions", "text": "Racial and ethnic health disparities are strongly associated with social determinants and individual behaviors (Shavers and Shavers 2006; Williams and Jackson 2005) . Genetics is one of a multitude factors that may help explain differences in the incidence of certain diseases within racial groups. We must, however, be cautious not to over exaggerate genetics in the study of health disparities (Sankar et al. 2004) . Despite the blurry correlation between race, genetics and ancestral geographic backgrounds, researchers and clinicians use race as a proxy for genetic disease risk (Kittles and Weiss 2003; Royal and Dunston 2004) . Evaluating the genetic contribution to disease will also demand that more is understood about gene-gene and gene-environment interactions (Manolio and Collins 2007; Sankar et al. 2004 ).", "cite_spans": [{"start": 138, "end": 164, "text": "Williams and Jackson 2005)", "ref_id": "BIBREF58"}, {"start": 396, "end": 416, "text": "(Sankar et al. 2004)", "ref_id": "BIBREF44"}, {"start": 583, "end": 607, "text": "(Kittles and Weiss 2003;", "ref_id": "BIBREF29"}, {"start": 608, "end": 631, "text": "Royal and Dunston 2004)", "ref_id": "BIBREF42"}, {"start": 772, "end": 798, "text": "(Manolio and Collins 2007;", "ref_id": "BIBREF34"}, {"start": 799, "end": 817, "text": "Sankar et al. 2004", "ref_id": "BIBREF44"}], "ref_spans": []}, {"section": "Discussion and Conclusions", "text": "Genomics research is quickly moving health services towards personalized medicine where patients' genetic profiles will be used in combination with behavioral and environmental factors when determining the best clinical treatment. However, the technology and financial feasibility for this type of care is not available for most people today. Until each individual has his or her genome sequenced and we understand it, we will remain dependent on group heuristics. Social and natural scientists must conduct interdisciplinary research to bridge the chasm that currently exists in order to move forward our understanding of race and the social and genetic basis of disease. Developing new analytical frameworks will require the expertise of social science researchers who understand the molecular biology of genetics and geneticists that understand the social theories of race and identity.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion and Conclusions", "text": "We cannot discount or exaggerate the correlations between genetics and social racial groups. Self-identified race can correlate with human genetic variation. Race, as a social construct, matters in the lives of people. There are dangers in having a society that doesn't recognize race and racism. Color-blindness can promote continued racial inequalities and create an illusion that race is no longer an issue (Gallagher 2003) . This can be especially detrimental for individual health outcomes (Williams and Jackson 2000) .", "cite_spans": [{"start": 410, "end": 426, "text": "(Gallagher 2003)", "ref_id": "BIBREF18"}, {"start": 495, "end": 522, "text": "(Williams and Jackson 2000)", "ref_id": "BIBREF57"}], "ref_spans": []}, {"section": "Discussion and Conclusions", "text": "What can we learn from the voices of these multiracial individuals? Race, identity and genetics are complex constructs that should encourage us to continually and critically evaluate their significance and appropriate applications to healthcare and biomedical research. The recognition of individuals of diverse ancestry challenges our conception of race and its connection to genetic group differences. This is more clearly illustrated in the experiences of people with a multiracial background, but is true for people of all backgrounds. Researchers and health professionals need to move beyond using race as \"the best proxy\" for genetic variation. Our society is diverse in culture, diet, language, faith and other characteristics outside of race. Improving health will demand that individuals are evaluated within the unique circumstances in which they live. Their health is affected by many factors including their individual genome as well as their education, household wealth, social status, social race and experiences of racism. The perspectives of multiracial individuals charge researchers to address the challenges that we face within our current racial classification system and biomedical research. 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The connection between race and genetics is tied to the understanding that race reflects ancestral geographic heritage. This connection is weakened among admixed populations, such as African Americans, that have a clear history of diverse ancestral background. On average, African Americans have about 80 percent West African ancestry with ranges from 20 percent to 100 percent", "type": "table"}, "TABREF1": {"text": "Participants' Demographic Characteristics", "type": "table"}, "TABREF2": {"text": "Participants' Demographic CharacteristicsTOTAL (N = 22) DC (N = 11) Atlanta (N = 11)", "type": "table"}, "TABREF3": {"text": ", I consider myself black. Even though I'm multiracial, I consider myself black, because when people see me, that's what they see. So I figured to make things simple, I'm black. 208 Well, I mean I think most biracial people probably always straddled the, like, black identity even if they do generally call themselves mixed or biracial because most of the time you are still perceived as being black by other people. 102", "type": "table"}, "TABREF4": {"text": "When I mark it generally, it's black. Growing up, my daddy kept telling me it's that one-drop theory -you're black. It doesn't matter if you're half white. They don't care. You're black. And it wasn't really in a negative way, but it was kind of like the way it is. 204", "type": "table"}, "TABREF5": {"text": "Participants' Self-Reported Race, Pre-and Post-interview", "type": "table"}, "TABREF6": {"text": "Participants' Self-Reported Race, Pre-and Post-InterviewSeveral of the participants also admitted that they identified themselves as black on medical forms and suggested that their health care provider had no knowledge of their European ancestry.Interviewer: And so do you think that your health care provider knows about your European ancestry at all? Participant: I don't think I put that on the form. No, probably not. 208", "type": "table"}, "TABREF7": {"text": "only for black people? Is there something only in our heritage? And since I'm half white, would it only work half way for me? Things like that don't necessarily sit well with me. 204 It seemed weird to me for several reasons. Once again, I just never heard of medicine working better for some than others. I mean, because although you know that there are some diseases that affect some people more than others, I still kind of operate under the assumption that we're all the same on the inside. You know? 102", "type": "table"}, "TABREF8": {"text": "'s a slippery slope, and it's dangerous for people to try to treat by race because race, once again, is a social construct. There's no biological basis. I mean there's more genetic variation within a racial group than between, I mean, often times. 107 Yeah, just because of, I understand on a pure level, like even if you could resolve it, like scientifically, and say, \"Yes, this helps this race more. It should be used for this race,\" I don't know how you deal with the social aspect of it, how people would actually interpret that and understand it. 109", "type": "table"}, "TABREF9": {"text": ", as people are multi-racial, you know, we sort of, as a race of people, are dwelling on proportionality, that it sets up for major gaps. And I think, you know, one of the big concerns for physicians is that they, mean, beyond the limited time they have with somebody, they don't get all the information. And part of it is because they don't ask the right questions. 108 I mean, what specifically are they targeting that only makes it available, or good or useful for black people? Then, as scientists, they need to specifically identify what makes you black. 205 Yeah, so when someone says, self-, like, identified as African American, there is so much variation within that group. You have someone from the Caribbean and then, you know, someone who's like from West Africa within this category, and there's a variety of different types of genetic components that make up an individual. So, I don't know if people really have accounted for different side effects or how people respond to it. 107", "type": "table"}, "TABREF10": {"text": "I feel like any disease or health issue that's gonna come predominately to one race you have to look at the social factors that may be contributing to this. I don't think it has anything to do with genetics at all. 110I just feel like class and just environment in general really informs how, your well-being, and definitely your social experiences would impact your well-being. And so that I see kind of a more definitive connection than the racial component if that makes sense. But again it is not to say that there isn't a racial component there. But I just don't know if my mind is willing to embrace that wholeheartedly. 203", "type": "table"}, "TABREF11": {"text": "linked than they are to race. But I think they all sort of envelop each other. 108 I think ancestry has a lot to do with your genetic make up. But I also think it has more to do -I think ancestry has more to do with your genetic make up than your race does. Because I just think of when I think aboutDad and that makes you. So part of that is one of the things that you inherit is the color of your skin, which is part of what it means to have racial identity. So I think there's some link between genetics and race in how we frame what we mean by race. 108 I think that there is, but I don't know to what degree that it -it's hard to separate out the environmental factors from the genetic factors, and so, because you can't do that, it's hard to tell, like, you know, whether genetics is like 90 percent, and environmental is 10, or whether environmental is 10, and -I mean 90, and genetics is 10. So I think that there are connections. I just don't know how strong connections they are. 209", "type": "table"}, "TABREF12": {"text": "I think it's going to go more towards ancestry and less towards race. Because I think, it's like I said, you have to be treated as an individual. You can't be treated as a race. I just think that's a big message I want to get across. 103Well, I mean I guess I see race already impacting healthcare. And so if anything I think it will just sort of intensify the boundaries and sort of cement differences that may or may not be real. And so I think it may be used as an excuse to provide care differently to different groups or different populations. 203 I could say that since it's [genetics] more science based, I could say that it would phase out the use of that question. Because if we see that I identify myself as black, but half of me or half of my genetics is white, me checking black will give you a skewed representation of my medical history or my family history. So I could see that I would say that the race question could be phased out to something else more specific targeting genetics. 204 I really believe that -and perhaps the genetic piece will show us more of how -we're alike and how we're different from each other. Because they say that, like, 99 percent of the human genome is the same. And then there's just, like, this little bit that's different. And so I really hope that the more that that is understood, the better we can bring people together and say that, \"I'm gonna treat you from a personal level as opposed to a racial level.\" And that that will actually be more effective. 207", "type": "table"}, "TABREF13": {"text": "But I don't think it's a good idea to just, you know, group people into races. I think that doctors need to get the memo that they need to test the person for a specific mutation. 209 I think that we have a unique perspective. And maybe since you brought it to my attention, but I think because we'd be caught in the crosshairs of a race-based medical system. 'Cause what would they do with us? You know what I'm saying? That that's how we can see the weaknesses in that system. It all -we can see the shortcomings\u2026 And so in all kinds of ways, we would put a challenge to trying to have a race-based health system. 207", "type": "table"}, "TABREF14": {"text": "I think in some ways having a parent who's white and a parent who's black, I understand the sort of surface genome type. That because of those two -that union, I have the skin color I have and the nose, I have the lips, and I have this of my mother's and this of my father's. I mean, I get that, but I think I also realize that race - because I have parents of different races, that race is probably so much more than just genetics. I mean, that realization is probably more had by me than maybe someone who has parents of the same race. 108", "type": "table"}}}
{"paper_id": "8331088", "_pdf_hash": "fa6961987aa8c4dfd06b92040e7e76006ef1a29d", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Muti-unit spike discrimination using Wavelet transforms", "authors": [{"first": "G", "middle": [], "last": "Zouridakis", "suffix": ""}, {"first": "D", "middle": ["C"], "last": "Tam", "suffix": ""}], "year": 1997, "venue": "Comput. Biomed", "link": null}, "BIBREF1": {"title": "Computer Separartion of multi-unit Neuroelectrical data: a review", "authors": [{"first": "E", "middle": ["M"], "last": "Schmidt", "suffix": ""}], "year": 1984, "venue": "J. NeuroSci. Meth", "link": null}, "BIBREF2": {"title": "Instruments for sorting Neuroelectrical data: a review", "authors": [{"first": "E", "middle": ["M"], "last": "Schmidt", "suffix": ""}], "year": 1984, "venue": "J. NeuroSci. Meth", "link": null}, "BIBREF3": {"title": "A course in Fuzzy Systems and Control", "authors": [{"first": "Li-Xin", "middle": [], "last": "Wang", "suffix": ""}], "year": 1997, "venue": "", "link": null}, "BIBREF5": {"title": "Neural Networks and dynamical Systems part I: A gradient approach to Hopfield Networks", "authors": [{"first": "K", "middle": ["S"], "last": "Narendra", "suffix": ""}, {"first": "K", "middle": [], "last": "Porthasarathy", "suffix": ""}], "year": 1988, "venue": "", "link": null}, "BIBREF6": {"title": "A Wavelet tour of signal processing", "authors": [{"first": "S", "middle": [], "last": "Mallat", "suffix": ""}], "year": 1997, "venue": "", "link": "122523543"}, "BIBREF7": {"title": "Introduction to wavelets and Wavelet transforms", "authors": [{"first": "S", "middle": [], "last": "Burrus", "suffix": ""}, {"first": "R", "middle": [], "last": "Gopinoth", "suffix": ""}, {"first": "G", "middle": [], "last": "Haitao", "suffix": ""}], "year": 1998, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "8331338", "_pdf_hash": "1cc453398f7d0edbd46c8323ed69deadd702d782", "abstract": [], "body_text": [{"section": "", "text": "journal.publications.chestnet.org", "cite_spans": [], "ref_spans": []}, {"section": "Response", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "To the Editor:", "text": "We thank Drs Chang and Hancox for their interest in our work on natriuretic peptides in community-acquired pneumonia. 1 -4 The current report 1 extends our previous observations and tries to highlight fi ndings that (1) apply to the whole family of natriuretic peptides in general and (2) provide a direct comparison of the clinical potential of all three commercially available natri uretic pep tides (B-type natriuretic peptide [BNP] , N-terminal pro-B-type natriuretic peptide, and midregional pro-atrial natriuretic peptide ). In this analysis, we used the data from all patients who presented to our institution with community-acquired pneu monia in whom we had the measurements of all three natriuretic peptides available. As correctly mentioned by Drs Chang and Hancox, some of these patients were in earlier cohorts that dealt exclusively with BNP. About one-third of the patients were included in the recruitment period from April 2006 to March 2007.", "cite_spans": [{"start": 216, "end": 219, "text": "(1)", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "To the Editor:", "text": "Drs Chang and Hancox are also correct in highlighting that in some patients, physicians used procalcitonin levels as additional information for the tailoring of the duration of antibiotic treatment. Regarding blinding, physicians were blinded to N-terminal pro-B-type natriuretic peptide and midregional pro-atrial natriuretic peptide levels in all patients. These levels were measured from frozen samples long after the discharge of patients. The blinding regarding BNP levels was not uniform. In about one-half of the patients, BNP levels were measured in a blinded fashion; in the other half, BNP levels would have been available to physicians via the electronic patient records. ", "cite_spans": [], "ref_spans": []}, {"section": "Preventing VTE in Outpatients With Cancer", "text": "To the Editor:", "cite_spans": [], "ref_spans": []}, {"section": "Preventing VTE in Outpatients With Cancer", "text": "We applaud the innovations pioneered by the American College of Chest Physicians evidence-based clinical practice guidelines on antithrombotic therapy and prevention of thrombosis (February 2012). However, we are concerned about the resulting recommendations regarding cancer-associated thrombosis, a signifi cant contributor to the public health burden of VTE and an area of particular interest to us.", "cite_spans": [], "ref_spans": []}, {"section": "Preventing VTE in Outpatients With Cancer", "text": "Regarding prevention of VTE in nonsurgical patients, 1 the panel suggested that outpatients with solid tumors with additional risk factors for VTE should receive prophylactic-dose lowmolecular-weight heparin or low-dose unfractionated heparin (recommendation 4.2.2). Additional risk factors cited by the panel include hormonal therapy and angiogenesis inhibitors. In our opinion, this recommendation (even as a grade 2B) does not refl ect an appropriate interpretation of the results of recent studies on cancer thromboprophylaxis and risk assessment. If these recommendations were to be followed, tens of thousands of women with breast cancer or men with prostate cancer on hormonal therapy for extended periods would receive low-molecularweight heparin or low-dose unfractionated heparin. The rate of VTE in these patients, however, is much lower than other cancer subgroups, and there are no studies showing a benefi t of thromboprophylaxis. 2 Similarly, the linkage between antiangiogenic agents, such as bevacizumab, and VTE has not been consistently demonstrated in pooled analyses. 3 (Although thalidomideand lenalidomide-based regimens are associated with VTE, these are used primarily in myeloma and not solid tumors.) Recommendation 4.2.2 further fails to cite important risk factors, such as site of cancer, and a risk assessment model for chemotherapyassociated VTE that has been externally validated in multiple studies; both are the basis for recent and ongoing prophylaxis studies. 4 The Institute of Medicine's 2011 report, Clinical Practice Guidelines We Can Trust , emphasized guideline development group composition and external review. 5 Inclusion of oncology content experts on the panel or as external reviewers could have provided a different interpretation of the data and more clinically sound recommendations. We urge the panel to consider such multidisciplinary input for the next iteration of the guidelines. Even weak recommendations formulated without scientifi c evidence can have a negative impact on patient care and future study design. It is quite possible that institutional review boards may identify these suggestions as the standard of care, affecting future study feasibility. As physicians and researchers involved in this fi eld, we disagree with recommendation 4.2.2 and suggest that clinicians consider recommendations from cancer-focused guidelines, such as those of the American Society of Clinical Oncology and the National Comprehensive Cancer Network.", "cite_spans": [{"start": 945, "end": 946, "text": "2", "ref_id": "BIBREF1"}, {"start": 1089, "end": 1090, "text": "3", "ref_id": "BIBREF2"}, {"start": 1497, "end": 1498, "text": "4", "ref_id": "BIBREF3"}, {"start": 1656, "end": 1657, "text": "5", "ref_id": "BIBREF4"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Prevention of VTE in nonsurgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines", "authors": [{"first": "S", "middle": ["R"], "last": "Kahn", "suffix": ""}, {"first": "W", "middle": [], "last": "Lim", "suffix": ""}, {"first": "A", "middle": ["S"], "last": "Dunn", "suffix": ""}], "year": 2012, "venue": "Chest", "link": "2695753"}, "BIBREF1": {"title": "Toxicity of adjuvant endocrine therapy in postmenopausal breast cancer patients: a systematic review and meta-analysis", "authors": [{"first": "E", "middle": [], "last": "Amir", "suffix": ""}, {"first": "B", "middle": [], "last": "Seruga", "suffix": ""}, {"first": "S", "middle": [], "last": "Niraula", "suffix": ""}, {"first": "L", "middle": [], "last": "Carlsson", "suffix": ""}, {"first": "A", "middle": [], "last": "Oca\u00f1a", "suffix": ""}], "year": 2011, "venue": "J Natl Cancer Inst", "link": "4890285"}, "BIBREF2": {"title": "Venous thromboembolic events with chemotherapy plus bevacizumab: a pooled analysis of patients in randomized phase II and III studies", "authors": [{"first": "H", "middle": ["I"], "last": "Hurwitz", "suffix": ""}, {"first": "L", "middle": ["B"], "last": "Saltz", "suffix": ""}, {"first": "E", "middle": [], "last": "Van Cutsem", "suffix": ""}], "year": 2011, "venue": "J Clin Oncol", "link": "24224948"}, "BIBREF3": {"title": "Risk assessment and prophylaxis for VTE in cancer patients", "authors": [{"first": "A", "middle": ["A"], "last": "Khorana", "suffix": ""}], "year": 2011, "venue": "J Natl Compr Canc Netw", "link": "30133709"}, "BIBREF4": {"title": "Committee on Standards for Developing Trustworthy Clinical Practice Guidelines; Board on Health Care Services; Institute of Medicine of the National Academies . Clinical Practice Guidelines We Can Trust", "authors": [{"first": "R", "middle": [], "last": "Graham", "suffix": ""}, {"first": "M", "middle": [], "last": "Mancher", "suffix": ""}, {"first": "D", "middle": ["M"], "last": "Wolman", "suffix": ""}, {"first": "S", "middle": [], "last": "Greenfi Eld", "suffix": ""}, {"first": "E", "middle": [], "last": "Steinberg", "suffix": ""}], "year": 2011, "venue": "", "link": null}}, "ref_entries": {"TABREF0": {"text": "References 1 . Nowak A , Breidthardt T , Christ-Crain M , et al . Direct com- parison of three natriuretic peptides for prediction of short- and long-term mortality in patients with community-acquired pneumonia . Chest . 2012 ; 141 ( 4 ): 974 -982 . 2 . Christ-Crain M , Breidthardt T , Stolz D , et al . Use of B-type natriuretic peptide in the risk stratifi cation of community- acquired pneumonia . J Intern Med . 2008 ; 264 ( 2 ): 166 -176 . 3 . M\u00fceller C , Laule-Kilian K , Scholer A , Perruchoud AP . B-type natriuretic peptide for risk stratifi cation in community-acquired pneumonia .", "type": "table"}}}
{"paper_id": "8331474", "_pdf_hash": "97b81ddfd779623748dae66bb4a9e3179c90a237", "abstract": [{"section": "Abstract", "text": "Family therapists' participation in therapeutic dialogue with clients is typically informed by evidence of how such dialogue is developing. In this article, we propose that conversational evidence, the kind that can be empirically analyzed using discourse analyses, be considered a contribution to widening psychotherapy's evidence base. After some preliminaries about what we mean by conversational evidence, we provide a genealogy of evaluative practice in psychotherapy, and examine qualitative evaluation methods for their theoretical compatibilities with social constructionist approaches to family therapy. We then move on to examine the notion of accomplishment in therapeutic dialogue given how such accomplishments can be evaluated using conversation analysis. We conclude by considering a number of research and pedagogical implications we associate with conversational evidence.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "Family therapists' participation in therapeutic dialogue with clients is typically informed by evidence of how such dialogue is developing. In this article, we propose that conversational evidence, the kind that can be empirically analyzed using discourse analyses, be considered a contribution to widening psychotherapy's evidence base. After some preliminaries about what we mean by conversational evidence, we provide a genealogy of evaluative practice in psychotherapy, and examine qualitative evaluation methods for their theoretical compatibilities with social constructionist approaches to family therapy. We then move on to examine the notion of accomplishment in therapeutic dialogue given how such accomplishments can be evaluated using conversation analysis. We conclude by considering a number of research and pedagogical implications we associate with conversational evidence.", "cite_spans": [], "ref_spans": []}, {"section": "CONVERSATIONAL EVIDENCE?", "text": "In family therapy, conversation is usually seen as part of the therapeutic process and evidence is viewed as outcome. Process (conversation) affects outcome (evidence); both are intertwined and inseparable. Yet, one usually characterizes evidence in outcome research as being something far more measurable and tangible than the unquantifiable properties of conversation and discourse. In psychotherapy research, evidence of successful outcome is predominantly defined by test scores usually employed after and outside of the therapeutic conversation. Still, the nature of conversation is valued by therapists as facilitating outcomes by establishing and maintaining a therapeutic alliance (Bordin, 1994; Horvath & Symonds, 1991; Luborsky, 1994) . In this article, we meld together two key process-outcome concepts, conversation and evidence, into ''conversational evidence'' for evaluating outcomes in psychotherapy. Larner (2004) recently pointed out that in family therapy, there are significant politics around what should constitute the evidence guiding practice. For us, conversational evidence is a tangible, empirical, and justifiable form of outcome evidence useful for examining therapeutic change. Accordingly, we present the case that family therapy outcome evaluation could involve conversational evidence as one form of evidence among other forms.", "cite_spans": [{"start": 689, "end": 703, "text": "(Bordin, 1994;", "ref_id": "BIBREF12"}, {"start": 704, "end": 728, "text": "Horvath & Symonds, 1991;", "ref_id": "BIBREF48"}, {"start": 729, "end": 744, "text": "Luborsky, 1994)", "ref_id": "BIBREF55"}, {"start": 917, "end": 930, "text": "Larner (2004)", "ref_id": "BIBREF52"}], "ref_spans": []}, {"section": "BACKGROUND", "text": "We share a view with a number of social constructionist practitioners and researchers; that, to be helpful, therapeutic dialogue needs to elicit meaningful change clients prefer (Andersen, 1991; Bird, 2000; Ferrara, 1994; Gale, 1991) . For dialogue to be meaningful speakers need a sense that they are understood, if not influential and mutual with each other. Such dialogue typically occurs in relationally responsive ways that speakers take for granted-that is, unless they feel misunderstood or at odds with each other. At such points speakers have conversational work to do. They turn to each other's responses for evidence that this work is creating shared understanding and perceived forward movement for them. In this sense, speakers are practical interpreters of each other, deriving what they say and do from what was said and done by their conversational partners as the dialogues they contribute to develop. Such dialogues typically occur without much need for conversational and interpretive work because history, cultural, and relational experiences have already created a common ground of understanding. But, through dialogue, speakers work out new understandings and ways of going forward together, and this is especially the case in rhetorical endeavors like family therapy.", "cite_spans": [{"start": 178, "end": 194, "text": "(Andersen, 1991;", "ref_id": "BIBREF1"}, {"start": 195, "end": 206, "text": "Bird, 2000;", "ref_id": "BIBREF9"}, {"start": 207, "end": 221, "text": "Ferrara, 1994;", "ref_id": "BIBREF28"}, {"start": 222, "end": 233, "text": "Gale, 1991)", "ref_id": "BIBREF32"}], "ref_spans": []}, {"section": "BACKGROUND", "text": "Depicting therapy as a rhetorical endeavor may, for some readers, seem repugnant. Such a depiction places therapists in the same league as salespeople or politicians, but therapy has long been depicted this way by researchers and therapists (Frank, 1973; Maranha\u02dco, 1986; Roy-Chowdhury, 2003) . Seen as a practice where an aim is to put language to effective use vis-a`-vis clients' presenting concerns, however, we feel rhetorical can be an apt word to reflect therapists' mindful awareness and use of talk. We regard therapeutic dialogue as the means by which therapists and clients use language and other forms of communication to accomplish understanding and shared actions on client-preferred outcomes. Just as speakers would-as they talk-look for evidence from their conversational partners that they are being understood and working collaboratively, we see therapeutic dialogue offering an abundance of such evidence. How family therapists and clients accomplish these therapeutically relevant developments in the immediacies of their talking is part of what we will term ''conversational evidence.'' Generally, therapists look beyond conversation for evidence of change, yet clearly their conversational actions are guided by how clients respond to them in the back-and-forth of their dialogues. For example, it is not unusual for a therapist to start saying one thing and end up saying another-in the course of a single utterance to a client. That kind of ''mid-course correction,'' a conversational option as available to clients as it is to therapists, in our view owes much to evidence regarding the receipt of speakers' utterances as they talk. In another sphere, how people ''change their minds'' is often portrayed as a development quite apart from conversation. Evidence that clients change in such ways is frequently depicted as psychological despite being initiated and made evident in conversational interaction (Heritage, 1998) .", "cite_spans": [{"start": 241, "end": 254, "text": "(Frank, 1973;", "ref_id": "BIBREF29"}, {"start": 255, "end": 271, "text": "Maranha\u02dco, 1986;", "ref_id": "BIBREF59"}, {"start": 272, "end": 292, "text": "Roy-Chowdhury, 2003)", "ref_id": "BIBREF69"}, {"start": 1931, "end": 1947, "text": "(Heritage, 1998)", "ref_id": "BIBREF45"}], "ref_spans": []}, {"section": "BACKGROUND", "text": "While clearly a change in words in one conversation does not necessarily translate to changes beyond that conversation, therapists normally turn to what clients say and do in response to them for evidence that they are on the ''right track'' as they talk. We will examine the notion that the sayings and doings of therapeutic conversation are a source of evidence for therapeutic change. We take seriously the claims of conversation analysts (Heritage, 1984; ten Have, 1999 ) that conversation is a means by which people accomplish relational outcomes with each other. We also recognize that clinical acumen is in part informed by conversational evidence, as therapists initiate, evaluate, and respond to emergent developments in the immediacies of therapeutic conversation-as do clients. Our interest is in seeing conversational evidence taken seriously as a means of evaluating therapeutic outcomes. To this end, we will situate our interest in conversational evidence in the broader context of psychotherapy evaluation, in a social constructionist understanding of therapy, and in empirical demonstrations from family therapy.", "cite_spans": [{"start": 442, "end": 458, "text": "(Heritage, 1984;", "ref_id": "BIBREF45"}], "ref_spans": []}, {"section": "THERAPY AND CONVERSATIONAL ACCOMPLISHMENTS", "text": "For us, therapy is a context where, to paraphrase Austin (1962) , clients and therapists do and accomplish things with their words and other ways of communicating. In this respect, we are echoing the views of social constructionist theorists (e.g., McNamee & Gergen, 1992; Shotter, 1993) and practitioners (e.g., Anderson, 1997; Bird, 2000; Gale, 1991) . Our interest in conversation and its evidential developments is like that of another important theorist, Harold Garfinkel (2002) ; we feel the heart of therapy occurs on ''conversation's shop floor.'' Clients do things with what they regard as therapy's significant developments beyond their dialogues with therapists. However, change begins in dialogues that take clients past the sameness or constraints of their present dialogues with self or others. We also join well-established hermeneutic (Gadamer, 1988) , discursive (Billig, 1996; Edwards, 1997) , and sociocultural thinkers (Vygotsky, 1978) in considering thought as an extension of dialogue. Thus, what does get spoken can be seen as a barometer of change, especially if one considers the birth of therapeutic change as primarily occurring in the dialogic interactions of clients and therapists.", "cite_spans": [{"start": 50, "end": 63, "text": "Austin (1962)", "ref_id": "BIBREF4"}, {"start": 313, "end": 328, "text": "Anderson, 1997;", "ref_id": "BIBREF2"}, {"start": 329, "end": 340, "text": "Bird, 2000;", "ref_id": "BIBREF9"}, {"start": 341, "end": 352, "text": "Gale, 1991)", "ref_id": "BIBREF32"}, {"start": 467, "end": 483, "text": "Garfinkel (2002)", "ref_id": "BIBREF34"}, {"start": 851, "end": 866, "text": "(Gadamer, 1988)", "ref_id": "BIBREF31"}, {"start": 895, "end": 909, "text": "Edwards, 1997)", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "THERAPY AND CONVERSATIONAL ACCOMPLISHMENTS", "text": "At a mundane level we believe therapists are constantly guided by conversational evidence. Their choices of question, response, even posture, are part of their responsive ways of being with clients. These choices, however, are not simply guided by theoretical models of change (as if therapists could put textbooks on their eyes and ignore clients), but by what happens as therapists use their theories in interacting with clients. This view is quite in keeping with notions of reflective practice advanced by Donald Scho\u00a8n (1983) and fits nicely with a dichotomy of professionalism recently articulated by Robert Hopper. For Hopper (2005) , there are ''pre-strategy professionals'' who develop and execute plans and work well from anticipatable developments (from which further pre-strategies can be deployed) in the course of professional activities. However, he described another group of professionals: ''emergent-when professionals,'' who improvise their interactions based on unanticipatable developments that arise in professional encounters. We see therapy as requiring lots of the latter kind of professionalism while each form of professionalism is significantly informed by conversational evidence.", "cite_spans": [], "ref_spans": []}, {"section": "THERAPY AND CONVERSATIONAL ACCOMPLISHMENTS", "text": "From a process perspective (Rice & Greenberg, 1984) , there are many important developments on the road to overall therapeutic success, whether in clients' or therapists' eyes. Seen this way, what gets constructed or deconstructed in therapy is marked by conversational actions which culminate in particular outcomes critical to next steps in therapy. So, for example, how rapport is accomplished, how goals are co-articulated in ways that suit clients and therapist, how problems are co-defined, how ''homework'' is worked up between client and therapist-many such activities get worked out in therapeutic dialogue. Our use of the ''co-'' prefix is no accident. We see relational accomplishments occurring in conversational work-in utterances used and responses given-evident to researchers as well as those engaged in the ''work'' itself.", "cite_spans": [{"start": 27, "end": 51, "text": "(Rice & Greenberg, 1984)", "ref_id": "BIBREF68"}], "ref_spans": []}, {"section": "THERAPY AND CONVERSATIONAL ACCOMPLISHMENTS", "text": "Speakers cannot use ''telementation'' (Harris, 1981) to peer inside each other's minds for proof that message sent equalled message received. Instead, they rely on lots of verbal and nonverbal evidence regarding how their utterance is received. They co-manage their talk (Goffman, 1967) as it develops from their participation-''on the fly'' conversationally from their sense of how the conversation is proceeding. Here is where we invite an ethnomethodological turn (Garfinkel, 2002; Heritage, 1984) in considering what to make of the evidence. Ethnomethodologists are interested in how people do their sense-making and social influencing in ways they attend and respond to. It is hard to try to understand a conversation from outside of it. But, ethnomethodologists challenge us to understand social interactions based on the observable, often mundane, aspects (i.e., evidence) that guide speakers as they talk to each other.", "cite_spans": [{"start": 38, "end": 52, "text": "(Harris, 1981)", "ref_id": "BIBREF44"}, {"start": 271, "end": 286, "text": "(Goffman, 1967)", "ref_id": "BIBREF35"}, {"start": 467, "end": 484, "text": "(Garfinkel, 2002;", "ref_id": "BIBREF34"}, {"start": 485, "end": 500, "text": "Heritage, 1984)", "ref_id": "BIBREF45"}], "ref_spans": []}, {"section": "THERAPY AND CONVERSATIONAL ACCOMPLISHMENTS", "text": "A further scenario here might help. Adopting an ethnomethodologist's stance you, witness a marriage proposal between two lovers. In observing or re-examining the conversation in which the proposal takes place, you note how one partner prepares the other for receipt of his or her proposal, the kinds of things that get said, how either responds, and so on. You witness the delivery of the actual proposal-how it is made as one partner carefully calibrates her or his language in accordance with how she or he sees her or his delivery being received. Looking really closely, you may see the very things that guide the partners in the course of their interaction around this proposal: how a tone of voice by one influences that of the other, for example. Conversationally, there is much to go on to indicate how they are responding to each other and building something in their dialogue. Key to an ethnomethodologist's analyses of a circumstance like this is to make evident what it is the speakers attended to and built on as they talked.", "cite_spans": [], "ref_spans": []}, {"section": "THERAPY AND CONVERSATIONAL ACCOMPLISHMENTS", "text": "While perhaps not as charged, therapeutic dialogue bears some similarities. Therapist and clients closely attend to each other's communications, responding in ways that are consequential for them. While one cannot get inside the heads of those talking, one can notice what they notice and respond to as they talk. It is in this sense that Harlene Anderson (1997) referred to therapists as ''participant co-managers'' of the therapeutic process. In the manner we described earlier as ''emergent-when'' professionalism, they turn to what emerges in therapeutic dialogue and deal with the momentary exigencies of conversational encounters they codevelop with clients.", "cite_spans": [{"start": 347, "end": 362, "text": "Anderson (1997)", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "RECONCEPTUALIZING EVIDENCE", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Issues, Controversies, and Movements", "text": "There is increasing and convincing justification to employ ethnomethodological (i.e., conversational analytic) and social constructionist research approaches to psychotherapy evaluation. Such research ranges from guidebooks illustrating the use of discursive approaches (e.g., McLeod, 2001; Siegfried, 1995) to psychotherapy studies that use discursive methodologies (e.g., Avidi, 2005; Burck, Frosh, Strickland-Clark, & Morgan, 1998; Frosh, Burck, StricklandClark, & Morgan, 1996; Madill & Barkham, 1997) . Given that therapists attend to conversational developments to inform their participation in therapy, it seems natural to examine the dialogical practices of clients and therapists for evidence of therapeutic change. Currently, however, there is a gap in the use of such methodologies in psychotherapy outcome research. While researchers such as Greenberg (1986) and others have helped shift attention to small ''o'' outcomes of the therapeutic process and the means by which these are attained, their analytic focus has largely been on ''task'' accomplishments where nonlinguistic behaviors or therapist \u2044 client ratings of dialogues where those accomplishments took place. We take seriously the claims of discursive researchers for whom conversation is the primary means by which relational outcomes are accomplished (e.g., Heritage, 1984; ten Have, 1999) .", "cite_spans": [{"start": 277, "end": 290, "text": "McLeod, 2001;", "ref_id": "BIBREF60"}, {"start": 291, "end": 307, "text": "Siegfried, 1995)", "ref_id": "BIBREF75"}, {"start": 374, "end": 386, "text": "Avidi, 2005;", "ref_id": "BIBREF5"}, {"start": 387, "end": 434, "text": "Burck, Frosh, Strickland-Clark, & Morgan, 1998;", "ref_id": "BIBREF14"}, {"start": 482, "end": 505, "text": "Madill & Barkham, 1997)", "ref_id": "BIBREF56"}, {"start": 854, "end": 870, "text": "Greenberg (1986)", "ref_id": "BIBREF39"}, {"start": 1334, "end": 1349, "text": "Heritage, 1984;", "ref_id": "BIBREF45"}], "ref_spans": []}, {"section": "Issues, Controversies, and Movements", "text": "The case for applying ethnomethodological and other alternative approaches is overshadowed by the taken-for-granted and near exclusive use of experimental methods and psychometric assessment in evaluating therapy outcomes. Such measurement-based modes of assessment constitute a key component of the empirically supported treatment (EST) and evidence-based practice (EBP) movements. While use of randomized-controlled trials (RCTs) dominates EBP, such use limits evidence to the measurement of predefined constructs that define therapy outcomes. However, the American Psychological Association's (APA) recent adoption of EBP has encouraged additional and alternative methodologies to RCTs to be employed (American Psychological Association Presidential Task Force on Evidence-Based Practice, 2006). We will borrow from developments within APA and from medicine to present our case for conversational evidence.", "cite_spans": [], "ref_spans": []}, {"section": "Issues, Controversies, and Movements", "text": "The concept of EBP, and the dominant framing of psychotherapy evaluation, is a relatively new development traceable through the 1990s. Evidence-based medicine (EBM), a term coined in 1988 by medical clinicians and epidemiologists (Donald, 2002) , facilitated the rise of EBP in mental health (Tanenbaum, 2003) . The rationale for EBM was to develop a structured framework for systematic clinical decision-making guided by evidence for best clinical practices.", "cite_spans": [{"start": 230, "end": 244, "text": "(Donald, 2002)", "ref_id": "BIBREF23"}, {"start": 292, "end": 309, "text": "(Tanenbaum, 2003)", "ref_id": "BIBREF80"}], "ref_spans": []}, {"section": "Issues, Controversies, and Movements", "text": "Research evidence derived from statistical methods and reliability estimates help to answer such questions as ''what is the chance that'' some intervention will benefit people. Answers framed by such questions look past ''how or why'' questions about people's efforts in moment-bymoment efforts to codevelop meanings and actions in therapy.", "cite_spans": [], "ref_spans": []}, {"section": "Issues, Controversies, and Movements", "text": "Emulating EBM, the Clinical Division (Division 12) of the APA produced a task force report on empirically validated treatments 1 in 1995. As with EBM's Oxford-based Centre for Evidence-Based Medicine's established evidence hierarchy (see Centre for Evidence-Based Medicine, 1998), the Clinical Division's task force produced a similar hierarchy with RCTs as the ''gold standard'' (Task Force on Promotion and Dissemination of Psychological Procedures, 1995) . The difference between the two evidence-based standards was that the Clinical Division relied exclusively on experimentally produced evidence. Such standards include ''well-established treatments'' and ''probably efficacious treatments'' demonstrated to be superior to pill, psychological placebo, or another treatment and that required adherence to a treatment manual. This is in contrast to the Centre for Evidence-Based Medicine (1998); although it included RCTs as the gold standard, it additionally included other forms of evidence in its hierarchy (e.g., case-series studies and expert clinical opinion).", "cite_spans": [], "ref_spans": []}, {"section": "Issues, Controversies, and Movements", "text": "Concurrently, the EBP movement was gaining ground in psychology. With the rise of evidence-based practice journals in the 1990s, 2 in 1999, the United Kingdom's Department of Health's (DoH) National Service Framework for Mental Health (Department of Health, 1999, p. 6) created another evidence hierarchy listing five grades of evidence from at least one good systematic review and at least one randomized-controlled trial (highest grade) to expert opinion (lowest grade). As EBP became more of a public policy ideal (Tanenbaum, 2003) , this clashed with Division 12's restrictive focus on RCT methodology to obtain evidence. ESTs have been classified according to their efficacy in addressing different symptomatic presentations (i.e., principally DSM-based diagnoses of anxiety and depression). Most ESTs that were rated as well established or probably efficacious were from behavioral and cognitive-behavioral therapy. This is principally because their theoretical and methodological stances fit hand-in-glove with RCTs (i.e., experimental epistemologies: knowledge gained primarily through hypothesis testing and experimental manipulation). Between 60% to 90% of Division 12-approved ESTs are cognitive-behavioral interventions (Norcross, Beutler, & Levant, 2006) . However, EST framing generally has not fit well with theory and practice in most humanistic, family, and social constructionist approaches to psychotherapy.", "cite_spans": [{"start": 517, "end": 534, "text": "(Tanenbaum, 2003)", "ref_id": "BIBREF80"}, {"start": 1232, "end": 1267, "text": "(Norcross, Beutler, & Levant, 2006)", "ref_id": "BIBREF64"}], "ref_spans": []}, {"section": "Issues, Controversies, and Movements", "text": "3 In 1997, Division 32 of the APA (the Division of Humanistic Psychology) produced a report critiquing Division 12's ESTs as well as its own guidelines for the provision of humanistic psychosocial services (Task Force for the Development of Practice Recommendations for the Provision of Humanistic Psychosocial Services, 2001 ). This is not surprising given that these approaches are constructivist and eschew mechanistic uses of therapeutic administration. Instead, these approaches see therapy as an open-ended process and a nonlinear, meaning-making endeavor where goals often change as the therapy progresses, and with clients seen as the ultimate experts on their own experience. Thus, such approaches to therapy are ill suited to RCTs requiring the reliable adherence to therapy manuals. The dissemination of ESTs, RCTs, and cognitive-behavioral therapy has also influenced third-party payers' perceptions: that what is best practice and fundable must involve such approaches (Greer & Rennie, 2006) , which inevitably positions non-CBT therapies as less fundable and degrades the status of nonexperimental approaches and stakeholders in process-outcome research. Such critique has been mirrored in the criticism of ESTs for their constrictive implications for research (Bohart, 2005; Bryceland & Stam, 2005; Dumont & Fitzpatrick, 2005; Honos-Webb, 2005; Levitt, Neimeyer, & Williams, 2005; Mahrer, 2005) . Such criticisms underscore the controversial nature of ESTs within psychology and created suggestions for alternative and additional research and therapeutic approaches (Beutler & Johannsen, 2006; Bohart, 2006; Duncan & Miller, 2006; Norcross & Lambert, 2006; Stricker, 2006; Wampold, 2006) .", "cite_spans": [{"start": 982, "end": 1004, "text": "(Greer & Rennie, 2006)", "ref_id": "BIBREF40"}, {"start": 1275, "end": 1289, "text": "(Bohart, 2005;", "ref_id": "BIBREF10"}, {"start": 1290, "end": 1313, "text": "Bryceland & Stam, 2005;", "ref_id": "BIBREF13"}, {"start": 1314, "end": 1341, "text": "Dumont & Fitzpatrick, 2005;", "ref_id": "BIBREF24"}, {"start": 1342, "end": 1359, "text": "Honos-Webb, 2005;", "ref_id": "BIBREF46"}, {"start": 1360, "end": 1395, "text": "Levitt, Neimeyer, & Williams, 2005;", "ref_id": "BIBREF53"}, {"start": 1396, "end": 1409, "text": "Mahrer, 2005)", "ref_id": "BIBREF58"}, {"start": 1581, "end": 1608, "text": "(Beutler & Johannsen, 2006;", "ref_id": "BIBREF7"}, {"start": 1609, "end": 1622, "text": "Bohart, 2006;", "ref_id": "BIBREF11"}, {"start": 1623, "end": 1645, "text": "Duncan & Miller, 2006;", "ref_id": "BIBREF25"}, {"start": 1646, "end": 1671, "text": "Norcross & Lambert, 2006;", "ref_id": "BIBREF65"}, {"start": 1672, "end": 1687, "text": "Stricker, 2006;", "ref_id": "BIBREF78"}], "ref_spans": []}, {"section": "Issues, Controversies, and Movements", "text": "Following considerable debate and controversy over the narrow framing of ESTs, in 2005 the APA revisited the issue and published a presidential task force report on evidence-based practice in psychology (EBPP). This report suggested widening the notion of what should be evidence-based to include the ''integration of the best available research with clinical expertise in the context of patient characteristics, culture, and preferences'' (American Psychological Association Presidential Task Force on Evidence-Based Practice, 2006, p. 273) . It also endorsed multiple types of research evidence and acknowledges differences in research design, including qualitative research data as evidence. Still, APA holds experimental methods above all other approaches and qualitative methods such as clinical observation or experientially focused interviews are seen as less stringent than RCTs. Proposing an expansion of what constitutes outcome evidence (e.g., see Chwalisz, 2003) has generated debate on the merits and limitations of EPB (Feltham, 2005; Hage, 2003; Stricker, 2003; Wampold, 2003) . Nevertheless, the EBPP report has opened space for additional and alternative evaluation methods in psychotherapy process and outcome. Here we intend to promote the inclusive use of qualitative and, more specifically, discursive analyses for psychotherapy outcome evaluations alongside current quantitative methods of analysis.", "cite_spans": [{"start": 959, "end": 974, "text": "Chwalisz, 2003)", "ref_id": "BIBREF16"}, {"start": 1033, "end": 1048, "text": "(Feltham, 2005;", "ref_id": "BIBREF27"}, {"start": 1049, "end": 1060, "text": "Hage, 2003;", "ref_id": "BIBREF41"}, {"start": 1061, "end": 1076, "text": "Stricker, 2003;", "ref_id": "BIBREF77"}], "ref_spans": []}, {"section": "Evaluating Therapeutic Change in a Discursive Context: Positioning", "text": "The inclusion of qualitative approaches in EBP has enabled alternative means for evaluating psychotherapy, especially with the use of positioning theory in discursive analyses. By ''positioning'' we are referring to discursive practices in which one's subjectivity is shown or performed in social interaction, in contrast to the formal, ''static,'' and transcendentalist concept of role (Davies & Harre\u00b4, 1990) . Each contributor, deliberately or implicitly, positions the other continuously through conversation while simultaneously positioning himself or herself (Harre\u00b4& van Langenhove, 1991) . Thus, shifts in client positions from problematic to counterproblematic positions in client-therapist dialogue, as evidenced in discourse, can be seen as indicators of ''little outcomes'' in therapy. Process research in family therapy has already used discursive positioning analyses, particularly the examination of changes in client positions (Avidi, 2005; Burck et al., 1998 ). An analysis of interactional positioning has also been useful in identifying markers for indicating early outcomes (Madill, Sermpezis, & Barkham, 2005) . Assuming that clients and therapists co-construct meanings and understand their interactions via language (Goolishian & Anderson, 1987) , it makes sense to identify shifts in meaning as evidence of therapeutic outcome as interactional changes in clients' subjective positions in therapy. In Anderson and Goolishian's (1988, p. 48) words: ''Change is the evolution of new meaning through dialogue.'' This is where empirically observable conversational accomplishments and new meaning can be considered as outcome evidence.", "cite_spans": [{"start": 387, "end": 410, "text": "(Davies & Harre\u00b4, 1990)", "ref_id": "BIBREF21"}, {"start": 565, "end": 595, "text": "(Harre\u00b4& van Langenhove, 1991)", "ref_id": "BIBREF42"}, {"start": 943, "end": 956, "text": "(Avidi, 2005;", "ref_id": "BIBREF5"}, {"start": 957, "end": 975, "text": "Burck et al., 1998", "ref_id": "BIBREF14"}, {"start": 1094, "end": 1130, "text": "(Madill, Sermpezis, & Barkham, 2005)", "ref_id": "BIBREF57"}, {"start": 1239, "end": 1268, "text": "(Goolishian & Anderson, 1987)", "ref_id": "BIBREF38"}], "ref_spans": []}, {"section": "EVIDENCE OF OUTCOME THROUGH A DISCURSIVE LENS", "text": "Here, we present examples of such accomplishments in therapeutic dialogue where agreements in dialogue have been taken up as signs of outcome. These examples are taken from discursive analyses of how a family with an adolescent used talk to move beyond a conversational impasse (Couture, 2005 (Couture, , 2006 . To evaluate macro-shifts in meaning, I (the third author) used Harre\u00b4and van Langenhove's (1999) notion of discursive positions. Discursive positions are locations (like conversational stances) from which people engage others as they converse, or differences in perspective from which people understand and act when conversing with one another. In this macro-analysis, I identified that conversational impasses arose from significant differences in these discursive positions of participants in therapy. As these differences were overcome in therapy, a forward-moving, more mutually satisfying, position was eventually constructed by the family and therapist. 4 By analyzing how such discursive positions featured and were altered in the interview, evidence could be found for important macro-shifts in meaning.", "cite_spans": [{"start": 278, "end": 292, "text": "(Couture, 2005", "ref_id": "BIBREF19"}, {"start": 293, "end": 309, "text": "(Couture, , 2006", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "EVIDENCE OF OUTCOME THROUGH A DISCURSIVE LENS", "text": "However, a more fine-grained, ethnomethodological analysis (conversation analysis) also showed specific conversational evidence of positive change in how the family talked.", "cite_spans": [], "ref_spans": []}, {"section": "EVIDENCE OF OUTCOME THROUGH A DISCURSIVE LENS", "text": "5 Below I present two exemplars illustrating the family at an impasse and one that demonstrates the accomplishment of forward movement. Using these exemplars I then first show how discursive analyses provide conversational evidence that family members mutually accomplished this forward movement and then briefly demonstrate one way I noticed these changes were achieved.", "cite_spans": [], "ref_spans": []}, {"section": "EVIDENCE OF OUTCOME THROUGH A DISCURSIVE LENS", "text": "The family who participated in this study included a father (Bob), mother (Sandra), and son (Joe), and a therapist (Dr. Karl Tomm). 6 The session analyzed was the first one after Joe, the 14-year-old son, was released from the hospital after concerns about his recent self-harming (''cutting'') behaviors. Before leaving the hospital, Joe had agreed to a contract that listed things that he could have done to keep himself safe. The family began the session firmly entrenched at an impasse. In our view, the two exemplars below offer strong baseline evidence of this impasse in contrast to positive changes shown in how the son and father relate in later exemplars. . . . and um (3) myself (1) and I can't speak 68 for everybody else but I want to make sure (.) . . . 69 J: {Joe picks up pop bottle} 70 B: I mean I understand that the way it was is not the way it is going Later in the session, Bob and Joe began to communicate in ways that showed they were speaking from a more forward-moving and common position (a positive outcome evident in the transcript), codeveloping what they said and how they said it. ", "cite_spans": [], "ref_spans": []}, {"section": "Conversational Evidence of Forward Movement", "text": "At the beginning of the session the parents were talking from a discursive position of certainty with respect to adherence to the contract. Joe, on the other hand, did not appear to be as certain about adhering to the contract; he spoke from a position of doubt. While the parents demanded unconditional certainty that their son would ensure his safety, Joe defended his doubts, saying he would try his best to accomplish what was expected of him, showing his hesitancy to adhere to the contract. Such opposing positions (doubt and certainty) exemplify a family stuck at an impasse-based on their use of incompatible ways of talking and understanding. This initial impasse was evident in what the father and son initially said. The father's certainty was reflected in comments about Joe and the contract: ''he is going to follow through . . . ,'' ''he is not going to cut anymore and hurt himself . . . ,'' and ''it is going to be totally different.'' Joe's doubt, conversely, came through when asked if he could live up to what was written in the contract, ''I don't know yet I guess''; or about his view of the contract's value, ''They (parents) probably think it is . . . '' The impasse was also evident in how they spoke.", "cite_spans": [], "ref_spans": []}, {"section": "Conversational Evidence of Forward Movement", "text": "Let us now look back to Exemplar 1. Bob articulates his position (lines 70 through 74) in a straightforward (certain) manner as shown by his few pauses or breaks in his talk (uhms, restarts, etc.) , and choice of words like ''totally'' or ''it has to be.'' Joe, however, shows little uptake 8 of Bob's position (in line 75), responding with a ''weak agreement'' (Kitzinger & Frith, 1999) that did not openly disagree with Bob but instead invites him to acknowledge Joe's ambivalence (doubtfulness). Here Joe leans back and looks away and speaks in a quiet voice tone; however, his invitation to his father to acknowledge his uncertainty is not accepted as Bob continues offering his opinion (line 76).", "cite_spans": [{"start": 362, "end": 387, "text": "(Kitzinger & Frith, 1999)", "ref_id": "BIBREF50"}], "ref_spans": []}, {"section": "Conversational Evidence of Forward Movement", "text": "From this initial impasse between certainty and doubt regarding the contract, with the help of Tomm they began to conversationally develop a middle ground position they could use in moving forward. Evidence of this positive outcome was more overtly seen in general macroshifts in meaning (the content of the talk) as they began discussing a two-way contract where both the parents and the son could take smaller steps to keeping Joe safe (forward-moving position). This broader part of the analysis concerned with general shifts in meaning is reminiscent of the previously discussed nondiscursive qualitative studies. However, a closer discursive look at the micro-details of the talk later in the session (e.g., Exemplar 3) offers specific evidence of a forward-moving shift: empirical evidence grounded in the actual talk of clients and therapist.", "cite_spans": [], "ref_spans": []}, {"section": "Conversational Evidence of Forward Movement", "text": "In Exemplar 3 Bob invited a mutual way of understanding the contract by highlighting his part in ensuring his son's safety. He used phrases such as ''stuff I have done (.) stuff I have done right stuff I've done wrong'' to show that he understood his actions matter in helping Joe keep himself safe. In addition, he began to use the word ''we.'' 534 B: = a::nd and it was (.) I think (.) ::I think we both kind of came up 535 out of there (.3) and >Joe you can (.) speak for yourself< but (.)  536 what I came out of it was that (.1) ummm >we need to do things 537 a little bit different< (.5) we need to start (.1) >do things a little bit 538 different<", "cite_spans": [], "ref_spans": []}, {"section": "Conversational Evidence of Forward Movement", "text": "The use of phrases such as ''we need to do things a little different'' or ''we need to start'' (lines 536 and 537) show Bob using the word ''we.'' Formerly, he had talked only about Joe's responsibility for making the small steps on his own. The use of ''we'' is also a device people use to show an assumed mutual acceptance of a notion being shared (Sacks, 1995) . Bob's use of ''we'' presupposes that they had worked out an understanding around a two-way contract to be shared by him and the family (especially Joe). Bob used ''we'' in lines 534, 536, and 537, indicating ''common ground'' where Bob and Joe both understood something well enough to invite one to speak for the other (Clark & Brennan, 1991) .", "cite_spans": [{"start": 350, "end": 363, "text": "(Sacks, 1995)", "ref_id": "BIBREF70"}, {"start": 685, "end": 708, "text": "(Clark & Brennan, 1991)", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Conversational Evidence of Forward Movement", "text": "Previously (Exemplar 1), as seen below, Bob preempted his turns 9 with statements that suggested his had shown his limited access to Joe's position (Miller & Silverman, 1995) .", "cite_spans": [{"start": 148, "end": 174, "text": "(Miller & Silverman, 1995)", "ref_id": "BIBREF62"}], "ref_spans": []}, {"section": "Conversational Evidence of Forward Movement", "text": ". . . and um (3) myself (1) and I can't speak 68 for everybody else but I want to make sure (.) . . . 72", "cite_spans": [], "ref_spans": []}, {"section": "Conversational Evidence of Forward Movement", "text": "And I don't know how Joe feels about that but um (.8)", "cite_spans": [], "ref_spans": []}, {"section": "Conversational Evidence of Forward Movement", "text": "However, in line 535 (Exemplar 3, shown above) Bob's statement, ''Joe you can (.) speak for yourself<'' actively created space for Joe to contest what Bob offered in his following turn.", "cite_spans": [], "ref_spans": []}, {"section": "Conversational Evidence of Forward Movement", "text": "In this turn, he assumed Joe had joined him in a new position as indicated by his continued use of the word ''we.'' Joe did not contest Bob's use of ''we''; 10 moreover, the language chosen led to a more engaged father-son dialogue, as discussed in the next section.", "cite_spans": [], "ref_spans": []}, {"section": "Conversational Evidence of Forward Movement", "text": "Bob's uncontested use of ''we'' suggests that he and Joe were coming closer to agreeing on a shared discursive position. This exchange showed evidence of outcome in the actual talk of the session; in therapy family members may offer such evidence to each other (and the therapist) in working out new, shared, forward-moving positions. Joe's responses changed throughout the transcribed dialogue (e.g., from early disagreements or weak agreements to solid uptakes). For example, in Exemplar 1 Joe responded to Bob's statements of certainty by leaning away from his dad, crossing his arms, fiddling with objects, looking down or away, moving from his dad's touch, or biting his nails as in the following exemplar.", "cite_spans": [], "ref_spans": []}, {"section": "73", "text": "B: JOE and I over the last couple of days (.6) {Looks at Joe} we had 74 a chance to talk one on one huh (.8) 75", "cite_spans": [], "ref_spans": []}, {"section": "73", "text": "J: {Joe leans back and looks away from Bob}*uhuh* (1) 76 B: just him and me (.5)", "cite_spans": [], "ref_spans": []}, {"section": "73", "text": "Although in line 75 Joe's words conveyed he agreed with his dad (''uhuh''), the way he offered those words and the accompanying nonverbal behavior communicated likely disagreement. This acknowledgment token (Jefferson, 1984) ''uhuh'' acts as a ''continuer'' (Bangerter & Clark, 2003; Goodwin, 1986; Schegloff, 1982) and stands in contrast to ''Yeah,'' which communicates a higher degree of engagement or readiness to extend a turn in talk. Toward the end of the transcript in Exemplar 3 (seen below), Joe's response showed an increased commitment. At first glance, ''Sure'' could be understood as another ambivalent response. However, given the tentativeness and ambivalence of his previous responses to Bob, Joe's ''Sure'' communicates a more solid uptake. Further evidence of shared commitment to a common ground came in how Bob showed he understood Joe's utterance as sincere (Bob paused, leaned back, and almost smiled in contemplating his son's previous utterance). In addition, when Tomm asked a similar question a bit further in the session, ''Are you willing to give it a try (spending time together talking and doing things) and see what happens see how it goes?'' Joe upgraded his commitment as he looked up at the therapist and said, ''Sure.'' With this very rare instance of eye contact, Joe built on his previous response to Bob and further acknowledged his commitment to the small two-way steps they were co-constructing in their dialogue.", "cite_spans": [{"start": 207, "end": 224, "text": "(Jefferson, 1984)", "ref_id": "BIBREF49"}, {"start": 258, "end": 283, "text": "(Bangerter & Clark, 2003;", "ref_id": "BIBREF6"}, {"start": 284, "end": 298, "text": "Goodwin, 1986;", "ref_id": "BIBREF37"}, {"start": 299, "end": 315, "text": "Schegloff, 1982)", "ref_id": "BIBREF72"}], "ref_spans": []}, {"section": "11", "text": "Accomplishing Change: Performative Advice Giving", "cite_spans": [], "ref_spans": []}, {"section": "11", "text": "As shown earlier in Exemplar 2, Bob and Joe initially struggled in their interactions. In the final exemplars, Bob and Joe demonstrated progress relative to their previous conversational attempts. Concurrent with progress in their dialogue, Bob adopted conversational practices previously used by Tomm (e.g., tentative packaging of his talk, attention to ambivalent responses) to engage Joe. Tomm's ways of engaging Joe throughout the session were where he ''performed advice'' or ''modeled'' how Bob might take small steps in talking with Joe.", "cite_spans": [], "ref_spans": []}, {"section": "11", "text": "Pomerantz (2003) The above exemplar shows Bob engaging Joe differently, especially in the more tentative and responsive ways he talks with him. Joe's response in line 539 (''No'') could be understood as another ''avoidance strategy''; his ''No'' was communicated such that he might have an answer to Bob's question, but was not prepared to share it. Instead of abandoning the talk, when faced with such ambivalence (e.g., ''don' know'' in the previous exemplar), Bob adopted a practice that Tomm used when faced with ambivalent responses from Joe: treating Joe's response as legitimate or at least selectively responding to a part of Joe's response that extended their dialogue (I. Hutchby, personal communication, April 1, 2004; O'Hanlon & Wilk, 1987) . Bob and Joe performed new, more acceptable ways of talking that could work to anchor change in how they would extend their conversations to come (Couture, 2005) .", "cite_spans": [{"start": 730, "end": 752, "text": "O'Hanlon & Wilk, 1987)", "ref_id": "BIBREF66"}, {"start": 900, "end": 915, "text": "(Couture, 2005)", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "11", "text": "Bob also used another strategy that Tomm repeatedly demonstrated; he reformulated his question in line 540. In this conversational ''repair, '' 13 Bob carefully repackaged 14 his question (lines 543 and 544) to bridge his talk with his son's. This careful construction of his question was evident in the pauses and verbal tokens 15 ''(.9) umm (.8)'' in line 540 and his self-correction of the content of the question in line 541 (''wouldn't it be neat (.5) o::r did you like . . . ''). In addition, instead of just answering for Joe, he invited Joe to join him in line 544 (''what'd you say?''). As when Tomm had used these practices, Bob used them successfully to engage Joe (line 545 below). In line 545, Joe offered a rare instance of clearly accepting his dad's invitation to extend dialogue. Increasingly, Bob and Joe come to speak from a discursive position more acceptable to them, one which shows both a shared understanding (in what gets said) and a shared way of talking (in how they ''perform'' their talking). In this case, Joe responded to his dad with a solid voice, showing evidence of his willingness to try out the small steps that Bob was suggesting. Bob then, again, selectively listened to Joe's potentially ambivalent 16 ''Sure,'' ''utilizing'' (O'Hanlon & Wilk, 1987) Joe's ''small step'' (''Sure''), showing that he accepted and extended Joe's assent, thereby assisting them both in moving forward in small increments. Finally, Bob later adopted a more cautious approach to inviting Joe into dialogue reminiscent of Tomm's verbal packaging to engage Joe earlier. Contrast Bob's previously insistent style of questioning from Exemplar 2 with the turn in later talk (Exemplar 3, following In the latter exemplar, he used both a turbulent delivery pattern (Silverman, 2001 ) to express caution in what he is saying (''that (.) umm >we . . .'' line 536) and a couple of restarts (''we talked about a lot of stuff (.2) we talked about (.9)'' line 530, ''(.) I think (.) ::I think . . . ,'' line 534) (Goodwin, 1980 ). Bob's movement from an insistent to a more tentative turn at talk facilitated how he and Joe, both, could begin taking these small steps in their dialogue.", "cite_spans": [{"start": 1776, "end": 1792, "text": "(Silverman, 2001", "ref_id": "BIBREF76"}, {"start": 2018, "end": 2032, "text": "(Goodwin, 1980", "ref_id": "BIBREF36"}], "ref_spans": []}, {"section": "11", "text": "Bob and Joe now ''walked their talk,'' as Tomm had invited them to do throughout the session. Not only was outcome evident in what they talked about (macro-shifts in meaning from two incommensurable positions to a forward-moving one), but it was also demonstrated in how they changed the ways they relate to one another as they enacted ''two-way small steps'' in their actual talk. As family members speak differently with therapists and each other in their sessions they are better poised to extend such enacted developments beyond the therapeutic context.", "cite_spans": [], "ref_spans": []}, {"section": "CONCLUSION: WHOSE EVIDENCE?", "text": "Constructionist social science would benefit from taking seriously the issue of construction. Rather than treating construction as a taken-for-granted start point, it should consider construction and deconstruction as a central and researchable feature of human affairs. (Potter, 1996, p. 206) .", "cite_spans": [], "ref_spans": []}, {"section": "CONCLUSION: WHOSE EVIDENCE?", "text": "Premised as it so often is on a medical metaphor of practice, psychotherapy evaluation has generally looked past the conversational arena where therapy actually takes place for evidence of therapeutic change. This makes sense given that the changes clients typically want are those required beyond the consultation room. Conversation itself can be about mere words-talking about states of affairs, present or desired. But, in another sense, psychotherapy evaluation has not escaped conversation entirely either. Arguably, completing a symptom checklist, a client satisfaction rating form, or any of the many other evaluation tools used by therapists to 'hear' from clients about their views on outcome involves client self-reports about outcomes. The difference between asking about those outcomes in therapy-or afterward-is in how they are asked and by whom. There can be a difference between clients rating their progress in therapy in face-to-face communication with their therapists, and completing an evaluative measure elsewhere. Regardless, either way of evaluating therapy involves clients' accounts of therapy outcomes; one offered in the immediacies of dialogue, the other extending a dialogue (on therapeutic satisfaction or efficacy) by means of paper and pencil.", "cite_spans": [], "ref_spans": []}, {"section": "CONCLUSION: WHOSE EVIDENCE?", "text": "Our point in looking inside conversations for evidence of change is not to build an argument for eliminating other means of evaluating therapeutic outcomes. For us, whether guided by clients' accounts of change, or attending to changes shown in the course of therapeutic dialogue, both clients and therapists are guided by conversational evidence as they talk. They build on that evidence when it seems to offer proof that things are going as preferred for both parties, or they often depart from it when the evidence suggests things are not developing in ways either prefer. We are genuinely interested in how developments occurring within therapy relate to changes outside therapy, but remain struck by how therapy itself is a primarily rhetorical endeavor. By using words, metaphors, discourses, gestures, tones of voice, and so on, both clients and therapists construct ways of talking, understanding, feeling, and acting from within their dialogue. In our view, these accomplishments in their dialogues are evident to the speakers in terms of client accounts and in evidence of shifts in meaning and ways of talking. From our meaning-focused and ethnomethodological perspectives, evidence for clients and therapists in the course of their dialogues is also evidence for those interested in evaluating the little 'o' outcomes associated with increments or decrements in the therapeutic process.", "cite_spans": [], "ref_spans": []}, {"section": "CONCLUSION: WHOSE EVIDENCE?", "text": "One aim of this article has been to suggest that the evidence to which therapists and clients turn in the course of their dialogues-the data that suggest their conversations are ''on track'' -can help refocus therapists' attention to their part in the emergent accomplishments of therapeutic interaction. Therapy in our view needs to proceed from a sense of destination clients provide in articulating initial goals or accounts of problems from which they seek better living. But, thereafter, clients do not simply hand their meanings and actions over to therapists-to be awoken once they have arrived at their destination. Instead, clients and therapists actively work out the meanings and actions to be used ''en route'' to client-chosen destinations. How these efforts to work things out fare is evident at virtually every turn of conversation, or in clients' accounts of how ''on track'' things are for them.", "cite_spans": [], "ref_spans": []}, {"section": "CONCLUSION: WHOSE EVIDENCE?", "text": "We have been putting forward a case for attending to the kinds of evidence we think most therapists pay considerable heed to in their discussions with clients, a case taken up in similar but slightly different ways by Roy-Chowdhury (2003) . Therapists typically are guided somewhat by their understandings of the meanings of clients' accounts of experience, and they track how clients are responding to them as they talk, often shifting what they say as they talk. Rather than a focus only on the big 'O' outcomes (''are we there yet''), which clients could confirm with an account of their experience, they attend to many little 'o' accomplishments (''are we on track?'') whether clients offer accounts about these accomplishments or their sense of evidence suggests these are occurring. The link between client accounts of change (offered in therapy, not outside it) and conversational accomplishments-and the bigger accomplishments most therapeutic evaluations look for-is a matter that could bear a lot of further scrutiny.", "cite_spans": [{"start": 218, "end": 238, "text": "Roy-Chowdhury (2003)", "ref_id": "BIBREF69"}], "ref_spans": []}, {"section": "CONCLUSION: WHOSE EVIDENCE?", "text": "Clinically, we are not alone (Gale, Dotson, Lindsey, & Negireddy, 1993; Strong, 2003) in seeing conversational evidence as a useful resource for enhancing practice. In this regard, any audio-or videotape of family therapy offers rich opportunities to see how outcomes are accomplished and relationships shaped by the hows and whats of therapeutic dialogue-turn by conversational turn, or over a sequence of such turns. We hope therapists can enhance their sense of how their talk performs in terms of what it elicits from clients, and vice versa, in family therapy's dynamic hermeneutic circle. In family therapy, this performance aspect of talk extends to therapists' observations about the effects family members' talk has on each other, thus showing possibly beneficial interactions in which to intervene. Finally, we see conversational evidence as the means by which therapists can orient to the moment-by-moment aliveness of therapeutic dialogue, seeing in such moments their participation in what is constructed.", "cite_spans": [{"start": 29, "end": 71, "text": "(Gale, Dotson, Lindsey, & Negireddy, 1993;", "ref_id": "BIBREF33"}, {"start": 72, "end": 85, "text": "Strong, 2003)", "ref_id": "BIBREF79"}], "ref_spans": []}, {"section": "CONCLUSION: WHOSE EVIDENCE?", "text": "As social constructionist practitioners and researchers interested in evaluating family therapy, we take literally the notion that therapy is about socially constructive processes (e.g., McNamee & Gergen, 1992 ) that occur on ''conversation's shop floor'' (Garfinkel, 2002) . For us, evaluation of therapy has held particular meanings for therapists that a generation of developments within qualitative research now can make more robust. This seemed to be one of the messages arising from the recent shift from empirically supported treatments to a wider framing of EBP by the American Psychological Association Presidential Task Force on Evidence-Based Practice (2006). For us, being able to draw on discursive analyses for evaluative purposes-for what we have been calling conversational evidence-can be a welcomed shift for all therapists.", "cite_spans": [{"start": 256, "end": 273, "text": "(Garfinkel, 2002)", "ref_id": "BIBREF34"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "American Psychological Association Presidential Task Force on Evidence-Based Practice", "authors": [], "year": 2006, "venue": "American Psychologist", "link": null}, "BIBREF1": {"title": "The reflecting team: Dialogues and dialogues about the dialogues", "authors": [{"first": "T", "middle": [], "last": "Andersen", "suffix": ""}], "year": 1991, "venue": "", "link": "145260647"}, "BIBREF2": {"title": "Conversation, language and possibilities", "authors": [{"first": "H", "middle": [], "last": "Anderson", "suffix": ""}], "year": 1997, "venue": "", "link": "149387135"}, "BIBREF3": {"title": "Human systems as linguistic systems: Preliminary and evolving ideas about the 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things that come between sentences", "authors": [{"first": "E", "middle": ["A"], "last": "Schegloff", "suffix": ""}], "year": 1982, "venue": "Analyzing discourse: Text and talk", "link": "142295195"}, "BIBREF73": {"title": "Repair after next turn: The last structurally provided defense of intersubjectivity in conversation", "authors": [{"first": "E", "middle": ["A"], "last": "Schegloff", "suffix": ""}], "year": 1992, "venue": "American Journal of Sociology", "link": "143535098"}, "BIBREF74": {"title": "The reflective practitioner: How professionals think in action", "authors": [{"first": "D", "middle": [], "last": "Scho\u00a8n", "suffix": ""}], "year": 1983, "venue": "Conversational realities", "link": "145408602"}, "BIBREF75": {"title": "Therapeutic discourse as behavior change: Towards a micro-analysis in psychotherapeutic process research", "authors": [{"first": "J", "middle": [], "last": "Siegfried", "suffix": ""}], "year": 1995, "venue": "", "link": null}, "BIBREF76": {"title": "The construction of 'delicate' objects in counselling", "authors": [{"first": "D", "middle": [], "last": "Silverman", "suffix": ""}], "year": 2001, "venue": "Discourse theory and practice: A reader", "link": null}, "BIBREF77": {"title": "Evidence-based practice: The wave of the past", "authors": [{"first": "G", "middle": [], "last": "Stricker", "suffix": ""}], "year": 2003, "venue": "The Counseling Psychologist", "link": "145293666"}, "BIBREF78": {"title": "Evidence-based practices in mental health: Debate and dialogue on the fundamental questions", "authors": [{"first": "G", "middle": [], "last": "Stricker", "suffix": ""}], "year": 2006, "venue": "", "link": null}, "BIBREF79": {"title": "Engaging reflection: A training exercise using conversation and discourse analysis. Counselor Education and Supervision", "authors": [{"first": "T", "middle": [], "last": "Strong", "suffix": ""}], "year": 2003, "venue": "", "link": null}, "BIBREF80": {"title": "Evidence-based practice in mental health: Practical weaknesses meet political strengths", "authors": [{"first": "S", "middle": [], "last": "Tanenbaum", "suffix": ""}], "year": 2003, "venue": "Journal of Evaluation in Clinical Practice", "link": "43916754"}, "BIBREF81": {"title": "Recommended principles and practices for the provision of humanistic psychosocial services: Alternative to mandated practice and treatment guidelines", "authors": [], "year": 2001, "venue": "Task Force for the Development of Practice Recommendations for the Provision of Humanistic Psychosocial Services", "link": null}}, "ref_entries": {"FIGREF1": {"text": "asked you if you would like to do more in the future what'", "type": "figure"}, "TABREF0": {"text": "Transcription NotationFor the majority of the initial dialogue, Joe and Bob labored as they did not often directly communicate. When they did, the interaction played out in ways similar to the example below.", "type": "table"}, "TABREF3": {"text": "discussed modeling as a form of ''invisible teaching'' in preceptor-intern interactions in medical training. By looking closely at the micro-details of the talk, we noticed actual positive outcomes that may have resulted in part from Tomm's ''invisible teaching.'' 12 In the exemplar above, Bob demonstrated what he previously did when faced with an ambivalent response; he abandoned direct dialogue in frustration. However, by the end of the transcript", "type": "table"}}}
{"paper_id": "8331996", "_pdf_hash": "d52c552b13e63fd3f2e6b719f428d5b229216f86", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "8333118", "_pdf_hash": "b3723aadb3faa16d3bd4b9cc8e55262af185fb38", "abstract": [{"section": "Abstract", "text": "This is an Open Access article licensed under the terms of the Creative Commons AttributionNonCommercial 3.0 Unported license (CC BY-NC) (www.karger.com/OA-license), applicable to the online version of the article only. Distribution permitted for non-commercial purposes only. ", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Department of Cardiothoracic", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Key Words miR-4500 \u2022 NSCLC \u2022 LIN28B \u2022 NRAS", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Background: Lung cancer is the lead cause of cancer-related mortality around the world. Nonsmall cell lung cancer (NSCLC) accounts for nearly 85% of all case of lung cancer. Accumulating evidence revealed the importance of miRNAs in the pathogenesis of NSCLC. Whether miR-4500 promotes NSCLC or not is still unknown. The potential targeted genes needed to be investigated. Methods: The level of miR-4500 was measured by qRT-PCR. The role of miR-4500 in patient survival was revealed by the Kaplan-Meier plot of overall survival of NSCLC patients. miR-4500 was up or down regulated by miRNAs mimics or ASO transfection. Cell proliferation and apoptosis were assayed by the MTT assay and FACS analysis separately. Targeted genes were predicted by a bioinformatic algorithm and confirmed by the Dual Luciferase reporter assay system. Results: NSCLC cell lines and tissues showed lower level of miR-4500. High miR-4500 expression was correlated with high patient survival rate. MiR-4500 overexpression inhibited NSCLC proliferation and induced apoptosis and vice versa. LIN28B and NRAS were targeted by miR-4500. Conclusions: Low expression of miR-4500 in NSCLC promoted tumor growth by targeting LIN28B and NRAS. MiR-4500 may be a prognosis predictor and potential target for NSCLC therapy.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Lung cancer is the leading cause of cancer-related mortality around the world [1, 2] . Lung cancer killed about 1.5 million people in 2010, and lung cancer has an extremely poor prognosis, with an overall 5 year survival of 16% in the USA and less than 10% in the UK [3] .", "cite_spans": [{"start": 78, "end": 81, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 82, "end": 84, "text": "2]", "ref_id": "BIBREF1"}, {"start": 267, "end": 270, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Introduction", "text": "In China, the cigarette smoking rate increased dramatically during the past 2 decades, and the lung cancer mortality has increased by 465% during the past 30 years. Not surprisingly, lung cancer has become the main cause of death in urbanites and the second leading cause of death in rural population after liver cancer [4] . Non-small cell lung cancer (NSCLC) comprises adenocarcinoma and squamous cell carcinoma. In the past decade the overall survival rate of NSCLC patients is11% approximately [5] . Thus, a deep understanding of the pathogenesis of NSCLC development and progression is urgently needed.", "cite_spans": [{"start": 320, "end": 323, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 498, "end": 501, "text": "[5]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Introduction", "text": "MicroRNAs (miRNAs) are a group of non-coding, small (approximately 22 nucleotides in length) RNAs, which suppress protein expression by inhibiting translation or inducing mRNA degradation by binding to the 3'-untranslational region (3'UTR) of targeted mRNAs [6] . Beyond their involvement in diverse biological processes, it has been amply demonstrated that deregulation or dysfunction of miRNAs contribute to cancer development [7] . Regarding NSCLC, accumulated data showed that specific miRNAs profiles may predict prognosis and disease recurrence in early-stage NSCLC [8] [9] [10] [11] [12] .", "cite_spans": [{"start": 258, "end": 261, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 429, "end": 432, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 572, "end": 575, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 576, "end": 579, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 580, "end": 584, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 585, "end": 589, "text": "[11]", "ref_id": "BIBREF11"}, {"start": 590, "end": 594, "text": "[12]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Introduction", "text": "MiR-4500 was identified, and its sequence was determined [13, 14] ; however, the function of miR-4500 remains unknown. Previously, we firstly predicted the potential target of miR-4500 by using a bioinformatic algorithm. The data indicated that miR-4500 may target the genes LIN28B and NRAS. Recent data indicate that LIN28B promotes growth and tumorigenesis of the intestinal epithelium via Let-7 [15] . NRAS is among the common oncogenes in human cancer [16] [17] [18] , and was initially identified in human neuroblastoma cells [19] . Secondly, we assayed the miR-4500 expression in NSCLC cells and found a low expression in NSCLC cells. Thus we conjectured that miR-4500 may play an important role in the pathogenesis of NSCLC.", "cite_spans": [{"start": 57, "end": 61, "text": "[13,", "ref_id": "BIBREF13"}, {"start": 62, "end": 65, "text": "14]", "ref_id": "BIBREF14"}, {"start": 398, "end": 402, "text": "[15]", "ref_id": "BIBREF15"}, {"start": 456, "end": 460, "text": "[16]", "ref_id": "BIBREF16"}, {"start": 466, "end": 470, "text": "[18]", "ref_id": "BIBREF18"}, {"start": 531, "end": 535, "text": "[19]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "Introduction", "text": "Here we tried to prove the role of miR-4500 in NSCLC by investigating NSCLC patient survival and regulating its expression level in in vitro experiments. We found that downregulation of miR-4500 promoted NSCLC growth and identified its targeted genes. We hope our finding may elucidate the role of miR-4500 and provided a potential therapy target for NSCLC.", "cite_spans": [], "ref_spans": []}, {"section": "Materials and Methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Patients", "text": "Surgical specimens from 70 NSCLC patients and matched control adjacent normal tissues were obtained postoperatively in 2009 from the Jinling Hospital, Nanjing University School of Medicine. Informed consent was obtained from each patient and the study was approved by the Ethics Committee of Nanjing University, Nanjing, China. All diagnoses were based on pathological and/or cytological evidence. Tissues were obtained before chemotherapy and radiotherapy and were immediately frozen and stored at \u221280 \u00b0C prior to qRT-PCR assay.", "cite_spans": [], "ref_spans": []}, {"section": "Cell culture and transfection", "text": "The human normal lung fibroblast cell line MRC-5, and the human NSCLC cell lines (SPC-A-1, LTEP-A-2, SK-MES-1, A549 and H1299), and HEK293 were obtained from the Cell Bank of Chinese Academy of Science (Shanghai, China). These cell lines were maintained in RPMI1640 (Invitrogen, Carlsbad, CA, USA) in the presence of 10% heat-inactivated fetal bovine serum, 100 IU/ml penicillin and 100 l g/ml streptomycin in a humidified 5% (v/v) atmosphere of CO2 at 37 \u00b0C. Transfections were performed using Lipofectamine 2000 reagent (Invitrogen) according to the manufacturer's protocol. The efficiency of transfection was evaluated by assay of miR-4500 level.", "cite_spans": [], "ref_spans": []}, {"section": "RNA extraction and Real time q-PCR", "text": "RNA was extracted with Trizol reagent (Invitrogen) according to the manufacturer's protocol. The cDNA synthesis and real-time qPCR were subsequently performed using the Qiagen system as described detail in previous studies [20] . Real-time quantitative PCR analysis was performed using standard protocols using an Applied Biosystems 7500 HT sequence Detection System. The miR-4500 expression was assessed \u2212\u0394\u0394Ct method. The primers used are as follows: GAPDH (5'-CCATGTTCGTCATGGGTGTGAACCA-3' and 5'-GCCAGTAGAGGCAGGGATGATGTTG-3') and LIN28B (5'-CTCTCCCTCGAGAAGTGGGA-3' and 5'-CAGACTCAGGCTCTCTCCCT-3'); NRAS (5'-CCAAATGAAGGTCACACTA -3' and 5'-AGAGACAGGATCAGGTCAGC -3').", "cite_spans": [{"start": 223, "end": 227, "text": "[20]", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "MTT assay", "text": "For the MTT assay, 500 cells per well were seeded, in triplicate, in a 96-well plate with complete growth medium. Cells were counted over 3 days using the MTT assay (Promega, Fitchburg, WI, USA) as previously described [21] [22] [23] . The data were measured by Microtiter plate reader with a 570-nm filters (Promega).", "cite_spans": [{"start": 219, "end": 223, "text": "[21]", "ref_id": "BIBREF21"}, {"start": 224, "end": 228, "text": "[22]", "ref_id": "BIBREF22"}, {"start": 229, "end": 233, "text": "[23]", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Apoptosis assay", "text": "Cells were labeled with Annexin V-FITC and propidium iodide (PI) using an apoptosis detecting kit (Invitrogen, Canada) following the manufacturer's instructions. Then samples were subjected to FACS analysis (Becton Dickinson, San Jose, CA, USA) [24] .", "cite_spans": [{"start": 245, "end": 249, "text": "[24]", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "MicroRNAs targets prediction", "text": "TargetScanHuman (http://www.targetscan.org/vert_61/) [25] [26] [27] [28] was applied to identify the potential target of miR-3928.", "cite_spans": [{"start": 53, "end": 57, "text": "[25]", "ref_id": "BIBREF25"}, {"start": 58, "end": 62, "text": "[26]", "ref_id": "BIBREF26"}, {"start": 63, "end": 67, "text": "[27]", "ref_id": "BIBREF27"}, {"start": 68, "end": 72, "text": "[28]", "ref_id": "BIBREF28"}], "ref_spans": []}, {"section": "The miRNAs mimics, the miRNAs antisense oligonucleotides and the overexpression plasmids", "text": "The miRNAs mimics and the miRNAs antisense oligonucleotides (ASO) were obtained from GenePharma (GenePharma, Shanghai, China). The miRNAs mimics, and the negative control (NC) were transfected into the cells at a concentration of 50nM using the Lipofectamine 2000 (Invitrogen, Canada) transfection reagent according to the manufacturer's instructions. Cells were collected 48h or 72h later for further experiments. The overexpression plasmids, pcDNA3.1-LIN28B and pcDNA3.1-NRAS, were constructed and confirmed by the Shengong Company (Shanghai, China).", "cite_spans": [], "ref_spans": []}, {"section": "3'UTR reporter analysis", "text": "The LIN28B and NRAS 3'UTR reporter plasmids (pRL-LIN28B and pRL-NRAS) were constructed by the Shengong Company (Shanghai). Mutations in the miR-4500 seed regions of the LIN28B 3'UTR were generated using QuikChang Multi site -directed mutagenesis kit (Stratagene, Shanghai, China). The RL reporter plasmids (3.6fmol) and the pGL3-control (500ng for normalization; Promega) were transfected with Lipofectamine 2000 (Invitrogen) into A549 or H1299 cells (6\u00d710 4 cells per well). Cells were collected after 48h for assaying using the Dual Luciferase reporter assay system (Promega) [29] .", "cite_spans": [{"start": 578, "end": 582, "text": "[29]", "ref_id": "BIBREF29"}], "ref_spans": []}, {"section": "Statistical Analysis", "text": "Data are presented as the mean \u00b1 s.d. from at least three independent experiments. The difference between groups were analyzed using the two-tailed Student's t test when only two groups were compared. The difference between groups were analyzed using the ANOVA test when three or more groups were compared. Correlation analysis was performed by two-tailed Person's correlation coefficient analysis. Patients survival was determined by Kaplan-Meier analysis. Statistical analyses were performed using the SPSS software version 17.0 (IBM Corporation, Armonk, NY, USA). P<0.05 was considered significantly different.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Low expression of miR-4500 in NSCLC", "text": "To identify the role of miR-4500 in NSCLC, the miR-4500 expression level was assayed in normal lung tissues, human normal lung fibroblast cell line (MRC-5) and NSCLC cell lines. We found that miR-4500 expression in all NSCLC cell lines, especially in A549 and H1299, was lower than in normal lung and the normal lung fibroblast cell line (Fig. 1A) . Next, the general Cellular Physiology and Biochemistry Cellular Physiology and Biochemistry expression of miR-4500 in NSCLC tissue samples from 70 NSCLC patients was compared with matched normal adjacent lung tissue samples; the qRT-PCR analysis showed the mean expression of miR-4500 in NSCLC tissue samples was lower than in normal adjacent lung tissue samples (Fig. 1B) . The analyses of 70 pairs of NSCLC tumor tissue samples and their matched normal adjacent tissue samples revealed that in 56 pairs, the expression of miR-4500 in NSCLC was lower in the NSCLC tumor samples than in the matched normal adjacent tissue samples; and in the other 14 pairs, the expression of miR-4500 was higher in the NSCLC tumor tissue samples than in the matched normal adjacent tissue samples (Fig. 1C) . These data above indicated that low expression of miR-4500 may promoted NSCLC. Kaplan-Meier curves of 70 patients with high or low miR-4500 expression. Seventy NSCLC patients were followed-up for 30 months, and deceased cases were recorded. Kaplan-Meier curves were drawn according to the miR-4500 expression. Expression of miR-4500 was assayed by qRT-PCR, and the mean value of all 70 cases was chosen as the cutoff point for separating miR-4500 high expression from miR-4500 low expression NSCLC cases.", "cite_spans": [], "ref_spans": [{"start": 338, "end": 347, "text": "(Fig. 1A)", "ref_id": "FIGREF0"}, {"start": 713, "end": 722, "text": "(Fig. 1B)", "ref_id": "FIGREF0"}, {"start": 1131, "end": 1140, "text": "(Fig. 1C)", "ref_id": "FIGREF0"}]}, {"section": "Low expression of miR-4500 in NSCLC", "text": "(B). The miR-4500 expression in tumor tissues and in adjacent normal tissues were assayed by qRT-PCR. The difference of miR-4500 expression between the tumor tissue samples and in adjacent normal tissue samples in each patient was compared (C). *P<0.05.", "cite_spans": [], "ref_spans": []}, {"section": "Cellular Physiology and Biochemistry Cellular Physiology and Biochemistry", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "High miR-4500 expression was correlated with high patient survival rate", "text": "To reveal the role of miR-4500 in the NSCLC patient survival, overall survival analysis was implemented. Seventy NSCLC patients were followed up for 30 months, and no case was dropped. During the 30 months follow-up period, 53 out of 70 (76%) patients were deceased. The Kaplan-Meier curves showed that the patients with high miR-4500 expression (N=20) had a significantly higher survival (p<0.05) rate than those with low miR-4500 expression (N=50) (Fig. 2) .", "cite_spans": [], "ref_spans": [{"start": 450, "end": 458, "text": "(Fig. 2)", "ref_id": "FIGREF1"}]}, {"section": "MiR-4500 overexpression inhibited NSCLC cells proliferation and induced apoptosis", "text": "To investigate the role of miR-4500 in NSCLC cells proliferation, the cell lines A549 and H1299 were chosen for in vitro cell proliferation analyses, as A549 and H1299 showed a lower miR-4500 level than other NSCLC cell line. We firstly over-expressed the miR-4500 in the A549 and H1299 cells by transfection with miR-4500 mimics. The miR-4500 level was assayed by qRT-PCR 48h or 72h later (Fig. 3A) . Subsequently, cell proliferation was analyzed by the MTT assay. We found that overexpression of miR-4500 inhibited the A549 and H1299 cells proliferation (Fig. 3B) . Next, we assayed the cells apoptosis rate after miR-4500 upregulation, we found miR-4500 overexpression resulted in higher apoptosis rate in both of the NSCLC cell lines (Fig. 3C) . ", "cite_spans": [], "ref_spans": [{"start": 390, "end": 399, "text": "(Fig. 3A)", "ref_id": "FIGREF2"}, {"start": 556, "end": 565, "text": "(Fig. 3B)", "ref_id": "FIGREF2"}, {"start": 738, "end": 747, "text": "(Fig. 3C)", "ref_id": "FIGREF2"}]}, {"section": "Down-regulation of miR-4500 promoted NSCLC proliferation and inhibited apoptosis", "text": "We down-regulated the expression of miR-4500 by transfecting miR-4500 ASO into the human normal lung fibroblast cell line (MRC-5). The miR-4500 level in MRC-5 cells was reduced 48 h after the transfection (Fig. 4A) . Next, the cells proliferation was analyzed by the MTT assay; the results showed that transfection with miR-4500 ASO promoted MRC-5 cells proliferation compared with cells transfected with miR-NC ASO (Fig. 4B) . Evaluation of cell apoptosis by FACS analysis revealed that miR-4500 down-regulation resulted in a lower apoptosis rate in MRC-5 (Fig. 4C) .", "cite_spans": [], "ref_spans": [{"start": 205, "end": 214, "text": "(Fig. 4A)", "ref_id": "FIGREF3"}, {"start": 416, "end": 425, "text": "(Fig. 4B)", "ref_id": "FIGREF3"}, {"start": 557, "end": 566, "text": "(Fig. 4C)", "ref_id": "FIGREF3"}]}, {"section": "miR-4500 targeted LIN28B and NRAS", "text": "To investigate the mechanism involved in miR-4500-mediated effects in NSCLC, the miR-4500 potential target genes were predicted by a bioinformatics algorithm. Numerous genes were predicted (some of the predicted genes are shown in Fig. 5A ). Based on their potential relevance to NSCLC, LIN28B and NRAS were chosen for further study. Firstly, the 3'UTR of LIN28B and NRAS were mutated (Fig. 5A) , and then the 3'UTR of the two genes were cloned into luciferase reporter plasmids. Lastly, the miR-4500 and the reporter plasmids were cotransfected into HEK293 cells. Our data showed that the 3'UTRs of LIN28B and NRAS were targeted by miR-4500 (Fig. 5B) . We next examined the correlation between the level of miR-4500 and the expression of LIN28B and NRAS in the NSCLC tissue samples. Pearson's correlation coefficient analysis revealed that miR-4500 level was inversely correlated with LIN28B and NRAS expression in the NSCLC tissue samples analyzed (Fig. 5C) . Moreover, the MTT assay data showed that in both cell lines, A549 and H1299, overexpression of LIN28B and NRAS, after separate plasmid transfections, partly reduced the cell proliferation inhibitory effect of miR-4500 (Fig. 5D ).", "cite_spans": [], "ref_spans": [{"start": 231, "end": 238, "text": "Fig. 5A", "ref_id": "FIGREF4"}, {"start": 385, "end": 394, "text": "(Fig. 5A)", "ref_id": "FIGREF4"}, {"start": 642, "end": 651, "text": "(Fig. 5B)", "ref_id": "FIGREF4"}, {"start": 950, "end": 959, "text": "(Fig. 5C)", "ref_id": "FIGREF4"}, {"start": 1180, "end": 1188, "text": "(Fig. 5D", "ref_id": "FIGREF4"}]}, {"section": "Discussion", "text": "To our knowledge, this study may be the first report demonstrating the role of miR-4500 in NSCLC, or even in cancer. In this study, the correlation between miR-4500 expression and survival of NSCLC patients was revealed. High miR-4500 expression was correlated with high patient survival rate. Thus miR-4500 expression in NSCLC may be considered as a predictor for the prognosis of NSCLC. Previous study indicated that four miRNAs (hsa-let7a, hsa-miR-221, hsa-miR-372, and hsa-miR-182) could predict the stage and histological cells/well) were transfected with miR-4500 ASO or miR-NC ASO separately; the miR-4500 expression was assayed by qRT-PCR, 48h later; data were normalized to U6 small nuclear RNA; the miR-4500 expression in normal lung control was considered as 100%; data are mean \u00b1 s.d. of three separate experiments (A). After miR-4500 ASO transfection, the cells proliferation was assayed by the MTT assay at the indicted time points; data are mean \u00b1 s.d. of three separate experiments (B). The cell apoptosis rate was assayed by Annex V PI-FACS analysis after 48 h of miR-4500 transfection in MRC-5; the apoptosis rate in miR-NC ASO group was considered as 100%; data are mean \u00b1 s.d. of three separate experiments (C). *P<0.05. Putative targeted genes were predicted by TargetScanHuman, the binding site of putative targeted gene, and mutated site of LIN28B and NRAS are shown (A). The RL reporter plasmids (RLcontrol, RL-LIN28B, RL-mutated LIN28B, RL-NRAS, RL-mutated NRAS) and miR-4500 or miR-NC were co-transfected into HEK293 cells, along with a firefly luciferase reporter (pGL control) for normalization. Luciferase activity was measured after 48h. Then the ratio of RL activity of firefly luciferase activity in the miR-4500-treated group were calculated and compared with the ratio in the miR-NC group (which was considered as 100%); data are mean\u00b1s.d. of three separate experiments (B). Inverse correlation between the levels of miR-4500 and LIN28B or NRAS in NSCLC tissue samples (n=6); statistical analysis was performed using Pearson's correlation coefficient (C). A549 and H1299 cells (6\u00d710 5 cells/ well) were transfected with miR-4500 or miR-NC (NC) separately; these cell were transfected with empty plasmid, or LIN28B or NRAS overexpression plasmid (pcDNA3.1-LIN28B or pcDNA3.1-NRAS) 12h later;", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "The NSCLC cell lines A549 and H1299 were chosen to assess the role of miR-4500 in NSCLC, because A549 and H1299 cells showed a lower miR-4500 level than other NSCLC cell lines. We investigated the NSCLC cells functions from two perspectives: up or down regulation of the miR-4500 level. We found that in A549 and H1299 cells, miR-4500 overexpression inhibited NSCLC proliferation and induced apoptosis, whereas down-regulation promoted proliferation and inhibited apoptosis. Interestingly, A549 cells expressed wild-type p53, while the H1299 cell line was p53-deficient. The TargetScan Bioinformatic algorithm predicted that p53 was a potential target of miR-4500 (data not shown). Our data indicated that after miR-4500 regulation, the A549 and H1299 cells exhibited a similar cellular behavior. Thus this discrepancy warranted further investigation.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "We proved that in NSCLC, miR-4500 targeted the genes LIN28B and NRAS. Previous study showed that Lin28B transactivation is necessary for the Myc-induced let-7-mediated repression and proliferation [30] ; and c-Myc oncogenic transcription factor (Myc) broadly influences miRNA expression and in particular leads to widespread miRNA down-regulation [31] . Consequently, in NSCLC, it is possible that Myc caused the down-regulation of miR-4500, which led to the expression of LIN28B. This potential causal chain needs further investigation.", "cite_spans": [{"start": 197, "end": 201, "text": "[30]", "ref_id": "BIBREF30"}, {"start": 347, "end": 351, "text": "[31]", "ref_id": "BIBREF31"}], "ref_spans": []}, {"section": "Discussion", "text": "Obviously, all our mechanistic data came from in vitro experiment. Hence, whether miR-4500 overexpression inhibited NSCLC proliferation and induced apoptosis in vivo needs to be studied.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "In conclusion, our data proved that down-regulation of miR-4500 promoted NSCLC cells proliferation by targeting LIN28B and NRAS. Our study revealed encouraging data which suggest the use of miR-4500 as a prognosis predictor and potential therapeutic target in NSCLC. However, there is a long way to clinically apply these findings. In the prospective studies, we plan to confirm the role of miR-4500 in NSCLC in vivo. 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Low expression of miR-4500 in NSCLC tissue samples and in NSCLC cell lines.After total RNA extraction, the miR-4500 level in normal lung tissues, MRC-5, SPC-A-1, LTEP-A-2, SK-MES-1, A549 and H1299 cell lines were assayed by qRT-PCR. The miR-4500 expression in normal lung tissues were considered as 100%; data are mean\u00b1s.d. of three separate experiments (A). The expression of miR-4500 in NSCLC tissue samples and adjacent normal tissue samples were assayed by qRT-PCR. The miR-4500 mean expression in normal lung tissues were considered as 100%; data are mean\u00b1s.d. of 70 samples", "type": "figure"}, "FIGREF1": {"text": "Fig. 2. Kaplan-Meier curves of 70 patients with high or low miR-4500 expression. Seventy NSCLC patients were followed-up for 30 months, and deceased cases were recorded. Kaplan-Meier curves were drawn according to the miR-4500 expression. Expression of miR-4500 was assayed by qRT-PCR, and the mean value of all 70 cases was chosen as the cutoff point for separating miR-4500 high expression from miR-4500 low expression NSCLC cases.", "type": "figure"}, "FIGREF2": {"text": "Fig. 3. Transfection of miR-4500 mimics inhibited NSCLC proliferation and induced apoptosis. A549 and H1299 cells (6\u00d710 5 cells/well) were transfected with miR-4500 mimics or miR-NC (NC) separately; the miR-4500 expression was assayed by qRT-PCR, 48h or 72h later; data were normalized to U6 small nuclear RNA; the miR-4500 expression in normal lung control was considered as 100%; data are mean \u00b1 s.d. of three separate experiments (A). After miR-4500 mimics transfection, the cells proliferation was assayed by the MTT assay at the indicated time points; data are mean \u00b1 s.d. of three separate experiments (B). The cell apoptosis rate were assayed by Annex V PI-FACS analysis after 48 h of miR-4500 transfection in A549 and H1299 cells; the apoptosis rate in miR-NC group was considered as 100%; data are mean \u00b1 s.d. of three separate experiments (C). *P<0.05.", "type": "figure"}, "FIGREF3": {"text": "Fig. 4. Transfection of miR-4500 ASO promoted NSCLC proliferation and inhibited apoptosis. MRC-5 (6\u00d710 5", "type": "figure"}, "FIGREF4": {"text": "Fig. 5. Prediction and validation of miR-4500 targeted genes. Putative targeted genes were predicted by TargetScanHuman, the binding site of putative targeted gene, and mutated site of LIN28B and NRAS are shown (A). The RL reporter plasmids (RLcontrol, RL-LIN28B, RL-mutated LIN28B, RL-NRAS, RL-mutated NRAS) and miR-4500 or miR-NC were co-transfected into HEK293 cells, along with a firefly luciferase reporter (pGL control) for normalization. Luciferase activity was measured after 48h. Then the ratio of RL activity of firefly luciferase activity in the miR-4500-treated group were calculated and compared with the ratio in the miR-NC group (which was considered as 100%); data are mean\u00b1s.d. of three separate experiments (B). Inverse correlation between the levels of miR-4500 and LIN28B or NRAS in NSCLC tissue samples (n=6); statistical analysis was performed using Pearson's correlation coefficient (C). A549 and H1299 cells (6\u00d710", "type": "figure"}, "TABREF0": {"text": "Austin, TX, USA). The primers were designed and synthesized by Shengong Company (Shanghai, China). Relative mRNA levels of LIN28B and NRAS were normalized to the levels of the housekeeping gene GAPDH and calculated by the 2", "type": "table"}}}
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{"paper_id": "8334256", "_pdf_hash": "83c37e1c9b2e45eb6499176b28ed87f6a2ea1866", "abstract": [{"section": "Abstract", "text": "The etiology of granulosa cell tumors (GCTs) is largely unknown. The primary mode of treatment is surgical, however not all women are cured by surgery alone. Thus, it is important to develop improved treatments through a greater understanding of the molecular mechanisms that contribute to this disease. Recently, it has been shown that a FOXL2 402C.G (C134W) mutation is present in 97% of human adult-type GCTs, suggesting an important role for this mutation in the development of GCTs. We have shown previously that gonadotropin-releasing hormone (GnRH)-I and -II induce apoptosis in cultured normal human granulosa cells. Moreover, it has been reported that FOXL2 can bind to the promoter of the mouse GnRH receptor gene and regulate its transcription. Thus, we hypothesized that C134W mutant FOXL2 could modulate the pro-apoptotic effects of GnRH via aberrant regulation of GnRH receptor levels. Using KGN cells, a human GCT-derived cell line which harbors the FOXL2 402C.G mutation, we show that treatment with GnRH-I and -II induces cell apoptosis, and that small interfering RNA-mediated depletion of GnRH receptor abolishes these effects. Overexpression of wild-type FOXL2 increases both mRNA and protein levels of GnRH receptor and consequently enhances GnRH-induced apoptosis. Importantly, neither the expression levels of GnRH receptor nor GnRH-induced apoptosis were affected by overexpression of the C134W mutant FOXL2. Interestingly, knockdown of endogenous FOXL2 down-regulates GnRHR expression in normal human granulosa cells with wild-type FOXL2, but not in KGN cells. These results suggest that the FOXL2 402C.G mutation may contribute to the development of human adult-type GCTs by reducing the expression of GnRH receptor, thus conferring resistance to GnRHinduced cell apoptosis.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Ovarian cancer is the most lethal gynecological malignancy in the Western world. Granulosa cell tumors (GCTs) account for approximately 5% of all ovarian cancers and occur at a frequency of 1 in 100,000. The peak incidence for GCTs is between 50 and 60 years of age [1] . To date, GCTs are a poorly understood cancer whose pathogenesis is unknown and for which there is no effective treatment beyond primary surgery.", "cite_spans": [{"start": 266, "end": 269, "text": "[1]", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Introduction", "text": "Gonadotropin-releasing hormone (GnRH) is a hypothalamic neuropeptide that functions as a key neuroendocrine regulator of the hypothalamic-pituitary-gonadal axis. Humans possess two distinct forms of GnRH, termed GnRH-I and GnRH-II, as well as one conventional GnRH receptor subtype (type I GnRHR). It is generally accepted that both forms of GnRH exert their biological effects by binding to the type I GnRHR [2] . We have previously demonstrated that GnRHR and both forms of GnRH are expressed in human granulosa-luteal cells [3, 4] . These data suggest putative regulatory roles for GnRHs in the development and function of ovarian follicles and/or corpus luteum. Indeed, we have shown that GnRH-I and -II can induce apoptosis in human granulosa cells [5] . However, whether GnRH can trigger apoptosis in human GCTs is still unknown.", "cite_spans": [{"start": 409, "end": 412, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 527, "end": 530, "text": "[3,", "ref_id": "BIBREF2"}, {"start": 531, "end": 533, "text": "4]", "ref_id": "BIBREF3"}, {"start": 754, "end": 757, "text": "[5]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Introduction", "text": "The FOXL2 gene encodes a member of the forkhead/wingedhelix family of transcription factors which contains a highly conserved forkhead DNA binding domain [6] . Germline loss-offunction mutations in FOXL2 are associated with BPES (blepharophimosis ptosis epicanthus inversus syndrome) which is characterized by shortening of the horizontal orbital fissure (blepharophimosis), congenital ptosis and epicanthus inversus [6, 7] . BPES is categorized into two types: Type I with premature ovarian failure and Type II with normal fertility [8] . Truncating mutations of FOXL2 generally lead to Type I disease whereas frameshifts or duplications downstream of the forkhead domain lead to Type II disease [9] . Recent studies have identified a FOXL2 402C.G (C134W) mutation that is present in 97% of human adult-type GCTs, but absent in unrelated ovarian or breast tumors [10] . These findings strongly suggest an important role for FOXL2 in granulosa cell tumorigenesis. Indeed, overexpression of FOXL2 in rat granulosa cells results in reduced cell viability [11] , and C134W mutant FOXL2 is a weaker inducer of apoptosis in human GCT-derived KGN cells [12] .", "cite_spans": [{"start": 154, "end": 157, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 417, "end": 420, "text": "[6,", "ref_id": "BIBREF5"}, {"start": 421, "end": 423, "text": "7]", "ref_id": "BIBREF6"}, {"start": 534, "end": 537, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 697, "end": 700, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 864, "end": 868, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 1053, "end": 1057, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 1147, "end": 1151, "text": "[12]", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "Introduction", "text": "FOXL2 can act as either a transcriptional activator or repressor to regulate variety of genes [13] . Interestingly, it has been shown that the mouse Gnrhr gene can be activated by FOXL2 in mouse pituitary cells [14] . Despite sharing a high degree of homology with the mouse sequence, we have shown that the human GnRHR promoter differs from the mouse promoter with respect to involvement of various transcriptional motifs, and that its regulation varies among human tissues [4] . Thus, it is not known whether FOXL2 is involved in the transcriptional regulation of GnRHR in human granulosa cells.", "cite_spans": [{"start": 94, "end": 98, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 211, "end": 215, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 475, "end": 478, "text": "[4]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Introduction", "text": "Human GCT-derived KGN cells are heterozygous for the somatic FOXL2 402C.G mutation and are a useful model to study the biology of GCTs [15] . In the present study, we report for the first time that GnRHR is expressed in KGN cells and that treatment with GnRH-I and GnRH-II induces apoptosis in KGN cells. Overexpression wild-type FOXL2, but not C134W mutant FOXL2, increases GnRHR expression and enhances GnRHinduced cell apoptosis. These results suggest that the 402C.G FOXL2 gene mutation may contribute to human granulosa cell tumorigenesis by diminishing GnRH/GnRHR-induced cell apoptosis.", "cite_spans": [{"start": 135, "end": 139, "text": "[15]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Materials and Methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Cell culture", "text": "The previously established human GCT-derived KGN cells [16] were obtained from the RIKEN Bioresource Center Cell Bank with the permission of Dr. Toshihiko Yanasehttp://www. rbej.com/content/8/1/61/ -ins4 (Department of Medicine and Bioregulatory Science, Kyushu University, Japan). This cell line was derived from a patient with an invasive ovarian granulosa cell tumor and it maintains many of the physiological characteristics of normal granulosa cells, including the expression of functional FSH receptor and the expression of aromatase [16] . SV40 large T antigen immortalized human granulosa-luteal (hGL) cells were established previously by our group [17] . KGN cells and immortalized hGL cells were grown in DMEM/F12 medium (Sigma-Aldrich, Oakville, ON) supplemented with 10% fetal bovine serum (FBS; Hyclone Laboratories Inc., Logan, UT). Cultures were maintained at 37uC in a humidified atmosphere of 5% CO 2 in air. ", "cite_spans": [{"start": 55, "end": 59, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 540, "end": 544, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 657, "end": 661, "text": "[17]", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Antibodies and reagents", "text": "The mouse monoclonal anti-GnRHR antibody was obtained from NeoMarkers (Fremont, CA). Goat polyclonal anti-FOXL2 antibody was obtained from IMGENEX (San Diego, CA). Rabbit polyclonal anti-caspase-3 antibody was obtained from Cell Signaling (Danvers, MA). The goat polyclonal anti-actin antibody was obtained from Santa Cruz Biotechnology (Santa Cruz, CA). Horseradish peroxidase-conjugated goat anti-rabbit and donkey anti-goat IgGs were obtained from Bio-Rad Laboratories (Hercules, CA) and Santa Cruz Biotechnology, respectively. GnRH-I agonist was obtained from Sigma and GnRH-II agonist was obtained from Bachem (Torrance, CA).", "cite_spans": [], "ref_spans": []}, {"section": "Plasmid constructs", "text": "The pcDNA3 expression vector encoding full-length wild-type human FOXL2 was kindly provided by Dr. Aaron Hsueh http:// www.rbej.com/content/8/1/61/ -ins4(Department of Obstetrics and Gynecology, Stanford University) [18] . The 402C.G (C134W) mutation was generated using the Quickchange II XL site directed mutagenesis kit (Stratagene, La Jolla, CA) with the wild-type FOXL2 construct as template and the following primers: 59 -CTG GAC GCT GGA CCC GGC CTG CGA AGA CAT GTT CGA GAA GGG C-39 (sense) and 59 -GCC CTT CTC GAA CAT GTC TTC CCA GGC CGG GTC CAG CGT CCA G-39 (antisense). Mutated constructs were sequenced to verify that only the desired mutation was present. To overexpress wild-type or C134W mutant FOXL2, cells were transfected with 1 mg of plasmid DNA using Lipofectamine 2000 (Invitrogen, Burlington, ON) and empty pcDNA3 plasmid was used as the transfection control.", "cite_spans": [{"start": 216, "end": 220, "text": "[18]", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "Small interfering RNA transfection", "text": "To knockdown endogenous GnRHR and FOXL2, cells were transfected with 50 nM ON-TARGETplus SMARTpool GnRHR or FOXL2 siRNA (Dharmacon, Lafayette, CO) using Lipofectamine RNAiMAX (Invitrogen). Wild-type and mutant FOXL2 mRNAs were equally targeted by all FOXL2 siRNA duplexes. ON-TARGETplus Non-Targeting Pool siRNA (Dharmacon) was used as a transfection control and knockdown efficiency was examined by reverse transcription quantitative real-time PCR (RT-qPCR) or Western blot analysis.", "cite_spans": [], "ref_spans": []}, {"section": "MTT assay", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "MTT", "text": "(3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; Sigma) assay was used to determine cell viability. KGN cells were seeded in 24-well plates (1610 4 cells/well in 500 mL of medium) and on the following day were treated every 24 hr with vehicle, GnRH-I or GnRH-II in medium containing 1% of FBS. MTT was added to a final concentration of 0.5 mg/ mL, the cells were incubated for 4 hr and the medium was removed. DMSO was added to each well and absorbances were measured at 490 nm using a microplate reader.", "cite_spans": [], "ref_spans": []}, {"section": "Western blots", "text": "Equal amounts of protein were separated by SDS-PAGE and transferred to PVDF membranes. Following blocking with Trisbuffered saline containing 5% non-fat dry milk for 1 hr, membranes were incubated overnight at 4uC with primary antibodies followed by incubation with secondary antibody. Immunoreactive bands were detected with enhanced chemiluminescent substrate. Membranes were stripped with stripping buffer (62.5 mM Tris, 10 mM DTT, 2% SDS, pH 6.7) at 50uC for 30 min, and reprobed with anti-actin as a loading control. Reverse transcription quantitative real-time PCR (RTqPCR)", "cite_spans": [], "ref_spans": []}, {"section": "Western blots", "text": "Total RNA was extracted using TRIzol reagent (Invitrogen) according to the manufacturer's instructions. Reverse transcription was performed with 3 mg RNA, random primers and M-MLV reverse transcriptase (Promega, Madison, WI). Each 20 mL RTqPCR reaction contained 1X SYBR Green PCR Master Mix (Applied Biosystems), 120 ng cDNA and 500 nM of each specific primer. The primers used were as follows: GnRHR, 59-ACC GCT CCC TGG CTA TCA C-39 (sense) and 59-GAC TGT CCG ACT TTG CTG TTG CT -39 (antisense); FOXL2, 59-CAT GTT CGA GAA GGG CAA CT -39 (sense) and 59-AGG AAG CCA GAC TGC AGG TA-39 (antisense) and GAPDH, 59-GAG TCA ACG GAT TTG GTC GT-39 (sense) and 59-GAC AAG CTT CCC GTT CTC AG-39 (antisense). RT-qPCR was performed on an Applied Biosystems 7300 Real-Time PCR System (Perkin-Elmer) equipped with a 96-well optical reaction plate. All RT-qPCR experiments were run in triplicate and a mean value was used for the determination of mRNA levels. Relative quantification of mRNA levels was performed using the compar- ative Cq method with GAPDH as the reference gene and with the formula 2 -DDCq .", "cite_spans": [], "ref_spans": []}, {"section": "Statistical analysis", "text": "Results are presented as the mean 6 SEM of at least three independent experiments. For experiments involving only two groups, the data were analyzed by Excel with a Two-Sample t-test assuming unequal variances. Multiple group comparisons were analyzed by one-way ANOVA followed by Tukey's multiple comparison test using PRISM software. Significant differences were defined as p,0.05.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "GnRH-I and GnRH-II decrease cell viability via GnRHR", "text": "To investigate the effects of GnRH on cell apoptosis we first confirmed the expression of GnRHR in KGN cells. Two human ovarian cancer cell lines, CaOV3 and OVCAR3, were used as positive controls because we have previously demonstrated that they express GnRHR [19] . Total cell lysates were collected and GnRHR protein levels were examined by Western blot. As shown in Figure 1A , GnRHR expression in KGN cells is similar to that of two ovarian cancer cell lines with demonstrated responsiveness to GnRH [19] .", "cite_spans": [{"start": 260, "end": 264, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 504, "end": 508, "text": "[19]", "ref_id": "BIBREF18"}], "ref_spans": [{"start": 369, "end": 378, "text": "Figure 1A", "ref_id": "FIGREF0"}]}, {"section": "GnRH-I and GnRH-II decrease cell viability via GnRHR", "text": "We have shown that both forms of GnRH can induce cell growth inhibition in human ovarian and endometrial cancer cells [20, 21] . To examine the anti-proliferative effects of GnRH on KGN cells, we treated the cells with different concentrations of GnRH-I or GnRH-II for 24, 48, 72 or 96 hr, and cell viability was examined by MTT assay. As shown in Figure 1B , cell viability was significantly reduced by treatment with GnRH-I or GnRH-II (10 26 and 10 27 M) for 72 and 96 hr, and both forms of GnRH have similar effects. To determine whether the effects of GnRH on cell viability are mediated by GnRHR, specific siRNA was used to knockdown endogenous GnRHR in KGN cells prior to treatment with GnRH. Transfection with GnRHR siRNA significantly reduced GnRHR protein levels ( Figure 1C ) and abolished the effects of GnRH-I or GnRH-II (10 27 M, 96 hr) on cell viability ( Figure 1D ).", "cite_spans": [{"start": 118, "end": 122, "text": "[20,", "ref_id": "BIBREF19"}, {"start": 123, "end": 126, "text": "21]", "ref_id": "BIBREF20"}], "ref_spans": [{"start": 348, "end": 357, "text": "Figure 1B", "ref_id": "FIGREF0"}, {"start": 774, "end": 783, "text": "Figure 1C", "ref_id": "FIGREF0"}, {"start": 870, "end": 879, "text": "Figure 1D", "ref_id": "FIGREF0"}]}, {"section": "GnRH-I and GnRH-II induce cell apoptosis", "text": "GnRH-induced reductions in the number of viable cells may result from the direct inhibition of cell proliferation or the induction of cell death. Having previously demonstrated GnRHinduced apoptosis in human immortalized granulosa cells [5] , we therefore examined the effect of GnRH on KGN cell apoptosis by measuring the levels of cleaved caspase-3 by Western blot. As shown in Figure 2 , treatment with GnRH-I or GnRH-II increased cleaved caspase-3 protein levels, as did the positive control, cycloheximide. Similar to the results from the MTT assay, GnRH-I and GnRH-II-induced increases in cleaved caspase-3 were abolished by siRNA-mediated knockdown of GnRHR. These results indicate that GnRH induces apoptosis in human granulosa tumor cells via type I GnRHR.", "cite_spans": [{"start": 237, "end": 240, "text": "[5]", "ref_id": "BIBREF4"}], "ref_spans": [{"start": 380, "end": 388, "text": "Figure 2", "ref_id": "FIGREF1"}]}, {"section": "Overexpression of wild-type but not C134W mutant FOXL2 increases GnRHR expression", "text": "Although it has been reported that FOXL2 can increase GnRHR expression in mouse pituitary cells [14] , whether or not the same is true for human tissues is unknown. Thus, KGN cells were transiently transfected with empty vector, wild-type FOXL2 or C134W mutant FOXL2 to investigate the effects of FOXL2 on GnRHR expression. Overexpression of wild-type and mutant FOXL2 was confirmed by Western blot analysis after 48 hr transfection ( Figure 3A) . Transfection with wild-type FOXL2 significantly increased GnRHR mRNA and protein levels compared to empty vector control. In contrast, overexpression of C134W mutant FOXL2 did not induce significant changes the mRNA and protein levels of GnRHR ( Figure 3B ). These results suggest that wild-type FOXL2 can regulate GnRHR expression in KGN cells, but that C134W mutant FOXL2 does not.", "cite_spans": [{"start": 96, "end": 100, "text": "[14]", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "GnRH-induced apoptosis is enhanced by wild-type but not C134W mutant FOXL2", "text": "To examine whether FOXL2-mediated changes in GnRHR expression affect GnRH-induced cell apoptosis, KGN cells were transfected with empty vector, wild-type FOXL2 or C134W mutant FOXL2 and then treated with vehicle, GnRH-I or GnRH-II. As shown in Figure 4A , GnRH-induced reductions in cell viability were enhanced in cells transfected with wild-type FOXL2 compared to empty vector control. In contrast, transfection with C134W mutant FOXL2 did not alter the effects of GnRH on cell viability, as assessed by MTT assay ( Figure 4A ). In agreement with these findings, Western blot analysis of cleaved caspase-3 levels confirmed the enhancement of GnRH-induced apoptosis in cells transfected with wild-type but not C134W mutant FOXL2 ( Figure 4B ).", "cite_spans": [], "ref_spans": [{"start": 244, "end": 253, "text": "Figure 4A", "ref_id": "FIGREF3"}, {"start": 518, "end": 527, "text": "Figure 4A", "ref_id": "FIGREF3"}, {"start": 732, "end": 741, "text": "Figure 4B", "ref_id": "FIGREF3"}]}, {"section": "Knockdown of FOXL2 in KGN cells does not alter GnRHR expression levels", "text": "Having established that forced-expression of wild-type FOXL2 can regulate GnRHR expression; we next investigated the effects of FOXL2 knockdown on GnRHR since KGN cells are heterozygous for the C134W mutation. As shown in Figure 5A , treatment with FOXL2 siRNA significantly down-regulated FOXL2 mRNA levels whereas GnRHR mRNA levels remained unchanged. Likewise, treatment with FOXL2 siRNA did not alter GnRHR protein levels in spite of profound reductions in FOXL2 protein levels. To further examine the role of endogenous FOXL2 in the regulation of GnRHR, we investigated the effects of FOXL2 knockdown on GnRHR mRNA and protein levels in immortalized human granulosa-luteal (hGL) cells with wild-type FOXL2. In contrast to the results obtained in KGN cells, FOXL2 siRNA treatment significantly reduced basal GnRHR mRNA and protein levels in immortalized hGL cells ( Figure 5B ). These results show that endogenous FOXL2 maintains elevated GnRHR levels in normal human granulosa cells, but not in heterozygous mutant KGN cells.", "cite_spans": [], "ref_spans": [{"start": 222, "end": 231, "text": "Figure 5A", "ref_id": "FIGREF4"}, {"start": 870, "end": 879, "text": "Figure 5B", "ref_id": "FIGREF4"}]}, {"section": "Discussion", "text": "Due to the low incidence of GCTs, representing 2-5% of all ovarian cancers, little is known about their pathogenesis. GCTs are generally thought to have a better prognosis than epithelial tumors, however recurrent disease still claims the lives of 20-30% of patients diagnosed with advanced tumors [1] . Recent studies identifying a somatic FOXL2 402C.G (C134W) mutation present in virtually all morphologically identified adult-type GCTs strongly suggest the involvement of FOXL2 in the pathogenesis of adult-type GCTs [10] . Yet, little is known about the function of FOXL2 in human granulosa cells or the biological implications of the 402C.G mutation. In a Foxl2 lacZ homozygous mutant mouse model, the transition from a squamous to cuboidal form of granulosa cell is blocked leading to the absence of secondary follicles, suggesting that Foxl2 is required for granulosa cell differentiation and maintenance of ovarian function [22] .", "cite_spans": [{"start": 298, "end": 301, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 520, "end": 524, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 932, "end": 936, "text": "[22]", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Discussion", "text": "Pro-apoptotic effects of GnRH-I and GnRH-II have been reported in cell lines derived from several human malignancies [2] .", "cite_spans": [{"start": 117, "end": 120, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Discussion", "text": "In rats, treatment with GnRH-I induces apoptosis in granulosa cells isolated from preovulatory follicles [23] . We have shown that treatment with GnRH-I or GnRH-II stimulates human immortalized granulosa cells to undergo apoptosis [5] . However, whether human GCTs express GnRHR or display pro-apoptotic responses to GnRH remains unknown. We now demonstrate that GnRH-I and GnRH-II induce cell apoptosis in human GCT-derived KGN cells. In addition, we used GnRHR siRNA to show that the apoptotic effects of GnRH are mediated by type I GnRHR. These results indicate that GnRH induces cell apoptosis in both normal and malignant granulosa cells.", "cite_spans": [{"start": 105, "end": 109, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 231, "end": 234, "text": "[5]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Discussion", "text": "It has been shown that AP-1, Smad3, Smad4 and Foxl2 can bind to the Gnrhr activating sequence (GRAS) and activate transcription of a Gnrhr promoter-luciferase construct in mouse aT3-1 gonadotrope cells [14] . Likewise, overexpression of Foxl2 resulted in a significant increase in murine Gnrhr promoter activity in mouse KK1 granulosa cells [24] . However, despite sharing a high degree of homology with the mouse sequence, the human gene possesses neither the AP-1 nor the GRAS site in the corresponding positions along the proximal promoter of GnRHR [25] . Studies suggest that transcription factors such as Oct-1, CREB, GATA-2, GATA-3, and c-Jun/c-Fos contribute to the transcriptional regulation of human GnRHR, however, the role of FOXL2 has not been investigated [2] . Here, for the first time, we show that overexpression of wild-type, but not C134W mutant, FOXL2 increases GnRHR mRNA and protein levels in human GCT cells. Our FOXL2 knockdown experiments show that basal GnRHR levels are maintained by wild-type FOXL2 in normal human granulosa cells. In contrast, depletion of FOXL2 in heterozygous mutant KGN cells did not affect GnRHR levels. Thus, our results reveal important differences in the regulation of basal GnRHR levels by FOXL2 between wild-type and mutant cells.", "cite_spans": [{"start": 202, "end": 206, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 341, "end": 345, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 552, "end": 556, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 769, "end": 772, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Discussion", "text": "In addition to demonstrating that wild-type FOXL2 regulates human GnRHR expression, we also show that C134W mutant FOXL2 is deficient in this capacity. Since we have demonstrated the pro-apoptotic effects of GnRH in human GCT cells, this might suggest a scenario where the mutation of FOXL2 leads to reduced GnRHR expression and consequent resistance to GnRH-induced apoptosis. Recently, Kim et al. demonstrated that overexpression of wild-type FOXL2 induced apoptosis and increased cleaved caspase-3 levels in KGN cells [12] . Moreover, they also found that C134W mutant FOXL2 was a weaker inducer of apoptosis, likely because of its reduced ability to induce the expression of tumor necrosis factor receptor 1 (TNFR1) and FAS. Thus by upregulating key pro-apoptotic receptors (GnRHR, TNFR1 and FAS), wild-type FOXL2 contributes to the homeostatic balance of human granulosa cells, and its mutation may result in resistance to apoptosis and lead to granulosa cell tumorigenesis.", "cite_spans": [{"start": 521, "end": 525, "text": "[12]", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "Discussion", "text": "In our study, overexpression of wild-type FOXL2 alone did not significantly affect cell viability or cleaved caspase-3 levels. However, it is important to consider that the time-points examined in our study (96 hr) differed significantly from those of Kim et al. (24 hr) [12] . Indeed, the purpose of our study was to investigate the effects of FOXL2 on GnRH-induced cell apoptosis (requiring prolonged treatment with GnRH), rather than the pro-apoptotic effects of FOXL2 itself. Importantly, accumulating evidence indicates that wild-type and mutant FOXL2 differentially regulate a variety of genes involved in cell proliferation and apoptosis. Thus, in addition to effects on pro-apoptotic ligands and receptors, mutant FOXL2 may contribute to granulosa cell tumorigenesis by de-regulating steroidogenesis [26] , TGF-b signaling [27] or interactions with various partner proteins [28] .", "cite_spans": [{"start": 271, "end": 275, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 808, "end": 812, "text": "[26]", "ref_id": "BIBREF25"}, {"start": 831, "end": 835, "text": "[27]", "ref_id": "BIBREF26"}, {"start": 882, "end": 886, "text": "[28]", "ref_id": "BIBREF27"}], "ref_spans": []}, {"section": "Discussion", "text": "Exactly how the substitution of tryptophan for cysteine at position 134 alters the function of FOXL2 remains unclear. The DNA-binding specificity of forkhead proteins is partially determined by highly variable wing regions (W1 and W2) whose conformations contribute to the precise positioning of the recognition helix [29] . The C134W mutation is predicted to affect the W2 wing region which suggests that it may alter the recognition of specific promoters. However, in silico homology modeling based on the crystal structures of FOXK2 or FOXP2 suggests that the substitution may disrupt protein-protein interactions rather than DNA binding [10, 30] . Recent studies also indicate that the C134W mutation does not affect the localization, mobility and transactivation abilities of FOXL2 [30] . Thus, it has been proposed that the C134W mutation is neither a dominantnegative nor a loss-of-function mutation [30] . Yet, virtually all studies examining the impact of the C134W mutation have measured promoter-luciferase activities rather than endogenous gene expression. For instance, 3xGRAS-luciferase activity was higher in KGN cells transfected with C134W mutant FOXL2 than wild-type FOXL2, whereas the opposite was observed in HeLa cells [30] . Our studies are the first to examine the effects of FOXL2 on endogenous GnRHR expression, and they show that C134W mutant FOXL2 is not an effective inducer of GnRHR expression in KGN cells. Moreover, our FOXL2 siRNA results are consistent with putative dominant-negative effects of C134W mutant FOXL2, and suggest that the expression profile of heterozygous KGN cells is biased towards the mutant allele, at least as it relates to GnRHR expression. Interestingly, it has been shown that a Smad3-Foxl2 heterodimer can bind to the GRAS sequence of the murine Gnrhr promoter [14] and subsequently, it was proposed that the C134W mutation may alter interactions between Foxl2 and Smad3 [30] . However, at present it is not known if Smad3 participates in FOXL2-induced human GnRHR expression, or whether the C134W mutation alters interactions between these two proteins. It is likely that FOXL2 interacts with many transcriptional regulators to orchestrate tissue specific gene expression. Thus, future studies investigating the roles of wild-type and mutant FOXL2 in the regulation of endogenous granulosa cell gene expression should provide important insights into the pathogenesis of adult-type GCTs.", "cite_spans": [{"start": 318, "end": 322, "text": "[29]", "ref_id": "BIBREF28"}, {"start": 641, "end": 645, "text": "[10,", "ref_id": "BIBREF9"}, {"start": 646, "end": 649, "text": "30]", "ref_id": "BIBREF29"}, {"start": 787, "end": 791, "text": "[30]", "ref_id": "BIBREF29"}, {"start": 907, "end": 911, "text": "[30]", "ref_id": "BIBREF29"}, {"start": 1240, "end": 1244, "text": "[30]", "ref_id": "BIBREF29"}, {"start": 1819, "end": 1823, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 1929, "end": 1933, "text": "[30]", "ref_id": "BIBREF29"}], "ref_spans": []}, {"section": "Discussion", "text": "In summary, our studies demonstrate that GnRH exerts proapoptotic effects on human GCT cells, and suggest that autocrine GnRH/GnRHR signaling may contribute to normal human granulosa cell function. Moreover, we show that overexpression of wild-type FOXL2 up-regulates GnRHR and enhances GnRHinduced apoptosis, whereas C134W mutant FOXL2 does not. 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GnRH-I and GnRH-II reduce cell viability via GnRH receptor (GnRHR). A, Total GnRHR protein levels were analyzed by Western blot. Two ovarian cancer cell lines, CaOV3 and OVCAR3, were used as positive controls. B, KGN cells were treated every 24 hr with GnRH-I or GnRH-II (10 26 -10 28 M) in medium containing 1% FBS for 24-96 hr, and MTT assay was used to measure cell viability. The results were analyzed at each time point. C, KGN cells were transfected for 72 hr with 50 nM control siRNA (si-Ctrl) or GnRHR siRNA (si-GnRHR) and GnRHR protein levels were examined by Western blot. D, KGN cells were transfected with control siRNA (si-Ctrl) or GnRHR siRNA (si-GnRHR) for 24 hr and treated with GnRH-I or GnRH-II (10 27 M) for a further 96 hr, and cell viability was examined by MTT assay. Results are expressed as mean 6 SEM of at least three independent experiments. Values without a common letter are significantly different (p,0.05). doi:10.1371/journal.pone.0055099.g001", "type": "figure"}, "FIGREF1": {"text": "Figure 2. GnRH-I and GnRH-II induce cell apoptosis via GnRHR. KGN cells were transfected with 50 nM control siRNA (si-Ctrl) or GnRHR siRNA (si-GnRHR) for 24 hr and then treated with GnRH-I (G-I) or GnRH-II (G-II) (10 27 M) for a further 72 hr. Cycloheximide (CHX; 100 mM for 24 hr) was used as a positive control and cleaved caspase-3 protein levels were examined by Western blot. Results are expressed as mean 6 SEM of at least three independent experiments. Values without a common letter are significantly different (p,0.05). doi:10.1371/journal.pone.0055099.g002 Figure 3. Overexpression wild-type but not C134W mutant FOXL2 increases GnRH receptor (GnRHR) expression. KGN cells were transfected with empty pcDNA3 plasmid (Ctrl), wild-type FOXL2 (WT) or C134W mutant FOXL2 (C134W). A, Western blot was used to measure FOXL2 protein (48 hr) levels in transfected cells. B, RT-qPCR and Western blot were used to measure GnRHR mRNA (24 hr) and protein (48 hr) levels in transfected cells. Results are expressed as mean 6 SEM of at least three independent experiments. Values without a common letter are significantly different (p,0.05). doi:10.1371/journal.pone.0055099.g003", "type": "figure"}, "FIGREF2": {"text": "Figure 2. GnRH-I and GnRH-II induce cell apoptosis via GnRHR. KGN cells were transfected with 50 nM control siRNA (si-Ctrl) or GnRHR siRNA (si-GnRHR) for 24 hr and then treated with GnRH-I (G-I) or GnRH-II (G-II) (10 27 M) for a further 72 hr. Cycloheximide (CHX; 100 mM for 24 hr) was used as a positive control and cleaved caspase-3 protein levels were examined by Western blot. Results are expressed as mean 6 SEM of at least three independent experiments. Values without a common letter are significantly different (p,0.05). doi:10.1371/journal.pone.0055099.g002 Figure 3. Overexpression wild-type but not C134W mutant FOXL2 increases GnRH receptor (GnRHR) expression. KGN cells were transfected with empty pcDNA3 plasmid (Ctrl), wild-type FOXL2 (WT) or C134W mutant FOXL2 (C134W). A, Western blot was used to measure FOXL2 protein (48 hr) levels in transfected cells. B, RT-qPCR and Western blot were used to measure GnRHR mRNA (24 hr) and protein (48 hr) levels in transfected cells. Results are expressed as mean 6 SEM of at least three independent experiments. Values without a common letter are significantly different (p,0.05). doi:10.1371/journal.pone.0055099.g003", "type": "figure"}, "FIGREF3": {"text": "Figure 4. GnRH-induced apoptosis is enhanced by wild-type but not C134W mutant FOXL2. A, KGN cells were transfected with empty pcDNA3 plasmid (Ctrl), wild-type FOXL2 (WT) or C134W mutant FOXL2 (C134W) for 24 hr and then treated with GnRH-I or GnRH-II (10 27 M) for 96 hr. Cell viability was examined by MTT assay. B, KGN cells were transfected as described in (A) and then treated with GnRH-I (G-I) or GnRH-II (G-II) (10 27 M) for 72 hr. Cleaved caspase-3 protein levels were measured by Western blot. Results are expressed as mean 6 SEM of at least three independent experiments. Values without a common letter are significantly different (p,0.05). doi:10.1371/journal.pone.0055099.g004", "type": "figure"}, "FIGREF4": {"text": "Figure 5. Knockdown of endogenous FOXL2 down-regulates GnRH receptor (GnRHR) in immortalized human granulosa-luteal cells but not KGN cells. A, KGN cells were transfected with 50 nM control siRNA (si-Ctrl) or FOXL2 siRNA (si-FOXL2). RT-qPCR and Western blot were used to measure the mRNA (left panel) and protein (right panel) levels of FOXL2 and GnRHR. B, Immortalized human granulosa-luetal cells (hGL) were transfected with 50 nM control siRNA (si-Ctrl) or FOXL2 siRNA (si-FOXL2). RT-qPCR and Western blot were used to measure the mRNA (left panel) and protein (right panel) levels of FOXL2 and GnRHR. Results are expressed as the mean 6 SEM of at least three independent experiments. Values without a common letter are significantly different (p,0.05). doi:10.1371/journal.pone.0055099.g005", "type": "figure"}, "TABREF0": {"text": "3. Overexpression wild-type but not C134W mutant FOXL2 increases GnRH receptor (GnRHR) expression. KGN cells were transfected with empty pcDNA3 plasmid (Ctrl), wild-type FOXL2 (WT) or C134W mutant FOXL2 (C134W). A, Western blot was used to measure FOXL2 protein (48 hr) levels in transfected cells. B, RT-qPCR and Western blot were used to measure GnRHR mRNA (24 hr) and protein (48 hr) levels in transfected cells. Results are expressed as mean 6 SEM of at least three independent experiments. Values without a common letter are significantly different (p,0.05). doi:10.1371/journal.pone.0055099.g003", "type": "table"}}}
{"paper_id": "8334412", "_pdf_hash": "93e29994f733d094067816a561c70a6e06c82ba0", "abstract": [{"section": "Abstract", "text": "The genus Amnestus is one of the most diverse genera of burrowing bugs. In recent years it has been possible to obtain great quantities of specimens, including some new species, due to collecting in special habitats and using different trapping techniques. In this paper we describe eleven new species for the state of Chiapas, Mexico. Full descriptions, illustrations of dorsal habitus, fore and hind legs, prosternal carina, external scent efferent system, and paramere of the new species: A. carinopilosus, A. chiapensis, A. cristobalensis, A. denticulatus, A. laevifemoralis, A. longinoi, A. lorenae, A. marcelae, A. puncticarinatus, A. santiagensis, A. septemclavatus, are included. Amnestus bergrothi and Amnestus stali are redescribed, also illustrated, and lectotypes assigned, because they were originally described based on females. The original description of Amnestus dallasi is also included, because it was described based on one female and it is the only specimen known. Brief descriptions of the other 14 Mexican known species and their distribution are also included. A key and a general discussion to separate the 28 Mexican species are also provided.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Amnestus Dallas (1851) and Lattinestus Eger (2008) are the only two extant genera in the subfamily Amnestinae. The species of Amnestus are recognized by their small size, and by the four or five marginal pegs on the juga (Froeschner, 1960) , while those of Lattinestus are distinguished by the lack of ocelli, and by the hemelytral membrane which is greatly reduced, occupying 1/7 or less of hemelytral length (Eger, 2008) . Froeschner (1960) revised the Amnestus and included 20 species distributed from western Ontario in Canada, through the United States, Mexico, Central America, Antilles and South America to Argentina. He also treated four de insectos asociada al maiz\" by Fundacion Produce (07-2004-5097) . We also want to thank Mick Webb and Luis Hernandez from the Natural History Museum in London for their attention to several visits to the collection and for providing photographs from some of the types. We appreciate the assistance of Edmundo Saavedra for drawing the adults of A. laevifemoralis and A. longinoi, and Marcela Baez for drawing the rest of the adult specimens.", "cite_spans": [{"start": 39, "end": 50, "text": "Eger (2008)", "ref_id": "BIBREF1"}, {"start": 221, "end": 239, "text": "(Froeschner, 1960)", "ref_id": "BIBREF2"}, {"start": 410, "end": 422, "text": "(Eger, 2008)", "ref_id": "BIBREF1"}, {"start": 425, "end": 442, "text": "Froeschner (1960)", "ref_id": "BIBREF2"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "1880-1893) Rhynchota. Hemiptera-Heteroptera", "authors": [{"first": "W", "middle": ["L"], "last": "Distant", "suffix": ""}], "year": "", "venue": "Biologia Centrali Americana", "link": null}, "BIBREF1": {"title": "A new genus and three new species of burrowing bugs (Hemiptera: Heteroptera: Cydnidae: Amnestinae). 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{"paper_id": "8334964", "_pdf_hash": "58399df748c99a25385d598c1945a8a8cf7d22fe", "abstract": [{"section": "Abstract", "text": "Flexible ureteroscopy will replace almost completely ESWL for the treatment of renal stones in few years, even in developing countries. This process is already ongoing and probably is irreversible. Let\u00b4s try to understand how and why this phenomenon is happening.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Since the development of the External Shockwave Lithotripsy (ESWL) in the late 70's (1), it has been the standard treatment for small renal stones (2). However, recent years have seen a significant shift towards endoscopic therapies (3). This can be attributed to the evolving surgical experience in the use of these techniques, but even more to major improvement in the technical equipment. The question of if the flexible ureteroscopy will substitute ESWL as the choice therapy for renal stones is controversial. First of all, they are not totally comparable, since ESWL is a non-invasive method. If ESWL is not an option no more, we lose a noninvasive method of treatment of renal stones. Otherwise, a non-invasive method doesn't means that it is not harmful, because its association with late development of diabetes and hypertension is still controversial, while a link between ESWL and phosphate calcium stones is possible (4). However, as flexible ureteroscopy has higher success rates, it can be justified, since the complications rates are low. Regarding the cost, in some services the flexible ureteroscopy is cost effective compared to ESWL (5).", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "If we see this issue from a current point of view only, it sounds almost absurd to state that ESWL will disappear. Almost 60% of renal stones today are treatment by ESWL, at low cost and low complications rates. No one should close an ESWL service that is established and working properly. The urological guidelines support the use of ESWL for renal and ureteral stones (2, 6). However, we are discussing the future of renal stones treatment, what includes search for better treatments, with lower costs, higher success rates and low complications rates, with a high acceptance and satisfaction of the patients.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "Flexible ureteroscopy will replace almost completely ESWL for the treatment of renal stones in few years, even in developing countries. This process is already ongoing and probably is irreversible. Let\u00b4s try to understand how and why this phenomenon is happening.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Since the development of the External Shockwave Lithotripsy (ESWL) in the late 70's (1), it has been the standard treatment for small renal stones (2) . However, recent years have seen a significant shift towards endoscopic therapies (3) . This can be attributed to the evolving surgical experience in the use of these techniques, but even more to major improvement in the technical equipment. The question of if the flexible ureteroscopy will substitute ESWL as the choice therapy for renal stones is controversial. First of all, they are not totally comparable, since ESWL is a non-invasive method. If ESWL is not an option no more, we lose a noninvasive method of treatment of renal stones. Otherwise, a non-invasive method doesn't means that it is not harmful, because its association with late development of diabetes and hypertension is still controversial, while a link between ESWL and phosphate calcium stones is possible (4). However, as flexible ureteroscopy has higher success rates, it can be justified, since the complications rates are low. Regarding the cost, in some services the flexible ureteroscopy is cost effective compared to ESWL (5).", "cite_spans": [{"start": 147, "end": 150, "text": "(2)", "ref_id": "BIBREF1"}, {"start": 234, "end": 237, "text": "(3)", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "", "text": "If we see this issue from a current point of view only, it sounds almost absurd to state that ESWL will disappear. Almost 60% of renal stones today are treatment by ESWL, at low cost and low complications rates. No one should close an ESWL service that is established and working properly. The urological guidelines support the use of ESWL for renal and ureteral stones (2, 6) . However, we are discussing the future of renal stones treatment, what includes search for better treatments, with lower costs, higher success rates and low complications rates, with a high acceptance and satisfaction of the patients. ", "cite_spans": [{"start": 370, "end": 373, "text": "(2,", "ref_id": "BIBREF1"}, {"start": 374, "end": 376, "text": "6)", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "DIfference of opInIon", "text": "What we observe worldwide and in Brazil currently is an increase in the use of flexible and a decrease in the ESWL (3, 7, 8) .", "cite_spans": [{"start": 115, "end": 118, "text": "(3,", "ref_id": "BIBREF2"}, {"start": 122, "end": 124, "text": "8)", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "DIfference of opInIon", "text": "Herein, we describe some reasons for this change that we have observed: 1. Flexible ureteroscopy has been taught for many years in residency programs, congresses and specific courses for that. So, more urologists are able to perform an adequate flexible ureteroscopy. 2. The flexible ureteroscope has suffering tremendous advances and nowadays it is more durable, with small caliber and with improved vision with the digital system. With adequate care, a flexible ureteroscope can last for a hundred procedures or more, what diminishes the total cost of the procedure (9, 10). 3. The cost of the flexible ureteroscopy has decreasing and is much more affordable today than it was a few years ago. Conversely, the cost of a new ESWL machine is still high and we do not observe a decrease in prices with the new equipment and there is considerable maintenance cost (11, 12). 4. The new ESWL machines fails in demonstrate better results than the old models. None modern ESWL equipment showed to be better than the Dornier HM-3, the first equipment developed (13). 5. New disposables devices have been introduced almost daily, as ureteral sheaths, baskets, laser fibers, what can improve the outcomes (14). 6. There is an undeniable commercial and marketing appeal on flexible, a fact that is less observed with the ESWL machines. 7. Residents and young urologists prefer to do a flexible rather than an ESWL (15). 8. Reimbursement for flexible ureteroscopy is usually higher than for ESWL. 9. Outcomes of flexible ureteroscopy are superior than ESWL in a single session (6) .", "cite_spans": [{"start": 1566, "end": 1569, "text": "(6)", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "DIfference of opInIon", "text": "Normally, ESWL equipment occupies a considerable physical space in the hospital, many times inside a surgical center, with a post-operative room for the patients. That room is expensive, because usually it is underused during the day and stays closed during the night and weekends. It could have others use, more rentable for the Hospital.", "cite_spans": [], "ref_spans": []}, {"section": "DIfference of opInIon", "text": "Movable lithotripsy services were proposed in the North America and Europe in order to solve this problem. A truck was built with an ESWL machine inside and went to the hospitals to treat the patients. Nevertheless, the success rates published recently are about 50% (16) . These poor results can compromise seriously the life of these mobile ESWL.", "cite_spans": [{"start": 267, "end": 271, "text": "(16)", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "DIfference of opInIon", "text": "If you or your Institution have an ESWL service, keep using it, because you are offering a good and recommended treatment for the patients and the acquisition cost of the machine must be paid. However, in a strict administrative point of view (and administrators that make purchases for the hospitals), who is going to buy a new ESWL machine today, that is expensive, has a considerable maintenance cost, is each time less indicated for the urologists, occupies a relatively big and expensive space in the Hospital, if you can buy 2 or 3 flexibles ureteroscopes that will have a lower total cost for the institution, treat the patients more efficiently and is required by the urologists?", "cite_spans": [], "ref_spans": []}, {"section": "DIfference of opInIon", "text": "So, ESWL will die? In my view, will not, and nor should die. But certainly it use will decrease a lot, until stabilize around 10 to 20% of all stone treatments. One possible solution is to create regional reference centers that will drain the cases of a determined region, with good machines (17) and a dedicate team focused in apply all the recommended techniques to improve the outcomes, including a good selection of the patients based on the CT scan analysis (18) , performing an adequate procedure, under sedation or general anesthesia, with good gel coupling, with frequency between 60 and 90 Hz (19) , progressive increase of potency, and use of alpha-blockers after the procedure, mainly for stones bigger than 10 mm (20) . This can give an extra life for the ESWL, making justice with one of the most incredible advances of the urology history.", "cite_spans": [{"start": 463, "end": 467, "text": "(18)", "ref_id": "BIBREF21"}, {"start": 602, "end": 606, "text": "(19)", "ref_id": "BIBREF22"}, {"start": 725, "end": 729, "text": "(20)", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "DIfference of opInIon", "text": "But, as stated in the beginning of this article, flexible ureteroscopy will probably replace almost completely the use of ESWL in the clinical practice in few years, even in developing countries, unless arising another non-invasive technology that is cheaper and with high success rates (21) .", "cite_spans": [{"start": 287, "end": 291, "text": "(21)", "ref_id": "BIBREF24"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Extracorporeal shockwave lithotripsy (ESWL) of kidney and ureteric stones", "authors": [{"first": "E", "middle": [], "last": "Schmiedt", "suffix": ""}, {"first": "C", "middle": [], "last": "Chaussy", "suffix": ""}], "year": 1984, "venue": "Int Urol Nephrol", "link": "8860135"}, "BIBREF1": {"title": "Chapter 1: AUA guideline on management of staghorn calculi: diagnosis and treatment recommendations", "authors": [{"first": "G", "middle": ["M"], "last": "Preminger", "suffix": ""}, {"first": "D", "middle": ["G"], "last": "Assimos", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Lingeman", "suffix": ""}, {"first": "S", "middle": ["Y"], "last": "Nakada", "suffix": ""}, {"first": "M", "middle": ["S"], "last": "Pearle", "suffix": ""}, {"first": "J", "middle": ["S"], "last": "Wolf", "suffix": ""}], "year": 2005, "venue": "AUA Nephrolithiasis Guideline Panel)", "link": "46044578"}, "BIBREF2": {"title": "Contemporary Trends of Inpatient Surgical Management of Stone Disease: National Analysis in an Economic Growth Scenario", "authors": [{"first": "G", "middle": ["S"], "last": "Marchini", "suffix": ""}, {"first": "M", "middle": ["F"], "last": "Mello", "suffix": ""}, {"first": "R", "middle": [], "last": "Levy", "suffix": ""}, {"first": "F", "middle": ["C"], "last": "Vicentini", "suffix": ""}, {"first": "F", "middle": ["C"], "last": "Torricelli", "suffix": ""}, {"first": "J", "middle": [], "last": "Eluf-Neto", "suffix": ""}], "year": 2015, "venue": "J Endourol", "link": "3026762"}, "BIBREF3": {"title": "Mechanism by which shock wave lithotripsy can promote formation of human calcium phosphate stones", "authors": [{"first": "A", "middle": ["P"], "last": "Evan", "suffix": ""}, {"first": "F", "middle": ["L"], "last": "Coe", "suffix": ""}, {"first": "B", "middle": ["A"], "last": "Connors", "suffix": ""}, {"first": "R", "middle": ["K"], "last": "Handa", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Lingeman", "suffix": ""}, {"first": "E", "middle": ["M"], "last": "Worcester", "suffix": ""}], "year": "", "venue": "", "link": "1364673"}, "BIBREF5": {"title": "Costeffectiveness comparison of renal calculi treated with ureteroscopic laser lithotripsy versus shockwave lithotripsy", "authors": [{"first": "E", "middle": ["B"], "last": "Cone", "suffix": ""}, {"first": "B", "middle": ["H"], "last": "Eisner", "suffix": ""}, {"first": "M", "middle": [], "last": "Ursiny", "suffix": ""}, {"first": "G", "middle": [], "last": "Pareek", "suffix": ""}], "year": 2014, "venue": "J Endourol", "link": "8370050"}, "BIBREF6": {"title": "Guidelines on urolithiasis", "authors": [{"first": "C", "middle": [], "last": "Turk", "suffix": ""}, {"first": "T", "middle": [], "last": "Knoll", "suffix": ""}, {"first": "A", "middle": [], "last": "Petrik", "suffix": ""}, {"first": "K", "middle": [], "last": "Sarica", "suffix": ""}, {"first": "A", "middle": [], "last": "Skolarikos", "suffix": ""}, {"first": "M", "middle": [], "last": "Struab", "suffix": ""}], "year": "", "venue": "Eur Assoc Urol. 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{"paper_id": "8335114", "_pdf_hash": "ab75c98587cb261d362b89335981a815277a960f", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
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{"paper_id": "8335295", "_pdf_hash": "01fb27e780457f9c09aaae5fc8981ccfec5a146c", "abstract": [], "body_text": [{"section": "", "text": "The field of anti-parasitic drugs has had a shaky history. The major pharmaceutical companies have increasingly focused their drug development efforts on the major markets, with potential annual sales of at least $100 million. This has not worked well for development of anti-parasitic drugs. Most patients develop parasitic infections due to poverty. Thus, while there may be millions of cases in developing countries, the number able to support the high prices of branded drugs is small. A few new drugs have come into the market. For example, mefloquine, albendazole, ivermectin, and atovaquone-proguanil have all come to the U.S. market since 1990. However, even this limited number of new drugs is somewhat deceiving. Mefloquine and atovaquone-proguanil are largely supported by their use in malaria prophylaxis. In this case, the millions of wealthy Western tourists provide a substantial market for these high-price drugs. In addition, the U.S. military initiated the development of mefloquine, and safety data for atovaquone was supported by its development for treatment of Pneumocystis pneumonia, for which there was a substantial market in the U.S. Ivermectin has never had a large market for human diseases. However, its development and manufacture were supported by the lucrative market as a prophylaxis for canine heartworms.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Between 1990 and 2000, the number of anti-parasitic drugs available for human use in the United States actually shrank. Diethylcarbamazine (DEC), quinacrine, and niclosamide were withdrawn from the U.S. market. Eflornithine was heralded as the \"resurrection\" drug for its dramatic effects in West African trypanosomiasis, yet its sole manufacturer stopped production. Finally, praziquantel was withdrawn from the U.S. market. It appeared that there was actually a \"disappearing arsenal\" of anti-parasitic drugs. 1 Some of these problems have been reversed in response to political pressure. Eflornithine itself was resurrected. The drug proved an effective topical depilatory, thus ensuring that the base compound was being manufactured. In response to pressure led by World Health Organization, and M\u00e9dicins San Fronti\u00e8re, the manufacturer agreed to formulate some drug for intravenous use and make it available for treatment of trypanosomiasis.", "cite_spans": [{"start": 512, "end": 513, "text": "1", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "", "text": "2 Praziquantel was re-instated when the marketing company realized that the public relations losses from withdrawing the drug out-weighed the cost savings from ending production.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "In this context, the development of nitazoxanide is quite remarkable. Nitazoxanide was originally discovered in the 1980s by Jean Fran\u00e7ois Rossignol at the Pasteur Institute. Initial studies demonstrated activity versus tapeworms. 3 In vitro studies demonstrated much broader activity. Dr. Rossignol subsequently led the preclinical and clinical development of albendazole and halofantrine. He co-founded Romark Laboratories, with the goal of bringing nitazoxanide to market as an anti-parasitic drug. Initial studies in the United States were conducted in collaboration with Unimed Pharmaceuticals, Inc. (Marietta, GA) and focused on development of the drug for treatment of cryptosporidiosis in acquired immunodeficiency syndrome. Controlled trials began shortly after the advent of effective anti-retroviral therapies. The trials were abandoned due to poor enrollment and the Food and Drug Administration rejected an application based on uncontrolled studies.", "cite_spans": [{"start": 231, "end": 232, "text": "3", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "", "text": "Rather than abandon their efforts, Romark launched an impressive series of controlled trials. No other agent has proven efficacy in the treatment of cryptosporidiosis. However, a placebo-controlled study of nitazoxanide in cryptosporidiosis demonstrated significant clinical improvement in adults and children with mild illness. 4 Among malnourished children in Zambia with chronic cryptosporidiosis, a threeday course of therapy not only led to clinical and parasitologic improvement, but also improved survival. 5 In Zambia 5 and in a study conducted in Mexico, 6 nitazoxanide was not successful in the treatment of cryptosporidiosis in advanced infection with human immunodeficiency virus at the doses used. However, it was effective in patients with higher CD4 counts. 6, 7 Also, higher doses seem to have some effect in uncontrolled and unpublished studies. In treatment of giardiasis, nitazoxanide was superior to placebo and comparable to metronidazole. 7 Nitazoxanide was successful in the treatment of metronidazole-resistant giardiasis. 8 Studies have suggested efficacy in the treatment of cyclosporiasis, isosporiasis, and amebiasis.", "cite_spans": [{"start": 329, "end": 330, "text": "4", "ref_id": "BIBREF3"}, {"start": 514, "end": 515, "text": "5", "ref_id": "BIBREF4"}, {"start": 526, "end": 527, "text": "5", "ref_id": "BIBREF4"}, {"start": 564, "end": 565, "text": "6", "ref_id": "BIBREF5"}, {"start": 773, "end": 775, "text": "6,", "ref_id": "BIBREF5"}, {"start": 776, "end": 777, "text": "7", "ref_id": "BIBREF6"}, {"start": 961, "end": 962, "text": "7", "ref_id": "BIBREF6"}, {"start": 1047, "end": 1048, "text": "8", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "", "text": "There have also been several controlled trials of nitazoxanide for treatment of infection with intestinal helminths. 9 As shown in the study by Diaz and others in this issue of the journal, nitazoxanide is effective against Ascaris, Trichuris, and Hymenolepis. 10 However, some patients require repeated dosing. Other controlled trials have demonstrated some activity against chronic fascioliasis, for which there is no currently licensed therapy available. 11 However, the response rates are lower than those described with triclabendazole. In all studies, nitazoxanide has been extremely well tolerated with adverse effects similar to placebo.", "cite_spans": [{"start": 117, "end": 118, "text": "9", "ref_id": "BIBREF8"}, {"start": 261, "end": 263, "text": "10", "ref_id": "BIBREF9"}, {"start": 458, "end": 460, "text": "11", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "", "text": "Studies have suggested a number of possible indications for treatment of specific parasites. Given its broad anti-parasitic spectrum, it is tempting to use nitazoxanide empirically. Can nitazoxanide be used as an alternative to albendazole or mebendazole in mass chemotherapy of intestinal helminths? Before this could be done, it will be important to confirm its activity against hookworm species. It will also be important to know whether it can be safely used in a variety of patient groups (e.g., Are there adverse effects in onchocerciasis and Loa loa infections seen with DEC in Africa?).", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "In both developing and developed countries, intestinal protozoans are important causes of persistent and chronic diarrhea. It is difficult to identify specific causes with currently available tests. Multiple stool examinations may be needed to identify Giardia. Cryptosporidium requires specialized tests (modified acid fast or fluorescent stains), which are not uni-formly performed by all laboratories unless requested. Antigen-detection assays may improve the diagnostic yield, but can be expensive and are underused. Currently, cryptosporidiosis is underdiagnosed. The cost and inconveniences of multiple stool examinations will usually be greater than the cost of treatment. Can nitazoxanide be used empirically instead of aggressively pursuing a parasitologic diagnosis? A comparison of empirical therapy versus pursuing diagnosis and specific treatment should be compared in post-travel diarrhea.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Finally, pre-clinical studies have suggested significant activity of nitazoxanide against some bacterial pathogens, including Campylobacter, Clostridium difficile, and Helicobacter pylori. Will these observations translate into clinical efficacy? Controlled trials are clearly indicated. If nitazoxanide proves effective for these indications, the potential market associated with these common infections may provide a major source of revenue that will help insure drug availability. For now, we should celebrate the arrival of an important new addition to the anti-parasitic arsenal.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "The disappearing arsenal of antiparasitic drugs", "authors": [{"first": "A", "middle": ["C"], "last": "White", "suffix": ""}], "year": 2000, "venue": "N Engl J Med", "link": "20754165"}, "BIBREF1": {"title": "Resurrecting the resurrection drug", "authors": [{"first": "P", "middle": [], "last": "Wickware", "suffix": ""}], "year": 2002, "venue": "Nat Med", "link": null}, "BIBREF2": {"title": "Nitazoxanide in the treatment of Taenia saginata and Hymenolepis nana infections", "authors": [{"first": "J", "middle": ["F"], "last": "Rossignol", "suffix": ""}, {"first": "H", "middle": [], "last": "Maisonneuve", "suffix": ""}], "year": 1984, "venue": "Am J Trop Med Hyg", "link": "45911270"}, "BIBREF3": {"title": "Treatment of diarrhea caused by Cryptosporidium parvum: a prospective randomized, double-blind, 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northern Peru", "authors": [{"first": "L", "middle": [], "last": "Favennec", "suffix": ""}, {"first": "Jave", "middle": [], "last": "Ortiz", "suffix": ""}, {"first": "J", "middle": [], "last": "Gargala", "suffix": ""}, {"first": "G", "middle": [], "last": "Lopez Chegne", "suffix": ""}, {"first": "N", "middle": [], "last": "Ayoub", "suffix": ""}, {"first": "A", "middle": [], "last": "Rossignol", "suffix": ""}, {"first": "J", "middle": ["F"], "last": "", "suffix": ""}], "year": 2003, "venue": "Aliment Pharmacol Ther", "link": "32274204"}}, "ref_entries": {}}
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{"paper_id": "8335314", "_pdf_hash": "235dc0e8293295dac0d0df0f5731b41adb4eeb1d", "abstract": [{"section": "Abstract", "text": "The body of scientific literature on slum mapping employing remote sensing methods has increased since the availability of more very-high-resolution (VHR) sensors. This improves the ability to produce information for pro-poor policy development and to build methods capable of supporting systematic global slum monitoring required for international policy development such as the Sustainable Development Goals. This review provides an overview of slum mapping-related remote sensing publications over the period of 2000-2015 regarding four dimensions: contextual factors, physical slum characteristics, data and requirements, and slum extraction methods. The review has shown the following results. First, our contextual knowledge on the diversity of slums across the globe is limited, and slum dynamics are not well captured. Second, a more systematic exploration of physical slum characteristics is required for the development of robust image-based proxies. Third, although the latest commercial sensor technologies provide image data of less than 0.5 m spatial resolution, thereby improving object recognition in slums, the complex and diverse morphology of slums makes extraction through standard methods difficult. Fourth, successful approaches show diversity in terms of extracted information levels (area or object based), implemented indicator sets (single or large sets) and methods employed (e.g., object-based image analysis (OBIA) or machine learning). In the context of a global slum inventory, texture-based methods show good robustness across cities and imagery. Machine-learning algorithms have the highest reported accuracies and allow working with large indicator sets in a computationally efficient manner, while the upscaling of pixel-level information requires further research. For local slum mapping, OBIA approaches show good capabilities of extracting both area-and object-based information. Ultimately, establishing a more systematic relationship between higher-level image elements and slum characteristics is essential to train algorithms able to analyze variations in slum morphologies to facilitate global slum monitoring.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Keywords: slums; informal areas; urban remote sensing; Global South; VHR imagery", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Currently, about one-quarter of the world's urban population lives in slums, which are defined by UN-Habitat as informal settlements [1] or areas deprived of access to safe water, acceptable sanitation, and durable housing; in addition to being areas that are overcrowded and lack land tenure security [2] . Over the last 15 years, there has been renewed interest in slum improvement and eradication by local and international organizations dealing with development issues. During this period, slums became a more prominent subject of remote sensing (RS) image analysis. Supported by increased availability of very-high-resolution (VHR) data and methodological advances, many RS studies [3] [4] [5] [6] [7] [8] aimed to produce information on the geography and dynamics of slums. Thus a multiplicity of images, concepts,", "cite_spans": [{"start": 133, "end": 136, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 687, "end": 690, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 691, "end": 694, "text": "[4]", "ref_id": "BIBREF4"}, {"start": 695, "end": 698, "text": "[5]", "ref_id": "BIBREF5"}, {"start": 699, "end": 702, "text": "[6]", "ref_id": "BIBREF6"}, {"start": 703, "end": 706, "text": "[7]", "ref_id": "BIBREF7"}, {"start": 707, "end": 710, "text": "[8]", "ref_id": "BIBREF9"}], "ref_spans": []}], "body_text": [{"section": "", "text": ". Morphological features typical for slum areas (adapted from [41, 54] ). This review analyzes the diversity of RS studies of the past 15 years that deal with the challenge of extracting slums. It is based on a systematic literature search, performed in December 2015, using several search engines (Web of Science, Science Direct, SpringerLink Journals, Taylor & Francis and Scopus) and covers the keywords \"slums,\" \"informal,\" \"unplanned,\" \"squatter,\" \"precarious,\" \"spontaneous,\" \"illegal,\" \"deprived,\" \"irregular\" or \"substandard settlement/area,\" \"self-help housing,\" \"shantytown,\" \"favela\" or \"bidonville\" and \"mapping\" or \"remote sensing.\" The review covers journal publications, book sections and conference publications that could be retrieved either via the employed research engines or websites of the main RS conferences. Only English-language papers are selected, and very similar publications by the same authors (e.g., journal and conference publication) were counted only once. In total, 87 key publications ( [3] [4] [5] [6] [7] 10, 23, 25, [31] [32] [33] [38] [39] [40] [41] [43] [44] [45] [46] The analytical framework ( Figure 2 ) for analyzing the retrieved publications, inspired by the outcome of the expert meeting on slum mapping [36] , forms the skeleton for this review. Figure 2 shows that slum formation and development in global cities are impacted by several contextual factors, Remote Sens. 2016, 8, 455 5 of 29 such as geographic location and climate, the topography of the city, the location within the city including proximity to services, and general socioeconomic and political factors (e.g., land governance). For example, slum dwellers often trade off accessibility to livelihood opportunities with locations exposed to hazards. Physical slum characteristics are often an expression of the slum-development processes: i.e., from low-density at their infancy stage to high-density mature slums, sometimes also including increasing building size and height. For example, slums can have multiple incrementally constructed floors [2] . Patterns of roads, building layouts and general site characteristics define the growth potential of a specific settlement. When mapping slums, physical slum characteristics need to be well understood for translating them into image-based proxies. The data and requirements of slum-mapping studies relate to imagery and ancillary data and the level (scale) of analysis, e.g., extraction of dwelling units (objects) versus delineation of settlements (areas). Thus the scale varies from small objects (e.g., slum buildings that can be below 20 m 2 ) to large settlements of several hectares [8, 82] . Furthermore, the required spatial, spectral and temporal resolution for slum mapping need to be specified. These requirements are closely linked to extraction methods. Across studies, a multiplicity of extraction methods for slum mapping have been employed, from classical visual image interpretation to OBIA or machine learning, or a combination of methods, with the main methodological challenge of translating a relevant set of slum characteristics into robust indicators (e.g., developing a slum ontology) for image-based slum mapping [23] that would ultimately allow for a global slum inventory.", "cite_spans": [{"start": 62, "end": 66, "text": "[41,", "ref_id": "BIBREF46"}, {"start": 67, "end": 70, "text": "54]", "ref_id": "BIBREF61"}, {"start": 1025, "end": 1028, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 1029, "end": 1032, "text": "[4]", "ref_id": "BIBREF4"}, {"start": 1033, "end": 1036, "text": "[5]", "ref_id": "BIBREF5"}, {"start": 1037, "end": 1040, "text": "[6]", "ref_id": "BIBREF6"}, {"start": 1041, "end": 1044, "text": "[7]", "ref_id": "BIBREF7"}, {"start": 1045, "end": 1048, "text": "10,", "ref_id": "BIBREF11"}, {"start": 1049, "end": 1052, "text": "23,", "ref_id": "BIBREF26"}, {"start": 1053, "end": 1056, "text": "25,", "ref_id": "BIBREF28"}, {"start": 1057, "end": 1061, "text": "[31]", "ref_id": "BIBREF34"}, {"start": 1062, "end": 1066, "text": "[32]", "ref_id": "BIBREF35"}, {"start": 1067, "end": 1071, "text": "[33]", "ref_id": "BIBREF36"}, {"start": 1072, "end": 1076, "text": "[38]", "ref_id": "BIBREF42"}, {"start": 1077, "end": 1081, "text": "[39]", "ref_id": "BIBREF44"}, {"start": 1082, "end": 1086, "text": "[40]", "ref_id": "BIBREF45"}, {"start": 1087, "end": 1091, "text": "[41]", "ref_id": "BIBREF46"}, {"start": 1092, "end": 1096, "text": "[43]", "ref_id": "BIBREF48"}, {"start": 1097, "end": 1101, "text": "[44]", "ref_id": "BIBREF49"}, {"start": 1102, "end": 1106, "text": "[45]", "ref_id": "BIBREF50"}, {"start": 1107, "end": 1111, "text": "[46]", "ref_id": "BIBREF51"}, {"start": 1428, "end": 1430, "text": "8,", "ref_id": "BIBREF9"}, {"start": 2658, "end": 2661, "text": "[8,", "ref_id": "BIBREF9"}, {"start": 2662, "end": 2665, "text": "82]", "ref_id": "BIBREF91"}, {"start": 3207, "end": 3211, "text": "[23]", "ref_id": "BIBREF26"}], "ref_spans": [{"start": 1139, "end": 1147, "text": "Figure 2", "ref_id": "FIGREF3"}, {"start": 1297, "end": 1305, "text": "Figure 2", "ref_id": "FIGREF3"}]}, {"section": "", "text": "Remote Sens. 2016, 8, 455 5 of 31 governance). For example, slum dwellers often trade off accessibility to livelihood opportunities with locations exposed to hazards. Physical slum characteristics are often an expression of the slumdevelopment processes: i.e., from low-density at their infancy stage to high-density mature slums, sometimes also including increasing building size and height. For example, slums can have multiple incrementally constructed floors [2] . Patterns of roads, building layouts and general site characteristics define the growth potential of a specific settlement. When mapping slums, physical slum characteristics need to be well understood for translating them into image-based proxies. The data and requirements of slum-mapping studies relate to imagery and ancillary data and the level (scale) of analysis, e.g., extraction of dwelling units (objects) versus delineation of settlements (areas). Thus the scale varies from small objects (e.g., slum buildings that can be below 20 m 2 ) to large settlements of several hectares [8, 82] . Furthermore, the required spatial, spectral and temporal resolution for slum mapping need to be specified. These requirements are closely linked to extraction methods. Across studies, a multiplicity of extraction methods for slum mapping have been employed, from classical visual image interpretation to OBIA or machine learning, or a combination of methods, with the main methodological challenge of translating a relevant set of slum characteristics into robust indicators (e.g., developing a slum ontology) for image-based slum mapping [23] that would ultimately allow for a global slum inventory. governance). For example, slum dwellers often trade off accessibility to livelihood opportunities with locations exposed to hazards. Physical slum characteristics are often an expression of the slumdevelopment processes: i.e., from low-density at their infancy stage to high-density mature slums, sometimes also including increasing building size and height. For example, slums can have multiple incrementally constructed floors [2] . Patterns of roads, building layouts and general site characteristics define the growth potential of a specific settlement. When mapping slums, physical slum characteristics need to be well understood for translating them into image-based proxies. The data and requirements of slum-mapping studies relate to imagery and ancillary data and the level (scale) of analysis, e.g., extraction of dwelling units (objects) versus delineation of settlements (areas). Thus the scale varies from small objects (e.g., slum buildings that can be below 20 m 2 ) to large settlements of several hectares [8, 82] . Furthermore, the required spatial, spectral and temporal resolution for slum mapping need to be specified. These requirements are closely linked to extraction methods. Across studies, a multiplicity of extraction methods for slum mapping have been employed, from classical visual image interpretation to OBIA or machine learning, or a combination of methods, with the main methodological challenge of translating a relevant set of slum characteristics into robust indicators (e.g., developing a slum ontology) for image-based slum mapping [23] that would ultimately allow for a global slum inventory. ", "cite_spans": [{"start": 19, "end": 21, "text": "8,", "ref_id": "BIBREF9"}, {"start": 1057, "end": 1060, "text": "[8,", "ref_id": "BIBREF9"}, {"start": 1061, "end": 1064, "text": "82]", "ref_id": "BIBREF91"}, {"start": 1606, "end": 1610, "text": "[23]", "ref_id": "BIBREF26"}, {"start": 2691, "end": 2694, "text": "[8,", "ref_id": "BIBREF9"}, {"start": 2695, "end": 2698, "text": "82]", "ref_id": "BIBREF91"}, {"start": 3240, "end": 3244, "text": "[23]", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "Contextual Factors", "text": "Context matters for slum mapping. We first provide an overview of the terminological differences regarding settlements with poor living conditions as they affect the choice and definition of indicators. We also summarize the purposes of slum-mapping studies linked to the socioeconomic and political context. The final section gives an overview of geographic locations mapped by slum studies linking to variation in climate and topography.", "cite_spans": [], "ref_spans": []}, {"section": "Terminological Differences", "text": "The nomenclatures of slum settlements vary depending on different connotations [41, 122] . To some extent, these terms reflect the different views on such settlements. Terms such as \"informal,\" \"illegal\" or \"squatter,\" for instance, focus on the land rights (tenure status) [24] , whereas \"unplanned\" relates to the planning context [41] . \"Spontaneous\" or \"irregular\" emphasizes the growth dynamics [123] , whereas \"deprived,\" \"shantytown\" and \"sub-standard\" are associated with poor physical and socioeconomic conditions [54] . The recent revival in popularity of the rather political term \"slum\" [122] is largely linked to the Habitat Agenda and the related development goals [27, 124] . The analysis of the retrieved publications with respect to these terms in combination with RS methods (see Table 2 ) identified \"informal settlement/area\" (47%) and \"slum\" (29%) as the most commonly used terms in the RS community, among which some researchers use both terms interchangeably (6%). Less frequently used terms that refer to the physical condition (e.g., \"deprived/sub-standard\") focus on a specific issue (e.g., \"refugee camps\") or on a specific national context (e.g., \"migrant housing\" or \"urban villages\" in China). Terms such as \"squatter\" or \"unplanned,\" which were common in the 1970s-1980s planning literature, are no longer commonly used. \"Informal settlement/area\" being the most frequently used term in the RS literature is actually awkward as it constitutes the legal (tenure) status of an area, which cannot be directly extracted from imagery. A change in tenure status does not necessarily affect the physical characteristics. In this review, we use the term \"slum\" to refer to urban areas with poor living conditions as this term expresses explicitly physical characteristics such as high densities or irregular patterns, indicators that can be derived by means of RS methods. Here, an ontological framework (e.g., developed by [5, 7] ) \"provides a comprehensive description of spatial characteristics and their relationships to represent and characterize slums in an image\" ( [31] , p. 155). Such an ontology framework-split in three phases: specification, conceptualization and implementation [5] -provides a clear conceptual foundation for developing robust image-based indicators, facilitating global knowledge acquisition and comparisons for the development of a global slum inventory. Table 2 .", "cite_spans": [{"start": 79, "end": 83, "text": "[41,", "ref_id": "BIBREF46"}, {"start": 84, "end": 88, "text": "122]", "ref_id": "BIBREF136"}, {"start": 274, "end": 278, "text": "[24]", "ref_id": "BIBREF27"}, {"start": 333, "end": 337, "text": "[41]", "ref_id": "BIBREF46"}, {"start": 400, "end": 405, "text": "[123]", "ref_id": "BIBREF137"}, {"start": 523, "end": 527, "text": "[54]", "ref_id": "BIBREF61"}, {"start": 599, "end": 604, "text": "[122]", "ref_id": "BIBREF136"}, {"start": 679, "end": 683, "text": "[27,", "ref_id": "BIBREF30"}, {"start": 684, "end": 688, "text": "124]", "ref_id": "BIBREF138"}, {"start": 1947, "end": 1950, "text": "[5,", "ref_id": "BIBREF5"}, {"start": 1951, "end": 1953, "text": "7]", "ref_id": "BIBREF7"}, {"start": 2096, "end": 2100, "text": "[31]", "ref_id": "BIBREF34"}, {"start": 2214, "end": 2217, "text": "[5]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Terminological Differences", "text": "Frequency of publications using a specific term (within the reviewed remote sensing publications). ", "cite_spans": [], "ref_spans": []}, {"section": "Terms", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Purposes of Slum Mapping Using Remote Sensing", "text": "Our second contextual topic concerns the different purposes of RS-based slum-mapping studies. The review has identified three key geographical questions-where, when and what?-as the main objectives of studies. Often, researchers aim at the provision of basic information on \"where\" the slums are located within the urban fabric and what their areal extent is. Such information allows compensating for the non-availability of socioeconomic information (e.g., income levels) in many cities of the Global South [31] . Besides its importance for urban development [68] , the where question is also relevant within a humanitarian context, for which several studies [67, 76, 109] developed methods to map refugee camps (e.g., under Copernicus) [125] .", "cite_spans": [{"start": 508, "end": 512, "text": "[31]", "ref_id": "BIBREF34"}, {"start": 560, "end": 564, "text": "[68]", "ref_id": "BIBREF76"}, {"start": 660, "end": 664, "text": "[67,", "ref_id": "BIBREF75"}, {"start": 665, "end": 668, "text": "76,", "ref_id": "BIBREF84"}, {"start": 669, "end": 673, "text": "109]", "ref_id": "BIBREF121"}, {"start": 738, "end": 743, "text": "[125]", "ref_id": "BIBREF139"}], "ref_spans": []}, {"section": "Purposes of Slum Mapping Using Remote Sensing", "text": "While development dynamics of slums at the city scale are of particular interest for local planning and decision support [10, 126] , only a few studies have focused on temporal slum dynamics (when) (e.g., [10] ). This could be related to challenges extracting these dynamics, in particular in terms of data availability and obtaining local knowledge. Examples of studies on dynamics are the analysis of the process of forced mass evictions in Harare (Zimbabwe) [104] , the investigation of built-up changes for large slum settlements such as Kibera-Nairobi [3] or the exploration of development dynamics of slums in Delhi, showing stagnation in the center versus growth in the periphery [127] . Such multi-temporal information can feed simulation models on the growth of slum areas, generating policy-relevant information of future growth scenarios [48, [128] [129] [130] [131] [132] .", "cite_spans": [{"start": 121, "end": 125, "text": "[10,", "ref_id": "BIBREF11"}, {"start": 126, "end": 130, "text": "126]", "ref_id": "BIBREF140"}, {"start": 205, "end": 209, "text": "[10]", "ref_id": "BIBREF11"}, {"start": 461, "end": 466, "text": "[104]", "ref_id": "BIBREF116"}, {"start": 557, "end": 560, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 687, "end": 692, "text": "[127]", "ref_id": "BIBREF141"}, {"start": 849, "end": 853, "text": "[48,", "ref_id": "BIBREF54"}, {"start": 854, "end": 859, "text": "[128]", "ref_id": "BIBREF142"}, {"start": 860, "end": 865, "text": "[129]", "ref_id": "BIBREF143"}, {"start": 866, "end": 871, "text": "[130]", "ref_id": "BIBREF145"}, {"start": 872, "end": 877, "text": "[131]", "ref_id": "BIBREF146"}, {"start": 878, "end": 883, "text": "[132]", "ref_id": "BIBREF147"}], "ref_spans": []}, {"section": "Purposes of Slum Mapping Using Remote Sensing", "text": "Several publications have focused on what'-related issues, such as the number of slum inhabitants, since many census statistics slums are not well covered (with high uncertainty about the number of inhabitants) [133] . Moreover, RS-based population estimates allow a more detailed spatial and temporal disaggregation [133, 134] . However, population estimates of slums can vary [4] as illustrated for the case of Kibera (Nairobi) [3] , where estimates differed by half a million people depending on the sample data used. For the slums in Hyderabad, India, Kit et al. [134] computed slightly lower image-based population figures than the figures reported by the census. Furthermore, relying on physical proxies for population estimations can lead to errors for areas that have not yet been fully occupied, e.g., new developments in outskirts [70] . Other what-related issues deal with boundaries and effectiveness of policies for health campaigns [84, 135] , allocation of public services and protection of environmentally sensitive areas [68] or spatial planning and policy formulation [69] . These efforts are related to the fact that local planning authorities often lack elementary information on slums, which \"has led to a deficit in policy for these areas, as without quality map data, it is often difficult to plan effectively for these areas\" ( [69] , p. 390), leading to ad hoc plans that do not consider the specific locational context. For example, for one settlement in Johannesburg, Gunter [69] mapped 10,000 more dwellings by using Google Earth (GE) images compared to the government estimates. Such discrepancies are problematic for policy development and monitoring and may point to conceptual differences in what constitutes a slum dwelling. Spatial information on slums can support local governments in better determining the demand of basic services and other relevant amenities [136] and monitor slums via RS-based proxies of \"human deprivation or well-being\" ( [137] , p. 68).", "cite_spans": [{"start": 211, "end": 216, "text": "[133]", "ref_id": "BIBREF148"}, {"start": 317, "end": 322, "text": "[133,", "ref_id": "BIBREF148"}, {"start": 323, "end": 327, "text": "134]", "ref_id": "BIBREF150"}, {"start": 378, "end": 381, "text": "[4]", "ref_id": "BIBREF4"}, {"start": 430, "end": 433, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 567, "end": 572, "text": "[134]", "ref_id": "BIBREF150"}, {"start": 841, "end": 845, "text": "[70]", "ref_id": "BIBREF78"}, {"start": 946, "end": 950, "text": "[84,", "ref_id": "BIBREF93"}, {"start": 951, "end": 955, "text": "135]", "ref_id": "BIBREF151"}, {"start": 1038, "end": 1042, "text": "[68]", "ref_id": "BIBREF76"}, {"start": 1086, "end": 1090, "text": "[69]", "ref_id": "BIBREF77"}, {"start": 1352, "end": 1356, "text": "[69]", "ref_id": "BIBREF77"}, {"start": 1502, "end": 1506, "text": "[69]", "ref_id": "BIBREF77"}, {"start": 1897, "end": 1902, "text": "[136]", "ref_id": "BIBREF152"}, {"start": 1981, "end": 1986, "text": "[137]", "ref_id": "BIBREF153"}], "ref_spans": []}, {"section": "Purposes of Slum Mapping Using Remote Sensing", "text": "The potential application areas for RS-based information on the morphology and temporal dynamics of slums are grouped into four major domains (Table 3 , [21, 54, 77, 120, [138] [139] [140] [141] [142] [143] [144] [145] [146] [147] [148] [149] [150] [151] [152] ): economy, environment, governance and planning, and social applications. These domains reflect the reported spatial information needs and lack of information on slums in locally available data sets [84] . Quite a rich body of literature is connected to social issues, where \"remotely sensed imagery can serve as data source for inferring socio-economic variables\" ( [93] , p. 69). Emerging applications areas are related to land management [144, 145] , quality of life and crime studies [151, 152] . ", "cite_spans": [{"start": 153, "end": 157, "text": "[21,", "ref_id": "BIBREF24"}, {"start": 158, "end": 161, "text": "54,", "ref_id": "BIBREF61"}, {"start": 162, "end": 165, "text": "77,", "ref_id": "BIBREF85"}, {"start": 166, "end": 170, "text": "120,", "ref_id": "BIBREF134"}, {"start": 171, "end": 176, "text": "[138]", "ref_id": "BIBREF155"}, {"start": 177, "end": 182, "text": "[139]", "ref_id": "BIBREF156"}, {"start": 183, "end": 188, "text": "[140]", "ref_id": "BIBREF158"}, {"start": 189, "end": 194, "text": "[141]", "ref_id": "BIBREF159"}, {"start": 195, "end": 200, "text": "[142]", "ref_id": "BIBREF160"}, {"start": 201, "end": 206, "text": "[143]", "ref_id": "BIBREF161"}, {"start": 207, "end": 212, "text": "[144]", "ref_id": "BIBREF162"}, {"start": 213, "end": 218, "text": "[145]", "ref_id": "BIBREF163"}, {"start": 219, "end": 224, "text": "[146]", "ref_id": "BIBREF164"}, {"start": 225, "end": 230, "text": "[147]", "ref_id": "BIBREF165"}, {"start": 231, "end": 236, "text": "[148]", "ref_id": "BIBREF166"}, {"start": 237, "end": 242, "text": "[149]", "ref_id": "BIBREF167"}, {"start": 243, "end": 248, "text": "[150]", "ref_id": "BIBREF168"}, {"start": 249, "end": 254, "text": "[151]", "ref_id": "BIBREF169"}, {"start": 255, "end": 260, "text": "[152]", "ref_id": "BIBREF170"}, {"start": 461, "end": 465, "text": "[84]", "ref_id": "BIBREF93"}, {"start": 629, "end": 633, "text": "[93]", "ref_id": "BIBREF103"}, {"start": 703, "end": 708, "text": "[144,", "ref_id": "BIBREF162"}, {"start": 709, "end": 713, "text": "145]", "ref_id": "BIBREF163"}, {"start": 750, "end": 755, "text": "[151,", "ref_id": "BIBREF169"}, {"start": 756, "end": 760, "text": "152]", "ref_id": "BIBREF170"}], "ref_spans": [{"start": 142, "end": 150, "text": "(Table 3", "ref_id": "TABREF1"}]}, {"section": "Geographic Locations, Climate and Topography", "text": "Given the aim of identifying relevant issues for developing a global slum inventory, we analyze the geographic distribution of RS-based information on slums by mapping the case study locations found in English-language publications on top of a population density map ( Figure 3 ). In the figure, \"slum cities\" are grouped into locations where object-level information (roofs or roads), area-based slum maps, or both were extracted. Object-level information is mainly available in SSA. Obviously, there is a spatial relationship between areas of high urban population densities in the Global South and the location of case studies. The highest concentrations are found in South-East Asia and SSA (East and South). Some clusters also exist in North and West Africa and South/Central America. Examples are even found in the Global North, dealing with the monitoring of informal development, e.g., in Greece [153] and the US [119] . The cities covered range from (sub)tropic, Mediterranean, arid and continental climates, as well as low-lying areas with rather flat terrain (e.g., Dhaka) up to high-lying cities (e.g., La Paz) with steep slopes. Still, many urban regions with very dynamic urban and slum developments are not well covered in English-language publications, e.g., areas in the Caribbean, West and Central Africa or in South-East Asia. Also, areas in Europe might become a future focus, considering the recent erection of refugee camps or examples of deprived Roma settlements in European countries [144] . Many of the regions not covered belong to the least developed countries with large income inequalities and/or instable political conditions, e.g., Liberia, Congo or Myanmar. In such countries, ground-truth or reference data accessibility might be even more of a problem. Moreover, many studies are about methodological developments and do not create exhaustive citywide slum maps, illustrating that we are still far away from a global slum inventory. ", "cite_spans": [{"start": 904, "end": 909, "text": "[153]", "ref_id": "BIBREF171"}, {"start": 921, "end": 926, "text": "[119]", "ref_id": "BIBREF133"}, {"start": 1509, "end": 1514, "text": "[144]", "ref_id": "BIBREF162"}], "ref_spans": [{"start": 269, "end": 277, "text": "Figure 3", "ref_id": "FIGREF8"}]}, {"section": "Geographic Locations, Climate and Topography", "text": "Given the aim of identifying relevant issues for developing a global slum inventory, we analyze the geographic distribution of RS-based information on slums by mapping the case study locations found in English-language publications on top of a population density map ( Figure 3 ). In the figure, \"slum cities\" are grouped into locations where object-level information (roofs or roads), area-based slum maps, or both were extracted. Object-level information is mainly available in SSA. Obviously, there is a spatial relationship between areas of high urban population densities in the Global South and the location of case studies. The highest concentrations are found in South-East Asia and SSA (East and South). Some clusters also exist in North and West Africa and South/Central America. Examples are even found in the Global North, dealing with the monitoring of informal development, e.g., in Greece [153] and the US [119] . The cities covered range from (sub)tropic, Mediterranean, arid and continental climates, as well as low-lying areas with rather flat terrain (e.g., Dhaka) up to highlying cities (e.g., La Paz) with steep slopes. Still, many urban regions with very dynamic urban and slum developments are not well covered in English-language publications, e.g., areas in the Caribbean, West and Central Africa or in South-East Asia. Also, areas in Europe might become a future focus, considering the recent erection of refugee camps or examples of deprived Roma settlements in European countries [144] . Many of the regions not covered belong to the least developed countries with large income inequalities and/or instable political conditions, e.g., Liberia, Congo or Myanmar. In such countries, ground-truth or reference data accessibility might be even more of a problem. Moreover, many studies are about methodological developments and do not create exhaustive citywide slum maps, illustrating that we are still far away from a global slum inventory. The majority of the reviewed publications are authored by academic researchers, both from universities in the Global North (48%) and Global South (21%) or combinations thereof (6%). Fewer publications stem from research centers (including national RS agencies), in the Global North (8%) and Global South (5%) and one by a commercial image provider (1%). Moreover, there is some cooperation between research centers and university in the Global North (5%) and South (2%), also across South and North (2%), or with an NGO (2%). The majority of English-language publications from the Global North links to the global slum debate. South\u00b4North and South\u00b4South cooperation are of particular relevance for knowledge exchanges and transfer, bridging technology gaps and for further expanding our knowledge to more cities including also very instable regions like the Sudan [125] .", "cite_spans": [{"start": 904, "end": 909, "text": "[153]", "ref_id": "BIBREF171"}, {"start": 921, "end": 926, "text": "[119]", "ref_id": "BIBREF133"}, {"start": 1508, "end": 1513, "text": "[144]", "ref_id": "BIBREF162"}, {"start": 2832, "end": 2837, "text": "[125]", "ref_id": "BIBREF139"}], "ref_spans": [{"start": 269, "end": 277, "text": "Figure 3", "ref_id": "FIGREF8"}]}, {"section": "Physical Characteristics of Slum Areas", "text": "VHR imagery provides a detailed representation of the physical elements of a landscape, capturing physical characteristics of slums. This section conceptualizes these characteristics derived from imagery and considers their diversity.", "cite_spans": [], "ref_spans": []}, {"section": "Characterization of Slum Areas", "text": "The definition of what constitutes a slum is complex. Variations exist between global, regional and local slum definitions [154] that can result in large differences of mapped slum areas [64] . Many publications adopted the global UN-Habitat definition of slums (e.g., [4, 43, 155] ), which consists of five well-established indicators: secure tenure, adequate access to safe water, access to acceptable forms of sanitation, overcrowding, and the durability of housing considering both the quality of the structures as well as site conditions in terms of hazards. For instance, based on the work of Weeks et al. [43] , Duque et al. [61] used these indicators (i.e., wall material, overcrowding, access to piped water, sanitation connection to sewers, and ownership) to build a slum index based on census data for the city of Medellin (Colombia). This index, compared with image-based information on land cover, structural and texture-based features, showed that the image-based information could explain 59% of the slum index. A major problem in employing the UN-Habitat definition in RS-based studies is that only the indicator \"durability of housing conditions\" has a direct link to information extracted from imagery, namely location aspects (such as location on steep slopes, along major drainage channels [112] ), compliance with building codes measured via density, distance or roofing material [2] . Slums do not have \"easily distinguishable spectral signatures\" ( [45] , p. 661), meaning that roofing material may vary within slums (e.g., plastic, iron, concrete, tin, asbestos) and between different slums and globally between cities. For the example of Accra (Ghana), Engstrom et al. [64] concluded that when using the UN-Habitat definition, most of the city is classified as slums, while an image-based identification matched much better the local delineation of slums. These examples indicate that global slum definitions need to be adjusted to the local context. However, most researchers fail to start with a local characterization of the slum morphology and the development of related image-based proxies. Table 4 presents an overview of physical characterizations of slums found in literature, split into five major dimensions: building geometry, density, arrangement (pattern/road), roofing material, and site characteristics. The most frequently used characteristics are small roof sizes, high density, and irregular patterns (visible by irregular and narrow streets combined with heterogeneous building orientation). Densities in Asian cities tend to have higher values than in SSA cities (Asia~80% and SSA~60%) [5, 41] . However, also in SSA, centrally located slums, such as those in Nairobi, Kenya with an estimated roof cover of 50%-60%, have high densities [156] . For the group of roofing material and physical site characteristics, there is a great deal of difference between cities across different geographic regions and even across slums. For instance, in Dehradun, slums are characterized by tone differences due to different roofing materials (e.g., plastic, wood etc.) [75] , but in Guangzhou [97] or Ahmedabad [5] , spectrally similar roofing material characterizes slums. Regarding physical site characteristics, there is also no general agreement; however, slums are often located in areas that are not suitable for constructions (e.g., on a flood plain, steep slope or other hazardous locations) [157] . To conceptualize such physical characteristics, Kohli et al. [5] developed a slum ontology (Figure 4 ), based on Hofmann et al. [7] , which consists of three spatial levels (object, settlement and environs). For each level, indicators identify specific physical slum characteristics. Yet the ontology requires a local adaption as not all indicators are relevant for a specific local slum identification [158] . Thus slums are different from non-slum areas, but are not homogeneous [4] . To conceptualize such physical characteristics, Kohli et al. [5] developed a slum ontology ( Figure  4 ), based on Hofmann et al. [7] , which consists of three spatial levels (object, settlement and environs). For each level, indicators identify specific physical slum characteristics. Yet the ontology requires a local adaption as not all indicators are relevant for a specific local slum identification [158] . Thus slums are different from non-slum areas, but are not homogeneous [4] . ", "cite_spans": [{"start": 123, "end": 128, "text": "[154]", "ref_id": "BIBREF172"}, {"start": 187, "end": 191, "text": "[64]", "ref_id": "BIBREF72"}, {"start": 269, "end": 272, "text": "[4,", "ref_id": "BIBREF4"}, {"start": 273, "end": 276, "text": "43,", "ref_id": "BIBREF48"}, {"start": 277, "end": 281, "text": "155]", "ref_id": "BIBREF173"}, {"start": 612, "end": 616, "text": "[43]", "ref_id": "BIBREF48"}, {"start": 632, "end": 636, "text": "[61]", "ref_id": "BIBREF69"}, {"start": 1310, "end": 1315, "text": "[112]", "ref_id": "BIBREF125"}, {"start": 1472, "end": 1476, "text": "[45]", "ref_id": "BIBREF50"}, {"start": 1694, "end": 1698, "text": "[64]", "ref_id": "BIBREF72"}, {"start": 2631, "end": 2634, "text": "[5,", "ref_id": "BIBREF5"}, {"start": 2635, "end": 2638, "text": "41]", "ref_id": "BIBREF46"}, {"start": 2781, "end": 2786, "text": "[156]", "ref_id": "BIBREF174"}, {"start": 3101, "end": 3105, "text": "[75]", "ref_id": "BIBREF83"}, {"start": 3125, "end": 3129, "text": "[97]", "ref_id": "BIBREF108"}, {"start": 3143, "end": 3146, "text": "[5]", "ref_id": "BIBREF5"}, {"start": 3432, "end": 3437, "text": "[157]", "ref_id": "BIBREF175"}, {"start": 3501, "end": 3504, "text": "[5]", "ref_id": "BIBREF5"}, {"start": 3568, "end": 3571, "text": "[7]", "ref_id": "BIBREF7"}, {"start": 3843, "end": 3848, "text": "[158]", "ref_id": "BIBREF176"}, {"start": 3921, "end": 3924, "text": "[4]", "ref_id": "BIBREF4"}, {"start": 3988, "end": 3991, "text": "[5]", "ref_id": "BIBREF5"}, {"start": 4057, "end": 4060, "text": "[7]", "ref_id": "BIBREF7"}, {"start": 4332, "end": 4337, "text": "[158]", "ref_id": "BIBREF176"}, {"start": 4410, "end": 4413, "text": "[4]", "ref_id": "BIBREF4"}], "ref_spans": [{"start": 2121, "end": 2128, "text": "Table 4", "ref_id": "TABREF4"}, {"start": 3531, "end": 3540, "text": "(Figure 4", "ref_id": "FIGREF10"}, {"start": 4020, "end": 4029, "text": "Figure  4", "ref_id": "FIGREF10"}]}, {"section": "The Diversity of Slums", "text": "Besides the commonalities of slums in terms of physical characteristics, we also explore the heterogeneity of slums. Already in 1962, Charles Stokes differentiated between \"slums of hope\" and \"slums of despair\" [159] . Slums vary between and within cities and within slums in terms of substandard living conditions [122, 160] . Therefore, recently, some researchers have been exploring different slum typologies based on building sizes, density, pattern or location (Table 5 ). However, slums are often not the worst off areas in terms of socioeconomic conditions [31, 114, 161] . Thus, such typologies include also fuzzy classes (i.e., semi-formal), reflecting the dilemma that some areas are formal but are physically and/or socioeconomically similar to slums, e.g., high-density resettlement colonies in Delhi [54] . On the contrary, areas can have morphological characteristics that align with slums, but on the ground, they are not slums like historic core areas. The established typologies (Table 5 ) range from two to five categories. The main factor that influenced authors to develop such typologies is the diversity on the ground, e.g., very deprived areas and areas that have an unsecure tenure status but are better off in terms of building characteristics. Some differences are visible in imagery and may assist in a semi-automatic slum identification. However, none of the reviewed studies established an (semi)-automatic imageclassification approach to extract slum typologies. ", "cite_spans": [{"start": 211, "end": 216, "text": "[159]", "ref_id": "BIBREF177"}, {"start": 315, "end": 320, "text": "[122,", "ref_id": "BIBREF136"}, {"start": 321, "end": 325, "text": "160]", "ref_id": "BIBREF178"}, {"start": 564, "end": 568, "text": "[31,", "ref_id": "BIBREF34"}, {"start": 569, "end": 573, "text": "114,", "ref_id": "BIBREF127"}, {"start": 574, "end": 578, "text": "161]", "ref_id": "BIBREF179"}, {"start": 813, "end": 817, "text": "[54]", "ref_id": "BIBREF61"}], "ref_spans": [{"start": 466, "end": 474, "text": "(Table 5", "ref_id": "TABREF6"}, {"start": 996, "end": 1004, "text": "(Table 5", "ref_id": "TABREF6"}]}, {"section": "The Diversity of Slums", "text": "Besides the commonalities of slums in terms of physical characteristics, we also explore the heterogeneity of slums. Already in 1962, Charles Stokes differentiated between \"slums of hope\" and \"slums of despair\" [159] . Slums vary between and within cities and within slums in terms of sub-standard living conditions [122, 160] . Therefore, recently, some researchers have been exploring different slum typologies based on building sizes, density, pattern or location (Table 5 ). However, slums are often not the worst off areas in terms of socioeconomic conditions [31, 114, 161] . Thus, such typologies include also fuzzy classes (i.e., semi-formal), reflecting the dilemma that some areas are formal but are physically and/or socioeconomically similar to slums, e.g., high-density resettlement colonies in Delhi [54] . On the contrary, areas can have morphological characteristics that align with slums, but on the ground, they are not slums like historic core areas. The established typologies (Table 5 ) range from two to five categories. The main factor that influenced authors to develop such typologies is the diversity on the ground, e.g., very deprived areas and areas that have an unsecure tenure status but are better off in terms of building characteristics. Some differences are visible in imagery and may assist in a semi-automatic slum identification. However, none of the reviewed studies established an (semi)-automatic image-classification approach to extract slum typologies.", "cite_spans": [{"start": 211, "end": 216, "text": "[159]", "ref_id": "BIBREF177"}, {"start": 316, "end": 321, "text": "[122,", "ref_id": "BIBREF136"}, {"start": 322, "end": 326, "text": "160]", "ref_id": "BIBREF178"}, {"start": 565, "end": 569, "text": "[31,", "ref_id": "BIBREF34"}, {"start": 570, "end": 574, "text": "114,", "ref_id": "BIBREF127"}, {"start": 575, "end": 579, "text": "161]", "ref_id": "BIBREF179"}, {"start": 814, "end": 818, "text": "[54]", "ref_id": "BIBREF61"}], "ref_spans": [{"start": 467, "end": 475, "text": "(Table 5", "ref_id": "TABREF6"}, {"start": 997, "end": 1005, "text": "(Table 5", "ref_id": "TABREF6"}]}, {"section": "Data Availability and Spatial Requirements", "text": "The complexity of physical slum characteristics requires advanced sensor systems for mapping purposes. This section focuses on available imagery data and the spatial requirements in terms of spatial resolution and extent (settlement to urban region level) of reviewed studies.", "cite_spans": [], "ref_spans": []}, {"section": "Our Remote Eyes: Available Sensors", "text": "The successful launch of Ikonos-2 on 24 September 1999 heralded a new era of urban RS. The increased availability of high and very-high-resolution imagery produced by sensors such as Ikonos, QuickBird, WorldView (very-high-resolution sensors (VHR) have spatial resolutions of the PAN band of 1 m and below, while high-resolution (HR) sensors have between 1 and 5 m spatial resolutions) have provided a new and rich data repository for urban research in general and for slum-related research in particular, as it allows for a more detailed spatial analysis [162] . Besides commercial VHR imagery, since 2005, GE has provided universal web-based access to VHR imagery, although not providing the original spectral bands, which limits potential analysis.", "cite_spans": [{"start": 556, "end": 561, "text": "[162]", "ref_id": "BIBREF181"}], "ref_spans": []}, {"section": "Our Remote Eyes: Available Sensors", "text": "An increasing number of multi-spectral (MS) and panchromatic (PAN) VHR sensors has become available (see Figure 5 ). For instance, since August 2014, the first commercial satellite with a spatial resolution of 0.31 m (PAN) and 1.24 m (MS) allows an improved object-level analysis. While the first sensors were launched by countries in the Global North, there is an increasing number of launches of (V)HR sensors by countries in the Global South (such as NigeriaSat). Also, China has launched a large number of (V)HR sensors; however, access to data from outside China is an issue. Besides optical systems, synthetic aperture radar (SAR) systems are gaining an increasing role in extracting information on slums, especially since the availability of (V)HR systems, e. ", "cite_spans": [], "ref_spans": [{"start": 105, "end": 113, "text": "Figure 5", "ref_id": "FIGREF14"}]}, {"section": "Data Availability and Spatial Requirements", "text": "The complexity of physical slum characteristics requires advanced sensor systems for mapping purposes. This section focuses on available imagery data and the spatial requirements in terms of spatial resolution and extent (settlement to urban region level) of reviewed studies.", "cite_spans": [], "ref_spans": []}, {"section": "Our Remote Eyes: Available Sensors", "text": "The successful launch of Ikonos-2 on 24 September 1999 heralded a new era of urban RS. The increased availability of high and very-high-resolution imagery produced by sensors such as Ikonos, QuickBird, WorldView (very-high-resolution sensors (VHR) have spatial resolutions of the PAN band of 1 m and below, while high-resolution (HR) sensors have between 1 and 5 m spatial resolutions) have provided a new and rich data repository for urban research in general and for slumrelated research in particular, as it allows for a more detailed spatial analysis [162] . Besides commercial VHR imagery, since 2005, GE has provided universal web-based access to VHR imagery, although not providing the original spectral bands, which limits potential analysis.", "cite_spans": [{"start": 555, "end": 560, "text": "[162]", "ref_id": "BIBREF181"}], "ref_spans": []}, {"section": "Our Remote Eyes: Available Sensors", "text": "An increasing number of multi-spectral (MS) and panchromatic (PAN) VHR sensors has become available (see Figure 5 ). For instance, since August 2014, the first commercial satellite with a spatial resolution of 0.31 m (PAN) and 1.24 m (MS) allows an improved object-level analysis. While the first sensors were launched by countries in the Global North, there is an increasing number of launches of (V)HR sensors by countries in the Global South (such as NigeriaSat). Also, China has launched a large number of (V)HR sensors; however, access to data from outside China is an issue. Besides optical systems, synthetic aperture radar (SAR) systems are gaining an increasing role in extracting information on slums, especially since the availability of (V)HR systems, e. Analyzing the imagery used in the reviewed studies ( Figure 5 ), we identify QuickBird, launched in 2001 with a spatial resolution of 0.61 and 2.44 m (PAN and MS) and a revisit time of 3 days, as the most frequently used sensor (33%). The revisit time does not equal repetition rate, e.g., WV-3 needs 4.5 days until capturing a scene with the same geometric characteristics (20\u02ddoff-nadir or less at exactly the same position). While, images taken <1 day might have different geometric characteristics, e.g., causing problems for multi-temporal image comparison. The second most frequently used sensor is Ikonos (11%), with a spatial resolution of 1 and 4 m and the same revisit time. This is followed by SPOT (mainly SPOT-5) (9%), with a slightly lower spatial resolution (SPOT-5: Pan: 2.5/5 m and MS: 10 m) and revisit time of 5 days; Landsat (9%) and aerial photos/imagery (8%). The latter have been an important spatial information source in mapping and analyzing (e.g., [163, 164] ), in monitoring growth processes (e.g., [73] ) and in extracting buildings in slums (e.g., [102] ). The main advantages of aerial photographs are that archives often cover long time series and have very high spatial resolutions (in cm range). Apart from the V(HR) imagery, some studies employed moderate resolution imagery (e.g., Landsat, Terra ASTER), e.g., analyzing vegetation cover in slums [110] , which is often a good proxy for deprivation [165] .", "cite_spans": [{"start": 1741, "end": 1746, "text": "[163,", "ref_id": "BIBREF182"}, {"start": 1747, "end": 1751, "text": "164]", "ref_id": "BIBREF183"}, {"start": 1793, "end": 1797, "text": "[73]", "ref_id": "BIBREF81"}, {"start": 1844, "end": 1849, "text": "[102]", "ref_id": "BIBREF114"}, {"start": 2148, "end": 2153, "text": "[110]", "ref_id": "BIBREF123"}, {"start": 2200, "end": 2205, "text": "[165]", "ref_id": "BIBREF184"}], "ref_spans": [{"start": 105, "end": 113, "text": "Figure 5", "ref_id": "FIGREF14"}, {"start": 820, "end": 828, "text": "Figure 5", "ref_id": "FIGREF14"}]}, {"section": "Spatial Requirements of Slum-Mapping Studies", "text": "Spectrally most of the imagery have 2-3 VIS bands and 1-2 IR bands, and the availability of more VHR sensors with more spectral bands (e.g., Worldview-2 with 8 bands) producing images of improved spatial resolutions raises the question of what is an optimal or minimum spatial resolution for slum mapping. In this respect, Jacobsen and B\u00fcy\u00fcksalih [166] determined the required GSD (ground sampling distance) for building objects to be 2 m and for footpaths 1-2 m, while for minor roads 5 m was considered sufficient. However, detailed building object information requires below 0.5 m and a sufficient contrast between buildings and their surrounding [167] . Moreover, this may vary in different urban environments. For instance, in cities with a high clustering of buildings, such as in many Asian cities, a resolution of 2 m does not allow the extraction of roof objects [41] . Furthermore, according to Pesaresi and Ehrlich ([168] , p. 45), when \"assuming a typical minimal built-up element in a settlement, having a size of 10\u02c610 m, we need at least 0.5 m.\" Many slum buildings are, however, considerably below 100 m 2 . Moreover, roof surfaces are frequently not homogeneous; for instance, when using a VHR sensor, the majority of the roof pixels will be \"mixed pixels\" (due to different materials/shadow/illumination) [168] . Consequently, not only the high densities of roofs, but also the heterogeneity of roof surfaces causes serious limitations for automatically extracting roof objects, subsequently requiring manual editing for producing reliable information [169] . There is as of yet no systematic study that analyzes the impact of different spatial and spectral resolutions on the accuracy of extracting object-level information in slums. It is also interesting that most studies on roof [55, 73, 87, 91] or road extraction [95] are from African cities (see also Figure 3 ), where coverage densities and clustering of roofs are in general a bit lower than in Asian cities [5] .", "cite_spans": [{"start": 347, "end": 352, "text": "[166]", "ref_id": "BIBREF185"}, {"start": 650, "end": 655, "text": "[167]", "ref_id": "BIBREF186"}, {"start": 872, "end": 876, "text": "[41]", "ref_id": "BIBREF46"}, {"start": 1323, "end": 1328, "text": "[168]", "ref_id": "BIBREF187"}, {"start": 1570, "end": 1575, "text": "[169]", "ref_id": "BIBREF188"}, {"start": 1802, "end": 1806, "text": "[55,", "ref_id": "BIBREF62"}, {"start": 1807, "end": 1810, "text": "73,", "ref_id": "BIBREF81"}, {"start": 1811, "end": 1814, "text": "87,", "ref_id": "BIBREF96"}, {"start": 1815, "end": 1818, "text": "91]", "ref_id": "BIBREF101"}, {"start": 1838, "end": 1842, "text": "[95]", "ref_id": "BIBREF105"}, {"start": 1986, "end": 1989, "text": "[5]", "ref_id": "BIBREF5"}], "ref_spans": [{"start": 1877, "end": 1885, "text": "Figure 3", "ref_id": "FIGREF8"}]}, {"section": "Spatial Requirements of Slum-Mapping Studies", "text": "Considering the high costs for commercial VHR imagery and the required processing resources, many studies have focused on methodological advances and therefore only used as spatial extent small areas, e.g., subsets of scenes (34%) and settlements (24%) or administrative units (9%) ( Table 6 ). Methods developed for one scene segment are not necessarily transferable to other scenes [105] . However, more than one-quarter performed the analysis for an entire city (28%) or at urban region scale (5%). The city and urban regional scale are important stepping stones for building a global slum inventory. A further stepping stone towards a global slum inventory is a recent pilot study to map slums of an entire country (South Africa) [77] . ", "cite_spans": [{"start": 384, "end": 389, "text": "[105]", "ref_id": "BIBREF117"}, {"start": 734, "end": 738, "text": "[77]", "ref_id": "BIBREF85"}], "ref_spans": [{"start": 284, "end": 291, "text": "Table 6", "ref_id": "TABREF8"}]}, {"section": "Slum-Mapping Approaches", "text": "Among the reviewed studies, multiple methods have been used to map slums. This section focuses on the most promising methods with respect to extracted information level (objects or areas) and achieved accuracies. In general, the level of analysis depends on the spatial resolution of available imagery, the specific urban morphology and the information requirements.", "cite_spans": [], "ref_spans": []}, {"section": "Methods Employed for Slum Mapping", "text": "In order to explore the discursive context of slum-mapping efforts, we analyze the actual information that is extracted in the reviewed case studies ( Table 7 rows). The majority (55%) of studies identify entire slum areas [74, 82, 100] , and fewer studies aim at extracting objects in slums (15%), i.e., roofs [40, 87] or roads [95] . The extraction of object-level information depends largely on the relation between (available) data sources and morphological characteristics of the study area, meaning that roof or road extraction works well when objects have clearly visible spacing and contrast in the imagery. The more classical focus on extracting land use/cover information is addressed by 17% of the publications (e.g., [96, 101] ). Within this category, a recent research stream aims at mapping built-up areas using, for example, texture measures. Here, the co-occurrence matrix (GLCM) is commonly used (e.g., [62, 170, 171] ), which is also the basis for the \"anisotropic rotation-invariant built-up presence index\" (Pantex) [172] . Finally, a limited number of studies develop methodologies to analyze the link between image-based and socioeconomic indicators (6%) (e.g., [173] ) or the diversity of slums (7%) (e.g., [85] ). Since the expert meeting on slum mapping in 2008 [36] , more methods and cases on slum cities have been explored, expanding the global knowledge repository of slum characteristics and their variability. Brito and Quintanilha [174] stated that in recent years many methods have been based on feature extraction but there is no clear agreement on the most successful method(s), where the majority of studies rely on optical data. The availability of imagery with sub-meter resolution still has many unresolved technical challenges for the characterization of slums, such as mixed pixels or the obliqueness of images. Thus, there is \"a strong need of new approaches for automatic image understanding on remote sensing data bridging the gap between visual and automatic image interpretation\" ( [175] , p. 3). In this respect, also complex (visual) interpretation elements (e.g., height, shadow, pattern and site) ( Figure 6 , [41, 176, 177] ) need to be more systematically explored [177] . Figure 6 , [41, 176, 177] ) need to be more systematically explored [177] . Already in 1998, Mason and Fraser [178] specified three main characteristics of an effective system to map/monitor slums, specifically low-cost (data acquisition and processing), semi-automated processes (fast and reliable results) and simple usage by low-skilled operators (standard software). The analysis of the employed methods in the reviewed slum publications shows that most studies used commercial and rather expensive imagery. Only very few studies used free data sources such as GE image, mostly for visual image interpretation (e.g., [69, 84, 119] ), visualization of slums [90] or combining GE with commercial imagery [72, 80] , whereas Praptono et al. [98] used GE images to automatically detect slums employing a Gabor filter and GLCM with a promising accuracy of 74%. Many of the methods used commercial software solutions, but to some extent also open-source software. Nevertheless, both are not easy to be operated by non-RS experts.", "cite_spans": [{"start": 223, "end": 227, "text": "[74,", "ref_id": "BIBREF82"}, {"start": 228, "end": 231, "text": "82,", "ref_id": "BIBREF91"}, {"start": 232, "end": 236, "text": "100]", "ref_id": "BIBREF112"}, {"start": 311, "end": 315, "text": "[40,", "ref_id": "BIBREF45"}, {"start": 316, "end": 319, "text": "87]", "ref_id": "BIBREF96"}, {"start": 329, "end": 333, "text": "[95]", "ref_id": "BIBREF105"}, {"start": 729, "end": 733, "text": "[96,", "ref_id": "BIBREF107"}, {"start": 734, "end": 738, "text": "101]", "ref_id": "BIBREF113"}, {"start": 920, "end": 924, "text": "[62,", "ref_id": "BIBREF70"}, {"start": 925, "end": 929, "text": "170,", "ref_id": "BIBREF189"}, {"start": 930, "end": 934, "text": "171]", "ref_id": "BIBREF190"}, {"start": 1036, "end": 1041, "text": "[172]", "ref_id": "BIBREF191"}, {"start": 1184, "end": 1189, "text": "[173]", "ref_id": "BIBREF192"}, {"start": 1230, "end": 1234, "text": "[85]", "ref_id": "BIBREF94"}, {"start": 1463, "end": 1468, "text": "[174]", "ref_id": "BIBREF193"}, {"start": 2028, "end": 2033, "text": "[175]", "ref_id": "BIBREF194"}, {"start": 2160, "end": 2164, "text": "[41,", "ref_id": "BIBREF46"}, {"start": 2165, "end": 2169, "text": "176,", "ref_id": "BIBREF195"}, {"start": 2170, "end": 2174, "text": "177]", "ref_id": "BIBREF196"}, {"start": 2217, "end": 2222, "text": "[177]", "ref_id": "BIBREF196"}, {"start": 2236, "end": 2240, "text": "[41,", "ref_id": "BIBREF46"}, {"start": 2241, "end": 2245, "text": "176,", "ref_id": "BIBREF195"}, {"start": 2246, "end": 2250, "text": "177]", "ref_id": "BIBREF196"}, {"start": 2293, "end": 2298, "text": "[177]", "ref_id": "BIBREF196"}, {"start": 2335, "end": 2340, "text": "[178]", "ref_id": "BIBREF197"}, {"start": 2846, "end": 2850, "text": "[69,", "ref_id": "BIBREF77"}, {"start": 2851, "end": 2854, "text": "84,", "ref_id": "BIBREF93"}, {"start": 2855, "end": 2859, "text": "119]", "ref_id": "BIBREF133"}, {"start": 2886, "end": 2890, "text": "[90]", "ref_id": "BIBREF100"}, {"start": 2931, "end": 2935, "text": "[72,", "ref_id": "BIBREF80"}, {"start": 2936, "end": 2939, "text": "80]", "ref_id": "BIBREF89"}, {"start": 2966, "end": 2970, "text": "[98]", "ref_id": "BIBREF109"}], "ref_spans": [{"start": 151, "end": 158, "text": "Table 7", "ref_id": "TABREF9"}, {"start": 2149, "end": 2157, "text": "Figure 6", "ref_id": "FIGREF16"}, {"start": 2225, "end": 2233, "text": "Figure 6", "ref_id": "FIGREF16"}]}, {"section": "Methods Employed for Slum Mapping", "text": "Overall, the methods to extract slums are rather diverse (Table 7 columns). The most frequently used method in the last 15 years was OBIA (32%), also referred to as GEOBIA [179] . For OBIA, the transferability [82] or robustness [71] of rules and indicators is a critical issue, which is a stronger feature of texture or morphology-based methods [82] , accounting for 16% of the studies. Significantly, Hofmann et al. [180] stressed that a systematic adaption of segmentation parameters is crucial to transfer rules from one image to another. Several studies focused on the optimization of scale parameters [181] , where the tool Estimation of Scale Parameters (ESP) allows optimizing the scale based on patterns in the data [182] .", "cite_spans": [{"start": 172, "end": 177, "text": "[179]", "ref_id": "BIBREF198"}, {"start": 210, "end": 214, "text": "[82]", "ref_id": "BIBREF91"}, {"start": 229, "end": 233, "text": "[71]", "ref_id": "BIBREF79"}, {"start": 346, "end": 350, "text": "[82]", "ref_id": "BIBREF91"}, {"start": 418, "end": 423, "text": "[180]", "ref_id": "BIBREF199"}, {"start": 607, "end": 612, "text": "[181]", "ref_id": "BIBREF200"}, {"start": 725, "end": 730, "text": "[182]", "ref_id": "BIBREF201"}], "ref_spans": [{"start": 57, "end": 65, "text": "(Table 7", "ref_id": "TABREF9"}]}, {"section": "Methods Employed for Slum Mapping", "text": "Apart from OBIA, visual image interpretation (17%) and standard pixel-based image classification were employed (13%). However, the reliance on standard pixel-based classification methods is not that appropriate for analyzing a complex urban environment having high spectral diversity, very small and clustered objects and diverse morphological characteristics. Therefore, many researchers used machine-learning algorithms (14%) such as neural networks [59] , random forest (RF) or support vector machines (SVM) [72] . Machine-learning approaches are information-driven approaches that allow for a repetitive learning from a large and rich set of training data [94] . However, those approaches are mainly pixel-based methods, which are \"not very effective in high-resolution urban image classification\" procedures ( [116] , p. 869). Therefore, a large spatial context of many neighboring pixels is necessary, such as multi-instant learning [116] or Markov random fields [46] . Given that neighborhoods or wards are relevant spatial units of policy and decision-making processes, the issue of aggregation is important, via segments (e.g., [41, 88] ), regular grids (e.g., [104] ) or nonoverlapping block [173] .", "cite_spans": [{"start": 452, "end": 456, "text": "[59]", "ref_id": "BIBREF67"}, {"start": 511, "end": 515, "text": "[72]", "ref_id": "BIBREF80"}, {"start": 660, "end": 664, "text": "[94]", "ref_id": "BIBREF104"}, {"start": 815, "end": 820, "text": "[116]", "ref_id": "BIBREF129"}, {"start": 939, "end": 944, "text": "[116]", "ref_id": "BIBREF129"}, {"start": 969, "end": 973, "text": "[46]", "ref_id": "BIBREF51"}, {"start": 1137, "end": 1141, "text": "[41,", "ref_id": "BIBREF46"}, {"start": 1142, "end": 1145, "text": "88]", "ref_id": "BIBREF97"}, {"start": 1170, "end": 1175, "text": "[104]", "ref_id": "BIBREF116"}, {"start": 1202, "end": 1207, "text": "[173]", "ref_id": "BIBREF192"}], "ref_spans": []}, {"section": "Methods Employed for Slum Mapping", "text": "Crossing the main foci and methods (Table 7) , OBIA appears to be the most common method for extracting both slum areas and objects in slums. Although rather labor intensive, visual Already in 1998, Mason and Fraser [178] specified three main characteristics of an effective system to map/monitor slums, specifically low-cost (data acquisition and processing), semi-automated processes (fast and reliable results) and simple usage by low-skilled operators (standard software). The analysis of the employed methods in the reviewed slum publications shows that most studies used commercial and rather expensive imagery. Only very few studies used free data sources such as GE image, mostly for visual image interpretation (e.g., [69, 84, 119] ), visualization of slums [90] or combining GE with commercial imagery [72, 80] , whereas Praptono et al. [98] used GE images to automatically detect slums employing a Gabor filter and GLCM with a promising accuracy of 74%. Many of the methods used commercial software solutions, but to some extent also open-source software. Nevertheless, both are not easy to be operated by non-RS experts.", "cite_spans": [{"start": 216, "end": 221, "text": "[178]", "ref_id": "BIBREF197"}, {"start": 727, "end": 731, "text": "[69,", "ref_id": "BIBREF77"}, {"start": 732, "end": 735, "text": "84,", "ref_id": "BIBREF93"}, {"start": 736, "end": 740, "text": "119]", "ref_id": "BIBREF133"}, {"start": 767, "end": 771, "text": "[90]", "ref_id": "BIBREF100"}, {"start": 812, "end": 816, "text": "[72,", "ref_id": "BIBREF80"}, {"start": 817, "end": 820, "text": "80]", "ref_id": "BIBREF89"}, {"start": 847, "end": 851, "text": "[98]", "ref_id": "BIBREF109"}], "ref_spans": [{"start": 35, "end": 44, "text": "(Table 7)", "ref_id": "TABREF9"}]}, {"section": "Methods Employed for Slum Mapping", "text": "Overall, the methods to extract slums are rather diverse (Table 7 columns). The most frequently used method in the last 15 years was OBIA (32%), also referred to as GEOBIA [179] . For OBIA, the transferability [82] or robustness [71] of rules and indicators is a critical issue, which is a stronger feature of texture or morphology-based methods [82] , accounting for 16% of the studies. Significantly, Hofmann et al. [180] stressed that a systematic adaption of segmentation parameters is crucial to transfer rules from one image to another. Several studies focused on the optimization of scale parameters [181] , where the tool Estimation of Scale Parameters (ESP) allows optimizing the scale based on patterns in the data [182] .", "cite_spans": [{"start": 172, "end": 177, "text": "[179]", "ref_id": "BIBREF198"}, {"start": 210, "end": 214, "text": "[82]", "ref_id": "BIBREF91"}, {"start": 229, "end": 233, "text": "[71]", "ref_id": "BIBREF79"}, {"start": 346, "end": 350, "text": "[82]", "ref_id": "BIBREF91"}, {"start": 418, "end": 423, "text": "[180]", "ref_id": "BIBREF199"}, {"start": 607, "end": 612, "text": "[181]", "ref_id": "BIBREF200"}, {"start": 725, "end": 730, "text": "[182]", "ref_id": "BIBREF201"}], "ref_spans": [{"start": 57, "end": 65, "text": "(Table 7", "ref_id": "TABREF9"}]}, {"section": "Methods Employed for Slum Mapping", "text": "Apart from OBIA, visual image interpretation (17%) and standard pixel-based image classification were employed (13%). However, the reliance on standard pixel-based classification methods is not that appropriate for analyzing a complex urban environment having high spectral diversity, very small and clustered objects and diverse morphological characteristics. Therefore, many researchers used machine-learning algorithms (14%) such as neural networks [59] , random forest (RF) or support vector machines (SVM) [72] . Machine-learning approaches are information-driven approaches that allow for a repetitive learning from a large and rich set of training data [94] . However, those approaches are mainly pixel-based methods, which are \"not very effective in high-resolution urban image classification\" procedures ( [116] , p. 869). Therefore, a large spatial context of many neighboring pixels is necessary, such as multi-instant learning [116] or Markov random fields [46] . Given that neighborhoods or wards are relevant spatial units of policy and decision-making processes, the issue of aggregation is important, via segments (e.g., [41, 88] ), regular grids (e.g., [104] ) or non-overlapping block [173] .", "cite_spans": [{"start": 452, "end": 456, "text": "[59]", "ref_id": "BIBREF67"}, {"start": 511, "end": 515, "text": "[72]", "ref_id": "BIBREF80"}, {"start": 660, "end": 664, "text": "[94]", "ref_id": "BIBREF104"}, {"start": 815, "end": 820, "text": "[116]", "ref_id": "BIBREF129"}, {"start": 939, "end": 944, "text": "[116]", "ref_id": "BIBREF129"}, {"start": 969, "end": 973, "text": "[46]", "ref_id": "BIBREF51"}, {"start": 1137, "end": 1141, "text": "[41,", "ref_id": "BIBREF46"}, {"start": 1142, "end": 1145, "text": "88]", "ref_id": "BIBREF97"}, {"start": 1170, "end": 1175, "text": "[104]", "ref_id": "BIBREF116"}, {"start": 1203, "end": 1208, "text": "[173]", "ref_id": "BIBREF192"}], "ref_spans": []}, {"section": "Methods Employed for Slum Mapping", "text": "Crossing the main foci and methods (Table 7) , OBIA appears to be the most common method for extracting both slum areas and objects in slums. Although rather labor intensive, visual interpretation is still used for slum identification, producing reliable results by skilled interpretations; however, texture/morphology and machine-learning methods are increasingly being used.", "cite_spans": [], "ref_spans": [{"start": 35, "end": 44, "text": "(Table 7)", "ref_id": "TABREF9"}]}, {"section": "Accuracy Levels and Employed Methods", "text": "The last dimension of the analysis deals with the performance of indicators and methods, measured by accuracy levels. Across the studies, there is much diversity with respect to these levels. For instance, Ella et al. [63] compared various texture features (e.g., local binary pattern (LBP), GLCM, lacunarity) by training a support vector machine. While LBP achieved the highest accuracy of 98%, GLCM had an accuracy of 94%. Based on single indicator approaches, lacunarity was identified as having a high utility for extracting slums (e.g., [45, 57] ); however, lacunarity cannot identify small slum pockets as it requires a rather large window size [10] . Verzosa and Gonzalez [118] suggested entropy for monitoring uncontrolled sprawl, while the morphology of slums can be described by spatial metrics [41, 83] with reported accuracies of not more than 70%. Besides the use of single or a small set of indicators, several studies used large sets of indicators. For example, Owen and Wong [6] performed a systematic comparison between indicators to distinguish formal and slum areas using 24 spectral, accessibility, texture, scale-based and morphological indicators. The result showed that the best indicators were entropy of roads, vegetation patch size, and vegetation patch compactness. Similarly, Graesser, Cheriyadat, Vatsavai, Chandola, Long and Bright [46] focused on the development of consistent predictors for formal and slum areas by a decision tree using GLCM, lacunarity, histogram gradients, linear feature distribution, line support regions, vegetation indices, and textons (texture patches). Their result showed that texton features were most robust for all included cities (i.e., Caracas, Kabul, Kandahar, and La Paz), achieving a maximum accuracy of 92% [43] . Thus, a fully automatic system for mapping slums with 100% accuracy is not in sight. However, reported accuracy levels show promising developments for semi-automatic methods.", "cite_spans": [{"start": 218, "end": 222, "text": "[63]", "ref_id": "BIBREF71"}, {"start": 542, "end": 546, "text": "[45,", "ref_id": "BIBREF50"}, {"start": 547, "end": 550, "text": "57]", "ref_id": "BIBREF64"}, {"start": 651, "end": 655, "text": "[10]", "ref_id": "BIBREF11"}, {"start": 679, "end": 684, "text": "[118]", "ref_id": "BIBREF132"}, {"start": 805, "end": 809, "text": "[41,", "ref_id": "BIBREF46"}, {"start": 810, "end": 813, "text": "83]", "ref_id": "BIBREF92"}, {"start": 991, "end": 994, "text": "[6]", "ref_id": "BIBREF6"}, {"start": 1362, "end": 1366, "text": "[46]", "ref_id": "BIBREF51"}, {"start": 1775, "end": 1779, "text": "[43]", "ref_id": "BIBREF48"}], "ref_spans": []}, {"section": "Accuracy Levels and Employed Methods", "text": "Apart from comparing the capacity of indicators, the performance of methods is evaluated. In general, advanced approaches (such as mathematical morphology analysis) have a better performance than standard classification approaches [67] . To evaluate the performance of methods, we compare the accuracy of all reviewed slum-mapping publications (Figure 7) . The highest mean accuracy is obtained by machine-learning approaches, but also texture and statistical-based approaches show promising results, while the variance of the performance of OBIA is rather large. The cases of lower accuracies of OBIA are often related to very complex urban environments such as Indian cities where slum areas are very diverse and often have similar spatial characteristics compared to formal areas. Thus obtained accuracy levels not only depend on the methodology, but also on the urban morphology and how well slum characteristics are captured by image-based proxies. To address this, Shekhar [105] proposed an OBIA procedure, identifying first formal areas; the remaining built-up areas are then classified as slums achieving an overall accuracy of 87%.", "cite_spans": [{"start": 231, "end": 235, "text": "[67]", "ref_id": "BIBREF75"}, {"start": 979, "end": 984, "text": "[105]", "ref_id": "BIBREF117"}], "ref_spans": [{"start": 344, "end": 354, "text": "(Figure 7)", "ref_id": "FIGREF18"}]}, {"section": "Accuracy Levels and Employed Methods", "text": "In conclusion, machine-learning methods seem to be more successful when aiming at extracting slum areas at the city scale, whereas OBIA was found to work well for the extraction of objects (e.g., roofs, roads) on settlement level when the urban morphology combined with a sufficient resolution image allowed their extraction. Both methods can be combined, e.g., using image segmentation together with machine-learning approaches [183] , which allows combining the advantages of both methods.", "cite_spans": [{"start": 429, "end": 434, "text": "[183]", "ref_id": "BIBREF202"}], "ref_spans": []}, {"section": "Accuracy Levels and Employed Methods", "text": "The cases of lower accuracies of OBIA are often related to very complex urban environments such as Indian cities where slum areas are very diverse and often have similar spatial characteristics compared to formal areas. Thus obtained accuracy levels not only depend on the methodology, but also on the urban morphology and how well slum characteristics are captured by image-based proxies. To address this, Shekhar [105] proposed an OBIA procedure, identifying first formal areas; the remaining built-up areas are then classified as slums achieving an overall accuracy of 87%. ", "cite_spans": [{"start": 415, "end": 420, "text": "[105]", "ref_id": "BIBREF117"}], "ref_spans": []}, {"section": "Challenges and Promising Aspects for a Global Slum Monitoring System", "text": "Based on the results presented in the previous sections, the most promising aspects of the reviewed studies (in terms of context, physical characteristics, data and requirements, and methodologies) for developing a global slum inventory are explored.", "cite_spans": [], "ref_spans": []}, {"section": "Access to Image Data and Contextual Factors", "text": "Our geographic \"ground\" knowledge on slums is limited to a few urban regions. Therefore, Owen and Wong [38] recommended more systematic comparisons between different slum settlements, done by very few studies (e.g., [46] ). It would be important to compare the performance of indicators, methods, and image data for different urban contexts across the globe to obtain an overview of robust indicators, methods, and required data. A major initiative in this respect is performed by the Oak Ridge National Laboratory, where researchers are working on \"a computationally efficient and automated framework that is capable of detecting new settlements (especially slums) across the globe\" ( [117] , p. 1425). To promote large-scale slum-mapping programs, clear guidelines and continuous political support is necessary, shown by the challenges of implementing, for instance, past slum-mapping programs in Indian cities (RAY; the vision of a slum-free India) [184] .", "cite_spans": [{"start": 103, "end": 107, "text": "[38]", "ref_id": "BIBREF42"}, {"start": 216, "end": 220, "text": "[46]", "ref_id": "BIBREF51"}, {"start": 686, "end": 691, "text": "[117]", "ref_id": "BIBREF130"}, {"start": 952, "end": 957, "text": "[184]", "ref_id": "BIBREF204"}], "ref_spans": []}, {"section": "Access to Image Data and Contextual Factors", "text": "A major bottleneck (besides image costs) is image availability due to frequent cloud cover in tropical cities. However, since the massive increase of VHR sensors, we can expect an improvement of image availability. To further overcome this problem, more (V)HR resolution SAR sensors are available (e.g., TerraSAR-X) that penetrate clouds, being suitable for texture analysis of slums [60, 89] . Also, LIDAR data have enormous potential for object extraction with their capability of extracting building heights [185] , a relevant indicator for slum mapping [4] . Furthermore, drones (UAVs) are able to fly below clouds to capture settlement details [186] , but to cover entire cities would be computational challenging, in addition to the inevitable privacy issues. In addition, other image data sources have potential, e.g., night-light images. Unfortunately, the resolution of sensors like OLS is too low to map detailed inner urban night-light variations. On a metropolitan scale, researchers successfully correlated poverty rates with observed night-time lights (e.g., [187] ). Alternative image sources for global slum mapping are, for instance, GE images that allow working with VHR imagery free of charge (democratizing data access), where texture-based image analysis showed promising accuracies [98] . To increase the classification accuracy, several studies have proposed the use of auxiliary data, such as the utility of DSM for built-up or roof extraction [153] or the usage of VGI (volunteered geographic information) [69] .", "cite_spans": [{"start": 384, "end": 388, "text": "[60,", "ref_id": "BIBREF68"}, {"start": 389, "end": 392, "text": "89]", "ref_id": "BIBREF99"}, {"start": 511, "end": 516, "text": "[185]", "ref_id": "BIBREF205"}, {"start": 557, "end": 560, "text": "[4]", "ref_id": "BIBREF4"}, {"start": 649, "end": 654, "text": "[186]", "ref_id": "BIBREF206"}, {"start": 1073, "end": 1078, "text": "[187]", "ref_id": "BIBREF207"}, {"start": 1304, "end": 1308, "text": "[98]", "ref_id": "BIBREF109"}, {"start": 1468, "end": 1473, "text": "[153]", "ref_id": "BIBREF171"}, {"start": 1531, "end": 1535, "text": "[69]", "ref_id": "BIBREF77"}], "ref_spans": []}, {"section": "Systematic Conceptualization of Slums: Methods and Slum Characteristics", "text": "Regarding the transferability and robustness of OBIA-based methods (across different data and locations), locally developed rule sets have their limitations, compared to the better performance of texture-based or machine-learning algorithms [188] . Furthermore, the latter have the capacity to deal with multilayer inputs of spectral, texture or spatial\u00b4physical indicators (e.g., [46] ). However, machine-learning algorithms (both parametric and non-parametric) mostly employ per-pixel classifiers. Only a few examples extracted area-based layers (e.g., via segments) [188] , which would be more relevant for slum mapping towards informing pro-poor policies. Thus, besides setting up a well-structured conceptual framework in form of a slum ontology [71] and developing a consistent framework for assessing the transferability and robustness of slum extraction methods [23] , the advantages of both methods-OBIA and machine learning-need be combined.", "cite_spans": [{"start": 241, "end": 246, "text": "[188]", "ref_id": "BIBREF208"}, {"start": 381, "end": 385, "text": "[46]", "ref_id": "BIBREF51"}, {"start": 569, "end": 574, "text": "[188]", "ref_id": "BIBREF208"}, {"start": 751, "end": 755, "text": "[71]", "ref_id": "BIBREF79"}, {"start": 870, "end": 874, "text": "[23]", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "Systematic Conceptualization of Slums: Methods and Slum Characteristics", "text": "One major dilemma when assessing the performance of slum-mapping methods is access to reference data. In general, studies use ground truth data (collected in the field) (e.g., [45] ), expert delineations (e.g., [82] ), or available municipal data sets (e.g., [183] ). All data sets have the inherent dilemma of \"what is a slum,\" as slum definitions vary between and within countries but even within a city, and different institutions can have different slum definitions and therefore slum maps (e.g., in Jakarta [189] ). These uncertainties have a negative impact on classification accuracies [158] , and reduces the comparability of the performance of different slum-mapping methods. In Sections 5 and 7 the role of systematically selected image-based proxies (e.g., in form of a slum ontology) for methodological advances in slum mapping has been stressed. Therefore, a more systematic exploration of potential proxies to describe differences within slums and slums versus formal areas is needed. A first starting point is the relation between classical visual image interpretation elements [116] and physical characteristics of slums. This would allow developing systematic rules for OBIA or training machine-learning approaches similar to how human interpreters recognize slums. An overview of proxies is presented in Table 8 . Roof density [4] , vegetation density [120] Line segment heterogeneity [78] Settlement form and distance to river [82] , accessibility and slope [6] , border length and distances to hazardous areas [105] To be explored Building distance and height [4] , building orientation [72] and shadow [71] Patch density pattern [41] Line orientation and distribution [46] , entropy of objects (e.g., roads) [6] , LBP [63] , vegetation pattern [54] , aggregation [41] , Fourier transformation [190] Vegetation patch compactness [6] To be explored Shadow variation Shadow density Connectivity of roads/footpaths", "cite_spans": [{"start": 176, "end": 180, "text": "[45]", "ref_id": "BIBREF50"}, {"start": 211, "end": 215, "text": "[82]", "ref_id": "BIBREF91"}, {"start": 259, "end": 264, "text": "[183]", "ref_id": "BIBREF202"}, {"start": 512, "end": 517, "text": "[189]", "ref_id": "BIBREF209"}, {"start": 593, "end": 598, "text": "[158]", "ref_id": "BIBREF176"}, {"start": 1093, "end": 1098, "text": "[116]", "ref_id": "BIBREF129"}, {"start": 1345, "end": 1348, "text": "[4]", "ref_id": "BIBREF4"}, {"start": 1370, "end": 1375, "text": "[120]", "ref_id": "BIBREF134"}, {"start": 1403, "end": 1407, "text": "[78]", "ref_id": "BIBREF86"}, {"start": 1446, "end": 1450, "text": "[82]", "ref_id": "BIBREF91"}, {"start": 1477, "end": 1480, "text": "[6]", "ref_id": "BIBREF6"}, {"start": 1530, "end": 1535, "text": "[105]", "ref_id": "BIBREF117"}, {"start": 1580, "end": 1583, "text": "[4]", "ref_id": "BIBREF4"}, {"start": 1607, "end": 1611, "text": "[72]", "ref_id": "BIBREF80"}, {"start": 1623, "end": 1627, "text": "[71]", "ref_id": "BIBREF79"}, {"start": 1650, "end": 1654, "text": "[41]", "ref_id": "BIBREF46"}, {"start": 1689, "end": 1693, "text": "[46]", "ref_id": "BIBREF51"}, {"start": 1729, "end": 1732, "text": "[6]", "ref_id": "BIBREF6"}, {"start": 1739, "end": 1743, "text": "[63]", "ref_id": "BIBREF71"}, {"start": 1765, "end": 1769, "text": "[54]", "ref_id": "BIBREF61"}, {"start": 1784, "end": 1788, "text": "[41]", "ref_id": "BIBREF46"}, {"start": 1814, "end": 1819, "text": "[190]", "ref_id": "BIBREF210"}, {"start": 1849, "end": 1852, "text": "[6]", "ref_id": "BIBREF6"}], "ref_spans": [{"start": 1322, "end": 1329, "text": "Table 8", "ref_id": "TABREF11"}]}, {"section": "Pattern of roofing material", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Pattern of vegetation cover", "text": "Secondary Shape/Size/Texture Asymmetry and size of roofs [71] , shape of roofs [149] NA Texton [46] ; GLCM [109] NA Vegetation patch size [6] or percentage [111] To be explored Shadow sizes Size variations (diversity/evenness)", "cite_spans": [{"start": 57, "end": 61, "text": "[71]", "ref_id": "BIBREF79"}, {"start": 79, "end": 84, "text": "[149]", "ref_id": "BIBREF167"}, {"start": 95, "end": 99, "text": "[46]", "ref_id": "BIBREF51"}, {"start": 107, "end": 112, "text": "[109]", "ref_id": "BIBREF121"}, {"start": 138, "end": 141, "text": "[6]", "ref_id": "BIBREF6"}, {"start": 156, "end": 161, "text": "[111]", "ref_id": "BIBREF124"}], "ref_spans": []}, {"section": "Object size and shape variations", "text": "Primary Color/Tone NA NA Roof colors/ material [82] NDVI [72] , road material [96] , soil index [104] , V-I-S model [43, 135] To be explored Pattern of roof material Variation of roof material Land cover variation", "cite_spans": [{"start": 47, "end": 51, "text": "[82]", "ref_id": "BIBREF91"}, {"start": 57, "end": 61, "text": "[72]", "ref_id": "BIBREF80"}, {"start": 78, "end": 82, "text": "[96]", "ref_id": "BIBREF107"}, {"start": 96, "end": 101, "text": "[104]", "ref_id": "BIBREF116"}, {"start": 116, "end": 120, "text": "[43,", "ref_id": "BIBREF48"}, {"start": 121, "end": 125, "text": "135]", "ref_id": "BIBREF151"}], "ref_spans": []}, {"section": "Object size and shape variations", "text": "In the literature, many interpretation elements have been employed-simple (primary) ones based on color, or complex (tertiary and higher) ones, based on pattern or site. However, many potentially interesting combinations have not been systematically explored (Table 8 ), e.g., homogeneity of roofing material at settlement level. Building height has only been used in an explorative study [4] . Other site/association-related proxies have only been used in a few OBIA studies (e.g., [78, 82] ). Promising proxies relate to distance to livelihood opportunities and services, road features (e.g., available from OSM) or general line features and their orientation and pattern. For example, we know that lines in slums are generally much more irregular and heterogeneous in orientation compared to formal settlements [78] . Furthermore, the analysis of heterogeneity (versus homogeneity) and patterns of density, roof materials, shadow, vegetation, and other land cover types could provide promising proxies. Thus a more systematic inclusion of all levels of interpretation elements will be important to improve slum extraction approaches. To avoid high dimensionality of large proxy sets, automatized feature selection will be the road forward [191] , allowing the selection of the most relevant features (indicators) while excluding redundant ones.", "cite_spans": [{"start": 389, "end": 392, "text": "[4]", "ref_id": "BIBREF4"}, {"start": 483, "end": 487, "text": "[78,", "ref_id": "BIBREF86"}, {"start": 488, "end": 491, "text": "82]", "ref_id": "BIBREF91"}, {"start": 814, "end": 818, "text": "[78]", "ref_id": "BIBREF86"}, {"start": 1242, "end": 1247, "text": "[191]", "ref_id": "BIBREF211"}], "ref_spans": [{"start": 259, "end": 267, "text": "(Table 8", "ref_id": "TABREF11"}]}, {"section": "Object size and shape variations", "text": "Presently, we know too little about the global diversity of slums and how to capture this diversity by robust image-based proxies. Thus, a more systematic exploration of potential proxies is required for the development of a global slum inventory. Besides the establishment of a global slum inventory, regular monitoring systems at local level are necessary for the detection of changes but also as an instrument to monitor policy implementation or to protect slum dwellers against illegal evictions.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "In this review, we identified the variety of methodological advances in slum-mapping studies that are relevant for developing a global slum inventory. The reviewed literature shows that the current geographic knowledge on slum characteristics is rather limited. This knowledge needs to be extended to cover the main urban regions in the Global South, especially where urban growth rates and poverty levels are high. Specifically, more comparative studies on proxies are needed across the globe, using a systematic depiction of established slum characteristics (i.e., building geometry, density, pattern, roof material and site characteristics) versus image (interpretation) elements for the development of robust image-based proxies. This also requires a clear conceptual frame to assess their transferability and robustness. The same is required for methodologies. On the basis of the reported accuracies and the ability to process larger data and indicator sets, the most promising methods for a global slum inventory use machine-learning approaches. Several important recommendations for future methodological developments are: (1) include better contextual properties (larger neighborhoods); (2) avoid pixel-based approaches; (3) employ scalable aggregation levels that allow the mapping of smaller slum pockets as well as larger slum areas; (4) include more complex interpretation elements (site and association) and proxies based on ancillary data; and (5) examine the impact of different sensor characteristics on classification accuracies.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "For OBIA, extracting object-level information on roofs or roads, often required for counting dwellings or estimating population, the availability of VHR imagery in the range of 30 cm might open up new avenues, in particular for very high-density slums in Asian cities. For the further development of OBIA approaches that are fit for city or settlement-level information extraction, the important recommendations and considerations are: (1) select suitable sensors for the local context; (2) systematic slum characterization should be translated into robust and transferable rule sets; (3) include readily available ancillary data in the classification process; (4) link image-derived products with socioeconomic data.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "Locally feasible and quick monitoring approaches could rely on both, OBIA or machine learning, but also single indicator approaches (e.g., GLCM or lacunarity) have the potential to capture quickly the location and extent of slum areas in support of pro-poor policy implementations. Therefore, capturing the local slum morphology with the most suitable indicator(s) transferable to imagery of different sensors or different years is crucial. Nevertheless, a global slum inventory must acknowledge the diversity of slums within and between cities. Therefore, besides the mapping of slums, the identification of contextual slum typologies is an important research direction; such information will allow the combination of image-based information with socioeconomic characteristics, which may ultimately lead to a better targeting of pro-poor policy interventions. 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Remote Sens", "link": "109918292"}}, "ref_entries": {"FIGREF0": {"text": ") high roof coverage densities \u201a Lack of public (green) spaces within or in the vicinity of slum areas \u201a Low to moderate density areas \u201a Provision of public (green spaces) within or in vicinity of planned areas Pattern \u201a Organic layout structure (no orderly road arrangement and noncompliance with set-back standards) \u201a Regular layout pattern (showing planned regular roads and compliance with set-back rules) Site Characteristics \u201a Often at hazardous locations (e.g., flood prone, close to industrial areas, steep slope) \u201a Proximity to infrastructure lines and livelihood opportunities \u201a Land has basic suitability for being built-up \u201a (Basic) infrastructure is provided", "type": "figure"}, "FIGREF1": {"text": ") are identified. A temporal analysis of the number of publications shows an increasing trend (Figure 1), having a high linear correlation with the number of satellite launches (r 2 = 0.75). Satellite launches were derived from the following websites (including only the earth observation satellites with a spatial resolution of 5 m and less): \u201a ITC's database of Satellites and Sensors: http://www.itc.nl/research/products/sensordb/ searchsat.aspx \u201a Gunter's Space Page: http://space.skyrocket.de/directories/chronology.htm \u201a Satellite on the Net: http://www.satelliteonthenet.co.uk/index.php/launch-schedule In the mid-2000s, when more VHR satellites became available the number of related publications increased. The same occurred for the period after 2010.", "type": "figure"}, "FIGREF2": {"text": "Figure 1. Number of publications on slums and remote sensing methods by year and successfully launched VHR satellites (r 2 is 0.75).", "type": "figure"}, "FIGREF3": {"text": "Figure 2. Analytical frame of the review: methodological challenge for a global slum inventory. The overall purpose of this review is the identification of the variety of methodological advances in slum mapping that are relevant for a global slum inventory. Four analytical sub-questions guide this review. First, what are the main contextual factors and related slum terminologies of published studies on slum identification via RS (Q1)? Second, what are the varieties of physical slum characteristics extracted in VHR imagery (Q2)? Third, what are the input data and requirements of", "type": "figure"}, "FIGREF4": {"text": "Figure 1. Number of publications on slums and remote sensing methods by year and successfully launched VHR satellites (r 2 is 0.75).", "type": "figure"}, "FIGREF5": {"text": "Figure 1. Number of publications on slums and remote sensing methods by year and successfully launched VHR satellites (r 2 is 0.75).", "type": "figure"}, "FIGREF6": {"text": "Figure 2. Analytical frame of the review: methodological challenge for a global slum inventory. The overall purpose of this review is the identification of the variety of methodological advances in slum mapping that are relevant for a global slum inventory. Four analytical sub-questions guide this review. First, what are the main contextual factors and related slum terminologies of published studies on slum identification via RS (Q1)? Second, what are the varieties of physical slum characteristics extracted in VHR imagery (Q2)? Third, what are the input data and requirements of", "type": "figure"}, "FIGREF7": {"text": "Figure 2. Analytical frame of the review: methodological challenge for a global slum inventory.", "type": "figure"}, "FIGREF8": {"text": "Figure 3. Case study cities in publications (N = 87) on slum mapping via RS methods on top of a population density map (base map: population density, Source: ESRI). Figure 3. Case study cities in publications (N = 87) on slum mapping via RS methods on top of a population density map (base map: population density, Source: ESRI).", "type": "figure"}, "FIGREF9": {"text": "Figure 3. Case study cities in publications (N = 87) on slum mapping via RS methods on top of a population density map (base map: population density, Source: ESRI). Figure 3. Case study cities in publications (N = 87) on slum mapping via RS methods on top of a population density map (base map: population density, Source: ESRI).", "type": "figure"}, "FIGREF10": {"text": "Figure 4. Slum ontology-indicators associated with the three spatial levels [5].", "type": "figure"}, "FIGREF11": {"text": "Figure 4. Slum ontology-indicators associated with the three spatial levels [5].", "type": "figure"}, "FIGREF14": {"text": "Figure 5. Overview spatial and temporal characteristics of very high and high-resolution satellites; in brackets: percentage of image data sources of reviewed publications (percentages are displayed for the MS bands (when available): this combines the percentage of MS and PAN bands) (N = 122, some publications use multiple image data, in addition to aerial sensors: 8.2%, GE: 6.6%, and moderate resolution systems: Landsat: 8.2%, Envisat ASAR: 4.9%, Terra ASTER: 2.5%, PALSAR: 1.6%, MODIS: 0.8%).", "type": "figure"}, "FIGREF15": {"text": "Figure 5. Overview spatial and temporal characteristics of very high and high-resolution satellites; in brackets: percentage of image data sources of reviewed publications (percentages are displayed for the MS bands (when available): this combines the percentage of MS and PAN bands) (N = 122, some publications use multiple image data, in addition to aerial sensors: 8.2%, GE: 6.6%, and moderate resolution systems: Landsat: 8.2%, Envisat ASAR: 4.9%, Terra ASTER: 2.5%, PALSAR: 1.6%, MODIS: 0.8%).", "type": "figure"}, "FIGREF16": {"text": "Figure 6. Complexity of image interpretation elements (adapted from [41,176,177]).", "type": "figure"}, "FIGREF17": {"text": "Figure 6. Complexity of image interpretation elements (adapted from [41,176,177]).", "type": "figure"}, "FIGREF18": {"text": "Figure 7. Reported accuracies for different image analysis methods on slum mapping. Figure 7. Reported accuracies for different image analysis methods on slum mapping.", "type": "figure"}, "FIGREF19": {"text": "Figure 7. Reported accuracies for different image analysis methods on slum mapping. Figure 7. Reported accuracies for different image analysis methods on slum mapping.", "type": "figure"}, "TABREF1": {"text": "Application domains of remote sensing-based information on the morphology and temporal dynamics of slums.", "type": "table"}, "TABREF3": {"text": "Application domains of remote sensing-based information on the morphology and temporal dynamics of slums.", "type": "table"}, "TABREF4": {"text": "Physical characteristics of slums in selected journal papers.", "type": "table"}, "TABREF6": {"text": "Slum typologies and their categories.", "type": "table"}, "TABREF7": {"text": "Slum typologies and their categories.", "type": "table"}, "TABREF8": {"text": "Spatial extent (scale) of slum-mapping case studies found in literature.", "type": "table"}, "TABREF9": {"text": "Frequency of methods versus main focus for slum mapping using VHR imagery.", "type": "table"}, "TABREF11": {"text": "Overview of successfully documented image-based proxies (indicators).", "type": "table"}}}
{"paper_id": "8335529", "_pdf_hash": "89a4437bc2dc3cde105572d957f228dcf25871dc", "abstract": [], "body_text": [{"section": "Background", "text": "Governments and local communities across the world have recognized that key to building prosperity and stimulate regional growth is fostering entrepreneurship among their people especially youth. Youth entrepreneurship has become a topic of interest for research scholars and also a subject of major concern for the Governments. Promoting youth entrepreneurship will not only help in reducing unemployment but more importantly make young people understand that they have alternatives to create their own destiny by starting their own companies and they need not keep waiting to get a job.", "cite_spans": [], "ref_spans": []}, {"section": "Background", "text": "Uttarakhand emerged as the 27th state of the Republic of India on 9th November 2000. Uttarakhand is a place with great diversity where snow-clad mountains, green hills, fertile valleys, flowing rivers several natural lakes add to its beauty. The place is an abode to several highly venerated pilgrimage places. Uttarakhand has lately been facing the challenges of increased unemployment and immigration which has prompted the state government to take appropriate measures to build youth entrepreneurship in the state. A host of incentives have been proposed by the state government to build entrepreneurship in the state. The Special Integrated Industrial Promotion Policy 2008 for hilly & remote areas of Uttarakhand offered a series of sops for promotion of industries in Uttarakhand. Some of the major provisions under the policy include providing 25% subsidy on investment in plant and machinery; in case of mega projects 50% cost of infrastructure is met by state. Government reimburses 75% of the expenses incurred on Intellectual property rights, ISO Certifications, ISI Certifications, Quality marking, FPO Licenses and Trademarks to a maximum of Rs. 1 Lac. All new industrial units engaged in manufacturing and production of goods including the industrial enterprises engaged in the activities in service sector are entitled for 100 percent rebate on electric bills for a period of ten years. Although the existing entrepreneurs have expanded their businesses because of these sanctions, a lot of big corporate houses were also lured into the state by these attractive economic policies but the incentives does not seem to affect the entrepreneurial inclination of the youth of Uttarakhand. In fact, nothing significant is seen in terms of entrepreneurship development from within the state. Some of the major perceived barriers to youth entrepreneurship identified in Uttarakhand are lack of capital, no prior experience and lack of guidance (Sharma & Madan, 2013) . The growing educated, idle, jobless and underemployed youth is a major societal problem which if not tackled and controlled timely could turn into a bigger trouble for the state government. This particular study tends to investigate the effect of individual factors like past experience, education and intelligence of the youth in developing entrepreneurial inclination. Individual factors play a significant role in entrepreneurship development and a lot of work has been done globally on these factors but we have tried to reassess it from the context of Uttarakhand.", "cite_spans": [{"start": 1952, "end": 1974, "text": "(Sharma & Madan, 2013)", "ref_id": "BIBREF62"}], "ref_spans": []}, {"section": "Background", "text": "Career choice is a cognitive process driven by beliefs, attitudes and experiences and prior research confirms that entrepreneurial careers fit a similar pattern (Davidsson, 1991; Katz, 1992; Shaver & Scott, 1992) . Simon (1979) posited that the formulation of goals of an individual would depend on existing knowledge and experience of the decision maker. Simon further supports the view that past experience is playing a role in career goal setting and decision making. A rise in experience implies \"an increased awareness of what is likely to happen in the future, as well as increased contemplation of the behavior and its consequence\" (Pomery et al. 2009 ). Individuals are less reactive and more thoughtful when they gain experience (Pomery et al. 2009 ). Students with previous working experiences are also seen to be interested in entrepreneurship. The study by Ghazali, et al. (1995) and Othman et al. (2006) showed that university students with working experiences have increased probability of being entrepreneurs. This supported the view that having previous working experience is an advantage for students as they acquire better knowledge about business creation, develop good networking which helps them in acquiring needed sources to confidently launch a venture. Interestingly, these students were studying in the non-business areas, supporting the findings of Kristiansen and Indarti (2004) who indicated that there is no significant impact of educational background of students on their entrepreneurial inclination. Prior experience as an entrepreneur has also been linked with the increased propensity of adults to start a new venture (Boyd & Vozikis, 1994; Cooper et al. 2004) where as a similar study conducted in Srilanka found that contribution of self employment experience for developing entrepreneurial intention among the business students is relatively low (Nishantha, 2009 ). This shows that the factor is probably dependant upon the region. Entrepreneurship education has been recognized as one of the vital determinants that could influence students' career decisions (Kolvereid & Moen 1997; Peterman & Kennedy, 2003) .Where as according to Chinoso (2010) technical and vocational education are the only alternative forms of education and training that can guarantee entrepreneurship development and job creation for youths. Another study by Wadhwa et al. (2010) on immigrant tech founders and U.S. born engineering and technology company founders found that although they were well-educated there was a significant difference in the types of degrees these entrepreneurs obtained. We have tried to understand the global perspective on these individual factors and broaden the research outcomes in these areas by evaluating the same in the context of Uttarakhand.", "cite_spans": [{"start": 161, "end": 178, "text": "(Davidsson, 1991;", "ref_id": "BIBREF16"}, {"start": 179, "end": 190, "text": "Katz, 1992;", "ref_id": "BIBREF33"}, {"start": 191, "end": 212, "text": "Shaver & Scott, 1992)", "ref_id": "BIBREF63"}, {"start": 215, "end": 227, "text": "Simon (1979)", "ref_id": "BIBREF66"}, {"start": 639, "end": 658, "text": "(Pomery et al. 2009", "ref_id": "BIBREF51"}, {"start": 738, "end": 757, "text": "(Pomery et al. 2009", "ref_id": "BIBREF51"}, {"start": 869, "end": 891, "text": "Ghazali, et al. (1995)", "ref_id": "BIBREF28"}, {"start": 896, "end": 916, "text": "Othman et al. (2006)", "ref_id": "BIBREF49"}, {"start": 1376, "end": 1406, "text": "Kristiansen and Indarti (2004)", "ref_id": "BIBREF37"}, {"start": 1653, "end": 1675, "text": "(Boyd & Vozikis, 1994;", "ref_id": "BIBREF7"}, {"start": 1676, "end": 1695, "text": "Cooper et al. 2004)", "ref_id": "BIBREF15"}, {"start": 2098, "end": 2121, "text": "(Kolvereid & Moen 1997;", "ref_id": "BIBREF36"}, {"start": 2122, "end": 2147, "text": "Peterman & Kennedy, 2003)", "ref_id": "BIBREF50"}, {"start": 2372, "end": 2392, "text": "Wadhwa et al. (2010)", "ref_id": "BIBREF77"}], "ref_spans": []}, {"section": "Purpose of the study", "text": "In spite of the increasing recognition of entrepreneurship as a source of job creation, regional development, and economic dynamism in a rapidly globalizing world, there has been no systematic attempt to look at it from the youth perspective. Youth entrepreneurship is picking up fast not only in developed countries but also in developing countries like India. Poor rate of entrepreneurship in the Uttarakhand state may be attributed to several different factors. With the state government having provided a host of incentives for industrial development, the rate of youth entrepreneurship remains to be low. Educated, skilled & unskilled youth need to turn into entrepreneurs. By January 2013, a total of 7,03000 people were registered with different employment exchanges of Uttarakhand, desperate to take up any job. The unregistered unemployed youth of Uttarakhand is not included in this number. This desperation of unemployed youth was evident at a recent drive for the recruitment of home-guards in the state, when scores of post-graduates turned up for interviews. The basic requirement was only eighth standard. Unemployment is giving fuel to immigration. The 2011 Census reveals migration from all 13 hill districts of Uttarakhand state. The state government is trying its best to foster entrepreneurship amongst the youth. Presently there is a general lack of accurate and systematic data on youth, especially as it relates to youth entrepreneurship. This study is an attempt to understand various individual factors that affect the preferred career choice decision of young students especially on becoming an entrepreneur.", "cite_spans": [], "ref_spans": []}, {"section": "Review of literature", "text": "The literature review has clearly emphasized the importance of studying 'intentions' in entrepreneurship. According to Krueger et al. (2000) , entrepreneurial activity can be predicted more accurately by studying 'intention' rather than 'personality traits' , 'demographic characteristics' or 'situational factors'. The theory of planned behavior contends that intentions are a function of three sets of factors: attitudes, subjective norms, and perceived behavioral control. Given that the decision to found a firm can be regarded as reasoned action or planned behavior, the relationship between intentions and actual behavior should be fairly strong (Ajzen, 1991; Sheppard et al. 1988) . Several authors (Reynolds, 1991; Stanworth et al. 1989) have emphasized that personal background characteristics have a more reliable influence on the decision to found one's own firm than psychological traits. The literature review for this study has been divided into four parts. The first part comprises of the studies related to the effect of past selfemployment experience of an individual on entrepreneurship development. The second part deals with the literature review on effect of past experience in job on building entrepreneurship. The third part comprises of the review of work on effect of intelligence of an individual on entrepreneurship development and finally we have tried to explore those works in which the effect of an educational background or the courses studied have any impact on entrepreneurship development.", "cite_spans": [{"start": 119, "end": 140, "text": "Krueger et al. (2000)", "ref_id": "BIBREF40"}, {"start": 652, "end": 665, "text": "(Ajzen, 1991;", "ref_id": "BIBREF0"}, {"start": 666, "end": 687, "text": "Sheppard et al. 1988)", "ref_id": "BIBREF64"}, {"start": 706, "end": 722, "text": "(Reynolds, 1991;", "ref_id": "BIBREF53"}, {"start": 723, "end": 745, "text": "Stanworth et al. 1989)", "ref_id": "BIBREF71"}], "ref_spans": []}, {"section": "Review of literature", "text": "Research has shown that an individual's past business experience influences their decision making and business performance (Dyke et al. 1992) . Several studies (Kets de Vries, 1977; Hisrich & Brush 1984; Scott & Twomey, 1988; Scherer et al. 1989; Taylor & Thorpe, 2004) exploring the reasons why individuals become entrepreneurs have identified previous exposure to business, role models and networks as important. Individuals who have family members or close friends who are entrepreneurs tend to be more likely to start their own business than those individuals who have not experienced the same level of exposure to entrepreneurship (Collins & Moore, 1970; Cooper & Dunkelberg, 1984) . Shapero & Sokol (1982) and Praag & Ophem (1995) suggested that willingness and presence of an opportunity are both necessary conditions for selfemployment to occur and both were found to be enhanced through experience gained in entrepreneurship. Krueger & Brazeal (1994) posited that an individual's situational perceptions based on past and current experiences can influence their entrepreneurial intention. Bandura (1986) has linked previous entrepreneurial experience to self efficacy and derived that previous entrepreneurial experience may lead to increased levels of entrepreneurial self-efficacy given the opportunities provided for role-modeling and learning through doing. The entrepreneurial inclination is an attitudinal measure which is related to both Shapero & Sokol (1982) and Ajzen's (1991) theories and is proposed to be influenced by students' previous entrepreneurial experience. Several researchers (Shapero & Sokol, 1982; Krueger & Carsrud, 1993; Fayolle & Degeorge, 2006; McMullen & Shepherd, 2006) have studied entrepreneurship education and previous entrepreneurial experience together and found both of them as important motivators and contributors to the formation of entrepreneurial intentions provided there is a feasibility of entrepreneurship & desirability of individual. Despite of all the positive studies noted above the results of Tkachev & Kolvereid (1999) indicated that demographic characteristics as family background and past self-employment experience affected entrepreneurial intentions however only through attitudes, subjective norms and perceived behavioral control. McStay (2008) supported that students in the entrepreneurship subject with 'low' previous entrepreneurial experience had a greater intention to be self employed than those students with 'high' previous entrepreneurial experience. Another study conducted in Srilanka found that contribution of self employment experience for developing entrepreneurial intention among the business students is relatively low (Nishantha, 2009 ). This clearly highlights that regional difference is an important factor which needs to be considered in determining the effect of self employment experience on youth entrepreneurship. Accordingly we have tried to understand the relationship between the two in context of Uttarakhand and formulated our first hypothesis.", "cite_spans": [{"start": 123, "end": 141, "text": "(Dyke et al. 1992)", "ref_id": "BIBREF22"}, {"start": 160, "end": 181, "text": "(Kets de Vries, 1977;", "ref_id": "BIBREF34"}, {"start": 182, "end": 203, "text": "Hisrich & Brush 1984;", "ref_id": "BIBREF32"}, {"start": 204, "end": 225, "text": "Scott & Twomey, 1988;", "ref_id": "BIBREF58"}, {"start": 226, "end": 246, "text": "Scherer et al. 1989;", "ref_id": "BIBREF57"}, {"start": 247, "end": 269, "text": "Taylor & Thorpe, 2004)", "ref_id": "BIBREF73"}, {"start": 636, "end": 659, "text": "(Collins & Moore, 1970;", "ref_id": "BIBREF12"}, {"start": 660, "end": 686, "text": "Cooper & Dunkelberg, 1984)", "ref_id": "BIBREF13"}, {"start": 689, "end": 711, "text": "Shapero & Sokol (1982)", "ref_id": "BIBREF61"}, {"start": 716, "end": 736, "text": "Praag & Ophem (1995)", "ref_id": "BIBREF52"}, {"start": 935, "end": 959, "text": "Krueger & Brazeal (1994)", "ref_id": "BIBREF38"}, {"start": 1098, "end": 1112, "text": "Bandura (1986)", "ref_id": "BIBREF3"}, {"start": 1454, "end": 1476, "text": "Shapero & Sokol (1982)", "ref_id": "BIBREF61"}, {"start": 1481, "end": 1495, "text": "Ajzen's (1991)", "ref_id": "BIBREF0"}, {"start": 1608, "end": 1631, "text": "(Shapero & Sokol, 1982;", "ref_id": "BIBREF61"}, {"start": 1632, "end": 1656, "text": "Krueger & Carsrud, 1993;", "ref_id": "BIBREF39"}, {"start": 1657, "end": 1682, "text": "Fayolle & Degeorge, 2006;", "ref_id": "BIBREF23"}, {"start": 1683, "end": 1709, "text": "McMullen & Shepherd, 2006)", "ref_id": "BIBREF44"}, {"start": 2055, "end": 2081, "text": "Tkachev & Kolvereid (1999)", "ref_id": "BIBREF74"}, {"start": 2301, "end": 2314, "text": "McStay (2008)", "ref_id": "BIBREF45"}], "ref_spans": []}, {"section": "Review of literature", "text": "Hypothesis H1a: Previous entrepreneurial experience has no influence on student's entrepreneurial inclination.", "cite_spans": [], "ref_spans": []}, {"section": "Review of literature", "text": "Authors (Matthews & Moser, 1995; Scott & Twomey, 1988) have suggested that work experience is influential in one's interest in an entrepreneurial career and in building entrepreneurial competencies (Bird, 1995) . Different authors have put forward their explanations as to how it is helpful. Krueger & Brazeal (1994) indicate that prior work experience could potentially improve one's skills and abilities, particularly in recognizing business opportunities. Maxwell & Westerfield (2002) argue that an entrepreneur's innovativeness, which is an aspect of his/ her competencies, depends largely on the level of his/her formal education as well as prior managerial experience. Box et al. (1994) and Chandler (1996) opined that industry experience may be most valuable in identifying the tangible and intangible needs of the early stage venture. Hart et al. (1995) posit that industry knowledge and related industry networks are important assets in specifying the new venture's need for resources, finding those resources, selecting partners and structuring flexible contracts with resource providers. The study by Samuelsson (2001) affirmed that experience in a similar industry was positively related to growth in innovative ventures. Lee & Tsang (2001) expressed that industrial and managerial experience is the dominating factor affecting venture growth. Venture capitalists note that industry experience that is tightly related with the products, processes, or business models proposed for financing as the most important characteristic of the team (Smith & Smith, 2000) . Various authors (Shrader & Siegel, 2007; Oakey, 2003) have also emphasized upon the importance of technical industry experience in building entrepreneurship. One of the recent studies by Wadhwa et al. (2009) also emphasized upon the industry experience to be relevant to entrepreneurs. The researchers surveyed 549 company founders in a variety of industries, including aerospace, defense, computers, electronics, health care, and services. The majority of respondents (75.4%) had worked as employees at other companies for more than six years before launching their own companies. Nearly half (47.9%) launched their first companies with more than ten years of work experience. Significant percentages of respondents started their first companies after working eleven to fifteen years (23.3%), sixteen to twenty years (14.3%), or greater than twenty years (10.3%) for someone else.", "cite_spans": [{"start": 33, "end": 54, "text": "Scott & Twomey, 1988)", "ref_id": "BIBREF58"}, {"start": 198, "end": 210, "text": "(Bird, 1995)", "ref_id": "BIBREF5"}, {"start": 292, "end": 316, "text": "Krueger & Brazeal (1994)", "ref_id": "BIBREF38"}, {"start": 459, "end": 487, "text": "Maxwell & Westerfield (2002)", "ref_id": "BIBREF43"}, {"start": 675, "end": 692, "text": "Box et al. (1994)", "ref_id": "BIBREF6"}, {"start": 697, "end": 712, "text": "Chandler (1996)", "ref_id": "BIBREF10"}, {"start": 843, "end": 861, "text": "Hart et al. (1995)", "ref_id": "BIBREF30"}, {"start": 1112, "end": 1129, "text": "Samuelsson (2001)", "ref_id": "BIBREF55"}, {"start": 1234, "end": 1252, "text": "Lee & Tsang (2001)", "ref_id": "BIBREF41"}, {"start": 1551, "end": 1572, "text": "(Smith & Smith, 2000)", "ref_id": "BIBREF69"}, {"start": 1591, "end": 1615, "text": "(Shrader & Siegel, 2007;", "ref_id": "BIBREF65"}, {"start": 1616, "end": 1628, "text": "Oakey, 2003)", "ref_id": "BIBREF48"}, {"start": 1762, "end": 1782, "text": "Wadhwa et al. (2009)", "ref_id": "BIBREF76"}], "ref_spans": []}, {"section": "Review of literature", "text": "Hypothesis H1b: Previous work experience of a student in job has no influence on his entrepreneurial inclination.", "cite_spans": [], "ref_spans": []}, {"section": "Review of literature", "text": "Wechsler (1944) defined intelligence as the aggregate or global capacity of the individual to act purposefully, to think rationally, and to deal effectively with his environment. Gardner (2006 Gardner ( , 2007 argues that intelligence refers to both the personal decisions and potentials of individuals. This potential comes out or develops according to cultural environment, values and opportunities. Similarly Demirel & Tikici (2010) posited that when education is based on ability and dominant multiple intelligence area rather than trying to fit individuals into particular patterns, left brain and right brain characteristics will be balanced and, accordingly, a society with a strong entrepreneurial spirit will be created. Gilad et al. (1989) surveyed 86 small business owners and 21 managers of small business in New Jersey & found that entrepreneurs spent more time thinking about business opportunities and development in comparison to their managers thereby supporting the view that entrepreneurs have better cognitive capacity. Authors have put forward different types of intelligence and their effect on entrepreneurs and entrepreneurship. According to Hartog et al. (2010) the effect of technical and social intelligence is larger for entrepreneurs than for employees whereas the effects of mathematical and verbal ability are stronger for employees. As per Shane & Venkataraman (2000) Creative intelligence, in particular, may be a predictor of success in new ventures that compete on the basis of technology. Baum et al. (2001) reported a positive relationship between practical intelligence and entrepreneurial processes and entrepreneurial characteristics. Sternberg (2004) posits that successful entrepreneurship requires a blend of analytical, creative, and practical aspects of intelligence, which, in combination, constitute successful intelligence. According to him successful intelligence, not just a subset of its components (analytical, creative, and practical abilities), is needed for entrepreneurial success. . However another view by Gartner (1988) holds that general intelligence is a person-centric variable that does not go far in explaining differences in entrepreneurs' behavior. To the best of our knowledge there are not many studies on effect of academic intelligence on entrepreneurial intentions. A few studies (De wit & Van Winden, 1989; Dewit, 1993) have been done on finding a relationship between the IQ Scores and self-employment propensity. The findings showed that IQ Scores measured at age 12 had a positive and significant effect on self employment propensity later in life. Another recent survey on this aspect is done by Wadhwa et al. (2009) . The researchers surveyed 549 company founders in a variety of industries and studied the academic performance of the company founders. The survey revealed that 75 percent of the founders ranked their academic performance among the top 30 percent of the high school class, with a majority (52.4 percent) ranking their performance among the top 10 percent. 67 percent founders ranked their academic performance among the top 30 percent of their undergraduate class, but a smaller percentage (37.5 percent) ranked their performance among the top 10 percent. The above study indicates that academic intelligence could be a major factor influencing entrepreneurship among the students. The field calls for more attention from the researchers and better understanding in this area. We investigated the relationship between academic intelligence and entrepreneurial inclination.", "cite_spans": [{"start": 179, "end": 192, "text": "Gardner (2006", "ref_id": "BIBREF25"}, {"start": 193, "end": 209, "text": "Gardner ( , 2007", "ref_id": "BIBREF26"}, {"start": 412, "end": 435, "text": "Demirel & Tikici (2010)", "ref_id": "BIBREF19"}, {"start": 730, "end": 749, "text": "Gilad et al. (1989)", "ref_id": "BIBREF29"}, {"start": 1166, "end": 1186, "text": "Hartog et al. (2010)", "ref_id": "BIBREF31"}, {"start": 1372, "end": 1399, "text": "Shane & Venkataraman (2000)", "ref_id": "BIBREF60"}, {"start": 1525, "end": 1543, "text": "Baum et al. (2001)", "ref_id": "BIBREF4"}, {"start": 1675, "end": 1691, "text": "Sternberg (2004)", "ref_id": "BIBREF72"}, {"start": 2064, "end": 2078, "text": "Gartner (1988)", "ref_id": "BIBREF27"}, {"start": 2351, "end": 2378, "text": "(De wit & Van Winden, 1989;", "ref_id": "BIBREF18"}, {"start": 2672, "end": 2692, "text": "Wadhwa et al. (2009)", "ref_id": "BIBREF76"}], "ref_spans": []}, {"section": "Review of literature", "text": "Hypothesis H2: Academic intelligence of a student has no influence on his entrepreneurial intentions.", "cite_spans": [], "ref_spans": []}, {"section": "Review of literature", "text": "A review of the literature showed that education in general has a positive effect on business success (Douglass, 1976; Robinson & Sexton, 1994; Vesper, 1990) . Peterman & Kennedy (2003) have emphasized that education programs can significantly change the entrepreneurial intentions of participants. Scott et al. (1998) argued that education plays two fundamental roles in the process of economic wealth. First, education increases the supply of highly educated entrepreneurs in the economy especially in industries that require high levels of education. Second, education improves the effectiveness of potential entrepreneurs through enhancing their interpersonal, management and business skills. Brockhaus & Horwitz (1986) and Sletten & Hulaas (1998) explained that since current and future entrepreneurs are younger and less experienced, educational backgrounds are vital to the development of new businesses. Gartner (1988) posited that in encouraging growth of new businesses, education plays a fundamental role. Therefore, it is necessary to understand the behaviors and educations of entrepreneurs who create new businesses. Whereas there are several authors who have supported that business founders/owners were educated than the general public (Douglass, 1976; Cooper & Dunkelberg, 1987 , Robinson & Sexton, 1994 Foley & Griffith, 1998; Scott, et al. 1998) , there are reports which have confronted the view. Ashmore's (1986) reported that the NFIB surveyed 5000 entrepreneurs and found that 40% had only a high school diploma or less and of that 38% had never taken a business course. A report by the Small Business Administration (2001) showed individuals with educational level of high school or less established nearly half of the new businesses and over 65% of the self-employed did not graduate from college. Vesper (1990) and Robinson & Sexton (1994) concluded that entrepreneurs with a good general education tend overall to be noticeably more successful than those with less favorable education and even more successful when general education is combined with experience. At the same time, they admitted their inability to study the effect of specific types of education as opposed to general levels of education. This sparks the need to understand the 'favorable educational background' for a budding entrepreneurs or what type of education or majors, if any, are more helpful for a person in building entrepreneurial intentions. A lot of authors (Kolvereid & Moen, 1997; Noel, 1998; Dyer 1994; Watson et al. 1998; Souitaris et al. 2007 ) have emphasized upon entrepreneurship education as being critical for raising entrepreneurial intentions and entrepreneurship development. But on the contrary Brockhaus (1982) in his study has cited the study of Robidox & Garnier held in 1973 who studied the level of education of entrepreneurs in high-tech firms. The study showed that the more educated the entrepreneurs, the higher the rate of growth of the firm; however, they found no differences between the performance of those with a management background and those with engineering training. This highlights the need to understand the effect of other education streams on building entrepreneurial inclination and entrepreneurial success. It also needs further investigation on whether any correlation really exists between the two. One of the studies by Kristiansen & Indarti (2004) affirmed that there is no statistically significant impact of age, gender & educational background of students on their entrepreneurial inclination. Despite the literature acknowledgment of the benefits of education in general to small business (Douglass, 1976; Kiesner, 1984; Robinson & Sexton, 1994) , a business degree may not necessarily be essential to successfully start and operate a business. College education, however, may help business owners and managers to understand and use such concepts as business plan, marketing strategy, locating and financing a business, dealing with legal issues, and managing human resources (Ashmore, 1986; Noll, 1993) . Douglass (1976) in his study conducted on 153 owner-operators of firms could not found any significant correlation between educational background and growth rate. Wadhwa et al. (2010) surveyed 652 U.S. born chief executive officers and heads of product development in 502 engineering and technology companies established from 1995 through 2005. These companies had more than $1 million in sales, twenty or more employees, and company branches with fifty or more employees. The results showed that nearly half of all these people had degrees in science, technology, engineering and mathematics (STEM) related disciplines and only one third held degrees in business, accounting, and finance. Finally we would also like to refer to Brockhaus & Horwitz's (1986) studies which showed that different characteristics of business founders including educational background are associated with what kind of business to start. Thus the study suggested that educational backgrounds associated with a service business might be different from those associated with a manufacturing business.", "cite_spans": [{"start": 102, "end": 118, "text": "(Douglass, 1976;", "ref_id": "BIBREF20"}, {"start": 119, "end": 143, "text": "Robinson & Sexton, 1994;", "ref_id": "BIBREF54"}, {"start": 144, "end": 157, "text": "Vesper, 1990)", "ref_id": "BIBREF75"}, {"start": 160, "end": 185, "text": "Peterman & Kennedy (2003)", "ref_id": "BIBREF50"}, {"start": 299, "end": 318, "text": "Scott et al. (1998)", "ref_id": "BIBREF59"}, {"start": 697, "end": 723, "text": "Brockhaus & Horwitz (1986)", "ref_id": "BIBREF9"}, {"start": 728, "end": 751, "text": "Sletten & Hulaas (1998)", "ref_id": "BIBREF67"}, {"start": 912, "end": 926, "text": "Gartner (1988)", "ref_id": "BIBREF27"}, {"start": 1252, "end": 1268, "text": "(Douglass, 1976;", "ref_id": "BIBREF20"}, {"start": 1269, "end": 1294, "text": "Cooper & Dunkelberg, 1987", "ref_id": "BIBREF14"}, {"start": 1295, "end": 1320, "text": ", Robinson & Sexton, 1994", "ref_id": "BIBREF54"}, {"start": 1321, "end": 1344, "text": "Foley & Griffith, 1998;", "ref_id": "BIBREF24"}, {"start": 1345, "end": 1364, "text": "Scott, et al. 1998)", "ref_id": "BIBREF59"}, {"start": 1417, "end": 1433, "text": "Ashmore's (1986)", "ref_id": "BIBREF1"}, {"start": 1823, "end": 1836, "text": "Vesper (1990)", "ref_id": "BIBREF75"}, {"start": 1841, "end": 1865, "text": "Robinson & Sexton (1994)", "ref_id": "BIBREF54"}, {"start": 2465, "end": 2489, "text": "(Kolvereid & Moen, 1997;", "ref_id": "BIBREF36"}, {"start": 2490, "end": 2501, "text": "Noel, 1998;", "ref_id": "BIBREF46"}, {"start": 2502, "end": 2512, "text": "Dyer 1994;", "ref_id": "BIBREF21"}, {"start": 2513, "end": 2532, "text": "Watson et al. 1998;", "ref_id": "BIBREF78"}, {"start": 2533, "end": 2554, "text": "Souitaris et al. 2007", "ref_id": "BIBREF70"}, {"start": 2716, "end": 2732, "text": "Brockhaus (1982)", "ref_id": "BIBREF8"}, {"start": 3370, "end": 3398, "text": "Kristiansen & Indarti (2004)", "ref_id": "BIBREF37"}, {"start": 3644, "end": 3660, "text": "(Douglass, 1976;", "ref_id": "BIBREF20"}, {"start": 3661, "end": 3675, "text": "Kiesner, 1984;", "ref_id": "BIBREF35"}, {"start": 3676, "end": 3700, "text": "Robinson & Sexton, 1994)", "ref_id": "BIBREF54"}, {"start": 4031, "end": 4046, "text": "(Ashmore, 1986;", "ref_id": "BIBREF1"}, {"start": 4047, "end": 4058, "text": "Noll, 1993)", "ref_id": "BIBREF47"}, {"start": 4061, "end": 4076, "text": "Douglass (1976)", "ref_id": "BIBREF20"}, {"start": 4224, "end": 4244, "text": "Wadhwa et al. (2010)", "ref_id": "BIBREF77"}, {"start": 4790, "end": 4818, "text": "Brockhaus & Horwitz's (1986)", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Review of literature", "text": "Hypothesis H3: Students studying different courses have different entrepreneurial inclinations.", "cite_spans": [], "ref_spans": []}, {"section": "Data analysis", "text": "Each of the hypotheses generated has been individually tested using various analytical tools through SPSS 16 software.", "cite_spans": [], "ref_spans": []}, {"section": "Research methodology", "text": "We have used quantitative research method to conduct this study. Self administered questionnaire was developed & used as the main data-gathering instrument. The target respondents were the final year students of Uttarakhand studying in B. Tech., MBA, PGDM, BHMCT, B.Pharm. and MCA courses, The sampling method used in this research is proportionate stratified sampling. The whole universe of the target respondents was nearly 20,300. To avoid skewness, the universe was broadly divided into two categories. The first category of students were those who had studied Entrepreneurship as a subject in their professional course and the second category of students did not study Entrepreneurship subject. The percentage of category 1 was approximately 15% and the percentage of category 2 was approximately 85% accordingly for a size of population which falls in the range of 20,000, the sample size for a 95% confidence level when parameter in population is assumed to be over 85% or under 15%, and with a reliability of \u00b13% the sample size suggested is 530 (Zikmund, 2003) . Accordingly the sample size taken for this research is 530. Based upon their prevalence in the universe, total number of seats in Uttarakhand state of each of the following courses -MBA, MCA, B.Tech., B. Pharm and BHM&CT were determined. These seats were then converted into the equivalent ratio of the sample size and finally separate samples were drawn from each course in order to properly represent the population.", "cite_spans": [{"start": 1054, "end": 1069, "text": "(Zikmund, 2003)", "ref_id": "BIBREF80"}], "ref_spans": []}, {"section": "Testing hypothesis H1a", "text": "Previous entrepreneurial experience has no influence on student's entrepreneurial inclination.", "cite_spans": [], "ref_spans": []}, {"section": "Testing hypothesis H1a", "text": "To test the above hypothesis, researcher has used Chi-square test. A direct question regarding whether they have any prior experience of doing business was asked from the students (Table 1) .", "cite_spans": [], "ref_spans": [{"start": 180, "end": 189, "text": "(Table 1)", "ref_id": "TABREF0"}]}, {"section": "Testing hypothesis H1a", "text": "Cross tabulation displays that out of 530 respondents 82 respondents had prior experience of doing business while rest 448 respondents had no prior experience of doing business (Table 2) . Since the calculated value of Chi-square is greater than the tabulated value. It is evident that variables 'Prior experience in business' and 'Intention after completion of Degree' are dependent. Hence we reject the hypothesis at 5% level of significance. This justifies the fact that there is an influence of student's prior experience in business on his entrepreneurial intentions. The crosstabs show that out of 82 students who had prior business experience only 11 were still interested to take entrepreneurship as a career whereas a majority 57 of them wanted to take up a job.", "cite_spans": [], "ref_spans": [{"start": 177, "end": 186, "text": "(Table 2)", "ref_id": "TABREF1"}]}, {"section": "Testing hypothesis H1b", "text": "Previous work experience of a student in job has no influence on his entrepreneurial inclination.", "cite_spans": [], "ref_spans": []}, {"section": "Testing hypothesis H1b", "text": "Based on their previous experience in job, students were divided into five categoriesStudents with no experience, with experience of less than 1 year, with experience between 1 to 2 years, with experience between 2 to 3 years and students with experience of 3 years and above (Table 3) . Cross tabulation displays the number of cases in each category defined by two grouping variables i.e. 'Work experience' of student and 'Intention after completion of degree'. Out of a total of 530 respondents, 439 respondents do not have any work experience, 63 respondents have experience of less than 1 year, 18 respondents have experience between 1 -2 years, 10 respondents have experience between 2 -3 years and no student had an experience of 3 years or more. We applied Chi-square test between the variables -'Work experience' and 'intention after completion of Degree (Table 4) .", "cite_spans": [], "ref_spans": [{"start": 276, "end": 285, "text": "(Table 3)", "ref_id": "TABREF2"}, {"start": 863, "end": 872, "text": "(Table 4)", "ref_id": "TABREF3"}]}, {"section": "Testing hypothesis H1b", "text": "The above table contains the output of the Chi-Square test. ' A high significance value of 0.347 and 0.456 of Pearson Chi-square test and likely hood ratio respectively (typically above 0.05) indicates that there is no relationship between the two variables. Since the tabulated value of Chi-square is greater than the calculated value, it is evident that data set obtained by the researcher confirms that variables 'Previous work experience in job' and 'Intention after completion of Degree' are independent. Hence we accept the hypothesis at 5% level of significance. This justifies the fact that previous work experience of student in job has got no influence on the entrepreneurial intentions of student.", "cite_spans": [], "ref_spans": []}, {"section": "Testing hypothesis H2", "text": "Academic intelligence of a student has no influence on his entrepreneurial intentions.", "cite_spans": [], "ref_spans": []}, {"section": "Testing hypothesis H2", "text": "To test the above hypothesis, researcher has used Chi-square test. The academic intelligence level of a student has been identified based on his/her academic performance from Class X th onwards. Students who have secured through out first division from Class X th onwards have been placed in the 'High' category, those who have mostly secured either first or second division from Class X th onwards have been placed in the 'Mediocre' category and those who have mostly secured second and/or third division from class X th onwards were placed in 'Low' category (Table 5 ).", "cite_spans": [], "ref_spans": [{"start": 560, "end": 568, "text": "(Table 5", "ref_id": "TABREF4"}]}, {"section": "Testing hypothesis H2", "text": "Cross tabulation displays that out of 530 respondents 325 respondents were placed in 'High' academic intelligence category, 180 students were found to be in 'Mediocre' academic intelligence category and 25 students were found to be in 'Low' intelligence level category (Table 6) . Table 6 contains the output of the Chi-Square test. A low significance value 0.001 of Pearson Chi-square test and Likelihood ratio respectively (typically above 0.05) indicates that there is a relationship between the two variables. Since the calculated value of Chi-square is greater than the tabulated value. It is evident that the variables 'Intelligence level of the student' and 'Intention after completion of Degree' are dependant. This justifies that the intelligence level of a student has an influence on his career choice intentions after completion of degree, specifically being an entrepreneur.", "cite_spans": [], "ref_spans": [{"start": 269, "end": 278, "text": "(Table 6)", "ref_id": "TABREF5"}, {"start": 281, "end": 288, "text": "Table 6", "ref_id": "TABREF5"}]}, {"section": "Testing hypothesis H3", "text": "Students studying different courses have different entrepreneurial inclinations.", "cite_spans": [], "ref_spans": []}, {"section": "Testing hypothesis H3", "text": "To test the above hypothesis, researcher has applied Chi-square test. The hypothesis was tested on the given five professional courses viz. MBA(Master of ) . A selective number of final year students, based on the proportionate stratified sampling were taken from each course and were asked about their preference towards their career choice after the completion of their degree (Table 7) . Out of a total of 530 respondents -365 respondents were the students of B. Tech, 90 respondents were the students of MBA, 43 respondents were the students of MCA, 21 respondents were the students of B.Pharm and 11 respondents were the students of BHMCT. The above data clearly indicates that a major lot among all the courses is inclined towards seeking a job after completion of their course. However if we compare the ratio of total number of students interviewed in a particular course and their intention after completion of Degree we find that the students studying MCA, BHMCT and MBA/PGDM are seen to be a little more inclined towards taking up entrepreneurship as a career choice in comparison to the rest of the courses (Table 8) .", "cite_spans": [], "ref_spans": [{"start": 379, "end": 388, "text": "(Table 7)", "ref_id": "TABREF6"}, {"start": 1119, "end": 1128, "text": "(Table 8)", "ref_id": "TABREF8"}]}, {"section": "Testing hypothesis H3", "text": "The above Since the calculated value of Chi-square is greater than the tabulated value. It is evident that the variables 'Course' and 'Intention after completion of Degree' are dependent. Hence we reject the hypothesis at 5% level of significance. This justifies the fact that the course of a student has an influence on his entrepreneurial inclination.", "cite_spans": [], "ref_spans": []}, {"section": "Result and discussion", "text": "Research indicated that the prior experience of a student in business has an influence on the student's decision to take up entrepreneurship as a career option. Students who had an earlier experience of doing business were seen to be less inclined towards taking up entrepreneurship as a career choice. A very few (13.4%) of the students with a selfemployment experience showed their intention of starting a business again. Where as a majority (69.5%) of the students with self-employment experience wanted to take up a job after completion of their course. It means that they probably did not have a good experience of doing a business earlier and they did not want to repeat that experience. The result may also indicate that probably doing a business in Uttarakhand is a difficult task or the business environment is not very favorable. While many authors (Shapero and Sokol, 1982; Krueger and Carsrud, 1993; Fayolle and Degeorge, 2006; McMullen and Shepherd, 2006) who have studied entrepreneurship education and previous entrepreneurial experience found both of them as important motivators and contributors to the formation of entrepreneurial intentions, they also emphasized upon the feasibility of entrepreneurship & desirability of individual. Corresponding to our study it may indicate that entrepreneurship feasibility in Uttarakhand could be low. Our findings complements the study of McStay (2008) who supported that students in the entrepreneurship subject with 'low' previous entrepreneurial experience had a greater intention to be self employed than those students with 'high' previous entrepreneurial experience. Although many authors (Krueger and Brazeal, 1994; Maxwell and Westerfield, 2002; Bird, 1995) have studied the positive influence of prior work experience on building entrepreneurial competencies and venture performance (Samuelsson 2001; Hart et al., 1995) . Our results showed that the previous work experience of student in job has got no relationship with the intention of student to become an entrepreneur after completion of degree. The results are in conflict to the suggestion given by Matthews & Moser, (1995) and Scott & Twomey, (1988) who put forward that work experience is influential in one's interest in an entrepreneurial career. The reason could probably be attributed to the sample surveyed. Our target sample comprised of 11.8% students who had experience less than a year, nearly 3.3% students had work experience between 1 to 2 years and only 1.8% students had work experience between 2 -3 years. None of the students had an experience of 3 years or more. Contrary to the study by Wadhwa et al. (2009) , wherein nearly half (47.9%) of the company founders launched their first company with more than ten years of work experience and the majority of respondents (75.4%) had worked as employees at other companies for more than six years before launching their own companies. This indicates that a small amount of experience (typically less than 3 years) is ineffective in creating any entrepreneurial intentions among the students. The research also revealed that there is an influence of intelligence level of student on his career choice intentions of becoming an entrepreneur. The students high on academic intelligence showed low propensity towards becoming an entrepreneurs. Referring to our data only 3% of the students who were placed in the 'High' intelligence level showed their interest in taking up entrepreneurship as a career whereas 72% of these students were interested in taking up a job. This could indicate the poor acceptance level of entrepreneurship in the family, society and the culture of Uttarakhand at large and reveal negative attitude of students towards entrepreneurship in comparison to jobs. The students who hold good academic record expect good jobs and are not interested to become entrepreneurs. This finding is in agreement with the recent study by Andrea Asoni (2011) who found that intelligence increases survival rates of existing firms, while it decreases the probability of starting new companies. Another finding of our study reveals that the course of a student which he is studying also has an influence on his decision to become an entrepreneur. Although the students of all the five courses, in general, did not show any significant interest towards entrepreneurship, the students of BHMCT (18%), MCA (9.3%) and MBA/PGDM (7.7%) were seen to be little better inclined towards entrepreneurship in comparison to B.Tech (4.3%) and B.Pharm (0%). The possible reason behind little better inclination of MBA/PGDM and BHMCT students towards entrepreneurship could be the presence of Entrepreneurship subject taught in the MBA/PGDM and BHMCT courses while this subject is not taught in other courses. The results are consistent with the studies by Kolvereid and Moen (1997) , Noel (1998) , Dyer (1994) , Watson et al. (1998) , Souitaris et al. (2007) and other authors who have emphasized upon entrepreneurship education as being critical for raising entrepreneurial intentions and entrepreneurship development. The better inclination of MCA students towards entrepreneurship could possibly be attributed to the Information Technology revolution which has prompted many young minds to begin IT enabled firms with low capital investment. The results support the studies by Sanghvi (1996) who pinpointed the need to provide entrepreneurship training to technical students for accelerated growth of the country. His studies have revealed that if necessary inputs are provided through properly designed training programmes, many young boys and girls can be groomed into successful entrepreneurs. This training will help the students in developing confidence in starting their own businesses and also generate self-employment.", "cite_spans": [{"start": 859, "end": 884, "text": "(Shapero and Sokol, 1982;", "ref_id": "BIBREF61"}, {"start": 885, "end": 911, "text": "Krueger and Carsrud, 1993;", "ref_id": "BIBREF39"}, {"start": 912, "end": 939, "text": "Fayolle and Degeorge, 2006;", "ref_id": "BIBREF23"}, {"start": 940, "end": 968, "text": "McMullen and Shepherd, 2006)", "ref_id": "BIBREF44"}, {"start": 1653, "end": 1680, "text": "(Krueger and Brazeal, 1994;", "ref_id": "BIBREF38"}, {"start": 1681, "end": 1711, "text": "Maxwell and Westerfield, 2002;", "ref_id": "BIBREF43"}, {"start": 1712, "end": 1723, "text": "Bird, 1995)", "ref_id": "BIBREF5"}, {"start": 1850, "end": 1867, "text": "(Samuelsson 2001;", "ref_id": "BIBREF55"}, {"start": 1868, "end": 1886, "text": "Hart et al., 1995)", "ref_id": "BIBREF30"}, {"start": 2152, "end": 2174, "text": "Scott & Twomey, (1988)", "ref_id": "BIBREF58"}, {"start": 2631, "end": 2651, "text": "Wadhwa et al. (2009)", "ref_id": "BIBREF76"}, {"start": 4834, "end": 4859, "text": "Kolvereid and Moen (1997)", "ref_id": "BIBREF36"}, {"start": 4862, "end": 4873, "text": "Noel (1998)", "ref_id": "BIBREF46"}, {"start": 4876, "end": 4887, "text": "Dyer (1994)", "ref_id": "BIBREF21"}, {"start": 4890, "end": 4910, "text": "Watson et al. (1998)", "ref_id": "BIBREF78"}, {"start": 4913, "end": 4936, "text": "Souitaris et al. (2007)", "ref_id": "BIBREF70"}, {"start": 5358, "end": 5372, "text": "Sanghvi (1996)", "ref_id": "BIBREF56"}], "ref_spans": []}, {"section": "Conclusion", "text": "The prior experience of a student in business has an influence on the student's intention to take up entrepreneurship as a career option. Students who had an earlier experience of doing business were seen to be less inclined towards taking up entrepreneurship as a career choice indicating bad experience and unfeasible business environment. The study revealed that previous work experience of student in job has got no relationship with the intention of student to become an entrepreneur after completion of degree. It highlights that a small amount of experience (typically less than 3 years) is insignificant in creating entrepreneurial intentions. The students who were placed in the 'High category' on academic intelligence were seen to be less inclined towards taking up entrepreneurship as a career. Research indicated that the course of a student which he is studying also has an influence on his decision to become an entrepreneur. The students of BHMCT, MCA and MBA/PGDM were seen to be little better inclined towards entrepreneurship than the rest of the courses. This could possibly be attributed to the presence of Entrepreneurship subject taught in the MBA/PGDM and BHMCT courses and an additional credit is due to the dot com revolution which has possibly given some boost to the entrepreneurial inclination of students with technical back ground as it requires less capital investment in comparison to other ventures. Capital investment has already been found to be a major perceived barrier among the students of Uttarakhand (Sharma & Madan, 2013) . 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Journal of Global Entrepreneurship Research", "link": null}}, "ref_entries": {"TABREF0": {"text": "Cross tabulationThe above table contains the output of the Chi-Square test. A low significance value 0.003 & .009 of Pearson Chi-square test and Likelihood ratio respectively (typically below 0.05) indicates that there is a relationship between the two variables.", "type": "table"}, "TABREF1": {"text": "Chi-Square test", "type": "table"}, "TABREF2": {"text": "Cross tabulation", "type": "table"}, "TABREF3": {"text": "Chi-Square", "type": "table"}, "TABREF4": {"text": "Cross tabulation", "type": "table"}, "TABREF5": {"text": "Chi-Square test", "type": "table"}, "TABREF6": {"text": "Cross tabulation", "type": "table"}, "TABREF7": {"text": "table contains the output of the Chi-Square test. 'df' equals the number of categories minus one. A significance value of 0.005 and 0.018 of Pearson Chi-square test and Likelihood ratio respectively (typically below 0.05) indicates dependence of 'course of a student' on 'intention of career choice of student' after completion of", "type": "table"}, "TABREF8": {"text": "Chi-square test", "type": "table"}}}
{"paper_id": "8335580", "_pdf_hash": "5dd02cedeef996dd1ff639a8a3896e177178d34b", "abstract": [{"section": "Abstract", "text": "Human land cover can degrade estuaries directly through habitat loss and fragmentation or indirectly through nutrient inputs that reduce water quality. Strong precipitation events are occurring more frequently, causing greater hydrological connectivity between watersheds and estuaries. Nutrient enrichment and dissolved oxygen depletion that occur following these events are known to limit populations of benthic macroinvertebrates and commercially harvested species, but the consequences for top consumers such as birds remain largely unknown. We used non-metric multidimensional scaling (MDS) and structural equation modeling (SEM) to understand how land cover and annual variation in rainfall interact to shape waterbird community composition in Chesapeake Bay, USA. The MDS ordination indicated that urban subestuaries shifted from a mixed generalist-specialist community in 2002, a year of severe drought, to generalist-dominated community in 2003, of year of high rainfall. The SEM revealed that this change was concurrent with a sixfold increase in nitrate-N concentration in subestuaries. In the drought year of 2002, waterbird community composition depended only on the direct effect of urban development in watersheds. In the wet year of 2003, community composition depended both on this direct effect and on indirect effects associated with high nitrate-N inputs to northern parts of the Bay, particularly in urban subestuaries. Our findings suggest that increased runoff during periods of high rainfall can depress water quality enough to alter the composition of estuarine waterbird communities, and that this effect is compounded in subestuaries dominated by urban development. Estuarine restoration programs often chart progress by monitoring stressors and indicators, but rarely assess multivariate relationships among them. Estuarine management planning could be improved by tracking the structure of relationships among land cover, water quality, and waterbirds. Unraveling these complex relationships may help managers identify and mitigate ecological thresholds that occur with increasing human land cover.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Citation: Studds CE, DeLuca WV, Baker ME, King RS, Marra PP (2012) Land Cover and Rainfall Interact to Shape Waterbird Community Composition. PLoS ONE 7(4): e35969.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Conversion of natural habitats to human dominated landscapes has led to worldwide deterioration of estuarine ecosystems [1] . In many regions, the continued spread of human land cover has been accompanied by greater variation in climatic conditions, such as strong cycles of drought and precipitation [2] . Together, human land cover and rainfall shape estuarine condition directly by reducing coastal habitat quality or indirectly by lowering water quality. Both agriculture and urban development directly impair estuaries through degradation or loss of coastal wetlands, modification of other natural shoreline areas, and habitat fragmentation and isolation [3] [4] [5] . These land cover types also indirectly degrade estuaries by carrying nutrients and contaminants from terrestrial watersheds into coastal water bodies. Rainfall events amplify the hydrological connectivity between watersheds and estuaries, potentially leading to severe eutrophication [6, 7] . With watersheds in many coastal areas undergoing dynamic changes in land cover and climate, management and restoration programs could benefit from understanding how rainfall interacts with expanding human development to shape estuarine condition.", "cite_spans": [{"start": 120, "end": 123, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 301, "end": 304, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 660, "end": 663, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 664, "end": 667, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 668, "end": 671, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 958, "end": 961, "text": "[6,", "ref_id": "BIBREF5"}, {"start": 962, "end": 964, "text": "7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Introduction", "text": "The greatest risk posed by eutrophication of coastal waters is the decrease in dissolved oxygen (DO) when blooms of aquatic algae die and are consumed through microbial respiration [8] . Hypoxia occurs when DO falls below 2 mg/L and has been shown to cause mortality of sessile benthic invertebrates and trigger emigration of commercially harvested crab and fish species to more oxygen-rich waters [9, 10] . Despite these well-documented responses of lower trophic level organisms, the consequences for higher order consumers are essentially unknown. Because conservation of upper trophic level wildlife is mandated by state and federal management agencies, there is a need to understand how these species respond to eutrophication and other disturbances associated with increasing human land cover.", "cite_spans": [{"start": 181, "end": 184, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 398, "end": 401, "text": "[9,", "ref_id": "BIBREF8"}, {"start": 402, "end": 405, "text": "10]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Introduction", "text": "Bird communities can be robust indicators of biological condition because they often occupy the highest trophic level in an ecosystem, causing them to integrate the effects of abiotic stressors acting on species at lower trophic levels [11, 12] . DeLuca et al. [13] developed an index of waterbird community integrity in Chesapeake Bay, USA and evaluated its sensitivity to anthropogenic disturbance. They found that even low levels of urban development, particularly when located close to the estuarine shoreline, severely impaired the waterbird community. This finding strongly suggests that waterbird communities are directly degraded by urban development, but, because this study did not assess potential indirect pathways that compromise water quality, the underlying causes remain unclear. Waterbird abundance depends on both habitat quality and food availability [14] . Therefore, waterbird communities should also be sensitive to changes in water quality because these species primarily consume fish and invertebrates, some of whose local abundances decline when eutrophic conditions prevail [15] .", "cite_spans": [{"start": 236, "end": 240, "text": "[11,", "ref_id": "BIBREF10"}, {"start": 241, "end": 244, "text": "12]", "ref_id": "BIBREF11"}, {"start": 261, "end": 265, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 870, "end": 874, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 1100, "end": 1104, "text": "[15]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Introduction", "text": "In 2002 and 2003, we monitored the waterbird community, nitrate-N concentrations, dissolved oxygen levels, and salinity in 27 subestuaries of Chesapeake Bay. In 2002, a severe region-wide drought limited freshwater flow and nutrient inputs to the Bay to near historic lows [16, 17] . In contrast, the Bay received more than twice the amount of freshwater in 2003 and the third highest amount since 1937, much of which was concentrated in the spring and summer months. This massive influx nearly tripled nitrogen export from the previous year, resulting in sustained hypoxia throughout the estuary [16] . Here, we explore how this temporal variation in rainfall interacted with spatial variation in land cover to shape waterbird community composition. We used non-metric multidimensional scaling and structural equation modeling to evaluate direct and indirect effects of land cover on waterbird community composition and to assess change in their strength between years. We predicted waterbird community composition would be limited directly by urban development in both years, and indirectly by lower water quality due to greater hydrological connectivity between watersheds and subestuaries in 2003.", "cite_spans": [{"start": 273, "end": 277, "text": "[16,", "ref_id": "BIBREF15"}, {"start": 278, "end": 281, "text": "17]", "ref_id": "BIBREF16"}, {"start": 597, "end": 601, "text": "[16]", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "Methods", "text": "Fieldwork was conducted from 2002-2003 in 27 subestuaries of Chesapeake Bay, USA (39u 239 N-36u 489 N, 76u 459 W-75u 449 W). Each subestuary had a distinct embayment that separated it from major tributaries of the Bay and a watershed drained by a third to fifth order stream [18] . We quantified land cover within each watershed by using ArcGIS software (ESRI, Redlands, CA, USA) and the 1992 National Land Cover Database derived from 30-m resolution Landsat Thematic mapper images [19] . We calculated the percentage watershed area covered by agriculture and urban development and the percentage area of emergent marsh within 500 m of the shoreline. We summarized the percentage of urban development in each watershed weighted by its squared inverse distance (IDW) to the shoreline because of past evidence that ecological indicators in Chesapeake Bay are sensitive to this land cover in close proximity to subestuaries [13, 18] . We sampled 17 subestuaries in 2002, 20 in 2003, and a subset of nine in both years ( Fig. 1) . This design permitted us to balance spatial coverage and temporal replication of data collection.", "cite_spans": [{"start": 275, "end": 279, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 482, "end": 486, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 921, "end": 925, "text": "[13,", "ref_id": "BIBREF12"}, {"start": 926, "end": 929, "text": "18]", "ref_id": "BIBREF17"}], "ref_spans": [{"start": 1017, "end": 1024, "text": "Fig. 1)", "ref_id": "FIGREF0"}]}, {"section": "Methods", "text": "We surveyed the waterbird community along three, 1-km transects in each subestuary. Transects were positioned in the upper, middle, and lower thirds of subestuaries and were oriented parallel to and 100 m from the shoreline (Fig. 1 inset) . Adjacent transects within subestuaries were separated by .500 m to reduce the probability of counting an individual more than once. We surveyed waterbirds with the double observer approach from a boat traveling at three knots along transects [20] . For this study, we defined waterbirds as all non-passerine bird species that forage exclusively or opportunistically on aquatic estuarine organisms (e.g., gulls, terns, waders, raptors, kingfishers, and waterfowl). Observers counted all individuals on the water, in the air, or perched along the shoreline within 100 m of transects. We surveyed each transect three times from 15 May-15 August between 0600 h and 1300 h and used program DOBSERV to calculate abundance estimates corrected for imperfect detection probabilities [20] . Deluca et al. [13] incorporated these corrected abundance estimates along with information about foraging and nesting niche breadth, migratory behavior, and regional rarity into an index of waterbird community integrity for each subestuary. We employed this index in the present study to characterize spatial and temporal variation in waterbird community composition (WCC) because subestuaries with high scores supported high abundances of specialist species with high conservation value and those with lower scores harbored high abundances of generalist species with lower conservation value (see Text S1 for index development).", "cite_spans": [{"start": 483, "end": 487, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 1015, "end": 1019, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 1036, "end": 1040, "text": "[13]", "ref_id": "BIBREF12"}], "ref_spans": [{"start": 224, "end": 238, "text": "(Fig. 1 inset)", "ref_id": "FIGREF0"}]}, {"section": "Methods", "text": "Six water quality sampling stations were distributed via a random sampling approach nearby to waterbird survey transects in each subestuary. Salinity, dissolved oxygen (DO), and nitrate-N were measured approximately 50 m from shore at two locations at every sampling station. Salinity (ppt) and DO (mg/L and percent saturation) were measured using an YSI 556 multiparameter instrument (YSI Inc., Yellow Springs, OH, USA) at 10 cm below the water surface and 10 cm above the bottom. The difference between percent saturation of DO at the surface and bottom (DO difference) was used as a metric of potential benthic hypoxia. This index also helped alleviate differences in DO due to diel fluctuations among sampling stations because measurements were not collected at the same time of day across all stations. Nitrate-N (mg/L) samples were collected near the water surface in acidwashed polyethylene bottles, stored on ice, and returned to the laboratory for analysis [21] . No specific permits were required for the described field studies.", "cite_spans": [{"start": 966, "end": 970, "text": "[21]", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Methods", "text": "We used non-metric multidimensional scaling (MDS) to describe spatial and temporal variation in the abundance of generalist and specialist species in each subestuary following steps outlined by [22] . We used corrected abundance estimates of each species to compute Bray-Curtis distances among subestuaries for each year separately. The number of MDS axes was chosen by minimizing stress, a measure of the mismatch between distance among species indicated by the Bray-Curtis matrix and distance in the ordination. Species centroids were mapped in ordination space by weighted averaging. We used rotational vector fitting to relate land cover and water quality indices to the ordination [23] . Significance of vectors was estimated using 1000 random permutations. Ordinations and vector fitting were performed in program R 2.11 using the vegan package [24, 25] .", "cite_spans": [{"start": 194, "end": 198, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 686, "end": 690, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 851, "end": 855, "text": "[24,", "ref_id": "BIBREF23"}, {"start": 856, "end": 859, "text": "25]", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Methods", "text": "We used structural equation modeling (SEM) to investigate a set of hypothesized causal relationships among land cover, water quality, and WCC. These relationships can be visualized through a path model in which arrows indicate the proposed effect of one variable on another. The path diagram was drawn based on past research from Chesapeake Bay and on established linkages between land cover and estuarine condition [13, 21, 26] . Direct paths were expected to act on WCC as a function of the amount of emergent marsh habitat and urban development in each subestuary [13] . Subestuaries with a high percentage of emergent marsh were predicted to have high WCC scores because many waterbirds forage in this habitat, and it serves as a nursery for many fish species consumed as prey. Subestuaries adjacent to watersheds with a high percentage of urban land cover were hypothesized to have low WCC scores due to degradation of marsh and shoreline habitat. Such an effect could occur through habitat fragmentation and isolation, habitat alteration from shoreline hardening, or prevalence of invasive vegetation [3, 18, 27] .", "cite_spans": [{"start": 416, "end": 420, "text": "[13,", "ref_id": "BIBREF12"}, {"start": 421, "end": 424, "text": "21,", "ref_id": "BIBREF20"}, {"start": 567, "end": 571, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 1107, "end": 1110, "text": "[3,", "ref_id": "BIBREF2"}, {"start": 1111, "end": 1114, "text": "18,", "ref_id": "BIBREF17"}, {"start": 1115, "end": 1118, "text": "27]", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "Methods", "text": "Indirect pathways proceeding from urban development and agriculture were hypothesized to act on WCC through their effect on water quality. Agriculture and urban development are important determinants of nitrate-N and DO levels in estuaries [28] . Subestuaries with a high percentage of these land cover types in nearby watersheds were predicted to have low WCC scores owing to high nitrate-N concentrations and large DO differences. The model posited that these two indices of water quality influence a conceptual and unmeasured latent variable labeled as ''Eutrophication''. We included a measure of surface salinity in the model to index the spatial position of subestuaries on the landscape. Freshwater inputs are higher in northern compared to southern reaches of Chesapeake Bay, and such gradients can lead to spatial variation in nutrient concentration in estuaries [29, 30] . At the northern end of the Bay, the Susquehanna River is a major source of freshwater, and agricultural discharges to this river account for a substantial fraction of nitrogen loads to the Bay [31] . Relationships among land cover and salinity were drawn using double-headed arrows because these variables often covary with one another, particularly in this landscape [32] .", "cite_spans": [{"start": 240, "end": 244, "text": "[28]", "ref_id": "BIBREF27"}, {"start": 872, "end": 876, "text": "[29,", "ref_id": "BIBREF28"}, {"start": 877, "end": 880, "text": "30]", "ref_id": "BIBREF29"}, {"start": 1076, "end": 1080, "text": "[31]", "ref_id": "BIBREF30"}, {"start": 1251, "end": 1255, "text": "[32]", "ref_id": "BIBREF31"}], "ref_spans": []}, {"section": "Methods", "text": "We used multi-group sampling to identify the path model that best fit annual variation in the data that could have occurred due to differences in rainfall. Multi-group sampling allows parameters of interest to be constrained to equality for subsets of data, thus permitting evaluation of a priori hypotheses [33] . In the first model, we allowed all paths to vary between years to test the hypothesis that annual variation in the data occurred due to differences in both direct and indirect effects. The second model tested the hypothesis that annual variation in the data was driven by differences in degradation of marsh and coastal habitat by requiring only indirect paths to be equal. In the third model, we fixed only the direct paths to be equal to test the hypothesis that data varied between years due to changes in water quality. The final model imposed equality constraints on all paths to test the hypothesis that there was no discernable annual variation in the data.", "cite_spans": [{"start": 308, "end": 312, "text": "[33]", "ref_id": "BIBREF32"}], "ref_spans": []}, {"section": "Methods", "text": "The path coefficients in each model are values that maximize the likelihood of the covariance structure in the data given the covariance structure proposed by the path model. We assessed the fit of each model with a chi-squared goodness-of-fit test, where a significant chi-squared indicates that the model does not fit the data. This statistic is an asymptotic approximation of a chi-squared distribution when the data follow a multivariate normal distribution. We also assessed model fit with the comparative fit index (CFI) and root mean square error (RMSEA), two commonly used indices that provide an approximate measure of model fit. Models with a CFI .0.95 and a RMSEA of ,0.05 indicate a good fit to the data [34] . Because our sample size was smaller than desired for structural equation models estimated through maximum likelihood, we performed Monte Carlo permutation tests with 1000 replicates to evaluate the robustness of each model fit. Significance of path coefficients for the best model was judged based on an empirical distribution generated from 1000 bootstrap replicates of the data. All SEM analyses were done with AMOS 19.0 [35] .", "cite_spans": [{"start": 716, "end": 720, "text": "[34]", "ref_id": "BIBREF33"}, {"start": 1146, "end": 1150, "text": "[35]", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "Methods", "text": "We used least squares regression to evaluate temporal change in the relationship among land cover, water quality, and WCC for the subset of subestuaries studied in both years. For this analysis, we considered only predictors judged important in the best-fit model from the SEM multi-group analysis. We expected statistical inference from this analysis might be somewhat limited given that only nine subestuaries were studied in both years. However, our primary goal in this analysis was to assess concordance between regression coefficients from this model and path coefficients from the best-fit multi-group model that were fit with data from all subestuaries. Regression analyses were done with program R 2.11 [24] .", "cite_spans": [{"start": 712, "end": 716, "text": "[24]", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Results", "text": "The MDS ordination of WCC revealed distinct inter-annual patterns in the distribution of generalist and specialist species across the 27 subestuaries. Two-dimensional solutions were chosen because stress was relatively low for both years Table S1 for species names and WCC scores). Conversely, when nutrient flow to the Bay reached a near record high in 2003, generalist species exhibited a pronounced shift toward subestuaries in developed watersheds with high nitrate-N concentrations and large differences between surface and bottom DO, whereas specialists exhibited a weaker but opposite trend (Fig. 2B) .", "cite_spans": [], "ref_spans": [{"start": 238, "end": 246, "text": "Table S1", "ref_id": "TABREF0"}, {"start": 598, "end": 607, "text": "(Fig. 2B)", "ref_id": "FIGREF3"}]}, {"section": "Results", "text": "The multi-group SEM indicated strong annual variation in the paths affecting WCC. The model in which all paths were unconstrained and thus required to vary between years provided the best fit to the data (x 2 = 11.49, df = 12, P = 0.487; RMSEA,10", "cite_spans": [], "ref_spans": []}, {"section": "23", "text": "; CFI = 1.00). The model that fixed direct paths to be equal between years provided a reasonable fit to the data based on the goodness of fit test, but CFI and RMSEA values indicated somewhat poor fit (x 2 = 17.40, df = 14, P = 0.236; RMSEA = 0.09; CFI = 0.96). Models that required either indirect paths or all paths in the model to be equal between years fit the data poorly (x 2 = 27.72, df = 19, P = 0.089; RMSEA = 0.12; CFI = 0.90 and x 2 = 35.33, df = 21, P = 0.026; RMSEA = 0.14; CFI = 0.83, respectively). Monte Carlo permutation tests indicated that these estimates of model fit were robust (all models P,0.05). Table S2 .", "cite_spans": [], "ref_spans": [{"start": 621, "end": 629, "text": "Table S2", "ref_id": "TABREF1"}]}, {"section": "23", "text": "Observed correlations among predictors showed strong concordance with those implied by the model (Table 1 ). These relationships suggested that differences between observed correlations and total effects resulted from non-causal or spurious correlations among predictors, most likely due to unanalyzed relationships or residual spatial autocorrelation that could not be accounted for by covariance relationships specified in the path model. Still, several predictors exhibited differences between their total effects and observed correlations with WCC. In particular, surface salinity (2002) and percent cropland (2002 and 2003) had moderate positive correlations with WCC, but had total effects that changed sign or were notably lower ( Table 1) . Conditioning of predictors by SEM, however, indicated that these correlations were enhanced partially by strong negative associations with urban development (Table 1) . Discrepancies in how land cover acted on DO difference were also apparent. Observed correlations, implied correlations, and total effects between percentage cropland and DO difference were consistently negative, whereas those between percentage development and DO difference were uniformly positive, an outcome most likely attributable to the strong negative correlation between these land cover types and differences in their pollutant export dynamics ( Table 1, Table S2 ).", "cite_spans": [], "ref_spans": [{"start": 97, "end": 105, "text": "(Table 1", "ref_id": "TABREF0"}, {"start": 738, "end": 746, "text": "Table 1)", "ref_id": "TABREF0"}, {"start": 906, "end": 915, "text": "(Table 1)", "ref_id": "TABREF0"}, {"start": 1373, "end": 1390, "text": "Table 1, Table S2", "ref_id": "TABREF0"}]}, {"section": "23", "text": "Fitted path coefficients indicated substantial annual variation in how land cover and water quality shaped WCC, but also revealed a consistent negative effect of urban development. In the dry year of 2002, only the direct effect of urban development was a strong predictor of WCC (Fig. 3A) . WCC scores were lower in subestuaries with a high percentage of urban development (l = 20.74, P = 0.046). The difference in percent saturation of DO between the surface and bottom of the water column was greater in subestuaries with more urban development (b = 0.67, P = 0.009), but did not markedly increase the estimated eutrophication variable (b = 20.34, P = 0.596). Nitrate-N levels were higher in subestuaries with lower salinity, reflecting elevated concentrations in relatively fresh northern compared to brackish southern subestuaries (l = 20.44, P = 0.048). This trend led to greater predicted values of the latent eutrophication variable (b = 1.00, P = 0.002), but it was not substantial enough to alter WCC (b = 0.18, P = 0.666).", "cite_spans": [], "ref_spans": [{"start": 280, "end": 289, "text": "(Fig. 3A)", "ref_id": "FIGREF5"}]}, {"section": "23", "text": "In the wet year of 2003, WCC again depended on the direct effect of urban development but also on the indirect effects of urban development and salinity on water quality. WCC scores remained lower in subestuaries with a high percentage of urban development (l = 20.52, P = 0.047; Fig. 3B ). Nitrate-N concen- Table S1 . IDW development is the percent urban development in each watershed weighted by the square of its inverse distance to the shoreline. The vector for percentage marsh in 2002 was short and was not plotted for clarity. doi:10.1371/journal.pone.0035969.g002 trations were greater in subestuaries surrounded by a high percentage of urban development (l = 0.36, P = 0.043), and in those with lower salinity (l = 20.54, P = 0.021), indicating elevated nutrient levels in northern compared to southern subestuaries. Together, these effects were associated with a mean nitrate-N concentration in subestuaries over six times greater than in the previous year and a marked rise in predicted values of the latent eutrophication variable (b = 0.87, P = 0.002; Table 2 ). DO difference was greater in subestuaries adjacent to watersheds with a lower percentage of cropland (l = 20.37, P = 0.049), however this negative pattern also reflected a large DO difference in subestuaries with a large amounts of urban development (Table 1 ). This latter relationship is more consistent with predicted responses of DO to land cover and with the observed deterioration in mean water quality from 2002 to 2003 (Table 2, Table 3 ). In contrast to 2002, predicted eutrophication in 2003 was strong enough to alter WCC (b = 20.32, P = 0.047), a change implied by the MDS ordination to include a decrease in the abundance of specialist species and an increase in generalists. Annual variation in WCC associated with elevated nitrate-N concentration in subestuaries was also evident when we considered this relationship in only the subset of nine subestuaries that were studied in both years. During the dry year of 2002, WCC did not vary in relation to nitrate-N levels ( ", "cite_spans": [], "ref_spans": [{"start": 280, "end": 287, "text": "Fig. 3B", "ref_id": "FIGREF5"}, {"start": 309, "end": 317, "text": "Table S1", "ref_id": "TABREF0"}, {"start": 1066, "end": 1073, "text": "Table 2", "ref_id": "TABREF1"}, {"start": 1327, "end": 1335, "text": "(Table 1", "ref_id": "TABREF0"}, {"start": 1504, "end": 1521, "text": "(Table 2, Table 3", "ref_id": "TABREF1"}]}, {"section": "Discussion", "text": "Our results support the hypothesis that increased hydrological connectivity between the terrestrial landscape and the aquatic environment can lower water quality enough to alter the composition of estuarine waterbird communities. The MDS ordination indicated that urban watersheds shifted from a mixed generalist-specialist community in 2002 to generalist-dominated community in 2003. The multi-group SEM revealed that this change in WCC was associated with higher overall trophic status of subestuaries as indicated by elevated nitrate-N concentrations. High nitrate-N concentrations in estuarine grab samples can indicate that nitrogen demand has been temporarily satisfied, that primary producers have yet to respond to continued enrichment, or both [28] . Even though our models did not incorporate rainfall or nitrogen loads explicitly, concurrent research, including longterm monitoring of Chesapeake Bay water quality, provides independent evidence that higher rainfall in 2003 facilitated a strong increase in nitrogen loading compared to 2002 [16, 17, 36] . Together, these data imply that continued expansion of urban development and strong rainfall events that flush accumulated pollutants from the landscape may interact to promote estuarine waterbird communities increasingly dominated by generalist species.", "cite_spans": [{"start": 753, "end": 757, "text": "[28]", "ref_id": "BIBREF27"}, {"start": 1052, "end": 1056, "text": "[16,", "ref_id": "BIBREF15"}, {"start": 1057, "end": 1060, "text": "17,", "ref_id": "BIBREF16"}, {"start": 1061, "end": 1064, "text": "36]", "ref_id": "BIBREF35"}], "ref_spans": []}, {"section": "Discussion", "text": "High predicted eutrophication in the wet year of 2003 likely represents elevated nitrate-N discharge from at least three distinct terrestrial sources that were differentiated from one another only after accounting for spatial autocorrelation among land cover types. Agricultural lands, and cropland in particular, typically supply the majority of nutrients to estuaries [21, 37, 38] . The Susquehanna River, situated at the northern end of the Bay, drains a region of extensive agriculture and accounts for a large fraction of annual nitrogen loads [31] . The increase in nitrate-N concentrations in lower salinity northern subestuaries probably reflects lagged nutrient discharges from the Susquehanna River ; CFI = 1.00). Values between variables are standardized path coefficients. Arrow widths are proportional to the size of path coefficients, but only values in color differed from zero based on a parametric bootstrap of the data with 1000 replicates. Estimated intercepts and the proportion of variance explained by that part of the model appear below variable names. IDW development is the percent urban development in each watershed weighted by the square of its inverse distance to the shoreline. doi:10.1371/journal.pone.0035969.g003 that originated from distant, upstream cropland, potentially as far north as New York. Conversely, local cropland in watersheds surrounding subestuaries appeared to have little effect on measured nitrate-N concentrations. One explanation for this pattern is that nitrogen export from cropland peaks in early spring before green vegetation emerges and evapotranspiration reduces flow rates of smaller rivers [16] . Nitrate-N arriving to subestuaries in spring would have been converted to algal biomass and organic detritus by the time water our quality sampling occurred. Nitrate-N enrichment from local cropland therefore was detectible primarily through its effect on bottom DO, whereas DO difference remained largely unresponsive to increasing cropland (Table 3) . Unlike those dominated by agriculture, urban watersheds have comparatively lower evapotranspiration and appeared to load similar amounts of nitrate-N throughout the summer, leading to greater observed concentrations, supersaturation in surface DO, pronounced DO difference, and high predicted values of the latent eutrophication variable (Table 3) . Therefore, the negative correlation between DO difference and cropland likely was driven by DO trends in urban watersheds and the negative correlation between cropland and development that exists in this region [32] . We did not measure the response of lower trophic level organisms to eutrophication, but it is likely that the increase in generalist waterbird species in 2003 reflected disturbance propagating from the base to the top of the estuarine food web [39, 40] . All of the specialists recorded in this study prey on fish species that concentrate near estuarine wetlands during the summer breeding season, whereas half of the generalists observed (mute swan [ [41] [42] [43] . Because some waterbirds travel long distances between breeding and foraging areas, their distribution while foraging should reflect the availability of prey and the overall quality of estuarine habitat [44, 45] . Thus, it is possible that the sensitivity of WCC to the annual change in water quality was due to piscivorous species tracking food resources to areas minimally affected by eutrophication and hypoxia. Low salinity in estuaries may also reduce fish abundance through temporary emigration to more saline waters [46] . Lower salinity in 2003 could therefore have facilitated the increase in generalist waterbird species, particularly in urban subestuaries at northern reaches of the Bay (Table 2) . Nonetheless, the total effect of salinity on WCC was less than half that of nitrate-N in 2003, suggesting that nutrient loading was the primary aspect of water quality affecting waterbirds (Table 1 ; Fig. 3B ).", "cite_spans": [{"start": 370, "end": 374, "text": "[21,", "ref_id": "BIBREF20"}, {"start": 375, "end": 378, "text": "37,", "ref_id": "BIBREF36"}, {"start": 379, "end": 382, "text": "38]", "ref_id": "BIBREF37"}, {"start": 549, "end": 553, "text": "[31]", "ref_id": "BIBREF30"}, {"start": 1653, "end": 1657, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 2575, "end": 2579, "text": "[32]", "ref_id": "BIBREF31"}, {"start": 2826, "end": 2830, "text": "[39,", "ref_id": "BIBREF38"}, {"start": 2831, "end": 2834, "text": "40]", "ref_id": "BIBREF39"}, {"start": 3034, "end": 3038, "text": "[41]", "ref_id": "BIBREF40"}, {"start": 3039, "end": 3043, "text": "[42]", "ref_id": "BIBREF41"}, {"start": 3044, "end": 3048, "text": "[43]", "ref_id": "BIBREF42"}, {"start": 3253, "end": 3257, "text": "[44,", "ref_id": "BIBREF43"}, {"start": 3258, "end": 3261, "text": "45]", "ref_id": "BIBREF44"}, {"start": 3573, "end": 3577, "text": "[46]", "ref_id": "BIBREF45"}], "ref_spans": [{"start": 2002, "end": 2011, "text": "(Table 3)", "ref_id": "TABREF2"}, {"start": 2352, "end": 2361, "text": "(Table 3)", "ref_id": "TABREF2"}, {"start": 3748, "end": 3757, "text": "(Table 2)", "ref_id": "TABREF1"}, {"start": 3949, "end": 3957, "text": "(Table 1", "ref_id": "TABREF0"}, {"start": 3960, "end": 3967, "text": "Fig. 3B", "ref_id": "FIGREF5"}]}, {"section": "Discussion", "text": "Two lines of evidence suggest that we were successful at capturing variation in water quality across years and that the observed effects were not due to spatial variation caused by sampling different subestuaries in each year. First, the intercept estimated for nitrate-N concentration in the best-fit model was more than six times greater in 2003 compared to 2002 (Table 2) . This difference is in line with annual variation in nitrate-N concentration in small streams and major rivers entering Chesapeake Bay found by other studies during the same time period [16, 36] . Second, annual variation in the relationship between nitrate-N and WCC in the subset of nine subestuaries studied in both 2002 and 2003 closely paralleled the trend found in the full data set, which included sites surveyed in only one of two years.", "cite_spans": [{"start": 562, "end": 566, "text": "[16,", "ref_id": "BIBREF15"}, {"start": 567, "end": 570, "text": "36]", "ref_id": "BIBREF35"}], "ref_spans": [{"start": 365, "end": 374, "text": "(Table 2)", "ref_id": "TABREF1"}]}, {"section": "Discussion", "text": "Even though elevated nitrate-N concentrations in 2003 were linked to a strong change in WCC, urban development directly limited the waterbird community in both years, an outcome likely due in part to fragmentation and loss of both near-shore terrestrial and wetland habitat. Fragmentation of terrestrial shoreline habitat by human development can reduce habitat suitability for piscivorous species that use shoreline foraging or nesting perches (e.g., belted kingfisher [Ceryle alcyon] and osprey [Pandion haliaetus]) or prefer unbroken stretches of natural shoreline (e.g., great egret [Ardea alba] and green heron [Butorides virescens]). In addition, shoreline modification can facilitate colonization of wetlands by terrestrial and invasive vegetation, especially Phragmites australis [18] . This species can fragment native vegetation and render even large wetlands inhospitable to foraging waterbirds. Moreover, fragmentation and isolation of natural vegetation by urban development may facilitate increases in mammalian predators and limit nesting habitat suitability, potentially forcing waterbirds to commute longer distances to foraging areas. Some unknown portion of the variation we have attributed to direct pathways could also have occurred through unmeasured aspects of indirect pathways, including phosphorus export, sewage overflow, and the presence of toxins [47] [48] [49] . Nitrate-N concentrations in subestuaries increased with the percentage developed land in watersheds not only in the wet year 2003, but also in the absence of substantial rainfall in 2002 (Fig. S1 ). This pattern is consistent with a greater contribution of distinct point sources of nitrate-N with high amounts of urban development in the dry year of 2002. Because urban areas can have point sources that do not require strong rainfall events to deliver nutrients to estuarine environments (e.g., water treatment facilities, sewage leaks), it is probable that they were responsible some of the negative effect of urban development on WCC, especially in the drought year of 2002. Urban environments also contain sources of nitrogen that may be continually replenished throughout the growing season (e.g., lawn fertilizers, atmospheric deposition). Increasing development has been shown to shift the mode of nitrogen export from base flows toward event flows, so flushing of these sources likely increases with more intense precipitation events [36, 50] .", "cite_spans": [{"start": 788, "end": 792, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 1376, "end": 1380, "text": "[47]", "ref_id": "BIBREF46"}, {"start": 1381, "end": 1385, "text": "[48]", "ref_id": "BIBREF47"}, {"start": 1386, "end": 1390, "text": "[49]", "ref_id": "BIBREF48"}, {"start": 2436, "end": 2440, "text": "[36,", "ref_id": "BIBREF35"}, {"start": 2441, "end": 2444, "text": "50]", "ref_id": "BIBREF49"}], "ref_spans": [{"start": 1580, "end": 1588, "text": "(Fig. S1", "ref_id": "FIGREF0"}]}, {"section": "Discussion", "text": "The expansion of human development in the Chesapeake Bay watershed is likely to result in greater nutrient inputs and enhanced conditions for foraging generalists, a situation that could be exacerbated by predicted increases in severe storms [2] . These changes may not only reduce foraging habitat quality for piscivorous specialists, but could also limit their populations through increased competition and predation by generalists. Agonistic interactions with double-crested cormorants (Phalacrocorax auritus) can reduce reproductive success of other colonial nesting species, and have been implicated in displacement of heron and egret rookeries [51, 52] . Cormorants can also severely deplete fish populations, potentially limiting prey availability for other piscivorous birds [53] . Greater black-blacked (Larus marinus) and herring gulls (Larus argentatus) are important nest predators of common tern (Sterna hirundo) and least tern (Sterna antillarum) nests, and growing populations of these species are thought to have contributed to the decline and abandonment of tern colonies in Chesapeake Bay [52] . In addition, herbivores such as Canada goose and mute swan may overgraze wetland vegetation and deteriorate nesting habitat for marsh-breeding birds. Moreover, guano from these species is rich in nitrogen and phosphorus, and large aggregations have been linked to changes in water chemistry that promote local eutrophication, although only in small water bodies [54] .", "cite_spans": [{"start": 242, "end": 245, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 650, "end": 654, "text": "[51,", "ref_id": "BIBREF50"}, {"start": 655, "end": 658, "text": "52]", "ref_id": "BIBREF51"}, {"start": 783, "end": 787, "text": "[53]", "ref_id": "BIBREF52"}, {"start": 1107, "end": 1111, "text": "[52]", "ref_id": "BIBREF51"}, {"start": 1476, "end": 1480, "text": "[54]", "ref_id": "BIBREF53"}], "ref_spans": []}, {"section": "Discussion", "text": "A critical challenge faced by restoration programs is to decide on criteria for management targets [55] . The ability of our model to describe spatial and short-term temporal variation in estuarine condition suggests a strategy for defining such targets using existing monitoring data. Many of the data analyzed in our research are also collected in a number of estuarine monitoring programs, yet statistical analyses typically are done using traditional ordination or regression approaches that may not be conducive to tracking long-term change in covariance relationships among ecological variables and a large set of potential stressors. Where long time series data are available, SEM or other casual models could be used in conjunction with techniques such as changepoint analysis to identify critical historical thresholds in estuarine condition that could then be used as targets for restoration or mitigation.", "cite_spans": [{"start": 99, "end": 103, "text": "[55]", "ref_id": "BIBREF54"}], "ref_spans": []}, {"section": "Discussion", "text": "Our findings also may contribute to adaptive management of estuarine waterbird communities. As in many coupled naturalhuman systems, management planning in Chesapeake Bay and other estuaries requires iterated decision making in the face of uncertainty about future changes in land cover and climate [56] . Restoring and maintaining fish and wildlife populations is mandated by state and federal management agencies, but current monitoring in Chesapeake Bay assigns a separate grade to each part of the system and therefore is not entirely consistent with the decision context [57] . Our results provide a snapshot of the chief pathways through which land cover and water quality interact to limit waterbird communities under two extremes of annual rainfall. By themselves, these findings may not cover a sufficient time scale to immediately facilitate management decisions; however, the strong linkages we illustrate among waterbirds, water quality, and land cover indicate the need for a long-term monitoring program to explicitly track the structure of these relationships. Such an approach could help align monitoring efforts with management decision-making and potentially facilitate the knowledge feedback that is central to adaptive management. 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Distribution of 27 watersheds and associated subestuaries in Chesapeake Bay, USA where relationships between land cover, water quality, and waterbird communities were studied in the dry year of 2002 (white), the wet year of 2003 (gray), and in both years (black). The inset shows an example distribution of the three waterbird sampling transects in the lower, middle, and upper reaches of the subestuary. doi:10.1371/journal.pone.0035969.g001", "type": "figure"}, "FIGREF1": {"text": "(2002: stress = 0.176; 2003: stress = 0.183). Both generalists and specialists were widely distributed among subestuaries in the drought year of 2002 and demonstrated no clear association with land cover or water quality indices (Fig. 2A, see", "type": "figure"}, "FIGREF2": {"text": "Examination of multivariate kurtosis values revealed moderate departure from multivariate normality (2002: kurtosis = 6.48, critical ratio = 1.12; 2003: kurtosis = 8.11, critical ratio = 1.62), but a Bollen-Stine bootstrap indicated that model fit was not compromised (P = 0.878). Based on these results, we interpreted the model in which all paths varied independently between 2002 and 2003. Pearson correlation coefficients, variances, and covariances among variables in these models are presented in", "type": "figure"}, "FIGREF3": {"text": "Figure 2. Non-metric multidimensional scaling (MDS) of Chesapeake Bay, USA waterbird communities in (A) 17 subestuaries in the drought year of 2002 (stress = 0.176) and (B) 20 subestuaries in the near record wet year of 2003 (stress = 0.183). Species centroids were mapped in 2-dimensional ordination space and rotational vector fitting was used to relate land cover, water quality, and waterbird community composition (WCC) scores to the ordination. WCC scores are a measure of waterbird community composition, where subestuaries with high abundances of specialist species (blue) received high scores and those with high abundances of generalists (red) received lower scores (DeLuca et al. 2008). Species codes and WCC scores are shown in Table S1. IDW development is the percent urban development in each watershed weighted by the square of its inverse distance to the shoreline. The vector for percentage marsh in 2002 was short and was not plotted for clarity. doi:10.1371/journal.pone.0035969.g002", "type": "figure"}, "FIGREF4": {"text": "r2 = 0.12. P = 0.368). In contrast, in the wet year of 2003, WCC scores in the same subestuaries decreased with increasing nitrate-N concentration (r2 = 0.51. P = 0.032). These data suggest that higher nitrate-N concentrations observed in 2003 were unlikely due to spatial variation resulting from sampling a group of different subestuaries in 2002 and 2003.", "type": "figure"}, "FIGREF5": {"text": "Figure 3. Structural equation models (SEM) testing hypothesized causal effects of land cover and rainfall on waterbird community composition (WCC) in Chesapeake Bay, USA. The best-fit model indicated variation in the strength of direct (red) and indirect paths (blue) between (A) 2002, a year of severe drought, and (B) 2003, a year of near record rainfall (x 2 = 11.49, df = 12, P = 0.487; RMSEA ,10 23", "type": "figure"}, "FIGREF6": {"text": "Figure 4. Relationship between nitrate-N concentration and waterbird community composition (WCC) in the nine subestuaries of Chesapeake Bay, USA that were sampled in both the drought year of 2002 and the wet year of 2003. Nitrate-N levels did not limit waterbird community composition during the drought year of 2002 (white; r 2 = 0.12. P = 0.368), but were associated with degraded waterbird communities during the wet year of 2003 (grey; r 2 = 0.51. P = 0.032). doi:10.1371/journal.pone.0035969.g004", "type": "figure"}, "FIGREF7": {"text": "Figure S1 Results of a generalized additive model showing the relationship between percent urban development in the watershed and the partial residuals of nitrate-N concentration (adjusted for percent cropland) during (A) the drought year of 2002 (r2 = 0.61, P = 0.001) and (B) the wet year of 2003 (r2 = 0.62, P = 0.001). Dashed lines depict 95% confidence intervals. (TIF) Text S1 Methods of WCC index development. (DOCX) Table S1 List of bird species detected on transect surveys in Chesapeake Bay, USA subestuaries in the dry year of 2002 and the wet year of 2003 and their waterbird community composition (WCC) scores. (DOCX) Table S2 Pearson's correlations (below diagonal), variances (diagonal; in bold), and covariances (above diagonal) for variables used in the best-fit structural equation model (SEM) in which all paths were free to vary between the drought year of 2002 and the wet year of 2003. (DOCX)", "type": "figure"}, "TABREF0": {"text": "Standardized total effects, model correlations, and observed correlations from the best-fit structural equation model (SEM) in which all paths were free to vary between the drought year of 2002 and the wet year of 2003.Differences between observed and model correlations give specific estimates of residual error in model fit. Total effects are the sum of all direct and indirect effects between predictor and response variables, where indirect effects are the product of all direct effects along a hypothesized casual pathway.", "type": "table"}, "TABREF1": {"text": "Water quality indices (mean 6 SE) from six sampling stations in each of 27 subestuaries of Chesapeake Bay, USA.", "type": "table"}, "TABREF2": {"text": "Dissolved", "type": "table"}, "TABREF3": {"text": "Cygnus olor], mallard [Anas platyrhynchos], domestic duck [Anas and Cairina spp.], and Canada goose [(Branta canadensis]) incorporate aquatic or terrestrial plants in their diet. Eutrophic, oxygen depleted conditions, such as those present in 2003, have been linked to reduced abundance and mortality of fish species consumed as prey by piscivorous waterbirds in Chesapeake Bay and other shallow estuaries", "type": "table"}}}
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An investigation of humidification properties of HME under clinical conditions", "authors": [{"first": "J", "middle": [], "last": "Rathgeber", "suffix": ""}, {"first": "K", "middle": [], "last": "Z\u00fcchner", "suffix": ""}, {"first": "D", "middle": [], "last": "Kietzmann", "suffix": ""}, {"first": "W", "middle": [], "last": "Weyland", "suffix": ""}], "year": 1995, "venue": "Anaesthesist", "link": null}, "BIBREF14": {"title": "Evaluation of a 3rd generation heat and moisture exchanger as an alternative to conventional humidifiers in ICU", "authors": [{"first": "M", "middle": [], "last": "Chiaranda", "suffix": ""}, {"first": "O", "middle": [], "last": "Pinamonti", "suffix": ""}, {"first": "L", "middle": [], "last": "Verona", "suffix": ""}, {"first": "G", "middle": [], "last": "Conti", "suffix": ""}, {"first": "G", "middle": [], "last": "Minoja", "suffix": ""}], "year": 1992, "venue": "Acta Anaesth Ital", "link": null}, "BIBREF15": {"title": "An evaluation of the heat and moisture exchange performance of four ventilator circuit filters", "authors": [{"first": "C", "middle": [], "last": "Jackson", "suffix": ""}, {"first": "A", "middle": ["R"], "last": "Webb", "suffix": ""}], "year": 1992, "venue": "Intensive Care Med", "link": "9420255"}, "BIBREF16": {"title": "Comparing two heat and moisture exchangers with one vaporizing humidifier in patients with minute ventilation greater than 10 l/min", "authors": [{"first": "C", "middle": [], "last": "Martin", "suffix": ""}, {"first": "L", "middle": [], "last": "Thomachot", "suffix": ""}, {"first": "B", "middle": [], "last": "Quinio", "suffix": ""}, {"first": "X", "middle": [], "last": "Viviand", "suffix": ""}, {"first": "J", "middle": [], "last": "Albanese", "suffix": ""}], "year": 1995, "venue": "Chest", "link": "41862334"}, "BIBREF17": {"title": "A comparative evaluation of disposable humidifiers", "authors": [{"first": "C", "middle": [], "last": "Mebius", "suffix": ""}], "year": 1983, "venue": "Acta Anaesthesiol Scand", "link": "9265109"}, "BIBREF18": {"title": "Conditioning of inspired air by a hygroskopic condenser humidifier", "authors": [{"first": "F", "middle": ["P"], "last": "Primiano", "suffix": ""}, {"first": "M", "middle": ["E"], "last": "Moranz", "suffix": ""}, {"first": "F", "middle": ["W"], "last": "Montague", "suffix": ""}, {"first": "R", "middle": ["B"], "last": "Miller", "suffix": ""}, {"first": "Dlp", "middle": [], "last": "Sachs", "suffix": ""}], "year": 1984, "venue": "Crit Care Med", "link": null}, "BIBREF19": {"title": "Conditioning of the inspired air with HMEs (heat and moisture exchangers) -an effective and cost saving alternative to heated humidifiers in long term ventilated patients. 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{"paper_id": "8336120", "_pdf_hash": "2254570e18c9762fd0d32d29db39a8d940843aa4", "abstract": [{"section": "Abstract", "text": "Background: The choice of antiretroviral drugs has evolved over the last decade. Recognition of trends and determinants of changes may help to make predictions on prescription patterns.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Longitudinal analyses were performed every 6 months from 1996 to 2006, of all HIV-infected individuals who attended at one HIV/AIDS referral centre located in Madrid, Spain.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Results: A total of 2602 different individuals attending during the study period were examined over 23 consecutive time-points. The number and proportion of patients under antiretroviral therapy significantly increased in the period 1996-99, with a plateau since then around 1100 patients, which represented around two-thirds of the patients seen at each time-point after the year 2000. The proportion of patients under antiretroviral therapy having undetectable viraemia significantly increased from 34.5% in 1996 to 80% in 2006. The relative use of nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors (PIs) has risen in recent years, while prescription of non-nucleoside reverse transcriptase inhibitors has declined compared with the period 1999 -2001, when it peaked. Among NRTIs, the use of zalcitabine, stavudine and didanosine has dramatically declined or vanished, while zidovudine, lamivudine, abacavir and tenofovir have gained relevance. Among PIs, indinavir and nelfinavir have almost disappeared, being replaced by ritonavir-boosted PIs, mainly atazanavir and lopinavir. After its first introduction in the year 1999, efavirenz has been generally preferred over nevirapine.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "The choice of antiretroviral drugs has evolved during the last decade, with safety and convenience issues driving most changes in prescription patterns, while antiviral success has dramatically increased.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Antiretroviral treatment has been a major medical achievement which, in combination with antibiotic prophylaxis, has been estimated to have saved more than 3 million patient-years of life in the USA alone. 1 Moreover, there is no doubt that the efficacy of antiretroviral therapy has increased over time. First, we learnt about the only transient benefit of mono-or bitherapy with nucleoside reverse transcriptase inhibitors (NRTIs), such as zidovudine, 2 didanosine 3 or zalcitabine. 4 In 1996, the appearance of two new NRTIs, namely stavudine and lamivudine, and the marketing of protease inhibitors (PIs) as a new class of drugs gave birth to the concept of highly active antiretroviral therapy (HAART). 5 For the first time, in patients under triple drug therapy, we assisted in dramatic CD4 count gains within months of treatment, with evidence of reduction in HIV replication below the limits of detection in most patients compliant with their medication. Altogether, these laboratory findings translated into remarkable reductions in morbidity and mortality in HIV-infected persons.", "cite_spans": [{"start": 206, "end": 207, "text": "1", "ref_id": "BIBREF0"}, {"start": 485, "end": 486, "text": "4", "ref_id": "BIBREF3"}, {"start": 708, "end": 709, "text": "5", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Introduction", "text": "Although virologically effective, the clinical performance of initial PI-containing triple drug regimens was far from optimal, mainly due to frequent adverse events. The simplification of HAART first became possible in 1998 with the appearance of non-nucleoside reverse transcriptase inhibitors (NNRTIs). These new drugs proved at least as effective as PI when used along with two NRTIs. 7 More recently, the co-formulation of different NRTIs in one pill 8 and the boosting of PI with low doses of ritonavir have further enhanced the efficacy of HAART, as a result of improved convenience. 9 There are currently 23 FDA-licensed compounds to treat HIV infection. The availability of new antiretroviral drugs and the increased knowledge of HIV disease have been accompanied by significant changes in antiretroviral prescription patterns. 10 -16 The aim of this study was to analyse the relative use of antiretroviral drugs, the factors influencing their prescription and the overall virological success of therapy over the last decade.", "cite_spans": [{"start": 388, "end": 389, "text": "7", "ref_id": "BIBREF6"}, {"start": 455, "end": 456, "text": "8", "ref_id": "BIBREF7"}, {"start": 590, "end": 591, "text": "9", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Methods", "text": "A retrospective review of antiretroviral drugs prescribed to HIVinfected patients was conducted at one AIDS/HIV referral centre located in Madrid, Spain. The assessment of drug prescription was made by 6 month consecutive cross-sections, specifically sampling patients every June and December, from December 1995 to December 2006. The total number of distinct HIV-infected patients, with or without antiretroviral drug treatment, attending at each time-point was recorded from the Pharmacy register and the clinic database.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "Only adults older than 18 years with a positive serology (reactive EIA and confirmatory western blot) who had started or were already receiving antiretrovirals within the month of the analysis were included. Their main demographics, including age, gender and risk group, as well as plasma HIV-RNA values, were registered the first time each patient entered the database. The proportion of patients with plasma HIV-RNA ,50 copies/mL (500 copies/mL before the year 2001) was determined at the closest time to each time-point, twice a year.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "The choice of the antiretroviral regimen was at the discretion of the doctor in charge. Antiretrovirals had been always given free of charge at the hospital's pharmacy, where each prescription was computerized into a central database, containing drugs and doses (dose per pill and per day), amount of tablets delivered and date of dispensing. As previously mentioned, it is the pharmacy policy to limit antiretroviral delivery to once per month, with a requirement for a new physician's prescription form every 3 months. Therefore, all HIV-infected patients under antiretroviral therapy visited the pharmacy monthly or in the event of any unplanned treatment change.", "cite_spans": [], "ref_spans": []}, {"section": "Statistical analyses", "text": "All descriptive results are given as total numbers and percentages. Comparisons of percentages were made using the x 2 test. All data were analysed using the SPSS v13.0 software (SPSS Inc., Chicago, IL, USA).", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "From December 1995 to December 2006, a total of 23 crosssectional analyses was performed. A total of 2602 different HIV-infected individuals on antiretroviral therapy was examined. Their main characteristics at the time of first inclusion in the database are summarized in Table 1 . There was a flux of patients who entered and left the HIV clinic during the study period due to a variety of reasons, including change of city or country of residence, deaths, voluntary transfer to other hospitals etc. On average, 190 new patients entered for follow-up per year and 40 stopped hospital visits. Overall, the mean number of patients on follow-up at different time-points in this 11 year study was 960 + 143, ranging from a minimum of 275 patients in December 1995 to a maximum of 1190 in December 2005. Figure 1 shows the evolution in the number of patients receiving antiretroviral treatment during the study period. There was a rapid increase in the rate of prescriptions up to mid-1999, while since year 2000 onwards the number of treated patients has remained fairly stable around 1100 patients. Among all HIV-infected individuals attending, the proportion under antiretroviral treatment increased from 37% in December 1996 to 55% in December 1998 (P , 0.001). From mid-1999 up to the end of the study, HAART has been given, on average, to 65% and 69% of all patients attending the outclinic. Figure 1 also shows the proportion of patients under antiretroviral treatment with undetectable plasma HIV-RNA during the study period. It should be highlighted that the proportion of treated patients with undetectable plasma viraemia steadily increased from 34.5% at the beginning of the study to up to 80% at the end of the year 2006. A simple view might recognize two periods: before the year 2000, when the proportion of patients with undetectable plasma viraemia was not much beyond 60%, and since then, with a steady increase up to 80% at the end of the study period.", "cite_spans": [], "ref_spans": [{"start": 273, "end": 280, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Results", "text": "The relative contribution of NRTIs, NNRTIs and PIs to the total consumption of antiretrovirals during the study period is depicted in Figure 2 . Drugs belonging to the NRTI family were the most prescribed medications at all time-points, in agreement with their role as the backbone of most HAART regimens. The prescription of PIs begun in 1996 and kept growing steadily up to June 1998, when NNRTIs started to be broadly used. The relative use of NNRTIs over PIs moved from 0.13 in June 1998 to 2.04 in June 2001, which means that by then NNRTIs were given twice more frequently than PIs. However, the relative use of NNRTIs began to decline by the end of 2004, when its prescription with respect to PIs was 0.98. This trend towards a lower use of NNRTIs over PIs has become more evident within the last few years, 0.79 being the relative use of these drugs by the end of 2006. ", "cite_spans": [], "ref_spans": []}, {"section": "Trends in antiretroviral therapy", "text": "The prescription of different NRTIs along the study period is depicted in Figure 3 . Zidovudine, didanosine and zalcitabine were the first antiretrovirals available. However, the prescription of zalcitabine was never .8% and lasted for a relatively short time, being almost absent by the end of 1998. The use of didanosine reached a maximum in 1996 (40% of treated patients), and a smaller second peak was seen in 2001 (20% of treated patients). Since then its prescription has steadily declined, being only 4% at the end of the study period.", "cite_spans": [], "ref_spans": []}, {"section": "Trends in antiretroviral therapy", "text": "The use of zidovudine, prescribed to more than half the patients at the beginning of the study, declined with the introduction of stavudine at the end of 1996. However, safety concerns (e.g. lipodystrophy, mitochondrial toxicity and lactic acidosis) caused a reduction in the prescription of stavudine from a peak of 40% in mid-1999 to ,1% by December 2006. 16 In contrast, zidovudine prescription has remained fairly stable over time, and even increased up to around 15% within the most recent years. It should be noted, however, that this was mainly driven by the availability of its co-formulation with lamivudine and/or abacavir. Tenofovir and emtricitabine are the most recent approved antiretroviral NRTIs, and are very often co-formulated in a single pill once a day. By the end of 2006, their prescription represented 16% of all NRTIs. The first available PIs back in 1996 were saquinavir, indinavir and ritonavir. While ritonavir prescription at full doses (600 mg twice daily) was rapidly abandoned, the use of indinavir and saquinavir declined more slowly ( Figure 4 ) and in parallel with the introduction of NNRTIs. The availability of nelfinavir in 1997 was followed by a rapid decline in indinavir use, which moved from 70% in 1996 to ,20% when nelfinavir was at its maximum at the end of the year 2000. Lopinavir, co-formulated with low doses of ritonavir, was introduced in 2001 and rapidly displaced other PIs; by mid-2004, it represented 80% of all PIs given. The availability of atazanavir during the last semester of 2004 was followed by a rapid switch in PI prescription patterns, mainly as a result of simplification strategies, and in an attempt to ameliorate lipid abnormalities and reduce the pill burden. 17 The use of amprenavir was fairly low until mid-2005, but experienced an increase since then, when fosamprenavir became available. Finally, tipranavir was only marketed early in the year 2006, and it has mainly been prescribed to heavily antiretroviral-experienced patients. Its relatively poor safety profile and the need for it to be given along with 200 mg of ritonavir twice a day have limited its broader use.", "cite_spans": [{"start": 358, "end": 360, "text": "16", "ref_id": "BIBREF15"}, {"start": 1732, "end": 1734, "text": "17", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "18", "text": "Only two NNRTIs, nevirapine and efavirenz, have been licensed in Spain. Figure 5 shows trends in their respective prescription. Nevirapine was first introduced in June 1998, and efavirenz, a year later. Prescription of both NNRTIs has remained balanced over time, with a slight trend towards increased use of efavirenz.", "cite_spans": [], "ref_spans": [{"start": 72, "end": 80, "text": "Figure 5", "ref_id": "FIGREF2"}]}, {"section": "Discussion", "text": "The achievement of an effective treatment for HIV infection has been one of the most remarkable milestones in the recent history of medicine. This is true not only for the number of lives that have been saved, but also for the amount of scientific ", "cite_spans": [], "ref_spans": []}, {"section": "Trends in antiretroviral therapy", "text": "information that has been generated alongside the daily treatment of HIV-infected individuals. The analysis of changes in the prescription of antiretroviral drugs is a good exercise of how clinical practice and research may meet to continuously improve the management of HIV-infected patients. Here, we describe the evolution of prescription patterns of antiretroviral medications during the first 11 years of the HAART era. Although similar studies have been conducted by others, 19 -22 this is the longest, and has a large population.", "cite_spans": [], "ref_spans": []}, {"section": "Trends in antiretroviral therapy", "text": "At the beginning of the HAART era, and somewhat under the influence of the attractive paradigm 'hit hard, hit early', 23 most patients were put under treatment regardless of immune status, in view of the rapid suppression of HIV replication achieved in most cases. 24 This was accompanied by a sharp decline in AIDS-related morbidity and mortality in the Western world. 25 -27 Both factors, treatment efficacy and physicians' readiness to start therapy, explain the rapid increase in antiretroviral drug prescriptions observed at our institution between 1996 and 2000.", "cite_spans": [{"start": 118, "end": 120, "text": "23", "ref_id": "BIBREF22"}, {"start": 265, "end": 267, "text": "24", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Trends in antiretroviral therapy", "text": "The initial enthusiasm generated by HAART success was somewhat blunted in the following 2 -3 years for three main reasons. First, the awareness that HIV eradication was not feasible despite long-term suppression of viral replication. 28 Second, the recognition of a significant impairment in the patient's quality of life as a result of adverse effects 29 and high pill burden 30 of the medication. Lastly, the relatively frequent occurrence of drug resistance in the event of viral breakthrough. 31 As a result, there was a progressive trend towards delayed initiation of HAART. This fact translated, in our clinic, into a slow-down in HAART exposure since 1998, which plateaued in mid-2000 to around 1100 patients. This figure has remained fairly stable up to December 2006. A similar trend in HAART prescription has been reported by others. 32, 33 As expected, the proportion of patients with undetectable plasma viraemia grew in parallel with the number of treated patients. By the end of 1999, however, it stabilized to around 60% of patients under HAART. This figure, on the other hand, may indirectly reflect the accumulation of patients who had failed NNRTI and the first PI generation. The wide prescription of NNRTIs as part of first-line therapy and ritonavir-boosted second-generation PIs since mid-1998 was the main factor explaining the regain of an increased efficacy of HAART since then. By the end of the study period, the rate of virological success increased up to 80% of all treated patients. The availability of easier-to-take forms of NRTI medications, including co-formulations, and the movement to once-daily dosing have been other important determinants of this enhanced HAART efficacy over time. 34 AlI these factors, along with the recommended use of two NRTIs as the backbone in most HAART regimens, explain why, as a whole, 70% of all prescribed antiretroviral medications belong to the NRTI family.", "cite_spans": [{"start": 234, "end": 236, "text": "28", "ref_id": "BIBREF26"}, {"start": 353, "end": 355, "text": "29", "ref_id": "BIBREF27"}, {"start": 377, "end": 379, "text": "30", "ref_id": "BIBREF28"}, {"start": 497, "end": 499, "text": "31", "ref_id": "BIBREF29"}, {"start": 844, "end": 847, "text": "32,", "ref_id": "BIBREF30"}, {"start": 848, "end": 850, "text": "33", "ref_id": "BIBREF31"}, {"start": 1722, "end": 1724, "text": "34", "ref_id": "BIBREF32"}], "ref_spans": []}, {"section": "Trends in antiretroviral therapy", "text": "The results of our study show that three major forces have driven the prescription of different antiretrovirals in the last decade, namely efficacy, safety profile and simpler administration. There is little doubt that lack of efficacy accounted for the disappearance of zalcitabine and that toxicity issues explained the rapid decline in stavudine use. 35 In contrast, zidovudine and lamivudine regained positions after 2001, when a co-formulation became available. 36 Tenofovir and emtricitabine were the latest NRTIs to enter the market, but they have rapidly gained positions, most likely due to a combination of good tolerance, convenience and potency. 37 It should be noted that no more than 15% of all antiretroviral medications prescribed since 2002 were PIs. These drugs were rapidly incorporated into the HIV armamentarium in 1996, once their efficacy in combination with NRTIs was proven. 34 However, as noticed by others, 38 the overall use of PIs began to decline as early as in 1998, when NNRTIs first became available, and when the first reports of the lipodystrophy syndrome appeared. 39 All first-generation PIs, namely indinavir, saquinavir, ritonavir and even nelfinavir, are now seldom used. These drugs have been replaced by novel PI compounds, such as lopinavir, atazanavir and tipranavir which, when boosted with low doses of ritonavir, are more effective and convenient. The introduction of the first NNRTI occurred in 1998. Enhanced convenience and lack of metabolic side effects drove the switching of strategies from PI to NNRTI. The use of NNRTIs has relatively declined over time, given its low genetic barrier for resistance and cross-resistance. Their use has been mainly restricted to first-line therapies in recent years. The use of either nevirapine or efavirenz has been well balanced over time at our clinic with a trend towards increased prescription of efavirenz over nevirapine, in agreement with the slight advantage seen in some clinical trials, 40 and by the fact that a relatively high proportion of our patient population had chronic hepatitis C, a condition that may be prone to development of hepatotoxicity using nevirapine. 41 Some limitations of our study should be acknowledged. The analysis of the prescription of antiretrovirals was performed in an open cohort, in which we had no information regarding the specific number of patients periodically entering or exiting. Most likely, prescription patterns would have been fairly different if drug-naive and treatment-experienced patients could have been considered separately, or if plasma HIV-RNA levels and/or CD4 counts had been taken into account. On the other hand, treatment changes occurring within a period shorter than 6 months may have been missed, causing underreporting of the use of drugs with very early toxicity profiles, such as abacavir, nevirapine or efavirenz. Finally, no assessment of associations between distinct antiretrovirals was made, which would have helped to better appreciate the reasons for some changes in prescription patterns.", "cite_spans": [{"start": 354, "end": 356, "text": "35", "ref_id": "BIBREF33"}, {"start": 467, "end": 469, "text": "36", "ref_id": "BIBREF34"}, {"start": 900, "end": 902, "text": "34", "ref_id": "BIBREF32"}, {"start": 934, "end": 936, "text": "38", "ref_id": "BIBREF35"}, {"start": 1101, "end": 1103, "text": "39", "ref_id": "BIBREF36"}, {"start": 2172, "end": 2174, "text": "41", "ref_id": "BIBREF37"}], "ref_spans": []}, {"section": "Trends in antiretroviral therapy", "text": "In summary, despite a relative stabilization in the number of patients under HAART seen at our institution since year 2000, there has been a steady increase in the proportion of treated patients with undetectable plasma HIV-RNA. The simplification of HAART regimens, by using antiretrovirals with simpler schedules and improved tolerance, together with enhanced potency, are good reasons to explain this observation. Convenience, safety and potency are the three major forces that drive antiretroviral prescription patterns in the clinical setting.", "cite_spans": [], "ref_spans": []}, {"section": "Funding", "text": "", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "The survival benefits of AIDS treatment in the United States", "authors": [{"first": "R", "middle": [], "last": "Walensky", "suffix": ""}, {"first": "A", "middle": [], "last": "Paltiel", "suffix": ""}, {"first": "E", "middle": [], "last": "Losina", "suffix": ""}], "year": 2006, "venue": "J Infect Dis", "link": "13239542"}, "BIBREF1": {"title": "The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. 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Number of patients on antiretroviral treatment and proportion of them with undetectable plasma HIV-RNA over time.", "type": "figure"}, "FIGREF1": {"text": "Figure 3. Trends in the relative prescription of distinct NRTIs.", "type": "figure"}, "FIGREF2": {"text": "Figure 5. Trends in the relative prescription of NNRTIs.", "type": "figure"}, "TABREF0": {"text": "Main characteristics of the study population", "type": "table"}}}
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{"paper_id": "8337033", "_pdf_hash": "f78efe654e2630cdeb9794e654c25e2b6c58f3a7", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Biological Mechanisms of Tooth Movement and Craniofacial Adaptation", "authors": [{"first": "B", "middle": [], "last": "Rifkin", "suffix": ""}, {"first": "L", "middle": ["M"], "last": "Golub", "suffix": ""}, {"first": "F", "middle": [], "last": "Sanavi", "suffix": ""}, {"first": "A", "middle": ["T"], "last": "Vernillo", "suffix": ""}, {"first": "A", "middle": ["P"], "last": "Kleckner", "suffix": ""}, {"first": "T", "middle": ["F"], "last": "Mcnamara", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Auszmann", "suffix": ""}, {"first": "N", "middle": ["S"], "last": "Ramamurthy", "suffix": ""}], "year": 1992, "venue": "", "link": "72945195"}, "BIBREF13": {"title": "The Extra Pharmacopoeia", "authors": [{"first": "", "middle": [], "last": "Martindale", "suffix": ""}], "year": 1989, "venue": "", "link": "70813555"}}, "ref_entries": {}}
{"paper_id": "8337351", "_pdf_hash": "72f68fdaba5781e5afb9456caa8275814855aa07", "abstract": [{"section": "Abstract", "text": "Prostate cancer is the most commonly diagnosed cancer in men and one of the leading causes of cancer deaths. There is strong genetic evidence indicating that a large proportion of prostate cancers are caused by heritable factors but the search for prostate cancer susceptibility genes has thus far remained elusive. TGFBR1*6A, a common hypomorphic variant of the type I Transforming Growth Factor Beta receptor, is emerging as a tumor susceptibility allele that predisposes to the development of breast, colon and ovarian cancer. The association with prostate cancer has not yet been explored. A total of 907 cases and controls from New York City were genotyped to test the hypothesis that TGFBR1*6A may contribute to the development of prostate cancer. TGFBR1*6A allelic frequency among cases (0.086) was slightly higher than among controls (0.080) but the differences in TGFBR1*6A genotype distribution between cases and controls did not reach statistical significance (p = 0.67). Our data suggest that TGFBR1*6A does not contribute to the development of prostate cancer.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Background", "text": "Transforming Growth Factor Beta (TGF-\u00df) is one of the most potent inhibitor of cell growth [1] . Almost all cancer cells loose the ability to be growth inhibited by TGF-\u00df, which makes loss of TGF-\u00df growth inhibition a hallmark of cancer development [2] . TGFBR1*6A is a common variant of the type I TGF-\u00df receptor, TGFBR1 [3] . TGFBR1*6A (*6A) has a deletion of three GCG triplets coding for alanine within a nine alanine (9A) repeat sequence of TGFBR1 (*9A) exon 1, resulting in a six alanine (6A) repeat sequence. The 9-bp deletion that differentiates *6A from *9A is located within the predicted signal sequence cleavage region. In vitro studies have demonstrated that TGFBR1*6A responds less effectively than TGFBR1 to TGF-\u00df growth inhibitory signals [4, 5] . The additional findings of an overrepresentation of TGFBR1*6A heterozygotes and homozygotes among patients with a diagnosis of cancer as compared with the general population led us to postulate that TGFBR1*6A might act as a tumor susceptibility allele [5] . Two recent meta-analyses show that TGFBR1*6A carriers may have an increased risk of breast, colon and ovarian cancer [6, 7] . To test the hypothesis that TGFBR1*6A may contribute to the development of prostate cancer, we conducted a case control study of patients with biopsy verified prostate cancer cases and geographically and ethnic-status matched controls.", "cite_spans": [{"start": 91, "end": 94, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 249, "end": 252, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 322, "end": 325, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 755, "end": 758, "text": "[4,", "ref_id": "BIBREF3"}, {"start": 759, "end": 761, "text": "5]", "ref_id": "BIBREF4"}, {"start": 1016, "end": 1019, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 1139, "end": 1142, "text": "[6,", "ref_id": "BIBREF5"}, {"start": 1143, "end": 1145, "text": "7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Results", "text": "A total of 907 cases and controls were genotyped for TGFBR1*6A. The mean age of cases was significantly higher than controls (p < 0.01) but there were no differences in ethnic status between the two groups. There were 59 TGFBR1*6A heterozygotes and three TGFBR1*6A homozygotes among cases, 62 TGFBR1*6A heterozygotes and 1 TGFBR1*6A homozygote among controls. TGFBR1*6A allelic frequency among cases (0.086) was slightly higher than among controls (0.080) but the differences in TGFBR1*6A genotype distribution between cases and controls did not reach statistical significance (p = 0.67) ( Table 1 ). Effect estimates from conditional logistic regression were similar (OR 1.01, 95% CI 0.29-3.52) to those from unconditional logistic regression (OR 0.96, 95% CI 0.56-1.64). Analyses restricted to subjects aged 40 years and above controlling age on a continuous scale produced essentially the same effect estimates (OR 0.94, 95% CI 0.56-1.60). To examine the possibility that TGFBR1*6A is associated with early onset prostate cancer, we determined the prostate cancer risk for individuals above and below the age of 55. Among younger patients with prostate cancer we found that 13 of 59 were TGFBR1*6A carriers yielding an allelic frequency of 0.119, one of the highest TGFBR1*6A allelic frequency ever reported. Only 45 of 367 controls in the same age range were TGFBR1*6A carriers yielding an allelic frequency of 0.063, which is similar to the TGFBR1*6A allelic frequency found among 3,451 healthy controls from Europe and the U.S. [7] . The association between carrier status of TGFBR1*6A and prostate cancer in younger age group was significant after adjustment for race (OR 2.13, 95% CI 1.06-4.27) but was not significant after adjustment for race and age strata within groups (OR 2.11, 95% CI 0.98-4.57) ( Table 2 ). While in the older age group we did not observe a significant association either (OR 0.57, 95% CI 0.30-1.10), the test for multiplicative interaction between age and carrier status of TGFBR1*6A was significant (p = 0.01).", "cite_spans": [{"start": 1534, "end": 1537, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": [{"start": 590, "end": 597, "text": "Table 1", "ref_id": "TABREF0"}, {"start": 1812, "end": 1819, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "Discussion", "text": "Prostate cancer is the most common cancer and the second most common cause of cancer death among U.S. men [8] . A similar pattern is observed throughout the western world. There is strong epidemiologic evidence indicating that a large proportion of prostate cancers are caused by heritable factors. The most convincing data is a study of 44,788 Scandinavian twins showing that 42% of prostate cancer cancers may be caused by shared genes [9] . Despite intense efforts led by several research teams, the search for prostate cancer susceptibility genes has thus far remained elusive. Recent studies suggest that carriers of deleterious mutations of the BRCA2 gene have an increased prostate cancer risk [10] . However, given the low prevalence of deleterious BRCA2 mutations in the general population, it is unlikely to account for a significant proportion of prostate cancer cases. Approximately 14% of the general population carries at least one copy of TGFBR1*6A, which makes it the most common candidate tumor susceptibility allele reported to date. While there is growing evidence that TGFBR1*6A predisposes to the development of breast, colon and ovarian cancer, our data do not suggest that it predisposes to the development of prostate cancer. We have previously shown that TGFBR1*6A homozygotes have an O.R of 2.69 and 2.02 for ovarian and colon cancer, respectively. The present study has the power to detect an O.R. for prostate cancer of 1.70 or higher and therefore rules out a major association between TGFBR1*6A and prostate cancer. However, it does not exclude a smaller O.R., which might have clinical relevance given the high TGFBR1*6A allelic frequency in the general population. It is possible that age differences in cases and controls affected the allele frequencies observed. If the TGFBR1*6A allele predisposes to a lethal malignancy such as prostate cancer, however, its frequency could be higher, not lower, in a younger cohort. Thus, the younger mean age of controls could result in a bias toward the null hypothesis, resulting in a stronger association than that observed. The intriguing findings of a high TGFBR1*6A allelic frequency among prostate cancer cases diagnosed before the age of 55 have to be cautiously interpreted given the fact that this group only included 46 patients. We have previously shown that TGFBR1*6A is not associated with an increased risk of bladder cancer [6] . Our results suggest that the association between TGFBR1*6A and prostate cancer is at best very weak but further studies are needed to formally exclude an association with early onset prostate cancer.", "cite_spans": [{"start": 106, "end": 109, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 438, "end": 441, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 701, "end": 705, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 2411, "end": 2414, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Methods", "text": "DNA was extracted from lymphocytes of blood specimens from 465 consecutive individuals diagnosed with adenocarcinoma of the prostate who received care at the outpatient urology clinic at Memorial Sloan-Kettering Cancer Center from April 2000 to September 2002. The blood samples were collected following completion of diagnostic studies. They were unselected for age or family history. Clinical and pathological records were reviewed to confirm the diagnosis of prostate cancer in all subjects. Once pathological diagnosis of prostate cancer was confirmed, the age of diagnosis was recorded, and all other identifying links were destroyed. The study design and anonymization method were approved by the Memorial SloanKettering Cancer Center Institutional Review Board.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "A population of 465 healthy male controls aged 20 to 87 years with well-defined ethnic background who had donated blood for various reasons (predominantly prenatal screening for non-cancer disease) constituted the control group. Controls were matched to the cases on ethnicity and were from the same geographic locations as the prostate cancer cases. None of the controls had any personal history of cancer at the time of blood donation. This was ascertained by a questionnaire completed by each control. Exact age information was not available for 205 controls since it was not collected prospectively but the age range (20 to 40) was known. All personal identifiers were permanently removed from both cases and controls.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "DNA was extracted by standard technique using the Qiagen DNA extraction kit. The PCR primers used were 5'-CCA CAG GCG GTG GCG GCG CGA TG-3' in the forward direction and 5'-CGT CGC CCC CGG GAF CAG CGC CGC-3' in the reverse direction. A standard solution was cycles of denaturation for 30 seconds at 94\u00b0C and annealing/extension for 2 minutes at 72\u00b0C, followed by a final extension step of 5 minutes at 72\u00b0C. Quality controls were run on a 2% agarose gel. The ABI Prism 310 Genetic Analyzer (Applied Biosystems, Foster City, CA) was used for data acquisition. A peak at 115 base pairs corresponded to TGFBR1 allele, whereas a peak at 107 base pairs corresponded to the TGFBR1*6A variant. The rare equivocal results were confirmed by cloning of the PCR product followed by automated sequencing. Samples were read by two independent investigators unaware of the case /control status. Ten percent of samples were randomly selected and run for quality assurance. Concordance rate was 100%.", "cite_spans": [], "ref_spans": []}, {"section": "Statistical analysis", "text": "Distributions of TGFBR1 genotypes, age, and ethnicity were compared between cases and controls using Fisher's exact tests. To test the hypothesis that the hypomorphic TGFBR1*6A gene is related to an increased prostate cancer risk, adjusted odds ratios of prostate cancer were estimated using both conditional and unconditional logistic regression models. Both models were run since the matched controls of cases with missing genotypes had to be excluded in the conditional models but could be included in the unconditional models. Adjusted odds ratios of prostate cancer were estimated comparing carriers of TGFBR1*6A versus non-carriers under dominant models. Potential confounders such as age (in four strata) and ethnicity were controlled in the analysis. Whether the effects of TGFBR1*6A on prostate cancer differ by age was evaluated by stratified analysis and tests for multiplicative interaction. A small p value indicates that interaction of age and gene is statistically significant on the multiplicative level. For the unconditional models, sensitivity analysis was conducted to evaluate the impact of the fact that the exact age of some controls with age 20-40 years is unknown (N = 126). With 442 cases and 465 controls, the power to detect an OR of 1.7 and 2 in the present study was 0.86 and 0.98, respectively, based on a two-tailed test at the 0.05 significance level.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Cytostatic and apoptotic actions of TGFbeta in homeostasis and cancer", "authors": [{"first": "P", "middle": ["M"], "last": "Siegel", "suffix": ""}, {"first": "J", "middle": [], "last": "Massague", "suffix": ""}], "year": 2003, "venue": "Nat Rev Cancer", "link": "38903300"}, "BIBREF1": {"title": "TGF-beta signaling alterations in cancer", "authors": [{"first": "Y", "middle": [], "last": "Bian", "suffix": ""}, {"first": "V", "middle": [], "last": "Kaklamani", "suffix": ""}, {"first": "J", "middle": [], "last": "Reich", "suffix": ""}, {"first": "B", "middle": [], "last": "Pasche", "suffix": ""}], "year": 2003, "venue": "Cancer Treat Res", "link": "2712848"}, "BIBREF2": {"title": "Massague J: Type I transforming growth factor beta 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{"paper_id": "8339108", "_pdf_hash": "5b269db03e93d62d7e34be595fc9b79ef6fcdcdf", "abstract": [{"section": "Abstract", "text": "Abstract In the present paper, a model for the prediction of the local strength and stiffness properties is developed. Compared to existing models, here the local material properties are described according to their morphological characteristics; i.e. the timber boards are subdivided into sections containing knots (knot sections) and sections without knots (clear wood sections). The strains of the corresponding sections are measured during non-destructive tensile tests using an optical camera device. Based on these measurements the tensile stiffness of each particular section is estimated. For the estimation of the tensile strength, destructive tensile tests are performed. Herewith, the tensile strength of the entire timber board is measured. The strength of the other knot clusters are estimated using censored regression analysis. Taking into account the results of the experimental investigation, material models are developed to predict the tensile strength and the tensile stiffness of knot clusters.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Timber is a natural grown material which has, compared to other building materials, a large variation in its loadbearing behaviour. This variation can be observed between different growth regions, between different boards within the same growth region and even within one particular timber board (e.g. Fewell 1982; K\u00f6hler et al. 2007; Sandomeer et al. 2008) . As a simplification, the variation can be subdivided into (a) the variation between the timber boards and (b) the variation within the timber boards. In the past, numerous models have been developed to describe the variability of the material properties; e.g. Isaksson (1999) for ultimate bending capacity, Taylor and Bender (1991) and Kohler et al. (2013) for ultimate tensile capacity and bending stiffness, Kline el al. (1986) for bending stiffness and for tensile stiffness.", "cite_spans": [{"start": 315, "end": 334, "text": "K\u00f6hler et al. 2007;", "ref_id": "BIBREF16"}, {"start": 335, "end": 357, "text": "Sandomeer et al. 2008)", "ref_id": "BIBREF22"}, {"start": 620, "end": 635, "text": "Isaksson (1999)", "ref_id": "BIBREF14"}, {"start": 696, "end": 716, "text": "Kohler et al. (2013)", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "Introduction", "text": "The variability between the timber boards or rather the variability of the undisturbed timber (knot free timberdenoted as clear wood) is related to different growth and sawing characteristics; e.g. growth region, sapwood-heartwood. For the predictions of the mean material properties, different non-destructive test methods have been developed in the last decades. The most common methods are the Eigenfrequency measurement (e.g. Kollmann and Krech 1960; G\u00f6rlacher 1990) , the Ultrasonic runtime measurement (Steiger 1996) and the density. In several studies, correlations between those parameters and the material properties are analysed (e.g. G\u00f6rlacher 1984; Steiger 1996; Denzler 2007 ). In particular the first two methods, which are Eigenfrequency and ultrasonic runtime, show an exceptionally good correlation to the mean material properties.", "cite_spans": [{"start": 430, "end": 454, "text": "Kollmann and Krech 1960;", "ref_id": "BIBREF18"}, {"start": 508, "end": 522, "text": "(Steiger 1996)", "ref_id": "BIBREF23"}, {"start": 645, "end": 660, "text": "G\u00f6rlacher 1984;", "ref_id": "BIBREF12"}, {"start": 661, "end": 674, "text": "Steiger 1996;", "ref_id": "BIBREF23"}, {"start": 675, "end": 687, "text": "Denzler 2007", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Introduction", "text": "The variability of the strength and stiffness properties within structural timber is highly dependent on morphological characteristics of the tree, especially it is dependent on knots and their arrangement. Accordingly, numerous studies have been conducted to identify knot related indicators that are capable of describing the influence of knots on the load-bearing behaviour of timber boards relevant for the design of timber structures. Various models that represent the interrelation between numeral knot indicators and the load-bearing capacity exist. E.g. Denzler (2007) , Isaksson (1999) , Boatright and Garrett (1979a; 1979b) , Courchene et al. (1996) , Mitsuhashi et al. (2008) and have analysed the interrelation between ultimate bending and/or tensile capacity for different knot indicators. Mention that many times the load-bearing capacity of the weakest section (e.g. the knot cluster with the highest tKAR-value) is assumed as the load-bearing capacity of the entire timber board. The interrelation between the stiffness properties and knot indicators are analysed in Samson and Blanchet (1992) and . In all studies described above, no knot-indicator could be found for an efficient prediction of the strength and stiffness properties of structural timber without considering additional indicators, such as the density. However, the so called tKAR-value (total knot area ratio) is established as one of the most efficient.", "cite_spans": [{"start": 562, "end": 576, "text": "Denzler (2007)", "ref_id": "BIBREF6"}, {"start": 579, "end": 594, "text": "Isaksson (1999)", "ref_id": "BIBREF14"}, {"start": 597, "end": 626, "text": "Boatright and Garrett (1979a;", "ref_id": "BIBREF1"}, {"start": 627, "end": 633, "text": "1979b)", "ref_id": "BIBREF2"}, {"start": 636, "end": 659, "text": "Courchene et al. (1996)", "ref_id": "BIBREF5"}, {"start": 662, "end": 686, "text": "Mitsuhashi et al. (2008)", "ref_id": "BIBREF19"}, {"start": 1083, "end": 1109, "text": "Samson and Blanchet (1992)", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Introduction", "text": "Regarding the between and within-member variability of the material properties it is obvious that an efficient model for the prediction of the local strength and stiffness properties should include at least two indicators: (a) one that describes the mean material properties of the entire timber board, to consider the between member-variability of the mean material properties, and (b) one that describes the local strength and stiffness reduction through the occurrence of knots and knot cluster, to consider the within-member variability. Such an approach has already been used within the model presented in Bla\u00df et al. (2008) . There, the material properties of 150 mm long board segments are predicted using the dry density q 0 and the tKARvalue based on material models developed by Glos (1978) and Ehlbeck et al. (1985) , see also Heimeshoff and Glos (1980) for the test set-up. The models are developed based on material properties measured on specimens having a testing length of 137.5 mm.", "cite_spans": [{"start": 611, "end": 629, "text": "Bla\u00df et al. (2008)", "ref_id": "BIBREF0"}, {"start": 805, "end": 826, "text": "Ehlbeck et al. (1985)", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Introduction", "text": "In this paper, models for the prediction of the local material properties, based on experimental investigations of full scale timber boards (testing length [3,300 mm) are developed. Thereby it is particular focused on the prediction of the tensile strength and the tensile stiffness of knot clusters. Models to predict the following material properties are developed: -Tensile stiffness of clear wood -Tensile stiffness of knot clusters -Tensile strength of timber boards -Tensile strength of knot clusters", "cite_spans": [], "ref_spans": []}, {"section": "Experimental analysis", "text": "The experimental investigation includes the estimation of the tensile stiffness, the tensile strength and the dynamic modulus of elasticity as well as the measurement of all knots with a diameter larger than 10 mm. For the estimation of the tensile stiffness, non-destructive tensile tests are performed. The specific characteristic of this part of the experimental investigation is that the timber boards are previously subdivided into (a) sections containing knot clusters or large single knots (referred to as knot sections-KS), and (b) sections between the knot sections (referred to as clear wood sections-CWS). From all those sections the corresponding expansion is measured using an optical camera device.", "cite_spans": [], "ref_spans": []}, {"section": "Material", "text": "The stiffness properties are analysed based on two samples, each of 100 specimens; the species is Norway spruce (Picea abies) from Southern Germany. The boards are graded into the strength classes L25 and L40 according to the European standard EN 14081-4. The dimensions are 126 9 44 9 4,000 mm 3 . According to EN 14081-4 the strength classes L25 and L40 require a minimum characteristic tension capacity of 14.5 and 26.0 MPa, respectively. The grading of the boards is performed by the GoldenEye-706 grading device manufactured by MiCROTEC (Brixen, IT) (Giudiceandrea 2005) .", "cite_spans": [{"start": 555, "end": 575, "text": "(Giudiceandrea 2005)", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "Material", "text": "The tensile capacity is analysed individually for three samples, each of 150 randomly selected Swiss grown Norway spruce specimens. The dimensions of these reference samples are 90 9 45 9 4,000 mm 3 , 1109 459 4,000 mm 3 , and 230 9 45 9 4,000 mm 3 , respectively. The timber boards are randomly selected and not graded, thus their material properties should represent the basic population of Swiss grown Norway spruce.", "cite_spans": [], "ref_spans": []}, {"section": "Material", "text": "In the following, the timber boards that are used to estimate the tensile stiffness are called Sample A, whereas the timber boards that are used to estimate the tensile strength are called Sample B.", "cite_spans": [], "ref_spans": []}, {"section": "Material", "text": "For all timber boards, the dimensions and the position of every knot with a diameter larger than 10 mm are assessed and recorded. Furthermore, on Sample B destructive tensile tests are performed to estimate the ultimate tensile capacity and on Sample A non-destructive tensile tests are performed to estimate the tensile stiffness. In order to ensure comparability of the test results, all tension tests are performed with standard moisture content according to EN 408; i.e. equilibrium moisture content of the specimen in standard climate: (20 \u00b1 2)\u00b0C and (65 \u00b1 5) % relative humidity.", "cite_spans": [], "ref_spans": []}, {"section": "Non-destructive tensile tests", "text": "The stiffness properties are measured with an infrared camera device during non-destructive tensile tests. The camera device, contains three interconnected cameras and the entire measured area (optical range of the infrared camera) is calibrated. The timber boards are subdivided into KS and CWS. At the beginning and the end of each section and at the edge of the total measured area, three high frequent infrared light emitting diodes (LEDs) are mounted (Figs. 1, 2) . The boards are loaded with an axial tension force, which represents 45 % of the estimated maximum tensile capacity. The maximum tension capacity has been estimated based on the measurements of the GoldenEye-706 grading device. Over the entire time of the tensile test, the LEDs send light impulses with a frequency of 20 Hz and based on this their positions are measured with the infrared camera device. Each timber board is measured twice (at the top and bottom side).", "cite_spans": [], "ref_spans": [{"start": 456, "end": 468, "text": "(Figs. 1, 2)", "ref_id": "FIGREF0"}]}, {"section": "Non-destructive tensile tests", "text": "For the estimation of the modulus of elasticity (denoted MOE), the strains over the board axis (calculated with the relative LED displacement of both sides) are used. The local strains within the KS are not considered separately. The assessment of the MOE is made by means of a linear regression model of the stress strain estimates according to EN 408; i.e. with strains between 10 and 40 % of the estimated maximum tensile capacity. However, it has to be noted that some configurations for the determination of the MOE do not completely conform to the requirements according to EN 408. According to EN 408, the calculation of the MOE by means of linear regression requires a coefficient of determination R 2 C 0.99 measured over a length of five times the width. For the investigated test specimens, this requirement would be equal to a range for the strain measurement of 630 mm. In the present study, the length is in general significantly shorter; e.g. the average length of KS being equal to 94 mm. Furthermore, the measured data show a random fluctuation (noise) by using this measurement device. As a result of the significantly reduced measurement length combined with the random fluctuation of the data, the requirements for the MOE estimation are reduced; i.e. the coefficient of determination R 2 C 0.96. The mean MOE over the total measured area is estimated based on the measured strain between the outmost LEDs.", "cite_spans": [], "ref_spans": []}, {"section": "Non-destructive tensile tests", "text": "The properties of the KS depend on parameters, such as size of the knots and/or the knot arrangement. Thus, the probabilistic characteristics of the properties of the KS are difficult to describe. Therefore, a weak section (WS) with a unit length c = 150 mm is introduced. The MOE of the KS is converted into the MOE of a WS according to Eq. (1). In this equation, the MOE of the WS E j,WS is calculated utilizing the estimated MOE of the corresponding KS E j,K-S , and the MOEs of the two adjacent CWS E j-1,CWS and E j?1,CWS . l j,KS denotes the length of the corresponding KS (see also .", "cite_spans": [], "ref_spans": []}, {"section": "Non-destructive tensile tests", "text": "for l j;KS 150 mm", "cite_spans": [], "ref_spans": []}, {"section": "Non-destructive tensile tests", "text": "In Fig. 3a , the estimated MOE of each section and the estimated mean MOE are illustrated for one timber board. For a more detailed description of the test procedure see Fink and Kohler (2012) .", "cite_spans": [{"start": 170, "end": 192, "text": "Fink and Kohler (2012)", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Destructive tensile tests", "text": "The reference boards were tested destructively in tension with the same tension machine as described in Chapter 2.2. The tests have been performed according to EN 408 which requires a testing range of at least nine times the width of the boards. In order to collect as much information as possible about the individual boards, the test range was maximized over the whole testable range of the boards just being limited by the clamping jaws of the tensile test device at both ends of the timber boards. The resulting testing range corresponds to 3,360 mm.", "cite_spans": [], "ref_spans": []}, {"section": "Eigenfrequency measurement", "text": "For the prediction of the material properties of the undisturbed timber an Eigenfrequency measurement is performed on all specimens (Sample A ? B). Therefore, in addition to the Eigenfrequency measurement f 0 the length l, the moisture content w, the density q (estimated through weight) and the dry density q 0 (estimated through w and weight) are measured. Based on the measurements the corresponding dynamic MOEs of each board E dyn,F are calculated according to Eq. (2)-the Equation is developed based on the differential equation of the longitudinal stress waves in solids (see Kollmann and Krech 1960; G\u00f6rlacher 1984 for a detailed description). The assessed values of the MOEs are corrected to a reference moisture content according to EN 384. The dynamic MOEs have to be considered as average values over the entire length of the timber board.", "cite_spans": [{"start": 583, "end": 607, "text": "Kollmann and Krech 1960;", "ref_id": "BIBREF18"}, {"start": 608, "end": 622, "text": "G\u00f6rlacher 1984", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Knot measurement", "text": "To consider the within-member variability of the timber boards the knots are measured. Each knot with a diameter larger than 10 mm is assessed and recorded. Based on this the tKAR-value is calculated. This value is defined as the ratio between the projected knot area within a length of 150 mm and the cross sectional area (Isaksson 1999) .", "cite_spans": [{"start": 323, "end": 338, "text": "(Isaksson 1999)", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Knot measurement", "text": "To show the influence of knots or rather the influence of the tKAR-value on the within-member variability, the estimated tensile stiffness and the corresponding tKARvalue of one specimen is illustrated in Fig. 3b . It is obvious that within the areas of the occurrence of knots the stiffness is significantly reduced.", "cite_spans": [], "ref_spans": []}, {"section": "Knot measurement", "text": "3 Model to predict the tensile stiffness", "cite_spans": [], "ref_spans": []}, {"section": "Knot measurement", "text": "As described above, timber shows a variability of its material properties, between and within the member. Therefore, it is obvious that an efficient model for the prediction of the local stiffness properties should include at least one indicator to consider the between-member variability, and one indicator to consider the within-member variability. To consider the between-member variability, the estimated dynamic MOE based on Eigenfrequency measurement E dyn,F is used. For considering the withinmember variability, the tKAR-value is chosen. In the following, two different models are developed. The first one can be used to predict the stiffness of the undisturbed timber, whereas the second one can be used to predict the local stiffness properties of a knot cluster.", "cite_spans": [], "ref_spans": []}, {"section": "Knot measurement", "text": "For both cases, a linear regression model (Eq. 3) is used, where Y is the predicted stiffness, b i are the regression coefficients, X are the input variables and e is the error term. The input variable X 1 stands for E dyn, F and the input variable X 2 stands for tKAR.", "cite_spans": [], "ref_spans": []}, {"section": "Knot measurement", "text": "The parameters of the regression model and their uncertainties are estimated using maximum likelihood method; see e.g. Benjamin and Cornell (1970) .", "cite_spans": [{"start": 119, "end": 146, "text": "Benjamin and Cornell (1970)", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Knot measurement", "text": "Based on the assumption of a normal distributed error term e; the parameters of the regression model b i and the standard deviation of the error term r e , can be calculated as follows:", "cite_spans": [], "ref_spans": []}, {"section": "Knot measurement", "text": "The uncertainties of the parameters b i and r e can be expressed with covariance matrix C HH ; where the diagonals are the variances of the parameters (b i and r e \u00de; and the other elements are the covariances between the parameters. The covariance matrix C HH is defined as the inverse of the Fisher information matrix H. The components of H are determined by the second order partial derivatives of the log-likelihood function; see e.g. Faber (2012) .", "cite_spans": [{"start": 439, "end": 451, "text": "Faber (2012)", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Knot measurement", "text": "3.1 Model to predict the stiffness of undisturbed timber", "cite_spans": [], "ref_spans": []}, {"section": "Knot measurement", "text": "The first stiffness model is developed in order to predict the mean stiffness properties of defect-free timber within one timber board E CWS : Here E CWS is calculated with the stiffness of all measured CWS within one board in accordance with Hook's law of serial springs (Eq. 8). In addition, a model for the prediction of the mean tensile stiffness of the entire timber board E is developed. For both models, only the first indicator E dyn,F is taken into account.", "cite_spans": [], "ref_spans": []}, {"section": "Knot measurement", "text": "The estimated regression coefficients, the standard deviation of the error term and their coefficients of variations are summarised in Tables 1 and 2 . A comparison between the two regression models shows that E CWS is in general about 700 MPa larger than E: The differences between E CWS and E are almost constant for all timber boards. However, with both models a large correlation coefficient q & 0.96 between the predicted and the measured stiffness properties is identified (Fig. 4a,b ).", "cite_spans": [], "ref_spans": [{"start": 135, "end": 149, "text": "Tables 1 and 2", "ref_id": "TABREF0"}, {"start": 479, "end": 489, "text": "(Fig. 4a,b", "ref_id": "FIGREF2"}]}, {"section": "Model to predict the stiffness of knot sections", "text": "In the following, a model is developed in order to predict the tensile stiffness of each particular WS (E WS ).", "cite_spans": [], "ref_spans": []}, {"section": "Model to predict the stiffness of knot sections", "text": "Therefore, the measured stiffness properties of altogether 864 WS are taken into account. As described above, the model contains two parameters (E dyn,F and tKAR). The estimated regression coefficients, the standard deviation of the error term and their coefficients of variations are summarised in Table 3 . Using this model a rather large correlation q = 0.912 between the measured and the predicted stiffness can be identified (Fig. 4c ). In order to control the outcome, a cross validation with four randomly selected sub-samples is performed (Hastie et al. 2001) . Thereby, the model is developed based on three sub-samples and the results are validated using the fourth sub-sample. This is done four times for every subsample. The estimated model parameters are only slightly different and the correlation between the measured and the estimated stiffness properties are 0.90 \\ q \\ 0.92.", "cite_spans": [{"start": 547, "end": 567, "text": "(Hastie et al. 2001)", "ref_id": "BIBREF13"}], "ref_spans": [{"start": 299, "end": 306, "text": "Table 3", "ref_id": "TABREF2"}, {"start": 430, "end": 438, "text": "(Fig. 4c", "ref_id": "FIGREF2"}]}, {"section": "Model to predict the stiffness of knot sections", "text": "The presented model is developed in order to predict the tensile strength of WS. If the model is used for the prediction of the stiffness of the CWS (using tKAR = 0) these are slightly underestimated. The difference of the measured and the predicted E CWS is about 3 %. However, the measured and the predicted stiffness still show a large correlation q = 0.953. Thus, the model can also be applied to the prediction of the E CWS ; when considering the underestimation.", "cite_spans": [], "ref_spans": []}, {"section": "Model to predict the stiffness of knot sections", "text": "In all the here described stiffness models, a very high correlation coefficient has been identified. This might be partly influenced by the investigated timber boards, which are two sub-samples of two different strength grades. However, the influence of the two sub-samples on the model parameters and the error term should be rather small as a result of the large variability of the measured stiffness properties within both strength grades.", "cite_spans": [], "ref_spans": []}, {"section": "Model to predict the tensile strength", "text": "In the following, two models for the prediction of the tensile strength are developed. The first one can be used for the prediction of the tensile capacity of the entire timber board f t , whereas the second model can be used to predict the tensile strength of each particular knot cluster f t,WS . For the estimation of both models the experimental results of the destructive tensile tests (Sample B) are used.", "cite_spans": [], "ref_spans": []}, {"section": "Model to predict the tensile strength of timber boards", "text": "The following model is developed in order to predict the tensile strength of the entire timber board. It is assumed that the tensile strength of the timber board corresponds to the tensile strength of the weakest section within the measured length. The weakest section is assumed to be the knot cluster having the largest tKAR-value. In order to ensure an optimal comparability to the stiffness model described above, the same parameters are chosen that are E dyn,F and tKAR. In Table 4 the estimated regression coefficients, the standard deviation of the error term and their coefficients of variations are summarised. Applying the model, a large correlation q = 0.782 between the estimated and the measured tensile capacities is identified (Fig. 5 ).", "cite_spans": [], "ref_spans": [{"start": 742, "end": 749, "text": "(Fig. 5", "ref_id": "FIGREF3"}]}, {"section": "Model to predict the tensile strength of timber boards", "text": "As known from several studies (e.g. Riberholt and Madsen 1979; Taylor and Bender 1991; Courchene et al. 1996; Isaksson 1999; K\u00f6hler 2006) , the characteristics of the weakest section within a member is related to its length. With increasing length, the largest tKAR-value within a timber board (tKAR max ) increases and thus the tensile capacity decreases (size effect). Accordingly, the developed model can (without considering the size effect) only be used for the prediction of the tensile capacity of specimens having similar dimensions.", "cite_spans": [{"start": 36, "end": 62, "text": "Riberholt and Madsen 1979;", "ref_id": "BIBREF20"}, {"start": 87, "end": 109, "text": "Courchene et al. 1996;", "ref_id": "BIBREF5"}, {"start": 110, "end": 124, "text": "Isaksson 1999;", "ref_id": "BIBREF14"}, {"start": 125, "end": 137, "text": "K\u00f6hler 2006)", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "Model to predict the tensile strength of knot clusters", "text": "The second strength model is developed to predict the tensile strength of knot clusters or rather the tensile strength of WS. For the calculation, all WS within the measured area are considered; that includes a total number of 2,577 WS. As described above, a WS is defined as a section with tKAR C0.1. Based on the results of the destructive tensile tests, the tensile capacity of the timber boards and thus the tensile strength of the weakest section within each board are known. Further it is known that the tensile strength of all other WS is at least the tensile capacity of the corresponding timber board. In case of a timber board (three WS, tensile capacity of the entire board f t = 30 MPa) the following information about the tensile strength of the WS can be obtained: Tensile strength of the weakest section f t,WS = 30 MPa and tensile strength of the other two WS f t,WS C 30 MPa.", "cite_spans": [], "ref_spans": []}, {"section": "Model to predict the tensile strength of knot clusters", "text": "With the given information it is possible to estimate the regression parameters by using linear regression analysis for censored data (see e.g. Buckley and James 1979; Catterjee and McLeich 1981) . In Fig. 6 , the principle of the regression analysis for censored data is illustrated. Figure 6a illustrates the measured tensile capacity f t,i of three timber boards (each timber board has two WS) and the corresponding parameter of each WS (e.g. tKAR-value). The weakest knot cluster within each member WS ? is represented by '?' and the other knot cluster WS o are represented by 'o'. Further, the illustration shows a linear regression line that describes the relation between the parameter of the weakest section and the corresponding tensile capacity. The regression curve and its corresponding r e are calculated with Eq. (4)-(5). They are used as the start value for following calculations.", "cite_spans": [{"start": 144, "end": 167, "text": "Buckley and James 1979;", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Model to predict the tensile strength of knot clusters", "text": "According to the principle of a linear regression model it is assumed that the error term e is normal distributed around the regression model e $ N\u00f00; r e \u00de: Based on this the strength of WS o f t,WS,o can be estimated by the expected value of the truncated normal distribution (grey area) according to Eq. (9). Here, f t,reg denotes the expected tensile strength according to the regression model.", "cite_spans": [], "ref_spans": []}, {"section": "Model to predict the tensile strength of knot clusters", "text": "The estimated strength is illustrated with a 'x' (Fig. 6b) . Using the estimated strength of WS o and the measured strength of WS ? a new regression model with a corresponding r e can be calculated. The new regression line is illustrated as dashed line. With the new regression line and the corresponding r e the strength of WS o can be estimated again, following the principle described above. The new estimated strengths are illustrated as black dots in Fig. 6c . With the new estimated strength of WS o and the measured strength of WS ? a new regression model (dashed-dotted line) with a corresponding r e can be estimated. This iteration has to be repeated up to the convergence criterion. In this study, a change between the estimated regression parameters in iteration step i and iteration step i ?1 of 0.005 % is chosen. The estimated regression parameters of the strength model are summarised in Table 5 . Furthermore, Fig. 7 illustrates the correlation between the measured/estimated tensile strength with the predicted tensile strength of all WS. It is obvious that the estimated tensile strength of the WS is located within the area near right of the regression model.", "cite_spans": [], "ref_spans": [{"start": 904, "end": 911, "text": "Table 5", "ref_id": "TABREF3"}]}, {"section": "Model to predict the tensile strength of knot clusters", "text": "At this point, it has to be mentioned that this model is developed for the prediction of the tensile strength of WS. If the model is used for the prediction of the tensile strength of CWS (using tKAR = 0), it will be slightly underestimated. Further it has to be considered that the standard deviation of the estimated error term r e will be underestimated using censored regression analysis. That results from the fact, that the regression model is developed by using measured and estimated material properties and the latter ones are in general located nearby the regression line. Another area of application of this model is the prediction of the tensile capacity of the entire timber board f t . Therefore, the tensile capacity of one timber board f t,i is defined as the tensile strength of the weakest section within the board (j denotes the number of WS within the board i):", "cite_spans": [], "ref_spans": []}, {"section": "Model to predict the tensile strength of knot clusters", "text": "A comparison between the measured and the predicted tensile capacity shows a rather large correlation q = 0.751 (see the '?' within Fig. 7 ). An advantage of this method is that the tensile capacity of timber boards can be predicted independent of the board length.", "cite_spans": [], "ref_spans": []}, {"section": "Comparisons between the models", "text": "In the following, the two strength models described above are compared with each other. The significantly higher value of parameter b 0 within the second model indicates an higher predicted tensile strength within areas with small tKAR. On the other hand, the higher absolute value of parameter b 2 explains larger local strength reduction due to knots.", "cite_spans": [], "ref_spans": []}, {"section": "Comparisons between the models", "text": "In Fig. 8 , the estimated tensile strength of all WS (calculated with both models) are illustrated. Here '?' denotes the predicted tensile strength of the weakest section WS ? and 'o' denotes the predicted strength of all other WS o . It is obvious that the first strength model (model to predict f t ) underestimates the tensile strength of the majority of the WS. On average, the difference between the two models is Df t;WS \u00bc 7:70 MPa. However, the prediction of the tensile capacity of the timber boards f t (which is assumed to be the tensile strength of the section with tKAR max ) is relatively similar, especially for timber boards with low resistance.", "cite_spans": [], "ref_spans": []}, {"section": "Comparisons between the models", "text": "The difference between the two models can be explained by the following example: let's assume that a timber board with a tensile capacity f t = 30 MPa contains a number of knot clusters. Let's assume further that the two largest knot clusters have the same tKAR-value (tKAR = 0.25). The first strength model is developed with the information about the tensile strength of one knot cluster with the specific tKAR-value; i.e. tKAR \u00bc 0:25 ! f t;WS \u00bc 30 MPa. The second model is calibrated with the information that only one knot clusters with the specific tKAR-value will fail tKAR \u00bc 0:25 ! f t;WS;1 \u00bc 30 MPa, whereas the second knot cluster shows a higher tensile strength tKAR \u00bc 0:25 ! f t;WS;2 ! 30 MPa.", "cite_spans": [], "ref_spans": []}, {"section": "Verification with existing models", "text": "In order to verify the introduced material model, it is compared with existing models. Therefore, the above mentioned material model presented in Bla\u00df et al. (2008) will be used as a reference model. Between the two model approaches fundamental difference exists: (a) The test configuration between the studies is different. (b) Specimen size/testing length: The reference model is developed based on experimental investigations with specimen having a testing length of 137.5 mm; in the present study the testing length is [3,300 mm. (c) Measurement length: In the present study, the measurement length for measuring the stiffness properties varies depending on the natural growth characteristics of the investigated specimen. (d) Sample selection: The reference model is developed based on randomly selected timber board segments. Here a model is developed to predict E WS and f t,WS -therefore only sections containing knot clusters are considered. (e) Input parameters: The reference model has used q 0 and tKAR, whereas in the present study the input parameters are E dyn,F and tKAR. However, all the required input parameters are investigated on the timber boards presented in this study.", "cite_spans": [{"start": 146, "end": 164, "text": "Bla\u00df et al. (2008)", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Verification with existing models", "text": "In the following, the stiffness properties E CWS and E WS as well as the tensile capacity of the timber boards f t (tensile strength of the WS with tKAR max ) are estimated using both approaches. The results are illustrated in Fig. 9 . In all illustrations an accordance between the estimated values (for both approaches) and the measured material properties exists within the upper part; i.e. timber boards or WS having relatively high strength and stiffness properties. However, within the lower part significant differences are detected. It is obvious that the here developed model shows good accordance-as it has been developed on the data-set itself. Nevertheless, all three illustrations indicate that the predictions using the reference model significantly overestimate the measured material properties, especially having low values of stiffness and strength. The overestimation is on average e\u00f0E CWS \u00de \u00bc 886 MPa, e\u00f0E WS \u00de \u00bc 374 MPa and e\u00f0f t \u00de \u00bc 9:80 MPa.", "cite_spans": [], "ref_spans": []}, {"section": "Verification with existing models", "text": "The differences in Fig. 9a might be a result of the measurement length. Within the present study the tensile stiffness of the clear wood E CWS is measured on the entire length between two adjacent knot clusters. Small defects between the knot clusters are not explicitly considered. Thus the measured stiffness might be lower as the stiffness of a defect-free specimen. However, it is still representing the mean stiffness properties of the clear wood sections.", "cite_spans": [], "ref_spans": []}, {"section": "Verification with existing models", "text": "It seems likely that the differences in Fig. 9b , c are resulting from the different dimensions of the test specimens. A drawback of small test specimens is that effects that are reducing the strength and stiffness properties, such as the influence of local grain deviation before and after the knot clusters are not considered. Further, lateral bending due to knots might be prevented. The influence is of particular importance for knot clusters having numerous knots and thus a large tKAR. Another reason for the differences might be the sample selection. As mentioned above, the emphasis of the present study is the investigation of the material properties of knot clusters and not of board sections. Thus, in particular sections containing knot clusters are considered.", "cite_spans": [], "ref_spans": []}, {"section": "Verification with existing models", "text": "For comparison of the tensile capacities, the different test setups have to be considered. When measuring the tensile strength using the test configuration described in Heimeshoff and Glos (1980) , the investigated timber boards are supported through glued timber boards within the transition area. Thus, knot clusters, where parts of the fracture are outside the testing length (137.5 mm), are reinforced. The influence might be significant as a result (c) Fig. 9 Verification of the material models to predict a E CWS ; b E WS , and c E t (MPa) that by the majority of the investigated timber boards, the area of the fracture is above 137.5 mm.", "cite_spans": [], "ref_spans": []}, {"section": "Modelling of the material properties", "text": "With the stiffness and strength models described above it is possible to model the material properties (tensile stiffness and tensile strength) over the entire board. Therefore, only information about the E dyn,F and the tKAR-value is necessary. In the following the material properties of a timber board will be predicted based on the measured values given in Table 6 . The tensile stiffness and the tensile strength are predicted with the models E WS and f t,WS . As described above, the tensile stiffness and the tensile strength of the clear wood will be slightly underestimated with this model. Thus in this example, both the estimated tensile stiffness and the estimated tensile strength of the clear wood are increased by 3 %. The results are illustrated in Table 7 and Fig. 10 .", "cite_spans": [], "ref_spans": [{"start": 361, "end": 368, "text": "Table 6", "ref_id": "TABREF4"}, {"start": 765, "end": 772, "text": "Table 7", "ref_id": "TABREF5"}]}, {"section": "Conclusion", "text": "In the present paper, a model for the prediction of the local strength and stiffness properties is developed. The specific characteristic of these models is that material properties are described according to their morphological characteristics; i.e. the boards are subdivided into sections containing knots (knot sections) and sections without knots (clear wood sections). From those sections, the material properties are estimated based on results of destructive and non-destructive tensile tests.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "The experimental investigation takes place on a total of 650 timber boards. From all boards, the dynamic modulus of elasticity based on Eigenfrequency measurement is estimated. Further, the dimension and position of all knots with a diameter larger than 10 mm are documented. Based on them the tKAR-value over the entire length of the timber boards is calculated. On 200 of the timber boards, non-destructive tensile tests are performed. Before testing, the timber boards are subdivided into knot sections and clear wood sections. From each section, the strains are measured using an optical camera device. Based on this, the corresponding stiffness is estimated. On the other 450 timber boards, destructive tensile tests are performed to estimate the tensile capacity.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "Based on the results, a model for the prediction of the tensile stiffness is developed. The model can be used for the prediction of the stiffness of each particular knot section and for the prediction of the clear wood. For both, large correlations between the measured and the predicted stiffness properties are identified, q = 0.912 and q = 0.953, respectively. Furthermore, a model for the prediction of the tensile strength of each particular knot section is developed. The parameters of the model are estimated using censored regression analysis. Within this method, information on the failed knot section and information on the other knot sections (within the timber board) are considered. The model can be used for the prediction of the tensile capacity of the entire timber board. Therefore, it has to be assumed that the tensile capacity of the entire timber board corresponds to the tensile capacity of the weakest knot section within the board. The analysis of the model shows a correlation q = 0.751 between the measured and the predicted tensile capacity. An advantage of this method is that the tensile capacity of timber boards can be predicted independent of their geometric shape.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "With the here developed material models it is possible to predict the strength and stiffness properties over the entire timber board based on information about E dyn,F and tKAR. Such a model can be used for the development of more efficient grading criteria. 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{"paper_id": "8339943", "_pdf_hash": "711d7d6ad3cc56d28ebf586ba0953556f5db5cd3", "abstract": [{"section": "Abstract", "text": "The mechanism responsible for the natal kicks of neutron stars continues to be a challenging problem. Indeed, many mechanisms have been suggested, and one hydrodynamic mechanism may require large initial asymmetries in the cores of supernova progenitor stars. Goldreich, Lai, & Sahrling (1997) suggested that unstable g-modes trapped in the iron (Fe) core by the convective burning layers and excited by the \u01eb-mechanism may provide the requisite asymmetries. We perform a modal analysis of the last minutes before collapse of published core structures and derive eigenfrequencies and eigenfunctions, including the nonadiabatic effects of growth by nuclear burning and decay by both neutrino and acoustic losses. In general, we find two types of g-modes: inner-core g-modes, which are stabilized by neutrino losses and outer-core g-modes which are trapped near the burning shells and can be unstable. Without exception, we find at least one unstable g-mode for each progenitor in the entire mass range we consider, 11 M \u2299 to 40 M \u2299 . More importantly, we find that the timescales for growth and decay are an order of magnitude or more longer than the time until the commencement of core collapse. We conclude that the \u01eb-mechanism may not have enough time to significantly amplify core g-modes prior to collapse.", "cite_spans": [{"start": 260, "end": 293, "text": "Goldreich, Lai, & Sahrling (1997)", "ref_id": "BIBREF13"}], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Observations indicate that many pulsars have high proper motions (Lyne & Lorimer 1994; Lorimer, Bailes, & Harrison 1997; Hansen & Phinney 1997; Cordes & Chernoff 1998) and that many neutron star systems require kicks at birth. For example, pulsar bow shock morphologies (Cordes, Romani, & Lundgren 1993) , misaligned spins of binary pulsars (Cordes, Wasserman, & Blaskiewicz 1990; Kramer 1998; Wex, Kalogera, & Kramer 2000; Kaspi et al. 1996; Lai, Bildsten, & Kaspi 1995; Lai 1996; Kumar & Quataert 1997) , the statistics of low-mass X-ray binaries (LMXBs) (Kalogera 1997; Kalogera & Webbink 1998) , the 1 Steward Observatory, The University of Arizona, Tucson, AZ 85721; jmurphy@as.arizona.edu, aburrows@as.arizona.edu 2 JINA Fellow.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "3 Theoretical Astrophysics Group, T-6, MS B227, Los Alamos National Laboratory, Los Alamos, NM 87544, U.S.A.; alex@t6.lanl.gov high orbital eccentricities of some Be star systems (Verbunt & van den Heuvel 1995) , and scenarios for double neutron star systems (Dewey & Cordes 1987; Fryer & Kalogera 1997; Fryer, Burrows, & Benz 1998; Dewi & van den Heuvel 2004; Willems & Kalogera 2004 ) all indicate that neutron stars experience significant natal kicks. Furthermore, Arzoumanian, Chernoff, & Cordes (2002) find a bimodal distribution of birth kick speeds with peaks at \u223c100 km s \u22121 and \u223c700 km s \u22121 and dispersions of 90 and 500 km s \u22121 . They suggest that roughly 50% of the pulsars in the solar neigborhood escape the Galaxy and that \u223c15% have kick speeds greater than 1000 km s \u22121 . The observations indicate that kicks seem to be hallmarks of neutron star formation.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "What is the mechanism producing the observed and inferred kicks? To give a 1.4 M \u2299 neutron star a speed of 1000 km s \u22121 , the mechanism must be able to impart \u223c10 49 erg of kinetic energy, which is just 1% of the canonical SN mechanical energy (\u223c10 51 erg) or 0.01% of the collapse energy (\u223c10 53 erg). Additionally, any explanation must address the distribution of speeds. If the distribution is bimodal, then it is possible that more than one mechanism is responsible for the kicks. Lai (2000b) has summarized the possible magnetic, neutrino (\u03bd), and hydrodynamic kick mechanisms, but in general many of the scenarios have trouble producing kicks larger than \u223c200 km s \u22121 .", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Of the many mechanisms propounded, hydrodynamic mechanisms are the most compelling. For example, neutrino-driven convection, which is inherently a nonspherical phenomenon, excites large-scale convective motions that stochastically jostle the protoneutron star (Burrows, Hayes, & Fryxell 1995; Janka & M\u00fcller 1994) . However, multi-dimensional calculations indicate that any kick imparted as a result of the convective jostling (\"Brownian motion\") has an average magnitude of \u223c200 km s \u22121 (Burrows et al. 1995; Janka & M\u00fcller 1994; Scheck et al. 2004 ) and cannot explain the highest velocities nor the second peak in a possible bimodal distribution.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "These analyses suggest the need for additional asymmetries before the onset of collapse. Burrows & Hayes (1996) state that global asymmetries in the progenitor may be prerequisites for large kicks. In a 2-D hydrodynamic simulation and with modest asymmetries, Burrows & Hayes (1996) are able to produce a recoil speed of \u223c550 km s \u22121 . However, these calculations are crude and the results, while suggestive, are not conclusive. Goldreich et al. (1997) have proposed that these asymmetries may be excited by the \u01eb-mechanism in which g-mode oscillations in the core are pumped by nuclear reactions.", "cite_spans": [{"start": 429, "end": 452, "text": "Goldreich et al. (1997)", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Introduction", "text": "As a prelude to more definitive multi-dimensional radiation hydrodynamic investigations of neutron star kicks in the supernova context, one would like to determine whether global asymmetries prior to core collapse in fact occur. Hence, a thorough analysis of the progenitor oscillations and their growth rates is necessary. In this paper, we explore the viability of the g-mode oscillation origin for putative pre-collapse anisotropies by performing such an eigenmode analysis.", "cite_spans": [], "ref_spans": []}, {"section": "Linear Perturbation Equations", "text": "To set the stage for our eigenmode analysis of the cores of nonrotating massive stars, we first describe linear stellar pulsation theory in the general case. In linear perturbation theory, a star is assumed to be in hydrostatic equilibrium, around which perturbations are small, making second-order or higher terms in the perturbation equations negligibly small. Therefore, if f 0 ( r) is a quantity satisfying the hydrostatic equations, then f ( r, t) \u2192 f 0 (r)+ f \u2032 ( r, t), where 0 denotes the background solution and \u2032 denotes the Eulerian perturbation. We assume that the perturbation is of the form f \u2032 ( r, t) = f \u2032 (r)Y lm (\u03b8, \u03c6)e i\u03c9t , where Y \u2113m (\u03b8, \u03c6) is a spherical harmonic in that \u2113 and m are the polar and azimuthal indeces, repsectively, and \u03c9 is the oscillation frequency. Under these assumptions and an assumption of adiabatic perturbations, if P , \u03c1, \u03c6, c s are the pressure, density, gravitational potential, and sound speed, respectively, the adiabatic linear peturbation equations", "cite_spans": [], "ref_spans": []}, {"section": "Linear Perturbation Equations", "text": "1 \u03c1 dp", "cite_spans": [], "ref_spans": []}, {"section": "Linear Perturbation Equations", "text": "and 1", "cite_spans": [], "ref_spans": []}, {"section": "Linear Perturbation Equations", "text": "\u03be r and \u03be h are the radial and horizontal components of the Lagrangian displacement vector, \u03be = r \u2212 r 0 , and are defined by", "cite_spans": [], "ref_spans": []}, {"section": "Linear Perturbation Equations", "text": "and", "cite_spans": [], "ref_spans": []}, {"section": "Linear Perturbation Equations", "text": "N and L \u2113 are the Brunt-V\u00e4is\u00e4l\u00e4 and Lamb frequencies, respectively, which are given by", "cite_spans": [], "ref_spans": []}, {"section": "Linear Perturbation Equations", "text": "and", "cite_spans": [], "ref_spans": []}, {"section": "Linear Perturbation Equations", "text": "where g = GM r /r 2 , G is the gravitational constant, and M r is the mass interior to r.", "cite_spans": [], "ref_spans": []}, {"section": "Linear Perturbation Equations", "text": "Equations (1), (2), and (3) represent a fourth-order boundary value problem. Near r \u223c 0, simplifications and regularity in the variables \u03c6 \u2032 , \u03be r , and (P \u2032 /\u03c1 + \u03c6 \u2032 ) dictate that the inner boundary conditions are", "cite_spans": [], "ref_spans": []}, {"section": "Linear Perturbation Equations", "text": "and", "cite_spans": [], "ref_spans": []}, {"section": "Linear Perturbation Equations", "text": "At the surface of the calculational domain, r = R or M r = M , one outer boundary condition, from the regularity of \u03c6 \u2032 , is d\u03c6", "cite_spans": [], "ref_spans": []}, {"section": "Linear Perturbation Equations", "text": "A second outer boundary condition allows for the possibility that the atmosphere is either evanescent to both p-and g-waves or progressive to outgoing p-waves (Lai 2000b) , depending upon the mode frequency:", "cite_spans": [], "ref_spans": []}, {"section": "Linear Perturbation Equations", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "Linear Perturbation Equations", "text": "and", "cite_spans": [], "ref_spans": []}, {"section": "Linear Perturbation Equations", "text": "If the mode frequency is such that this boundary condition represents leakage of mode energy by progressive p-waves then the eigensolutions are complex, with the imaginary part of \u03c9, \u03c9 I , being related to the rate of leakage.", "cite_spans": [], "ref_spans": []}, {"section": "Linear Perturbation Equations", "text": "The solutions to the boundary and eigenvalue problem as defined by eqs. (1)- (3) with the boundary conditions, eqs. (8)- (11), are the eigenmodes of the perturbed star. The eigenvalue, \u03c9 2 , and eigensolution depend on the stellar structure and spherical harmonic index, \u2113, but without rotation are degenerate for different values of m. We have found solutions to this boundary value problem using a shooting technique, in which we search for all modes within a region of the complex plane of \u03c9 2 . This is accomplished with a 2-D Newton-Raphson technique, where convergence to one part in 10 6 , or better, in the eigenvalue is required. We compare our eigensolutions and eigenfrequencies for the standard Solar model (Christensen-Dalsgaard et al. 1996) with the eigenmodes determined by a publicly accessible Fortran code 2 designed to solve the adiabatic linear perturbation equations. The agreement between the two is better than 0.1%.", "cite_spans": [], "ref_spans": []}, {"section": "Work Integral", "text": "In general, non-adiabatic effects such as nuclear burning and neutrino emission are included in the perturbation equations. However, if these terms are small, the contributions to the imaginary part of \u03c9, \u03c9 I , which is directly related to the rate of growth or decay of the mode, can be obtained from the time-averaged work integral, W j (Unno et al. 1989) . For a quasi-adiabatic oscillation,", "cite_spans": [], "ref_spans": []}, {"section": "Work Integral", "text": "where \u01eb j (erg g \u22121 s \u22121 ) is the deposition or loss of energy by either nuclear heating if j = nuc or neutrino losses if j = \u03bd. Furthermore, \u01eb jT = (\u2202ln\u01eb j /\u2202lnT ) \u03c1 , \u01eb j\u03c1 = (\u2202ln\u01eb j /\u2202ln\u03c1) T , and \u0393 3 \u2212 1 \u2261 (\u2202lnT /\u2202\u03c1) S , where S is the entropy. The radial distribution of the Lagrangian perturbation in temperature is given by", "cite_spans": [], "ref_spans": []}, {"section": "Work Integral", "text": "where \u2207 ad = (\u2202lnT /\u2202ln\u03c1) s and V = gr\u03c1/P .", "cite_spans": [], "ref_spans": []}, {"section": "Work Integral", "text": "When \u03c9 is complex, as is the case when the mode gains or loses energy, the time dependence of the modes may be written as", "cite_spans": [], "ref_spans": []}, {"section": "Work Integral", "text": "where \u03c9 R is the real part of \u03c9, and \u03c4 is the timescale for growth (+) or decay (-) and is a composite effect determined by the equation", "cite_spans": [], "ref_spans": []}, {"section": "Work Integral", "text": "\u03c4 nuc , \u03c4 \u03bd , and \u03c4 leak include the effects of nuclear gains, neutrino losses, and acoustic losses, respectively. The nuclear and neutrino timescales are related to their respective work integrals by", "cite_spans": [], "ref_spans": []}, {"section": "Work Integral", "text": "where E W is the energy in the mode:", "cite_spans": [], "ref_spans": []}, {"section": "Work Integral", "text": "and \u03c4 leak is directly determined by the imaginary part of \u03c9, Im(\u03c9) = \u22121/\u03c4 leak . This quantity is the solution to the adiabatic linear perturbation equations when eq. (11) is the fourth boundary condition. The modes are stable or unstable for \u03c4 < 0 or \u03c4 > 0, respectively.", "cite_spans": [], "ref_spans": []}, {"section": "Massive Star Structures", "text": "To investigate the character of the eigenmodes as a function of progenitor mass and time, t, prior to the onset of collapse, we consider the cores of nonrotating, massive stars with masses of 11 M \u2299 , 13 M \u2299 , 15 M \u2299 , 25 M \u2299 , 30 M \u2299 , 35 M \u2299 and 40 M \u2299 (Rauscher et al. 2002; Woosley, Heger, & Weaver 2002) and at t = 3600, 600, 60, 30, 25, 20, 15, 10, 5 , 2, 1, and 0 (start of collapse) seconds before the onset of collapse. The commencement of collapse is defined at the time when the peak infall velocity exceeds 900 km s \u22121 . This is about 200 to 250 ms before core bounce. The structure of each stellar model uniquely determines its eigenmodes. Thus, an indentification of important trends in the models is helpful in characterizing these modes. In the top panel of Fig. 1 we see that more massive models have higher entropy, translating into lower central densities and more extended density (\u03c1) versus interior mass, M r , profiles. Consequently, prominent boundaries which are associated with discontinuities in entropy and Y e and which affect the character of the modes are also located at larger radii for higher-mass progenitors. These discontinuities are the boundary between the fossil Fe core (the residue of core Si burning) and the most recent Fe ashes from shell Si burning (circles on Fig. 1 ), the edge of the Fe core (includes the fossil Fe core and recent Fe ashes) and the Si burning shell (stars on Fig. 1) , and the interface between the Si burning and O burning shells (triangles on Fig. 1 ). The general structural profiles and these distinct boundaries (Table 1) together determine the eigenfunctions and eigenfrequencies.", "cite_spans": [], "ref_spans": [{"start": 774, "end": 780, "text": "Fig. 1", "ref_id": "FIGREF2"}, {"start": 1307, "end": 1313, "text": "Fig. 1", "ref_id": "FIGREF2"}, {"start": 1426, "end": 1433, "text": "Fig. 1)", "ref_id": "FIGREF2"}, {"start": 1512, "end": 1518, "text": "Fig. 1", "ref_id": "FIGREF2"}, {"start": 1584, "end": 1593, "text": "(Table 1)", "ref_id": "TABREF1"}]}, {"section": "Massive Star Structures", "text": "The role of structure in affecting the general character of the solutions can be understood using the local dispersion relation for plane waves of the form e i( k\u00b7 r\u00b1\u03c9t) :", "cite_spans": [], "ref_spans": []}, {"section": "Massive Star Structures", "text": "where k r is the radial component of the wave vector (Unno et al. 1989 ). This relation implies that for \u2113 , the equivalent period has been presented for each. These periods are P Brunt = 2\u03c0/ |N 2 | and", "cite_spans": [], "ref_spans": []}, {"section": "Massive Star Structures", "text": "\u2113 . An important feature illustrated in Fig. 2 is that N 2 rises and then falls, creating a resonant cavity for g-modes. The fall is partly due to the density and pressure structures, but on the outside it dramatically plummets due to convection in the O-burning shell, thereby confining g-waves within the core. For higher frequencies (lower periods), p-waves are allowed. However, they are free to propagate throughout the entire star. Since the sound-crossing time in the outer stellar mantle is extremely long and dissipative processes exist, the establishment of standing p-modes is prevented. Hence, for all models and times, g-modes are trapped in the core, encompassing the Fe core and frequently the Si burning shell.", "cite_spans": [], "ref_spans": [{"start": 40, "end": 46, "text": "Fig. 2", "ref_id": "FIGREF3"}]}, {"section": "Massive Star Structures", "text": "Other salient features evident in Fig. 2 are the spikes in P Brunt , or equivalently, N 2 . These spikes are the result of S, Y e , and \u03c1 discontinuities at the boundaries indicated in Table 1 . As impedance mismatches these spikes effectively reflect g-waves. Therefore, even though most g-modes have their greatest amplitude near the center of the core, the reflecting boundaries imply that there might be sub-regions within the overall resonating cavity in which modes may be trapped.", "cite_spans": [], "ref_spans": [{"start": 34, "end": 40, "text": "Fig. 2", "ref_id": "FIGREF3"}, {"start": 185, "end": 192, "text": "Table 1", "ref_id": "TABREF1"}]}, {"section": "Massive Star Structures", "text": "By prodigious neutrino emission, the cores of massive stars continue to change their structures prior to the onset of core collapse (Woosley et al. 2002) . Figure 3 illustrates the changes of the propagation diagram for the 13 M \u2299 model during the last ten minutes of evolution. As the inner regions quickly evolve and contract, the Brunt-V\u00e4is\u00e4l\u00e4 frequency increases with time, gradually increasing the modal frequencies. In contrast, the model corresponding to t = 0 s (onset of collapse) exhibits a dramatic truncation in the size of the resonating cavity, in that N 2 drops to negative values as the convective region grows due to implosive burning. However, collapse happens on a dynamical timescale, and will take 200 to 250 ms. Given that the convective turnover times and the periods of oscillation are longer than this, the assumption of steady-state mixing-length convection is probably violated. Although for completeness, results for the t = 0 s models are presented here, the quantitative results at t = 0 s should be viewed with healthy skepticism. At other times, the structural changes are gradual enough for our peturbation theory to be reliable.", "cite_spans": [], "ref_spans": [{"start": 156, "end": 164, "text": "Figure 3", "ref_id": "FIGREF4"}]}, {"section": "Massive Star Structures", "text": "In this paper, the major sources and sinks of energy considered are nuclear burning, neutrino losses, and losses by coupling to outward propagating p-waves (Lai 2000b) . Since losses by radiation is overwhelmed by neutrino emission, perturbations in the radiative flux is ignored. Throughout the Fe core, neutrino losses dominate over energy deposition. Only in the Si-and O-burning shells do nuclear reactions allow the \u01eb-mechanism to operate. For the typical g-mode with its largest amplitudes in the center, neutrino losses will dominate in eq. (21), resulting in stability. However, potentially unstable modes are those that are trapped mostly in the outer part of the core near or in the Si-burning region by the discontinuities in entropy, Y e , and density (Lai 2000b ).", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "The results of our analysis are summarized in Table 2 , which lists all unstable modes found, and Figs. 4-11, which are described in detail below. Even though we did find modes for \u2113 = 1, 2, 3, and higher \u2113s, we present the results only for \u2113 = 1, 2, and 3 in Table 2 . since the trends at higher \u2113s are adequatly demonstrated with the set presented in this paper. In general, the most interesting spherical harmonics to consider are those with odd \u2113, or those with a top-bottom asymmetry. However even \u2113s are interesting as well, as the nonlinear evolution of the perturbations into a kick may be triggered by any low order \u2113. Since the dipole, \u2113 = 1, spherical harmonic most closely resembles the desired kick geometry, we focus in this section on \u2113 = 1, with peripheral mention of \u2113 = 2 and 3.", "cite_spans": [], "ref_spans": [{"start": 46, "end": 53, "text": "Table 2", "ref_id": "TABREF2"}, {"start": 260, "end": 267, "text": "Table 2", "ref_id": "TABREF2"}]}, {"section": "Results", "text": "Stable and unstable modes are found in all progenitor models. Figures 4 and 5 display the propagation diagram for the 13 M \u2299 and 30 M \u2299 models, at t = 5 s before the commencement of collapse. These diagrams represent modes of the compact and extended profiles, respectively. Note again, the spikes resulting from Y e and \u03c1 discontinuities in P Brunt and the existence of a resonance cavity confined by O-shell convection in the 13 M \u2299 model (Fig. 4) . Because the O shell is farther out in mass for the more massive 30 M \u2299 model (Fig. 5) , the density and pressure profiles are more relevant in defining the resonant region. In both figures each horizontal line corresponds to a specific mode; the shading encodes | \u03be| 2 . Dark and lighter shading signify low and high displacement, respectively, while blues denote stable modes and reds identify the unstable modes. Figures 4 and 5 show that there are many more stable modes than unstable modes, which is true for all models at all times and for all \u2113s. We also identify two classes of g-modes, inner-core and outer-core g-modes. Inner-core g-modes have their greatest displacements toward the center and diminish with radius. Their spacing in log 10 (P eriod) systematically decreases with increasing period and increasing number of half-wavelengths, n. In contrast outer-core g-modes do not have their greatest amplitude in the center. They are trapped by discontinuites between the fossil Fe core and the O shell in the case of the 13 M \u2299 model and within the Si burning shell in the case of the 30 M \u2299 model. Similar trapping exists for all other progenitors we consider.", "cite_spans": [], "ref_spans": [{"start": 529, "end": 537, "text": "(Fig. 5)", "ref_id": "FIGREF5"}]}, {"section": "Results", "text": "Less than half of the outer-core g-modes are modes trapped entirely under the spikes (i.e. surface gmodes). While these modes satisfy the adiabatic linear oscillation equations, their physical significance is not well constrained. Their eigenfunctions and eigenfrequencies depend on the spike widths and heights, which in turn depend upon the interface between convective and radiative regions in mixing-length theory. However, the results and conclusions we present in this paper are not predicated on their character or existence.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "A sample of inner-core g-modes for the 13 M \u2299 , t = 5 s, model with \u2113 = 1 is plotted versus interior mass in Fig. 6 . The decreasing envelope of the eigenfunction and systematic increase in period with increasing half-wavelengths, n, is well explained by a WKB analysis (Unno et al. 1989) . The quantization condition, n\u03c0 = k r dr, integrated over an appropriate resonant cavity, for g-waves gives", "cite_spans": [], "ref_spans": [{"start": 109, "end": 115, "text": "Fig. 6", "ref_id": "FIGREF6"}]}, {"section": "Results", "text": "Numerically, the inner core frequencies are proportional to [\u2113(\u2113 + 1)] 1/2 /n, and integrating eq. (25) over the appropriate resonance cavity gives approximately the same value. Following the conservation of wave flux arguments in Goldreich & Wu (1999) , the envelope for the aribtrarily scaled amplitudes of \u03be r /R and \u03be h /R in Fig. 6 also correspond with those from the WKB analysis. In contrast, a simple WKB analysis fails to predict either the shape or the period of the outer-core g-mode shown in Fig 7. Instead, this mode's period and large displacement farther out in mass are determined by both resonance in the overall cavity and resonant trapping between disontinuities in density, Y e , and entropy.", "cite_spans": [], "ref_spans": [{"start": 330, "end": 336, "text": "Fig. 6", "ref_id": "FIGREF6"}]}, {"section": "Results", "text": "In the context of losses and gains in energy, Fig. 8 displays | \u03be| 2 versus interior mass for two representative inner-core g-modes (top panel) and an outer-core g-mode (bottom panel) for the 13 M \u2299 , t = 5 s model for \u2113 = 1, in addition to \u01eb nuc and \u01eb \u03bd in erg g \u22121 s \u22121 . Figure 9 presents similar information for the 30 M \u2299 model. The overlap of | \u03be| 2 with \u01eb nuc and \u01eb \u03bd is an excellent diagnostic proxy for the integrand in the work integral (eq. (18)). Clearly, neutrino losses dominate the work integral for the case of inner-core g-modes in both models. For the particular outer-core g-modes plotted for the 13 M \u2299 and 30 M \u2299 progenitors in the bottom panels of Figs. 8 and 9 , respectively, the large amplitude in the Si-burning region allows for instability. While all outer-core g-modes in Fig. 5 are unstable, two of the three 13 M \u2299 outer-core g-modes in Fig. 4 are stablized by neutrino and acoustic losses. In general, at least one outer-core g-mode has the requisite radial perturbation distribution to be unstable.", "cite_spans": [], "ref_spans": [{"start": 46, "end": 52, "text": "Fig. 8", "ref_id": "FIGREF8"}, {"start": 670, "end": 683, "text": "Figs. 8 and 9", "ref_id": "FIGREF8"}, {"start": 801, "end": 807, "text": "Fig. 5", "ref_id": "FIGREF5"}]}, {"section": "Results", "text": "The growth timescales versus period for \u2113 = 1, 2, and 3, t = 60, 30, 25, 20, 15, 10, 5, 2, 1, and 0 s before the onset of collapse are plotted for 11 M \u2299 13 M \u2299 , and 30 M \u2299 models in Figs. 12, 10, and 11, respectively. As expected, these figures illustrate that for higher \u2113 the periods are smaller. Even though we find many unstable modes for the 11 M \u2299 we do not find clear trends in the \u03c4 versus period plane. In contrast, as represented by the 13 M \u2299 and 30 M \u2299 models, all other masses we consider demonstrate a distinct trend. The arrows in Figs. 10 and 11 indicate the direction in which the modes evolve with time in the \u03c4 versus period plane. Specifically, later models are more compact and have shorter period oscillations. In addition, the later, more compact, models have slightly higher densities and temperatures in the burning regions, thereby dramatically increasing the burning rates and decreasing \u03c4 in Figs. 10 and 11. Also note that at no point in any of the models are the growth timescales shorter than the times until the start of collapse. These trends continue to the onset of collapse, which is marked on Figs. 10 and 11 with red symbols. In fact, for the latest models, t = 0 s and 1 s before the start of collapse, \u03c4 becomes comparable to the period, calling into question the assumption in \u00a72.1 of small nonadiabatic effects. While dramatic changes imposed by dynamical collapse and implosive burning for the t = 0 s models make the effects listed above more pronounced, the qualitative trends highlighted still obtain for the t = 0 s models.", "cite_spans": [], "ref_spans": [{"start": 548, "end": 563, "text": "Figs. 10 and 11", "ref_id": "FIGREF2"}]}, {"section": "Results", "text": "For all unstable modes found Table 2 lists the progenitor mass, time until onset of collapse, the period, growth timescale, \u03c4 , and the contributions, \u03c4 nuc , \u03c4 \u03bd , and \u03c4 leak . From tens of minutes before commencement of collapse until collapse itself, unstable modes exist in all progenitor models. However, at every evolutionary stage the timescale for growth is an order-of-magnitude or two longer than the time until onset of collapse. The rates of growth or decay we derive are too long compared to the time to onset of collapse to significantly alter the mode amplitudes. It seems that even though the \u01eb-mechanism is present in the later evolutionary stages of the cores of massive stars, the timescales imply that its effect is not large.", "cite_spans": [], "ref_spans": [{"start": 29, "end": 36, "text": "Table 2", "ref_id": "TABREF2"}]}, {"section": "Analytic Estimates", "text": "Consistently, we find that the timescales for growth are longer than the time until the onset of collapse. As such the \u01eb-mechanism is not able to significantly affect the amplitudes of the unstable g-modes. Hence, our evaluation of the succesfulness of the \u01eb-mechanism depends upon the validity of the timescale calculations. In this section we corroborate, with an analytic estimate for \u03c4 nuc , our numerical evaluations for the growth timescales.", "cite_spans": [], "ref_spans": []}, {"section": "Analytic Estimates", "text": "W j , given by eq. (18), is the rate of energy gained or lost, and E W , eq. (23), is the energy in the mode. Assuming the region where nuclear burning interacts with a growing mode is small and the mode itself may be represented by a top-hat function located entirely and only within the burning region with maximum displacement \u2206r/r, then the integrand in eq. (18) is roughly constant. Therefore,", "cite_spans": [], "ref_spans": []}, {"section": "Analytic Estimates", "text": "and eq. (19), simplifies to \u03b4T T \u223c V \u2207 ad \u2206r r .", "cite_spans": [], "ref_spans": []}, {"section": "Analytic Estimates", "text": "As a harmonic oscillation, g-modes are the oscillations of isodensity contours about their equilibrium positions in hydrostatic equilibrium. The harmonic potential is U \u223c 1 2 \u2202 2 \u03c6 ef f /\u2202r 2 x 2 , where x = \u2206re i\u03c9t . From \u2207\u03c6 = \u2207P/\u03c1, we get \u03c6 ef f \u223c \u03c6 \u223c P/\u03c1 \u223c GM r /r. Hence, the potential energy, u, is given by", "cite_spans": [], "ref_spans": []}, {"section": "Analytic Estimates", "text": "Since E W = 2 < u > dM r , where <> denotes the time average over one period of oscillation, then", "cite_spans": [], "ref_spans": []}, {"section": "Analytic Estimates", "text": "Finally, taking the ratio of eq. (29) and eq. (26) gives a rough estimate for \u03c4 :", "cite_spans": [], "ref_spans": []}, {"section": "Analytic Estimates", "text": "In the burning region, for the 30 M \u2299 t = 5 s model and the 8.67 s, \u2113 = 1 mode, P/\u03c1 \u223c 2.2 \u00d7 10 17 erg g \u22121 , \u01eb nuc \u01eb nucT \u223c 2 \u00d7 10 16 erg g \u22121 s \u22121 , \u2207 ad \u223c 1/4, and V \u223c 2, giving \u03c4 nuc \u223c 320 s from eq. (30). The numerical solution in Table 2 is \u03c4 nuc = 328 s. Similarly for the 8.45 s, \u2113 = 1 mode of the 13 M \u2299 progenitor model at t = 1 s, P/\u03c1 \u223c 1.4 \u00d7 10 17 erg g \u22121 , \u01eb nuc \u01eb nucT \u223c 10 17 erg g \u22121 s \u22121 , \u2207 ad \u223c 1/4, and V \u223c 3, giving \u03c4 nuc \u223c 30 s from eq.(30). The numerical solution (Table 2 ) is \u03c4 nuc = 15.5 s. That the simple analytic arguments and estimates approximately reproduce the numerical results is reassuring. Even though the nuclear rates increase toward later times, at no time is this trend enough to cause significant growth prior to collapse.", "cite_spans": [], "ref_spans": [{"start": 235, "end": 242, "text": "Table 2", "ref_id": "TABREF2"}, {"start": 487, "end": 495, "text": "(Table 2", "ref_id": "TABREF2"}]}, {"section": "Summary and Conclusions", "text": "For all progenitors, we find stable and unstable g-modes with oscillation periods in the range from \u223c1 to \u223c10 seconds. The stable g-modes are often concentrated in the inner core and are stabilized by neutrino emission. Unstable g-modes on the other hand are trapped in the outer radii of the core by discontinuities in S, density, and Y e . Their typical growth timescales determined numerically and analytically range from 10s to 10,000s of seconds, which are long compared to the time until the start of collapse. Therefore, we conclude that the \u01eb-mechanism is an unlikely source for large perturbations in the progenitor prior to the onset of collapse.", "cite_spans": [], "ref_spans": []}, {"section": "Summary and Conclusions", "text": "There are several caveats to our conclusion. Our results are for a set of 1-D nonrotating models from Rauscher et al. (2002) and Woosley et al. (2002) . Rotation in the late stages of massive stellar evolution may significantly effect the structure of the star prior to collapse (Heger, Langer, & Woosley 2000; Heger, Woosley, & Langer 2003) , thereby altering the analysis in this paper. However, with modest Fe core rotation periods ( 10 s) we expect little deviation from our results, and the simple energy arguments in \u00a74.1 should hold. We also have not considered a different suite of progenitor models (Nomoto & Hashimoto 1988; Limongi & Chieffi 2003) , which may have different eigenmodes. In addition, calculating full 3-D, non-linear, dynamical convection with nuclear reactions during the final stages of massive star evolution is a task for the future; the progenitors and their g-modes may be significantly different than assumed or calculated here.", "cite_spans": [{"start": 311, "end": 341, "text": "Heger, Woosley, & Langer 2003)", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "Summary and Conclusions", "text": "We also have not considered coupling between convective modes and g-modes, which provides an excellent mechanism for the excitation of the 5-minute p-modes in the Sun (Goldreich & Kumar 1990 ). In such analyses, the amplitudes of the modes are estimated by assuming steady state is achieved in the nonlinear time-dependent amplitude equations. However, the short timescales until the onset of collapse would violate the assumption of steady state and invalidate such analyses. More importantly, it would be unlikely that the short timescales until the onset of collapse would allow for significant excitation of g-modes by convection.", "cite_spans": [], "ref_spans": []}, {"section": "Summary and Conclusions", "text": "On the other hand, the growth of perturbations in the supersonic regions during collapse does occur (Lai 2000a; Lai & Goldreich 2000) . Because we have not ruled out all possible sources of perturbations prior to collapse, asymmetries in the progenitor may still be relevant in producing the largest kicks. For example, convection in the last stages of evolution is often quite vigorous and may have Mach numbers in the range 0.1 to 0.2 and density perturbations, \u03b4\u03c1/\u03c1, in the range 0.01 to 0.05 (Bazan & Arnett 1998) . These perturbations may indeed be sufficient to produce the observed kicks (Burrows & Hayes 1996) .", "cite_spans": [], "ref_spans": []}, {"section": "Summary and Conclusions", "text": "In performing a stellar pulsational and stability analysis of the late-time cores of massive stars, we have identified many stable and unstable modes. We note that stability is predominantly determined by the neutrino losses or energy deposition by nuclear reactions. Compared with the time until the onset of collapse, the timescales for growth and decay are long. In \u00a74.1, we argue that the long growth timescales (compared with the time until the start of collapse) are confirmed by energetic arguments. We suggest that the \u01eb-mechanism for g-mode growth does not generate the requisite perturbations prior to collapse needed to stimulate large kicks during the supernova explosion. Therefore, we conclude that if the hydrodynamic mechanism in combination with progenitor perturbations is to succeed in explaining neutron star kicks other sources of seed perturbations must be investigated. This preprint was prepared with the AAS L A T E X macros v5.2. The location of the fossil Fe core, which was formed by convective core Si burning, at 5 s before collapse.", "cite_spans": [], "ref_spans": []}, {"section": "Summary and Conclusions", "text": "3 The location of the base of the Si burning shell or the top of the Fe core, which inludes the fossil Fe core and the more recent ashes from the Si burning shell. A C indicates that the shell is convective, R indicates that it is radiative, and M inidicates that the shell is radiative in its inner portion and convective in its outer portion. Fig. 2 . Notice that the evolution aburptly changes for t = 0 s. This is due to the dramatic increase in nuclear rates during implosive burning, which causes new regions to become convective in the mixing-length calculation. Fig. 4 .-The propagation diagram for \u2113 = 1 and the 13 M \u2299 model at 5 s before the onset of collapse with P Brunt (solid) and P Lamb (\u2113 = 1) (dashed), as defined in Fig. 2 . The horizontal lines correspond to each eigenmode and period and are quantized. The shading in the lines is a measure of the magnitudes of the square of the amplitude, |\u03be| 2 . Within a single line brighter portions indicate a higher amplitude while the darker color signifies a lower amplitude. The blues indicate modes which are stable (\u03c4 < 0), and the reds correspond to the modes which are unstable (\u03c4 > 0). 51, 9.28, 8.17 , and 7.07 s, for \u2113 = 1, 13 M \u2299 , and 5 s before the start of collapse. Each mode is distinguished by its period. The top panel plots \u03be r /R, where \u03be r is the radial component of perturbation and R is the calculation domain size. The amplitude is arbitrarily scaled to 1.0 at its peak value. The bottom panel plots the corresponding horizontal amplitude, \u03be h /R. 2 (browns and oranges), the local deposition of energy by nuclear processes, \u01eb nuc (solid and black), and the local losses of energy due to neutrinos, \u01eb \u03bd (dashed), versus interior mass (M \u2299 ) for the 13 M \u2299 model, \u2113 = 1, and 5 s before the onset of collapse. The top panel illustrates this comparison for two representative stable modes (periods = 10.51 and 9.28 s), while the bottom panel plots an unstable mode (period = 9.5 s). Note that the inner-core g-modes have their largest relative amplitudes where neutrino losses dominate, but that the outer-core g-modes have their largest relative amplitudes trapped in the recent Si burning ashes as well as the Si burning layer giving rise to instability. ", "cite_spans": [], "ref_spans": [{"start": 345, "end": 351, "text": "Fig. 2", "ref_id": "FIGREF3"}, {"start": 734, "end": 740, "text": "Fig. 2", "ref_id": "FIGREF3"}]}], "bib_entries": {"BIBREF13": {"title": "Unsolvde Problems in Astrophysics", "authors": [{"first": "P", "middle": [], "last": "Goldreich", "suffix": ""}, {"first": "D", "middle": [], "last": "Lai", "suffix": ""}, {"first": "M", "middle": [], "last": "Sahrling", "suffix": ""}], "year": 1997, "venue": "", "link": null}, "BIBREF17": {"title": "IAU Symposium", "authors": [{"first": "A", "middle": [], "last": "Heger", "suffix": ""}, {"first": "S", "middle": ["E"], "last": "Woosley", "suffix": ""}, {"first": "N", "middle": [], "last": "Langer", "suffix": ""}], "year": 2003, "venue": "", "link": null}, "BIBREF34": {"title": "Same as Fig. 8, but for the M = 30 M \u2299 progenitor, stable modes with periods of 10.48 s and", "authors": [{"first": "", "middle": [], "last": "Fig", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF35": {"title": "Note the clear, uninterupted evolution of specific g-modes up to the onset of collapse", "authors": [], "year": "", "venue": "Same as Fig. 10, but for the M = 30 M \u2299 progenitor", "link": null}}, "ref_entries": {"FIGREF0": {"text": "they are p-waves, and for \u03c9 2 < N 2 < L 2 \u2113 , they are g-waves (Unno et al. 1989). A propagation diagram, which plots N 2 and L 2 \u2113 versus M r or r, shows where in the star each type of wave is allowed to propagate. The propagation diagrams for the 13 M \u2299 (top panel) and 30 M \u2299 (bottom panel) models and their corresponding density and Y e profiles, are presented in Fig. 2. The positions of the prominent discontinuities are marked as in Fig. 1. Rather than plotting N 2 and L 2", "type": "figure"}, "FIGREF2": {"text": "Fig. 1.-Density (top panel) and electron fraction, Y e , (bottom panel) versuses interior mass, M , for the 11 M \u2299 (solid and dark blue), 13M \u2299 (dotted and light blue), 15 M \u2299 (dashed and green), 20 M \u2299 (dot-dash and olive green), 30 M \u2299 (dot-dot-dot-dash and red), 35 M \u2299 (long dashed and orange), and 40 M \u2299 (solid orange) models, all at 5 s before the onset of collapse. Note in the top panel that the lower mass models have higher central densities, but that the higher mass models have shallower density gradients. Included on the Y e plot are points indicating significant features in the star, which greatly affect the modes. Circles represent the farthest extent of the fossil Fe core, which was formed during convective core Si burning. Stars represent the base of the Si burning shell at 5 seconds before the start of collapse (i.e., the extent of the Fe core, including the fossil Fe and the most recent ashes from Si shell burning), which generally aren't convective until collapse. The triangles represent the base of the convective O burning shell", "type": "figure"}, "FIGREF3": {"text": "Fig. 2.-Density (solid green) and Y e (solid red) versuses interior mass in comparison to the propagation diagram for the 13 M \u2299 model at 5 s before the onset of collapse. Usually, the square of the Brunt-V\u00e4is\u00e4l\u00e4 (N 2 ) and Lamb (L 2 \u2113 ) frequencies are plotted. In this case, an equivalent period of oscillation is displayed instead, defined by P Brunt = 2\u03c0/ (|N 2 |) and P Lamb = 2\u03c0/ (|L 2 \u2113 |). The circles, stars, and triangles represent the same structural boundaries as in Fig. 1. The vertical spikes are from discontinuous density and Y e changes in the profiles and are real. The bottom panel provides the equivalent information for the 30 M \u2299 model.", "type": "figure"}, "FIGREF4": {"text": "Fig. 3.-A time series of the propagation digram for the 13 M \u2299 model from 600 s to 0 s before the start of collapse. P Brunt and P Lamb are defined as in Fig. 2. Notice that the evolution aburptly changes for t = 0 s. This is due to the dramatic increase in nuclear rates during implosive burning, which causes new regions to become convective in the mixing-length calculation.", "type": "figure"}, "FIGREF5": {"text": "Fig. 5.-This figure is similar to Fig. 4, but for the 30 M \u2299 model.", "type": "figure"}, "FIGREF6": {"text": "Fig. 6.-The dimensionless eigenfunctions of stable g-mode oscillations with periods of 10.51, 9.28, 8.17, and 7.07 s, for \u2113 = 1, 13 M \u2299 , and 5 s before the start of collapse. Each mode is distinguished by its period. The top panel plots \u03be r /R, where \u03be r is the radial component of perturbation and R is the calculation domain size. The amplitude is arbitrarily scaled to 1.0 at its peak value. The bottom panel plots the corresponding horizontal amplitude, \u03be h /R.", "type": "figure"}, "FIGREF7": {"text": "Fig. 7.-Plotted are the same attributes depicted in Fig. 6, but for a representative unstable mode with period 9.50 s.", "type": "figure"}, "FIGREF8": {"text": "Fig. 8.-The Lagrangian displacement squared, |\u03be| 2 (browns and oranges), the local deposition of energy by nuclear processes, \u01eb nuc (solid and black), and the local losses of energy due to neutrinos, \u01eb \u03bd (dashed), versus interior mass (M \u2299 ) for the 13 M \u2299 model, \u2113 = 1, and 5 s before the onset of collapse. The top panel illustrates this comparison for two representative stable modes (periods = 10.51 and 9.28 s), while the bottom panel plots an unstable mode (period = 9.5 s). Note that the inner-core g-modes have their largest relative amplitudes where neutrino losses dominate, but that the outer-core g-modes have their largest relative amplitudes trapped in the recent Si burning ashes as well as the Si burning layer giving rise to instability.", "type": "figure"}, "FIGREF9": {"text": "Fig. 10.-The growth timescales, \u03c4 , in seconds, for the unstable modes versus their periods, in seconds, for the 13 M \u2299 model. The plots are for \u2113 = 1 (circle), 2 (triangle), and 3 (square) and for times of 60 (blue), 30, 25, 20, 15, 10, 5, 2, 1, and 0 (red) seconds before the onset of collapse. The arrow indicates the evolution of the period and growth timescales for particular modes as the models approach collapse.", "type": "figure"}, "FIGREF10": {"text": "Fig. 12.-Same as Fig. 10 but for the M = 11 M \u2299 progenitor. While plenty of growing modes exist, their timescales are far too long for any significant growth to occur.", "type": "figure"}, "TABREF0": {"text": "Unno, W., Osaki, Y., Ando, H., Saio, H., & Shibahashi, H. 1989, Nonradial oscillations of stars (Nonradial oscillations of stars, Tokyo: University of Tokyo Press, 1989, 2nd ed.)", "type": "table"}, "TABREF1": {"text": "The initial mass of the model.", "type": "table"}, "TABREF2": {"text": "Growing Modes", "type": "table"}, "TABREF3": {"text": "Continued Mass (M \u2299 )", "type": "table"}}}
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{"paper_id": "45911948", "_pdf_hash": "89ea499af3ff3de890d3bb57dc717ac6e87865fc", "abstract": [{"section": "Abstract", "text": "Objective: To describe vitamin D levels and prevalence of vitamin D sufficiency, insufficiency and deficiency in a large, ethnically/racially diverse population of youth with type 1 diabetes (T1D) and type 2 diabetes (T2D) in comparison to national data and examine the associations between clinical/demographic factors and vitamin D levels. Methods: 25-hydroxy vitamin D (25OHD) levels were measured in 215 youth with T1D and 326 youth with T2D enrolled in the Pediatric Diabetes Consortium (PDC). These levels were compared with those of youth of the same age without diabetes from the 2005-2006 NHANES Survey. Results: Vitamin D deficiency (<21 ng/mL) was present in 36% of PDC participants, and insufficiency (21-29 ng/mL) was present in an additional 34%. About 36% of age-matched youth in the NHANES Survey were vitamin D deficient and an additional 41% were insufficient. Deficiency or insufficiency varied by race/ethnicity, being highest in African-Americans (86%), intermediate in Hispanics (77%), and lowest in non-Hispanic whites (47%). Lower 25OHD levels were observed in African-American and Hispanic youth, during fall and winter, and at sites in the northern United States (all p-values < 0.001). Youth with T2D had significantly lower 25OHD levels than youth with T1D (p < 0.001), but this difference was largely eliminated after adjusting for race/ethnicity and socio-economic status. Conclusions: Vitamin D deficiency/insufficiency is present in a substantial proportion of youth with diabetes, particularly minorities, but the prevalence appears similar to that in youth without diabetes. Further studies are needed to examine whether youth with diabetes would benefit from vitamin D supplementation.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "The classic role of vitamin D is in calcium-phosphate metabolism and bone formation and the non-classic role is as a potential anti-inflammatory and immunemodulating hormone. Vitamin D insufficiency and deficiency are common in youth (1) ; especially in youth with type 1 diabetes (T1D) (2-4) and type 2 diabetes (T2D) (5, 6) . Proposed mechanisms of an increased prevalence of vitamin D insufficiency and deficiency include genetic inheritance (7, 8) , increased body-mass index (BMI) (9) , and concurrent albuminuria with enhanced excretion of vitamin D binding protein (10) and less healthy diets in youth with diabetes. In addition to bone health, youth with diabetes may have additional benefits from being vitamin D sufficient. Past research has demonstrated that vitamin D insufficiency/deficiency in pediatric diabetes may contribute to insulin resistance (3, 5, 11, 12) , poor glycemic control (13) , and the development of microvascular and macrovascular complications (14) (15) (16) .", "cite_spans": [{"start": 319, "end": 322, "text": "(5,", "ref_id": "BIBREF4"}, {"start": 323, "end": 325, "text": "6)", "ref_id": "BIBREF5"}, {"start": 445, "end": 448, "text": "(7,", "ref_id": "BIBREF6"}, {"start": 449, "end": 451, "text": "8)", "ref_id": "BIBREF7"}, {"start": 486, "end": 489, "text": "(9)", "ref_id": "BIBREF8"}, {"start": 572, "end": 576, "text": "(10)", "ref_id": "BIBREF10"}, {"start": 864, "end": 867, "text": "(3,", "ref_id": "BIBREF2"}, {"start": 868, "end": 870, "text": "5,", "ref_id": "BIBREF4"}, {"start": 871, "end": 874, "text": "11,", "ref_id": "BIBREF11"}, {"start": 875, "end": 878, "text": "12)", "ref_id": "BIBREF12"}, {"start": 903, "end": 907, "text": "(13)", "ref_id": "BIBREF13"}, {"start": 979, "end": 983, "text": "(14)", "ref_id": "BIBREF14"}, {"start": 984, "end": 988, "text": "(15)", "ref_id": "BIBREF15"}, {"start": 989, "end": 993, "text": "(16)", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "", "text": "In 2009, the Pediatric Diabetes Consortium (PDC) was formed with the objective of improving the care of children with diabetes through sharing of best practices, collecting outcomes data with a common database, and collectively advocating for improvements in pediatric diabetes care focused on evidence-based education. A cohort of youth with newly diagnosed T1D was enrolled in the PDC T1D NeOn registry by seven US pediatric diabetes centers between 2009 and 2011 and a cohort of youth with T2D was enrolled by eight pediatric diabetes centers between 2012 and 2014. The large size and broad geographic distribution of patients within the two registries, as well as the differences in racial/ethnic and socio-economic characteristics between the two registries, prompted us to examine the prevalence of vitamin D sufficiency, insufficiency, and deficiency in these two groups of youth with diabetes.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Patients", "text": "This study of the PDC T1D and T2D cohorts included 215 participants with T1D and 326 with T2D who had 25OHD levels measured between April 2012 and December 2013 and who were \u226510 years old at the time of testing. Participants who were <10 and >22 years of age were excluded from this study to balance age distribution between the two cohorts. The protocols were approved by the Institutional Review Board (IRB) at each of the participating centers. Informed consent was obtained from participants older than 18 years of age and from parents of those less than 18 years of age. Assent was also obtained from participants <18 years of age as required by local IRB regulations.", "cite_spans": [], "ref_spans": []}, {"section": "Patients", "text": "On enrollment, participants in the PDC T1D NeOn registry had to be managed at one of the participating PDC centers within 3 months of diagnosis. A detailed description of the PDC T1D NeOn registry has been published previously (17) . The PDC T2D registry included participants who were diagnosed with T2D using the criteria of the American Diabetes Association including being antibody negative, BMI > 85th percentile for age and gender prior to diabetes-associated weight loss and at least one of the following: (i) HbA1c \u2265 6.5% (\u226548 mmol/mol), (ii) random glucose > 200 mg/dL (11.1 mmol/L), (iii) fasting glucose \u2265 126 mg/dL (7.0 mmol/L), or (iv) 2-hour OGTT glucose \u2265 200 mg/dL (11.1 mmol/L).", "cite_spans": [{"start": 227, "end": 231, "text": "(17)", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "Data collection", "text": "Demographic, socio-economic, and clinical characteristics data were collected from medical records and from interviews with the patient and/or parent. Vitamin D (25OHD) levels were measured by the IDS-iSYS analyzer at the Mineral Metabolism Laboratory (Yale University, New Haven, CT, USA). This assay has been found to be highly accurate (18) . Vitamin D deficiency was defined according to the Endocrine Society Clinical Practice Guideline as a 25OHD level < 21 ng/mL and vitamin D insufficiency was defined as 25OHD level between 21 and 29 ng/mL (19) . Blood was drawn from 107 fasting and 434 non-fasting participants. HbA1c levels were measured by point of care device or local laboratory within 28 days of the collection of the vitamin D sample.", "cite_spans": [{"start": 339, "end": 343, "text": "(18)", "ref_id": "BIBREF18"}, {"start": 549, "end": 553, "text": "(19)", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "Statistical analysis", "text": "In order to compare our results with the national population, the distribution of 25OHD levels from the NHANES survey 2005-2006 were calculated for the same age range as our sample (10-<22 years). Mean 25OHD levels, 95% confidence interval, percent of vitamin D deficiency and insufficiency were calculated from our diabetes cohort and the NHANES 2005-2006 data, and sampling weights were used to make the NHANES survey reflective of the general US population. (http://wwwn.cdc.gov/ nchs/nhanes/search/nhanes13_14.aspx). Race-specific 25OHD levels were also compared.", "cite_spans": [], "ref_spans": []}, {"section": "Statistical analysis", "text": "Least squares regression was used to determine the association of demographic/clinical factors with vitamin D levels. Multivariable models were constructed using stepwise selection methods and included all factors with the p-value < 0.10. Due to multiple comparisons, only factors with p-values < 0.01 were considered statistically significant while factors with p-value < 0.10 were included to adjust for possible confounding. Adjusted means from multivariable analysis were defined to be the least squares means (ls-means) from the regression model. Interactions among all possible pairwise combination of factors remaining in the multiple regression model were also assessed and none were found to be significant (p-value < 0.01). Residual plots from the final multivariate model were evaluated for approximate normal distribution, outliers, and homogeneity of variance. All reported p-values are two-sided. All analyses were conducted using SAS version 9.4 (SAS Institute, Cary, NC, USA).", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "The demographic characteristics of the 215 study participants with T1D and 326 with T2D are shown in Table 1 . There were substantial differences between the two cohorts with a larger percentage of racial/ethnic minorities in the T2D cohort: 29% of the T1D cohort were Hispanic or Latino and 8% were African-American compared with 59% Hispanic or Latino and 27% African-American in the T2D cohort; 46% of youth with T1D were female compared with 63% of youth with T2D. Mean age was 14.5 \u00b1 2.7 and 16.1 \u00b1 2.5 years for T1D and T2D, respectively.", "cite_spans": [], "ref_spans": [{"start": 101, "end": 108, "text": "Table 1", "ref_id": "TABREF1"}]}, {"section": "Results", "text": "The overall mean 25OHD level was 24.8 (99% confidence interval 23.7 to 25.9) ng/mL (Table 2) . Vitamin D deficiency occurred in 36% of youth and vitamin D insufficiency occurred in an additional 34%, with the remaining 30% of youth having a 25OHD level above 29 ng/mL. The prevalence of vitamin D deficiency and insufficiency varied according to race/ethnicity. Deficiency was present in 14% of non-Hispanic whites, 38% of Hispanics, and 65% of African-Americans, and insufficiency was present in 33% of non-Hispanic whites, 39% of Hispanics, and 21% of African-Americans. Of note, 9% of T2D participants indicated they were taking vitamin D supplements (data on dose were not available), mean 25OHD level in these youth was 27 \u00b1 9 ng/mL; these data were not available for the T1D cohort. A sensitivity analysis excluding the 9% T2D participants who were taking vitamin D supplements generated similar results (data not shown).", "cite_spans": [], "ref_spans": [{"start": 83, "end": 92, "text": "(Table 2)", "ref_id": "TABREF4"}]}, {"section": "Results", "text": "From the NHANES 2005-2006 data, mean age was 15.4 years (99% confidence interval 15.0-15.9 years), 48% female, and median (interquartile range) BMI was 71% (40%, 91%).The national mean 25OHD level in the same age range was 24.0 (99% confidence interval 21.9-26.1) ng/mL, with vitamin D deficiency in 36% of youth and vitamin D insufficiency in 41%. From the NHANES database, deficiency was present in 18% of non-Hispanic whites, 56% of Hispanics, and 83% of African-Americans, and insufficiency was present in 48% of non-Hispanic whites, 37% of Hispanics, and 15% of African-Americans ( Table 2 ). The 25OHD level from NHANES data was significantly lower than the level from PDC cohort among each race/ethnicity group (p < 0.001 for all three groups).", "cite_spans": [], "ref_spans": [{"start": 587, "end": 594, "text": "Table 2", "ref_id": "TABREF4"}]}, {"section": "Results", "text": "Differences in unadjusted vitamin D levels were present when youth with T1D and T2D were compared (Table S1 , Supporting Information). However, this was largely, though not entirely, explained by differences in race/ethnicity distribution between diabetes types. As seen in Fig. 1 , the distribution of vitamin D levels was similar comparing non-Hispanic white T1D and T2D youth and comparing African-American T1D and T2D youth, though for both diabetes types the vitamin D levels were substantially lower in the African-American than white participants. For the Hispanic youth, the levels in T1D appeared to be slightly higher than in T2D.", "cite_spans": [], "ref_spans": [{"start": 98, "end": 107, "text": "(Table S1", "ref_id": "TABREF1"}, {"start": 274, "end": 280, "text": "Fig. 1", "ref_id": "FIGREF2"}]}, {"section": "Results", "text": "In addition to race/ethnicity and diabetes type, in univariable models, lower 25OHD levels were associated with older age, female sex, BMI \u2265 85%, non-private insurance, lower parental education level, and lower household income. In addition, 25OHD levels varied substantially among the eight study sites and by season with the highest levels in summer and lowest levels in winter. HbA1c levels and diabetes duration were not significantly associated with 25OHD levels (Table S1 ). There was no statistically significant interaction between site and race/ethnicity. In multivariable analysis, only race/ethnicity (p < 0.001), study site (p < 0.001), and season (p<0.001) were significantly associated with 25OHD levels; diabetes type was no longer significant (p = 0.05) (Table S1 ).", "cite_spans": [], "ref_spans": [{"start": 468, "end": 477, "text": "(Table S1", "ref_id": "TABREF1"}, {"start": 770, "end": 779, "text": "(Table S1", "ref_id": "TABREF1"}]}, {"section": "Discussion", "text": "In this large, multi-center study of a diverse group of youth with diabetes, we found that vitamin D deficiency and insufficiency were common (36 and 34%, respectively). In multivariate analysis, lower vitamin D levels were seen in African-American and Hispanic youth, in fall/winter months, and in those living in the northern United States. When other variables were taken into account in a multivariate analysis, diabetes type was no longer significantly associated with 25OHD levels. The lower vitamin D levels seen in the African-American youth when compared to the non-Hispanic white youth in our study may be explained by lower levels of vitamin D binding protein secondary to genetic polymorphisms in the vitamin D binding protein gene (7, 8) . In addition, the lower vitamin D levels in the Hispanic and African-American participants also could be explained by increased skin pigmentation because this inhibits the synthesis of cholecalciferol, the metabolic precursor of 25OH vitamin D (20) . Individuals with T1D have also been demonstrated to have enhanced urinary excretion of vitamin D binding protein when compared with nondiabetic controls (10) . In this study by Thrailkill et al., participants with albuminuria had more exaggerated urinary losses of vitamin D binding protein than participants with normoalbuminuria, and therefore, this explanation is unlikely to be a major factor in our study of youth with diabetes of relatively short duration.", "cite_spans": [{"start": 744, "end": 747, "text": "(7,", "ref_id": "BIBREF6"}, {"start": 748, "end": 750, "text": "8)", "ref_id": "BIBREF7"}, {"start": 996, "end": 1000, "text": "(20)", "ref_id": "BIBREF20"}, {"start": 1156, "end": 1160, "text": "(10)", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Discussion", "text": "The prevalence of vitamin D deficiency in healthy American youth of a similar age varies between 19 and 24% when vitamin D deficiency is defined as <12 ng/mL (1) . Using this cut point, only 7% (N=38) in our study had vitamin D deficiency. Although the overall level of vitamin D was similar in the NHANES and PDC groups, differences emerged when vitamin D levels were compared by race/ethnicity. When we compared our results with the 2005-2006 NHANES data from youth of the same age, the vitamin D level among each race/ethnicity group was significantly higher in our study participants (p<0.001 for all three groups). (19) . It is a limitation of our study that we did not obtain data on dietary vitamin D intake in our participants or dose of vitamin D supplements being used by our participants with T2D. Amount of sun exposure is influenced by season of year and latitude. Indeed, in multivariate analysis of our PDC cohort, season and study site were important predictors of vitamin D levels. While previous reports have suggested that obese individuals have lower vitamin D levels because vitamin D is fat-soluble and is sequestered in body fat (9) , when vitamin D levels were adjusted for race/ethnicity and study site in the multivariate analysis of our study results, the influence of differences in BMI was no longer significant. Thus in our cohorts, skin pigmentation and sun exposure appear to have a greater impact on circulating vitamin D levels than either obesity or the type of diabetes.", "cite_spans": [{"start": 620, "end": 624, "text": "(19)", "ref_id": "BIBREF19"}, {"start": 1152, "end": 1155, "text": "(9)", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Discussion", "text": "Prevalence of vitamin D deficiency in American youth with T1D as reported in the literature has varied from 15-68.5%. For example, Svoren et al. (4) (2) , and 49% of youth with T1D (n = 1426) followed in the SEARCH study had deficient vitamin D levels < 20 ng/mL (3). Only the Florida study included a non-diabetic control group, and they found that 25OHD levels in a group of controls were similar to children with T1D and their first degree relatives. Much of this variation in prevalence can be explained by the disparate definitions of vitamin D deficiency applied in each study, the racial/ethnic composition of the patient population, the geographic location/latitude of the study sites, and the season of the year when samples were drawn. In our study, the three variables most highly associated with vitamin D levels were race/ethnicity, study site, and season.", "cite_spans": [{"start": 149, "end": 152, "text": "(2)", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Discussion", "text": "Reports in the literature of the prevalence of vitamin D deficiency in youth with T2D are less common. De las Heras et al. reported that 59% of 27 youth with T2D were vitamin D deficient with levels < 20 ng/mL (5). To our knowledge only Di Cesar et al. (6) compared the prevalence of vitamin D deficiency (<20 ng/mL) in T1D (n = 50) and T2D (n = 63), but the participants were all adults. They found that adults with T2D had more vitamin D deficiency than adults with T1D (63.5 vs. 36%). This difference persisted after adjusting for BMI and was unrelated to age, sex, or insulin treatment. Importantly, race/ethnicity was not examined in this study. In our cohort, we found that youth with T1D and T2D had a comparable prevalence of vitamin D deficiency after adjusting for site, race/ethnicity, season, gender, health insurance, and family income.", "cite_spans": [{"start": 253, "end": 256, "text": "(6)", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Discussion", "text": "Strengths of our study include the large sample size, and the racial/ethnic and geographic diversity of the participant population. In particular, this is the largest cohort of youth with T2D that have had vitamin D levels systematically measured. One weakness of our study is the lack of a control group of youth without diabetes, so we are unable to directly compare the prevalence of vitamin D deficiency in youth with and without diabetes. However, we were able to compare the prevalence in our cohorts with an age-matched population from the NHANES study. Limitations of this comparison are the use of different vitamin D assays for each and the fact that the NHANES data was collected in 2005-2006, while ours were taken in 2012-2013. Our data is also limited by the fact that we do not have complete data on dietary vitamin D intake or dose of vitamin D supplements being used by our T1D participants.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Despite these limitations, our findings demonstrate that youth with T1D and T2D had similar vitamin D levels, after controlling for race/ethnicity. In addition, vitamin D deficiency and insufficiency were equally common in youth with and without diabetes after adjusting for race/ethnicity and socio-economic status. From these data, we conclude that the evaluation of vitamin D status should be considered in pediatric patients, especially in those with diabetes and from a racial/ethnic minority population. Additional research is needed to confirm whether youth with diabetes would have benefits, such as improved insulin resistance (3, 5, 11, 12) , glycemic control (13) , and prevention of diabetes related complications (14) (15) (16) , from vitamin D supplementation.", "cite_spans": [{"start": 636, "end": 639, "text": "(3,", "ref_id": "BIBREF2"}, {"start": 640, "end": 642, "text": "5,", "ref_id": "BIBREF4"}, {"start": 643, "end": 646, "text": "11,", "ref_id": "BIBREF11"}, {"start": 647, "end": 650, "text": "12)", "ref_id": "BIBREF12"}, {"start": 670, "end": 674, "text": "(13)", "ref_id": "BIBREF13"}, {"start": 726, "end": 730, "text": "(14)", "ref_id": "BIBREF14"}, {"start": 731, "end": 735, "text": "(15)", "ref_id": "BIBREF15"}, {"start": 736, "end": 740, "text": "(16)", "ref_id": "BIBREF16"}], "ref_spans": []}], "bib_entries": {"BIBREF1": {"title": "Vitamin D levels in subjects with and without type 1 diabetes residing in a solar rich environment", "authors": [{"first": "L", "middle": 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""}], "year": 1960, "venue": "Advance Data", "link": null}, "BIBREF23": {"title": "Personnel are listed as (PI) for Principal Investigator, (I) for co-Investigator and (C) for Coordinators.) (1) Baylor College of Medicine", "authors": [], "year": "", "venue": "Clinical Centers: (Listed clinical center name, city, and state", "link": null}, "BIBREF27": {"title": "Children's Hospital of Los Angeles", "authors": [{"first": "Andrene", "middle": [], "last": "Mcdonald", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF33": {"title": "MD (I)", "authors": [{"first": "Michael", "middle": ["J"], "last": "Haller", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF40": {"title": "Children's Hospital of Philadelphia", "authors": [{"first": "Ashley", "middle": [], "last": "Eason", "suffix": ""}], "year": "", "venue": "", "link": null}}, "ref_entries": {"FIGREF2": {"text": "Fig. 1. Vitamin D levels by race/ethnicity and diabetes type. The bottom and top of each box denote the 25th and 75th percentiles, the line inside the box denotes the median and the dot is the mean.", "type": "figure"}, "FIGREF3": {"text": "Possible explanations for higher vitamin D levels in our PDC cohort include the fact that samples were drawn in 2012-2013 compared to 2005-2006 for the NHANES cohort. It is possible that the PDC cohorts were getting more nutritional counseling as part of their diabetes education that included dietary and vitamin D supplement recommendations resulting in higher vitamin D levels. Very few foods naturally have or are fortified with vitamin D, and therefore, the major source of vitamin D for children and adults is sun exposure. With increased sedentary behaviors occurring indoors and increased use of sunscreen to prevent skin cancer, dietary vitamin D intake and vitamin D supplements are very important contributors to the vitamin D status of youth", "type": "figure"}, "TABREF1": {"text": "Demographic and clinical characteristics at testing by diabetes type", "type": "table"}, "TABREF4": {"text": "Comparing vitamin D levels between PDC sample and US general population*", "type": "table"}, "TABREF5": {"text": "defined vitamin D deficiency as \u2264 20 ng/mL and reported that 15% of 128 youth with T1D living in Massachusetts were vitamin D deficient. In 110 patients with T1D (5-65.1 years of age) living in Florida, 68.5% had a suboptimal vitamin D level \u2264 30 ng/mL", "type": "table"}}}
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The journal publishes original research articles, review articles, clinical reports, case studies, commentaries, editorials, and letters to the Editor. For more information please visit us at following: Aims and Scope", "authors": [], "year": "", "venue": "Cite this article International Journal of Rare Diseases & Orphan Drugs International Journal of Rare Diseases &", "link": null}}, "ref_entries": {}}
{"paper_id": "45916542", "_pdf_hash": "04a8a24554859c82da6640681930b85162f55d66", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "A rapid propagation system for cassava", "authors": [{"first": "J", "middle": ["H"], "last": "Cock", "suffix": ""}, {"first": "D", "middle": [], "last": "Wholey", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Lozano", "suffix": ""}], "year": 1976, "venue": "CIAT Series EE", "link": null}, "BIBREF1": {"title": "The application of tissue culture for the vegetative propagation of plants", "authors": [{"first": "G", "middle": [], "last": "Hussey", "suffix": ""}], "year": 1978, "venue": "Sci Prog", "link": null}, "BIBREF2": {"title": "A new technique for the rapid propagation of cassava (Manihot esculenta Crantz)", "authors": [{"first": "P", "middle": [], "last": "Kamalam", "suffix": ""}, {"first": "P", "middle": ["G"], "last": "Rajendran", "suffix": ""}, {"first": "N", "middle": [], "last": "Hrishii", "suffix": ""}], "year": 1977, "venue": "Trop Agric (Trinidad)", "link": null}, "BIBREF3": {"title": "Regeneration of cassava plants from apical meristems", "authors": [{"first": "K", "middle": ["K"], "last": "Kartha", "suffix": ""}, {"first": "O", "middle": ["L"], "last": "Gamborg", "suffix": ""}, {"first": "F", "middle": [], "last": "Constabel", "suffix": ""}, {"first": "J", "middle": ["P"], "last": "Shyluk", "suffix": ""}], "year": 1974, "venue": "Plant Sci Lett", "link": "85093489"}, "BIBREF4": {"title": "A revised medium for rapid growth and bioassays with tobacco tissue cultures", "authors": [{"first": "T", "middle": [], "last": "Murashige", "suffix": ""}, {"first": "F", "middle": [], "last": "Skoog", "suffix": ""}], "year": 1962, "venue": "Physiol Plant", "link": "84645704"}, "BIBREF5": {"title": "Handbook of plant cell culture", "authors": [{"first": "W", "middle": ["M"], "last": "Roca", "suffix": ""}], "year": 1984, "venue": "", "link": null}, "BIBREF6": {"title": "Improvement of a propagation technique for cassava using single leaf-bud cuttings: A preliminary report", "authors": [{"first": "W", "middle": ["M"], "last": "Roca", "suffix": ""}, {"first": "A", "middle": [], "last": "Rodriguez", "suffix": ""}, {"first": "L", "middle": ["F"], "last": "Patena", "suffix": ""}, {"first": "R", "middle": ["C"], "last": "Barba", "suffix": ""}, {"first": "J", "middle": ["C"], "last": "Toro", "suffix": ""}], "year": 1980, "venue": "Cassava Newsletter", "link": "106993945"}}, "ref_entries": {}}
{"paper_id": "45916588", "_pdf_hash": "704c7488953ba63b9d9b3f56bb3f0f671dff3d00", "abstract": [{"section": "Abstract", "text": "Handwashing is one of the most important factors in controlling the spread of micro-organisms and in preventing the development of infections. Children are taught this basic principle very early in life and are given daily reinforcements by parents. However, when children are in school, reinforcement of handwashing by parents often decreases. Previous research documented that middle-and upper-school girls washed their hands after bathroom use 58% of the time and boys 48% of the time. 1 Soap usage was only 28% for girls and 8% for boys. Similar results were reported by Early and colleagues 2 who found a 58%-compliance rate for handwashing after bathroom use in a female elementary age-group. In 1999, an observational study conducted on handwashing after bathroom use in a single-sex (girl) high school in Oxford, United Kingdom, found that compliance to handwashing was higher (86%), but soap usage was only 10% and hand-drying only 25%. 3 Further investigation revealed that low soap usage was due to the fact that soap dispensers were often not refilled and that lack of drying was due to the use of hot air dryers, which were too time-consuming.", "cite_spans": [{"start": 946, "end": 947, "text": "3", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Abstract", "text": "Although our research has focused on lack of handwashing after bathroom use and did not address the effect on absenteeism, several articles have documented the effect of handwashing education on absenteeism. Master and colleagues 4 reported that mandatory handwashing programs reduced acute gastrointestinal illnesses in elementary school-age children. Classroom presentations and follow-up programs about handwashing resulted in a significant decrease in absenteeism due to illness during the 2 months after the presentations. 5 Hammond and colleagues 6 reported similar results in a population of more than 6000 elementary-age students representing 18 public schools in 4 states. Handwashing helped to reduce colds at a child-care center when education on handwashing was required in the curriculum. 7 Similar results in day care were reported by Butz and colleagues. 8 They found a significant reduction in symptoms of enteric disease when a hand hygiene intervention program was introduced.", "cite_spans": [{"start": 802, "end": 803, "text": "7", "ref_id": "BIBREF6"}, {"start": 870, "end": 871, "text": "8", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Abstract", "text": "However, to our knowledge there have been no studies evaluating the effect of a comprehensive program of education and placement of hand sanitizers in the classroom on absenteeism. Therefore, the Handwashing is one of the most important factors in controlling the spread of micro-organisms and in preventing the development of infections. The objective of this study was to determine the effectiveness of a comprehensive handwashing program on absenteeism in elementary grades. Two hundred ninety students from 5 independent schools were enrolled in the study. Each test classroom had a control classroom, and only the test classroom received the intervention (education program and hand sanitizer). Absenteeism data were collected for 3 months. The number of absences was 50.6% lower in the test group (P < .001). The data strongly suggest that a hand hygiene program that combines education and use of a hand sanitizer in the classroom can lower absenteeism and be cost-effective. (Am J Infect Control 2002;30:217-20.) From the Agnes Irwin School, Rosemont a ; the University of Pennsylvania, College of General Studies, Young Scholars Program,", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "Handwashing is one of the most important factors in controlling the spread of micro-organisms and in preventing the development of infections. Children are taught this basic principle very early in life and are given daily reinforcements by parents. However, when children are in school, reinforcement of handwashing by parents often decreases. Previous research documented that middle-and upper-school girls washed their hands after bathroom use 58% of the time and boys 48% of the time. 1 Soap usage was only 28% for girls and 8% for boys. Similar results were reported by Early and colleagues 2 who found a 58%-compliance rate for handwashing after bathroom use in a female elementary age-group. In 1999, an observational study conducted on handwashing after bathroom use in a single-sex (girl) high school in Oxford, United Kingdom, found that compliance to handwashing was higher (86%), but soap usage was only 10% and hand-drying only 25%. 3 Further investigation revealed that low soap usage was due to the fact that soap dispensers were often not refilled and that lack of drying was due to the use of hot air dryers, which were too time-consuming.", "cite_spans": [{"start": 489, "end": 490, "text": "1", "ref_id": "BIBREF0"}, {"start": 946, "end": 947, "text": "3", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "", "text": "Although our research has focused on lack of handwashing after bathroom use and did not address the effect on absenteeism, several articles have documented the effect of handwashing education on absenteeism. Master and colleagues 4 reported that mandatory handwashing programs reduced acute gastrointestinal illnesses in elementary school-age children. Classroom presentations and follow-up programs about handwashing resulted in a significant decrease in absenteeism due to illness during the 2 months after the presentations. 5 Hammond and colleagues 6 reported similar results in a population of more than 6000 elementary-age students representing 18 public schools in 4 states. Handwashing helped to reduce colds at a child-care center when education on handwashing was required in the curriculum. 7 Similar results in day care were reported by Butz and colleagues. 8 They found a significant reduction in symptoms of enteric disease when a hand hygiene intervention program was introduced.", "cite_spans": [{"start": 230, "end": 231, "text": "4", "ref_id": "BIBREF3"}, {"start": 528, "end": 529, "text": "5", "ref_id": "BIBREF4"}, {"start": 553, "end": 554, "text": "6", "ref_id": "BIBREF5"}, {"start": 802, "end": 803, "text": "7", "ref_id": "BIBREF6"}, {"start": 870, "end": 871, "text": "8", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "", "text": "However, to our knowledge there have been no studies evaluating the effect of a comprehensive program of education and placement of hand sanitizers in the classroom on absenteeism. Therefore, the ", "cite_spans": [], "ref_spans": []}, {"section": "METHODS Subjects", "text": "Five independent elementary schools in Pennsylvania were enrolled in the study. Written permission was obtained from the headmaster/headmistress at each school before student enrollment in the study. Each school was asked to provide 2 test and 2 control classrooms of the same grade. The median class size was 15 (range, 11-20 students). Three schools were coed, one was single sex (boys), and one was single sex (girls). Students in the test group received the intervention of education and hand sanitizer. Those in the control group did not receive any intervention.", "cite_spans": [], "ref_spans": []}, {"section": "Education", "text": "The educational components of this program consisted of a 10-minute talk on the importance of handwashing, when to wash hands, and when to remind your buddy to wash his or her hands. This was followed by a video on micro-organisms and disease transmission. Students in kindergarten and first grade were shown a 2-minute video titled \"The Sneeze,\" and children in grades 2 and 3 saw a 10-minute video titled \"Haley's Germs\" (GOJO Industries, Inc., Akron, Ohio). 9 After the video, each student received a \"Buddies Handwashing Pamphlet\" (Fig 1) , on which kindergartners and firstgraders completed the exercise of connecting dots that formed a hand and a bar of soap. Second-and third-graders completed a word search of common handwashing words, such as soap, water, and towel. The total time for conducting the education component was 1 hour. For this research, the presenter was the same individual, a junior high school student.", "cite_spans": [{"start": 461, "end": 462, "text": "9", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Hand sanitizer", "text": "Each test classroom was equipped with a dispenser of Purell Instant Hand Sanitizer with Aloe (GOJO Industries). The active ingredient in Purell is ethyl alcohol at 62%. It is formulated with skin moisturizers such as glycerin and propylene glycol. Running water was not available in any classrooms. During the program, proper handwashing techniques with the hand sanitizer were demonstrated, and each student was asked to wash his or her hands. Students were asked to line up in small groups of 4 or 5. Each student was directed to the hand sanitizer. Under the directions of the program presenter, each was asked to wash his or her hands. Directions were given if proper technique was not followed. After completing the handwashing, students were given cards identifying them as \"Ambassadors of Hygiene\" (GOJO Industries). 9", "cite_spans": [], "ref_spans": []}, {"section": "Data collection/analysis", "text": "Absenteeism was defined as the number of episodes of illness per child per month. A new episode of absenteeism that followed the initial one was considered unrelated if there was a lapse of 5 days. Illness was defined as an infectious process such as cold, flu, and gastroenteritis. Teachers were given a form to monitor each episode of illness. They were asked to determine either through parent or child the nature of absenteeism. Students were told during the education program that their teachers would be asking why they were absent and it was important for them to tell the teacher if the absenteeism was due to a personal situation, such as longer vacation, or injury, such as a broken arm. Absenteeism data were collected by the teachers for 3 months (March-May 2000) after initiation of the \"Buddies Handwashing Program.\"", "cite_spans": [], "ref_spans": []}, {"section": "Data collection/analysis", "text": "Four schools had 2 test classrooms, and 1 school had 1 test classroom, for a total of 9 test observations. Each school served as its own control. Data were collected for 3 months, resulting in 27 observations (n = 27). Data were reviewed as a set of independent observations on grades by month and by school with use of a binomial distribution with parameters of n = 27 and P = .05.", "cite_spans": [], "ref_spans": []}, {"section": "Cost data/analysis", "text": "Cost data associated with absenteeism was defined as the following:", "cite_spans": [], "ref_spans": []}, {"section": "Cost data/analysis", "text": "\u2022 Teacher time: One hour of teacher time per episode (for remedial work, take-home assignment) at an hourly rate of $50. Time was determined by averaging the estimates reported by each school for preparing assignments and remedial work. The hourly rate was determined on the basis of the substitute teacher salary rate for the county in which the test schools are located. Table 1 shows the number of episodes of absenteeism by school and month. There was lower absenteeism in 23 of the 27 months the test groups (P < .001) compared with the control groups. The test group had 50.6% fewer episodes of absenteeism than the control group (277 vs 140 episodes). Table  2 shows the cost-savings associated with a reduction in absenteeism. Teacher time in the test and control groups represents the hourly rate multiplied by the episodes of illness (1 hour of teacher work per episode). On the basis of these factors, the cost in the control group for absenteeism was $13,850 per quarter. In the test group, the teacher time was $7000 per quarter. However, for the test group, the costs of the school nurse's in-service time, hand sanitizer, and activity pamphlets were an additional $775, for a total cost of $7775, which is still a savings of $6075 per quarter for the test group compared with the control group. On the basis of these estimations, the yearly projected savings would be $24,300, or $167 per student enrolled.", "cite_spans": [], "ref_spans": [{"start": 373, "end": 380, "text": "Table 1", "ref_id": "TABREF1"}, {"start": 659, "end": 667, "text": "Table  2", "ref_id": "TABREF2"}]}, {"section": "RESULTS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Two hundred and ninety students (145 controls and 145 tests)", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "Schools, like hospitals, have significant predisposing factors for the transmission of micro-organisms and cross-contamination, such as a close environment, inanimate objects serving as vehicles of transmission, and often inadequate supplies for handwashing. The number of lost school days annually among kindergarten through twelfth-grade students is 164 million, with an average of 4.5 days a year per student. 10 A report by the Carnegie Foundation 11 for education noted that 83% of teachers think that absenteeism is the main problem they face in school. In 1999, Cramer and colleagues 12 reported on a survey of parents' expectations of a school health program. They found that 96% of the 1200 respondents listed \"preventing and controlling infections or contagious disease\" as extremely important, ranking it No. 2 in a list of 24 health activities in a school health program.", "cite_spans": [{"start": 413, "end": 415, "text": "10", "ref_id": "BIBREF10"}, {"start": 591, "end": 593, "text": "12", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "Since hands are the primary vehicle of transmission of many infectious diseases, teaching children appropriate hand hygiene and providing accessible hand sanitizer in the classroom can be an effective Total episodes of absenteeism: control group = 277, test group = 140; % difference = 50.6% (P < .001). program for potentially decreasing absenteeism. Our data, like that of Hammond, 6 show a significant decrease in absenteeism when a hand sanitizer is placed in the classroom. However, the lower absenteeism seen in our study is much higher than that reported by Hammond and colleagues (50.6% vs 19.8%). This may be because the control classrooms in the Hammond study were given instruction on handwashing, whereas the students in our control group were not aware of the study. This awareness in the control group could account for increased handwashing compliance in the control group, resulting in a lower percent of absenteeism in the test group.", "cite_spans": [{"start": 384, "end": 385, "text": "6", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "Implementing a program on hand hygiene must first gain administration support, and this support is often determined on the basis of cost rather than research data. This study has shown that a program of education and placement of a hand sanitizer in the classroom has the potential to save a school $24,300 per year, or roughly $167 per student enrolled.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "The limitations of this study are 4-fold, including limited geographic location of the schools and a homogeneous student population (middle-class and upperclass private school students). Another limitation was that seasonal absenteeism was not determined. However, Hammond and colleagues 6 followed-up 6000 students for 1 year after a handwashing program with a hand sanitizer and documented that the lowest absenteeism occurred in September through January and that absenteeism in the largest school district peaked in March and continued through May (our study was February through May). The fourth limitation was that variables related to the home environment, such as smokers in house, hygiene, number of siblings, health status of siblings, and health provider visits, were not measured.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "This research strongly suggests that a successful hand hygiene program for elementary schools should include the following components:", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "1. Administrative support 2. One-hour hand hygiene educational in-service by a school nurse for all students 3. Placement of hand sanitizer in classrooms and bathrooms", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "Research on the importance of hand hygiene in the school setting is only beginning to appear in the literature. It is clear that a program involving both education and the availability of innovative products will form the basis of a school program. Future areas of research need to address the effect such programs have on specific diseases such as gastroenteritis, flu, and common cold. Also, there is a need to look at the effect of such programs not only on the student but also on the teacher.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Who washes hands after using the bathroom?", "authors": [{"first": "M", "middle": [], "last": "Guinan", "suffix": ""}, {"first": "M", "middle": [], "last": "Mcguckin", "suffix": ""}, {"first": "A", "middle": [], "last": "Sevareid", "suffix": ""}], "year": 1997, "venue": "Am J Infect Control", "link": "34470105"}, "BIBREF1": {"title": "Effect of several interventions on the frequency of handwashing among elementary public school children", "authors": [{"first": "E", "middle": [], "last": "Early", "suffix": ""}, {"first": "K", "middle": [], "last": "Battle", "suffix": ""}, {"first": "E", "middle": [], "last": "Cantwell", "suffix": ""}, {"first": "J", "middle": [], "last": "English", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Lavin", "suffix": ""}, {"first": "E", "middle": ["L"], "last": "Larsen", "suffix": ""}], "year": 1998, "venue": "Am J Infect Control", "link": "1534845"}, "BIBREF2": {"title": "Hand hygiene practices in a school setting in UK", "authors": [{"first": "M", "middle": [], "last": "Guinan", "suffix": ""}], "year": 1999, "venue": "", "link": null}, "BIBREF3": {"title": "Scheduled hand washing in an elementary school population", "authors": [{"first": "D", "middle": [], "last": "Master", "suffix": ""}, {"first": "S", "middle": ["H"], "last": "Longe", "suffix": ""}, {"first": "H", "middle": [], "last": "Dickson", "suffix": ""}], "year": 1997, "venue": "Fam Med", "link": "24591649"}, "BIBREF4": {"title": "Handwashing education can decrease illness absenteeism", "authors": [{"first": "L", "middle": ["S"], "last": "Kimel", "suffix": ""}], "year": 1996, "venue": "J School Nurs", "link": "26832243"}, "BIBREF5": {"title": "Effect of hand sanitizer use on elementary school absenteeism", "authors": [{"first": "B", "middle": [], "last": "Hammond", "suffix": ""}, {"first": "Y", "middle": [], "last": "Ali", "suffix": ""}, {"first": "E", "middle": [], "last": "Fendler", "suffix": ""}, {"first": "M", "middle": [], "last": "Dolan", "suffix": ""}, {"first": "S", "middle": [], "last": "Donovan", "suffix": ""}], "year": 2000, "venue": "Am J Infect Control", "link": "44695050"}, "BIBREF6": {"title": "Proper handwashing promotes wellness in child care", "authors": [{"first": "J", "middle": ["P"], "last": "Niffingger", "suffix": ""}], "year": 1997, "venue": "J Pediatr Health Care", "link": "7695296"}, "BIBREF7": {"title": "Occurence of infections symptoms in children in day care homes", "authors": [{"first": "A", "middle": ["M"], "last": "Butz", "suffix": ""}, {"first": "E", "middle": ["L"], "last": "Larson", "suffix": ""}, {"first": "P", "middle": [], "last": "Fosarelli", "suffix": ""}, {"first": "R", "middle": [], "last": "Yolken", "suffix": ""}], "year": 1990, "venue": "Am J Infect Control", "link": null}, "BIBREF8": {"title": "Healthy Hands/Healthy Kids Program", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF10": {"title": "US Centers for Disease Control and Prevention and the National Center for Health Statistics. Vital Health and Statistics, Current Estimates from the National Health Interview Survey, 1995.The Centers", "authors": [], "year": 1998, "venue": "", "link": null}, "BIBREF11": {"title": "The Carnegie Foundation for Annual report. New York:The Foundation", "authors": [], "year": 1990, "venue": "", "link": null}, "BIBREF12": {"title": "Parent expectations of the school health program in Nebraska", "authors": [{"first": "M", "middle": ["V"], "last": "Cramer", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "Iversen", "suffix": ""}], "year": 1999, "venue": "J School Health", "link": "25600857"}}, "ref_entries": {"FIGREF0": {"text": "\u2022 School nurse time: One hour per in-service and 1- hour preparation time per class at $35. Although a school nurse was not part of this study, we fac- tored in this cost since the school nurse would be responsible for the implementation of the pro- gram. \u2022 Hand sanitizers: One fourth of the yearly cost for soap per child ($2 per year or 50 cents per quarter) \u2022 Activity booklet and ambassador card: 50 cents per child", "type": "figure"}, "TABREF1": {"text": "Episodes of absenteeism", "type": "table"}, "TABREF2": {"text": "Cost-effectiveness of a hand hygiene program (in dollars)", "type": "table"}}}
{"paper_id": "45916839", "_pdf_hash": "659d092b24c9f5312ae75933c525e3664fcb8d7f", "abstract": [], "body_text": [{"section": "", "text": "Purpose: We present a surgical technique for maxillary auto-bone grafting complementary and simultaneously to Le Fort I orthognathic surgery that was used on 123 patients. This graft has two main objectives: to reduce the dead space between the two bone parts of the maxilla and increase the volume of the cheeks, para-nasal spaces or cheekbones to improve the aesthetic result of the intervention.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Methods: From 2007 to 2012, 123 patients underwent a Le Fort I surgery with the conventional technique of Bell. Bone debris collected during the intervention were then wrapped in a sheet of Surgicel\u00ae and then grafted at the dead space left in the osteotomy by maxillary movement, or on the anterior maxilla in the paranasal area or on the malar bone. The records of 80 patients were collected to evaluate the postoperative course and 29 postoperative scans were studied to measure the size of the bone pieces.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Results Background and objectives: Airway management in the craniomaxillofacial trauma surgery may require some modifications of the standard intubation techniques. Submental endotracheal intubation may serve as an effective and safe alternative route in these conditions. In standard technique of submentotracheal intubation, the tube is fixed extra orally at the submental incision site with sutures to prevent displacement of the tube during the surgical intervention. But still it leaves a possibility of accidental extubation during the conversion of orotracheal to submental route and vice versa. To counteract this problem we in our institution, fix the tube at two points, one at molar teeth intraorally and second at skin surface externally near submental incision site ensuring a secured airway.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Method used: A total of 10 patients were included with panfacial trauma and were divided into two equal groups of five patients each. Group 1 (test) is intubated using two point fixation technique of submental intubation and Group 2 (control) using standard one point fixation technique. The primary outcome is displacement of tube during orotracheal to submental conversion and vice versa, which was evaluated using fibreoptic endoscope. Secondary outcomes are complications like accidental extubation or endobronchial intubation.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Results: Mean displacement of ET tube in two point fixation group was found to be 3 mm during orotracheal to submental conversion and 2 mm during submental to orotracheal conversion. While in one point fixation group mean displacement of ET tube was found to be 12 mm and 10 mm, respectively. Endobronchal intubation occurred in one patient of group 2.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Conclusion: Two point fixation technique has given better outcomes than standard one point fixation technique. The decrease in tube displacement during submental or orotracheal conversion and vice versa help in avoiding adverse complications like accidental extubation and endobronchal intubation in the patients.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Key words: submentotracheal intubation; fixation techniques; panfacial injuries http://dx.doi.org/10.1016/j.ijom.2013.07.548", "cite_spans": [], "ref_spans": []}, {"section": "T26.OR023", "text": "Rapid correction of dento-facial deformities combining accelerated osteogenic orthodontics (AOO) and orthognathic surgery", "cite_spans": [], "ref_spans": []}, {"section": "C. Hasse", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Center for Oral Facial Reconstruction, USA", "text": "Background and objectives: Heinrich Kole first introduced the corticotomy procedure to accelerate tooth movements, 1 Epker 2 and others 3 modified the technique but corticotomy surgery has gained little acceptance in the modern era of orthognathic surgery. Wilcko et al. 4 introduced a technique combining coorticotomies, stippling and alveolar ridge grafting. The technique termed AOO or Wilckodontics has been shown to be very successful in correcting dental malocclusions. 5 The purpose of this paper is to report the author's results combining AOO and orthognathic surgery.", "cite_spans": [], "ref_spans": []}, {"section": "Center for Oral Facial Reconstruction, USA", "text": "Methods: The author reviewed 30 cases in which both AOO and orthognathic surgery was utilized. The type of deformity, the treatment time frame, sequencing of surgeries and any complications were analyzed.", "cite_spans": [], "ref_spans": []}, {"section": "Center for Oral Facial Reconstruction, USA", "text": "Results: A retrospective study of the 30 cases surveyed showed that the average set-up time for orthognathic surgery was 17 weeks. This resulted in the orthognathic surgery being performed in 1/3 to 1/4 of the time normally required utilizing conventional orthodontia. Furthermore, the average total treatment time for correcting all of the cases was 34 weeks.", "cite_spans": [], "ref_spans": []}, {"section": "Center for Oral Facial Reconstruction, USA", "text": "Conclusions: Combining AOO with orthognathic surgery results in an exceptionally fast timeframe for correcting dento-facial deformities. The results are stable with a reproducible occlusion and a minimum of post-operative complications. Furthermore, it is advantageous in that pre-treatment bone dehiscences and fenestrations remain covered as confirmed by CT scans. The AOO surgery can be performed as an outpatient (office type) procedure, resulting in less hospital operating time and costs. The need for surgically assisted rapid palatal expansion (SARPE) and muti-piece osteotomies has been eliminated with this approach.", "cite_spans": [], "ref_spans": []}, {"section": "Center for Oral Facial Reconstruction, USA", "text": "Key words: AOO; Wilckodontics; orthognathic surgery; RAP; dento-facial deformities", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Surgical operations of the alveolar ridge to correct occlusal abnormalities. 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Seven cases or 8.4% of patients had a postoperative maxillary persistent edema. One case (1.2%) presented a sinus infection without any etiology determined. Conclusion: This technique, simple and easy, to use allows improved bone healing and cosmetic results without causing excess morbidity. It seems to be a good alternative to bone grafting technique sometimes long and complicated. It can be applied to all Le Fort I osteotomy. http://dx.doi.org/10.1016/j.ijom.2013.07.547 T26.OR022 Comparison of two point versus one point fixation techniques in submentotracheal intubation during craniomaxillofacial surgeries-a pilot study A. Gupta 1, * , D. Kapoor 2 1 Lady Hardinge Medical College, India 2 Government Medical College Hospital, India", "type": "table"}}}
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{"paper_id": "91047588", "_pdf_hash": "7ea2db0a32aa5d200f423bcbd5239082a1628d0e", "abstract": [{"section": "Abstract", "text": "The immune response against platelets is a complex process involving many aspects of the innate and adaptive immune system. Immune destruction of platelets and megakaryocytes and the thrombocytopenia that ensues can cause different clinically significant haematological disorders such as foetal and neonatal alloimmune thrombocytopenia (FNAIT), transfusion-induced platelet refractoriness or immune thrombocytopenia (ITP). These conditions are frequently difficult to manage so an understanding of the biological nature of these adverse conditions is critical for an understanding of how to potentially reduce them. Superimposed on these immune platelet attack mechanisms are the immune characteristics of the platelets themselves. This paper will give an overview of how the immune system recognizes platelet antigens and mounts efficient effector mechanism to mediate thrombocytopenia. It will also present evidence to suggest that platelets also play a role in stimulating these responses and suppressing them: a scenario where the 'prey' can become the 'predator'.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Innate and adaptive immunity and platelets", "text": "Innate immunity occurs naturally and is the result of the inherent genetic composition of the host. The innate immune system is comprised of non-specific defence mechanisms and is activated by danger signals derived from a wide variety of insults from tissue damage to infectious assaults. These signals affect many different aspects of host physiology such as anatomical barriers, for example the skin, secretions like stomach acid or lysozyme and cellular players such as neutrophils, macrophages and Natural Killer cells [1] [2] [3] [4] [5] . These different aspects work closely in unison to defend the host against infections in a relatively non-specific but direct manner within minutes to hours upon antigen appearance. One of the major functions of innate immunity is to recruit leucocytes to sites of inflammation caused by, for example, infections. This recruitment is mediated via the initial generation of potent molecules including lipid moieties, for example prostaglandins, chemokines and cytokines. Once recruited, leucocytes then initiate several host mechanisms of defence such as targeting infectious agents for destruction, enhancing the clearance of dangerous cells and, if necessary, recruitment and activation of the adaptive immune system through, for example, antigen presentation [1] [2] [3] [4] [5] .", "cite_spans": [{"start": 524, "end": 527, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 528, "end": 531, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 532, "end": 535, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 536, "end": 539, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 540, "end": 543, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 1306, "end": 1309, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 1310, "end": 1313, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 1314, "end": 1317, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 1318, "end": 1321, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 1322, "end": 1325, "text": "[5]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Innate and adaptive immunity and platelets", "text": "On the other hand, adaptive immunity refers to the antigen-specific immune response comprised exclusively of B and T lymphocytes and, in contrast to innate immunity, this system is slow to react to infectious agents as its activation is dependent on whether the innate immune system calls it into play. Once recruited and activated, however, T and B lymphocytes are exquisitely specific for antigens via the expression of genetically rearranged receptors and are able to uniquely generate memory pools to mount a quick anamnestic response to a reoccurrence of the offending infection [1, 4] . It is now clear that adaptive and innate immunity are inextricably linked where the innate immune system appears to be the ultimate controller of both.", "cite_spans": [{"start": 584, "end": 587, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 588, "end": 590, "text": "4]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Innate and adaptive immunity and platelets", "text": "Platelets are the smallest circulating cells in the blood and are generated in the bone marrow from large parental cells called megakaryocyte in a process termed proplatelet-formation. Their primary physiological role is to maintain vascular integrity by responding to endothelial injury which leads to the eventual formation of a clot to arrest bleeding and initiate wound repair [6] [7] [8] . Platelets can also be targeted by the innate and adaptive immune system through for example, transfusion of allogeneic platelets, foetal/maternal incompatibility and autoimmune processes that attack the host's own platelets. What is fascinating though is that although platelets can be targeted by immunity and prematurely destroyed there are multiple lines of evidence to suggest that the platelets themselves have a critical role in the modulation of inflammatory and immune processes. In this scenario, the platelet 'prey' can, in some circumstances, become the 'predator' and significantly modulate host immunity and potentially dictate their own immunological fate. This paper will discuss how platelets are targeted by innate and adaptive immune processes and, perhaps more interestingly, how the platelets themselves may modulate host immunity.", "cite_spans": [{"start": 381, "end": 384, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 385, "end": 388, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 389, "end": 392, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Platelets as both prey and predator", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Allo-and autoimmune destruction of platelets", "text": "Platelets express a cluster of human platelet antigens (HPAs) and their diversity has evolved due to singlenucleotide polymorphisms resulting in amino acid substitutions localized on the main platelet receptors: GPIIb/IIIa (integrin aIIbb3 or CD41/CD61: the fibrinogen receptor), the GPIb-V-IX (von Willebrand factor receptor) and the GPIa/IIa complex (a2b1, CD29, a collagen receptor) [9, 10] . HPA-15 is localized on the platelet membrane protein CD109 [a glycosylphosphatidylinositol (GPI)-linked glycoprotein located on the plasma membrane and belonging to the transforming growth factor-b receptor system] [11] . GPIIb-IIIa integrin also harbours the HPA1a/b antigens, the most clinically relevant platelet antigens in foetal or neonatal alloimmune thrombocytopenia (FNAIT) which is a potentially devastating bleeding disorder resulting in destruction of foetal platelets and which occurs when an HPA-negative mother is pregnant with a HPA-positive foetus and becomes alloimmunized against the foetal HPA antigens, upon mixing of foetal blood with the mother's blood [12, 13] . This results in the formation of anti-HPA-specific IgG-alloantibodies, which cross the placenta and destroy the foetal or neonatal platelets. This destruction occurs by phagocytes via their FcgRs which recognize and subsequently internalize the antibody-opsonized platelets via the Fc-tail of the anti-HPA alloantibody resulting in antibody-mediated platelet phagocytosis leading to foetal thrombocytopenia [12, 13] . Because antibody titre or isotype does not strictly correlate with FNAIT disease severity, other factors are likely to be involved. The strength of the interaction between IgG and FcgR indeed depends on several factors, such as the IgG subclass formed during the immune response, the relative affinity to FcgRs, the expression levels of FcgR allotypes, the FcgR copy number variation, various cytokines and importantly also the IgG-Fc glycosylation patterns [14] . IgG antibodies are glycoproteins which contain a branched sugar moiety attached to the Asn297 residue in their Fc region and this glycan is thus essential for the maintenance of a functional structure and for binding of IgG with FcgR [15] [16] [17] [18] . These glycans may contain variable amounts of galactose and sialic acid and may additionally carry a bisecting N-acetylglucosamine (GlcNAc) and core fucose. Variations in this carbohydrate composition can significantly affect antibody affinity to the FcgR and thereby antibody-mediated effector functions. It was found that anti-HPA-1a alloantibodies display lowered Fc-fucosylation [15] , which was shown to increase binding to FcgRIIIa/b, which enhanced antibody-mediated platelet phagocytosis [15] . Moreover, these fucosylation patterns correlated with increased clinical disease severity [15] . A follow-up study investigating 166 FNAIT cases confirmed these results and found using multiple logistic regression analysis that anti-HPA-1a-fucosylation combined with galactosylation and antibody levels correlated with bleeding severity [19] . Another factor which was found to influence anti-HPA-1a-mediated platelet phagocytosis in vitro, as well as antibody-mediated thrombocytopenia in vivo, was the acute phase protein C-reactive protein (CRP) [20] . CRP is a well-established biomarker for acute infections and inflammation. As CRP levels rapidly increase during acute infections and inflammation, they also seem to be functionally active in promoting antibody-mediated platelet destruction. Elevated CRP levels may therefore at least provide one explanation of why acute infections may trigger thrombocytopenia.", "cite_spans": [{"start": 386, "end": 389, "text": "[9,", "ref_id": "BIBREF8"}, {"start": 390, "end": 393, "text": "10]", "ref_id": "BIBREF9"}, {"start": 611, "end": 615, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 1072, "end": 1076, "text": "[12,", "ref_id": "BIBREF11"}, {"start": 1077, "end": 1080, "text": "13]", "ref_id": "BIBREF12"}, {"start": 1490, "end": 1494, "text": "[12,", "ref_id": "BIBREF11"}, {"start": 1495, "end": 1498, "text": "13]", "ref_id": "BIBREF12"}, {"start": 1959, "end": 1963, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 2200, "end": 2204, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 2205, "end": 2209, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 2210, "end": 2214, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 2215, "end": 2219, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 2605, "end": 2609, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 2718, "end": 2722, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 2815, "end": 2819, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 3062, "end": 3066, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 3274, "end": 3278, "text": "[20]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "Allo-and autoimmune destruction of platelets", "text": "Allogeneic platelet transfusions also frequently trigger the formation of anti-human leucocyte antigen (HLA)-specific alloantibodies, which destroy the platelets in subsequent transfusions inducing a state of platelet refractoriness and depriving the transfused recipient from an effective transfusion [21] . Interestingly, anti-HLA antibodies from refractory thrombocytopenia patients do not display a decrease in Fc-fucosylation [15] , indicating a difference with anti-HPA-1a-mediated platelet destruction in FNAIT.", "cite_spans": [{"start": 302, "end": 306, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 431, "end": 435, "text": "[15]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Allo-and autoimmune destruction of platelets", "text": "Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder characterized by low platelet counts (<100*10 9 /l) [22] . In ITP, platelets are opsonized by platelet-specific IgG-autoantibodies, leading to FcgR-mediated platelet phagocytosis by splenic macrophages [23, 24] . However, the pathogenesis of ITP is highly complex [25, 26] , and two other forms of platelet destruction are also described in ITP, which are due to CD8+ cytotoxic T lymphocytes [27] or due to antiplatelet GPIIIa49-66 IgG antibodies which enabled platelet fragmentation independent of complement and through induction of reactive oxygen species (ROS) [28] . Initial management of ITP may include treatment with intravenous immunoglobulin (IVIg) [29] . The working mechanism of IVIg is actively under investigation and still a matter of debate. In the disease setting of ITP, IVIg may be effective therapeutically by activating FccRs on DCs [30] while other studies have suggested that IVIg is effective via sialic acid and SIGN-R1 (murine ortolog of human DC-SIGN on DCs) [31] . In addition, it has been described that IVIg may raise platelet counts in ITP by increasing peripheral numbers of tolerizing DCs [32] and CD4+CD25+FoxP3+ T regulatory cells [33] . Interestingly, CRP levels were also found to be increased in paediatric ITP patients and treatment with IVIg correlated with increased platelet counts, decreased levels of CRP and with reduced clinical bleeding severity [20] . Moreover, an increased CRP value at diagnosis appeared to be predictive for slower platelet count recovery after 3 months [20] . This was recently validated in a cohort of newly diagnosed adult ITP patients, in which increased CRP levels at diagnosis were shown to negatively predict platelet count recovery after treatment with steroids [34] .", "cite_spans": [{"start": 117, "end": 121, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 267, "end": 271, "text": "[23,", "ref_id": "BIBREF22"}, {"start": 272, "end": 275, "text": "24]", "ref_id": "BIBREF23"}, {"start": 329, "end": 333, "text": "[25,", "ref_id": "BIBREF24"}, {"start": 334, "end": 337, "text": "26]", "ref_id": "BIBREF25"}, {"start": 457, "end": 461, "text": "[27]", "ref_id": "BIBREF26"}, {"start": 630, "end": 634, "text": "[28]", "ref_id": "BIBREF27"}, {"start": 724, "end": 728, "text": "[29]", "ref_id": "BIBREF28"}, {"start": 919, "end": 923, "text": "[30]", "ref_id": "BIBREF29"}, {"start": 1051, "end": 1055, "text": "[31]", "ref_id": "BIBREF30"}, {"start": 1187, "end": 1191, "text": "[32]", "ref_id": "BIBREF31"}, {"start": 1231, "end": 1235, "text": "[33]", "ref_id": "BIBREF32"}, {"start": 1458, "end": 1462, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 1587, "end": 1591, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 1803, "end": 1807, "text": "[34]", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "Platelets as immune cells: the 'prey' becomes the 'predator'", "text": "Despite the fact that platelets are targeted for destruction in an allo-or autoimmune setting, it has now increasingly become clear that platelets are also capable of conveying non-haemostatic immune functions [35] [36] [37] . Platelets are able to battle invading pathogens and communicate with a variety of effector cells via sophisticated channels, thereby controlling immune responses. Platelets can sense the threat of invading pathogens or damage during inflammation, via their immune receptors called pattern recognition receptors. These include immunoglobulin or complement receptors as well as Toll like receptors (TLR, TLR1-9 are expressed on human and murine platelets) [23] . These receptors directly bind invading pathogens and microbes, including their derived products. Platelets can not only sense external danger signals, but also internal danger signals via TLR9, which was shown to be active during oxidative stress, through stimulation of platelet activation and granule secretion, aggregation in vitro and thrombosis in vivo [38] . Besides recognizing pathogens, platelets can also harbour pathogens on their plasma membrane as well as internally [39, 40] , including viruses [40, 41] , bacteria [42] [43] [44] and parasites [45] . Platelets can also surround or encapsulate the bacterium Staphylococcus aureus, driving the pathogen into clusters, thereby restricting the bacterial growth [46] . This was shown to occur via secretion of the antimicrobial peptide b-defensin and signalling through neutrophil extracellular traps (NETs) [46] . Bacteria (methicillin-resistant S. aureus and Bacillus cereus) were also trapped on hepatic Kupffer cells, dependent upon platelet-adhesion receptor GP1b [47] . Additionally, during sepsis neutrophils were also shown to be activated by platelet TLR4, which triggered the release of NETs in blood vessels, trapping bacteria in liver and lungs [48] . Platelets also appear to be involved in the clearance of bacterial infections, such as in infective endocarditis, where thrombin-stimulated platelets facilitated the clearance of streptococci [49] . Platelets could also redirect the course of the bacteria Listeria monocytogenes from less immunogenic phagocytes towards the more immunologically active splenic CD8a + dendritic cells, via GP1b and complement component C3 [50] . Furthermore, platelets can communicate with target cells via release of CD40L upon platelet activation, secretion of varies cytokines and chemokines, shedding of platelet microparticles and through their MHC class I [35] [36] [37] . Platelet-derived CD40L has been shown to enhance CD8+ T cell responses during infection with Listeria monocytogenes [51, 52] , bind to dendritic cells impairing differentiation, suppressing pro-inflammatory dendritic cell cytokines and increasing the anti-inflammatory dendritic cell cytokine IL-10 [53] . Platelets can also stimulate B cell differentiation and antibody-class switching through CD40L [54, 55] . Regarding the various cytokines and chemokines secreted by platelets, TGF-b levels for instance, seem regulated by platelets during ITP, as low levels of TGF-b were observed during active disease, while the levels normalized again upon effective treatment of ITP which increased the platelet counts [56, 57] . Platelets also facilitate communication via shedding of their platelet microparticles. Platelets can equip their microparticles with a hetergenous cargo, which can consist of various cytokines and chemokines, potent lipid mediators, enzymes, surface receptors (e.g., CD40L), autoantigens, nucleic acids (e.g., micro RNA), transcription factors or respiratory competent mitochondria [58] [59] [60] [61] [62] [63] [64] . So through their microparticles, platelets can efficiently regulate various immune functions, dependent on their specific cargo. Platelets carry two different MHC class I molecules: plasma membrane bound and intracellularly [65] . The MHC class I molecules on the platelet plasma membrane are mainly adsorbed from plasma and consist predominantly of denatured heavy chains. The membrane-bound MHC appears to be unstable because the molecules can passively dissociate from the platelet surface upon blood bank storage or upon elution with chloroquine diphosphate or acid washing without influencing the integrity of the platelet membrane [66] [67] [68] [69] [70] [71] [72] . Interestingly, these denatured MHC class I molecules are incapable of stimulating CD8+ T cell-mediated cytotoxicity [72] but can mediate an immunosuppressive-like reaction to transfused blood cells. In syngeneic settings, platelet activation can lead to expression of nascent MHC class I molecules, which are capable of presenting antigens to CD8+ T cells. Activated platelets were shown to present malarial peptides to malaria-specific T cells, resulting in enhanced immunity against the parasite [73] . Therefore, the response towards T cells (suppression or activation) seems to be dependent upon the type of MHC class I, plasma membrane-bound or intracellularly.", "cite_spans": [{"start": 210, "end": 214, "text": "[35]", "ref_id": "BIBREF34"}, {"start": 215, "end": 219, "text": "[36]", "ref_id": "BIBREF35"}, {"start": 220, "end": 224, "text": "[37]", "ref_id": "BIBREF36"}, {"start": 681, "end": 685, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 1046, "end": 1050, "text": "[38]", "ref_id": "BIBREF37"}, {"start": 1168, "end": 1172, "text": "[39,", "ref_id": "BIBREF38"}, {"start": 1173, "end": 1176, "text": "40]", "ref_id": "BIBREF39"}, {"start": 1197, "end": 1201, "text": "[40,", "ref_id": "BIBREF39"}, {"start": 1202, "end": 1205, "text": "41]", "ref_id": "BIBREF40"}, {"start": 1217, "end": 1221, "text": "[42]", "ref_id": "BIBREF41"}, {"start": 1222, "end": 1226, "text": "[43]", "ref_id": "BIBREF42"}, {"start": 1227, "end": 1231, "text": "[44]", "ref_id": "BIBREF43"}, {"start": 1246, "end": 1250, "text": "[45]", "ref_id": "BIBREF44"}, {"start": 1410, "end": 1414, "text": "[46]", "ref_id": "BIBREF45"}, {"start": 1556, "end": 1560, "text": "[46]", "ref_id": "BIBREF45"}, {"start": 1717, "end": 1721, "text": "[47]", "ref_id": "BIBREF46"}, {"start": 1905, "end": 1909, "text": "[48]", "ref_id": "BIBREF47"}, {"start": 2104, "end": 2108, "text": "[49]", "ref_id": "BIBREF48"}, {"start": 2333, "end": 2337, "text": "[50]", "ref_id": "BIBREF49"}, {"start": 2556, "end": 2560, "text": "[35]", "ref_id": "BIBREF34"}, {"start": 2561, "end": 2565, "text": "[36]", "ref_id": "BIBREF35"}, {"start": 2566, "end": 2570, "text": "[37]", "ref_id": "BIBREF36"}, {"start": 2689, "end": 2693, "text": "[51,", "ref_id": "BIBREF50"}, {"start": 2694, "end": 2697, "text": "52]", "ref_id": "BIBREF51"}, {"start": 2872, "end": 2876, "text": "[53]", "ref_id": "BIBREF52"}, {"start": 2974, "end": 2978, "text": "[54,", "ref_id": "BIBREF53"}, {"start": 2979, "end": 2982, "text": "55]", "ref_id": "BIBREF54"}, {"start": 3284, "end": 3288, "text": "[56,", "ref_id": "BIBREF55"}, {"start": 3289, "end": 3292, "text": "57]", "ref_id": "BIBREF56"}, {"start": 3677, "end": 3681, "text": "[58]", "ref_id": "BIBREF57"}, {"start": 3682, "end": 3686, "text": "[59]", "ref_id": "BIBREF58"}, {"start": 3687, "end": 3691, "text": "[60]", "ref_id": "BIBREF59"}, {"start": 3692, "end": 3696, "text": "[61]", "ref_id": "BIBREF60"}, {"start": 3697, "end": 3701, "text": "[62]", "ref_id": "BIBREF61"}, {"start": 3702, "end": 3706, "text": "[63]", "ref_id": "BIBREF62"}, {"start": 3707, "end": 3711, "text": "[64]", "ref_id": "BIBREF63"}, {"start": 3938, "end": 3942, "text": "[65]", "ref_id": "BIBREF64"}, {"start": 4351, "end": 4355, "text": "[66]", "ref_id": "BIBREF65"}, {"start": 4356, "end": 4360, "text": "[67]", "ref_id": "BIBREF66"}, {"start": 4361, "end": 4365, "text": "[68]", "ref_id": "BIBREF67"}, {"start": 4366, "end": 4370, "text": "[69]", "ref_id": "BIBREF68"}, {"start": 4371, "end": 4375, "text": "[70]", "ref_id": "BIBREF69"}, {"start": 4376, "end": 4380, "text": "[71]", "ref_id": "BIBREF70"}, {"start": 4381, "end": 4385, "text": "[72]", "ref_id": "BIBREF71"}, {"start": 4504, "end": 4508, "text": "[72]", "ref_id": "BIBREF71"}, {"start": 4886, "end": 4890, "text": "[73]", "ref_id": "BIBREF72"}], "ref_spans": []}, {"section": "Conclusion", "text": "Platelets can be targeted and destroyed by the immune system in a variety of ways; however, evidence is accumulating that platelets themselves can critically modulate and regulate inflammatory immune responses as well. 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{"paper_id": "91047629", "_pdf_hash": "0e7d31d7d7a0deb71c948c15a392813243842cbd", "abstract": [{"section": "Abstract", "text": "Abstract Purpose: To optimize the extraction conditions of polysaccharides from the root of Senecio scandens Buch,-Ham. (PRS) and evaluate its anti-tumor effect on hepatocellular carcinoma.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": ". Treatment with PRS (20, 40 and 80 \u03bcg/mL) ", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION", "text": "Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide with a high incidence and mortality [1, 2] . Besides surgical management, chemotherapy is another important therapeutic option for HCC, but it would cause severe toxicities which are commonly difficult to tolerate by HCC patients [3, 4] ; for instance, fluorouracil and doxorubicin, two drugs currently used for treating HCC, are not satisfactory since they can produce severe side effects and are not too effective [5] . Thus, searching for new candidate agents with better effectiveness and lower toxicity for treating HCC have received more and more attention.", "cite_spans": [{"start": 120, "end": 123, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 124, "end": 126, "text": "2]", "ref_id": "BIBREF1"}, {"start": 314, "end": 317, "text": "[3,", "ref_id": "BIBREF2"}, {"start": 318, "end": 320, "text": "4]", "ref_id": "BIBREF3"}, {"start": 500, "end": 503, "text": "[5]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "Traditional Chinese Medicines (TCMs) have a long history in the treatment of various cancers, and they were reported to have low cost and less side effects [6, 7] . Senecio scandens Buch,-Ham. (Asteraceae), known as \"Qianliguang\" in Chinese, is one of the most popular species used as a Chinese folk medicine, and it is mainly distributed in southwest China [8] . It is used for the treatment for various ailments, such as enteritis, bacterial diarrhea, respiratory tract infections, and conjunctivitis in China [9] . However, there is no report on the anti-tumor effect of S. scandens and its related active components. In the present study, the antitumor effects of polysaccharides extracted from the root of S. scandens (PRS) against HCC were investigated, which could lead to further development of PRS as a potential drug for treating HCC.", "cite_spans": [{"start": 156, "end": 159, "text": "[6,", "ref_id": "BIBREF6"}, {"start": 160, "end": 162, "text": "7]", "ref_id": "BIBREF7"}, {"start": 358, "end": 361, "text": "[8]", "ref_id": "BIBREF8"}, {"start": 512, "end": 515, "text": "[9]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "EXPERIMENTAL Chemicals and reagents", "text": "Fetal bovine serum (FBS) and Roswell park memorial institute (RPMI)-1640 culture medium were purchased from Thermo Fisher Scientific (Waltham, MA USA); 5-Fluorouracil (5-FU) and MTT were obtained from Sigma-Aldrich Inc. (St. Louis, MO, USA); primary antibodies of caspase-3, caspase-9, Bcl-2 and Bax were from R&D Systems, Ltd. (Minneapolis, USA). All the other chemicals and reagents were of analytical grade.", "cite_spans": [], "ref_spans": []}, {"section": "Extraction of polysaccharides from S. scandens", "text": "The dried whole plant of S. scandens was powdered, and defatted with 95 % ethanol for 24 h. The pretreated powder of S. scandens (50 g) were extracted by refluxing with distilled water at selected extraction times (2, 3 and 4 h), number of extraction (1, 2 and 3), and ratio of water to raw material (10, 15 and 20 mL/g). After filtration, the solution were concentrated and precipitated with ethanol to a final concentration of 80 % (v/v) overnight at 4 \u00b0C. After centrifugation (8000 rpm for 10 min), the precipitates were collected, and then washed respectively with 95 % ethanol, anhydrous ethanol and acetone. The crude polysaccharides were dried, and the percentage yield (%) was calculated as the following formula: PRS extraction yield (%) = Y 0 /Y, where Y 0 (g) is the weight of dried crude polysaccharides (PRS); Y (g) is the weight of dried powder of S. scandens.", "cite_spans": [], "ref_spans": []}, {"section": "Experimental design of response surface methodology (RSM)", "text": "RSM with a Box-Behnken design (BBD, three levels and three factors) was applied to determine the effect of extraction time, number of extractions, and ratio of water to raw material on the extraction yield of PRS. Based on the results of single factor experiment, the experimental range of each factor was determined. The experimental arrangement is shown in Table 1 .", "cite_spans": [], "ref_spans": [{"start": 359, "end": 366, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Cell culture", "text": "A549, HL60, S180 and H22 cell lines were obtained from the Type Culture Collection of Chinese Academy of Sciences (Shanghai, China). All cells were maintained in RPMI medium supplemented with 10 % FBS, 100U/mL penicillin and 100 \u03bcg/mL streptomycin. The cell lines were cultured in a cell incubator (Thermo Scientific, Waltham, MA, USA) at 37 \u00b0C in 5 % CO 2 /95 % air. ", "cite_spans": [], "ref_spans": []}, {"section": "Animals", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Determination of anti-tumor effect of PRS in vitro", "text": "A549, HL60, S180 and H22 cell proliferations were determined by using MTT assay as previously described [10] . Briefly, cells (2.0 \u00d7 10 4 /0.2 mL) were seeded into 96-well plates and allowed to attach for 24 h. A series of concentrations of PRS (10, 20, 40, 80, 160, 320 and 640 \u03bcg/mL) were added and incubated for 48 h. Subsequently, 5 mg/mL MTT (10 \u03bcL) solutions were added. After incubating at 37 o C for 4 h, the supernatant was discarded and dimethyl sulfoxide (100 \u03bcL) was added to each well. The plates were read at 570 nm with a Mode 680 96-well microplate reader (Bio-Rad, Tokyo, Japan). Inhibition rate (H) was calculated as in Eq 1.", "cite_spans": [], "ref_spans": []}, {"section": "Determination of anti-tumor effect of PRS in vitro", "text": "H (%) = {(A 0 -A x )/A 0 }100 \u2026\u2026\u2026\u2026. (1) where A 0 is the absorbance of controls and A x the absorbance of cells treated with PRS.", "cite_spans": [], "ref_spans": []}, {"section": "Determination of anti-tumor effect of PRS in vivo", "text": "The diluted tumor cells were subcutaneously inoculated (0.2 mL, 1 \u00d7 10 6 cells/mouse) into the right armpits of the mice to establish the animal model. After 24 h, mice were divided randomly into five groups. PRS was administered orally (ig) to each group at different dosages (20, 40 , 80 mg/kg). The positive control group was treated with 5-FU at a dosage of 5 mg/kg intraperitoneally (ip), and the control group was treated with normal saline (ig). The weights of the mice were recorded before drug administration which lasted for 14 days. On the 15th day, all the mice were sacrificed and the segregated tumor weights were recorded.", "cite_spans": [{"start": 277, "end": 281, "text": "(20,", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Western blot assay", "text": "Western blot assay was used to investigate the apoptotic mechanisms of PRS on H22 cells [11] . Different concentrations of PRS (20, 40 and 80 \u03bcg/mL) were added to the H22 cells and incubated for 48 h. Then, the cells were harvested and total proteins were extracted. Total protein sample (40 \u03bcg) was separated using SDS/PAGE. The separated proteins were transferred onto polyvinylidene difluoride (PVDF) membrane, and subsequently subjected to immunoblotting analysis with corresponding primary antibodies and horseradish peroxidaseconjugated secondary antibodies (Beyotime Biotech, Haimen, China). After that, chemiluminescence reagents (Beyotime Biotech, Haimen, China) were added for visualization of the protein bands. Antibodies against \u03b2-actin was used to normalize for protein loading.", "cite_spans": [{"start": 127, "end": 131, "text": "(20,", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Statistical analysis", "text": "The data are expressed as mean \u00b1 standard deviation (SD) and were analyzed by ANOVA. Significance of differences between groups was evaluated using Student's t-test. RSM was analyzed with Design Expert Version 8.0.5 software (State-Ease, USA). P < 0.05 was regarded as statistically significant.", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Model fitting and statistical analysis", "text": "As shown in Table 1 , independent variables (extraction time, number of extraction, and ratio of water to raw material) on the extraction yield of PRS were examined by BBD design (Table 1) . The analysis results of ANOVA are shown in Table 2 . The \"lack of fit F-value\" (3.01) was not significant due to the relative pure error. Based on the validity analysis of the three variables, it showed that the independent variables of B and C, the interaction term of B \u00d7 C, and the two quadratic terms of A 2 , B 2 and C 2 significantly affected the yield of PRS (p < 0.001). The R 2 and R 2 Adj values (0.9890 and 0.9750, respectively) showed a high degree correlation between the observed values and the predicted values. In addition, the statistical analysis also showed a very low p-value (< 0.0001) and a very high F value (585.70), indicating the established model was highly significant.", "cite_spans": [], "ref_spans": [{"start": 12, "end": 19, "text": "Table 1", "ref_id": "TABREF0"}, {"start": 179, "end": 188, "text": "(Table 1)", "ref_id": "TABREF0"}, {"start": 234, "end": 241, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "Optimized PRS extraction conditions and validated models", "text": "By using the Design-Expert software, 3D graphic surface for the effects of three independent variables are shown in Figure 1 . From the model, the optimal conditions for obtaining the highest PRS yield were: extraction time 3.06 h, number of extractions 2.27, and ratio of water to raw material 16.17 mL/g. The maximum yield of PRS predicted by the model was 6.83 %. To validate the accuracy of the model, the optimal condition was modified as follows: extraction time 2.11 h, number of extractions 2, and ratio of water to raw material 16.17 mL/g. A verification experiment was carried out under the modified conditions. As a result, the mean yield of PRS obtained from actual experiments was 6.85 \u00b1 0.12 %. The results indicated that the RSM was effective for optimizing the extraction conditions for PRS.", "cite_spans": [], "ref_spans": [{"start": 116, "end": 124, "text": "Figure 1", "ref_id": "FIGREF2"}]}, {"section": "Effect of PRS on cells growth in vitro", "text": "The cytotoxic effect of PRS on A549, S180, HL60 and H22 cell lines were evaluated by MTT assay. As a result, PRS significantly inhibited the cell proliferations of H22, A549, S180 and HL60 cell lines, and the IC 50 values were shown in Table 3 . PRS showed higher inhibitory effect against the proliferation of H22 cells (IC 50 value of 42.4 \u03bcg/mL ) than the other cell lines with the highest inhibition ratio of 73.3% at 320 \u03bcg/mL. ", "cite_spans": [], "ref_spans": [{"start": 236, "end": 243, "text": "Table 3", "ref_id": "TABREF2"}]}, {"section": "In vivo anti-tumor effect of PRS", "text": "The in vivo antitumor effect of PRS on transplanted H22 tumors in mice was showed in Figure 2 . The results indicated that oral administration of PRS (20, 40 and 80 mg/kg; p < 0.05, p < 0.05 and p < 0.01, respectively) could significantly reduce the tumor weight in a dosedependent manner. Also, the body weights of the mice treated with PRS were higher than that of control, especially at the doses of 40 and 80 mg/kg (p < 0.05, p < 0.05). The 5-FU could also significantly (p < 0.01) reduce the tumor weight, but the body weight of the mice was sharply decreased in this group (p < 0.01).", "cite_spans": [], "ref_spans": [{"start": 85, "end": 93, "text": "Figure 2", "ref_id": "FIGREF5"}]}, {"section": "In vivo anti-tumor effect of PRS", "text": "Effect of PRS on expressions of Bcl-2, Bax, caspase-3 and caspase-9 To study the pharmacological mechanisms for the anti-tumor effects of PRS, the effects of PRS on apoptosis related proteins including Bcl-2, Bax, caspase-3 and caspase-9 were investigated in H22 cells. As shown in Figure 3 , PRS treatment (20, 40 and 80 \u03bcg/mL) significantly upregulated the expression of Bax, and downregulated Bcl-2. Furthermore, similar to Bax, caspase-3 and caspase-9 were up-regulated following treatment with PRS (20, 40 and 80 \u03bcg/mL), compared with the control (Figure 4 ). ", "cite_spans": [{"start": 307, "end": 311, "text": "(20,", "ref_id": "BIBREF21"}], "ref_spans": [{"start": 282, "end": 290, "text": "Figure 3", "ref_id": "FIGREF3"}, {"start": 552, "end": 561, "text": "(Figure 4", "ref_id": "FIGREF4"}]}, {"section": "DISCUSSION", "text": "Polysaccharides from various origins including wild plants, fungi and animals are often identified to be biological response modifiers. In recent years, researches on polysaccharides from medicinal plants have attracted much attention because of their potential biological and pharmacological activities, such as anti-tumor, immunomodulating, anti-inflammatory, cardiovascular, antidiabetic and antioxidant activities [12, 13] . In the present study, polysaccharides from S. scandens (PRS) were extracted and the extraction conditions were optimized by employing response surface methodology (RSM), and furthermore the anti-tumor effects were investigated in vivo and in vitro. It is well known that RSM is an effective method for optimizing the experimental conditions of complex processes [14] . The main advantage of RSM technique over other statistical techniques is that it can evaluate multiple parameters and their interactions, but the number of experiments needed is reduced [15, 16] . Many researches have showed that RSM is an appropriate method used to optimize polysaccharide extraction processes [17, 18] . RSM applied with a threelevel three-factor BBD was employed in the present study, and the optimal conditions for PRS were as follows, extraction time, 2.11 h, number of extractions 2, and ratio of water to raw material, 16.17 mL/g.", "cite_spans": [{"start": 418, "end": 422, "text": "[12,", "ref_id": "BIBREF10"}, {"start": 423, "end": 426, "text": "13]", "ref_id": "BIBREF13"}, {"start": 791, "end": 795, "text": "[14]", "ref_id": "BIBREF14"}, {"start": 984, "end": 988, "text": "[15,", "ref_id": "BIBREF15"}, {"start": 989, "end": 992, "text": "16]", "ref_id": "BIBREF16"}, {"start": 1110, "end": 1114, "text": "[17,", "ref_id": "BIBREF17"}, {"start": 1115, "end": 1118, "text": "18]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "There is increasing evidence showed that natural products and many antitumor chemotherapeutic agents can induce apoptosis of cancer cells [19] . It has also been indicated that the ratio of Bax/Bcl-2 is a key factor in the regulation of the apoptotic process, and a high ratio of Bax/Bcl-2 might promote apoptosis activity [19, 20] . Furthermore, caspase-9 and caspase-3 are important activators in mitochondria-mediated apoptosis pathway, and caspase-3 can be activated by caspase-9 [21] . Thus, after treating with PRS, the expression of caspase-9 and caspase-3 proteins were up-regulated and Bax/Bcl-2 ratio increased in the H22 cells, indicating that PRS could induce mitochondrialmediated apoptosis.", "cite_spans": [{"start": 138, "end": 142, "text": "[19]", "ref_id": "BIBREF20"}, {"start": 323, "end": 327, "text": "[19,", "ref_id": "BIBREF20"}, {"start": 328, "end": 331, "text": "20]", "ref_id": "BIBREF21"}, {"start": 484, "end": 488, "text": "[21]", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "CONCLUSION", "text": "The findings of the present study indicate that PRS possesses significant anti-tumor effect on H22 tumor in vitro and in vivo, and that the mechanism of the anti-tumor effect is closely related to the induction of mitochondria-mediated apoptosis. 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The mice were housed under controlled environment (23 \u00b1 1 \u00b0C and a 12-h light/12-h dark cycle) with free access to food and water. Research and animal experimental procedures were strictly in accordance with \"Principles of Laboratory Animal Care\" (NIH publication no. 85-23, revised 1985) and approved by the Animal Care and Use Committee of the First Affiliated Hospital of Chinese PLA General Hospital (approval no. A 90-12-2015t09).", "type": "figure"}, "FIGREF2": {"text": "Figure 1: 3D graphic surface for t effects of extraction time, number of extraction, and ratio of water to raw material", "type": "figure"}, "FIGREF3": {"text": "Figure 3: Changes in Bcl-2 and Bax proteins in H22 cells after treating with PRS", "type": "figure"}, "FIGREF4": {"text": "Figure 4: Changes in caspase-3 and caspase-9 proteins in H22 cells after treating with PRS.", "type": "figure"}, "FIGREF5": {"text": "Figure 2: Effect of PRS on transplanted H22 tumor growth and body weight; *p < 0.05 vs control group; ** p < 0.01 vs control group", "type": "figure"}, "TABREF0": {"text": "Experimental design and test results of RSM", "type": "table"}, "TABREF1": {"text": "Test results of significance for regression coefficient", "type": "table"}, "TABREF2": {"text": "IC50 values of PRS on tumor cell lines", "type": "table"}, "TABREF3": {"text": "10. Liu A, Liu D, Zhao S, Zheng J, Cao D, Zhang H. Up11. Lin CH, Chen PS, Kuo SC, Huang LJ, Gean PW, Chiu TH. The role of mitochondria-mediated intrinsic death", "type": "table"}}}
{"paper_id": "91047712", "_pdf_hash": "28d65e2eee1aa9b4011199472bc8a25809e63403", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "91048065", "_pdf_hash": "3aa16f5c048059a83a654f32835dcd5310b8ce6c", "abstract": [{"section": "Abstract", "text": "Background: Pseudogenes are non-functional sequences in the genome with homologous sequences that are functional (i.e. genes). They are abundant in eukaryotes where they have been extensively investigated, while in prokaryotes they are significantly scarcer and less well studied. Here we conduct a comprehensive analysis of the evolution of pseudogenes in prokaryotes. For this analysis we consider a broad range of bacteria, but also focus on the leprosy pathogen Mycobacterium leprae, which contains an unusually large number of pseudogenes which comprise approximately 40% of its entire genome. Results: We have developed an informatics-based approach to characterize the evolution of pseudogenes. This approach combines tools from phylogenomics, genomics, and transcriptomics. The results we obtain suggest the presence of two mechanisms for pseudogene formation: failed horizontal gene transfer events and disruption of native genes. Conclusions: We conclude that while in most bacteria the former is most likely responsible for the majority of pseudogenization events, in mycobacteria, and in particular in M. leprae with its exceptionally high pseudogene numbers, the latter predominates. We believe that our study sheds new light on the evolution of pseudogenes in bacteria, by utilizing new methodologies that are applied to the unusually abundant M. leprae pseudogenes and their orthologs. As such, we anticipate that it will be of broad interest to both evolutionary biologists as well as microbiologists.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Pseudogenes are inactive copies of genes that are functional in other contexts [40, 27] . A functional copy of a pseudogene may reside either within the same organism, suggesting it is a paralog of the pseudogene, or in other organisms, in which case they are orthologs [10] . Pseudogenes are more prevalent in eukaryotes where genome compactness is less critical and their loss confers minor fitness benefits to the organism [15] . They also serve as a reservoir for future genes and functionality. Therefore pseudogenes play an important evolutionary role.", "cite_spans": [{"start": 79, "end": 83, "text": "[40,", "ref_id": "BIBREF39"}, {"start": 84, "end": 87, "text": "27]", "ref_id": "BIBREF26"}, {"start": 270, "end": 274, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 426, "end": 430, "text": "[15]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Introduction", "text": "The term pseudogene was first coined by [16] as part of their research on the Xenopus laevis genome. In fact, for many years pseudogene studies were mostly focused in eukaryotes where the phenomenon is prevalent [33, 38, 24] . By contrast, in prokaryotes pseudogene were generally regarded as rare [23] . Consequently, considerably less effort was devoted to pseudogene research in prokaryotes. Nevertheless, the existence of mycobacteria with large numbers of pseudogenes suggest tha pseudogenzation may also play an important evolutionary role in prokaryotes. Moreover, the formation of pseudogenes may differ between prokaryotes and eukaryotes, in part due to differing rates of horizontal transfer.", "cite_spans": [{"start": 40, "end": 44, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 212, "end": 216, "text": "[33,", "ref_id": "BIBREF32"}, {"start": 217, "end": 220, "text": "38,", "ref_id": "BIBREF37"}, {"start": 221, "end": 224, "text": "24]", "ref_id": "BIBREF23"}, {"start": 298, "end": 302, "text": "[23]", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "Introduction", "text": "The intracellular pathogen Mycobacterium leprae (M. leprae), the causative of the skin disease leprosy, provides an extraordinary model to study gene loss, or reductive evolution [15] . M. leprae's genome includes 1133 pseudogenes and 1614 protein-coding genes [4, 14] . The pseudogene content of M. leprae is significantly higher than most other bacteria, and also higher than the closely related Mycobacterium tuberculosis [23] . It is likely that within the intracellular environment of the host cell in which M. leprae grows, these pseudogenes are dispensable, and therefore the introduction of premature stop codons in these genes does not lead to a fitness loss [36] . From the study of M. leprae we can attempt to understand why these genes are no longer necessary for the pathogen to thrive within its host.", "cite_spans": [{"start": 179, "end": 183, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 261, "end": 264, "text": "[4,", "ref_id": "BIBREF3"}, {"start": 265, "end": 268, "text": "14]", "ref_id": "BIBREF13"}, {"start": 425, "end": 429, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 668, "end": 672, "text": "[36]", "ref_id": "BIBREF35"}], "ref_spans": []}, {"section": "Introduction", "text": "A phylogenomic analyses in which individual gene histories are constructed and compared across bacteria can be used to characterize the evolution of pseudogenes. While the history of speciation is normally perceived as a vertical ancestor-descendant process, which translates to a tree-like structure, in prokaryotes, the vertical signal is partly obscured by the massive influence of horizontal gene transfer (HGT) [7, 29] . HGT creates a widespread discordance between evolutionary histories of different genes, where each gene evolves along its own gene tree. Thus, the Tree of Life (TOL) concept has been questioned as an appropriate representation of the evolution of prokaryotes [13, 19] . Nevertheless, prokaryotic evolution is primarily tree-like, and we often distill the tree-like signal from all the conflicting signals.", "cite_spans": [{"start": 416, "end": 419, "text": "[7,", "ref_id": "BIBREF6"}, {"start": 420, "end": 423, "text": "29]", "ref_id": "BIBREF28"}, {"start": 685, "end": 689, "text": "[13,", "ref_id": "BIBREF12"}, {"start": 690, "end": 693, "text": "19]", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Introduction", "text": "In light of the above discussion, in this work we perform a comprehensive phylogenomic study of pseudogenes formation, over both broad and narrow phylogenetic ranges, where the focus of the narrow range is on M. leprae. More precisely, we contrast the origin of pseudogenes in the narrow range to the broad range. The motivation for such a study stems from the finding by Liu et al. [23] according to which a substantial portion of pseudogenes result from failed HGTs. By contrast, the prevailing assumption for pseudogene formation in M. leprae is the degradation scenario in which a native functional gene becomes non functional as a result of a disruption. For example, G\u00f3mez-Valero et al. [14] estimated that most M. leprae pseudogenes were created in a relatively short time interval, which led them to conclude that they were caused in a single event.", "cite_spans": [{"start": 383, "end": 387, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 693, "end": 697, "text": "[14]", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Introduction", "text": "However, they also presupposed that each pseudogene originated from a functional gene. Similar results were obtained by Babu [26] . Singh and Cole [36] investigated several degradation scenarios but also state that \"The mechanism by which pseudogenes arise is not yet known\", while Dagan et al. [6] studied pseudogenes as the outcome of gene death in obligate symbiotic bacterial pathogens (while HGTs were assumed to be negligible and therefore ignored). To the best of our knowledge the relative contribution of HGT or gene degradation to the evolution of pseudogenes has never been fully characterized.", "cite_spans": [{"start": 125, "end": 129, "text": "[26]", "ref_id": "BIBREF25"}, {"start": 147, "end": 151, "text": "[36]", "ref_id": "BIBREF35"}, {"start": 295, "end": 298, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Introduction", "text": "Motivated by the discussion above, here we assess the relative contribution of HGT and degradation to the formation of pseudogenes across bacteria. To address this question we use novel HGT-oriented tools, and the results are confirmed by other previously developed HGT methods. We discuss the case of M. leprae, with its exceptionally high fraction of pseudogenes, and use functional genes as a control group to search for distinct characteristics between the two groups. Pseudogenes and functional genes are contrasted using homologs both from broad and narrow phylogenetic ranges. To generate our evolutionary inferences over narrow ranges, we compare M. leprae pseudogenes to their orthologs in other mycobacteria, paying particular attention to M. tuberculosis due to its close evolutionary relationship. We confirm and augment our phylogenomic results with insights from other evolutionary footprints such as gene synteny and functional enrichment, as well as expression assays. Thus, our work presents a comprehensive view of pseudogene formation, including the role of the two different mechanisms that are responsible for pseudogenization -the degradation process and failed HGT.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "We report three results regarding the evolutionary analyses of pseudogenes. In all these analyses we compared two sets of genes: genes (or rather COGs -clusters of orthologous genes) whose M. leprae ortholog is a pseudogene, and genes whose M. leprae ortholog is functional (it is important to note that we analyzed only genes with orthologs in M. leprae). We looked for distinct characteristics between these two sets by investigating several different evolutionary markers. We note that the word \"orthologs\" may sometimes be misused. According to [12] , and more conspicuously to a later clarification by the same author [11] , a distinction is made between orthologs and xenologs. Specifically, orthologs are two homologs whose common ancestor lies in the last common ancestor of the taxa from which the two homologs were obtained, while xenologs are two homologs whose history, since their common ancestor, involves horizontal gene transfer. Since we conclude that some pseudogenes are the result of failed horizontal gene transfer, it is possible that some so-called orthologs may in fact be xenologs.", "cite_spans": [{"start": 549, "end": 553, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 623, "end": 627, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Phylogenetic Analysis", "text": "Our first approach focused on a phylogenetic analysis of the genes. Our goal here was to see if by using the plurality approach, as in [42] , but once for the pseudogenes and once for the non-pseudogenes, we obtain a significant difference.", "cite_spans": [{"start": 135, "end": 139, "text": "[42]", "ref_id": "BIBREF41"}], "ref_spans": []}, {"section": "Phylogenetic Analysis", "text": "We focused on the species that were studied in [23] and built all relevant gene trees as follows. A preliminary step was to identify, through the Mycobrowser database [17, 22] , all M. leprae orthologs in M. tuberculosis. Using Mycobrowser we divided these M. tuberculosis orthologs into those that are annotated as functional in M. leprae and those that are not, henceforth non-pseudogenes (NPGs) and pseudogenes (PGs) respectively. More specifically, pseudogenes were determined as inactive reading frames with functional counterparts in M. tuberculosis [5] or M. avium [14] . For every such M. tuberculosis gene, we constructed its COG using all its orthologous genes in the taxa set of [23] . We identified orthologs of M. leprae in M. tuberculosis since COGs were determined using EggNOG [30] , which only includes sequences of amino acids, and therefore does not contain information about M. leprae pseudogenes. Next we constructed the gene tree over each COG (see Methods). This resulted in two sets of gene trees, derived from PGs and NPGs, where each tree contains a gene (leaf) of M. tuberculosis. We decomposed the two gene trees sets into their constituent quartets and for every 4-taxa set found its plurality quartet (see Methods). The latter yielded the plurality quartet (QP) set. We also kept the underlying set of all quartets (QA).", "cite_spans": [{"start": 47, "end": 51, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 167, "end": 171, "text": "[17,", "ref_id": "BIBREF16"}, {"start": 172, "end": 175, "text": "22]", "ref_id": "BIBREF21"}, {"start": 556, "end": 559, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 572, "end": 576, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 690, "end": 694, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 793, "end": 797, "text": "[30]", "ref_id": "BIBREF29"}], "ref_spans": []}, {"section": "Phylogenetic Analysis", "text": "In order to examine whether the PG and NPG sets are distinct, we constructed a maximum quartet compatibility (MQC) tree for each set. We remark that while in [42] only eleven species were analyzed, here we interrogate a significantly larger set of sixty-four species. As MQC is computationally expensive, we used the heuristic quartet MaxCut (QMC) approach [2] . Additionally, we constructed the respective 16S rRNA tree as a robust approximation to the species tree (see Methods for more details on all these procedures).", "cite_spans": [{"start": 158, "end": 162, "text": "[42]", "ref_id": "BIBREF41"}, {"start": 357, "end": 360, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Phylogenetic Analysis", "text": "The above procedure yielded five trees over the same taxa set: the QP trees both for PGs and NPGs, the QA trees both for PGs and NPGs, and the 16S tree. We compared these trees to test whether there were significant difference between them. Tree similarity was measured using Qfit [9] , that computes the percentage of identical quartets between two trees, and was found in previous studies of ours [2, 35] to be more robust than other measures for tree comparisons. The resulting scores appear in Table 1 (a).", "cite_spans": [{"start": 281, "end": 284, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 399, "end": 402, "text": "[2,", "ref_id": "BIBREF1"}, {"start": 403, "end": 406, "text": "35]", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "Phylogenetic Analysis", "text": "By the theoretical result of [34] , the plurality quartets should be consistent with the species tree. As we do not have the species tree, the convention is to use one or more ribosomal genes, normally the 16S rRNA gene, as a proxy. We aimed to measure the similarity of each of the quartet-based trees to the species tree proxy. As can be seen from Table 1(a), the results show that PG and NPG trees are equally distant from the 16S tree. Of particular interest are the similarities between the species tree -the 16S tree -to all four other trees (bottom line in the table). We expected these numbers to show a difference between the two gene sets (pseudogenes versus non-pseudogenes), or between the different approaches (plurality quartets versus all quartets) or any combination of them. However, we could not identify any significant difference between them. None of the quartet based trees brought us significantly closer to the species tree than the other quartet based trees.", "cite_spans": [{"start": 29, "end": 33, "text": "[34]", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "Phylogenetic Analysis", "text": "One may hypothesize that this result is due to the similarity among the quartet trees themselves, and that therefore the dissimilarity to the 16S tree is due to the methodology we use. However, these quartet-based trees also exhibit significant dissimilarity among themselves. We note however that there are several other, possibly artefactual, reasons for this dissimilarity. First, the genes cataloged as pseudogenes are indeed pseudogenes in M. leprae, however in all other species, they are functional. Secondly, it is possible that the level of HGT is high, reducing any signal (as might be suggested by the fact that the trees are significantly different from the 16S tree). Finally, as indicated by several other studies (e.g. [39] ), even conserved genes like the 16S are subjected to HGT, obfuscating the central trend of evolution. Due to the lack of detectable signal in the tree distances, we resorted to another tool that is also based on quartet analysis, but may reveal other properties. For a plurality quartet topology, its quartet vote is the percentage of votes it obtained from all the votes for this 4-taxa set. For example, if 60% of the gene trees agree with the plurality quartet, then its quartet vote is 60%. Since we have three different topologies for a 4-taxa set, the sum over these three topologies votes is 100% and the vote of the plurality quartet is at least one-third. Now, for a set of gene trees G we define the composite quartet vote (CQV) as the average quartet vote over the entire quartet set. We can easily observe that under no HGT, every quartet in every gene tree will have a topology identical to its topology in the species tree, yielding a vote of 100% for that plurality quartet. As this holds for every quartet (4-taxa set) we will have a CQV of 100% for our gene tree set G. In contrast, if every gene tree is a random tree (this can be obtained by e.g. assigning a random permutation to the leaves of the gene tree), it can be easily observed that for every quartet, each of the corresponding three topologies occurs at equal probability (1/3) and so its vote will be 1/3. Thus, in this case, the CQV will be 1/3. We therefore see that the CQV ranges between 1/3 and 1 for high levels of HGT activity (where HGT rates are infinite) and for no HGT at all, respectively. The CQV provides a summary of the intensity of HGT among the species under study (we note though that the donors of the HGTs need not be from the studied species set and even the recipients can be ancestors of the studied species, corresponding to ancient HGTs).", "cite_spans": [{"start": 734, "end": 738, "text": "[39]", "ref_id": "BIBREF38"}], "ref_spans": []}, {"section": "Phylogenetic Analysis", "text": "Therefore, seeking distinguishing characteristics between the PG and NPG gene sets, we compared their CQVs. Applying the CQV measure to the two quartet plurality sets, pseudogenes and non-pseudogenes, we obtained the scores shown in Table 1 (b). The scores indicate a difference of 4.21 between the two CQVs. Normally, estimating the significance of this difference is based on an approximation that relies on the central limit theorem. However, this approximation requires that the quartet votes of different plurality quartets are independent random variables, which they are generally not. Instead, we used the Kolmogorov-Smirnov (KS) test, to check if the quartet votes, based on the pseudogenes and on the non-pseudogenes, are distributed in two statistically significant different ways. Indeed, the calculated KS statistic (0.16) was much greater than the threshold needed (0.006) to reject the null hypothesis of equal distribution with a confidence level of 99%. Combined with our previous computation showing the difference between the two CQVs, we believe this result suggests that M. leprae pseudogene orthologs are less prone to HGT than non-pseudogenes across the broad spectrum of bacteria we examine.", "cite_spans": [], "ref_spans": []}, {"section": "Phylogenetic Analysis", "text": "We remark that we repeated this test for a different set of gene trees, based on the same species set, and divided into pseudogenes and non-peudogenes using the same Mycobrowser classification as before, but this time allowing gene duplications. This set of gene trees is interesting since studying it may provide a more complete picture of gene evolution, while maintaining the general trend of the species phylogeny. The results of this test are presented in Table 1 (c). Despite the expected decline in the CQV score (when multiple copies of a gene are represented in a tree, the number of conflicting quartet topologies is expected to increase), a similar difference between the two CQVs equal to 5.17 was found, and a KS statistic of roughly 0.16 suprpassed the 0.003 threshold indicative of a statistically significant difference between the two distributions of quartet votes. For more information, see supplementary text.", "cite_spans": [], "ref_spans": []}, {"section": "Phylogenetic Analysis", "text": "It is important to note that we searched for evidence corroborating our claim using other tools as well. Specifically, we computed the number of HGT events needed to transform the 16s tree (hypothesized to represent the correct underlying species phylogeny) to each one of the gene trees. The results of this computation, performed using RIATA-HGT [28] are presented in Figure 1 . For each pair of trees, comprised of the 16s tree and one other pseudogene tree (or non-pseudogene gene tree), we plotted a blue circle (or red dot), representing the result of the RIATA computation. We then plotted the linear regression line that best suits the pseudogenes data (in magenta). Since it is clear that the putative number of HGT events is dependent on tree size, in order to determine if our collection of pseudogenes is unique in any way, we sampled 10000 subgroups from our entire collection of gene trees, while insuring those subgroups have the same distribution of tree sizes as the pseudogene trees. The linear regression lines corresponding to those subgroups are plotted as dark blue lines. Since roughly 80% of the blue lines pass below the regression line of the pseudogenes (and roughly 20% above), this test does not offer sufficient evidence to support a claim of an unusual HGT pattern in the set of psedogenes. We propose two possible explanations to this inconclusive outcome. First, the fact that RIATA is a heuristic which attempts to solve a computationally intractable problem (specifically, to minimize the number of SPR operations -Subtree Pruning and Regrafting -that are necessary to convert a species tree into a gene tree). Second, that the species tree itself may be inaccurate. This, coupled with the tree distance comparisons that were also inconclusive (Table 1) , emphasizes the need to use methods that are not dependent on reference trees. ", "cite_spans": [{"start": 348, "end": 352, "text": "[28]", "ref_id": "BIBREF27"}], "ref_spans": [{"start": 370, "end": 378, "text": "Figure 1", "ref_id": "FIGREF0"}]}, {"section": "Synteny Analysis", "text": "While the tools applied in the previous part are effective mainly for large taxa sets, and preferably with a large evolutionary span (in particular the 16S gene), in smaller and closer sets, where the signal is less pronounced, their effectiveness diminishes. We now report on another evolutionary difference between the two gene sets -pseudogenes and non-pseudogenes -that we measured only between mycobacterial species. The tool we employ here to analyze the gene sets, the synteny index (SI, see expansion on the procedure in the supplementary text and [1, 35] ) relies on a different evolutionary signal that is useful when analyzing closely related taxa.", "cite_spans": [{"start": 556, "end": 559, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 560, "end": 563, "text": "35]", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "Synteny Analysis", "text": "In order to check whether the two gene types exhibit different patterns of mobility and hence also different patterns of synteny, we pursued the following procedure. To conduct an SI study between two genomes, an orthology mapping is necessary. In such a mapping, genomes are lists of genes, where the genes are ordered by their physical location on the genome and pairs of orthologs are connected. Briefly, a k-neighborhood of a gene is the set of genes at distance at most k from it along the genome (i.e. at most k genes upstream or downstream). The k-SI value of a gene common to two species is the portion of common genes in the two k-neighborhoods of this gene in both genomes. Clearly, the more genes those neighborhoods have in common, the greater the k-SI value is. In this paper we fix k = 10 and simply refer to the SI value.", "cite_spans": [], "ref_spans": []}, {"section": "Synteny Analysis", "text": "As M. tuberculosis is related to M. leprae, most of the pseudogenes in M. leprae still exist in M. tuberculosis. Hence, we built a \"star of orthology mapping\" where we placed the M. tuberculosis genome at the center of the star and mapped four other genomes to it. In this star center (M. tuberculosis genome) we marked genes that are pseudogenes in M. leprae. Therefore, we obtained four pairs of genomes such that in all pairs, one genome is M. tuberculosis in which the M. leprae pseudogenes' orthologs are marked (it is important to note that in M. tuberculosis these marked genes are non-pseudogenes). We complemented each of the genomes with genes for which no orthologs were found. We then computed the average synteny index (SI) in the fashion described in Methods. However, instead of averaging over the whole genome, we averaged once over the pseudogenes and once over the non-pseudogenes, hence obtained two values of SI (and this is for every pair of genomes in our star). We applied this procedure to the four data sets corresponding to M. tuberculosis vs.", "cite_spans": [], "ref_spans": []}, {"section": "Synteny Analysis", "text": "(1) M. leprae, (2) M. smegmatis, (3) M. bovis, and (4) M. marinum. In order to obtain significance value for the numbers obtained we followed the same approach as in the CQV above (assuming SI distributes normally). The results (two SI's) and the p-values (natural log values) appear in Table 2 . As can be seen, the p-values obtained for all four data sets were highly significant (all smaller that e \u221211 ). The numbers in the table show a consistent trend of lower synteny for pseudogenes, that is very significant in all four pairs. Therefore, under our assumption of non-homologous recombination the neighborhood of an acquired gene in the recipient differs from its neighborhood in the donor, and we can infer that orthologs of M. leprae pseudogenes are more inclined to HGT than orthologs of functional genes. As detailed below, this suggests that while orthologs of M. leprae pseudogenes are not more inclined to HGT over a broad phylogenetic spectrum, as we discussed in the previous section, over shorter evolutionary timescales the trend is reversed.", "cite_spans": [], "ref_spans": []}, {"section": "Synteny Analysis", "text": "We note that the above analysis is based on the assumption that low SI is an outcome of HGT. However, low SI can result from events of duplication as well, complicating the interpretation of our conclusions. In the supplementary text we describe the procedure we used to discard the possibility of a low SI value caused by gene duplications.", "cite_spans": [], "ref_spans": []}, {"section": "Functional Analysis", "text": "In this section we focus solely on M. leprae genes and extend our analysis by showing a relationship between expression levels of the pseudogenes and their synteny values (based on a comparison with M. tuberculosis). As synteny, or lack thereof, is evidence for a recombination event at a gene, this measure will lead to a grouping of pseudogenes into two classes -high SI and low SI, and we regard these as native genes versus alien genes, respectively. To examine whether", "cite_spans": [], "ref_spans": []}, {"section": "Synteny Index", "text": "Number Genes", "cite_spans": [], "ref_spans": []}, {"section": "Synteny distribution across Nonpseudogenes", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Synteny Index", "text": "Number Genes Synteny distribution across Pseudogenes there is a functional consequence to this grouping of the pseudogenes, we used expression data from human leprosy skin lesions to measure the in vivo M. leprae transcriptome This allows a unique perspective of the expression profile of M. leprae in its natural host at the site of disease. Expression data was extracted as described in Methods. The results (Figure 2(a) ) show the trends for both pseudogenes and non-pseudogenes. The green curve represents expression data for non-pseudogenes and serves as a control for the pseudogenes data. It is evident from the figure that the expression level of functional genes is largely unaffected by their degree of synteny (except for a small decrease for very low synteny). This is expected as these genes are functional and are expressed regardless of whether they were acquired by HGT or are native in the genome. In contrast, for pseudogenes we can see a strong association between expression and synteny, and hence between expression and HGT (recall that we used SI as a proxy to HGT).", "cite_spans": [], "ref_spans": [{"start": 410, "end": 422, "text": "(Figure 2(a)", "ref_id": "FIGREF3"}]}, {"section": "Synteny Index", "text": "The expression profile of these low SI genes, shows that they are lowly expressed, therefore we conclude that these are failed HGT pseudogenes. However, Figure 2 (b) indicates that these failed HGT pseudogenes are relatively infrequent. By contrast, the other pseudogenes, that are assumed to be native in M. leprae due to their higher synteny indeces, comprise the majority of pseudogenes in M. leprae. The latter are expressed at modest levels as they became non functional as a result of a mutation. The conclusion arising from these two results is that failed HGTs comprise the minority of pseudogenization events and are very lowly expressed, while mutation-origin (vertical evolution) pseudogenes are the majority in M. leprae and expressed at slightly higher levels.", "cite_spans": [], "ref_spans": [{"start": 153, "end": 161, "text": "Figure 2", "ref_id": "FIGREF3"}]}, {"section": "Synteny Index", "text": "We next asked how these results relate to gene functions. Previous analyses have shown that M. leprae pseudogenes tend to be enriched for genes involved in lipid metabolism [36] . This was consistent with the notion that the lack of M. leprae lipid metabolism genes caused by the formation of pseudogenes was compensated by the lipid rich environment of the host macrophage in which M. leprae resides. Therefore we analyzed the frequency of different functional categories in both PG and NPG, and further separated these into high and low synteny subsets. In Figure 3 (and Table 3 ), we show the results of this analysis for two families relating to metabolism: intermediate/respiration versus lipid metabolism. We find that PGs are enriched for lipid metabolism compared to NPGs and that this trend is even more significant for genes with high synteny. Recall that low synteny indicates HGT and conversely high synteny genes tend to be native genes. This result supports our expectation that lipid metabolism in M. leprae is carried out by the macrophages of the host in which the mycobacteria reside, leading to a loss of native lipid metabolism genes that become pseudogenes due to mutations. On the other hand, the same cannot be said about intermediary metabolism, where we find that PGs are depleted with respect to NPGs. In addition, further examination of Table 3 shows that cell wall and cell processes genes are more abundant in the functional genes set (in both the low SI and the high SI categories) and that regulatory proteins genes are unusually prevalent in the low SI category of functional genes. It is possible that, compared to free living bacteria, cell wall and cell processes genes in M. leprae are more critical to help the bacillus cope with threats from the immune system of its host. Finally, we notice that there are 76 low SI pesodugenes and only 56 low SI functional genes (Table 3 ). This fact suggests that the transfer of such genes (low SI) has a higher likelihood of becoming non-fuctional rather than functional, fitting with the notion that the low synteny subset corresponds to a failed HGT process [23] .", "cite_spans": [{"start": 173, "end": 177, "text": "[36]", "ref_id": "BIBREF35"}, {"start": 2137, "end": 2141, "text": "[23]", "ref_id": "BIBREF22"}], "ref_spans": [{"start": 559, "end": 567, "text": "Figure 3", "ref_id": "FIGREF4"}, {"start": 573, "end": 580, "text": "Table 3", "ref_id": "TABREF3"}, {"start": 1364, "end": 1371, "text": "Table 3", "ref_id": "TABREF3"}, {"start": 1903, "end": 1911, "text": "(Table 3", "ref_id": "TABREF3"}]}, {"section": "Methods", "text": "Gene Trees and Species Tree Preparation: We denote by the species tree the main course of speciation events yielding a given species set. In contrast, a gene tree represents the (evolutionary) history of a specific set of orthologous genes. Gene trees for a set of species, may differ from the respective species tree due to reticulation events such as horizontal gene transfer (HGT). Gene trees for our phylogenetic study were prepared as follows: First, we searched all M. leprae orthologs in M. tuberculosis using Mycobrowser [22] . Then, for each COG this search yielded, we used EggNOG [30] to find all genes in that COG that are single copy representitives of one of the 64 species in [23] . For COGs with at least four species thus found, the relevant sequences were aligned using MUSCLE [8] . Due to the large number of genes, trees were constructed using the fast tree construction FASTTREE [31] . In order to construct a species tree we used the accepted marker for this task, the 16S rRNA gene. We found 61 relevant copies of the 16S for our 64 taxa in the RDP database [3] . Sequences were extracted and aligned using MAFFT [18] using an auto alignment strategy (the one that was chosen was L-INS-i) and constructed a tree using RAxML (version 7.0.4 [37] , assuming the GTR-\u0393 model).", "cite_spans": [{"start": 529, "end": 533, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 591, "end": 595, "text": "[30]", "ref_id": "BIBREF29"}, {"start": 691, "end": 695, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 795, "end": 798, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 900, "end": 904, "text": "[31]", "ref_id": "BIBREF30"}, {"start": 1081, "end": 1084, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 1136, "end": 1140, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 1262, "end": 1266, "text": "[37]", "ref_id": "BIBREF36"}], "ref_spans": []}, {"section": "Methods", "text": "The Quartet Plurality Method: The topology of a given 4-taxa a, b, c, d, induced by a given gene tree, may be one of three options -a, b|c, d, or a, c|b, d, or a, d|b, c. As a result of HGT in a certain gene, the topology of the respective gene tree changes, possibly affecting the topology of the quartets. We note that tree incongruence can result also from a sequence of duplication and loss events. However, as the rates of gene loss and gain are at least an order of magnitude greater than the gene duplication rate [20, 32] , and by our procedure described above of removing from the analysis species with multiple copies in a COG, we believe our main source of incongruence is HGT. As every gene is affected by different HGT events, we normally find gene trees of substantially different topologies. Consequently, the quartets induced by these gene trees may exhibit different topologies than the original, i.e., the topology induced by the species tree. In a study of eleven species of cyanobacteria using a multitude of genes [42] , the topology over a given 4-taxa set that is induced by the maximum number of gene trees, was denoted as the plurality quartet or plurality topology. In [42] , the set of plurality quartets over all possible 4-taxa sets was constructed and used as input to a supertree algorithm in order to overcome the frequent occurrence of HGT in these organisms. This approach was later studied from a theoretical perspective [34] . It was shown analytically that under reasonable and prevalent assumptions regarding HGT, for any 4-taxa set, its plurality quartet is the correct topology, i.e., the one induced for this 4-taxa set by the species tree. Since any tree is uniquely defined by the set of quartets it induces, this result provides us with a theoretically sound scheme of phylogenetic reconstruction that relies on the above plurality inference rule. It is important to note that even for relatively small sets of several dozens of species, the number of gene trees required to ensure that all plurality quartets will be correct with high probability is far greater than the number of genes found in any known genome. Also, as this result is theoretical, it assumes no errors in the gene trees. In reality, we do not expect all plurality quartets to be correct and hence also the plurality quartet set is inconsistent. In this case we look for the tree that satisfies the maximum number of these quartets, i.e., the MQC tree.", "cite_spans": [{"start": 521, "end": 525, "text": "[20,", "ref_id": "BIBREF19"}, {"start": 526, "end": 529, "text": "32]", "ref_id": "BIBREF31"}, {"start": 1035, "end": 1039, "text": "[42]", "ref_id": "BIBREF41"}, {"start": 1195, "end": 1199, "text": "[42]", "ref_id": "BIBREF41"}, {"start": 1456, "end": 1460, "text": "[34]", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "Methods", "text": "Expression Analysis: Total RNA was isolated from frozen skin biopsies from lepromatous leprosy patients at time of diagnosis, before any treatment was started. Bacterial ribosomal RNA depletion was performed on total RNA by Ribozero epidemiology rRNA removal kit (Illumina). Illumina TruSeq libraries were prepared and sequenced on a HiSeq2000 and mapped to the M. leprae Br4923 genome using Bowtie2 [21] . Raw gene counts were normalized using DESeq2 [25] across all samples. To determine the RNA expression per gene, the DESeq normalized counts were divided by the length in kilobases of each gene.", "cite_spans": [{"start": 400, "end": 404, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 452, "end": 456, "text": "[25]", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Conclusions", "text": "In this work we investigated several evolutionary and functional properties of pseudogenes, i.e. non-functional genes, in M. leprae with a special emphasis on gene mobility. The analysis was performed on orthologs of M. leprae genes, across both broad and narrow phylogenetic ranges. It is important to note that while the M. leprae copy of each pseudogene is non-functional, the orthologous copies in other species are mostly functional (i.e. non-pseudogenes). These differences across species might be related to the unique environment in which M. leprae thrives, the intracellular environment within human skin [36] .", "cite_spans": [{"start": 614, "end": 618, "text": "[36]", "ref_id": "BIBREF35"}], "ref_spans": []}, {"section": "Conclusions", "text": "Our analysis is divided into three parts. In the first we carry out a broad phylogenetic analysis to show that over the entire bacterial domain, non-pseudogenes are more mobile than pseudogenes. This was inferred by the higher CQV of the non-pseudogenes with respect to the pseudogenes, extracted from gene trees over the entire bacterial domain. By contrast, in the second analysis, we use synteny as a proxy for HGT to show that among the Mycobacteria, the tendency to HGT is inverted compared to the broad phylogenetic analysis, and pseudogenes exhibit more mobility.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "To understand this reversal of pseudogene mobility across different evolutionary scales, we note that our functional analysis, carried out in the third part, provides a possible explanation for this observation. M. Leprae PGs are enriched for lipid metabolism enzymes, a function that is compensated by the lipid rich environment of the host macrophage -the environment in which M. Leprae thrives in leprosy lesions. However, the opposite holds when we consider orthologs of these genes across the entire bacterial domain, as most of these bacteria thrive in extracellular environments, where presumably, lipid metabolism is critical to their survival. In these extracellular environments, lipid metabolism enzymes are likely essential and therefore we expect the respective genes to be less horizontally acquired, as was previously observed and discussed in [41] . Thus the mobility of the orthologs of M. Leprae pseudogenes appears to depend on whether the bacteria examined are intracellular (and thus can dispense of lipid genes) or extracellular (and require lipid genes to be intact).", "cite_spans": [{"start": 859, "end": 863, "text": "[41]", "ref_id": "BIBREF40"}], "ref_spans": []}, {"section": "Conclusions", "text": "The last analysis extends the second by incorporating expression data of M. leprae genes. While PGs are not translated into functional proteins, they are often transcribed at levels similar to functional genes (i.e. NPGs). By comparing synteny (i.e. tendency to HGT) with the expression of these genes, we can distinguish between two different processes likely responsible for pseudogene formation. In the first, the gene is acquired by HGT and hence exhibits a low SI. This gene confers no advantage to the organism and remains a non functional PG. This mechanism for PG evolution corresponds to that described in [23] associated with failed HGTs as a source for pseudogenes. As such, these genes are poorly expressed in their new genome. The other mechanism corresponds to native genes that became nonfunctional as a result of a mutation in their sequence. These genes continue to be expressed, however, the transcribed RNA is not translated due to the insertion of a stop codon mutation. Figure 2(b) shows the distribution of the SI values among PG and NPG. We see that the bulk of PG and NPG reside at the higher end of the spectrum between low SI and high SI. These largely correspond to genes inherited vertically. most PGs have high synteny and high expression levels, indicating that they have not likely been gained through HGT. Thus, in contrast to the conclusion drawn in [23] , our results show that pseudogenes formed by the first mechanism (failed HGT) are in fact a small minority of the M. leprae pseudogene population. The explanation to this apparent contradiction, is that [23] analyzed a wide phylogenetic range, and the pseudogenes referred to there are entirely a different gene population than the pseudogenes in our study, the orthologs of M. leprae pseudogenes. 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(a) Tree Similarities: The percentage pairwise Qfit similarity measure between the 5 trees: the QP trees both for PGs and NPs, the QA trees both for PGs and NPs, and the 16S tree. (b) CQV data: The CQV score, representing the average plurality vote over all plurality quartets. Below is the estimated STD, and number of samples (quartets). (c) CQV data: The CQV score for gene trees that may contain gene duplications, representing the average plurality vote over all plurality quartets. Below is the estimated STD, and number of samples (quartets).", "type": "figure"}, "FIGREF1": {"text": "Figure 1: RIATA results. The parameters of the linear regression line of the pseudogenes are incorporated in the figure. Examining the number of putative HGTs vs. the number of leaves in the gene trees does not lead to an identification of an unusual HGT pattern in the pseudogenes.", "type": "figure"}, "FIGREF2": {"text": "Pseudogenes vs. non-pseudogenes SI difference: Average synteny index results for pseudogenes and non-pseudogenes with confidence (natural log) values. Four pairs of species were compared: M. tuberculosis vs. (1) M. leprae, (2) M. smegmatis, (3) M. bovis, and (4) M. marinum.", "type": "figure"}, "FIGREF3": {"text": "Figure 2: (a) Gene Expression vs. Synteny Index: Synteny index values between the M. leprae and M. tuberculosis genomes were calculated and compared to median gene expression in pseudogenes, non-pseudogenes, or all genes at each synteny index value. (b) SI Distribution at Pseudogenes and non Pseudogenes: Gene SI distribution as measured between M. leprae and M. tuberculosis divided to pseudogenes (right) and non-pseudogenes (left).", "type": "figure"}, "FIGREF4": {"text": "Figure 3: Functional analysis of PGs and NPGs: Percent of pseudogenes and nonpseudogenes, divided by low (0.125-0.375) and high (0.625-1.0) SI, that are part of (a) intermediary metabolism and respiration and (b) lipid metabolism. (c) total number of genes in each category.", "type": "figure"}, "TABREF1": {"text": "", "type": "table"}, "TABREF3": {"text": "PGs and NPGs Divided into Functional Categories: Pseudogenes and non- pseudogenes, divided into functional categories and separated by low", "type": "table"}}}
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{"paper_id": "41512642", "_pdf_hash": "2683a8b448bd4b73d08b69f4e97f406f081f5033", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Effect of dalteparin on healing of chronic foot ulcers in diabetic patients with peripheral arterial occlusive disease: a prospective, randomized, double-blind, placebo-controlled study", "authors": [{"first": "M", "middle": [], "last": "Kalani", "suffix": ""}, {"first": "J", "middle": [], "last": "Apelqvist", "suffix": ""}, {"first": "M", "middle": [], "last": "Blomb\u00e4ck", "suffix": ""}], "year": 2003, "venue": "Diabetes Care", "link": "17024182"}, "BIBREF1": {"title": "Does this patient with diabetes have large-fiber peripheral neuropathy?", "authors": [{"first": "J", "middle": ["N"], "last": "Kanji", "suffix": ""}, {"first": "R", "middle": ["E"], "last": "Anglin", "suffix": ""}, {"first": "D", "middle": ["L"], "last": "Hunt", "suffix": ""}, {"first": "A", "middle": [], "last": "Panju", "suffix": ""}], "year": 2010, "venue": "JAMA", "link": "31091784"}, "BIBREF2": {"title": "High rates of amputation among Indigenous people in Western Australia", "authors": [{"first": "P", "middle": ["E"], "last": "Norman", "suffix": ""}, {"first": "D", "middle": ["E"], "last": "Schoen", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Gurr", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "Kolybaba", "suffix": ""}], "year": 2010, "venue": "Med J Aust", "link": "46333789"}, "BIBREF3": {"title": "Lower extremity foot ulcers and amputations in diabetes", "authors": [{"first": "G", "middle": ["E"], "last": "Reiber", "suffix": ""}, {"first": "E", "middle": ["J"], "last": "Boyko", "suffix": ""}, {"first": "D", "middle": ["G"], "last": "Smith", "suffix": ""}], "year": 1995, "venue": "National Institutes of Health", "link": "38081170"}, "BIBREF4": {"title": "Treatment of diabetic foot ulcers", "authors": [{"first": "S", "middle": [], "last": "Vuorisalo", "suffix": ""}, {"first": "M", "middle": [], "last": "Venermo", "suffix": ""}, {"first": "M", "middle": [], "last": "Lep\u00e4ntalo", "suffix": ""}], "year": 2009, "venue": "J Cardiovasc Surg (Torino)", "link": "25749789"}, "BIBREF5": {"title": "Systematic reviews of wound care management: (5) beds; (6) compression; (7) laser therapy, therapeutic ultrasound, electrotherapy and electromagnetic therapy", "authors": [{"first": "N", "middle": [], "last": "Cullum", "suffix": ""}, {"first": "E", "middle": ["A"], "last": "Nelson", "suffix": ""}, {"first": "K", "middle": [], "last": "Flemming", "suffix": ""}, {"first": "T", "middle": [], "last": "Sheldon", "suffix": ""}], "year": 2001, "venue": "Health Technol Assess", "link": "42721958"}, "BIBREF6": {"title": "Ultraviolet light C in the treatment of chronic wounds with MRSA: a case study", "authors": [{"first": "T", "middle": ["P"], "last": "Thai", "suffix": ""}, {"first": "P", "middle": ["E"], "last": "Houghton", "suffix": ""}, {"first": "K", "middle": ["E"], "last": "Campbell", "suffix": ""}, {"first": "M", "middle": ["G"], "last": "Woodbury", "suffix": ""}], "year": 2002, "venue": "Ostomy Wound Manage", "link": "24053659"}, "BIBREF7": {"title": "Comparison of ultrasound/ultraviolet-C and laser for treatment of pressure ulcers in patients with spinal cord injury", "authors": [{"first": "E", "middle": ["L"], "last": "Nussbaum", "suffix": ""}, {"first": "I", "middle": [], "last": "Biemann", "suffix": ""}, {"first": "B", "middle": [], "last": "Mustard", "suffix": ""}], "year": 1994, "venue": "Phys Ther", "link": "19855668"}, "BIBREF8": {"title": "Reduction of IKKalpha expression promotes chronic ultraviolet B exposure-induced skin inflammation and carcinogenesis", "authors": [{"first": "X", "middle": [], "last": "Xia", "suffix": ""}, {"first": "E", "middle": [], "last": "Park", "suffix": ""}, {"first": "B", "middle": [], "last": "Liu", "suffix": ""}], "year": 2010, "venue": "Am J Pathol", "link": "207378537"}, "BIBREF9": {"title": "Laser treatment for scars and wounds", "authors": [{"first": "J", "middle": ["F"], "last": "Sobanko", "suffix": ""}, {"first": "T", "middle": ["S"], "last": "Alster", "suffix": ""}], "year": 2009, "venue": "G Ital Dermatol Venereol", "link": "76146857"}, "BIBREF10": {"title": "Using lasers in diabetic wound healing", "authors": [{"first": "R", "middle": [], "last": "Forney", "suffix": ""}, {"first": "T", "middle": [], "last": "Mauro", "suffix": ""}], "year": 1999, "venue": "Diabetes Technol Ther", "link": "37971809"}}, "ref_entries": {}}
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{"paper_id": "41513180", "_pdf_hash": "292ba1c9a576d25177d6b8531e34e88d5c4bbef8", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Modelling Propagation Dynamics of Social Network Worms", "authors": [{"first": "Sheng", "middle": [], "last": "Wen", "suffix": ""}, {"first": "Wei", "middle": [], "last": "Zhou", "suffix": ""}, {"first": "Jun", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "Wanlei", "middle": [], "last": "Yang Xiang", "suffix": ""}, {"first": "Wenjia", "middle": [], "last": "Zhou", "suffix": ""}, {"first": "", "middle": [], "last": "Jia", "suffix": ""}], "year": 2013, "venue": "IEEE Transaction of Parallel and Distributed System", "link": "206770835"}, "BIBREF1": {"title": "Eliminating Errors in Worm Propagating Model", "authors": [{"first": "Yini", "middle": [], "last": "Wang", "suffix": ""}, {"first": "Sheng", "middle": [], "last": "Wen", "suffix": ""}, {"first": "Silvio", "middle": [], "last": "Cesare", "suffix": ""}, {"first": "Wanlei", "middle": [], "last": "Zhou", "suffix": ""}, {"first": "Yang", "middle": [], "last": "Xiang", "suffix": ""}], "year": 2011, "venue": "IEEE Communication letters", "link": null}, "BIBREF2": {"title": "On Modelling Malware Propagation in Generalized Social Networks", "authors": [{"first": "Ming", "middle": [], "last": "Shing", "suffix": ""}, {"first": "Weng", "middle": [], "last": "Cheng", "suffix": ""}, {"first": "Pin-Yu", "middle": [], "last": "Chon Ao", "suffix": ""}, {"first": "Kwangcheng", "middle": [], "last": "Chen", "suffix": ""}, {"first": "", "middle": [], "last": "Cheu", "suffix": ""}], "year": 2011, "venue": "IEEE Communication Network", "link": "16489068"}, "BIBREF3": {"title": "Modelling Propagation Dynamics of Bluetooth Worms", "authors": [{"first": "Stephaneidenbenz", "middle": [], "last": "Guanhuayan", "suffix": ""}], "year": 2009, "venue": "IEEE Transaction on Mobile Computing", "link": "2559407"}, "BIBREF4": {"title": "Worm Epidemics in Vehicular Networks", "authors": [{"first": "Oscar", "middle": ["Trullols"], "last": "Cruces", "suffix": ""}, {"first": "Marco", "middle": [], "last": "Fiore", "suffix": ""}, {"first": "Jose", "middle": ["M"], "last": "Barcelo-Ordienes", "suffix": ""}], "year": 2015, "venue": "IEEE Transaction on Mobile Computing", "link": "489324"}, "BIBREF5": {"title": "Modelling and Analysis on the Propagation Dynamics of Modern Email Malware", "authors": [{"first": "Sheng", "middle": [], "last": "Wen", "suffix": ""}, {"first": "Wei", "middle": [], "last": "Zhou", "suffix": ""}, {"first": "Jun", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "Wanlei", "middle": [], "last": "Yang Xiang", "suffix": ""}, {"first": "Wenjia", "middle": [], "last": "Zhou", "suffix": ""}, {"first": "Cliff", "middle": ["C"], "last": "Jia", "suffix": ""}, {"first": "", "middle": [], "last": "Zou", "suffix": ""}], "year": 2015, "venue": "IEEE Transaction on Dependable and Secure Computing", "link": "3799304"}, "BIBREF7": {"title": "Network Immunization and Virus Propagation in Email Networks: Experimental Evaluation and Analysis", "authors": [{"first": "C", "middle": [], "last": "Gao", "suffix": ""}, {"first": "J", "middle": [], "last": "Liu", "suffix": ""}, {"first": "N", "middle": [], "last": "Zhong", "suffix": ""}], "year": 2011, "venue": "Knowledge and Information Systems", "link": "27120219"}, "BIBREF8": {"title": "Modeling and Simulation Study of the Propagation and Defense of Internet E-Mail Worms", "authors": [{"first": "C", "middle": ["C"], "last": "Zou", "suffix": ""}, {"first": "D", "middle": [], "last": "Towsley", "suffix": ""}, {"first": "W", "middle": [], "last": "Gong", "suffix": ""}], "year": 2007, "venue": "IEEE Trans. Dependable and Secure Computing", "link": "14896896"}, "BIBREF9": {"title": "Complement Bloom Filter For Identifying True Positiveness of Bloom Filter", "authors": [{"first": "Hyesook", "middle": [], "last": "Lim", "suffix": ""}, {"first": "Jungwon", "middle": [], "last": "Lee", "suffix": ""}, {"first": "Chenghoon", "middle": [], "last": "Yim", "suffix": ""}], "year": 2015, "venue": "IEEE Communicationletters", "link": "26468122"}}, "ref_entries": {}}
{"paper_id": "41513499", "_pdf_hash": "4d3366827a02bfe3b6e6c66cdee1e8c5b4126760", "abstract": [{"section": "Abstract", "text": "Lynch syndrome is a hereditary cancer syndrome that accounts for up to 15% of all colorectal cancers diagnosed at a young age. The disease is caused by germinal mutations in mismatch repair genes. To date, hundreds of small pathogenic and possibly pathogenic DNA variants (small insertions, deletions and substitutions) have been described for Lynch syndrome worldwide. Because of the variety of small changes in mismatch repair genes only full screening (exon by exon) by DHPLC/sequencing or HRM/sequencing seems to be the appropriate screening option. However, full screening is still too expensive and time consuming. A solution that uses the opportunity to reduce costs and improve diagnosis is the detection of recurrent mutations. This approach has been successfully applied as a pre-screening method. We have compared all identified changes in MMR genes detected to date from populations emanating from Estonia, Latvia, Lithuania and Poland to ascertain if there are any similarities in the mutation spectra that can be used in designing a rapid diagnostic test for recurrent mutations characteristic for the Eastern Baltic Sea region.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "Lynch syndrome is a hereditary cancer syndrome that accounts for up to 15% of all colorectal cancers diagnosed at a young age. The disease is caused by germinal mutations in mismatch repair genes. To date, hundreds of small pathogenic and possibly pathogenic DNA variants (small insertions, deletions and substitutions) have been described for Lynch syndrome worldwide. Because of the variety of small changes in mismatch repair genes only full screening (exon by exon) by DHPLC/sequencing or HRM/sequencing seems to be the appropriate screening option. However, full screening is still too expensive and time consuming. A solution that uses the opportunity to reduce costs and improve diagnosis is the detection of recurrent mutations. This approach has been successfully applied as a pre-screening method. We have compared all identified changes in MMR genes detected to date from populations emanating from Estonia, Latvia, Lithuania and Poland to ascertain if there are any similarities in the mutation spectra that can be used in designing a rapid diagnostic test for recurrent mutations characteristic for the Eastern Baltic Sea region. ", "cite_spans": [], "ref_spans": []}], "bib_entries": {}, "ref_entries": {"FIGREF0": {"text": "10.1186/1897-4287-13-S1-A11 Cite this article as: Dymerska et al.: Lynch syndrome mutations in Poland and the Baltic States. Hereditary Cancer in Clinical Practice 2015 13(Suppl 1):A11. Submit your next manuscript to BioMed Central and take full advantage of: \u2022 Convenient online submission \u2022 Thorough peer review \u2022 No space constraints or color figure charges \u2022 Immediate publication on acceptance \u2022 Inclusion in PubMed, CAS, Scopus and Google Scholar \u2022 Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit", "type": "figure"}}}
{"paper_id": "41514756", "_pdf_hash": "5190f309f5e87b4846adbf9c6e948336c21924fc", "abstract": [], "body_text": [{"section": "ORIGINAL ARTICLE", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "THE WORLD HEALTH CRISIS", "text": "The world is heading for a public health crisis. At least 30 new diseases such as AIDS, ebola, several kinds of hepatitis and other deadly viruses have emerged over the past 20 years (see Table I ) [compiled from WHO Report, 1996 (1) , and other sources (2) ], while old infectious diseases such as tuberculosis, cholera, malaria and diphtheria are coming back worldwide. Practically all the pathogens are resistant to drug treatment, many to multiple antibiotics. One third of the 52 million deaths from all causes in the world in 1995 were due to infectious diseases; over half of these in young children. The top killers were tuberculosis (3.1 million, mostly adults), malaria (2.1 million, including 1 million children), hepatitis B (1.1 million) and AIDS (more than 1 million). ' The optimism of a relatively few years ago that many of these diseases could easily be brought under control has led to a fatal complacency among the international community,' says the Director-General of WHO, Dr. Hiroshi Nakajima in a press release. Emerging diseases have become a major public health concern during the 1990s.", "cite_spans": [{"start": 254, "end": 257, "text": "(2)", "ref_id": "BIBREF1"}], "ref_spans": [{"start": 188, "end": 195, "text": "Table I", "ref_id": "TABREF0"}]}, {"section": "Ha6e infectious diseases and drug resistance gone up recently?", "text": "Precise epidemiological data are not yet available, but the signs are that both the incidence and severity of outbreaks of multi-drug resistant pathogens may have experienced a sharp upturn within the past 10 to 15 years. For example, Salmonella infections have gone up 20-fold in some countries in Europe since 1980 (3) . Similar increases are reported for haemorhagic E. coli 0157 food poisoning: between 1986 and 1996, the frequency of infection increased 10-fold in England and Wales, and 100-fold in Scotland (4) .", "cite_spans": [{"start": 514, "end": 517, "text": "(4)", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Ha6e infectious diseases and drug resistance gone up recently?", "text": "The first widely used anti-malarial drug, chloroquine, came into use during world war II, and resistance did not appear until the early 1960s. By contrast, the new drug mefloquine, released in 1985, became useless in 60% of malaria cases within 5 years (5) . Comparable accelerations in the development of antibiotic resistances have taken place in the same period. Antibiotics were introduced in the early 1940s to treat infectious diseases, and resistance did not appear until the early 1950s (6) . Resistance to penicillin, ampicillin and antipseudomonas penicillins in Staphyloccocus aureus went from almost 0% in 1952 to more than 95% in 1992 (7) . By the 1980s, S. aureus has also developed high levels of resistance to the synthetic penicillin, methicillin and all other i-lactams. The new fluoroquinolone antimicrobial, ciprofloxacin, was introduced in the mid-1980s, but resistance to it had reached more than 80% by 1992. A study carried out by the Centers for Disease Control showed that ciprofloxacin resistance in S. aureus went from less than 5% to greater than 80% within one year (7) .", "cite_spans": [{"start": 253, "end": 256, "text": "(5)", "ref_id": "BIBREF4"}, {"start": 495, "end": 498, "text": "(6)", "ref_id": "BIBREF5"}, {"start": 648, "end": 651, "text": "(7)", "ref_id": "BIBREF6"}, {"start": 1096, "end": 1099, "text": "(7)", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Ha6e infectious diseases and drug resistance gone up recently?", "text": "By 1990, nearly every common pathogenic bacterial species had developed varying degrees of antibiotic resistance, often, multiple resistances. These include, besides Staphylococcus aureus (Toxic Shock Syndrome, postoperative infections), Streptococcus aureus (Toxic Shock-like Syndrome) S. pneumoniae (pneumonia) S. pyogenes (rheumatic fever) Haemophilus influenzae (mennigitis) Mycobacterium leprae (leprosy), Neisseria gonorrhoeae (gonorrhea), Shigella dysenteriae (dysentry) and several other species of microbes that infect the human gut: E. coli, Klebsiella, Proteus, Salmonella, Serrratia marcescens, Pseudomonas, Enterococcus faecium, Enterobacteriaceae and Vibrio cholerae (cholera) (6) . A strain of Staphylococcus isolated in Australia was resistant to 31 different drugs including cadmium, penicillin, kanamycin, neomycin, streptomycin, tetracycline and trimethyloprim (8) . The various resistance capabilities were due to genes carried on different plasmids (independently replicating units of genetic material) that could be separately passed on from one bacterium to another. Two strains of E. coli isolated in a transplant ward outside Cambridge were resistant to 21 out of 22 common antibiotics: imipenen, as well as cefotaxime, ceftazdime, ciprofloxacin, gentamicin, ampicillin, azlocillin, coamoxiclav, timentin, cephalexin cefuroxime, cefotaxime, cefamandole, streptomycin, neomycin, kanamycin, tobramycin, trimethoprim, sulfamethoxazole, chloramphenicol and nitrofurantoin (9) . These multi-resistant strains of bacteria are rapidly becoming totally invulnerable to treatment. Scientists in Japan have already isolated a strain of Staphylococcus aureus that is resistant even to the last resort antibiotic, vancomycin (10) . Recent data showed that vancomycin resistance in Enterococci grew from 3% in 1993 to 95% in 1997 in hospitals in San Francisco (11) In Italy, erythromycin resistance in Streptococcus increased 20-fold just between 1993 and 1995 (12).", "cite_spans": [{"start": 691, "end": 694, "text": "(6)", "ref_id": "BIBREF5"}, {"start": 880, "end": 883, "text": "(8)", "ref_id": "BIBREF7"}, {"start": 1493, "end": 1496, "text": "(9)", "ref_id": "BIBREF8"}, {"start": 1738, "end": 1742, "text": "(10)", "ref_id": "BIBREF9"}, {"start": 1872, "end": 1876, "text": "(11)", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Factors contributing to the recent resurgence of infectious diseases", "text": "The precise reasons for the resurgence of infectious diseases since the 1980s are not known. Many contributing factors have been suggested (1) , among them, -population growth combined with rapid urbanization, -wars, civil turmoil and natural disasters, -rapid increases in international air travel and the growing traffic in trade, -expanding areas of human habitation and the consequent environmental destruction, -social changes including the clustering of young children in day-care centers and growing numbers of the elderly in nursing homes, -complacency towards infectious disease in the public health sector and collapse of public health systems due to economic or social crises, -the overuse and abuse of antibiotics in intensive farming and medicine.", "cite_spans": [], "ref_spans": []}, {"section": "Factors contributing to the recent resurgence of infectious diseases", "text": "One factor which has not yet been considered is genetic engineering biotechnology.", "cite_spans": [], "ref_spans": []}, {"section": "Gene technology and gene ecology", "text": "Gene ecology is an emerging discipline. It is prompted by recent findings that the genetic material-DNA or in some instances, RNA-can transfer horizontally from one organism to another through the external environment, instead of 6ertically by reproduction. Gene ecology is the totality of how genes function, mutate, move, transfer and recombine subject to feedback regulation from the interconnected levels of the genome, the physiology of the organism and the external ecological conditions.", "cite_spans": [], "ref_spans": []}, {"section": "Gene technology and gene ecology", "text": "Gene technology, or genetic engineering, can profoundly disturb the ecology of genes. The past 15-20 years witnessed the rise of genetic engineering biotechnology on a commercial scale. It is a technology for manipulating and transferring genes horizontally between species that do not normally interbreed. It is designed to break down species barriers and, increasingly, to overcome the species' defence mechanisms which degrade or inactivate foreign genes (13, 14) .", "cite_spans": [{"start": 458, "end": 462, "text": "(13,", "ref_id": "BIBREF12"}, {"start": 463, "end": 466, "text": "14)", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Gene technology and gene ecology", "text": "For the purpose of manipulating, replicating and transferring genes, a range of artificial 6ectors have been constructed. Natural vectors for horizontal gene transfer comprise replicating, often mobile units of genetic material: viruses, plasmids and transposons. However, other pieces of DNA can also be taken up by cells and hence act as agent for horizontal gene transfer. While viruses consist of genetic material wrapped in a protein coat, plasmids and transposons are, to varying extent, naked DNA. Plasmids generally replicate in the cytoplasm, while transposons are integrated into the chromosome, but can move from one site to another in the same or different chromosome, or from chromosome to plasmid and 6ice 6ersa. Plamids and transposons typically carry virulence genes and genes for antibiotic resistance.", "cite_spans": [], "ref_spans": []}, {"section": "Gene technology and gene ecology", "text": "Artificial vectors are made by joining together parts of the most infectious natural vectors in order to enhance horizontal gene transfer. The artificial vectors are 'crippled', which means that most, if not all of the genes causing disease and infectivity are removed. But it does not mean those functions cannot be supplied by, or regained from, other viruses and parasitic genetic agents that are always present in the environment and in the cells of all organisms. The gene to be transferred is as a rule integrated into the genetic material of the vector; viruses, however, can also transfer genes that are not integrated, but merely packaged within the protein coat.", "cite_spans": [], "ref_spans": []}, {"section": "Gene technology and gene ecology", "text": "To make a transgenic organism, the vector carrying the foreign gene to be transferred -transgene-is allowed to infect the cells of the organism. Once inside the cell, the vector can either multiply many copies of itself or become integrated into the genome of the cell. Most artificial vectors possess one or more antibiotic resistance marker genes, so transformed cells can be selected with the appropriate antibiotic(s).", "cite_spans": [], "ref_spans": []}, {"section": "Gene technology and gene ecology", "text": "There are three main routes for horizontal gene transfer: infection with viruses (transduction), through pieces of genetic material taken up into cell from the environment (transformation); or by unusual mating taking place between unrelated species (conjugation). As the entire orientation of genetic engineering is to facilitate horizontal gene transfer, it is to be expected that antibiotic resistance genes as well as virulence genes will inadvertently spread and recombine to generate new, drug and antibiotic resistant pathogens.", "cite_spans": [], "ref_spans": []}, {"section": "Gene technology and gene ecology", "text": "Indeed, the evolution of virulence and the spread of drug and antibiotic resistances are now linked to the extensive horizontal gene transfer and recombination events among bacteria and viruses, many of which may have occurred in recent years. For example, horizontal gene transfer and subsequent genetic recombination have given rise to the new bacterial strains responsible for the cholera outbreak in India in 1992 (15 -17) , and for the Streptococcus epidemic in Tayside in 1993 (18 -21) . The E. coli 0157:07 strain involved in the recent outbreaks in Scotland is believed to have originated from horizontal gene transfer from the pathogen, Shigella (22) . Many unrelated bacterial pathogens, causing diseases from bubonic plague to tree blight, are now found to share an entire set of genes for invading cells, which have spread widely by horizontal gene transfer (23) . Similarly, genes for antibiotic resistances have been transferred horizontally and have recombined with one another to generate multiple antibiotic resistances throughout the bacterial populations (24) . Antibiotic resistance genes spread readily between human beings, and from bacteria inhabiting the gut of farm animals to those in human beings (25) . Antibiotic resistant strains of pathogens have been endemic in many hospitals for years. In the USA, up to 60% of hospital-acquired infections are antibiotic resistant (1) . A special form of multiple which confer resistance to a wide range of chemically unrelated drugs made its appearance among pathogens in the early 1990s (see Section 3.2), although it has been produced in E. coli in the laboratory since the 1980s (26) .", "cite_spans": [{"start": 655, "end": 659, "text": "(22)", "ref_id": "BIBREF21"}, {"start": 870, "end": 874, "text": "(23)", "ref_id": "BIBREF22"}, {"start": 1074, "end": 1078, "text": "(24)", "ref_id": "BIBREF23"}, {"start": 1224, "end": 1228, "text": "(25)", "ref_id": "BIBREF24"}, {"start": 1651, "end": 1655, "text": "(26)", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "Gene technology and gene ecology", "text": "Even more disturbing is the finding that antibiotics can increase the frequency of horizontal gene transfer 10-10000-fold (27 -30) . Thus, antibiotics create the very conditions facilitating the spread of antibiotic resistance. The evolution and spread of antibiotic resistance predate genetic engineering, and are largely due to the profligate use of antibiotics in intensive farming, and in medicine (31, 32 This question is all the more important in the light of yet other recent findings indicating that microorganisms genetically engineered for 'contained use' may not be effectively contained, while our regulators are contemplating further relaxations of the guidelines on contained use 1 . Thus, biologically 'crippled' strains of bacteria have actually been found to survive in the environment to exchange genes with other species (reviewed in (34, 35) ). Naked viral DNA may be more infectious than the virus itself (36) . DNA released from cells is not readily broken down in the environment, thereby retaining the ability to transform organisms (reviewed in (34, 37, 38) ); and routine chemical treatments for inactivating pathogenic microorganisms and viruses, before they are discharged into the environment, may be ineffective, leaving a large percentage of pathogens in an active, infectious state (39) . The combination of evidence is sufficiently compelling, especially in view of the precautionary principle, to warrant, at the very least, an independent public enquiry into the possible contributions of the industry to the etiology of infectious diseases. This paper will review the following topics: On account of the enormity of the subject areas, it is impossible for us to be exhaustive in our review. Our goal is to supply enough information for readers to judge for themselves whether the strength of the evidence together with the precautionary principle will justify the public enquiry proposed.", "cite_spans": [{"start": 402, "end": 406, "text": "(31,", "ref_id": "BIBREF30"}, {"start": 853, "end": 857, "text": "(34,", "ref_id": "BIBREF32"}, {"start": 858, "end": 861, "text": "35)", "ref_id": "BIBREF33"}, {"start": 926, "end": 930, "text": "(36)", "ref_id": "BIBREF34"}, {"start": 1070, "end": 1074, "text": "(34,", "ref_id": "BIBREF32"}, {"start": 1075, "end": 1078, "text": "37,", "ref_id": "BIBREF36"}, {"start": 1079, "end": 1082, "text": "38)", "ref_id": "BIBREF37"}, {"start": 1314, "end": 1318, "text": "(39)", "ref_id": "BIBREF38"}], "ref_spans": []}, {"section": "ANTIBIOTICS AND EMERGING PATHOGENS", "text": "When antibiotics were first introduced, microbial geneticists did not believe antibiotic resistance would pose any problems, based on the very low spontaneous mutation rates observed (24) . Mutation-random changes in the genetic material -and selection-survival of the fittestwere thought, by most biologists, to sufficiently explain all characteristics of organisms. If the mutation rates are very low, then 'selection pressure' would have to be very strong for the character to spread. Soon after antibiotics were used in medicine, it was discovered that livestock lived longer and grew faster when they were fed antibiotics to overcome infections. This led to 'prophylactic' treatments. In fact, antibiotics were routinely fed to promote growth, to chickens, cattle, pigs and dairy cows, which also extended the shelf-life of meat, poultry, eggs and dairy product. In the 1970s. it was discovered that chickens given high doses of antibiotics resulted in resistant Salmonella strains in both the meat and the eggs. By 1983, mutant strains of antibiotic resistant Salmonella that attacked human beings had emerged (6) . The emergence of new pathogens is strongly associated with mutant strains that cross species barriers.", "cite_spans": [{"start": 183, "end": 187, "text": "(24)", "ref_id": "BIBREF23"}, {"start": 1116, "end": 1119, "text": "(6)", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "ANTIBIOTICS AND EMERGING PATHOGENS", "text": "One of the clearest and most disturbing examples of mutant bacteria crossing from domestic animals to human beings, and of the transformation of a previously benign strain into a pathogen, is Escherichia coli, a common bacterium inhabiting the intestine of all human beings and many other mammalian species. Most of the time, E. coli is harmless, which is why it has been the major tool for genetic engineers, who have used it and its plasmids routinely to clone genes since the 1970s (40) . E. coli is the most intensively manipulated organism, and genes from species in every Kingdom have been transferred to and cloned in it. Perhaps it is not surprising that E. coli has emerged as a major pathogen.", "cite_spans": [{"start": 485, "end": 489, "text": "(40)", "ref_id": "BIBREF39"}], "ref_spans": []}, {"section": "ANTIBIOTICS AND EMERGING PATHOGENS", "text": "The most prominent among pathogenic strains, E. coli 0157: H7, appeared in 1982, which, far from being benign, caused dangerous haemorrhages of the colon, bowel and kidneys of human beings; and it broke out suddenly and simultaneously in several states in the USA (41) . Like most E. coli strains in the 1980s, it was moderately resistant to the antibiotics ampicillin and tetracycline. Since then, many outbreaks have occurred all over the world, and in increasing frequencies. A mass outbreak in Japan in 1996 affected 10000, with 12 deaths in children. A series of outbreaks in Scotland in 1997 claimed 20 lives and made hundreds ill (42, 43) .", "cite_spans": [{"start": 264, "end": 268, "text": "(41)", "ref_id": "BIBREF40"}, {"start": 637, "end": 641, "text": "(42,", "ref_id": "BIBREF41"}, {"start": 642, "end": 645, "text": "43)", "ref_id": "BIBREF42"}], "ref_spans": []}, {"section": "ANTIBIOTICS AND EMERGING PATHOGENS", "text": "Genetic fingerprinting -a technique that fragments the DNA using specific enzymes and reading the fragmentsbacks up epidemiological evidence that E. coli 0157:H7 arose recently; and up to 1993, was endemic only to cattle in USA, Canada and Great Britain, and absent in cattle in the Far East (Thailand) (44) . E. coli mutates fairly rapidly, hence the low degree of genetic variation observed among the 0157:H7 isolates before 1993 suggests they originated recently from a single clone. Most cases came from contaminated meat. However, outbreaks have also been asso-ciated with cheese, salami, raw vegetables, unpasteurized apple juice and water (45) . The E. coli 0157, like other water-borne pathogens such as Cryptosporidium, Giardia and Shigella, had developed resistance to chlorine ((6), p.430). The mass outbreaks in Japan in 1996 were thought to be linked to white radishes (43) , which may have come from contaminated soil. The specific toxicity of the strain is attributed to the Shiga-like toxin genes acquired by horizontal gene transfer from Shigella (22, 46) . One of these genes, VT1, is almost completely identical in base sequence to that of Shigella, indicating again, that the gene transfer was a very recent event.", "cite_spans": [{"start": 303, "end": 307, "text": "(44)", "ref_id": "BIBREF43"}, {"start": 646, "end": 650, "text": "(45)", "ref_id": "BIBREF44"}, {"start": 882, "end": 886, "text": "(43)", "ref_id": "BIBREF42"}, {"start": 1064, "end": 1068, "text": "(22,", "ref_id": "BIBREF21"}, {"start": 1069, "end": 1072, "text": "46)", "ref_id": "BIBREF45"}], "ref_spans": []}, {"section": "ANTIBIOTICS AND EMERGING PATHOGENS", "text": "Studies of dozens of emergent species of pathogens showed that genes for antibiotic resistance and virulence often reside in the same regions of the bacterial DNA, in plasmids or transposons, which may be passed horizontally from one species to another, picking up extra genes, recombining and generating novel combinations in the process (6, 24).", "cite_spans": [], "ref_spans": []}, {"section": "A profusion of mechanisms and genes for antibiotic resistance", "text": "A profusion of biochemical mechanisms and genes are involved in antibiotic resistances, fully matching, if not surpassing the variety of targets at which antibiotics are aimed (7, 24, (46) (47) (48) . Most antibiotics have a single primary target, usually a single step in the synthesis of macromolecules essential to the bacterial cell, and preferably do not affect their eukaryotic host cells. Thus several classes of antibiotics are aimed at different steps in synthesizing the bacterial cell wall. These include the penicillins or i-lactams, vancomycin and ristocetin, D-cycloserine, fosfomycin and bacitracin. Other classes of antibiotics are aimed at bacterial enzymes involved in the synthesis of DNA, RNA and proteins. These enzymes differ from their eukaryotic counterparts, although the effects of the antibiotics may not always be so selective, and are accompanied by varying degrees of toxicity for the eukaryotic host. Metronidazole, quinolones, nalidixic acid and novobiocin target DNA and DNA synthesis, while actinomycin and rifamycin inhibit transcription (RNA synthesis). Translation (protein synthesis) is targetted by a wide variety of antibiotics: streptomycin and other aminoglycosides such as kanamycin, neomycin, gentamicin, tobramycin, aikacin and netilmicin; tetracyclines, puromycin, chloramphenicol, erythromycin, lincomycin and clindamycin, and fusidic acid. In addition, antimetabolites such as sulfonamides and trimethoprim inhibit the synthesis of essential metabolites.", "cite_spans": [{"start": 176, "end": 179, "text": "(7,", "ref_id": "BIBREF6"}, {"start": 180, "end": 183, "text": "24,", "ref_id": "BIBREF23"}, {"start": 184, "end": 188, "text": "(46)", "ref_id": "BIBREF45"}, {"start": 189, "end": 193, "text": "(47)", "ref_id": "BIBREF46"}, {"start": 194, "end": 198, "text": "(48)", "ref_id": "BIBREF47"}], "ref_spans": []}, {"section": "A profusion of mechanisms and genes for antibiotic resistance", "text": "Resistances to every class of antibiotics have been identified (see Table II ) [modified from (24) ], the genes responsible may be found on the chromosome or in plasmids.", "cite_spans": [{"start": 94, "end": 98, "text": "(24)", "ref_id": "BIBREF23"}], "ref_spans": [{"start": 68, "end": 76, "text": "Table II", "ref_id": "TABREF0"}]}, {"section": "A profusion of mechanisms and genes for antibiotic resistance", "text": "One of the commonest mechanism of resistance is the degradation or modification of the antibiotic by specific enzymes. Thus, the i-lactams are degraded by lactamases Active efflux mechanisms are especially important for the multiple resistance to broad ranges of structurally unrelated antibiotics and drugs that have appeared in pathogenic bacteria within the past 10 years. These will be dealt with in Section 3.2.", "cite_spans": [], "ref_spans": []}, {"section": "A profusion of mechanisms and genes for antibiotic resistance", "text": "Quite often, several biochemical mechanisms are involved in giving protection against a single antibiotic, resulting in a very high level of resistance. Cross resistances are also common within a class of antibiotics such as the aminoglycosides, so at least one kanamycin resistance gene used as a genetic marker has been found to confer cross-resistance to two new generation aminoglycosides, amikacin and tobramycin (49) . A recently documented case of antibiotic cross resistance is even more serious. Enterococcus faecium inhabiting the gut of turkeys on farms using avoparcin as growth promoter are found to have developed cross-resistances to vancomycin and teicoplanin (50), the last defence against multidrug resistant Staphlococcus aureus.", "cite_spans": [{"start": 418, "end": 422, "text": "(49)", "ref_id": "BIBREF48"}], "ref_spans": []}, {"section": "A profusion of mechanisms and genes for antibiotic resistance", "text": "Where do the genes conferring antibiotic resistances come from? And how do they manage to spread so quickly? Let us first address the question of the origin of the genes.", "cite_spans": [], "ref_spans": []}, {"section": "ORIGINS OF ANTIBIOTIC RESISTANCE GENES", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Biochemically specific mechanisms", "text": "There are several sources of antibiotic resistance genes [reviewed by Davies (24) ]. The first is from organisms producing the natural antibiotic, such as penicillin, which also produce the inactivating enzyme. As new i-lactams are introduced, the genes encoding the i-lactamases undergo mutational changes, often involving only one base substitution and a single amino-acid difference in the enzyme. That would be sufficient to enable the enzyme to recognize the new drug and to break it down. In this way, the enzyme extends its spectrum of resistances to new drugs. Numerous mutational variants of i-lactamase have already been identified, showing the ease with which appropriate mutational changes can arise in this gene. The variants derive from different genes which are themselves traced to a single ancestral gene. The versatility of the i-lactamase gene is such that when a series of inhibitors were made against the enzyme and used in combination with the i-lactam antibiotic-a kind of belt and braces approach-mutant enzymes arose, which not only break down the new antibiotic, but are, at the same time insensitive to the inhibitor.", "cite_spans": [], "ref_spans": []}, {"section": "Biochemically specific mechanisms", "text": "More often, however, it is not at all clear where the antibiotic resistance genes come from. New genes seem to appear from nowhere. For example, the 30 or more genes involved in resistances to different aminoglycosides are not related to one another. Some are thought to have arisen from mutations of pre-existing genes encoding enzymes catalyzing normal metabolic reactions in the cell. Others may involve activation of previously 'cryptic' or hidden genes in the bacterial genome (see Section 3.2 below). Or they may have been acquired by gene transfer from another bacterium.", "cite_spans": [], "ref_spans": []}, {"section": "Acti6e efflux mechanisms", "text": "Active efflux mechanisms are due to 20 or more genes in at least 4 gene families (see Table III ) [modified from (47) ], members of which can be found on plasmids or on the chromosomes. The genes code for transporter proteins situated across the cell membrane, that pump substances out of the cell, using ATP or protons as the source of energy. Recently, it has been shown that the genes for several efflux pumps are modulated in response to environmental conditions, and that many of the systems are also inducible by the substances to which they give resistance.", "cite_spans": [{"start": 113, "end": 117, "text": "(47)", "ref_id": "BIBREF46"}], "ref_spans": [{"start": 86, "end": 95, "text": "Table III", "ref_id": "TABREF0"}]}, {"section": "Acti6e efflux mechanisms", "text": "The chromosomally encoded efflux genes in E. coli belong to one or another of four inducible operons, marRAB, soxRS, emrAB and acrAB (reviewed in (26) ). There is a great deal of homology among the genes comprising different operons. For example, the proteins encoded by the regulatory genes, marR and emrR are two of the 15 proteins belonging to the MarR family, members of which are found, not only in Gram negative bacteria inhabiting the gut, but also in Gram positive bacteria, and the mycobacteria, including plant and animal pathogens, as well as free-living species.", "cite_spans": [{"start": 146, "end": 150, "text": "(26)", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "Acti6e efflux mechanisms", "text": "One member of the MarR family, HpcR, found in soil-dwelling E. coli C strains, is a repressor of an operon encoding the enzymes that break down homoprotocatechuate (Hpc), a phenolic compound derived from plants. The repressor protein, HpcR. binds to the operator and represses the synthesis of enzymes that breakdown Hpc when Hpc is absent. But when Hpc is present, the repressor protein binds to it instead, freeing the operator, so that transcription and synthesis of the enzymes can takes place. These observations suggest that naturally occurring noxious substances in the environment are the original inducers of the multiple antibiotic resistance operons.", "cite_spans": [], "ref_spans": []}, {"section": "Acti6e efflux mechanisms", "text": "Further observations in support of the idea are that other naturally occurring compounds, such as salicylic acid, dinitrophenol and naphtho-quionones, stimulate the expression of both soxS and marRAB. The natural naphthoquinolones, plumagin and menadine, are effective inducers at relatively low concentrations, and mutants lacking both the marRAB and soxRS operons are notably hypersensitive to those compounds, while sensitivity to salicylic acid is only marginally affected. The marRAB operon expression is enhanced at 30\u00b0C compared with 37\u00b0C, as consistent with its origin in free-living bacteria (26) . The multiple antibiotic resistance operons have, therefore, evolved from free-living bacteria. The enteric bacteria have simply reactivated or mutated the genes in the operons to allow them to cope with drugs and antibiotics. This class of mechanisms is reminiscent of the multidrug resistance which all mammalian and plant cells are able to develop in the presence of sublethal doses of noxious substances (see next Section). Streptomyces fradiae * Gram positive and negative bacteria are the traditional major divisions of bacteria. The Gram positive bacteria are surrounded by a thick peptidoglycan cell wall, which, however is permeable to small molecules; Gram negative bacteria, such as E. coli, are surrounded by a second membrane, which functions as an effective barrier to small molecules.", "cite_spans": [{"start": 601, "end": 605, "text": "(26)", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "'RANDOM' VERSUS 'DIRECTED' MUTATIONS", "text": "To measure the rate of 'spontaneous' mutations to antibiotic resistance in a bacterial strain, a small amount of a dilute suspension of bacteria is spread on a nutrient agarplate impregnated with a concentration of the antibiotic high enough to kill nonresistant bacteria, so that only those with a pre-existing mutation which happens to confer resistance will survive and form colonies. The spontaneous mutation rate for antibiotic resistance estimated in this way is typically 10 \u2212 9 or lower, and is about the same for all other genes in the genome. This is the rate of random mutations, in other words, mutations that have no direct correlation to the environment, or the 'selective' regime. Based on these estimates, microbiologists did not believe that resistance to antibiotics would pose a problem when antibiotics first came into use (24) . So why did antibiotic resistance evolve and spread so rapidly?", "cite_spans": [{"start": 843, "end": 847, "text": "(24)", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "'RANDOM' VERSUS 'DIRECTED' MUTATIONS", "text": "The usual explanation for antibiotic resistance, according to neo-Darwinian theory, is that it is due to the intense 'selection pressures' exerted by the antibiotics, so that even extremely low rates of spontaneous random mutations that happen to confer resistance to the antibiotic will be rapidly selected for, while those which do not happen to have the mutation will die out (see for example (32)). Antibiotic resistance has been assumed to be a classic case of the natural selection of random mutations. What actually happens is something else.", "cite_spans": [], "ref_spans": []}, {"section": "'RANDOM' VERSUS 'DIRECTED' MUTATIONS", "text": "First of all, the mutations are not random in the sense that they pre-exist in the population, before exposure to antibiotics. All bacteria, with the exception of those that live in hot springs, are killed by boiling or cooking, which is therefore the surest way to prevent infection. They can also be killed by high enough concentrations of antiseptics or antibiotics to which they are susceptible. However, at lower concentrations of the noxious agent, the bacterium may fail to grow at first, but after some time, develop the required resistance to the drug which enables it to grow, multiply and form colonies. This ability to develop drug resistance is common to cells of all species-bacteria, fungi, plant and animal without exception (51) (52) (53) (54) . It is a physiological response shared by all the cells or organisms in the population, and is not due to selection of pre-existing random mutations. It is similar to the 'directed mutations' or 'adaptive mutations' (see Section 5 below), whereby starving, non-growing bacteria eventually acquire mutations that enable them to feed on new substrates (55) (56) (57) . Secondly, competition is irrelevant among bacteria in the evolution of antibiotic resistance: they share their most valuable assets for survival-genes encoding resistance mechanisms against antibiotics-by passing them on horizontally between species.", "cite_spans": [{"start": 741, "end": 745, "text": "(51)", "ref_id": "BIBREF50"}, {"start": 746, "end": 750, "text": "(52)", "ref_id": "BIBREF51"}, {"start": 751, "end": 755, "text": "(53)", "ref_id": "BIBREF52"}, {"start": 756, "end": 760, "text": "(54)", "ref_id": "BIBREF53"}, {"start": 1112, "end": 1116, "text": "(55)", "ref_id": "BIBREF54"}, {"start": 1117, "end": 1121, "text": "(56)", "ref_id": "BIBREF55"}, {"start": 1122, "end": 1126, "text": "(57)", "ref_id": "BIBREF56"}], "ref_spans": []}, {"section": "'RANDOM' VERSUS 'DIRECTED' MUTATIONS", "text": "In fact, the evolution of antibiotic resistance turns out to be a paradigm case of the 'fluid genome' in the new genetics, in which genes and genomes can mutate and undergo other changes when the ecological conditions call for them, and genes can even travel through the external environment from one organism to another (35, 58) . We shall first consider 'adaptive mutations' in the broader context of the lessons which have been learned from molecular genetics within the past two decades.", "cite_spans": [{"start": 321, "end": 325, "text": "(35,", "ref_id": "BIBREF33"}, {"start": 326, "end": 329, "text": "58)", "ref_id": "BIBREF57"}], "ref_spans": []}, {"section": "'NATURAL' GENETIC ENGINEERING AND 'ADAPTIVE MUTATIONS'", "text": "In a recent review, Shapiro (59) offers an appropriate perspective of bacterial evolution that sums up the recent discoveries of molecular genetics on how genomes are organized, on the biochemical mechanisms of genetic change and the cellular control networks regulating genetic change.", "cite_spans": [], "ref_spans": []}, {"section": "'NATURAL' GENETIC ENGINEERING AND 'ADAPTIVE MUTATIONS'", "text": "Bacterial genomes are organized in modular fashion at successive levels of a genetic hierarchy. At the lowest level of the hierarchy are genes composed of different domains (or subunits) that are reshuffled and recombined to give different genes. Different combinations of similar genes give rise to multigene units or operons, and different combinations of operons make up larger units or 'regulons' for complex functions such as chemotaxis, symbiosis and protein secretion. Regulons may coincide with independently replicating 'replicons', such as plasmids and viruses, each with its own signal for replication (origin of replication). Thus, mosaicism, or cut-and-splice genetic recombination is involved in every level of genome organization, and plays a key role in generating genetic diversity rapidly. But these mechanisms are by no means random.", "cite_spans": [], "ref_spans": []}, {"section": "'NATURAL' GENETIC ENGINEERING AND 'ADAPTIVE MUTATIONS'", "text": "Bacteria may have 'little tolerance for purely random variability' (59) . Bacterial cells possess a wide range of repair and proof-reading functions to remove accidental change to DNA sequences and correct errors resulting from physiological insults. But the same cells also possess numerous biochemical mechanisms for changing and reorganizing DNA, suggesting that such changes are the result of the 'natural genetic engineering' ability of bacteria to respond to environmental challenges.", "cite_spans": [{"start": 67, "end": 71, "text": "(59)", "ref_id": "BIBREF58"}], "ref_spans": []}, {"section": "'NATURAL' GENETIC ENGINEERING AND 'ADAPTIVE MUTATIONS'", "text": "The possibility of 'natural' genetic engineering mechanisms responding to the environment gained considerable support in the discovery of 'adaptive mutation', in which starving bacteria acquire the appropriate genetic mutation enabling them to metabolize a new substrate, when the substrate is present in the 'selective' medium. A wide variety of mechanisms are involved in generating adaptive mutations, including point mutations (single base changes), deletions or insertions of nucleotides, conversions of gene sequences from one to another, site-specific integration of genetic material, DNA rearrangement and transposition (gene jumping) [reviewed in (59)].", "cite_spans": [], "ref_spans": []}, {"section": "'NATURAL' GENETIC ENGINEERING AND 'ADAPTIVE MUTATIONS'", "text": "There is much current debate as to whether those mutations are specifically 'directed' by the environmental challenge, or simply the consequence of a hyper-mutable state of stressed cells that generates many mutations indiscriminately at a high rate, increasing the chances of a lucky hit. In either case, however, it means that genes and genomes change as the result of built-in mechanisms that are subject to metabolic and environmental feedback regulation (57) . As Shapiro points out, the ability to activate those mechanisms under stress can significantly accelerate evolutionary change in crisis without threatening genetic stability under ordinary circumstances. He surmises that further studies of mobile genetic elements and DNA rearrangements will ultimately uncover truly directed mutations. Just as signaltransduction systems of the cell can direct the transcriptional apparatus to specific locations in the genome to activate those genes, so it is possible that the mutational apparatus(es) can be similarly directed to mutate specific genes.", "cite_spans": [{"start": 459, "end": 463, "text": "(57)", "ref_id": "BIBREF56"}], "ref_spans": []}, {"section": "'NATURAL' GENETIC ENGINEERING AND 'ADAPTIVE MUTATIONS'", "text": "Shapiro regards the evolution of antibiotic resistance and virulence as clear examples of 'natural' genetic engineering mechanisms at work, and goes no further than that. This can easily lead human genetic engineers to justify what they do on grounds that bacteria themselves have been at it, probably for hundreds of millions of years. That kind of reasoning is fallacious and dangerous. As recent studies indicate, 'normal circumstances' for the vast majority of microbes in the environment as well as in our bodies may be a non-proliferating but metabolically active, non-virulent state (60, 61) . This state is associated with layers of extracellular matrices or 'biofilms' in which typically mixed communities of microbes are embedded, where they enjoy a cooperative, multicellular existence rather like the cells and tissues in our body [see Ho (35) , Chapter 14] .", "cite_spans": [{"start": 590, "end": 594, "text": "(60,", "ref_id": "BIBREF59"}, {"start": 595, "end": 598, "text": "61)", "ref_id": "BIBREF60"}, {"start": 851, "end": 855, "text": "(35)", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "'NATURAL' GENETIC ENGINEERING AND 'ADAPTIVE MUTATIONS'", "text": "Furthermore, there is nothing 'natural' about the 'manmade' environmental conditions that have provoked microbes to engineer their genes and genomes. The discharge of toxic wastes, the destruction of the environment, and the overuse and abuse of antibiotics, have already thrown the 'natural' ecology of microbes seriously out of balance. And over the past 20 years, the extensive manipulation of genes and genomes by human genetic engineers is very likely to have exacerbated the situation. The ecology of microbes consists, not only of the usually understood interrelationships with other organisms, but also of genes within the genome, of the genome within the physiological state of the cell and the organism, which is in constant intercommunication with the external environment. Disease, we are told, cannot be understood apart from the ecological context (62) . More importantly, it must be understood in terms of the nested levels in the ecology of genes (36) and microbes, which is inextricably entangled with the ecology of human beings.", "cite_spans": [{"start": 862, "end": 866, "text": "(62)", "ref_id": "BIBREF61"}, {"start": 963, "end": 967, "text": "(36)", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "HORIZONTAL GENE TRANSFER", "text": "The major role of horizontal gene transfer in spreading antibiotic resistance has only been recognized since the late 1980s, when a Conference on Antibiotic Resistance was co-sponsored by the Environment Protection Agency and the National Science Foundation of the USA to look into the mechanisms and factors affecting such gene transfer (63) . The first definitive evidence for horizontal gene transfer came from DNA sequence analysis of the genes for neomycin-kanamyin resistance from Staphylococcus aureus, Streptococci and Campylobacter sp. (64) which were found to be essentially identical. Identity of sequence not only gives evidence for horizontal gene transfer, but also indicates that the transfer is a very recent event. Further evidence of horizontal gene transfer was subsequently obtained for a wide range of antibiotic resistances, by DNA sequencing or other methods of characterizing DNA (65 -70).", "cite_spans": [{"start": 338, "end": 342, "text": "(63)", "ref_id": "BIBREF62"}], "ref_spans": []}, {"section": "The scope of horizontal gene transfer", "text": "The scope of horizontal gene transfer is essentially the entire biosphere (13, 14, 36, 38, (71) (72) (73) (74) (75) (76) (77) . Genes are found to have been transferred, not only among microorganisms and viruses, but among eukaryote species and across traditional Kingdoms of organisms. Among eukaryotes, the main transfers have involved transposable elements (36, 77) such as the P element among Drosophilids, and transposable introns among lower eukaryotes and bacteria (36) . Some especially promiscuous elements such as mariner have been found in arthropods and vertebrates, including primates and humans, where it is associated with a neurological wasting disease (78) . Gene transfer mediated by transposable elements do not require DNA base sequence homologies.", "cite_spans": [{"start": 74, "end": 78, "text": "(13,", "ref_id": "BIBREF12"}, {"start": 79, "end": 82, "text": "14,", "ref_id": "BIBREF13"}, {"start": 83, "end": 86, "text": "36,", "ref_id": "BIBREF34"}, {"start": 87, "end": 90, "text": "38,", "ref_id": "BIBREF37"}, {"start": 91, "end": 95, "text": "(71)", "ref_id": "BIBREF70"}, {"start": 96, "end": 100, "text": "(72)", "ref_id": "BIBREF71"}, {"start": 101, "end": 105, "text": "(73)", "ref_id": "BIBREF72"}, {"start": 106, "end": 110, "text": "(74)", "ref_id": "BIBREF73"}, {"start": 111, "end": 115, "text": "(75)", "ref_id": "BIBREF74"}, {"start": 116, "end": 120, "text": "(76)", "ref_id": "BIBREF75"}, {"start": 121, "end": 125, "text": "(77)", "ref_id": "BIBREF76"}, {"start": 360, "end": 364, "text": "(36,", "ref_id": "BIBREF34"}, {"start": 365, "end": 368, "text": "77)", "ref_id": "BIBREF76"}, {"start": 472, "end": 476, "text": "(36)", "ref_id": "BIBREF34"}, {"start": 669, "end": 673, "text": "(78)", "ref_id": "BIBREF77"}], "ref_spans": []}, {"section": "The scope of horizontal gene transfer", "text": "Transfers have occurred from bacteria to higher plants and 6ice 6ersa. The best known example is the direct demonstration of transfer between the soil bacterium, Agrobacterium and plants. In a process bearing a strong resemblance to conjugation between bacteria (see Section 7.3), the tumour (T) segment of the tumour-inducing (Ti ) bacterial plasmid is transferred and incorporated into the plant genome (79, 80) . However, it must be noted that nearly all cases of directly demonstrated horizontal gene transfer, especially those involving phylogenetically distant species, made use of already modified hybrid shuttle vectors that can transfer between species and replicate in both. These shuttle vectors possess signals for replication (origins of replication) in more than one species as well as the signal for DNA transfer (origin of transfer), and are hence much more likely to be successful in horizontal transfer than unmodified plasmids found naturally. The Ti plasmid is, indeed, the basis of a gene transfer vector system widely used for genetically engineering crop-plants (see Table IV ).", "cite_spans": [{"start": 405, "end": 409, "text": "(79,", "ref_id": "BIBREF78"}, {"start": 410, "end": 413, "text": "80)", "ref_id": "BIBREF79"}], "ref_spans": [{"start": 1090, "end": 1098, "text": "Table IV", "ref_id": "TABREF0"}]}, {"section": "The scope of horizontal gene transfer", "text": "Cross-Kingdom horizontal gene transfer by conjugation has also been demonstrated between bacteria and yeast using shuttle vectors derived from broad host-range promiscuous plasmids (see Section 7.3) which are already transferable between many bacterial species (71, 74, 81) . Such vectors can even substitute for the Ti plasmid in transferring genes from Agrobacterium to plants (82) . Recent evidence documented the direct transfer of transgenes and marker genes from transgenic plants to soil fungi (83) and soil bacteria (84) , indicating that secondary, unintended gene transfers can occur from genetically engineered crop-plants which are now released commercially into the environment. Despite the title of their publication, Schlutter et al. (84) actually observed a high 'optimal' gene transfer frequency of 6.2 \u00d7 10 \u2212 2 in the laboratory, from which they 'calculated' a frequency of 2.0 \u00d710 \u2212 17 under extrapolated 'natural conditions'. The natural conditions, are of course, largely unknown (36) . In a recent Workshop at the German Environmental Protection Agency, two research groups reported secondary transfer of antibiotic resistance marker genes from transgenic plants to soil microorganisms (85, 86) . Debris and exudates from transgenic plants will, therefore, be expected to transform bacteria and other microorganisms in the soil. E. coli cells have been successfully transformed by T-DNA, simply using total DNA from a transgenic plant; and the T-DNA vector was recovered as a circular plasmid in the transformed cells (79) . In addition, other vectors such as viruses, insects and nematodes can also mediate unintended, secondary horizontal gene transfer (36) .", "cite_spans": [{"start": 261, "end": 265, "text": "(71,", "ref_id": "BIBREF70"}, {"start": 266, "end": 269, "text": "74,", "ref_id": "BIBREF73"}, {"start": 270, "end": 273, "text": "81)", "ref_id": "BIBREF80"}, {"start": 379, "end": 383, "text": "(82)", "ref_id": "BIBREF81"}, {"start": 501, "end": 505, "text": "(83)", "ref_id": "BIBREF82"}, {"start": 524, "end": 528, "text": "(84)", "ref_id": "BIBREF83"}, {"start": 749, "end": 753, "text": "(84)", "ref_id": "BIBREF83"}, {"start": 1001, "end": 1005, "text": "(36)", "ref_id": "BIBREF34"}, {"start": 1540, "end": 1544, "text": "(79)", "ref_id": "BIBREF78"}, {"start": 1677, "end": 1681, "text": "(36)", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "The scope of horizontal gene transfer", "text": "Mammalian cells are known to take up foreign genes by a number of mechanisms including anastomosis, endosymbiosis, phagocytosis (87, 88) and also endocytosis, a process dependent on specific cell-membrane receptors binding to DNA or to macromolecules (most frequently proteins) complexed to DNA, so that the DNA can be internalized (36) . It has even been suspected that gene transfer from bacteria to animal cells can occur by conjugation, a mating process previously thought to be confined to bacterial cells (see Section 11.3). The ability of certain viruses (retroviruses) to capture and transfer genes among mammalian cells is well-known and is associated with many animal cancers (see entries in (89)). Numerous illegitimate recombinations requiring no sequence homologies are due to retroviral insertion into the genome transferring genes horizontally between individuals of the same or different species (36) . In short, a given gene from any organism has the potential to spread to all other organisms in the biosphere (13, 14) .", "cite_spans": [{"start": 128, "end": 132, "text": "(87,", "ref_id": "BIBREF86"}, {"start": 133, "end": 136, "text": "88)", "ref_id": "BIBREF87"}, {"start": 332, "end": 336, "text": "(36)", "ref_id": "BIBREF34"}, {"start": 912, "end": 916, "text": "(36)", "ref_id": "BIBREF34"}, {"start": 1028, "end": 1032, "text": "(13,", "ref_id": "BIBREF12"}, {"start": 1033, "end": 1036, "text": "14)", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "The scope of horizontal gene transfer", "text": "However, DNA uptake by itself is not sufficient for successful gene transfer. Important barriers operate after the uptake of foreign DNA which break down, or otherwise block the integration, use and maintenance of the foreign genes (40, 77) . Plasmid DNA requires an origin of replication that is recognized and used by the host cell before it can be replicated and maintained. Similarly, promoter sequences which can be recognized by the host are necessary for expressing the viral genes that make the virus, as well as expressing any other foreign genes carried by the virus. (Though, of course, origin of replication and promoter sequences can be acquired by recombination.) However, degraded DNA coding for parts or domains of proteins, or short regulatory motifs that bind transcription factors or otherwise enhance or repress gene expression may also be integrated, with significant genetic effects including cancer (36) . Recombination of domains is already known to be a major factor in generating new proteins (59) .", "cite_spans": [{"start": 232, "end": 236, "text": "(40,", "ref_id": "BIBREF39"}, {"start": 237, "end": 240, "text": "77)", "ref_id": "BIBREF76"}, {"start": 922, "end": 926, "text": "(36)", "ref_id": "BIBREF34"}, {"start": 1019, "end": 1023, "text": "(59)", "ref_id": "BIBREF58"}], "ref_spans": []}, {"section": "The scope of horizontal gene transfer", "text": "While the host cell DNA has its own origins of replication, methylation patterns (chemical markers) and promoter sequences which are specific to the species, artificial gene transfer vectors and other manipulated DNA have recombined origins of replication and promoter sequences from different species which can be recognized by different host species. In addition, they are designed to overcome the restriction systems which break down and 'silence' foreign DNA. Thus, genetic engineering may ha6e created new a6enues and possibilities for increasing the scope of horizontal gene transfer. We shall consider this in more detail in Section 10.", "cite_spans": [], "ref_spans": []}, {"section": "The scope of horizontal gene transfer", "text": "The scope of horizontal gene transfer among bacterial species has to be appreciated in the light of the revised phylogeny of the living world based on comparing ribosomal RNA (rRNA) sequences, a procedure first proposed by Carl Woese (90) . Ribosomal RNAs are the most conservative molecules in evolution, and have not been subject to horizontal transfer between species. For these reasons, phylogenies based on rRNA sequences are generally considered to be the most reliable.", "cite_spans": [{"start": 234, "end": 238, "text": "(90)", "ref_id": "BIBREF89"}], "ref_spans": []}, {"section": "The scope of horizontal gene transfer", "text": "Comparisons of rRNA and other conserved sequences give a universal phylogenetic tree ( Fig. 1) (91 But even the revised phylogeny of the living world greatly underestimates the genetic diversity of Bacteria. The known bacterial species are less than 1% of all species that exist, as more than 99% cannot be cultivated in the laboratory by routine techniques (91) . This highlights the dangers of releasing genetically engineered microorganisms or DNA into the environment.", "cite_spans": [{"start": 358, "end": 362, "text": "(91)", "ref_id": "BIBREF90"}], "ref_spans": [{"start": 87, "end": 98, "text": "Fig. 1) (91", "ref_id": "FIGREF1"}]}, {"section": "The scope of horizontal gene transfer", "text": "All known pathogens belong to the Bacteria and some to the Eucarya Domain. None belongs to Archaea despite the fact that some archaean species share our environment and are part of our normal bowel flora. Strauss and Falkow (92) suggest there may be more fundamental differences between organisms that can become pathogens and those that do not. Another reason, however, may be that, until fairly recently, archaean organisms have not been genetically manipulated to the same extent as have bacterial species. Will the current trend towards increasing manipulation of archaean species also turn previously benign organisms into pathogens? Judging from the recent history of genetic engineering, it may only take a few years of intensive genetic manipulation of new (archaean) species for new pathogens to emerge. There are essentially no barriers left to horizontal gene transfer and recombination, particularly as the result of genetic engineering.", "cite_spans": [], "ref_spans": []}, {"section": "MECHANISMS OF HORIZONTAL GENE TRANSFER", "text": "There are three main mechanisms for gene transfer in bacteria, 1) by direct uptake of DNA (transformation) 2) through genes being carried by viruses that infect bacterial cells (transduction) and 3) through a mating process requiring cell to cell contact (conjugation). These processes have been studied most extensively in E. coli, although it is becoming clear that what is true for E. coli does not necessarily apply to other species. The scope of our present ignorance is enormous, but what is known already gives us serious cause for concern.", "cite_spans": [], "ref_spans": []}, {"section": "Transformation frequencies are high", "text": "Transformation among microbes in the environment has been extensively reviewed recently (36 -38) , showing that it is extremely widespread. The process involves DNA being released into the environment, its binding to the surface of bacteria, entry into the cell and recombination with the bacterial chromosome, or in the case of plasmids, reconstituting the plasmid. All these stages are facilitated by bacterial proteins. Both chromosomal and plasmid DNA are able to transform bacteria, the frequency of transformation varying with the physiological state of the cell, diffusible factors excreted from the bacteria and the presence of salts in the environment. In addition, the nature of the DNA, its source, size, and state may also be important. Generally, transformation is most frequent if the DNA is from the same species, as its successful integration into the recipient genome depends on the degree of homology, i.e. the similarity in base sequence between the transforming DNA and the host DNA. It also depends on the DNA being resistant to the restriction enzymes in the host cell which break down foreign DNA. In one experiment, brief heat treatment (9 min at 48.5\u00b0C) dramatically increased the competence of cells for receiving foreign DNA by 4 orders of magnitude (73) . This was attributed to the heat inactivation of restriction enzymes, thereby increasing the success of gene transfer. Cross species, cross-genera and even cross-order transfers have been observed with chromosomal DNA. Plasmid DNA, in particular, has effected cross-Kingdom transformations among Eubacteria, Proteobacteria and Cyanobacteria (37).", "cite_spans": [{"start": 1277, "end": 1281, "text": "(73)", "ref_id": "BIBREF72"}], "ref_spans": []}, {"section": "Transformation frequencies are high", "text": "DNA is not only released into the environment when the cells die, but is actively excreted by living cells during growth. Some species export DNA wrapped in membranebound vesicles. The DNA in a culture slime can be more than 40% of the dry weight. Thus, the environment is extremely rich in DNA. Marine water contains between 0.2 to 44 vg per liter, and fresh water contains between 0.5 to 7.8 vg per liter; while freshwater sediment has an upper concentration of 1 vg per gram. Although enzymes breaking down DNA (deoxyribonucleases, DNases) are found in the environment, DNA is protected from degradation by adsorbing to detritis, humic acid, and in particular, clay and sand particles. Adsorbed DNA is equally efficient in transforming cells. Thus, the half-lives of DNA in soil is 9.1 h for loamy sand soil, 15.1 h for silty clay soil and 28.2 h for clay soil. While half-lives (time for half of the DNA to be broken down) in waste water are typically fractions", "cite_spans": [], "ref_spans": []}, {"section": "Transformation frequencies are high", "text": "transformant per viable cell. In fact, transformation frequencies are often higher under natural conditions than in the laboratory. In a recent study in soil microcosms, activity due to earthworms was found to significantly enhance gene transfer between spatially separated bacterial species innoculated into the soil (93) . A special form of bidirectional transformation by cell contact and fusion is now known to be widespread (38) . The release, or escape of naked recombinant DNA into the environment is a growing ecological problem, not only in the form of transgenic organisms, but also in vaccines, gene therapy vectors, and antisense oligonucleotide -short sequences of RNA complementary to the base sequence in the transcript of the genes-and ribozymes-RNA that act as enzymes to splice out intron sequences from transcribed genes-used in various forms of gene therapy (36) . As mentioned earlier, even short sequences can have significant genetic effects when integrated into the genome of organisms for which they are not intended. The hazard of naked DNA is highlighted by the discovery that some viral DNA may infect non-permissive hosts for which the virus itself is noninfective (36) . Intravenous injection of naked, circular polyoma viral DNA into rabbits and mice gave a powerful genetic expression with the development of antibodies and the production of new virus particles (94) , whereas the native virus had no effect. Similarly, intravenous injections of recombinant plasmids in liposomes gave gene expression in several organs including the ovaries, indicating the possibility of an inherited genetic change (36) . These findings are the basis for developing many recombinant DNA vaccines (95), for which ecological risk assessment has hardly even been considered.", "cite_spans": [{"start": 318, "end": 322, "text": "(93)", "ref_id": "BIBREF92"}, {"start": 429, "end": 433, "text": "(38)", "ref_id": "BIBREF37"}, {"start": 878, "end": 882, "text": "(36)", "ref_id": "BIBREF34"}, {"start": 1194, "end": 1198, "text": "(36)", "ref_id": "BIBREF34"}, {"start": 1394, "end": 1398, "text": "(94)", "ref_id": "BIBREF93"}, {"start": 1632, "end": 1636, "text": "(36)", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "Transformation frequencies are high", "text": "DNA vaccines are inherently dangerous due to their ability to infect non-permissive hosts, thus crossing wide species barriers, with many opportunities for recombination to generate new viruses. Recombinant DNA vaccines are worse, as even small modifications of a virus can result in significant, unpredictable changes in its host range and virulence (36) . In addition, they are more prone to recombine with other viruses to generate new viruses. Similar hazards are associated with the gene therapy vectors which are currently being developed (see also Section 11.3).", "cite_spans": [{"start": 351, "end": 355, "text": "(36)", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "Transduction is substantial in aquatic en6ironments", "text": "Transduction takes place by means of bacteriophages which are usually host specific, and are hence not expected to transfer genes between unrelated species. However, promiscuous phages with broad host ranges are capable of transducing genes between unrelated species (38) . A bacteriophage consists of viral DNA wrapped in a protein coat, which binds to specific receptor sites on the bacteria. Once bound to the receptor sites, the bacteriophage injects its DNA into the bacterium. The internalized phage DNA either directs the synthesis of many bacteriophages which eventually break open (lyse) the cell, or the phage DNA may insert itself into the bacterial chromosome (as pro6irus or prophage) to become replicated with the chromosome. The bacteriophage can transfer genes by mispackaging a piece of bacterial DNA in the viral protein coat, or by packaging a viral DNA that has a piece of bacterial DNA incorporated into it. When such a virus infects a second cell, the bacterial DNA is transferred and may then become integrated into the new bacterial chromosome. The transducing phage may serve as a vehicle for a transposon that can then establish itself in an unrelated host, even though the phage DNA cannot do so, and hence contribute to cross-species, cross-genera gene transfer. Also, bacteriophages themselves evolve by horizontal gene transfer and recombination, leading to broadening of their host ranges (96) . One study (97) found as many as 108 bacteriophages per milliliter in aquatic environments, so that onethird of the total bacterial populations is subjected to a phage attack every 24 h, each capable of transducing foreign genes into the cell. Recently, Miller (98) reports 1011 virus particles per milliliter in fresh and marine waters.", "cite_spans": [{"start": 267, "end": 271, "text": "(38)", "ref_id": "BIBREF37"}, {"start": 1420, "end": 1424, "text": "(96)", "ref_id": "BIBREF95"}, {"start": 1437, "end": 1441, "text": "(97)", "ref_id": "BIBREF96"}], "ref_spans": []}, {"section": "Transduction is substantial in aquatic en6ironments", "text": "Phages are now known to be intimately involved in the horizontal transfer of entire blocks of virulence genes into the bacterial chromosome, turning a previously benign strain into a pathogen in a single step. Co-integrates of phage and plasmids are also involved in the trafficking of blocks of virulence genes (see Section 9.1).", "cite_spans": [], "ref_spans": []}, {"section": "Conjugation is essentially promiscuous", "text": "Conjugation was previously thought to be a species-specific process requiring complex, complementary interactions between the genetic 'donor' and the genetic 'recipient'. Conjugation depends on certain conjugative plasmids, extrachromosomal pieces of DNA that are replicated independently of the chromosome. They carry genes required for the process of conjugation. These plasmids fall into different incompatibility groups. Ippen-Ihler and Skurray (99) listed seven or more incompatibility groups of over a hundred known plasmids, most of them carrying one or more antibiotic resistance genes. Plasmids in the same incompatibility group cannot be maintained in the same bacterial cell at the same time. However, there are common mechanisms for gene transfer that are interchangeable. One of these codes for the pilus, a tube-like structure connecting the donor with recipient cells in conjugation, through which plasmid DNA passes from the donor to the recipient. In other cases, such as the genes involved in the transfer of the plasmid, the gene products are specific to the plasmid and its host, and not interchangeable. Several of the incompatibility groups comprise 'promiscuous plasmids' with broad host ranges.", "cite_spans": [], "ref_spans": []}, {"section": "Conjugation is essentially promiscuous", "text": "Conjugative plasmids can integrate themselves into the bacterial chromosome. In such cases, when conjugation takes place, the integrated plasmid will drag the bacterial chromosome with it across the conjugation tube from donor to recipient, leading to transfer of bacterial DNA as well as plasmid DNA. Donor DNA will then recombine with recipient DNA to generate new genetic recombinations. The DNA is thought to be passed in a single stranded form, which is resistant to breakdown by enzymes attacking double-stranded DNA (nucleases and restriction enzymes), thus ensuring a high success rate of gene transfer. The single-stranded DNA then directs the synthesis of the complementary strand to restore doublestranded DNA in both donor and recipient.", "cite_spans": [], "ref_spans": []}, {"section": "Conjugation is essentially promiscuous", "text": "Recent studies indicate that conjugation has an extraordinarily wide host range, involving diverse, complex mechanisms that are not yet well understood (38, 100) . 'Promiscuous' plasmids overcome species barriers, transferring genes promiscuously between phylogenetically distant species. At least several of the promiscuous conjugative plasmids have been exploited in constructing artificial shuttle vectors between E. coli and other distant species. One promiscuous conjugative plasmid is routinely used in Agrobacterium-mediated gene transfer to make transgenic plants (see Table IV ). Shuttle vectors are essentially unstoppable, as they typically carry the origins of replication for both species as well as the origin of conjugative transfer. The strength of conjugative transfer is in the single-stranded DNA transferred directly, which escapes destruction by restriction enzymes. While the shuttle vectors are constructed to require 'helper' transfer functions provided by other plasmids, those plasmids can be present in the donor or recipient, or in a third species altogether. These 'tripartite' matings can easily occur in all environments, which are full of known and especially, unknown bacterial species.", "cite_spans": [{"start": 152, "end": 156, "text": "(38,", "ref_id": "BIBREF37"}, {"start": 157, "end": 161, "text": "100)", "ref_id": "BIBREF99"}], "ref_spans": [{"start": 577, "end": 585, "text": "Table IV", "ref_id": "TABREF0"}]}, {"section": "Conjugation is essentially promiscuous", "text": "In addition to conjugative plasmids, conjugative transposons mediate their own transfer to recipient cells during conjugation and insert into the recipient chromosome (101, 102) . They can also jump from one site to another on the same chromosome, or from chromosome into plasmids and 6ice 6ersa. These have also been exploited in constructing gene transfer vectors (see Table IV ). A special class of such conjugative transposons, 'integrons' (103 -105) are thought to be especially involved in the evolution of the multiresistance R plasmids within the past five decades (24) . An integron carries its own gene encoding an enzyme, integrase, that catalyzes the site-specific integration of antibiotic resistant gene 'cassettes' within the integron, such that each inserted 'cassette' is provided with a ready-made promoter for expression. An integron can carry several cassettes, each encoding a different antibiotic resistance. The integron can facilitate recombination between cassettes to form exotic gene-fusions that code for multifunctional proteins. Integrons can also jump from the bacterial chromosome into plasmids and become transferred to another bacterium during conjugation.", "cite_spans": [{"start": 167, "end": 172, "text": "(101,", "ref_id": "BIBREF100"}, {"start": 173, "end": 177, "text": "102)", "ref_id": "BIBREF101"}, {"start": 573, "end": 577, "text": "(24)", "ref_id": "BIBREF23"}], "ref_spans": [{"start": 371, "end": 379, "text": "Table IV", "ref_id": "TABREF0"}]}, {"section": "Conjugation is essentially promiscuous", "text": "During conjugation, genetic material not only goes from donor to recipient, but also in reverse, from recipient to donor, in a recently discovered process, retrotransfer (38).", "cite_spans": [], "ref_spans": []}, {"section": "Effect of en6ironmental pollutants on horizontal gene transfer", "text": "Horizontal gene transfer is sensitive to many physical and chemical factors. In routine laboratory procedures for genetic transformation, heavy metals, singly or in combination, are used to greatly increase the competence of cells for transformation, as are enzymes such as muraminidases or proteases. Freezing and thawing, treatment with EDTA or other chelating agents, exposing cells to electric fields, or to DNA wrapped in liposomes (vesicles made from membrane lipids), are all effective in increasing the frequency of transformation. Yet, very few experimental investigations have been carried out into the effects of environmental pollutants on horizontal gene transfer. This is a glaring omission in view of the hundreds, if not thousands, of xenobiotics that currently circulate in our environment. And to which genetic engineering biotechnology is releasing, or discharging large volumes of agents -transgenic plants and animals, microorganisms, vectors, vaccines, and a range of naked DNA and oligonucleotides -all capable of taking part in horizontal gene transfer (36) . We shall define xenobiotics as compounds released by human beings into the environment in concentrations that create harmful effects.", "cite_spans": [{"start": 1077, "end": 1081, "text": "(36)", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "Effect of en6ironmental pollutants on horizontal gene transfer", "text": "Xenobiotics can affect horizontal gene transfer in two ways (36) . Some xenobiotics mutate DNA, thus influencing its uptake into cells. Kipling and Kearsey (106) have reported examples of minor changes in a DNA sequence which alter the host range of a transferable genetic element. Other xenobiotics can affect the cell membrane and/or intracellular functions thereby influencing the ability of cells to take up DNA, or to engage in conjugation and other forms of gene exchange.", "cite_spans": [{"start": 60, "end": 64, "text": "(36)", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "Effect of en6ironmental pollutants on horizontal gene transfer", "text": "As mentioned in the Introduction, antibiotics can increase horizontal gene transfer 10 to 10000-fold. Antibiotics are heavily used in medicine and intensive agriculture, especially in fish farming, and constitute an important class of xenobiotics that already affect horizontal gene transfer significantly. It is known that ancestral antibiotic resistance genes have originated from antibioticproducing microorganisms themselves. The possibility has been suggested (24) , therefore, that what we call antibiotics may actually be sex hormones for the bacteria, enhancing conjugation between cells. The process is naturally regulated by the product of the 'antibiotic resistance' gene, which shuts off the signal. Thus, the use of antibiotics not only leads to directed mutations of antibiotic resistance genes (see Section 5), it promotes the spread of those very genes among pathogens. The case for phasing out the use of antibiotics in intensive agriculture and fish farming is overwhelming. Antibiotics are also routinely used in genetic engineering biotechnology to select for transformed cells and recombinants.", "cite_spans": [{"start": 465, "end": 469, "text": "(24)", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Effect of en6ironmental pollutants on horizontal gene transfer", "text": "The importance of synergistic interactions between xenobiotics is increasingly recognized. Recent research has shown that chemicals that are apparently harmless when tested singly, can have enhanced effects in mixtures at very low concentrations (107) . As xenobiotics never occur singly in the environment, it is necessary to test drugs and chemicals in combination for realistic risk assessment. But this is a logistically and financially impossible task. To test just 1000 of the commonest toxic chemicals in combinations of three (at a standardized dosage) would require at least 166 million different experiments. An increasing number of scientists are calling for a drastic reduction in the number of chemicals to which we are exposed. They wish to see the introduction of reverse onus, in which a chemical must be regarded as potentially harmful until proven otherwise. Xenobiotics are not made by living organisms, possibly for the good reason that they are incompatible with healthy cellular activities. The synergistic effects of xenobiotics on horizontal gene transfer are, for the most part, unknown and unpredictable. The precautionary principle demands that we should strive to limit the release/escape of genetically engineered organisms, naked DNA and RNA sequences into the environment as much as possible.", "cite_spans": [{"start": 246, "end": 251, "text": "(107)", "ref_id": "BIBREF106"}], "ref_spans": []}, {"section": "HORIZONTAL TRANSFER OF ANTIBIOTIC RESISTANCE GENES", "text": "There could be very few barriers remaining to horizontal gene transfer. Antibiotic resistance genes, especially those carried on R (Resistance) plasmids and transposons, can in principle, cross species as well as genera and Kingdoms and even Domains. Evidence for transfer is obtained wherever and whenever it has been looked for, either by sequence analyses or by direct experimental investigations, as mentioned in Sections 1 and 6. We cite further examples below.", "cite_spans": [], "ref_spans": []}, {"section": "HORIZONTAL TRANSFER OF ANTIBIOTIC RESISTANCE GENES", "text": "Tetracycline resistant genes are now found to be shared between many genera of bacteria, one of them, the (111) . Antibiotic producing Streptomyces are believed to be the ancestral source of many aminoglycoside antibiotic resistance genes, but it is now gaining more of these genes back from the other species. These findings are of particular significance, as they 'suggest the potential for the spread of an antibiotic resistance gene into all environmental mycobacteria, including Mycobacterium leprae.' ((111) , p. 1411).", "cite_spans": [{"start": 106, "end": 111, "text": "(111)", "ref_id": "BIBREF110"}], "ref_spans": []}, {"section": "HORIZONTAL TRANSFER OF ANTIBIOTIC RESISTANCE GENES", "text": "Even chromosomally encoded penicillin-resistance genes (penicillin-binding proteins, pbps, required for the uptake of penicillin) are readily transferred. Transfers of pbp genes were found between Streptococcus pneumoniae and Neisseria gonorrhea which subsequently recombined to generate new hybrid genes (112).", "cite_spans": [], "ref_spans": []}, {"section": "HORIZONTAL GENE TRANSFER AND THE EMERGENCE OF NEW AND OLD VIRULENT STRAINS", "text": "The very same genetic mechanisms for horizontal gene transfer have been involved in the emergence of virulence among old and new pathogens since the mid 1980s. For example, there has been an increase since then, in sporadic cases of very severe invasive Streptococcus pyogenes infections in Europe, North America and elsewhere. In an analysis of 108 isolates from patients in the USA with Streptococal toxic-shock syndrome (113) . A toxin frequently found is encoded by a gene, SpeA, belonging to a bacteriophage, which has become inserted into the bacterial genome. This gene has spread horizontally among different strains of S. pyogenes. In addition, genes encoding membrane surface proteins which determine binding properties and virulence of the bacteria, have also undergone numerous recombination events subsequent to horizontal gene transfer, giving rise to mosaic structures of the genes. This is superimposed on the accumulation of point mutations acquired as the result of interactions of the pathogens with the immunological system of the human host, which make antibodies against the membrane surface proteins of the bacteria. A similar picture emerged on analysis of group A streptococci isolated from a cluster of cases of serious infections over a 3-month period in Tayside, Scotland in 1993 (21) . DNA sequence analysis of virulence factors suggests that they may have been recently acquired by horizontal gene transfer.", "cite_spans": [{"start": 423, "end": 428, "text": "(113)", "ref_id": "BIBREF112"}, {"start": 1308, "end": 1312, "text": "(21)", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "HORIZONTAL GENE TRANSFER AND THE EMERGENCE OF NEW AND OLD VIRULENT STRAINS", "text": "In the past, only Vibrio cholerae strains of the type O1 are known to have caused epidemcs, while non-O1 strains are associated with sporadic cases. However, the recent epidemic in Asia was caused by a non-O1 strain, Vibrio cholerae O139. It turns out that the new strain is identical to an earlier pandemic strain, O1 EL Tor, except for proteins involved in the capsule and the Oantigen synthesis (which is used in typing the strains). This was due to the acquisition of DNA inserted into, and replacing part of the O antigen gene cluster. This suggests that O139 arose by horizontal gene transfer from a non-O1 strain into a type O1 strain (15) (16) (17) .", "cite_spans": [{"start": 642, "end": 646, "text": "(15)", "ref_id": "BIBREF14"}, {"start": 647, "end": 651, "text": "(16)", "ref_id": "BIBREF15"}, {"start": 652, "end": 656, "text": "(17)", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "HORIZONTAL GENE TRANSFER AND THE EMERGENCE OF NEW AND OLD VIRULENT STRAINS", "text": "Pathogenic mycoplasmas possess proteins called adhesins and related accessory proteins which are required for adhering to cells and subsequent disease development. Mycoplasma genitalium, implicated in urethritis, pneumonia, arthritis and AIDS progression, was found to encode one adhesin and 2 adhesin-related proteins that shared substantial sequence similarities, as well as genome organization, with those of another species, M. penumoniae (114) . These were attributed to horizontal gene transfer events between the two species.", "cite_spans": [{"start": 443, "end": 448, "text": "(114)", "ref_id": "BIBREF113"}], "ref_spans": []}, {"section": "HORIZONTAL GENE TRANSFER AND THE EMERGENCE OF NEW AND OLD VIRULENT STRAINS", "text": "Most disturbing of all is the recent discovery that at least 10 unrelated bacterial pathogens, causing diseases from bubonic plague to tree blight, share an entire set of genes for invading host cells, which have spread by horizontal gene transfer, as they reside as a block, often in the bacterial chromosome, forming 'pathogenicity islands' (see Section 9.1) (23). More than 20 genes are involved in a system that secretes damaging proteins directly into host cells. They were first discovered in Yersinia, a genus of several species that cause human disease including bubonic plague and intestinal infections. At least some of the proteins are typical of eukaryotic cells, and are targeted at eukaryotic biochemistry (115) , leading to the speculation that the genes were originally acquired from eukaryotic cells. We shall look at some of these systems in more detail later.", "cite_spans": [{"start": 720, "end": 725, "text": "(115)", "ref_id": "BIBREF114"}], "ref_spans": []}, {"section": "HORIZONTAL GENE TRANSFER AND THE EMERGENCE OF NEW AND OLD VIRULENT STRAINS", "text": "Like antibiotic resistance genes, many virulence genes reside on transposons or plasmids. For example, the ST-enterotoxin genes of E. coli are part of a transposon; while important virulence factors of Gram-negative pathogens (Shigella flexneri, Salmonella spp., Yersinia spp.) as well as Gram-positive pathogens (Clostridium tetani) are encoded in plasmids. Other factors, including the Shiga-like toxins of E. coli, the cholera toxin of Vibrio cholerae, diphtheria toxin of Corynebacterium diphtheriae, neurotoxins of Clostridium bolulinum and cytotoxin of Pseudomonas aeruginosa, are encoded by bacteriophage (116, 117) . All these toxins and virulence factors obviously have the capacity to spread horizontally and to create new pathogens by recombination.", "cite_spans": [{"start": 612, "end": 617, "text": "(116,", "ref_id": "BIBREF115"}, {"start": 618, "end": 622, "text": "117)", "ref_id": "BIBREF116"}], "ref_spans": []}, {"section": "HORIZONTAL GENE TRANSFER AND THE EMERGENCE OF NEW AND OLD VIRULENT STRAINS", "text": "Virulence factors are often also located on the chromosome, where they form large blocks, which came to be called pathogenicity islands.", "cite_spans": [], "ref_spans": []}, {"section": "Pathogenicity islands", "text": "The term 'pathogenicity island' (Pai ) refers to large chromosomal regions in pathogenic bacteria that encode virulence genes acquired by bacteria from unrelated organisms. Hacker et al. (118) reviewed the subject recently. They define a Pai according to the following criteria:", "cite_spans": [], "ref_spans": []}, {"section": "Pathogenicity islands", "text": "1. Carriage of (often many) virulence genes. 2. Presence in pathogenic strains, and absence or sporadic distribution in less-pathogenic strains of one species or a related species. 3. Different G + C content in comparison to DNA of host bacteria, indicative of a foreign source. 4. Occupation of large chromosomal regions (often more than 30 kb). 5. Represents compact, distinct genetic units, often flanked by direct repeats (like many viruses and transposons). 6. Association with tRNA genes and/or insertion sequence (IS), a special class of mobile genetic elements, at their boundaries. 7. Presence of (often cryptic) mobility genes (IS elements, integrases, transposases, origins of plasmid replication). 8. Instability.", "cite_spans": [], "ref_spans": []}, {"section": "Pathogenicity islands", "text": "A bacterial pathogen may have one or more pathogenicity islands. For example, uropathogenic (causing infection of the urinary tract) E. coli strain 536 has two Pais: Pai I encodes only h-haemolysin, responsible for haemolysis, while Pai II carries the h-haemolysin gene, (hly), as well as the P-related fimbriae gene (prf) involved in attachment of the bacterium to the host cell. Pai I is flanked by the selC gene encoding the selenocysteine-specific tRNA and two direct 16 bp repeats, while Pai II is associated with leuX, which encodes a leucyl tRNA, and two direct 18 bp repeats. The direct repeats in both cases are attachment sites for bacteriophages (R73 in Pai I, and P4 in Pai II). Cryptic integrase genes of these phages are located near the respective tRNA genes. Thus, the Pais probably originate from integrated prophages which have picked up a range of virulence genes to turn them into pathogenicity islands. In addition, sequences homologous to the origins of replication of plasmids, parts of IS elements, and 'recombination hot spots' (sites which are most frequently involved in recombination) are also present. All these indicate that Pais are highly mosaic, and many recombination events have contributed to their evolution. Have some of these recombinations been inadvertently created by genetic engineering?", "cite_spans": [], "ref_spans": []}, {"section": "Pathogenicity islands", "text": "Phages, plasmids and pathogenicity islands are involved in rapid evolutionary changes of bacteria by 'quantum leaps'. Pais often exhibit features of both plasmids and phages, reflecting the formation of co-integrates of both types of extra-chromosomal elements. Enteropathogenic bacterial strains (infecting the gastrointestinal tract), including E. coli 0157:H7, have the ability to remodel the actin cytoskeleton of infected cells, producing so-called 'attaching and effacing' (AE) lesions in the host cell. A 35.4 kb pathogenicity island in enteropathic E. coli, called the locus of enterocyte effacement, (LEE), has been found to contain all the known genes necessary for AE lesions (119) . Several features of the LEE suggest that it has been acquired recently by the enteropathogenic E. coli and other AE bacteria. These include, (i) a G+C content of 38.4%, compared with the 51% of the bacterial chromosome as a whole. (ii) the strict conservation of LEE base sequences within AE pathogens of 3 genera of bacteria, including the distantly related Hafnia al6ei, and (iii) insertion within selC tRNA gene, the same site of insertion for paiI in uropathogenic E. coli and the bacteriophage R73. The LEE is one among a whole class of genetic systems (type III systems) that are extremely sophisticated in exploiting host cell functions (see below).", "cite_spans": [{"start": 687, "end": 692, "text": "(119)", "ref_id": "BIBREF118"}], "ref_spans": []}, {"section": "Exploitation of host cell functions by bacterial pathogens", "text": "Recent studies reveal the common strategies used by a wide range of pathogenic bacteria as well as the unique tactics adopted by individual species in establishing infection. Many host cell functions are exploited by the pathogens, including signal transduction pathways and rearrangements of the cytoskeleton (115) .", "cite_spans": [{"start": 310, "end": 315, "text": "(115)", "ref_id": "BIBREF114"}], "ref_spans": []}, {"section": "Exploitation of host cell functions by bacterial pathogens", "text": "Adhesion to host cells is the first stage in disease development. Bacterial pathogens produce a range of proteins, adhesins, which mediate adhesion to host cells. These adhesins interact with surface membrane components of mammalian cell, many of which serve as receptors for the bacterial adhesins. The host cell is often an active participant in adhesion by synthesizing the receptors for adhesion. For example, enteropathogenic E. coli adheres to intestinal epithelial cell surfaces by destroying host microvilli and rearranging the cytoskeleton to form a pedestal on the host cell surface on which the bacterium resides (the AE lesions). To achieve this, the bacterium secretes at least two proteins, EspA and EspB, which activate host cells by inducing a series of events involved in signal transduction: calcium flux, inositol phosphate production, phosphorylation of the amino-acid tyrosine in a membrane protein, and finally, rearrangement of the cytoskeleton. The secretion of the proteins that activate epithelial cells is mediated by a specialized secretion system called the type III secretion system, version of which are being identified in an ever-increasing number of human, animal and plant pathogens. They allow the bacteria to attach to cells, to enter the cells, or to prevent themselves from being swallowed by phagocytic cells.", "cite_spans": [], "ref_spans": []}, {"section": "Exploitation of host cell functions by bacterial pathogens", "text": "Type III secretion systems comprise at least 20 gene products which are essential for the virulence of these pathogens; the genes encode both secreted effector proteins and the machinery necessary for secretion and translocation into target cells. Enhanced secretion of the virulence factors often occurs after contact with host cell surfaces. Although the secreted virulence factors differ among pathogens which cause different diseases, the secretion machinery is often interchangeable. The same type III system is involved in invading cells by activating host signalling pathways, leading to appropriate changes in the cytoskeleton which internalize the pathogens. One type of internalization mechanism is shared by Yersinia and Listeria, while another is shared by Salmonella and Shigella. In Salmonella, the type III secretion system responsible for invading host cells forms a pathogenicity island on the chromosome, while in Shigella, the system is found in a large virulence plasmid.", "cite_spans": [], "ref_spans": []}, {"section": "Exploitation of host cell functions by bacterial pathogens", "text": "In addition to invasion systems for entering epithelial cells, Yersinia species have evolved mechanisms to a6oid uptake by phagocytic cells. The anti-phagocytosis strategy relies on the expression of Yop proteins, which also involves type III secretion systems. One protein, Yop E paralyzes the cellular cytoskeleton, while another, Yop H is a broad-spectrum tyrosine kinase that interrupts phosphotyrosine signaling associated with phagocytosis. Yet another protein, Yop O, has homology to mammalian enzymes, serine and threonine kinases involved in signal transduction, and like Yop H, is targetted to the inner surface of the host-cell plasma membrane.", "cite_spans": [], "ref_spans": []}, {"section": "Exploitation of host cell functions by bacterial pathogens", "text": "Among Gram-positive bacteria, Listeria monocytogenes enters mammalian intestinal cells by means of a surface protein, internalin. Internalin contains multiple copies of a 22-amino acid leucine-rich tandem repeat (LRR), a feature of several eukaryotic proteins that are generally involved in protein -protein interactions. Another surface protein, InlB, belonging to the internalin multigene family and displaying similar LRRs, mediates entry into cultured hepatocytes, Hela cells and Chinese Hamster Ovarian cells.", "cite_spans": [], "ref_spans": []}, {"section": "Exploitation of host cell functions by bacterial pathogens", "text": "Type III secretion systems have also been identified in the plant pathogens Ralstonia, Pseudomonas, Xanthomonas and Erwinia, and are involved in their ability to cause diseases (120).", "cite_spans": [], "ref_spans": []}, {"section": "HAS HORIZONTAL GENE TRANSFER INCREASED RECENTLY?", "text": "The evidence is now overwhelming that horizontal gene transfer has been responsible for both the rapid spread of antibiotic resistances and for the emergence of virulent strains of pathogens in recent years. Has horizontal gene transfer increased in scope and frequency since genetic engineering biotechnology began?", "cite_spans": [], "ref_spans": []}, {"section": "HAS HORIZONTAL GENE TRANSFER INCREASED RECENTLY?", "text": "In the Introduction, we have alluded to the apparently accelerated rates in the evolution of drug and antibiotic resistance and of new pathogens since the 1980s. Furthermore, sequence identity or near-identity in both virulence and antibiotic genes from unrelated species indicate that a high proportion of the horizontal gene transfers may be very recent.", "cite_spans": [], "ref_spans": []}, {"section": "HAS HORIZONTAL GENE TRANSFER INCREASED RECENTLY?", "text": "A study carried out in 1983 on strains of bacteria isolated between 1917 to 1954, at least ten years into the antibiotics era, but well before genetic engineering got underway, showed that none of the strains carried any antibiotic resistance (121) . By contrast, it takes one to two years in the post-genetic engineering era for resistance to develop and spread, rendering new antibiotics useless in 4 years (11, 25) . However, 24% of the strains from the pre-genetic engineering era encode genetic information for the transfer of DNA from one bacterium to another; and from at least 19% of the strains, conjugative plasmids carrying no antibiotic resistance were transferred to the laboratory strain E. coli K12 (121) . Thus, while conjugative plasmids and other mechanisms for horizontal gene transfer may predate both the antibiotics and genetic engineering eras, their prevalence and the range of drugs to which they confer resistance have greatly increased, especially since genetic engineering got underway.", "cite_spans": [{"start": 243, "end": 248, "text": "(121)", "ref_id": "BIBREF120"}, {"start": 409, "end": 413, "text": "(11,", "ref_id": "BIBREF10"}, {"start": 414, "end": 417, "text": "25)", "ref_id": "BIBREF24"}, {"start": 714, "end": 719, "text": "(121)", "ref_id": "BIBREF120"}], "ref_spans": []}, {"section": "HAS HORIZONTAL GENE TRANSFER INCREASED RECENTLY?", "text": "It would also be of interest to screen these strains from the pre-genetic engineering era for pathogenicity islands, which will contribute to our understanding of how pathogenicity islands have evolved since.", "cite_spans": [], "ref_spans": []}, {"section": "Barriers to horizontal gene transfer", "text": "The frequency of horizontal gene transfer may therefore be determined, not so much by the actual mechanisms that exist for mediating transfer as on the existence of barriers that act against the process (77, 122, 123) . In bacteria, a major mechanism for limiting horizontal gene transfer is restriction -the destruction, or inactivation of foreign DNA. There are 11 restriction/modification systems in enteric bacteria which fall into three families, hsdR, hsdM and hsdS. The alleles (different variants) of the hsdR family are responsible for destroying foreign DNA, while those of hsdM and hsdS families are responsible for methylating, thereby protecting DNA molecules that escape restriction and facilitating their recombination into the genome. A second barrier is the mismatch DNA repair system encoded by the mutL, mutS and mutH genes of E. coli and S. typhimurium, which severely inhibits recombination of nonhomologous DNA. However, another genetic system, the error-prone SOS system, activated under stress, stimulates such recombination. In addition, as mentioned in Sections 6.1 and 7.3, there are origins of replication and origins of transfer specific to DNA from different species, so that even if DNA is transferred, they cannot be replicated and maintained, so that the chances of integration into the chromosome would also have been much reduced, unless, of course, the DNA has been manipulated to combine origins of replication from different species.", "cite_spans": [{"start": 203, "end": 207, "text": "(77,", "ref_id": "BIBREF76"}, {"start": 208, "end": 212, "text": "122,", "ref_id": "BIBREF121"}, {"start": 213, "end": 217, "text": "123)", "ref_id": "BIBREF122"}], "ref_spans": []}, {"section": "Barriers to horizontal gene transfer", "text": "Another important influence on the frequency of horizontal gene transfer is the ecology of the microbes concerned, as mentioned in Section 5. Stressful conditions appear to reduce the effectiveness of restriction and to encourage recombination (124, 125) . Starving bacteria are also more competent in taking up DNA from the environment, and hence to become transformed (126) . And heat treatment greatly increases the frequency of transformation (Section 7.1); while the effects of xenobiotics in the environment on horizontal gene transfer, apart from antibiotics, remain largely unknown (see Section 7.4).", "cite_spans": [{"start": 244, "end": 249, "text": "(124,", "ref_id": "BIBREF123"}, {"start": 250, "end": 254, "text": "125)", "ref_id": "BIBREF124"}, {"start": 370, "end": 375, "text": "(126)", "ref_id": "BIBREF125"}], "ref_spans": []}, {"section": "Genetic engineering biotechnology breaks down species barriers", "text": "One main contributing factor to the recent increase in the scope and frequency of horizontal gene transfer may be the deliberate acts of genetic engineers to break down species barriers. They do so by constructing a range of chimaeric vectors for cloning and transferring genes. These artificial vectors have the following important characteristics that enhance horizontal gene transfer.", "cite_spans": [], "ref_spans": []}, {"section": "Genetic engineering biotechnology breaks down species barriers", "text": "-They are already derived from elements that mediate horizontal gene transfer most effectively. -Their chimaeric nature means that they possess sequence homologies to DNA from widely different species and their viral pathogens, plasmids and transposons, thus facilitating successful horizontal transfer and recombination. -They routinely contain antibiotic resistance marker genes enhancing their successful transfer in the presence of antibiotics, either intentionally applied or as xenobiotics in the environment. -They often have origins of replication and transfer sequences (see Section 6.1), all of which facilitate horizontal gene transfer and recombination. In this context, the fact that they are 'crippled', so that genes for mobility and/or virulence are removed, is irrelevant, as helper functions can be supplied by other viruses, plasmids and mobile genetic elements present in the donor, recipient or a third strain of bacteria. And virulence genes can be regained by recombination. -It is well-known that chimaeric plasmids and viral vectors are subject to structural instabilities which make them more prone to recombine (40) . Vector instability is a continuing problem for genetic engineers and the biotech industry as far as the stability of the transferred genes is concerned. It also increases the probability and scope for unintended, secondary horizontal gene transfer, which has already been directly demonstrated (see Section 6.1). -The now routine incorporation of strong promoters and enhancers in vectors to boost expression of transgenes is one main cause of structural instability, which is in addition to the instability arising from the attendant metabolic stress to the organism, that again, may increase unintended horizontal gene transfer (127). -Finally, vectors are designed to escape restriction (128) thereby also enhancing the probability of successful horizontal gene transfer.", "cite_spans": [{"start": 1138, "end": 1142, "text": "(40)", "ref_id": "BIBREF39"}, {"start": 1835, "end": 1840, "text": "(128)", "ref_id": "BIBREF127"}], "ref_spans": []}, {"section": "Genetic engineering biotechnology breaks down species barriers", "text": "The construction of artificial vectors is fundamental to genetic engineering. Some examples of the vectors used are given in Table IV (compiled mainly from (40)). All classes of genetic elements that mediate horizontal gene transfer have been used in constructing vectors: plasmids, phages, transposons, plus a range of pathogenic plant and animal viruses. As stated in a standard textbook on genetic manipulation, 'Many animal viruses have been subjugated as vectors. Virtually every virus that has been studied in any detail and that has a DNA genome or a DNA stage in its replication cycle has been manipulated in this way' ( (40), p. 225).", "cite_spans": [], "ref_spans": [{"start": 125, "end": 155, "text": "Table IV (compiled mainly from", "ref_id": "TABREF0"}]}, {"section": "Genetic engineering biotechnology breaks down species barriers", "text": "Although different classes of vectors are distinguishable on the basis of the main framework sequence, practically everyone of them is chimaeric. Important chimaeric vectors are the shuttle vectors which enable genes to be cloned (multiplied) in E. coli and transferred (transfected) into unrelated species in every Kingdom. Similarly, vectors used in manipulating plants and animals typically contain sequences from a range of plant and animal viral pathogens, as well as antibiotic resistance genes, often originating from promiscuous resistance plasmids and transposons. Phage vectors and phasmid vectors (hybrid of phage and plasmid) are also extensively used, and may have special relevance for the evolution of pathogenicity islands in bacterial pathogens (see Section 9.1).", "cite_spans": [], "ref_spans": []}, {"section": "Genetic engineering biotechnology breaks down species barriers", "text": "Thus, genetic engineering biotechnology has effectively opened up highways for horizontal gene transfer and recombination, where previously, there was only restricted access through narrow, tortuous footpaths. These gene transfer highways connect species in every Domain and Kingdom with the microbial populations via the universal mixing vessel, E. coli. We review further circumstantial evidence that artificial gene transfer vectors increase the scope and frequency of horizontal gene transfer.", "cite_spans": [], "ref_spans": []}, {"section": "Artificial gene transfer 6ectors increase horizontal gene transfer", "text": "It is not easy to transfer genes successfully between species as we have already emphasized, there are barriers to horizontal gene transfers (see Section 10.1). That is why, apart from transposons which are promiscuous, such events were relatively rare in our evolutionary past. For example, analyses of 145 nonvertebrate globin gene sequences showed that there were probably two cases of horizontal gene transfer, one from the common ancestor of ciliates and the green algae to the ancestor of cyanobacteria and the other, from the ancestor of the yeasts to the ancestor of bacteria (129) . Natural gene transfer vectorsviruses, plasmids and transposons -have probably always existed, especially in the microbial species; but they were to varying degrees host specific, so that the frequency of conjugal transfers are higher between the same species than with other species (130) . Naturally isolated vectorseven those that carry antibiotic resistance genes and have therefore already undergone evolution by horizontal gene transfer -have not exhibited the same wide range of transfer capabilities.", "cite_spans": [{"start": 584, "end": 589, "text": "(129)", "ref_id": "BIBREF128"}, {"start": 875, "end": 880, "text": "(130)", "ref_id": "BIBREF129"}], "ref_spans": []}, {"section": "Artificial gene transfer 6ectors increase horizontal gene transfer", "text": "Horizontal gene transfers have been directly demonstrated between bacteria in the marine environment (30, 131, 132) , in the freshwater environment (133) , and in the soil (134) . Again, in all the experiments, horizontal gene transfers were mediated by specially constructed hybrid plasmid vectors, of the sort used in genetic engineering. Horizontal gene transfer occurs preferentially in interfaces between air and water and in the sediment, and especially under nutrient depletion conditions (135) , thus refuting the claim that nutrient-rich media are necessary to support horizontal gene transfer. Horizontal gene transfer of antibiotic resistances has even been demonstrated in wastewater treatment ponds, the effluent from which is increasingly being used for irrigation in developing countries (136) . As pointed out in Section 7.1, frequencies of horizontal gene transfer may be greater under natural conditions than in the laboratory (93) .", "cite_spans": [{"start": 101, "end": 105, "text": "(30,", "ref_id": "BIBREF29"}, {"start": 106, "end": 110, "text": "131,", "ref_id": "BIBREF130"}, {"start": 111, "end": 115, "text": "132)", "ref_id": "BIBREF131"}, {"start": 148, "end": 153, "text": "(133)", "ref_id": "BIBREF132"}, {"start": 172, "end": 177, "text": "(134)", "ref_id": "BIBREF133"}, {"start": 496, "end": 501, "text": "(135)", "ref_id": "BIBREF134"}, {"start": 803, "end": 808, "text": "(136)", "ref_id": "BIBREF135"}, {"start": 945, "end": 949, "text": "(93)", "ref_id": "BIBREF92"}], "ref_spans": []}, {"section": "Artificial gene transfer 6ectors increase horizontal gene transfer", "text": "Horizontal gene transfer is not limited to the external environment. It has been demonstrated between gut bacteria in mice and chickens (137, 138) and in the gut (139, 140) as well as urogenital and respiratory tract of human beings (141) .", "cite_spans": [{"start": 136, "end": 141, "text": "(137,", "ref_id": "BIBREF136"}, {"start": 142, "end": 146, "text": "138)", "ref_id": "BIBREF137"}, {"start": 162, "end": 167, "text": "(139,", "ref_id": "BIBREF138"}, {"start": 168, "end": 172, "text": "140)", "ref_id": "BIBREF139"}, {"start": 233, "end": 238, "text": "(141)", "ref_id": "BIBREF140"}], "ref_spans": []}, {"section": "Artificial gene transfer 6ectors increase horizontal gene transfer", "text": "Stephenson and Warnes (142) wrote, 'The threat of horizontal gene transfer from recombinant organisms to indigenous ones is\u2026very real and mechanisms exist whereby, at least theoretically, any genetically engineered trait can be transferred to any prokaryotic organism and many eukaryotic ones' (p. 5).", "cite_spans": [], "ref_spans": []}, {"section": "Artificial gene transfer 6ectors increase horizontal gene transfer", "text": "A year later, another molecular geneticist, who works on transgenic plants, admitted that, '\u2026the potential for horizontal (gene) transfer may be greater than thought previously' (143).", "cite_spans": [], "ref_spans": []}, {"section": "BIOLOGICAL CONTAINMENT MAY BE INEFFECTIVE", "text": "When Paul Berg and others (144) published their letter on 'Potential biohazards of recombinant DNA molecules' in Science, the main areas of concern were the possibilities of survival and spread of genetically engineered microorganisms (GEMs) and the dissemination of the new recombinant gene sequences to bacterial hosts throughout the different bacterial communities via horizontal gene trans-fer (34) . To address those concerns and to comply with their own recommendations, general risk assessments were made on the survival and spread of GEMs and the stability of isolated DNA. However, those assessments were often based on little more than plausible assumptions and not on experimental results [see (34) ]. One assumption was that because GEMs carried genetically engineered plasmids, they would not survive due to their extra burden of genetic information (145) . Moreover, laboratory strains were 'biologically contained' due to crippling mutations, which meant that they required specific nutrients for survival. Consequently, the general perception was that even if the GEMs were accidentally released, they would not survive in the environment, and would therefore have no negative impacts. Similarly, released DNA would be rapidly degraded by DNAses in the environment and in the digestive tract, if ingested. These 'impact assessments' made it unnecessary to investigate the actual survivals of GEMS in the environment, and allowed genetic engineering biotechnology to proceed without extensive safety measures. The same arguments were later used to promote relaxation of the already lax safety guidelines. And further relaxations are now being contemplated (see Section 11.6).", "cite_spans": [{"start": 398, "end": 402, "text": "(34)", "ref_id": "BIBREF32"}, {"start": 705, "end": 709, "text": "(34)", "ref_id": "BIBREF32"}, {"start": 863, "end": 868, "text": "(145)", "ref_id": "BIBREF144"}], "ref_spans": []}, {"section": "BIOLOGICAL CONTAINMENT MAY BE INEFFECTIVE", "text": "It is clear that current 'risk assessment' is strongly based on assumptions rather than scientific data. These assumptions, furthermore, can be totally at odds with reality, as they are now revealed to be, which is why such risk assessments are a source of hazard in themselves. 'Risk' is technically the probability of a hazardous event multiplied by the hazard caused. If the hazard is great, even a 'very low probability' will give significant, unacceptable risk. This is a proper application of the precautionary principle. It is often claimed that the hazards are unknown. That is not so. We have identified at least some of the hazards in the spread of virulence, drug and antibiotic resistance in the recent resurgence of infectious diseases.", "cite_spans": [], "ref_spans": []}, {"section": "BIOLOGICAL CONTAINMENT MAY BE INEFFECTIVE", "text": "Our limited enquiry has led us to conclude that the original concerns of Paul Berg and other scientists on the hazards of genetic engineering may have been borne out by scientific evidence that has accumulated since: horizontal gene transfer (and recombination) is the greatest threat to public health facing us to-day, especially if commercial scale genetic engineering biotechnology is allowed to continue unchecked. We may only be seeing the tip of the iceberg, as far as the possible contribution of genetic engineering biotechnology to the etiology of infectious diseases is concerned. In this final Section, we shall review other relevant findings indicating that microorganisms genetically engineered for 'contained use' may not have been effectively contained.", "cite_spans": [], "ref_spans": []}, {"section": "DNA can persist in the en6ironment", "text": "Genes carried by vectors as naked DNA as well as chromosomal DNA can survive indefinitely, especially when adsorbed to solid particles in all environment; on surfaces of water, as sediment, in the soil, where they are efficiently taken up by other microbes [reviewed by (34, 146) ] (see Section 7.1). Although DNA is rapidly broken down in waste water, adsorption to solid particles in the sludge, which happens very quickly, will stabilize it and prolong its transforming capacity. In addition, DNA is now found to persist for long periods in the laboratory clinging to many different surfaces. As already pointed out in Section 7.1, transformation by the uptake of DNA is a major route of horizontal gene transfer in the environment. DNA is not only released when cells die, but are actively secreted by living cells, and even fragments of genes can have significant effects when transferred (Section 7.1). As increasing amounts of recombinant DNA, especially of the 'naked' variety, are discharged into the environment, the risks associated with DNA transformation will rise exponentially.", "cite_spans": [{"start": 270, "end": 274, "text": "(34,", "ref_id": "BIBREF32"}, {"start": 275, "end": 279, "text": "146)", "ref_id": "BIBREF145"}], "ref_spans": []}, {"section": "DNA can resist digestion in the gut", "text": "Earlier studies supported the assumption that DNA is broken down into small fragments in the stomach and subsequently further degraded by nucleases in the digestive system. But more recently, Schubbert and coworkers (147) , using the much more sensitive PCR (polymerase chain reaction) technique, were able to detect large fragments of the M13 phage DNA, which were fed to mice, in the faeces, the blood stream and within white blood cells. The persistence of DNA in the gastrointestinal tract suggests that transformation of gut bacteria may occur. This is very relevant to the spread of antibiotic resistance marker genes which are currently in nearly all commercially approved transgenic food crops.", "cite_spans": [{"start": 216, "end": 221, "text": "(147)", "ref_id": "BIBREF146"}], "ref_spans": []}, {"section": "DNA can resist digestion in the gut", "text": "Subsequent studies by the same group revealed that the DNA fed to mice was taken up, not only by white blood cells, but also by spleen and liver cells. The M13 phage DNA was reisolated from spleen cells and some were found to be attached to mouse DNA (148, 149) , suggesting that it had become integrated. This raises general questions on the ability of gene transfer vectors to invade mammalian cells directly, and indeed, that has been known to occur.", "cite_spans": [{"start": 251, "end": 256, "text": "(148,", "ref_id": "BIBREF147"}, {"start": 257, "end": 261, "text": "149)", "ref_id": "BIBREF148"}], "ref_spans": []}, {"section": "In6asion of mammalian cells by 6ector DNA and 6iral DNA", "text": "Studies made since the 1970s have documented the ability of bacterial plasmids carrying a mammalian SV40 virus (originally specific to monkeys) to infect cultured mammalian cells, which then proceeded to synthesize the virus (87) . Similarly, bacterial viruses and baculovirus (attacking insects) can also be taken up by mammalian cells (88, 150) . One main route for the uptake of DNA by mammalian cells is by phagocytosis of bacteria containing the vector DNA. But baculovirus can gain access by itself. It is so good at getting into human liver cells that it is being engineered as a vector for gene replacement therapy (88, 150 ) at the same time that it is being engineered in agriculture to be a more effective insecticide, which should raise serious safety concerns (127) . An important route for horizontal gene transfer from bacteria to mammalian cells may be conjugation. Bacterial conjugative plasmids can mobilize DNA transfer between bacteria and yeast (see Section 7.3). It was predicted that these plasmids raise the possibility that 'conjugation could occur between bacteria and animal cells and between bacteria and plant cells' ((71), p. 209). This prediction has been borne out. Recently, the prokaryote-eukaryote shuttle vectors pAT497 and pAT498 were both transferred from E. coli cells into mammalian cells by conjugation, with a helper plasmid from Shigella (151) .", "cite_spans": [{"start": 225, "end": 229, "text": "(87)", "ref_id": "BIBREF86"}, {"start": 337, "end": 341, "text": "(88,", "ref_id": "BIBREF87"}, {"start": 342, "end": 346, "text": "150)", "ref_id": "BIBREF149"}, {"start": 773, "end": 778, "text": "(127)", "ref_id": "BIBREF126"}, {"start": 1381, "end": 1386, "text": "(151)", "ref_id": "BIBREF150"}], "ref_spans": [{"start": 628, "end": 631, "text": "150", "ref_id": "FIGREF1"}]}, {"section": "In6asion of mammalian cells by 6ector DNA and 6iral DNA", "text": "Once inside cells, the DNA may integrate at random into the host cell genome, causing correspondingly random genetic disturbances. Of particular concerns in this regard are vector DNA engineered with oncogenes (genes associated with cancer development) and other viral sequences which can cause cancers. Recombination between vector DNA and endogenous viruses can also generate new viral pathogens implicated in several types of animal cancers ((35), Chapter 13).", "cite_spans": [], "ref_spans": []}, {"section": "'Crippled' laboratory strains of bacteria can sur6i6e in the en6ironment", "text": "There are a number of studies documenting the survival of 'crippled' laboratory strains of bacteria in the environment. E. coli K12 has been reisolated from lab coats after 20 days (152). Dott et al. (153) inoculated 6 different strains of GEMs into drinking water, surface water, sewage water and different kinds of soil. On introduction into the sewage under aerobic conditions, the GEMs died off quickly, but not under anaerobic conditions, where only one strain failed to survive the test period of 31 days. However, in sandy soil and nutrient rich garden soil, the GEM that survived least well in any kind of water had the longest life span.", "cite_spans": [{"start": 200, "end": 205, "text": "(153)", "ref_id": "BIBREF152"}], "ref_spans": []}, {"section": "'Crippled' laboratory strains of bacteria can sur6i6e in the en6ironment", "text": "Survival rates estimated by routine culture methods may be quite misleading. It is now well-known that all bacteria can survive starvation and undergo 'adaptive mutations' when presented with substrates that they cannot use initially (see Section 5) . Furthermore, bacteria can survive indefinitely in a non-proliferating, dormant form. This has been documented for a laboratory strain of E. coli K12, which when introduced into the sewage, went dormant and undetectable for 12 days before reappearing, having acquired a new plasmid for multidrug resistance that enabled it to compete with the naturally occurring bacteria (25) . Dormant forms of bacteria and viruses can survive indefinitely as biofilms (see Section 5) . In this state, the bacteria continue to accumulate new mutations, and to exchange genes, to come back with a vengeance, when the ecological conditions are ripe.", "cite_spans": [{"start": 623, "end": 627, "text": "(25)", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Direct documentation of the acquisition of antibiotic resistance, its spread by horizontal gene transfer and persistence", "text": "A study in Eastern Germany (25) gives an idea of the rapidity with which antibiotic resistance can develop and spread by horizontal gene transfer, and yet persist after the antibiotic ceased to be administered. The antibiotic streptothricin was administered to pigs beginning in 1982. By 1983, plasmids encoding streptothricin resistance was found in the pig gut bacteria. This has spread to the gut bacteria of farmworkers and their family members by 1984, and to the general public and pathological strains of bacteria the following year. The antibiotic was withdrawn in 1990. Yet the prevalence of the resistance plasmid has remained high when monitored in 1993, confirming the ability of microbial populations to serve as stable reservoirs for replication, recombination and horizontal gene transfer, in the absence of 'selective pressure'.", "cite_spans": [{"start": 27, "end": 31, "text": "(25)", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Direct documentation of the acquisition of antibiotic resistance, its spread by horizontal gene transfer and persistence", "text": "In a direct test of persistence of streptomycin-resistance (154), researchers cultured many independent lines of a streptomycin-resistant mutant of E. coli in the absence of the antibiotic. They found that all retained the resistance after 180 generations. Furthermore, the lines have, in the mean time, accumulated compensatory mutations in other parts of the genome which increased their competitive ability relative to the wild-type. Again, this demonstrates the irrelevance of conventional explanations of the 'natural selection of random mutations' with regard to the evolution of antibiotic resistance.", "cite_spans": [], "ref_spans": []}, {"section": "Chemical inacti6ation may be ineffecti6e", "text": "The above findings take on additional significance in the light of the recent report that the chemical treatment in waste-tanks of commercial aircrafts are insufficient to inactivate up to ten percent of viral and bacterial pathogens (39) . Commercial-scale contained users of GEMs routinely release large amounts of wastes after chemical or physical 'inactivation'. How adequate are these inactivation measures? Even if inactivation is effective, we now know that the large amounts of recombinant DNA released can still be readily transferred to other bacteria by direct uptake (i.e. transformation). What is the current status of safety regulation in the light of all the recent findings?", "cite_spans": [{"start": 234, "end": 238, "text": "(39)", "ref_id": "BIBREF38"}], "ref_spans": []}, {"section": "Safety regulations are grossly inadequate, and further relaxation is contemplated", "text": "Novo Nordisk is a biotech company that prides itself on being environmentally conscious and transparent in its safety practices. Their 1996 Environmental Report (kindly sent to M.W.H. by the Environment Director) gives the following limits-set by the Danish authority-for untreated release of GEMs in terms of colony-forming units (roughly equivalent to live bacteria): waste water, 10000/ ml, air 10000/ml, solid waste, 10000/g. These 'tolerated releases' have to be seen in the light of the minimum infective dose for E. coli 0157:H7, which is less than 50 bacteria (4). The same company also recycles inactivated GEMs as fertilizers for crops, under the trade name NovoGro 2 . Even if chemical inactivation methods are 100% effective, large amounts of recombinant DNA have already been, and continue to be routinely released into the environment in one form or another, either in the sewage or directly spread onto fields. Many kinds of dangerous recombinant DNA, containing pathogenic sequences, cancer-causing viruses, as well as antibiotic resistance genes can almost certainly transform bacteria in the environment and further recombine, spreading not only antibiotic and virulence genes in bacteria, but also generating new viral pathogens.", "cite_spans": [], "ref_spans": []}, {"section": "Safety regulations are grossly inadequate, and further relaxation is contemplated", "text": "There is an urgent need to re-assess the safety regulation, not only of deliberate releases, but also of contained use. Instead of which, our regulators are contemplating further relaxations.", "cite_spans": [], "ref_spans": []}, {"section": "Safety regulations are grossly inadequate, and further relaxation is contemplated", "text": "The UK Health and Safety Executive (HSE) has drafted a document, circulated for consultation in June 1997, which would allow commercial and other contained users to release certain classes of live GEMs as liquid wastes into the environment, without dilution or chemical inactivation 3 . In September the same year, the US Environmental Protection Agency (EPA) has authorized a biotech company to sell 500000 lb of a genetically engineered Rhizobium melitoti strain, for coating alfalfa seeds before planting. The GE Rhizobium 'contains an extra copy of the gene controlling nitrogenase production, genes to increase internal energy production, a gene conferring resistance to the antibiotics streptomycin and spectinomycin, and some uncharacterized DNA 4 '. The antibiotics are currently used in treating TB, the top killer in the world to-day. This news item was put out by one of the EPA's own officials, who has been protesting on the internet against the agency's effective lack of biosafety oversight on genetically engineered products.", "cite_spans": [{"start": 753, "end": 754, "text": "4", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "CONCLUSION", "text": "In this paper, we have reviewed a variety of evidence-inductive, deductive and circumstantial-linking genetic engineering biotechnology to the recent resurgence in infectious diseases. A summary of the evidence is presented below.", "cite_spans": [], "ref_spans": []}, {"section": "CONCLUSION", "text": "Possible links between genetic engineering biotechnology and the recent resurgence of infectious diseases Inducti6e 1. Horizontal gene transfer (and consequent recombination) is found to be responsible for the spread of virulence and antibiotic resistance. 2. Direct experimental evidence of horizontal gene transfer, some between phylogenetically distant species, has been obtained in all natural environments as well as in the gastrointestinal tract. These were all accomplished using artificially constructed vectors. 3. Genetic engineering biotechnology makes extensive use of antibiotic resistance genes as selectable markers, thereby increasing the spread of antibiotic resistance genes. 4. The presence of antibiotics increases the frequency of horizontal gene transfer 10 to 10000-fold, thereby encouraging the horizontal transfer and recombination of virulence as well as antibiotic resistance genes. 'Crippled' strains of bacteria can survive in the environment to exchange genes with bacteria in the environment. 5. DNA released from dead cells (as well as live cells) are not readily broken down in the general environment, nor in the gastroinstestinal tract, where they may retain the ability to transform other bacteria. 6. Some viral DNA is more infectious than the virus itself. 7. Routine chemical inactivation of geneticially engineered microorganisms prior to disposal in the general environment may be ineffective, leaving a substantial proportion of viruses and bacteria in an infective state. 8. Current legal limits of 'tolerated releases' of GEMs from contained use vastly exceed the minimal infective dose of pathogens and potential pathogens. The totality of evidence is sufficiently compelling, especially in view of the precautionary principle, to warrant, at the very least, an independent, full public enquiry into genetic engineering biotechnology and the etiology of infectious diseases. In addition, we urgently need research directed at understanding general mechanisms for horizontal gene transfer, which aim to strengthen the barriers against the transfer of recombinant DNA, and which can form the basis for scientific risk assessment. Such research must be carried out by independent research groups dedicated to the task, and not left in the hands of those who are involved in commercial exploitation of genetic engineering biotechnology. Executive has agreed, in a letter dated 10 October, 1997, that 'some important issues' were raised, which were to be discussed by the Technical Sub-Committee (TSC) of the Advisory Committee for Genetic Manipulation. The result of the deliberation was communicated to M.W.H. in a letter dated 17 December, which stated, 'The Committee felt that some of the issues that had been raised went wider than just the hazards associated with any possible discharge of Group 1 GMMS and there were implications for the disposal of both inactivated and non-inactivated waste. 'While the issues you raised are not new, we agree that they are important. We believe that most aspects are already covered sufficiently in the current guidance, however, some of the issues discussed perhaps warrant further attention as part of our continuing programme of update in the light of scientific evidence. HSE has decided therefore to commission an independent, thorough and critical review of the literature, in particular focusing on any new data available on the hazards which may be associated with gene transfer from GMMs in the environment and the hazards associated with free DNA released by such micro-organisms\u2026' However, we doubt that further literature review is sufficient. We need targetted experimental research on horizontal gene transfer, and DNA sequence comparisons between, say, pathogenicity islands and phage and phasmid vectors, for example.4. 'First commercial release of microorganism under TSCA' E-mail message from Suzanne Wuerthele, 22 September, 1997.", "cite_spans": [], "ref_spans": []}, {"section": "NOTES", "text": "", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF1": {"title": "Infectious disease as an evolutionary paradigm", "authors": [{"first": "J", "middle": [], "last": "Lederberg", "suffix": ""}], "year": 1997, "venue": "Emerging Infectious Diseases", "link": "17999865"}, "BIBREF3": {"title": "Vero cytotoxin-producing Escherichia coli 0157: cause for concern", "authors": [{"first": "H", "middle": ["R"], "last": "Smith", "suffix": ""}], "year": 1997, "venue": "SGM Quarterly", "link": null}, "BIBREF4": {"title": "Poor man's plague. 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(c) The evolution of virulence and its spread by horizontal gene transfer. (d) Genetic engineering and horizontal gene transfer. (e) Other recent findings relevant to the possible contribu- tion of genetic engineering biotechnology to the etiol- ogy of infectious diseases.", "type": "figure"}, "FIGREF1": {"text": "Fig. 1. The universal phylogenetic tree of the living world.", "type": "figure"}, "FIGREF2": {"text": "The accelerated emergence of infectious diseases and of drug and antibiotic resistance coincide with the development of commercial genetic engineering bio- technology. 2. Many horizontal gene transfer events responsible for the spread of virulence and antibiotic resistance are recent, based on the high degree ( \\ 99%) of homolo- gies in sequences of genes found in unrelated species.", "type": "figure"}, "TABREF0": {"text": "New diseases within the past 20 years (incomplete list)Encephalitozoon hellem, parasite, conjunctivities 1991: New species of Babesia, parasite, infection 1992: New strain Vibro cholerae O139, epidemic cholera 1992: Bartonella henselae, bacteria cat-scratch disease, bacil-", "type": "table"}, "TABREF1": {"text": "). However, the abuse of antibiotics per se does not account for the emergence of new viruses and new virulent strains of bacteria. Fifty new viruses have been identified just between 1988 and 1996 (33). The urgent question which needs to be addressed is the extent to which genetic engi- neering biotechnology, by facilitating horizontal gene trans- fer and recombination, is contributing to the resurgence of infectious, drug-resistant diseases, and will continue to do so if allowed to proceed unchecked.", "type": "table"}, "TABREF2": {"text": "summary of mechanisms for antibiotic resistance", "type": "table"}, "TABREF3": {"text": "Examples of acti6e efflux systems in bacteria CCCP, carbonyl cyanide m-chlorophenylhydrazone, SDS, sodium dodecylsulphate", "type": "table"}, "TABREF4": {"text": "), revealing the true phylogenetic status of bacterial species. The tree is tripartite, with Bacteria (Eubacteria), Archaea (Archebac- teria) and Eucarya (Eukaryotes) forming three more or less equal Domains. The traditional Kingdoms -Plants, Animals and Fungi (Coprinus) -are but twigs on a small peripheral branch of the Eucarya Domain, each twig hav- ing the same phylogenetic status as traditional Orders of bacteria. Within the Bacteria Domain, E. coli (a Gram- negative bacterium) is as distant from the Gram-positive bacteria, Bacillus, or Heliobacterium, as Homo sapiens is from the single-celled ciliate, Paramecium.", "type": "table"}, "TABREF5": {"text": "TetL gene, is found in Actinomyces, Clostridium, Enterococcus, Listeria, Peptostreptococcus, Streptococcus, Staphylococcus and Bacillus. Another gene, the TetK, is found in Bacillus, Clostridium, Enterocococcus, Eubacterium, Listeria, Pep- tostreptococcus, Staphylococcus and Streptococcus. (108- 110). More recently, both TetL and TetK have been found for the first time in soil bacterial species belonging to the genera Mycobacterium and Streptomyces, which can cause soft-tissue and skin infections", "type": "table"}, "TABREF6": {"text": "The acquisition of new genes following horizontal gene transfer results in the generation of new variants of pathogens. Drug-resistant strains of Mycobacterium tuberculosis and Streptococcus penumoniae, the new V. cholerae serotype 0139, E. coli 0157, Haemophilus influenzae biotype aegypticus, are ex- amples of such new types of pathogens generated by horizontal gene transfer.", "type": "table"}, "TABREF7": {"text": "Examples of 6ectors constructed for genetic manipulationscoli and yeast Cloning and transfection E. coli plasmids and yeast plasmids YEp E. coli plasmids and yeast centromeres YCp E. coli and yeast Cloning and transformation E. coli and yeast Cloning of large human genome YACs E. coli plasmids and yeast telomeres fragments pPK252 (Group P, with KanR) polylinker,bacterial neo or XGPRT marker or mouse DHFR insert Rous sarcoma virus promoter Phage vectors u phage with E. coli lac ugt11 E. coli Cloning and expression E. coli u gtWES.T5622Phasmid vectors Phages u, M13, T3, T7, E. coli lac, RSF2124 ApBroad host range plasmid vectors E. coli and others Cloning in other bacteria RSF1010 (group Qm, SuR, SmR,) added KmR KT230 RK2 with Km R cloned into Col E1 pRK203 E. coli and others Mobilize plasmids into other hosts Broad host range transposon vectors E. coli and others Cloning in other bacteria Tn7 (transposon with Tp R and SmVI and its strong 35S promoter used rou- CaMV E. coli and others Boost Transgene expression in plants tinely in vectors for plants Animal viral vectors tk gene incorporated into a range of vectors for Herpes simplex E. coli, humans, Selectable marker virus others animal cells hybrid vector with E. coli plasmid promoter and SV40 E. coli, monkey, Transformation and transgene expression in animal cells others enhancer genes in a range of vectors Rous Sarcoma virus promoter incorporated into a range of vectors for E. coli, chicken, Transgene expression in animal cells animal cells others E. coli, bovine, hybrid vector with E. coli plasmid Bovine papilloma Transformation of animal cells virus others promoter incorporated into a range of vectors MMTV E. coli, mouse Expression E. coli, human, Vaccinia virus many recombinant viruses with e.g. hepatitis, Vaccines AIDS, HTLV, rabies antigen gene others many recombinant viruses with toxins against", "type": "table"}, "TABREF8": {"text": "Continued)Cytomegalovirus promoter gene in a range of vectors E. coli, humans Transfection transformation Retroviral vectors hybrid vectors with E. coli plasmid neo markers Transformation and transgene expression E. coli, animals MuLV broadened host range hybrid vector E. coli, mammals, birds Transposons as vectors and related uses Transformation P element with polylinker Drosophila E. coli, Drosophila Mutagenesis with E. coli ori Enhancer trapping E. coli, Drosophila with E. coli lacZ, AmpR", "type": "table"}, "TABREF9": {"text": "Non-pathogens are transformed into pathogens by horizontal gene transfer of unit blocks of virulence genes. 10. Horizontal gene transfers are bi-directional. Released non-pathogens can be readily converted into patho- gens in one step, by acquiring unit-blocks of virulence genes. Deducti6e 1. Genetic engineering is based on facilitating horizontal gene transfer between distant species by constructing vectors that break down species barriers. 2. The artificial vectors constructed for genetic engineer- ing are chimaeric combinations of viral pathogens and other invasive genetic elements that can generate new cross-species viral pathogens. 3. The artificial vectors constructed for genetic engineer- ing are inherently unstable and prone to recombina- tion, thereby enhancing horizontal gene transfer and recombination. 4. Shuttle vectors made by genetic engineering are essen- tially unstoppable, as they contain signals for transfer and replication in different species; and helper func- tions for mobilization and transfer can be supplied by viruses, plasmids and transposons which occur natu- rally in bacteria in all environments.", "type": "table"}, "TABREF10": {"text": "The UK Health and Safety Executive, on the recom- mendation of the Advisory Committee on Genetic Modification (ACGM), produced a consultation docu- ment, Draft Guidance on Certificate of Exemption No. 1, which would allow commercial and other contained users to release certain classes of live GEMs directly into the environment as liquid wastes on notification, without the need to monitor for the survival and subse- quent evolution of the GEMs. 2. M.W.H. wrote to Lise Kingo, Novo Nordisk's Director of Environment on 30 June, 1997, expressing her reser- vations on existing practice and regulations on con- tained use, requesting more information on their monitoring of released GEMs and whether it included monitoring for horizontal gene transfer. Kingo replied by e-mail two weeks later, stating that their scientists were on holiday. M.W.H. raised the matter again, during the UN Biosafety meeting in Montreal in Octo- ber 1997, with Mr. J.L. Mahler, Novo Nordisk's Vice President of External Affairs, who also attended the meeting. Mr. Mahler agreed to remind their scientists to send a reply. This came from Lise Kingo more than two months later, stating that horizontal gene transfer is nothing new. 'It is a well known and naturally occur- ring phenomenon which was taken into account by legislators both when the present contained use direc- tive was written and when its current revision was proposed.' Therefore, they saw no need to review exist- ing practice and regulations. Again, they failed to an- swer M.H.W.'s questions on monitoring for GEM survival and for horizontal gene transfer. 3. The consultation document, Draft Guidance on Certifi- cate of Exemption No. 1, was not widely circulated even within the genetic engineering community. After several exchanges of correspondence between M.W.H. and members of parliament, the Health and Safety", "type": "table"}}}
{"paper_id": "41516060", "_pdf_hash": "c8bd96b1ab443eac4670c94861b427241db6257b", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Electrolysis of D 2 O with a palladium cathode compared with electrolysis of H 2 O with a platinum electrode: procedure and experimental details", "authors": [{"first": "A", "middle": [], "last": "Ambadkar", "suffix": ""}, {"first": "J", "middle": [], "last": "Dash", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF1": {"title": "Proc. ICCF11", "authors": [{"first": "J", "middle": [], "last": "Dash", "suffix": ""}, {"first": "A", "middle": [], "last": "Ambadkar", "suffix": ""}], "year": 2004, "venue": "", "link": null}, "BIBREF2": {"title": "Proc. ICCF10", "authors": [{"first": "E", "middle": [], "last": "Storms", "suffix": ""}], "year": 2003, "venue": "", "link": null}, "BIBREF3": {"title": "Proc. ICCF7", "authors": [{"first": "B", "middle": [], "last": "Bush", "suffix": ""}, {"first": "J", "middle": ["J"], "last": "Lagowski", "suffix": ""}], "year": 1998, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "10700030", "_pdf_hash": "00a0bafa73fc0368881651525422f6f9935b580d", "abstract": [{"section": "Abstract", "text": "Objective. To estimate the prevalence of inadequate pain relief (IPR) among patients with symptomatic knee OA prescribed analgesic therapy and to characterize patients with IPR.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Methods. Patients 550 years old with physician-diagnosed knee OA who had taken topical or oral pain medication for at least 14 days were recruited for this prospective non-interventional study in six European countries. Pain and function were assessed using the Brief Pain Inventory (BPI) and the WOMAC; quality of life (QoL) was assessed using the 12-item short form. IPR was defined as an average pain score of >4 out of 10 on BPI question 5.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Results. Of 1187 patients enrolled, 68% were female and the mean age was 68 years (S.D. 9); 639 (54%) met the definition of IPR. Patient responses for the BPI average pain question were well correlated with responses on the WOMAC pain subscale (Spearman r = 0.64, P < 0.001). In multivariate logistic regression, patients with IPR had greater odds of being female [adjusted odds ratio (adjOR) 1.90 (95% CI 1.46, 2.48)] and having OA in both knees [adjOR 1.48 (95% CI 1.15, 1.90)], higher BMI, longer OA duration, depression or diabetes. Patients with IPR (vs non-IPR) were more likely to have worse QoL, greater function loss and greater pain interference.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Conclusion. IPR is common among patients with knee OA requiring analgesics and is associated with large functional loss and impaired QoL. Patients at particular risk of IPR, as characterized in this study, may require greater attention towards their analgesic treatment options.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Trial registration: https://clinicaltrials.gov/ (NCT01294696).", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Since 1990 the prevalence of musculoskeletal disorders has increased 45% and these disorders represent the second largest cause of disability worldwide, accounting for 21% of global years lived in disability [1] . Of the musculoskeletal disorders, OA represents the most common form of joint disease [2, 3] . Risk factors including older age, female gender, obesity and a history of manual labour result in susceptibility of the joints to damage, repair failure and OA [35] .", "cite_spans": [{"start": 208, "end": 211, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 300, "end": 303, "text": "[2,", "ref_id": "BIBREF1"}, {"start": 304, "end": 306, "text": "3]", "ref_id": "BIBREF2"}, {"start": 469, "end": 473, "text": "[35]", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "Introduction", "text": "OA of the knees accounts for 83% of the total OA burden and ranks among the top 10 non-communicable diseases for global disability-adjusted life years (DALYs; i.e. years of life lost and years lived with disability) [1, 3] . Clinical outcomes for people with knee OA typically involve pain, limitations of daily living activities, physical disability and overall reduction of quality of life (QoL).", "cite_spans": [{"start": 216, "end": 219, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 220, "end": 222, "text": "3]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Introduction", "text": "As there is no cure for OA, the goals of OA therapies are to reduce the levels of pain and inflammation, slow cartilage degradation, improve function and reduce disability. Evidence-based guidelines recommend a broad range of pharmacological and non-pharmacological therapies for OA pain management [613] . Commonly used therapies and treatment modalities include paracetamol, NSAIDs, opioids, topical analgesics and IA injection of corticosteroid [512] . It is not possible to predict which therapy will work for any individual patient, and response is not uniform across populations [9, 14] .", "cite_spans": [{"start": 585, "end": 588, "text": "[9,", "ref_id": "BIBREF8"}, {"start": 589, "end": 592, "text": "14]", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Introduction", "text": "In both OA clinical trials and clinical practice, outcome assessments have traditionally been limited to evaluation of pain intensity [15] . The focus of clinical trials for OA analgesic therapies has been on treatment response, while the consequences of inadequate response are less well investigated [16] . Moreover, the outcomes of clinical trials do not directly translate to the real world, where patients may experience greater pain, have multiple comorbidities and use their pain medications intermittently.", "cite_spans": [{"start": 302, "end": 306, "text": "[16]", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "Introduction", "text": "Thus an important issue facing people with OA and their health care providers is inadequate pain relief (IPR). As a concept, IPR has not been widely explored in OA, and there is limited understanding of the relationship between IPR and patient factors, treatment patterns and QoL. A better understanding of IPR-and of the characteristics of patients likely to experience IPR-may help clinicians to identify patients who require close monitoring and careful selection of therapy for OA.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The objectives of this multinational prospective observational study, the Study of Osteoarthritis Real World Therapies (SORT), were (i) to estimate the prevalence of IPR among patients with symptomatic knee OA prescribed analgesic therapy, (ii) to assess the characteristics of patients with IPR and (iii) to examine the relationship between IPR and health outcomes, comparing patients with IPR versus non-IPR in terms of history and clinical care at baseline.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Study design and patients", "text": "This prospective longitudinal cohort study was conducted at 53 centres in six European countries (the UK, France, Germany, Portugal, The Netherlands and Italy). Centres included both general and specialist practices, varying by country (see supplementary Table S1 , available at Rheumatology Online). Patients were recruited from November 2011 to January 2012. This analysis presents baseline pain data, demographic data and medication use, as well as the associations with other health outcomes at baseline. Clinical and demographic data for patients who declined to participate were not collected.", "cite_spans": [], "ref_spans": [{"start": 241, "end": 263, "text": "supplementary Table S1", "ref_id": "TABREF0"}]}, {"section": "Study design and patients", "text": "Patients eligible for study enrolment were 550 years old with a physician's diagnosis of OA of one or both knees [17] and were prescribed, at the direction of a physician, topical or oral pain medications for at least 14 days before entering the study. Patients were excluded if they had any arthritis other than primary OA, partial or total joint replacement in the affected knee(s) or treatment with DMARDs.", "cite_spans": [{"start": 113, "end": 117, "text": "[17]", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Study design and patients", "text": "As this was a real-world observational study, no medications or interventions were provided under the study protocol. Participation in the study did not influence the choice of treatment; patients' treatments were determined by their attending physicians. Patients could elect to withdraw at any time without impact on their medical care. The study protocol was approved by the local ethics committee at each site and each patient gave written informed consent according to the Declaration of Helsinki. The study was registered with ClinicalTrials.gov (NCT01294696).", "cite_spans": [], "ref_spans": []}, {"section": "Data collection", "text": "At study entry, demographic information, medical history and medication use were collected. Patients completed questionnaires regarding their knee OA, including assessments of pain level, joint stiffness, physical functioning, satisfaction with and response to treatment and QoL. All questionnaires were provided to patients in their local language.", "cite_spans": [], "ref_spans": []}, {"section": "Data collection", "text": "Patients were instructed to assess pain caused by OA in the affected knee(s) using the Brief Pain Inventory (BPI). The BPI is a comprehensive instrument validated in several languages for assessing pain severity and pain interference with function [1821] . Pain relief was derived using question 5 of the BPI, which assesses average pain: Please rate your pain by circling the one number that best describes your pain on the average. The numerical rating scale ranges from 0 (no pain) to 10 (pain as bad as you can imagine). This single question is similar to how physicians would evaluate their patients' pain in most clinical encounters and is of clear clinical relevance.", "cite_spans": [], "ref_spans": []}, {"section": "Data collection", "text": "Other patient self-assessments were collected, including pain, stiffness and physical function in the knee as measured by the WOMAC questionnaire (0100 mm visual analogue scale) [22] and QoL as assessed by the Medical Outcomes Trust 12-item Short Form Health Survey (SF-12) [23] .", "cite_spans": [{"start": 178, "end": 182, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 274, "end": 278, "text": "[23]", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "Data collection", "text": "Patients also reported their satisfaction with symptomatic treatment for knee OA, as measured by two questions regarding pain relief and tolerability of medication over the previous 7 days. These questions were assessed on a fiveitem categorical scale ranging from very dissatisfied to very satisfied. Patients and investigators reported the response to therapy on a five-item scale from no response to excellent response using the Patient Global Assessment of Response to Therapy Questionnaire (PGART) and the Investigator Global Assessment of Response to Therapy Questionnaire (IGART) [24] , respectively.", "cite_spans": [{"start": 587, "end": 591, "text": "[24]", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Data collection", "text": "www.rheumatology.oxfordjournals.org", "cite_spans": [], "ref_spans": []}, {"section": "Study endpoint", "text": "The primary endpoint was the patient's assessment of pain relief at study entry. In clinical trials, assessments of pain caused by OA are based on cut-off points for patient-reported pain, function and global assessments [25] . Different pain cut-off points have been used previously to categorize pain severity [26] and manageable pain [27] . In a recent review of pain measures and associated cut-off points, it was reported that patients reported that 43 on a 10 point scale is thought to be no worse than mild pain [28] Question 5 of the BPI, which assesses average pain, defines mild pain as a pain score of 04, moderate pain as 56 and severe pain as 710 [29] . In this study, IPR was defined as a score >4 (moderate or severe pain) on BPI question 5; scores of 04 were classified as non-IPR.", "cite_spans": [{"start": 221, "end": 225, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 312, "end": 316, "text": "[26]", "ref_id": "BIBREF25"}, {"start": 337, "end": 341, "text": "[27]", "ref_id": "BIBREF26"}, {"start": 519, "end": 523, "text": "[28]", "ref_id": "BIBREF27"}], "ref_spans": []}, {"section": "Statistical analyses", "text": "The primary analysis was a cross-sectional comparison of IPR vs non-IPR patient cohorts at baseline. Study endpoints, patient characteristics and treatments for knee OA were summarized using descriptive statistics. Categorical variables were compared using the 2 test or Fisher's exact test, while continuous variables were compared using the MannWhitney Wilcoxon test. We examined the robustness of the cut-off point of 4 on the BPI in identifying the prevalence of IPR by comparing adjacent cut-off points found in the literature (pain 43 as no worse than mild pain and pain >5 [29] ) and observed the distribution of patients classified as IPR. In addition, we reviewed the distribution of the BPI average score and its association with the WOMAC pain subscale using Spearman's rank-order correlation coefficient. We also compared the different IPR cut-off points using the WOMAC pain subscale, WOMAC physical function subscale and SF-12 Physical Component Summary scores. To accomplish this, following Tan et al. [30] , we employed an analysis of variance (ANOVA) using IPR categories derived from the BPI average score as the independent variable and the other measures as dependent variables.", "cite_spans": [{"start": 1017, "end": 1021, "text": "[30]", "ref_id": "BIBREF29"}], "ref_spans": []}, {"section": "Statistical analyses", "text": "To identify the characteristics of patients who were more likely to have IPR, a multivariate logistic regression model was employed, adjusting for country effects. The following variables were assessed: age, female sex, BMI, years since OA diagnosis, clinical diagnosis of both knees, co-morbidities (cardiovascular disease, renal impairment/ failure, diabetes, depression, hyperlipidaemia, hypertension) and a number of different classes of medication.", "cite_spans": [], "ref_spans": []}, {"section": "Statistical analyses", "text": "All analyses were conducted using SAS version 9.3 (SAS Institute, Cary, NC, USA). Statistical significance was set at P < 0.05.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "A total of 1187 consenting patients were enrolled in the study at 53 centres in six countries. Table 1 summarizes  patient characteristics at baseline and Supplementary  Table S2 , available at Rheumatology Online, presents patient enrolment numbers by country. The mean patient age was 68 years, 68% of patients were women and only 19% of patients were in paid employment at the time of study enrolment. The most common physician-reported co-morbidity was hypertension, affecting 58% of patients. Just over half of the patients (52%) had OA affecting both knees, while nearly one-quarter each had an affected left or right knee (Table 1) .", "cite_spans": [], "ref_spans": [{"start": 95, "end": 178, "text": "Table 1 summarizes  patient characteristics at baseline and Supplementary  Table S2", "ref_id": "TABREF0"}, {"start": 629, "end": 638, "text": "(Table 1)", "ref_id": "TABREF0"}]}, {"section": "Prevalence of IPR", "text": "At the baseline assessment, 639/1187 patients [54% (95% CI 51%, 57%)] reported IPR as measured on the BPI average pain score. The prevalence of IPR was quite robust to the definition using different cut-off points. With a cut-off point of 43 defining patients with no worse than mild pain, the inverse number of patients was 846/1187 [71% (95% CI 69%, 74%)] meeting the definition for IPR (i.e. a BPI score > 3). A cut-off point > 5 classified 414 [35% (95% CI 32%, 38%)] patients as having IPR.", "cite_spans": [], "ref_spans": []}, {"section": "Prevalence of IPR", "text": "Patient responses for the BPI average pain question were well correlated with responses on the WOMAC pain subscale (Spearman's r = 0.64, P < 0.001, n = 1109), further demonstrating that the concept of IPR is not an artefact of how IPR is defined and assessed. Fig. 1 depicts the distribution of patients in the IPR and non-IPR cohorts according to WOMAC pain subscale scores, which were converted to a 010 point scale to facilitate comparison.", "cite_spans": [], "ref_spans": [{"start": 260, "end": 266, "text": "Fig. 1", "ref_id": "FIGREF0"}]}, {"section": "Prevalence of IPR", "text": "The cut-off point of 4 was optimal in our sample, with the highest F values in the ANOVAs when BPI pain severity, BPI pain interference and SF-12 Physical Component Summary scores were the dependent variables and near optimal when the WOMAC pain subscale and WOMAC physical function subscale were the dependent variables (see Supplementary Table S3 , available at Rheumatology Online).", "cite_spans": [], "ref_spans": [{"start": 326, "end": 348, "text": "Supplementary Table S3", "ref_id": "TABREF2"}]}, {"section": "Characteristics of patients with IPR", "text": "While patients in both the IPR and non-IPR cohorts were of similar mean age (68 years) and included similar percentages of current smokers (8%), the two groups were significantly different for multiple characteristics, as outlined in Table 1 . Patients reporting IPR were more likely to be female and less likely to be employed; they had a higher mean BMI and a longer mean duration of OA; and they had a greater likelihood of co-morbid hypertension, current or prior depression, diabetes and current or prior renal impairment or failure (P 4 0.027 for all comparisons). In addition, a significantly greater percentage of patients with IPR had OA affecting both knees (P < 0.001) and physician-reported partial or total disability (P = 0.009; Table 1 ). While NSAIDs were the most commonly prescribed medication in both cohorts (65% overall), patients in the IPR cohort were significantly more likely (P < 0.001) to be prescribed paracetamol (44% vs 34% in non-IPR cohort) or opioid-containing medication (26% vs 16%).", "cite_spans": [], "ref_spans": [{"start": 234, "end": 241, "text": "Table 1", "ref_id": "TABREF0"}, {"start": 743, "end": 750, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Characteristics of patients with IPR", "text": "After adjusting for country fixed effects, there were several significant predictors of IPR (Table 2) . Specifically, patients who reported IPR had greater odds of being female and having higher BMI, more years with OA diagnosis, a clinical diagnosis of OA in both knees, current or prior depression and a diagnosis of diabetes.", "cite_spans": [], "ref_spans": [{"start": 92, "end": 101, "text": "(Table 2)", "ref_id": "TABREF1"}]}, {"section": "IPR and health outcomes", "text": "As shown in Table 3 , patients in the IPR cohort had significantly greater overall pain severity and much worse pain interference on the BPI compared with patients in the non-IPR cohort (P < 0.001 for all comparisons). Similarly, the WOMAC subscale scores (pain, physical function and stiffness) were significantly worse (P < 0.001) for patients in the IPR cohort.", "cite_spans": [], "ref_spans": [{"start": 12, "end": 19, "text": "Table 3", "ref_id": "TABREF2"}]}, {"section": "IPR and health outcomes", "text": "The Patient and Investigator Global Assessments of Response to Therapy showed significantly worse responses (P 4 0.004) to immediate prior therapy for patients in the IPR cohort versus the non-IPR cohort (Table 3 ). In addition, responses for all QoL domains on the SF-12 were significantly worse for those with IPR (Table 4 ). Overall, 51% of patients in the IPR cohort reported their general health status to be fair or poor as compared with 31% of the non-IPR cohort (P < 0.001). At baseline, 48% of patients with IPR reported dissatisfaction with response to treatment and 38% reported dissatisfaction with tolerability of medication.", "cite_spans": [], "ref_spans": [{"start": 204, "end": 212, "text": "(Table 3", "ref_id": "TABREF2"}, {"start": 316, "end": 324, "text": "(Table 4", "ref_id": "TABREF3"}]}, {"section": "Discussion", "text": "The results of this observational study indicate that IPR is a highly prevalent problem among patients with OA. After 52 weeks of physician-prescribed treatment, more than half of patients with knee OA reported IPR, as defined by moderate to severe pain (score >4) using the BPI average pain question. The prevalence of IPR could be as high as 70% if a pain score 43 (no worse than mild pain [29] ) was used as the appropriate treatment target. As www.rheumatology.oxfordjournals.org demonstrated in this study, patient responses on the BPI were well correlated with responses on the WOMAC pain subscale. Moreover, patients in the IPR cohort reported significantly worse scores on pain severity, pain interference, WOMAC function subscale and QoL (SF-12 Physical Component Summary) than patients in the non-IPR cohort.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Patients with IPR were a largely identifiable population who were more likely to be female and have longer disease duration, bilateral knee OA, greater opioid use and a higher prevalence of certain co-morbidities (hypertension, depression and diabetes). Clinicians should recognize this constellation of characteristics as constituting special risk, since patients with IPR were significantly more likely to be unemployed and to be considered partially or totally disabled by their physician (15% vs 10% of those in the non-IPR cohort).", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "The fact that 54% of patients in this real-world setting had persistent moderate to severe pain suggests that currently prescribed pain treatments for knee OA are not meeting the needs of the majority of patients. The most commonly prescribed analgesic medications reported by patients were NSAIDs, followed by paracetamol and opioid-containing medications. These findings are consistent with those of prior observational studies indicating that management of OA in primary care may not conform to the recommendations in clinical practice guidelines or to the intensity of patients' pain [3136] .", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "For patients with knee OA, the importance of pain relief and functional improvement was evident in the results of a recently reported discrete choice experiment that assessed patient preferences with regard to NSAID-related benefits [36] . The patients with self-reported OA in that study ranked reduction in ambulatory pain and reduced difficulties associated with daily activities as the most important benefits.", "cite_spans": [{"start": 233, "end": 237, "text": "[36]", "ref_id": "BIBREF35"}], "ref_spans": []}, {"section": "Discussion", "text": "The clinical characteristics of our patient population reflect those reported for the general population with OA with regard to age, sex and co-morbidities [4] , suggesting that study patients are representative of patients with knee OA and that our findings are generalizable. Patient and investigator assessments of response to therapy were generally in agreement. Study results across the multiple and varied assessments of pain and functional outcomes were consistent, reinforcing the robustness of the findings as well as illustrating the marked differences between patients with IPR and non-IPR. It is noteworthy that patient assessments of pain relief were associated with other patient-reported assessments of function and Overall significance of the model: likelihood ratio 2 = 143.69, df = 17, P < 0.001. OR: odds ratio.", "cite_spans": [{"start": 156, "end": 159, "text": "[4]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Discussion", "text": "QoL. This finding suggests that assessing pain relief in the clinic is an efficient way of assessing the patient's overall health status.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "A possible limitation of the study is that of selection bias, as not all invited patients consented to participate in the study, and we are not certain that non-participants were similar to patients. Evidence of selective nonparticipation (by patients 580 years, of lower socioeconomic group and currently employed) was seen in an earlier prospective study of knee pain and knee OA in the general population, although the authors found no effect on the distribution of WOMAC scores [37] . Our analysis is cross-sectional, therefore the causal link between IPR and functional status cannot be fully characterized. The 12-month follow-up period of this study will enable us to document the clinical course of pain and pain management in patients with OA. From the longitudinal analysis we can demonstrate an association between pain intensity and variability to a range of other health benefits (e.g. QoL, functional status and productivity). Scoring on the BPI ranges from 0 (best) to 10 (worst); scoring on the WOMAC ranges from 0 (best) to 100 (worst). 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"suffix": ""}, {"first": "J", "middle": [], "last": "Handy", "suffix": ""}], "year": 2006, "venue": "BMC Musculoskelet Disord", "link": null}}, "ref_entries": {"FIGREF0": {"text": "FIG. 1 Score distribution for the WOMAC pain subscale score (converted to a 010 scale) by score on BPI question 5 as IPR (score >4) and non-IPR (score 44)", "type": "figure"}, "FIGREF1": {"text": "score is the mean of responses to questions 36; the BPI interference score is the mean of responses to questions 9AG. IPR: inadequate pain relief; BPI: Brief Pain Inventory; PGART: Patient Global Assessment of Response to Therapy; IGART: Investigator Global Assessment of Response to Therapy; IQR: interquartile range.", "type": "figure"}, "TABREF0": {"text": "Baseline demographic characteristics of all patients and by knee pain relief at baselineGI conditions included IBD, active peptic ulceration or GI bleeding, perforation related to previous NSAID use, recurrent peptic ulcer or GI haemorrhage. f Alternative therapies included glucosa- mine, chondroitin and hyaluronate. GI: gastrointestinal; IQR: interquartile range; IPR: inadequate pain relief.", "type": "table"}, "TABREF1": {"text": "Multivariable analyses examining the odds of IPR, adjusted for country fixed effects (n = 1187)", "type": "table"}, "TABREF2": {"text": "IPR and health outcomes by pain relief status", "type": "table"}, "TABREF3": {"text": "Questionnaire results for QoL on the SF-12QoL: quality of life; SF-12: 12-item Short Form Health Survey. Data are presented as mean (S.D.) unless otherwise specified. Scoring on the SF-12 subscales ranged from 0 (worst) to 100 (best). IPR: inadequate pain relief. www.rheumatology.oxfordjournals.org Conclusion IPR is common among patients with knee OA requiring analgesics, affecting 54% of patients in this study, and is associated with large functional loss and impaired QoL. There appears to be a patient profile at particular risk of IPR. Practitioners should actively evaluate pain man- agement and the effectiveness of treatment response. In discussions with patients, practitioners should ensure that patients are communicating their concerns about pain medication and have a thorough understanding of their analgesic treatment options.key messages . Inadequate pain relief is common among patients with knee OA requiring analgesics. . Patients with inadequate pain relief have functional loss and reduced quality of life. . Inadequate pain relief predictors include female sex, higher BMI, longer OA duration, bilateral knee OA, depression and diabetes.", "type": "table"}}}
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{"paper_id": "10700409", "_pdf_hash": "6797ae19594e44e7da9081627185ffd3c4b51994", "abstract": [{"section": "Abstract", "text": "We recorded event-related potentials (ERPs) in 2-month-old infants in two di\u00a1erent states of alertness: awake and asleep. Syllables varying in vowel duration (long vs short) were presented in an oddball paradigm, known to elicit a mismatch brain response. ERPs of both groups showed a mismatch response re\u00a3ected in a positivity followed by a frontal negativity. While the positivity was present as a function of the stimulus type (present for long deviants only), the negativity varied as a function of the state of alertness (present for awake infants only). These data indicate a functional separation between precognitive and cognitive aspects of duration mismatch essential for the distinction between long and short vowels during early infancy. NeuroReport 13:1251^1254", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION", "text": "Language comprehension crucially depends on the hearer's ability to discriminate between different phonemes. There are numerous studies indicating that the adult brain produces a response as early as 100-200 ms after stimulus onset in a so-called oddball paradigm (for a recent review see [1] ). This response is a negative component which is elicited by any discriminable change (deviant) in some repetitive (standard) aspect of auditory stimulation, named mismatch negativity (MMN) [2] . The MMN has been interpreted to reflect the detection of a deviance in the auditory input from information established in sensory memory. This auditory process itself is assumed to be preperceptual but to trigger frontal cortex activity (reflected by the frontal MMN subcomponent) in adults [3, 4] . The MMN appears to depend on the state of alertness as it has been shown to disappear during sleep stage 2-4 of the adult [5] [6] [7] [8] [9] . Instead of a negativity some researchers observed a positivity around 250 ms during sleep [10, 11] . The neural process underlying this positivity has been interpreted by some researchers to reflect selective refractoriness [12, 13] .", "cite_spans": [{"start": 912, "end": 915, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 920, "end": 923, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 1158, "end": 1162, "text": "[12,", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "The oddball paradigm has been used to investigate the sensitivity to phonemic contrasts in normal infants [14] [15] [16] as well as infants at risk for dyslexia [17, 18] . Some of these studies reported a negativity as a mismatch response [15, 19] whereas others reported a positivity [16] [17] [18] . It is not clear, however, what determines the polarity of the observed mismatch response. Given the data from adult hearers the question arises whether the state of alertness in infants may have an influence on the mismatch response. While some of the infant studies clearly state that their participants were either asleep [17] or awake [20] during ERP recording, others seem to have mixed recordings from awake and asleep infants [21] or did not report the infants' cognitive state [16] .", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "The present study systematically separated a group of asleep infants from awake infants in an ERP study applying a mismatch negativity paradigm. This paradigm which has been shown to tap the automatic ability to detect changes in a stimulus stream was used to investigate the infants ability to detect vowel duration changes in a consonant vowel syllable /ba/ vs /ba:/. Vowel duration is a critical phonemic difference in German, the target language of our participants. In German the duration of a vowel is a discriminative feature indicating differences in meaning: for example the word /la:m/, lahm (lame) vs the word /lam/, Lamm (lamb). In contrast to earlier studies on vowel duration which only used the short syllable as a deviant [17, 18] the present study used both the short and the long syllable as a deviant in two different experimental conditions.", "cite_spans": [], "ref_spans": []}, {"section": "SUBJECTS AND METHODS", "text": "Participants: The present study is part of the German Language Development Study (GLaD, www.glad-study.de) established at the Children's Hospital Lindenhof, Charit\u00e9, Medical Faculty of the Humboldt University Berlin. Families expecting a baby were contacted and requested to participate in the study according to institutional informed consent procedures. The infants were healthy and without neurological or developmental problems (according to Prechtl and Griffiths scales). The recordings were taken when the infants were 8 weeks (7 5 days) old. Prior to the experiment the infants hearing was tested by an otoacoustic emission screening (OAE). All children had a normal hearing. A total of 39 infants entered the study as they were identified to either be awake in an experimental run or asleep. Twenty-nine infants (10 female) were asleep whereas only 10 infants (four female) remained awake during a whole experimental run.", "cite_spans": [], "ref_spans": []}, {"section": "SUBJECTS AND METHODS", "text": "Procedure, stimuli and ERP recording: In a passive oddball paradigm (standard: p \u00bc 5/6, deviant: p \u00bc 1/6) two experimental runs were created: (1) a frequently occurring short CV-syllable (/ba/, duration 202 ms) was occasionally replaced by a deviant, i.e. a long CV-syllable (/ba:/, duration 341 ms) and (2) a frequently occurring long CVsyllable /ba:/ replaced by an occasionally occurring short CV-syllable /ba/.", "cite_spans": [], "ref_spans": []}, {"section": "SUBJECTS AND METHODS", "text": "The short syllable /ba/ was infant directed spoken by a young mother who is a native speaker of standard German. After recording and digitalization (44.1 kHz, 16 bit sampling rate) the steady state part of the vowel was lengthened (starting 30 ms after syllable onset) to obtain the second syllable /ba:/ (Fig. 1 ). During each experimental run 600 trials were presented with a fixed ISI (offset to onset) of 855 ms. The order of the two runs was counterbalanced across the infants. Stimuli were presented via a loudspeaker with an intensity of 64 dB SPL. The infants were lying in a child's safety seat while ERP were recorded. Their alertness state was determined every 2 min by both the infants monitored behavior and the on-line EEG.", "cite_spans": [], "ref_spans": [{"start": 305, "end": 312, "text": "(Fig. 1", "ref_id": "FIGREF1"}]}, {"section": "SUBJECTS AND METHODS", "text": "The ERPs were registered with Ag-AgCL electrodes attached to frontal (F3, Fz, F4), central (C3, Cz, C4) and parietal (P3, Pz, P4) scalp sites according to the International 10-20 electrode system. An electrode cap was used. Electrooculograms (EOG) were bipolar recorded from supraorbital and infraorbital electrodes on the right eye as well as from electrodes located lateral to the left and to the right eye. The ERP electrodes were referred to A1. The EEG was amplified with PORTI-32/MREFA (Twente Medical Systems), digitalized on-line at a rate of 250 Hz, and stored on hard disk. Further analyses were processed off-line. The EEG was high-pass filtered with 0.3 Hz and algebraically rereferred to the average of both mastoids. Trials with a s.d. 4 80 mV within a sliding window of 200 ms were rejected automatically. Epochs of 1000 ms from stimuli onset were averaged according to a 200 ms pre-stimulus baseline. At least 60 artifact free trials were required for an individual average to be included in further analyses. The statistical analyses were carried out for consecutive time windows of 200 ms.", "cite_spans": [], "ref_spans": []}, {"section": "SUBJECTS AND METHODS", "text": "A four-way ANOVA with the factors stimulus (long vs short), condition (deviant vs standard), site (F3/Fz/F4/C3/ Cz/C4/P3/Pz/P4) and group (awake vs asleep) as a random factor was conducted to reveal possible interactions of the experimental manipulated conditions with the alertness state. To separately determine the differences between standard and deviant one-way analyses with the factor condition were calculated for long and short stimuli within each group. Both the awake and the asleep group showed a mismatch response for the long deviant condition. For awake infants we observed a frontal positivity significant between 400 and 600 ms (Fz: F(1,18) \u00bc 4.679, p \u00bc 0.044) followed by a right frontally distributed negativity significant between 800 and 1000 ms (F4: F(1,18) \u00bc 5.241, p \u00bc 0.034; Fig. 2a ). Infants that were asleep (Fig. 2b) This difference between the groups might be caused by an overlapping non-significant negative deflection within the time window between 200 and 400 ms which can be observed for awake infants. In the asleep group, moreover, a late centro-parietal negativity was found to be significant at electrode C4 for the long deviant condition (800-1000 ms, F(1,56) \u00bc 4.996, p \u00bc 0.029). For a direct comparison of the two groups see Fig. 3 .", "cite_spans": [], "ref_spans": [{"start": 800, "end": 807, "text": "Fig. 2a", "ref_id": "FIGREF2"}, {"start": 836, "end": 845, "text": "(Fig. 2b)", "ref_id": "FIGREF2"}, {"start": 1267, "end": 1273, "text": "Fig. 3", "ref_id": "FIGREF3"}]}, {"section": "SUBJECTS AND METHODS", "text": "For the short deviant neither group showed an effect in the positivity time range. Again, there was a group difference with respect to the negativity: awake infants (Fig. 2c) showed a right frontal negativity (F4: F(1,18) \u00bc 8.038, p \u00bc 0.011) similar to that of the long stimulus, whereas asleep infants did not. For a direct comparison of the two groups see Fig. 3 .", "cite_spans": [], "ref_spans": [{"start": 165, "end": 174, "text": "(Fig. 2c)", "ref_id": "FIGREF2"}, {"start": 358, "end": 364, "text": "Fig. 3", "ref_id": "FIGREF3"}]}, {"section": "DISCUSSION", "text": "Clear differences were observed for phoneme change detection as a function of the infant's state of alertness and as a function of stimulus type (duration). Two different ERP components were observed as a mismatch response: a positivity with a frontal maximum peaking at 500 ms and a frontally distributed negativity with a maximum between 800 and 900 ms. While the positivity varied as a function of stimulus type, the frontal negativity varied as a function of alertness.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "The positivity was only present for long deviants clearly demonstrating that it is easier to detect a long syllable as a deviant in a sequence of short syllables than a short syllable as a deviant in a sequence of long syllables. This can be explained by a greater perceptual saliency of a larger element in the context of smaller elements than of a smaller element in the context of larger elements. The finding that the positivity was present for both groups indicates that this effect reflects a precognitive aspect of change detection. The further result that the positive deflection for both deviant and standard condition was larger for infants that were asleep than for infants that were awake, furthermore, can be taken as additional evidence for the notion that the positivity reflects precognitive aspects of auditory processing.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "The frontal negativity was present only for the awake group. This suggests that this negativity reflects an aspect of the mismatch response which is related to alertness and may therefore be viewed to reflect a cognitive aspect. A second late negativity with a centro-parietal maximum was observed to the long deviant for asleep infants. As this negativity's presence depends on both the stimulus type as well as on the infants' state of alertness it functionally resembles the late negativity reported for adults during sleep [22] . For adults a late negativity (N360) was observed as part of a biphasic pattern following a positivity (P240) in an auditory oddball paradigm, which also was modulated by the state of alertness and by the stimulus type with a larger amplitude for high than for low deviants.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "The present results for the asleep infants are in general agreement with earlier findings [17] . In a study which only used a short syllable as a deviant and in which infants were asleep during ERP recordings, a positivity between 200 and 450 ms was found for 6-month-old Finnish infants [17] . This study also tested newborn infants for two ISI conditions. A similar positivity was not observed for both ISI conditions, but in an earlier window (155-200 ms) a positivity was found at P3 in the long ISI condition [18] . Thus, it appears that a mismatch response to duration decrements in vowels cannot easily be found at birth but it occurs in form of a positivity with a maximum between 200 and 450 ms at the age of 6 months [17] . At the age of 2 months a mismatch response to duration decrement could still not be observed in asleep infants (present study). However, at this age a positive mismatch response with a maximum between 400 and 600 ms occurred to the more salient duration increment (present study). The ability to discriminate different consonants in 4-month-old French infants was also reflected in a positive deflection present between 320 and 480 ms [16] . Unfortunately, this latter paper does not report the state of alertness of their participants.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "Thus, the occurrence of the positive mismatch response not only depends on the age of the infants but also on the saliency of the deviant stimulus. Furthermore, the combined data from the different studies seem to indicate that the latency of the positivity as a mismatch response decreases as a function of age: 400-600 ms at the age of 2 months, 320-480 ms at the age of 4 months, 200-450 ms at the age of 6 months. This pattern is quite suggestive even though we are comparing findings across different languages and different stimulus types.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "Phoneme discrimination was also investigated in older infants, i.e., in 6-month-old and 12-month-old infants with respect to differences relevant in the particular target language or not [15] . Infants at 6 months responded with a negative deflection between 300 and 500 ms to the acoustical change whereas 12-months-old infants responded with a negativity as a function of the phoneme relevant in the target language. In this study infants were tested while being awake.", "cite_spans": [], "ref_spans": []}, {"section": "CONCLUSION", "text": "Given the different states of alertness in the various infant studies it is not unlikely that the frontal negativity present in the time range between 300 and 900 ms in young infants reflects processes that require an alert cognitive state. The conclusion that this negativity is an indication of cognitive aspects of mismatch discrimination is compatible with the notion that the late negativity observed in early infancy has an MMN-like function [21] . The positivity in response to a mismatch, in contrast, may rather reflect a precognitive brain response.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF4": {"title": "Event-related potentials to pitch change in an auditory stimulus sequence during sleep", "authors": [{"first": "P", "middle": [], "last": "Paavilainen", "suffix": ""}, {"first": "R", "middle": [], "last": "Cammann", "suffix": ""}, {"first": "K", "middle": [], "last": "Alho", "suffix": ""}], "year": 1987, "venue": "Current Trends in Event-related Potential Research (EEG supplement 40)", "link": "22604597"}, "BIBREF6": {"title": "Mismatch negativity in sleep", "authors": [{"first": "R", "middle": [], "last": "N\u00e4\u00e4t\u00e4nen", "suffix": ""}, {"first": "H", "middle": [], "last": "Lyytinen", "suffix": ""}], "year": 1994, "venue": "Sleep onset: Normal and Abnormal Processes", "link": "147339431"}, "BIBREF11": {"title": "Attention and Brain Function", "authors": [{"first": "R", "middle": [], "last": "N\u00e4\u00e4t\u00e4nen", "suffix": ""}], "year": 1992, "venue": "", "link": "143269766"}}, "ref_entries": {"FIGREF0": {"text": "RESULTS ERP differences between standard and deviant were found as a function of stimulus type and state of alertness in three different time windows (stimulus \u00c2 conditions \u00c2 group, 200-400 ms: F(1,8) \u00bc 36.076, p o 0.001; 600-800 ms: F(1,8) \u00bc 7.073, p \u00bc 0.029; 800-1000 ms: F(1,8) \u00bc 16.381, p \u00bc 0.004). In the fourth time window between 400 and 600 ms different processing of long and short stimuli within the standard and deviant conditions was not affected by the alertness state (stimulus \u00c2 condition \u00c2 group, 400-600 ms: F(1,8) \u00bc 1.192, p 4 0.05).", "type": "figure"}, "FIGREF1": {"text": "Fig. 1. Stimulus plot. Short naturally produced syllable (below) and lengthened syllable (above).", "type": "figure"}, "FIGREF2": {"text": "Fig. 2. Averaged ERPs to long deviants for 10 infants in awake state (a) and for 29 infants asleep (b), and to short deviants for 10 infants in awake state (c) and for 29 infants asleep (d). Solid lines for deviants and broken lines for standards. Pos. \u00bc frontal positivity; Neg. \u00bc frontal negativity.", "type": "figure"}, "FIGREF3": {"text": "Fig. 3. Di\u00a1erence waves for 10 infants in awake state (solid lines) for 29 infants asleep (broken lines) and for long stimuli (a) and short stimuli (b).", "type": "figure"}, "TABREF0": {"text": "demonstrated a positivity which was spatially and temporally more extended than the one observed for the awake group (200-400 ms, Fz: F(1,56) \u00bc 8.953, p \u00bc 0.004; F3: F(1,56) \u00bc 8.068, p \u00bc 0.006; F4: F(1,56) \u00bc 8.008, p \u00bc 0.006; Cz: F(1,56) \u00bc 8.431, p \u00bc 0.005; C3: F(1,56) \u00bc 7.893, p \u00bc 0.007; C4: F(1,56) \u00bc 6.644, p \u00bc 0.013; Pz: F(1,56) \u00bc 7.689, p \u00bc 0.008; P3: F(1,56) \u00bc 5.665, p \u00bc 0.021; 400- 600 ms, Fz: F(1,56) \u00bc 5.033, p \u00bc 0.029; F3: F(1,56) \u00bc 4.739, p \u00bc 0.034; F4: F(1,56) \u00bc 5.131, p \u00bc 0.027; Cz: F(1,56) \u00bc 4.390, p \u00bc 0.041; C3: F(1,56) \u00bc 4.294, p \u00bc 0.043).", "type": "table"}}}
{"paper_id": "10700842", "_pdf_hash": "15dc88be7ceebebe694515b039da44ee84db42bb", "abstract": [{"section": "Abstract", "text": "Our purpose in this study was to evaluate the reliability and validity of a Turkish version of the Passionate Love Scale (PLS). Participants in the study were 150 undergraduate students. We assessed the construct validity of the PLS using confirmatory factor analysis. To assess the reliability of the PLS we calculated the internal consistency coefficient and found that the Cronbach's alpha was .89. Our results indicated that the PLS was a valid and reliable measure of passionate love with a Turkish population.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "by, the other. The emotional components of passionate love include physiological sexual arousal and sexual attraction to the other person, positive feelings when the relationship with the other is going well or negative feelings when they are not, and desire for complete union with the other person. Behavioral components of passionate love include working for the other, serving the other, and actions aimed toward determining the other's feelings (Hatfield & Sprecher, 1986 , 2010 . These components of passionate love have been investigated in almost all age groups, including with married couples, singles, children, and adolescents, and adult passionate love has been examined from anthropological, neural, genetic, biological, historical, and cultural perspectives (Cacioppo, Bianchi-Demicheli, Hatfield, & Rapson, 2012; Cacioppo & Hatfield, 2013; Hatfield & Rapson, 2008; Hatfield, Rapson, & Martel, 2007) .", "cite_spans": [{"start": 450, "end": 476, "text": "(Hatfield & Sprecher, 1986", "ref_id": "BIBREF21"}, {"start": 477, "end": 483, "text": ", 2010", "ref_id": "BIBREF22"}, {"start": 772, "end": 827, "text": "(Cacioppo, Bianchi-Demicheli, Hatfield, & Rapson, 2012;", "ref_id": "BIBREF7"}, {"start": 828, "end": 854, "text": "Cacioppo & Hatfield, 2013;", "ref_id": "BIBREF6"}, {"start": 855, "end": 879, "text": "Hatfield & Rapson, 2008;", "ref_id": "BIBREF19"}, {"start": 880, "end": 913, "text": "Hatfield, Rapson, & Martel, 2007)", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "", "text": "In the literature, the findings indicate that a romantic relationship begins with flirting, especially during adolescence, and is experienced as dating or sexual intercourse during emerging adulthood (Arnett, 2004; Atak & Tastan, 2012) . Researchers have found that, for young people, their experience of passionate love is associated with many factors, for example, sociodemographic characteristics of age and gender (Graham & Christiansen, 2009 ) and the culture of the society in which they live (e.g., Kim & Hatfield, 2004; Landis & O'Shea, 2000) . However, many of the factors that scholars have suggested are associated with passionate love, have been described in studies conducted in Western societies.", "cite_spans": [{"start": 200, "end": 214, "text": "(Arnett, 2004;", "ref_id": "BIBREF0"}, {"start": 215, "end": 235, "text": "Atak & Tastan, 2012)", "ref_id": "BIBREF1"}, {"start": 418, "end": 446, "text": "(Graham & Christiansen, 2009", "ref_id": "BIBREF14"}, {"start": 506, "end": 527, "text": "Kim & Hatfield, 2004;", "ref_id": "BIBREF26"}, {"start": 528, "end": 550, "text": "Landis & O'Shea, 2000)", "ref_id": "BIBREF28"}], "ref_spans": []}, {"section": "", "text": "Although there is some research available on the attitude of young people in Turkey towards, and experience with, passionate love (Budak, 2011; Bugay & Tezer, 2008) , it is not comprehensive, and is insufficient to be able to understand the experiences and attitudes of young Turkish men and women in regard to passionate love. Furthermore, the instruments developed to collect data measuring the attitude of young people in Turkey towards love (Buyuksahin & Hovardaoglu, 2004) and their romantic relationships (Kilincer & Tuzlugol-Dost, 2013 ) are inadequate to enable assessment of the cognitive, emotional, and behavioral components of passionate love. In order to improve the quality of life of young people in Turkey (Hatfield & Bensman, 2012; Treger, Sprecher, & Hatfield, 2013) , it is important to identify their experiences (positive or negative) when they passionately love someone, when they are unable to find someone who loves them back with the same passion, or when they break up with such a person. Data collecting tools are needed in Turkey for determining the similarities or differences in components of passionate love among Turkish young people by comparing different cultures, because, in the literature, scholars have also considered whether or not culture has an influence on passionate love (Hatfield & Rapson, 2006; Kim & Hatfield, 2004) . Therefore, our aim in this study was to assess the validity and reliability of the Passionate Love Scale (PLS; Hatfield & Sprecher, 1986 ) with a group of Turkish undergraduates.", "cite_spans": [{"start": 130, "end": 143, "text": "(Budak, 2011;", "ref_id": "BIBREF3"}, {"start": 445, "end": 477, "text": "(Buyuksahin & Hovardaoglu, 2004)", "ref_id": "BIBREF4"}, {"start": 511, "end": 542, "text": "(Kilincer & Tuzlugol-Dost, 2013", "ref_id": "BIBREF24"}, {"start": 722, "end": 748, "text": "(Hatfield & Bensman, 2012;", "ref_id": "BIBREF15"}, {"start": 749, "end": 784, "text": "Treger, Sprecher, & Hatfield, 2013)", "ref_id": "BIBREF33"}, {"start": 1316, "end": 1341, "text": "(Hatfield & Rapson, 2006;", "ref_id": "BIBREF18"}, {"start": 1342, "end": 1363, "text": "Kim & Hatfield, 2004)", "ref_id": "BIBREF26"}, {"start": 1477, "end": 1502, "text": "Hatfield & Sprecher, 1986", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Method Participants", "text": "By simple random sampling we selected 150 volunteer undergraduates, 75 females and 75 males, who were studying at Ankara University in the Faculty of Health Sciences and whose average age was 21.04 years (SD = 1.05). We interviewed the participants and collected data between April and June 2012.", "cite_spans": [], "ref_spans": []}, {"section": "Measures", "text": "We translated the 15 items of the PLS into Turkish (see Appendix for all items in both Turkish and English) and this was the version of the instrument we used to collect data in our research. The questions to which participants were asked to respond included indicating if they were passionately in love at the time of our study, if they had been passionately in love previously, or if they had never been passionately in love. Participants responded on a 9-point Likert scale to describe their feelings (1 = not at all true and 9 = definitely true). The highest score that can be derived from the scale is 135 and the lowest score is 15, with scores from 106 to 135 points indicating wildly, even recklessly, in love; 86 to 105 points indicating passionate, but less intense, feelings; 66 to 85 points indicating occasional bursts of passion; 45 to 65 points indicating tepid, infrequent passion; and 15 to 44 points indicating the thrill is gone. Thus, the degree of passion increases as the score increases and, conversely, decreases as the score decreases (Hatfield & Sprecher, 2010) .", "cite_spans": [{"start": 1060, "end": 1087, "text": "(Hatfield & Sprecher, 2010)", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "Measures", "text": "In addition to completing the PLS, the participants provided demographic information of their sex and age.", "cite_spans": [], "ref_spans": []}, {"section": "Procedure", "text": "We examined both the language validity and construct validity of the PLS in the Turkish context. To ensure language validity, the original scale was first translated from English into Turkish by three English-language linguists as well as eight academics at Ankara University, including two in the Social Work Department, one in the Psychology Department, two in the Department of Nutrition, two in the Department of Child Development, and one in the Department of Nursing. Then three English-language experts translated the Turkish version back into English. All translators worked independently of each other. The original version of the scale was carefully compared to its backtranslation. Then the PLS was reviewed by five academics in the Faculty of Health Sciences at Ankara University, and the scale was finally structured in accordance with their recommendations.", "cite_spans": [], "ref_spans": []}, {"section": "Procedure", "text": "Lecturers in the relevant field of research consented to approach students to participate. We distributed the survey instrument to the undergraduates who volunteered to take part in the teaching rooms or within the campus. After participants had read the informed consent form, we responded to any questions they had, and volunteer participants only were included in the study. Then the participants were instructed to complete the PLS. No time limit was imposed for the participants to complete the scale and supply the demographic information, but most took approximately five minutes to do so.", "cite_spans": [], "ref_spans": []}, {"section": "Data Analysis", "text": "In this study we tested the applicability of the PLS to the Turkish culture. In this context, we performed analysis of the factor loadings. We also performed a confirmatory factor analysis (CFA) to validate the one-factor and 15-item structure of the PLS. We calculated Cronbach's alpha reliability coefficients to test the reliability and the internal consistency of the PLS.", "cite_spans": [], "ref_spans": []}, {"section": "Ethical Considerations", "text": "We emailed Elaine Hatfield, one of the authors of the scale (Hatfield & Sprecher, 1986 ) to obtain permission to use the PLS in this study. We also obtained the necessary permission from Ankara University's Faculty of Health Sciences, where the study was conducted.", "cite_spans": [{"start": 60, "end": 86, "text": "(Hatfield & Sprecher, 1986", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Passionate Love", "text": "Of the participants 43.3% reported that they passionately loved at the time of the study, 33.3% that they had never passionately loved someone, and 23.3% indicated that they had previously been passionately in love with someone.", "cite_spans": [], "ref_spans": []}, {"section": "Passionate Love", "text": "According to their responses to the PLS, 30.7% of the participants reported that they were wildly, and even recklessly, in love, 29.3% felt less passion for their beloved, 21.3% occasionally felt passion for their beloved, 13.3% of the participants were tepid and felt passion infrequently, and 5.3% reported that the thrill of their love had faded away.", "cite_spans": [], "ref_spans": []}, {"section": "Validity of the Passionate Love Scale", "text": "The factor loadings of each item in the PLS were analyzed and found to be .53 or higher (see Table 1 ). Note. P1-P15 = items in the Passionate Love Scale.", "cite_spans": [], "ref_spans": [{"start": 93, "end": 100, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Validity of the Passionate Love Scale", "text": "We performed a CFA, as evidence for structural validity, to test the applicability of the 15-item PLS to the Turkish culture. This analysis is intended to assess to what extent a factorial model of factors (latent variables), consisting of many observable variables, conforms to the real data. The model to be investigated may define a structure that is established using the data of an empirical study, or a design based on a specific theory (Sumer, 2000) . A large number of fit indices are used in the CFA to assess the validity of the model including: chi-square (\uf063 2 ), root mean square error of approximation (RMSEA), comparative fit index (CFI), nonnormed fit index (NNFI), normed fit index (NFI), and goodness-of-fit index (GFI; Cole, 1987; Sumer, 2000) . On a scale, values of 4 < \uf063 2 /df < 5; .05 < RMSEA < .08; .95 \u2264 NNFI \u2264 .97; .95 \u2264 CFI \u2264 .97; .90 \u2264 GFI \u2264 .95 and .90 \u2264 NFI \u2264 .95 indicate an acceptable fit (Kline, 2004; Sumer, 2000) .", "cite_spans": [{"start": 443, "end": 456, "text": "(Sumer, 2000)", "ref_id": "BIBREF29"}, {"start": 737, "end": 748, "text": "Cole, 1987;", "ref_id": "BIBREF8"}, {"start": 749, "end": 761, "text": "Sumer, 2000)", "ref_id": "BIBREF29"}, {"start": 920, "end": 933, "text": "(Kline, 2004;", "ref_id": "BIBREF27"}, {"start": 934, "end": 946, "text": "Sumer, 2000)", "ref_id": "BIBREF29"}], "ref_spans": []}, {"section": "Validity of the Passionate Love Scale", "text": "In the initial CFA applied to the PLS we aimed to analyze the items with t values that were statistically nonsignificant. As a result of this analysis, no nonsignificant t values were found (see Table 2 and Figure 1 ). In Figure 1 the path diagram derived is illustrated. The fit indices were as follows: \uf063 2 = 223.84, \uf063 2 /SD = 2.49, CFI = .94, NNFI = .93, NFI = .90, and GFI = .83. The fit index appeared to be sufficient after evaluating these coefficients that demonstrated the relationship between the observable variables and the factors of the model, indicating the factorial structure of the scale (see Figure 1) .", "cite_spans": [], "ref_spans": [{"start": 195, "end": 202, "text": "Table 2", "ref_id": "TABREF2"}, {"start": 207, "end": 215, "text": "Figure 1", "ref_id": "FIGREF0"}, {"start": 222, "end": 230, "text": "Figure 1", "ref_id": "FIGREF0"}, {"start": 611, "end": 620, "text": "Figure 1)", "ref_id": "FIGREF0"}]}, {"section": "Validity of the Passionate Love Scale", "text": "Given the fit statistics that were calculated by the CFA, we considered that the previously determined one-factor structure of the scale was consistent with the data collected. As seen in Figure 1 , the final form given to the scale consisted of 15 items and one factor. Table 2 provides the regression values and t values of the items, the regression coefficients. As the t values of each scale item in the table are higher than critical value of 1.96, all of the items are statistically significant. Note. P1-P15 = items in the Passionate Love Scale. The values arrowed here are the t values shown in Table 2 .", "cite_spans": [], "ref_spans": [{"start": 188, "end": 196, "text": "Figure 1", "ref_id": "FIGREF0"}, {"start": 271, "end": 278, "text": "Table 2", "ref_id": "TABREF2"}, {"start": 603, "end": 610, "text": "Table 2", "ref_id": "TABREF2"}]}, {"section": "Validity of the Passionate Love Scale", "text": "P 1 P 2 P 3 P 4 P 5 P 6 P 7 P 8 P 9 P 10 P 11 P 12 P 13 P 14 P 15 That is, all of the items highly explain the variance in the scale. As both the regression coefficients and t values were significant, the model was validated. ", "cite_spans": [], "ref_spans": []}, {"section": "Reliability of the Passionate Love Scale", "text": "According to the statistics derived, the Cronbach's alpha of the PLS was .89. In addition, the correlations of items in the scale ranged between .47 and .74 (see Table 1 ).", "cite_spans": [], "ref_spans": [{"start": 162, "end": 169, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Discussion", "text": "In this study our aim was to test the validity and reliability of a Turkish version of the Passionate Love Scale. The results of the study are similar to those obtained by Hatfield and Sprecher (1986) , who developed the original scale. Additionally, the results in our study revealed that the factor loadings for the PLS were .53 or higher and the results from the CFA demonstrated that the scale had one factor, as did the original scale.", "cite_spans": [{"start": 172, "end": 200, "text": "Hatfield and Sprecher (1986)", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Discussion", "text": "In addition, the internal consistency coefficient for the scale was .89 in our study, which was consistent with the reliability coefficient (.91) obtained by Hatfield and Sprecher (1986) . Tezbasaran (1997) reported that a reliability coefficient that is considered adequate for a Likert scale is required to approximate 1 as closely as possible. Thus, the reliability of the PLS in our study can be considered as high.", "cite_spans": [{"start": 158, "end": 186, "text": "Hatfield and Sprecher (1986)", "ref_id": "BIBREF21"}, {"start": 189, "end": 206, "text": "Tezbasaran (1997)", "ref_id": "BIBREF31"}], "ref_spans": []}, {"section": "Discussion", "text": "On the other hand, subsequent researchers (Fehr, 1994; Graham & Christiansen, 2009 ) have supported the reliability and validity of the PLS developed by Hatfield and Sprecher (1986) . This scale was translated into Portuguese by Feybesse, Neto, and Hatfield (2011) and administered to 204 undergraduates to assess its validity and reliability. Furthermore, Feybesse et al. demonstrated that the factor loading of all items in the scale were higher than .45 and the scale had one factor. Thus, the factor loading of .53 or higher that we derived in our research were slightly higher than those derived by Feybesse et al. Their Cronbach's alpha value was .92 for the PLS. Feybesse, Coudin, and Hatfield (in preparation) have since translated the PLS from English to French and administered it to 190 French undergraduates. They reported that the French version of this scale was valid and reliable. We have not provided details of this study conducted by Feybesse and colleagues in our study as their article has not yet been published.", "cite_spans": [{"start": 42, "end": 54, "text": "(Fehr, 1994;", "ref_id": "BIBREF10"}, {"start": 55, "end": 82, "text": "Graham & Christiansen, 2009", "ref_id": "BIBREF14"}, {"start": 153, "end": 181, "text": "Hatfield and Sprecher (1986)", "ref_id": "BIBREF21"}, {"start": 229, "end": 264, "text": "Feybesse, Neto, and Hatfield (2011)", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Discussion", "text": "In sum, we confirmed the validity and reliability of the PLS as a measure of passionate love among young Turkish people and these findings have been supported by many previous researchers. The PLS appears to have adequate psychometric properties to assess the cognitive, emotional, and behavioral aspects of passionate love.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "The results we obtained were different from the results obtained by Feybesse et al. (2011) in terms of young people's experience of passionate love. Of our participants, 33.3% responded that they had never passionately loved, whereas approximately 5% made this response in the study conducted by Feybesse et al. As mentioned above, it has been found that the meaning and importance of passionate love can vary depending on the experience of the young people studied in love, their biological characteristics, and their culture (Hatfield, Forbes, & Rapson, 2013; Kim & Hatfield, 2004; Landis & O'Shea, 2000) . In this regard, it is likely that intimate relationships may differ in Turkey, which has a more communitarian culture than do Western societies. On the other hand, although Turkey differs from Western societies in terms of sociocultural features and social structure, it is in the process of becoming more Westernized. In addition, although the basic structure of Turkish families has undergone some changes, the emotional attachment among family members remains important despite reduced material dependency (Kagitcibasi, 1990) . Thus, the decisions of families or relatives can have a greater influence on romantic relationships in Turkey than occurs in Western cultures, and in Turkey prearranged marriages do still take place (Ercan, 2008) . According to Turkish family values, behaviors such as kissing and having sexual intercourse prior to marriage can be regarded as inappropriate in a passionate-love relationship. Therefore, families may not approve of passionate relationships. Moreover, young people may perceive their relationships as a private matter because they assume that their family might oppose their passionate love. In evaluation of the study results, when nearly one in every three of the young men and women who took part in the research stated that they had never passionately loved before, this response may be attributable to the Turkish culture or to the sociodemographic characteristics of the undergraduates in our research being different from those of participants in previous studies.", "cite_spans": [{"start": 68, "end": 90, "text": "Feybesse et al. (2011)", "ref_id": "BIBREF12"}, {"start": 527, "end": 561, "text": "(Hatfield, Forbes, & Rapson, 2013;", "ref_id": "BIBREF16"}, {"start": 562, "end": 583, "text": "Kim & Hatfield, 2004;", "ref_id": "BIBREF26"}, {"start": 584, "end": 606, "text": "Landis & O'Shea, 2000)", "ref_id": "BIBREF28"}, {"start": 1118, "end": 1137, "text": "(Kagitcibasi, 1990)", "ref_id": "BIBREF23"}, {"start": 1339, "end": 1352, "text": "(Ercan, 2008)", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Limitations", "text": "As in the study of Hatfield and Sprecher (1986) who developed the PLS, the participants in our study were undergraduates. This may limit the generalizability of our findings. However, further study of our findings using a more extensive sample could provide further information on the psychometric properties of the scale. Despite these limitations, this study is important in that it is the first to in which it is demonstrated that the PLS is a reliable and valid instrument when used with Turkish undergraduates.", "cite_spans": [{"start": 19, "end": 47, "text": "Hatfield and Sprecher (1986)", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Future Directions", "text": "We recommend that scholars, particularly those who desire to conduct research in this field in Turkey, should study the experience of young people in passionate love using a larger sample and the 15-item version of PLS that we confirmed as reliable and valid in this study. In addition, they could adapt and translate the 30-item version of PLS into Turkish, in order to derive further information on the cognitive, emotional, and behavioral components of passionate love.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "As a result of this research, we gained evidence about the psychological features of the PLS, including its behavioral, cognitive, and emotional components. Thus, we concluded that the 15-item Turkish version of PLS was valid and reliable when used with a sample of Turkish undergraduates. As reported by Hatfield and Sprecher (2010) , this scale will be a helpful instrument to evaluate the attitude of undergraduates towards love using these components, especially in the field of psychology. The scale can also be useful for sociologists working in the field of sociology of youth and of emotions to evaluate attitudes towards passionate love. Additionally, in order to improve young people's psychological well-being and quality of life, the PLS can be used by psychologists and specialists in the field of social psychology of youth to develop intervention programs for behavioral, cognitive, and emotional aspects of passionate love experienced by young people. This scale would also be helpful for professionals engaged in marriage and counseling services.", "cite_spans": [{"start": 305, "end": 333, "text": "Hatfield and Sprecher (2010)", "ref_id": "BIBREF22"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Emerging adulthood: The winding road from the late teens through the twenties", "authors": [{"first": "J", "middle": ["J"], "last": "Arnett", "suffix": ""}], "year": 2004, "venue": "", "link": "143320157"}, "BIBREF1": {"title": "Romantik ili\u015fkiler ve a\u015fk", "authors": [{"first": "H", "middle": [], "last": "Atak", "suffix": ""}, {"first": "N", "middle": [], "last": "Tastan", "suffix": ""}], "year": 2012, "venue": "", "link": "197648650"}, "BIBREF3": {"title": "\u00dcniversite \u00f6\u011frencilerinin a\u015fka ili\u015fkin tutumlar\u0131 ve ili\u015fki doyumlar\u0131n\u0131n ki\u015filik \u00f6zellikleri ile ili\u015fkisi [Attitudes of university students towards love and the relationship of relation satisfaction with 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"last": "\u2026\u2026", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF36": {"title": "mutlu etmek i\u00e7in bir \u015fey yapt\u0131\u011f\u0131mda kendimi mutlu hissederim", "authors": [{"first": "", "middle": [], "last": "\u2026\u2026", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF39": {"title": "ile ilgili her \u015feyi \u00f6\u011frenmek i\u00e7in can atar\u0131m", "authors": [{"first": "", "middle": [], "last": "\u2026\u2026", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF41": {"title": "ilgisini sonsuz bir \u015fekilde arzular\u0131m", "authors": [{"first": "", "middle": [], "last": "\u2026\u2026", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF42": {"title": "kusursuz romantik bir hayat arkada\u015f\u0131d\u0131r", "authors": [{"first": "\u2026\u2026", "middle": [], "last": "Bana G\u00f6re", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF43": {"title": "bana dokundu\u011funda v\u00fccudumun tepki g\u00f6sterdi\u011fini hissederim", "authors": [{"first": "", "middle": [], "last": "\u2026\u2026", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF45": {"title": "beni tan\u0131mas\u0131n\u0131 -d\u00fc\u015f\u00fcncelerimi, korkular\u0131m\u0131 ve umutlar\u0131m\u0131 bilmesini isterim", "authors": [{"first": "", "middle": [], "last": "\u2026\u2026", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF46": {"title": "beni arzulad\u0131\u011f\u0131n\u0131 g\u00f6steren belirtiler arar\u0131m", "authors": [{"first": "", "middle": [], "last": "B\u00fcy\u00fck Bir Hevesle\u2026\u2026", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF47": {"title": "kar\u015f\u0131 etkileyici cazibem vard\u0131r", "authors": [{"first": "", "middle": [], "last": "\u2026\u2026", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF48": {"title": "ile olan ili\u015fkimde bir \u015feyler yolunda gitmedi\u011finde, \u015fiddetli \u015fekilde bunal\u0131ma girerim. Items of the PLS in English", "authors": [{"first": "", "middle": [], "last": "\u2026\u2026", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF49": {"title": "I would feel deep despair if\u2026\u2026", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF50": {"title": "Sometimes I feel I can't control my thoughts; they are obsessively focused on\u2026\u2026", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF51": {"title": "I feel happy when I am doing something to make\u2026\u2026", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF52": {"title": "I'd get jealous if I thought\u2026\u2026..was falling in love with someone else", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF53": {"title": "I yearn to know all about\u2026\u2026", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF54": {"title": "physically, emotionally, and mentally", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF55": {"title": "I have an endless appetite for affection from\u2026\u2026", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF56": {"title": "is the perfect romantic partner", "authors": [{"first": "\u2026\u2026", "middle": [], "last": "For Me", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF57": {"title": "to know me -my thoughts, my fears, and my hopes", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF58": {"title": "I eagerly look for signs indicating\u2026\u2026..'s desire for me", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF59": {"title": "I possess a powerful attraction for\u2026\u2026", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF60": {"title": "I get extremely depressed when things don't go right in my relationship with\u2026\u2026", "authors": [], "year": "", "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Figure 1. Path diagram for the Passionate Love Scale. Note. P1-P15 = items in the Passionate Love Scale. The values", "type": "figure"}, "TABREF0": {"text": "Factor Loadings and Item Total Correlations of the Passionate Love Scale", "type": "table"}, "TABREF2": {"text": "Regression and t Values for Verifying the Factor AnalysisNote. The values in this table are unstandardized versions of the values in Table 1.", "type": "table"}}}
{"paper_id": "10700853", "_pdf_hash": "cb23106bda082f12aab0ef426f9ef8e3b1e7ed44", "abstract": [{"section": "Abstract", "text": "Dural substitutes are used to achieve watertight closure of the dura mater when adequate closure is not possible. The purpose of this study was to evaluate the efficacy and safety of a new collagen matrix dural substitute (Duradry, Technodry, Belo Horizonte MG) in the repair or expansion of cranial and spinal dura mater. Method: Thirty patients, operated on between March and September, 2008, were studied. Surgical records were reviewed for sex, age, location of graft, technique, and presence of fistula or infection. The patients were followed up for at least 3 months, and presence of complications, such as cerebrospinal fluid leakage, infection, asseptic meningitis hydrocephalus, pseudomeningocele, was analyzed. Results: Only one patient presented cerebrospinal fluid fistula. No patients presented wound infections, hydrocephalus, pseudomenigocele, meningites, brain abscesses or signs of toxicity related to the dural substitute. Conclusion:", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "The new dural substitute used in this study is effective and safe, and the initial results are similar to those of other dural substitutes reported in the literature. Key words: cerebrospinal fluid leak, duraplasty, collagen matrix.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Experi\u00eancia cl\u00ednica com um novo substituto dural derivado de matriz de col\u00e1geno bovino RESUMO Substitutos de dura m\u00e1ter s\u00e3o utilizados quando n\u00e3o conseguimos um fechamento dural herm\u00e9tico. O objetivo deste estudo foi avaliar a efic\u00e1cia e seguran\u00e7a de um novo substituto dural derivado de matriz col\u00e1gena bovina (Duradry, Tecnodry, Belo Horizonte MG) no reparo ou expans\u00e3o da dura m\u00e1ter craniana ou espinhal. M\u00e9todo: Trinta pacientes operados entre mar\u00e7o e setembro de 2008 foram estudados. Foram analisados sexo, idade, localiza\u00e7\u00e3o do enxerto, t\u00e9cnica e presen\u00e7a de f\u00edstula ou infec\u00e7\u00e3o. Os pacientes foram acompanhados por, pelo menos, 3 meses e a presen\u00e7a de complica\u00e7\u00f5es como f\u00edstula liqu\u00f3rica, infec\u00e7\u00e3o, meningite ass\u00e9ptica, hidrocefalia, pseudomeningocele foram analisadas. Resultados: Apenas um paciente apresentou f\u00edstula liqu\u00f3rica. Nenhuma infec\u00e7\u00e3o de ferida cir\u00fargica foi observada. Tamb\u00e9m n\u00e3o ocorreram casos de hidrocefalia, pseudomeningocele, meningite, abscesso ou sinais de toxicidade relacionada ao implante. Conclus\u00e3o: O novo substituto dural utilizado neste estudo \u00e9 seguro e efetivo e os resultados iniciais s\u00e3o semelhantes aos de outros substitutos durais descritos na literatura. Palavras-chave: f\u00edstula liqu\u00f3rica, duroplastia, matriz de col\u00e1geno.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "injury during craniotomy, or neoplastic invasion. Some other times, it is important to have an expansion of the dura mater, as in decompressive craniotomy and surgical treatment of Chiari malformation 3 . In both cases, the use of dural substitutes could be indicated.", "cite_spans": [{"start": 201, "end": 202, "text": "3", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "", "text": "A dural substitute should ideally not induce immunological or inflammatory response nor present neurotoxicity. Besides, as the graft provides biomatrix for a new conjunctive tissue structure to develop, for the endogenous neodura to grow, it must be promptly absorbed. But it should not adhere to the normal surrounding tissues (brain, cortex, bone). The material should provide watertight closure, keep its shape, and not rupture. Other very important features of an ideal dural substitute are the absence of viral and prion risk of infection and an adequate final cost.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "The substitutes derived from collagen have recently been highly accepted as they are close to this ideal substitute.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "The purpose of this study was to investigate the efficacy and safety of a new dural substitute, derived from bovine collagen (Duradry, Technodry, Belo Horizonte MG) in the peroperative repair or expansion of the cranial and spinal dura mater.", "cite_spans": [], "ref_spans": []}, {"section": "METHOD", "text": "The present study was carried out in the Neurosurgical Department at Santa Casa Hospital of Belo Horizonte (Minas Gerais, Brazil), including 30 patients operated between March and September, 2008. The project was previously approved by the Ethics in Research Committee of the Hospital. The decision to perform a duroplasty was the assessment of the neurosurgical team during the procedure. Eleven patients were male and 19 female, and age ranged between 18 and 76 years, with an average of 48.4 years.", "cite_spans": [], "ref_spans": []}, {"section": "METHOD", "text": "All the patients included in this study were followed up in the postoperative period for at least 3 months, except for 2 patients who died before this period. None of the deaths was directly related to the duroplasty. Distribution by sex, age, location of the graft, technique, and presence of fistula or infection in the postoperative period were analyzed.", "cite_spans": [], "ref_spans": []}, {"section": "METHOD", "text": "The graft (Duradry, Technodry, Belo Horizonte MG) is presented in two forms: film and sponge. The film is used whenever suture is possible, whereas the sponge is applied when suture is impossible, being used or not together with fibrin glue (TISSUCOL -Baxter). Table 1 shows the types of grafts and the techniques used on the patients included in this study. In most cases, the sponge graft was placed directly on the brain without glue or suture, covering the dural lesion. In the five cases film was used, the graft was fixed by stitches or completely sutured to the remaining dura mater. The surgical team decided the choice of graft type and technique during the surgery, as the conditions of the surgical field were faced.", "cite_spans": [], "ref_spans": [{"start": 261, "end": 268, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "METHOD", "text": "The film was cut into a size and shape compatible with the dural lesion and then sutured to the dura mater with 4-0 Prolene\u00ae. The sponge was cut slightly larger than the dural lesion and placed either under or over the defect. Fibrin glue was applied if necessary, on interface between the graft and the remaining dura mater.", "cite_spans": [], "ref_spans": []}, {"section": "METHOD", "text": "All patients were followed up after discharge, on the 30 th and 90 th postoperative days. The presence of cerebrospinal fluid leak, infection or new neurological deficits was investigated.", "cite_spans": [], "ref_spans": []}, {"section": "METHOD", "text": "All the patients followed a computerized tomography (CT) protocol for the skull in the first postoperative week in order to investigate hemorrhagic complications associated with the graft. The choice for a CT scan in such an early postoperative period was due to better accuracy in diagnosing acute hemorrhages. A new CT scan was performed 30 and 90 days after the surgery so as to make sure there were no possible inflammatory reactions to the graft.", "cite_spans": [], "ref_spans": []}, {"section": "METHOD", "text": "Magnetic resonance (MRI) can be useful in order to detect delayed inflammatory reaction and was performed in most of the patients. However, as it was not available for all the patients, the second CT was used as part of the protocol so as to standardize the results.", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "Only one patient, operated on a Chiari malformation type I, presented postoperative CSF fistula. None of the patients presented wound infections, hydrocephalus, pseudomenigocele, meningites or brain abscesses. No alterations were found in the postoperative CT scans, such as pneumocephalus, dural thickening, or graft-related problems. Two patients died during the study. One of them developed a severe brain edema secondary to venous injury at surgery on a giant olfactory groove meningioma. The other, operated on an intraventricular tumor, died after a bleeding in the posterior fossa right after surgery. It is clear that neither of the deaths were related to the dural graft. Table 2 shows the topographic distribution of the treated lesions. The age average of patients with supratentorial dural lesions was 57 years, different from the overall mean age of 48.4 years, pointing to age as a relevant factor when considering the need for duroplasty in the supratentorial location. It is also possible to notice that the need for duroplasty is considerably higher in the posterior fossa, as the dura tends to retract and, therefore, makes it more difficult to obtain a watertight closure.", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "The indication for duroplasty was decided by the neurosurgical team during surgery. All patients participating in the study signed an informed consent term prior to surgery. Table 2 shows the indications for the use of the implant (Duradry) in this series. The use of the heterologous graft facilitated the operation considerably, reducing surgical time and the need for a new surgical incision in order to later remove other possible grafts, such as fascia lata 4, 5 . In spinal surgeries, where it is usually difficult to suture a graft, the use of Duradry was also useful so as to reduce surgical time. Moreover, no fistula was observed in such cases 6 . There was only one case of CSF fistula in this series. It was the surgical treatment of a Chiari malformation in which the matrix collagen graft was used. The patient developed a fistula and also meningitis, being treated with external lumbar drainage for 7 days and antibiotics. As the fistula remained, he was re-operated and a hole in the dura was found. A new film graft was used so as to close the fistula and the patient recovered well.", "cite_spans": [{"start": 463, "end": 465, "text": "4,", "ref_id": "BIBREF3"}, {"start": 466, "end": 467, "text": "5", "ref_id": "BIBREF4"}, {"start": 654, "end": 655, "text": "6", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "Galea aponeurotica or fascia lata are the most usual autologous grafts used in duroplasty. In cases it is not possible to use them, 6 heterologous dural substitutes are needed. All dural substitutes, particularly the heterologous ones, may be the cause of potentially serious complications, such as infections and inflammatory reaction to a foreign body. In the 1950's, lyophilized dura mater of cadavers was used, as it was easy to obtain and to handle. However, complications like prion infection made it impossible to keep its use [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] . Dural grafts obtained from various animal tissues, such as pericardium, intestinal mucosa and peritoneum, were progressively tested, used and, later, abandoned, due to the risk of zoonoses transmission, particularly bovine spongiform encephalopathy 4, 7 . Various synthetic materials have been developed for dural grafting [18] [19] [20] [21] . In theory, those would be the ideal grafts because of the availability and standardization in production. However, several reports on the use of such grafts showed severe complications related to their non-incorporation and development of chronic inflammatory reactions, even though several synthetic dural grafts are still in use with good results 17, 22, 23 . More recently, dural substitutes made from animal purified collagen have been increasingly used with good outcomes. These grafts are prepared in such a manner that they contain only chemically acellular collagen with no other animal protein. This reduces the potential antigenic and infectious risk 2, 6, 24, 25 . The grafts based on animal collagen naturally have a network of fibrils that promotes adherence, growth and proliferation of fibroblasts which will incorporate the graft and produce a new dural coverage. The low antigenic potential tends to prevent from adherence to the brain.", "cite_spans": [{"start": 534, "end": 537, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 538, "end": 541, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 542, "end": 545, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 546, "end": 550, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 551, "end": 555, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 556, "end": 560, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 561, "end": 565, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 566, "end": 570, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 571, "end": 575, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 576, "end": 580, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 832, "end": 834, "text": "4,", "ref_id": "BIBREF3"}, {"start": 835, "end": 836, "text": "7", "ref_id": "BIBREF6"}, {"start": 906, "end": 910, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 911, "end": 915, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 916, "end": 920, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 921, "end": 925, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 1277, "end": 1280, "text": "17,", "ref_id": "BIBREF16"}, {"start": 1281, "end": 1284, "text": "22,", "ref_id": "BIBREF21"}, {"start": 1285, "end": 1287, "text": "23", "ref_id": "BIBREF22"}, {"start": 1589, "end": 1591, "text": "2,", "ref_id": "BIBREF1"}, {"start": 1592, "end": 1594, "text": "6,", "ref_id": "BIBREF5"}, {"start": 1595, "end": 1598, "text": "24,", "ref_id": "BIBREF23"}, {"start": 1599, "end": 1601, "text": "25", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "The material used in this study is similar to some dural grafts already available in the market (TissuduraBaxter, Duragen -Integra) [26] [27] [28] [29] [30] . Our goal was to demonstrate the ease of use, the quality and the low incidence of reactions to this new dural substitute, derived from acellular bovine collagen.", "cite_spans": [{"start": 132, "end": 136, "text": "[26]", "ref_id": "BIBREF25"}, {"start": 137, "end": 141, "text": "[27]", "ref_id": "BIBREF26"}, {"start": 142, "end": 146, "text": "[28]", "ref_id": "BIBREF27"}, {"start": 147, "end": 151, "text": "[29]", "ref_id": "BIBREF28"}, {"start": 152, "end": 156, "text": "[30]", "ref_id": "BIBREF29"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "In the present study, inflammatory reactions related to the use of the product were not observed, and no specific technical difficulty in its management was noticed. Regarding the prevention of CSF fistula, the result was also appropriate.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "Our results show that the dural substitute used in this study is effective and safe. Longer term follow-up and a larger number of patients are necessary to confirm the absence of complications and adverse effects related to Duradry. 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{"paper_id": "10701359", "_pdf_hash": "efd37909a791c0ae0e820724c544bac6d36fc4f9", "abstract": [], "body_text": [{"section": "Introduction", "text": "Evaluation of genetic toxicity is an important component of the safety assessment of chemicals, including pharmaceuticals, agricultural chemicals, food additives and industrial chemicals. Up to the present time, genotoxicity has been regulated mainly on the basis of qualitative outcomes of hazard identification assays, i.e. decisions are often based on classification as positive or negative for genotoxic potential. Recently, the field is moving towards quantitative risk assessments and with more reliance on weight of evidence (WOE) approaches (1) (2) (3) . In vivo assays are critical components of both WOE analysis and of quantitative risk assessments. The in vivo micronucleus (MN) assay using rodent haematopoietic cells from bone marrow or peripheral blood is widely used for the assessment of clastogenicity/aneugenicity of chemicals, both as a hazard screening assay and as a component of exposure-based risk assessments. The assay is usually incorporated into the standard genotoxicity test battery as a representative in vivo assay together with an in vitro gene mutation assay using bacteria and an in vitro chromosomal aberration assay using cultured mammalian cells (4) . The MN assay was originally established using rodent erythrocytes as a simple method of assessing cytogenetic damage, taking advantage of two important characteristics of the haematopoietic system: (i) the ease of scoring MN in the newly formed anucleate reticulocytes derived from bone marrow and (ii) the ability to identify the newly formed erythrocytes that had completed their last division during or shortly after exposure to the test agent as those staining positive for RNA content (5, 6) . These important advantages initially led to an almost exclusive focus on the haematopoietic cells as the target. However, in principle, MN can be scored in any dividing cell population, and the assay was soon extended to tissues other than bone marrow.", "cite_spans": [{"start": 549, "end": 552, "text": "(1)", "ref_id": "BIBREF0"}, {"start": 553, "end": 556, "text": "(2)", "ref_id": "BIBREF1"}, {"start": 557, "end": 560, "text": "(3)", "ref_id": "BIBREF2"}, {"start": 1184, "end": 1187, "text": "(4)", "ref_id": "BIBREF3"}, {"start": 1680, "end": 1683, "text": "(5,", "ref_id": "BIBREF4"}, {"start": 1684, "end": 1686, "text": "6)", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Introduction", "text": "One of the early extensions of the assay was to male germ cells, which are a key cell population for genetic studies and which undergo continuous active division (7, 8) . The assay was also extended to liver by stimulating regeneration and hence cell replication, by partial hepatectomy (9) (10) (11) (12) or pretreatment with hepatotoxicants (13, 14) . Later, colon, skin and young rodent liver were studied extensively and shown to be suitable for MN analysis. Studies using human tissues or cell preparations include corneal cells and exfoliated cells from urinary bladder, oesophagus, cells of the nasal cavity and oral buccal mucosa (15, 16) . Rodent embryonic cells have also been used to evaluate effects of transplacental application of test chemicals. In addition, human lymphocytes have been used to assess cytogenetic damage in epidemiology studies of environmentally or occupationally exposed individuals, as summarised previously. The MN assay using peripheral lymphocytes or other human tissues is reviewed separately in this special issue.", "cite_spans": [{"start": 162, "end": 165, "text": "(7,", "ref_id": "BIBREF6"}, {"start": 166, "end": 168, "text": "8)", "ref_id": "BIBREF7"}, {"start": 287, "end": 290, "text": "(9)", "ref_id": "BIBREF8"}, {"start": 291, "end": 295, "text": "(10)", "ref_id": "BIBREF9"}, {"start": 296, "end": 300, "text": "(11)", "ref_id": "BIBREF10"}, {"start": 301, "end": 305, "text": "(12)", "ref_id": "BIBREF11"}, {"start": 343, "end": 347, "text": "(13,", "ref_id": "BIBREF12"}, {"start": 348, "end": 351, "text": "14)", "ref_id": "BIBREF13"}, {"start": 638, "end": 642, "text": "(15,", "ref_id": "BIBREF14"}, {"start": 643, "end": 646, "text": "16)", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "Introduction", "text": "In regulatory testing, the rodent erythrocyte MN assay is the most common first choice among in vivo assays used for subsequent testing when in vitro genotoxicity test(s) are found to be positive. The unscheduled DNA synthesis assay using rat liver has also been used in this situation, but its sensitivity has been questioned (17) . The single-cell gel electrophoresis (comet) assay and gene mutation assays using transgenic animals are frequently considered for use as follow-up assays when in vitro gene mutation assay(s) are positive. It is important to evaluate cytogenetic damage in those cell populations or tissues that are the relevant sites of distribution and metabolism in vivo, and so bone marrow haematopoietic cells alone cannot satisfy this need.", "cite_spans": [{"start": 327, "end": 331, "text": "(17)", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Introduction", "text": "Scientific considerations as well as the animal welfare movement, which emphasises the reduction, replacement and/ or refinement of animal use (the '3Rs'), have contributed to the implementation of protocols that allow the integration of genotoxicity end points into general toxicological tests. Assays that have been shown to be appropriate for integration with repeat-dose general toxicology studies include the bone marrow and peripheral blood erythrocyte MN assays, the peripheral blood lymphocyte assay and a new MN assay method using rat liver after an extended period of repeated dosing (18) . The liver is a key site of xenobiotic metabolism and accumulation in vivo, and therefore the repeat-dose method, which appears to be applicable in adult rats, promises to be an important assay that could be incorporated into general toxicological studies.", "cite_spans": [{"start": 594, "end": 598, "text": "(18)", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "Introduction", "text": "MN assays using tissues other than bone marrow have previously been reviewed in conjunction with two International Workshops on Genotoxicity Testing (IWGT) (19, 20) and have been discussed by Kirkland et al. (17, 21) . Here, we update the previous publications of the IWGT groups and revise the previous table of assay results to include studies published after 2000.", "cite_spans": [{"start": 156, "end": 160, "text": "(19,", "ref_id": "BIBREF18"}, {"start": 161, "end": 164, "text": "20)", "ref_id": "BIBREF19"}, {"start": 213, "end": 216, "text": "21)", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Literature search", "text": "The literature search was conducted by using PubMed (http:// www.ncbi.nlm.nih.gov/sites/entrez) and search terms that included 'micronucleus', 'rat', 'mouse' and specific tissue names with limitations of year and English language. The time limit was from 2000 to present, except for colon, liver and skin, in which cases the limit was set to 2005 or later because these tissues were evaluated in the third and fourth IWGT reviews (19, 20) . All abstracts identified in the searches were reviewed and then suitable articles were selected for further review and inclusion. Certain literature, for example publications of in vitro or in vivo studies of irradiation (e.g. X-ray, magnetic field), some MN studies on mouse models of human genetic disease or dietary deficiency and human studies were excluded. The tissues identified in which the rodent MN assays had been reported were alveolar, bladder, buccal mucosa, colon, liver, skin, spleen, stomach, vagina and foetal or neonatal tissues. No additional literature related to sperm or spermatid MN assays after 2000 was found. The identified assay results published within the above time periods are listed in Table I .", "cite_spans": [{"start": 430, "end": 434, "text": "(19,", "ref_id": "BIBREF18"}, {"start": 435, "end": 438, "text": "20)", "ref_id": "BIBREF19"}], "ref_spans": [{"start": 1160, "end": 1167, "text": "Table I", "ref_id": "TABREF0"}]}, {"section": "MN assays using tissues other than bone marrow", "text": "Liver Liver is often a site of carcinogenic response, but liver cells replicate relatively slowly in adult animals. Therefore, in the early development stage of the liver MN assay, cell division was stimulated by partial hepatectomy (9) (10) (11) (12) or treatment with hepatotoxicants (13, 14) . Early protocols were improved by subsequent investigators (25, 59) who recognised that in rodents there is active cell division in liver soon after birth, i.e. up to 5-6 weeks in rat. Based on this characteristic, young rats (22, 23, 26, 27, 29) or mice (28) can be used for MN frequency determination without any additional physical or chemical treatment.", "cite_spans": [{"start": 233, "end": 236, "text": "(9)", "ref_id": "BIBREF8"}, {"start": 237, "end": 241, "text": "(10)", "ref_id": "BIBREF9"}, {"start": 242, "end": 246, "text": "(11)", "ref_id": "BIBREF10"}, {"start": 247, "end": 251, "text": "(12)", "ref_id": "BIBREF11"}, {"start": 286, "end": 290, "text": "(13,", "ref_id": "BIBREF12"}, {"start": 291, "end": 294, "text": "14)", "ref_id": "BIBREF13"}, {"start": 355, "end": 359, "text": "(25,", "ref_id": "BIBREF24"}, {"start": 360, "end": 363, "text": "59)", "ref_id": "BIBREF58"}, {"start": 522, "end": 526, "text": "(22,", "ref_id": "BIBREF21"}, {"start": 527, "end": 530, "text": "23,", "ref_id": "BIBREF22"}, {"start": 531, "end": 534, "text": "26,", "ref_id": "BIBREF25"}, {"start": 535, "end": 538, "text": "27,", "ref_id": "BIBREF26"}, {"start": 539, "end": 542, "text": "29)", "ref_id": "BIBREF28"}], "ref_spans": []}, {"section": "MN assays using tissues other than bone marrow", "text": "As noted above, recently a new protocol using adult rat liver in combination with repeated treatments is now under development (Narumi et al., submitted for publication). This method should be easily integrated with general toxicological studies. As an example, adult rats that received daily Nnitrosodiethylamine (DEN) or 2,4-diaminotoluene (2,4-DAT) for 5, 14 and 28 days orally without any additional treatment had elevated frequencies of micronucleated hepatocytes after repeated treatments with DEN for !5 days or with 2,4-DAT for !14 days. The observed frequencies increased with the number of treatments, as expected. To verify the reliability of this method, cell proliferation in liver has been investigated with bromodeoxyuridine intake. Atrazine also induced MN in rat liver treated for 21 days (24) . This method promises to allow monitoring of genetic damage in this important tissue during routine repeated-dose toxicology assays.", "cite_spans": [{"start": 806, "end": 810, "text": "(24)", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Colon and intestinal epithelium", "text": "The colon and digestive tract are important target sites of carcinogens (e.g. hydrazines). In addition, colon is an important tissue for metabolism by the intestinal microflora and excretion by feces (30) . Therefore, the MN assay in colon and/or intestine is appropriate for hazard identification and risk evaluation of environmental chemicals that enter the human body through the food chain, such as pesticides and food ingredients, as well as for orally administrated pharmaceuticals (33) . The colon MN assay with the mouse was developed by Goldberg et al. (60) , and it has been improved by Vanhauwaert et al. (61) and Ohyama et al. (62) . The colon MN assay has been used for the confirmation of the presence or absence of genotoxic activity in colon (30) (31) (32) (33) . Because cells in the colon originate from stem cells at the base of the crypts that are vascularised, it is also possible that MN in colon cells may be induced via blood-borne genotoxicants.", "cite_spans": [{"start": 200, "end": 204, "text": "(30)", "ref_id": "BIBREF29"}, {"start": 488, "end": 492, "text": "(33)", "ref_id": "BIBREF32"}, {"start": 562, "end": 566, "text": "(60)", "ref_id": "BIBREF59"}, {"start": 639, "end": 643, "text": "(62)", "ref_id": "BIBREF61"}, {"start": 758, "end": 762, "text": "(30)", "ref_id": "BIBREF29"}, {"start": 763, "end": 767, "text": "(31)", "ref_id": "BIBREF30"}, {"start": 768, "end": 772, "text": "(32)", "ref_id": "BIBREF31"}, {"start": 773, "end": 777, "text": "(33)", "ref_id": "BIBREF32"}], "ref_spans": []}, {"section": "Skin", "text": "Skin is the major site of exposure to many chemicals, including industrial chemicals, pesticides, consumer products, cosmetics and pharmaceuticals. Skin is also an important tissue for protection from environmental agents, including light and chemicals. Although the use of in vitro photo-genotoxicity assays is diminishing because of oversensitivity and low specificity, the skin MN assay provides a more relevant method of assessing the risk of in vivo photo-genotoxicity associated with exposure to chemical and physical agents (35, 36) . The skin MN assay in the mouse was introduced around 1990 (63, 64) , and it was then developed in the rat and hairless mouse by Nishikawa et al. (34, 65, 66) . In this assay, acridine orange fluorescent staining is playing an important role not only to identify MN but also to identify the appropriate cell population to be analyzed (34, 35) . Although many studies have been conducted using skin application with or without ultraviolet irradiation, detection of systemic effects in skin following oral administration is also important (67) .", "cite_spans": [{"start": 531, "end": 535, "text": "(35,", "ref_id": "BIBREF34"}, {"start": 536, "end": 539, "text": "36)", "ref_id": "BIBREF35"}, {"start": 600, "end": 604, "text": "(63,", "ref_id": "BIBREF62"}, {"start": 605, "end": 608, "text": "64)", "ref_id": "BIBREF63"}, {"start": 687, "end": 691, "text": "(34,", "ref_id": "BIBREF33"}, {"start": 692, "end": 695, "text": "65,", "ref_id": "BIBREF64"}, {"start": 696, "end": 699, "text": "66)", "ref_id": "BIBREF65"}, {"start": 875, "end": 879, "text": "(34,", "ref_id": "BIBREF33"}, {"start": 880, "end": 883, "text": "35)", "ref_id": "BIBREF34"}, {"start": 1078, "end": 1082, "text": "(67)", "ref_id": "BIBREF66"}], "ref_spans": []}, {"section": "Spleen", "text": "The spleen MN assay with mouse splenocytes has been developed by Shindo et al. (68) , using splenocytes as the target cell population. Evaluation of genotoxic effects in splenocytes during subchronic exposures provides another relevant target tissue in addition to haematopoietic cells in bone marrow or peripheral blood (37) (38) (39) (40) . In vitro and/or in vivo methods have been used in many studies (38, (40) (41) (42) .", "cite_spans": [{"start": 321, "end": 325, "text": "(37)", "ref_id": "BIBREF36"}, {"start": 326, "end": 330, "text": "(38)", "ref_id": "BIBREF37"}, {"start": 331, "end": 335, "text": "(39)", "ref_id": "BIBREF38"}, {"start": 336, "end": 340, "text": "(40)", "ref_id": "BIBREF39"}, {"start": 406, "end": 410, "text": "(38,", "ref_id": "BIBREF37"}, {"start": 411, "end": 415, "text": "(40)", "ref_id": "BIBREF39"}, {"start": 416, "end": 420, "text": "(41)", "ref_id": "BIBREF40"}, {"start": 421, "end": 425, "text": "(42)", "ref_id": "BIBREF41"}], "ref_spans": []}, {"section": "Lung", "text": "Lung is one of the major target sites of those carcinogens for which inhalation is the major route of exposure. Therefore, lung cells are an important target site for detection of local genotoxic effects of environmental or industrial chemicals following or during inhalation exposures (43, (45) (46) (47) . Intratracheal instillation is also often used as a means of delivery to the lung in animal experiments (43) . Studies of long-term exposure (several weeks or months) by inhalation are also possible (44, 47) . A lung MN assay was developed as an in vivo/in vitro assay in early 1990s (69, 70) , and in more recent ", "cite_spans": [{"start": 286, "end": 290, "text": "(43,", "ref_id": "BIBREF42"}, {"start": 291, "end": 295, "text": "(45)", "ref_id": "BIBREF44"}, {"start": 296, "end": 300, "text": "(46)", "ref_id": "BIBREF45"}, {"start": 301, "end": 305, "text": "(47)", "ref_id": "BIBREF46"}, {"start": 411, "end": 415, "text": "(43)", "ref_id": "BIBREF42"}, {"start": 506, "end": 510, "text": "(44,", "ref_id": "BIBREF43"}, {"start": 511, "end": 514, "text": "47)", "ref_id": "BIBREF46"}, {"start": 591, "end": 595, "text": "(69,", "ref_id": "BIBREF68"}, {"start": 596, "end": 599, "text": "70)", "ref_id": "BIBREF69"}], "ref_spans": []}, {"section": "Lung", "text": "Rodent MN assays using multiple tissues (46, 47) .", "cite_spans": [{"start": 40, "end": 44, "text": "(46,", "ref_id": "BIBREF45"}, {"start": 45, "end": 48, "text": "47)", "ref_id": "BIBREF46"}], "ref_spans": []}, {"section": "T. Morita", "text": "et al. studies, several types of lung cells have been used, including bronchoalveolar lavage cells, alveolar type II cells, Clara cells or pulmonary alveolar macrophages", "cite_spans": [], "ref_spans": []}, {"section": "Stomach", "text": "Stomach is important because it is the first site of direct contact of many chemicals. Several in vivo genotoxicity assays using stomach have been developed, including the unscheduled DNA synthesis assay, comet assay and transgenic mutation assay. Recently, a stomach MN assay has been established by Okada et al. (48) . Though data obtained are at present limited to two known stomach carcinogens (N-methyl-N#-nitro-N-nitrosoguanidine and N-nitroso-N-methylurea) , the assay appears promising for further development.", "cite_spans": [{"start": 314, "end": 318, "text": "(48)", "ref_id": "BIBREF47"}], "ref_spans": []}, {"section": "Stomach", "text": "Bladder Urinary bladder is a tumour target site of certain chemical classes such as naphthylamines, benzidines or aminobiphenyls. Because it is the tissue that collects urine excreted by kidneys, it will be exposed to water-soluble chemicals excreted via the urine. A bladder MN assay has been developed as a tool for studies of cancer risk, including intervention studies, in humans (71) . Exfoliated or epithelial cells from urinary bladder have also been used in animal studies in which acute or subchronic exposures by several routes of administration were employed (32, 44, (49) (50) (51) . The bladder MN assay is a good biomonitoring tool for humans exposed to carcinogenic or genotoxic chemicals, and analogous studies with animals can be used for identification and/or confirmation of genotoxic action in the bladder.", "cite_spans": [{"start": 384, "end": 388, "text": "(71)", "ref_id": "BIBREF70"}, {"start": 570, "end": 574, "text": "(32,", "ref_id": "BIBREF31"}, {"start": 575, "end": 578, "text": "44,", "ref_id": "BIBREF43"}, {"start": 579, "end": 583, "text": "(49)", "ref_id": "BIBREF48"}, {"start": 584, "end": 588, "text": "(50)", "ref_id": "BIBREF49"}, {"start": 589, "end": 593, "text": "(51)", "ref_id": "BIBREF50"}], "ref_spans": []}, {"section": "Buccal mucosa", "text": "Buccal mucosal cells have been used for biomonitoring of DNA damage potentially leading to oral cancer in humans (15, 72) . Although many studies have been conducted in humans, animal data are scant (52) or limited to animal models of human disease such as Alzheimer's disease (73) . This may indicate that analysis of MN in buccal mucosal cells in rodents may not be suitable at present for detection of genotoxic effects and that technical development will be needed for general use of the detection of local genotoxic effects at this site in animals.", "cite_spans": [{"start": 113, "end": 117, "text": "(15,", "ref_id": "BIBREF14"}, {"start": 118, "end": 121, "text": "72)", "ref_id": "BIBREF71"}, {"start": 199, "end": 203, "text": "(52)", "ref_id": "BIBREF51"}, {"start": 277, "end": 281, "text": "(73)", "ref_id": "BIBREF72"}], "ref_spans": []}, {"section": "Vagina", "text": "Carcinoma of the uterine cervix is important in humans and has been shown to be inducible by chemical exposure in the mouse (55) . A vaginal MN assay could be a useful tool for screening new chemopreventive agents in the rodent. Chakrabarti and Dutta (74) described a vaginal MN assay that could detect known MN inducers, but there is not yet sufficient data to evaluate the utility of this model (53) (54) (55) (56) .", "cite_spans": [{"start": 124, "end": 128, "text": "(55)", "ref_id": "BIBREF54"}, {"start": 397, "end": 401, "text": "(53)", "ref_id": "BIBREF52"}, {"start": 402, "end": 406, "text": "(54)", "ref_id": "BIBREF53"}, {"start": 407, "end": 411, "text": "(55)", "ref_id": "BIBREF54"}, {"start": 412, "end": 416, "text": "(56)", "ref_id": "BIBREF55"}], "ref_spans": []}, {"section": "Vagina", "text": "Foetal/neonatal tissues Assays using MN induction to evaluate transplacental genotoxicity were developed around 1980 (75) (76) (77) and many studies were published before 2000. Those studies have been summarised in previous IWGT reports (19, 20) . In the late 1980s, MacGregor et al. (78, 79) showed that additional kinetic information could be obtained in the foetal blood MN assay by categorising newly formed red blood cells into age groups based on RNA aggregation state. Additional data from studies using peripheral blood from neonates or peripheral blood and liver from foetuses, found in our search of the literature published after 2005 are summarised in Table I (57, 58) . Foetal/ neonatal MN assays using transplacental exposure will be useful for evaluation of agents associated with embryotoxicity, congenital malformations, tumours, heritable mutations in germ cells or other adverse developmental effects.", "cite_spans": [{"start": 117, "end": 121, "text": "(75)", "ref_id": "BIBREF74"}, {"start": 122, "end": 126, "text": "(76)", "ref_id": "BIBREF75"}, {"start": 127, "end": 131, "text": "(77)", "ref_id": "BIBREF76"}, {"start": 237, "end": 241, "text": "(19,", "ref_id": "BIBREF18"}, {"start": 242, "end": 245, "text": "20)", "ref_id": "BIBREF19"}, {"start": 284, "end": 288, "text": "(78,", "ref_id": "BIBREF77"}, {"start": 289, "end": 292, "text": "79)", "ref_id": "BIBREF78"}, {"start": 672, "end": 676, "text": "(57,", "ref_id": "BIBREF56"}, {"start": 677, "end": 680, "text": "58)", "ref_id": "BIBREF57"}], "ref_spans": [{"start": 664, "end": 671, "text": "Table I", "ref_id": "TABREF0"}]}, {"section": "Vagina", "text": "Spermatogonia/spermatids A spermatogonial MN assay was proposed in the early 1980s (7, 8) , and early results of this assay were summarised in the previous IWGT reports (19, 20) . No new data were identified in our PubMed search. Initially, it was difficult to identify the specific developmental stage of spermatogonial cells and to restrict the cell population to be analysed. A fluorescent staining method using acridine orange and 4#,6-diamino-2-phenylindole concomitantly has now been introduced and it facilitates identification of the spermatogonial cells to be analysed (80) . This staining method has also been applied to other tissues successfully because the cytoplasm and nucleus are clearly stained and provide increased accuracy of scoring micronucleated cells.", "cite_spans": [{"start": 83, "end": 86, "text": "(7,", "ref_id": "BIBREF6"}, {"start": 87, "end": 89, "text": "8)", "ref_id": "BIBREF7"}, {"start": 169, "end": 173, "text": "(19,", "ref_id": "BIBREF18"}, {"start": 174, "end": 177, "text": "20)", "ref_id": "BIBREF19"}, {"start": 578, "end": 582, "text": "(80)", "ref_id": "BIBREF79"}], "ref_spans": []}, {"section": "Vagina", "text": "The evaluation of MN in reproductive tissue is obviously important in the evaluation of adverse effects to subsequent generations. The United Nations (UN) 'Globally Harmonised System of Classification and Labelling of Chemicals (GHS)' requests hazard classification of chemicals based on germ cell mutagenicity (81, 82) and identifies the spermatid MN assay as an example of a mutagenicity test applicable to germ cells.", "cite_spans": [{"start": 311, "end": 315, "text": "(81,", "ref_id": "BIBREF80"}, {"start": 316, "end": 319, "text": "82)", "ref_id": "BIBREF81"}], "ref_spans": []}, {"section": "Discussion", "text": "Many tissues other than bone marrow or peripheral blood have been used for evaluation of MN frequencies in vivo in rodents. In our literature search, liver, colon epithelium, skin, spleen, lung, stomach, bladder, buccal mucosa, vagina and foetal/neonatal tissues were identified as target tissues used for such assays. No new data on MN incidence in spermatogonia or spermatids were identified after the previous IWGT reviews (19, 20) . These MN assays have been used to detect local or systemic genotoxic effect in important tissues, including germ cells and progeny.", "cite_spans": [{"start": 426, "end": 430, "text": "(19,", "ref_id": "BIBREF18"}, {"start": 431, "end": 434, "text": "20)", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "Discussion", "text": "These assays are important tools for the prediction and evaluation of chemical carcinogenicity and also for the identification and study of agents with the potential to induce transmissible germ line mutations. Currently, there is emphasis on extending hazard identification techniques to evaluate genotoxic risk more quantitatively (1, 2, 83) . One important objective of genotoxicity evaluation is the assessment of the mechanism of carcinogenicity, and whether genotoxic mechanisms are involved or not. Another is to assess adverse heritable effects of chemicals that may appear in subsequent generations. For the former purpose, assays are needed that permit assessment in the appropriate target tissues and allow development of mode of action (MOA) and a WOE of information in conjunction with information about exposure and metabolic transformation (84) . The tissues with most active cell division are bone marrow, gastrointestinal tract, skin and reproductive tissues in mammals. These tissues have been used as experimental materials for the analysis of chromosomal damage, including evaluation of induction of chromosomal aberrations, and the ability to monitor MN frequencies in these same tissues is therefore important.", "cite_spans": [{"start": 333, "end": 336, "text": "(1,", "ref_id": "BIBREF0"}, {"start": 337, "end": 339, "text": "2,", "ref_id": "BIBREF1"}, {"start": 340, "end": 343, "text": "83)", "ref_id": "BIBREF82"}, {"start": 855, "end": 859, "text": "(84)", "ref_id": "BIBREF83"}], "ref_spans": []}, {"section": "Discussion", "text": "Given the recent emphasis on genotoxic risk characterisation, MOA determination and WOE approaches (84) , the ability to study a wide range of tissues will become increasingly important. However, validated standard protocols (e.g. Organization for Economic Co-operation and Development test guidelines) have not yet been established for most of these tissues, and methods remain primarily research oriented. Even liver, colon, skin and spermatogonia/spermatid MN assays, which have been used relatively frequently for research purposes, are still infrequently used for regulatory purposes. The target cell populations, cell preparation, suitable sampling time(s), cytotoxicity evaluation (dose selection) and/or historical background data are less well established in other tissues, such as lung, bladder, buccal mucosa, nasal epithelium and vagina. Investigation of cell division is a critical issue when studying MN in any tissue. Suitable sampling time(s) after the final treatment varies in different tissues or study designs including the parameters of treatment duration or route of exposure. Further development, especially to establish standard protocols and validation of these MN assays, is highly desirable and will facilitate their increasing application to support more meaningful and relevant assessments of clastogenic/aneugenic risks associated with chemical and physical exposures (1, 2, 17, 21, 83) .", "cite_spans": [{"start": 99, "end": 103, "text": "(84)", "ref_id": "BIBREF83"}, {"start": 1398, "end": 1401, "text": "(1,", "ref_id": "BIBREF0"}, {"start": 1402, "end": 1404, "text": "2,", "ref_id": "BIBREF1"}, {"start": 1405, "end": 1408, "text": "17,", "ref_id": "BIBREF16"}, {"start": 1409, "end": 1412, "text": "21,", "ref_id": "BIBREF20"}, {"start": 1413, "end": 1416, "text": "83)", "ref_id": "BIBREF82"}], "ref_spans": []}, {"section": "Funding", "text": "Health and Labor Sciences Research Grants (H21-ChemistryGeneral-002).", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Strategy for genotoxicity testing: hazard identification and risk assessment in relation to in vitro testing", "authors": [{"first": "V", "middle": [], "last": "Thybaud", "suffix": ""}, {"first": "M", "middle": [], "last": "Aardema", "suffix": ""}, {"first": "J", "middle": [], "last": "Clements", "suffix": ""}], "year": 2007, "venue": "Mutat. 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{"paper_id": "10702174", "_pdf_hash": "9986551073207298e3f38a52403328ce9c17a74a", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
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{"paper_id": "10702685", "_pdf_hash": "ab7dc6a605875917ea97eccb209d2e12441ddeed", "abstract": [{"section": "Abstract", "text": "Background: A single sampled faecal immunochemical test (FIT) has moderate sensitivity for colorectal cancer and advanced adenomas. Repeated FIT sampling could improve test sensitivity. The aim of the present study is to determine whether any of three different strategies of double FIT sampling has a better combination of sensitivity and specificity than single FIT sampling. Methods: Test performance of single FIT sampling in subjects scheduled for colonoscopy was compared to double FIT sampling intra-individually. Test positivity of double FIT sampling was evaluated in three different ways: 1) \"one of two FITs+\" when at least one out of two measurements exceeded the cut-off value, 2) \"two of two FITs+\" when both measurements exceeded the cut-off value, 3) \"mean of two FITs+\" when the geometric mean of two FITs exceeded the cut-off value. Receiver operator curves were calculated and sensitivity of single and the three strategies of double FIT sampling were compared at a fixed level of specificity. Results: In 124 of 1096 subjects, screen relevant neoplasia (SRN) were found (i.e. early stage CRC or advanced adenomas). At any cut-off, \"two of two FITs+\" resulted in the lowest and \"one of two FITs+\" in the highest sensitivity for SRN (range 35-44% and 42%-54% respectively). ROC's of double FIT sampling were similar to single FIT sampling. At specificities of 85/90/95%, sensitivity of any double FIT sampling strategy did not differ significantly from single FIT (p-values 0.07-1). Conclusion: At any cut off, \"one of two FITs+\" is the most sensitive double FIT sampling strategy. However, at a given specificity level, sensitivity of any double FIT sampling strategy for SRN is comparable to single FIT sampling at a different cut-off value. None of the double FIT strategies has a superior combination of sensitivity and specificity over single FIT.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Background", "text": "In the United States of America and in Europe, colorectal cancer (CRC) ranks second as cause of cancer related death [1, 2] . Screening is the most realistic approach to decrease CRC related mortality. Screening with guaiacbased faecal occult blood tests (g-FOBTs) has been shown to decrease disease specific mortality [3] [4] [5] . Faecal immunochemical tests (FITs or i-FOBTs) have been shown to be superior to g-FOBTs [6] [7] [8] [9] . A major benefit of (semi-) quantitative FITs is that by adjustment of the threshold for positivity, test characteristics and number of follow-up colonoscopies can be tuned to local resources [10, 11] . Since sensitivity of FIT for CRC is in the range of 66-87% [8, 12, 13] , and sensitivity for advanced adenomas is even lower (27-38% depending on the cut-off value) [8, 13, 14] , there is still room for improvement. One approach for improving the sensitivity of FIT based screening could be to increase the number of samples tested, which is common practice for gFOBTs [3] [4] [5] .", "cite_spans": [{"start": 117, "end": 120, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 121, "end": 123, "text": "2]", "ref_id": "BIBREF1"}, {"start": 319, "end": 322, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 323, "end": 326, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 327, "end": 330, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 421, "end": 424, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 425, "end": 428, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 429, "end": 432, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 433, "end": 436, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 630, "end": 634, "text": "[10,", "ref_id": "BIBREF9"}, {"start": 635, "end": 638, "text": "11]", "ref_id": "BIBREF10"}, {"start": 700, "end": 703, "text": "[8,", "ref_id": "BIBREF7"}, {"start": 704, "end": 707, "text": "12,", "ref_id": "BIBREF11"}, {"start": 708, "end": 711, "text": "13]", "ref_id": "BIBREF12"}, {"start": 806, "end": 809, "text": "[8,", "ref_id": "BIBREF7"}, {"start": 810, "end": 813, "text": "13,", "ref_id": "BIBREF12"}, {"start": 814, "end": 817, "text": "14]", "ref_id": "BIBREF13"}, {"start": 1010, "end": 1013, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 1014, "end": 1017, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 1018, "end": 1021, "text": "[5]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Background", "text": "So far, most studies on double FIT sampling either did not perform colonoscopy in FIT negative individuals [15, 16] , did not evaluate different definitions of positivity for double FIT sampling [14, 17, 19] , or did not assess the effect of different cut-off values [17, 20] . In addition, none of these studies evaluated the effect of multiple sampling on specificity.", "cite_spans": [{"start": 107, "end": 111, "text": "[15,", "ref_id": "BIBREF14"}, {"start": 112, "end": 115, "text": "16]", "ref_id": "BIBREF15"}, {"start": 195, "end": 199, "text": "[14,", "ref_id": "BIBREF13"}, {"start": 200, "end": 203, "text": "17,", "ref_id": "BIBREF16"}, {"start": 204, "end": 207, "text": "19]", "ref_id": "BIBREF18"}, {"start": 267, "end": 271, "text": "[17,", "ref_id": "BIBREF16"}, {"start": 272, "end": 275, "text": "20]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "Background", "text": "This prospective, multi-centre cohort study aims to investigate whether sensitivity for the detection of screen relevant neoplasia (CRC stage I, II or advanced adenomas) of single FIT sampling can be increased by double FIT sampling, without substantially affecting specificity. Primary goal is to compare sensitivity and specificity of single FIT sampling and different strategies of double FIT sampling, at a predefined range of cut-off values, in a colonoscopy controlled population. In this study, we report that double and single FIT sampling have a comparable combination of sensitivity and specificity, at a different cut-off value.", "cite_spans": [], "ref_spans": []}, {"section": "Methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Study population", "text": "From June 2008 to October 2009, all ambulatory patients (\u226518 years) scheduled for elective colonoscopy in three participating medical centres in and around Amsterdam, were invited to participate in this study irrespective of their indication for colonoscopy (i.e. screening, surveillance, or presence of symptoms). Exclusion criteria were either hospitalization, age below 18 years, colostomy, total colectomy, colitis with ulcer(s), or a documented history or subsequent diagnosis of inflammatory bowel disease (IBD). In addition, individuals in which colonoscopic examination remained incomplete due to insufficient bowel lavage or technical difficulties, who did not adhere to the instructions on FIT sampling (e.g. failed to provide the dates of FIT sampling), or could not provide informed consent, were excluded from analysis. The local Medical Ethics Review Boards of each of the hospitals approved this study.", "cite_spans": [], "ref_spans": []}, {"section": "Study design", "text": "All eligible individuals were asked to perform a FIT on two subsequent days prior to colonoscopy. Elective patients were invited to participate in this study by telephone. Individuals interested in the study received a more detailed information package by mail, including two FITs, sampling instructions and an informed consent form. Subjects who could repetitively not be reached by telephone were send the same package with an additional explanatory letter.", "cite_spans": [], "ref_spans": []}, {"section": "Study design", "text": "An automated FIT was used (OC-sensor \u00ae , Eiken Chemical Co., Tokyo, Japan). This semi-quantitative test is considered positive when the haemoglobin concentration in the test tube exceeds the pre-determined cut-off value. Patients were instructed to perform this test on two separate days, before bowel preparation by laxatives was started, and write the date of performance on the FIT container.", "cite_spans": [], "ref_spans": []}, {"section": "Study design", "text": "The baseline FIT was defined as the sample taken from a bowel movement one day prior to colonoscopy (t = -1), whereas the additional FIT for double sampling was performed on stool produced two days before colonoscopy (t = -2; see Figure 1 ). Illustrated and written instructions explained participants to sample their stool without contamination with water or urine. All FITs were sampled at home and there were no restrictions in diet or medication during the week in which stool was sampled. Participants were instructed to obtain FIT samples at a maximum of 72 hours prior to colonoscopy, and to put the FIT samples in the zip lock bags that were included in the mail package. Participants were requested to store the zip lock bags in the refrigerator until departure for the endoscopy department.", "cite_spans": [], "ref_spans": [{"start": 230, "end": 238, "text": "Figure 1", "ref_id": "FIGREF0"}]}, {"section": "Study design", "text": "Completed FITs and informed consent forms were collected at the endoscopy-department at the day of colonoscopy. All FITs were stored at minus 20 degrees Celsius on arrival. Tests were analyzed according to the manufacturer's instructions by an experienced technician, who was unaware of the clinical data, using the OC sensor MICRO desktop analyzer (Eiken Chemical co., Tokyo, Japan) [21] .", "cite_spans": [{"start": 384, "end": 388, "text": "[21]", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Colonoscopy and lesions", "text": "All colonoscopies were performed or supervised by experienced gastroenterologists, who were unaware of the FIT results. Patients were offered to take conscious sedation by Midazolam. A complete colonoscopy was defined as intubation of the caecum with identification of the ileocaecal valve or appendiceal orifice, or intubation up to CRC (irrespective of the location and visualisation of the whole colon). Incomplete colonoscopies or colonoscopies with insufficient bowel preparation, as judged by the individual endoscopist, were excluded unless CRC was found. However, if a barium enema, virtual colonography or second colonoscopy was performed within six months, evaluation of the colon was considered complete and the subject was included in analysis. Patients were classified based on the most advanced lesion detected.", "cite_spans": [], "ref_spans": []}, {"section": "Colonoscopy and lesions", "text": "Histology of tissue samples obtained was evaluated routinely. Lesion size was estimated by the endoscopist. Adenomas \u22651.0 cm, adenomas with a villous component (i.e. tubulovillous or villous adenoma) or adenomas with high-grade dysplasia were defined as advanced adenomas [22] . Colorectal carcinoma was staged according to the AJCC cancer and TNM staging manual [23] . Screen relevant neoplasia were defined as advanced adenoma and/or early stage cancer (i.e. stage I and II).", "cite_spans": [{"start": 272, "end": 276, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 363, "end": 367, "text": "[23]", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "Statistical analysis", "text": "Primary outcome measures were sensitivity and specificity of the baseline FIT (t = -1; henceforth single FIT) and three strategies for double FIT sampling (results of t = -1 and t = -2) for the detection of screen relevant neoplasia. Results of single and double sampling were compared intra-individually and colonoscopy and histopathology were considered as gold standard. This study did not have the intention to determine the cut-off value with optimal sensitivity and specificity for screening. Instead, we evaluated whether a combination of sensitivity and specificity for double FIT sampling exists that is superior to single FIT sampling.", "cite_spans": [], "ref_spans": []}, {"section": "Statistical analysis", "text": "Three different strategies for positive reading of double FIT sampling were used:", "cite_spans": [], "ref_spans": []}, {"section": "Statistical analysis", "text": "1. \"one of two FITs+\": haemoglobin concentrations exceed the cut-off value in at least one out of two samples. 2. \"two of two FITs+\": haemoglobin concentrations exceed the cut-off value in both samples. 3. \"mean of two FITs+\": the geometric mean of haemoglobin concentrations from both samples exceeds the cut-off value.", "cite_spans": [], "ref_spans": []}, {"section": "Statistical analysis", "text": "Test sensitivities and specificities were assessed at cutoff values of 50, 75, 100, 150, and 200 ng/ml. The Exact method was used to calculate 95% confidence intervals. Receiver operator curves (ROC's) for detecting screen relevant neoplasia were calculated for single FIT and all three strategies of double FIT sampling. In addition, sensitivities of all three strategies for double FIT sampling were compared to single FIT sampling at a specificity of 85%, 90% and 95% using McNemar's test for ", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Participants", "text": "Samples were returned by 1589 patients, 493 of which were excluded from further analysis because of reasons listed in Figure 2 . In 33 cases repeated colonoscopy or radiology was performed. Mean age of the participants included was 60, 0 years (range 19-91 yrs, SD 12.5) and 48% of the study cohort was male. Table 1 shows the primary indications for colonoscopy in individuals eligible for analysis. In this cohort 59% (N = 646) of individuals were referred for colonoscopy because of symptoms, whereas 37% (N = 408) of subjects were referred for screening or surveillance colonoscopy. In 4% (N = 42) of all individuals the indication remained unspecified.", "cite_spans": [], "ref_spans": [{"start": 118, "end": 126, "text": "Figure 2", "ref_id": "FIGREF2"}, {"start": 309, "end": 316, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Colonoscopy results", "text": "Colorectal cancer was found in 35 (3, 2%) of 1096 included individuals. Malignancies were classified as stage I in 7 (20%), stage II in 13 (37%), stage III in 6 (17%) and stage IV in 3 (9%) patients. Six rectal cancers (17%) could not be staged accurately due to the effects of preoperative radiation. In 104 (9, 5%) individuals, one or more advanced adenomas were found. Consequently, screen relevant neoplasia were found in 124 (11, 3%) subjects.", "cite_spans": [], "ref_spans": []}, {"section": "Colorectal neoplasia detection and positivity rates", "text": "At a cut-off value of 50 ng/ml, the positivity rate of single FIT was 17%, resulting in detection of 91, 4% (32/35) of CRCs and 60, 6% (63/104) of all advanced adenomas found at colonoscopy. In subjects who tested negative for occult blood on single FIT, the additional FIT detected 2 more CRCs and 7 additional advanced adenomas.", "cite_spans": [], "ref_spans": []}, {"section": "Colorectal neoplasia detection and positivity rates", "text": "Positivity rates ranged from 17-10% (with increasing cutoff values) for single FIT, from 22-12% for \"one of two FITs+\", from 12-7% for \"two of two FITs+\", and from 17-9% for \"mean of two FITs+\".", "cite_spans": [], "ref_spans": []}, {"section": "Sensitivity and specificity of single and double FIT strategies", "text": "Performance characteristics of single FIT and different strategies of double FIT sampling for detecting screen At each cut-off value, maximum sensitivity for screen relevant neoplasia was obtained with \"one of two FITs+\". Compared to single FIT, the highest increase in sensitivity was obtained with \"one of two FITs+\" at either 50, 75 or 100 ng/ml (6.4% increase over single FIT). However, the confidence intervals of the sensitivity of single FIT and \"one of two FITs+\" overlapped, and the specificity of \"one of two FITs+\" (83.0, 87.4 and 89.8% at 50, 75, and 100 ng/ml, respectively) was lower than for single FIT (88.2, 90.5, and 92.5% at 50, 75, and 100 ng/ml, respectively).", "cite_spans": [], "ref_spans": []}, {"section": "Sensitivity and specificity of single and double FIT strategies", "text": "At each cut-off value, maximum specificity was found with \"two of two FITs+\". The highest specificity (97, 5%) of all double FIT strategies was observed for \"two of two FITs+\" at the highest cut-off value (200 ng/ml). However, \"two of two FITs+\" resulted in lower sensitivities than single FIT. Moreover, by using single FIT, comparable specificities as for \"two of two FITs+\" could be reached (up to 95%) by using higher cut-off values (see table 2 ).", "cite_spans": [], "ref_spans": [{"start": 442, "end": 449, "text": "table 2", "ref_id": "TABREF1"}]}, {"section": "Sensitivity and specificity of single and double FIT strategies", "text": "Test characteristics of double FIT sampling strategies were comparable to single FIT sampling at a different cut-off value. For example at 75 ng/ml, the sensitivity of \"one of two FITs+\" (52%) was higher than the sensitivity of single FIT (46%). However, when the cut-off value of single FIT was decreased to 50 ng/ml, sensitivity became 48% (CI 39-57) which is close to sensitivity of \"one of two FITs+\" (52%; CI 43-61). The accompanying specificity of single FIT at 50 ng/ml (88, 2%) was virtually equivalent to the specificity of \"one of two FITs+\" (87, 4%). As shown in table 2, test characteristics of \"mean of two FITs+\" were comparable to single FIT.", "cite_spans": [], "ref_spans": []}, {"section": "Receiver operator curves", "text": "For single FIT and the three double FIT strategies, ROC's were constructed (see Figure 3) . Highest sensitivities were reached with \"one of two FITs+\" and \"mean of two FITs+\", whereas the highest specificities were reached with \"two of two FITs+\". For all double FIT strategies, ROC's and area under the curves (AUC's) either overlapped or were very close to each other (see Figure 3) . Although the highest AUC was found for \"mean of two FITs+\", all AUC's were within the 95% confidence interval of the AUC of single FIT.", "cite_spans": [], "ref_spans": [{"start": 80, "end": 89, "text": "Figure 3)", "ref_id": "FIGREF3"}, {"start": 375, "end": 384, "text": "Figure 3)", "ref_id": "FIGREF3"}]}, {"section": "Comparison at fixed specificities", "text": "To evaluate to what extent an increase in sensitivity by double FIT sampling went at the cost of decreased specificity, single FIT and the three double FIT strategies were analyzed at equal specificities. Table 3 shows cut-off values and sensitivities at 85%, 90% and 95% specificity, for each strategy. At any of these specificities, no strategy for double FIT sampling yielded a sensitivity that differed significantly from the sensitivity of single FIT.", "cite_spans": [], "ref_spans": [{"start": 205, "end": 212, "text": "Table 3", "ref_id": "TABREF2"}]}, {"section": "Additional analysis", "text": "All analyses described above were repeated for the outcomes advanced adenomas and CRC. Results are shown in additional file 1: tables S1-S4 and additional file 1: figures S1 and S2. The results found were very similar to those for screen relevant neoplasia. In total 251 cases were excluded because of an error in FIT sampling. The majority of 155 cases was excluded as the date of sampling of one or both of the tests was unsure. These cases were included in additional analysis, to evaluate if exclusion of these cases would cause bias. As shown in the Additional file 1, the results of these analysis were similar. The remaining 96 sampling errors were due to sampling on or after the day of colonoscopy, performance of only one test, or failure in FIT analysis.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "In the present study three different strategies of double FIT sampling were compared to single FIT sampling. In total, 1096 subjects were included and evaluated by colonoscopy. None of the double FIT strategies proved to have a superior combination of sensitivity and specificity compared to single FIT sampling, as is clear from the comparable ROC's and similar AUC's found for all strategies. When comparing sensitivities of single FIT and the three double FIT strategies at fixed specificities of 85%, 90% and 95%, no relevant differences were observed. In fact, at every level of specificity, a comparable sensitivity as observed for \"one of two FITs+\" could be obtained by single FIT by simply lowering the cut off value.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "A priori expectations were that double FIT sampling would increase sensitivity, as this has been observed previously for g-FOBT and FIT [18, 19, 24] . Accordingly, it was shown in the present study that the highest sensitivity was obtained for ''one of two FITs+''. However, this strategy resulted in the lowest specificity.", "cite_spans": [{"start": 136, "end": 140, "text": "[18,", "ref_id": "BIBREF17"}, {"start": 141, "end": 144, "text": "19,", "ref_id": "BIBREF18"}, {"start": 145, "end": 148, "text": "24]", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Discussion", "text": "Our findings are in line with a recent study in a population with an increased risk for CRC, in which AUC's for the highest out of one, two or three FITs did not differ [18] . Although a direct comparison with a recent Italian screening study is difficult due to different methodology, the authors could also not find a clear superior performance of double over single FIT sampling either [15] . Two other studies on double FIT sampling lacked calculation of direct sensitivity and specificity, as colonoscopy was not performed in FIT negative individuals [15, 16] . These characteristics are needed to determine how an increase in sensitivity is counterbalanced by a decrease in specificity. Less recent studies did not use quantitative FITs or did not evaluate test characteristics at different cut-off values [17, 20] . In a recent study with a high CRC prevalence, average risk individuals sampled stool before screening colonoscopy. The authors found that the sensitivity increased and specificity decreased when a lower cut-off value or multiple tests were used. However, no Test characteristics at different cut-off values (ng/ml) of single and three strategies of double FIT sampling for detection of screen relevant neoplasia in 1081* individuals referred for colonoscopy (SRN in 124, no AA nor CRC in 957). *15 cases of late stage CRC were excluded since they were not considered screen relevant. FIT = faecal immunochemical test, SRN = screen relevant neoplasia, AA = advanced adenoma, CRC = colorectal cancer, \"one of two FITs+\" = at least one of both FITs above the cut-off value, \"two of two FITs+\" = both FITs above the cut-off value, \"mean of two FITs+\" = geometric mean of both FITs above the cut-off value, CI = confidence interval, sens = sensitivity, spec = specificity comparison was made at an equal specificity. The AUC's for advanced neoplasia for one, two or three FITs did not differ [19] . In the present study, the full potential of double FIT sampling was further studied by evaluation of several definitions of positivity. The present study adds important information as it is the first to determine if any of three strategies of double FIT sampling could increase sensitivity for screen relevant neoplasia, without substantially affecting specificity, at different cut-off values and in a colonoscopy controlled population. A limitation of the present study is that not a screening population was tested but a referral population, partially containing high risk individuals. Therefore, test characteristics that depend on the prevalence of disease, i.e. positive and negative predictive values, cannot be generalized from this study to the screening population.", "cite_spans": [{"start": 169, "end": 173, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 389, "end": 393, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 556, "end": 560, "text": "[15,", "ref_id": "BIBREF14"}, {"start": 561, "end": 564, "text": "16]", "ref_id": "BIBREF15"}, {"start": 812, "end": 816, "text": "[17,", "ref_id": "BIBREF16"}, {"start": 817, "end": 820, "text": "20]", "ref_id": "BIBREF19"}, {"start": 1910, "end": 1914, "text": "[19]", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Discussion", "text": "However, the present study focused on sensitivity and specificity, test characteristics that are not influenced by the prevalence of the disease [25] . Still, in this referral population, sensitivity may be overestimated and specificity underestimated due to work-up bias [26] . This may occur as symptomatic participants have an increased likelihood for having both a positive FIT and a colorectal neoplasm. In particular, it should be noted that lower sensitivities for FIT in a screening population have been reported [19, 27] . On the other hand, we carried out a formal comparison of FIT results in CRC cases from a screening and referral cohort and found similar FIT results after correcting for tumour stage [28] . Since for screening, only early stage cancers are relevant, in the present study late stage cancers were excluded from the analysis. Although possible differences in FIT results between referral populations, like in the present study, and screening populations cannot fully be excluded, the present study design still allows for comparing the sensitivities of different sampling schemes for FIT for early stage colorectal cancer. However, a complete correction of work-up bias cannot be ascertained. One should keep in mind that alternative study designs also have limitations like absence of a gold standard because no colonoscopies were performed, or in case colonoscopies were performed, relatively low numbers of cancers found [15, 16, 27] . In addition, in many studies different FITs, different endpoints (advanced adenoma, advanced neoplasia, screen relevant neoplasia), a different amount of cases, and a different selection of participants (e.g. subjects participating in colonoscopy screening) are used.", "cite_spans": [{"start": 145, "end": 149, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 272, "end": 276, "text": "[26]", "ref_id": "BIBREF26"}, {"start": 521, "end": 525, "text": "[19,", "ref_id": "BIBREF18"}, {"start": 526, "end": 529, "text": "27]", "ref_id": "BIBREF27"}, {"start": 715, "end": 719, "text": "[28]", "ref_id": "BIBREF28"}, {"start": 1453, "end": 1457, "text": "[15,", "ref_id": "BIBREF14"}, {"start": 1458, "end": 1461, "text": "16,", "ref_id": "BIBREF15"}, {"start": 1462, "end": 1465, "text": "27]", "ref_id": "BIBREF27"}], "ref_spans": []}, {"section": "Test characteristics screen relevant neoplasia", "text": "To evaluate the effect of work-up bias, analyses were repeated after exclusion of subjects with rectal blood loss, anaemia and clinical suspicion of CRC (data not shown). Although the sensitivities for advanced adenomas found were 4.5-10% lower, our results were similar in the sense that double FIT sampling did not yield any superior combination of sensitivity and specificity compared to single FIT. For CRC data were similar, although too few cases remained to draw firm conclusions (data not shown).", "cite_spans": [], "ref_spans": []}, {"section": "Test characteristics screen relevant neoplasia", "text": "In the current study the number of excluded participants was relatively high. This was mainly due to our stringent protocol on FIT sampling. Of the 251 individuals that were excluded from further analysis, in the majority of cases this was because date of sampling was not registered correctly on the FIT container, as described in the study protocol. Additional analysis including these cases showed similar results. The percentage of incomplete colonoscopies in the present study is in line with previous studies [7, 29] .", "cite_spans": [{"start": 515, "end": 518, "text": "[7,", "ref_id": "BIBREF6"}, {"start": 519, "end": 522, "text": "29]", "ref_id": "BIBREF29"}], "ref_spans": []}, {"section": "Test characteristics screen relevant neoplasia", "text": "According to our study protocol all FITs should be stored in the refrigerator close to the moment of handing in. In addition, both FITs are sampled maximum 72 hours prior to colonoscopy. As such, the time that the tests are at room temperature is kept as limited as possible. FITs kept at higher temperatures, are more susceptible to a decrease in sensitivity as a result of haemoglobin degradation. When compared to at least one of the screening studies [7] this is still a relative short period of time. Therefore, only a slight decrease in haemoglobin concentration is to be expected [30] .", "cite_spans": [{"start": 455, "end": 458, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 587, "end": 591, "text": "[30]", "ref_id": "BIBREF30"}], "ref_spans": []}, {"section": "Test characteristics screen relevant neoplasia", "text": "An important asset of the present study is the relatively high tumour yield, which allowed analyzing FIT performance for early and late stage CRC separately. As the potential health gain is highest for individuals with early stage cancer [31] , this is relevant for population based screening programs. A second strength of this study is the fact that colonoscopy results were available for all participants, allowing the direct calculation of sensitivities and specificities.", "cite_spans": [{"start": 238, "end": 242, "text": "[31]", "ref_id": "BIBREF31"}], "ref_spans": []}, {"section": "Conclusion", "text": "In conclusion, this study strongly suggests that double FIT sampling, regardless of the definition of test positivity, does not provide a superior combination of sensitivity and specificity compared to single FIT sampling. Moreover, if it is aimed to increase sensitivity at the cost of specificity, this can be achieved equally well by lowering the cut-off value of single FIT sampling rather than by double FIT sampling. 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FIT = faecal immunochemical test.", "type": "figure"}, "FIGREF2": {"text": "Figure 2 Study flow diagram of 1589 subjects who participated in FIT sampling and subsequently underwent colonoscopy. \u00b9Incomplete colon evaluation in spite of possible additional evaluation by repeated colonoscopy, barium enema or virtual colonography. FIT = faecal immunochemical test, IBD = inflammatory bowel disease.", "type": "figure"}, "FIGREF3": {"text": "Figure 3 ROC curves of single and double FIT sampling strategies for the detection of screen relevant neoplasia. FIT = faecal immunochemical test, \"one of two FITs+\" = at least one of both FITs above the cut-off value, \"two of two FITs+\" = both FITs above the cut-off value, \"mean of two FITs+\" = geometric mean of both FITs above the cut-off value, AUC = area under the curve, CI = confidence interval.", "type": "figure"}, "TABREF0": {"text": "Primary indications for colonoscopy among 1096 consecutive patients enrolled for evaluation of double FIT samplingFIT = faecal immunochemical test, IBD = inflammatory bowel disease, CRC = colorectal cancer", "type": "table"}, "TABREF1": {"text": "Test characteristics of single and double FIT sampling for detection of screen relevant neoplasia", "type": "table"}, "TABREF2": {"text": "Comparison of sensitivity of single and double FIT sampling for screen relevant neoplasia, at fixed specificities Single FIT \"one of two FITs+\" \" two of two FITs+\" \" mean of two FITs+\"", "type": "table"}}}
{"paper_id": "10702764", "_pdf_hash": "35df5ed7fda44f7715b91cebb434ab9811406f0b", "abstract": [{"section": "Abstract", "text": "Infective endocarditis is a serious complication of intravenous (IV) ", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "The incidence of infective endocarditis (IE) remained relatively stable from 1950 through 2000 at about 3.6 to 7.0 cases per 100,000 patient-years.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "1 In selected areas, the incidence may rise because of the concentration of populations at uniquely high risk of infection, specifically intravenous (IV) drug abusers. The risk of IE among IV drug abusers, 2 to 5% per patient-years, is several-fold greater than that for patients with rheumatic heart disease or prosthetic valves. IE is located on the tricuspid valve in 46 to 58% of patients with IV drug abuse. IV drug abuse is a risk factor for recurrent native valve endocarditis. Staphylococcus aureus causes more than 50% of IE occurring in IV drug abusers overall and 60 to 70% of infection involving the tricuspid valve.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The clinical manifestation of IE in IV drug abusers depends on the valve involved and, to a lesser degree, on the infecting organism. The sensitivity of transthoracic echocardiography (TTE) for the detection of vegetations in patients with native valve endocarditis (NVE) is approximately 65%, whereas that of transesophageal echocardiography (TEE) in these patients is 85 to 95%.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "2 TEE is the preferred approach in patients in whom TTE is technically suboptimal and is the procedure of choice for imaging the pulmonic valve.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "3 When initial TEE is negative and the clinical suspicion of IE remains, repeating TEE within 7 to 10 days is advocated. 4 Perivalvular abscess or intracardiac fistula formation occurs in 10 to 14% of patients with NVE.", "cite_spans": [{"start": 121, "end": 122, "text": "4", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Introduction", "text": "6 Persistent, otherwise unexplained, fever despite appropriate antimicrobial therapy in patients with IE suggests infection extending beyond the valve leaflet. Perivalvular abscess of the tricuspid valve is very rare. TEE is superior to TTE for detecting invasive infection in patients with NVE and prosthetic valve endocarditis (PVE). Cardiac surgery should be considered to debride abscesses, allowing the eradication of uncontrolled infection, and to reconstruct cardiac structures, restoring homodynamic and alleviating congestive heart failure.", "cite_spans": [], "ref_spans": []}, {"section": "Perivalvular Abscess of Tricuspid Valve: A Rare Complication of Infective Endocarditis", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Case report", "text": "A 21-year-old man, who was an IV drug abuser, presented with fever and dyspnea. TTE showed highly mobile, large vegetation on the anterior leaflet of the tricuspid valve and no vegetation on the aortic valve, mitral valve, and pulmonic valve. The patient was admitted to the cardiology ward for antibiotic therapy and received vancomycin and gentamycin. The blood culture of the patient became positive for staphylococcus areus 3 times in 24-hour intervals. Despite the antibiotic therapy for 10 days, the patient remained febrile and developed severe dyspnea. TEE revealed severe aortic insufficiency, moderate tricuspid regurgitation, and an echo-lucent space between the tricuspid and aortic valves (Figures 1) . (Figure 2 ). After consultation with a cardiac surgeon, the patient was transferred to the operating room, where he unfortunately expired due to severe bleeding and disseminated intravascular coagulation.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "IE is a serious complication of IV drug abuse, with a reported mortality of 5 to 10%.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "1 Endocarditis in IV drug abusers commonly involves the tricuspid valve, and Staphylococcus aureus is the most common causative organism. Fever and chills are the most common symptoms. Dyspnea, cough, and chest pain are the common complaints of IV drug users. This is likely related to the predominance of tricuspid valve endocarditis in this group and secondary embolic showering of the pulmonary vasculature. Within a week after the initiation of effective antimicrobial therapy, almost 70% of patients with NVE or PVE are afebrile and 90% have defervesced by the end of the second week of treatment.", "cite_spans": [], "ref_spans": []}, {"section": "5", "text": "Persistence or recurrence of fever more than 10 days after the initiation of antibiotic therapy identifies patients with increased mortality rates and with complications of infection or therapy.", "cite_spans": [], "ref_spans": []}, {"section": "5", "text": "5 Patients with a prolonged or recurrent fever should be evaluated for intracardiac complications.", "cite_spans": [], "ref_spans": []}, {"section": "5", "text": "Perivalvular infection beyond the valve leaflet results in abscesses in the annulus or adjacent structures, intracardiac fistulas, and purulent pericarditis. Periannular extension is common, occurring in 10 to 40% of all native valve IE and complicates aortic valve endocarditis more commonly than mitral or tricuspid valve endocarditis.", "cite_spans": [], "ref_spans": []}, {"section": "5", "text": "3 Intra-cardiac fistulas are rarely seen and they are estimated to account for < 1% of all cases of IE.", "cite_spans": [], "ref_spans": []}, {"section": "5", "text": "6 Fistulization of the paravalvular abscess has been found in 6 to 9% of all cases.", "cite_spans": [], "ref_spans": []}, {"section": "5", "text": "7 Perivalvular abscess and intracardiac fistula of the tricuspid valve is very rare. TEE is the method of choice for abscess detection. IE is a lethal disease if not treated aggressively with parental antibiotics, often in combination with surgery. Cardiac surgery should be considered in patients with perivalvular abscess and intracardiac fistula to debride abscesses and to reconstruct cardiac structures, restoring homodynamic and alleviating congestive heart failure.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "Perivalvular abscess of the tricuspid valve is a rare complication of infective endocarditis. 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Short axis view shows the echo lucent space (abscess) between the tricuspid and aortic valve (arrow) LA, Left atrium; RA, Right atrium; AV, Aortic valve; TV, Tricuspid valve", "type": "figure"}}}
{"paper_id": "10702854", "_pdf_hash": "df00dd111946c055a761782a34f86a11489f330a", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "10703684", "_pdf_hash": "691265a155cc875dc35c3a8da732cb7bd63db1db", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "77.4 1, 77 .85; MS (relative intensity) : mlz 164 (M+ I, 60%)", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF1": {"title": "6-tetra-, 5.0 mmoles) and ethanolamin e (362 mL, 0.3 67 g, 6.0 mmoles) in di oxane (5 mL)", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF6": {"title": "MS (relative intensity) 248 (M+ I, 70%), 230 (20%)", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF7": {"title": "2Hydroxyethyl)-3,4,5,6-tctrahydroxyazcpane Sc. Compound 5c was prepared analogously to compound Sa using azepane 3c (1 .0 mmole, 247 mg) and trifluoroacetic acid (80%, 2 mL", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF8": {"title": "Compound Sc was isolated as a brown viscous liquid", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF11": {"title": "190 (70%), 176 (100%). (3S,4R,5R ,6S)-1-N-( 4-H yd roxybu tyl)-3,4,S,6-tetrahydroxy-4,5-0-isopropylidcneazepane 3d. Compound 3d was prepared analogou~ly to compound 3a using bisepoxide 1 (186 mg, 1.0 mmole) and 4-hydroxybutylamine", "authors": [], "year": "", "venue": "MS (relative intensity): 208 (M+ I, 50%)", "link": null}, "BIBREF12": {"title": "Compound 3d was isolated as a white solid, yield 57%; mp 55\u00b0C", "authors": [], "year": "", "venue": "CH)OH", "link": null}, "BIBREF13": {"title": "879 em-I; 11-1 NMR (CDCh): 8 !.42 (s, 6H), 1.57 (m", "authors": [{"first": "", "middle": [], "last": "Ir (kbr", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF14": {"title": "mlz 276 (M+ I, 40%)", "authors": [], "year": 1950, "venue": "", "link": null}, "BIBREF15": {"title": "Compound Sd was isolated as a pa le ye llow liqu id", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF16": {"title": "IH NMR (CD)OD): 8 1.66 (m, 2H), 1.78 (m, 2H)", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF17": {"title": "MS (relative intensity) : mlz 236 (M + I, 10%)", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF18": {"title": "-Hydroxymethyl)propyl-3,4, 5,6-tetra hyd roxy-4,S-O-isopropylidene azepane 3e. Compound 3e was prepared an alogously to compound 3a using the bi sepoxide 1 ( 186 mg, 1.0 mm ole) and D-2-amino-l-butano l in di oxa ne (2 mL). Com pound 3e was iso lated as a brown so lid oi l, yield 55%", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF21": {"title": "42 (s, 6H), 1.51 -\\.54 (m, I H), 2.66-2 .78 (m , 4H), 2.88 (m, 4H), 3.36 (I, J= I 0.4 Hz, I H), 3.60 (dd, ./=4.6 and 12.1 Hz, IH). 3.84 (brs, 4H)", "authors": [{"first": "", "middle": [], "last": "Ih Nmr (cdc I", "suffix": ""}], "year": "", "venue": "0.88 (I, J=7 .5 Hz, 3H), 1.19-1.25 (m , I H)", "link": null}, "BIBREF22": {"title": "-Hyd roxymethyl)propyl-3,4, S,6-tctra hydroxyazepanc 5e. Compound 5e was prepared analogously to compound Sa lIsing azepanc 3e (19 mg, 0.72 mmole) and trifluoroacetic acid (80%, 2 mL). Compound Se was isolated as a pale yellow liquid, yi eld 67%", "authors": [{"first": "(", "middle": [], "last": "3s", "suffix": ""}, {"first": "", "middle": [], "last": "4r", "suffix": ""}, {"first": "", "middle": [], "last": "Sr", "suffix": ""}, {"first": "", "middle": [], "last": "6s)-1-N-", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF24": {"title": "IH NMR (CD)OD): 8 1.06 (I. J=6.8 Hz, 3H), 1.52-1.70 (m, 1 H)", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF25": {"title": "Dihyd roxypropyl)-3,4, S,6-tetrahyd roxy-4,S-O-isopro pylidcne aze pane 3f. Compound 3f was prepared analogo usly to compound 3a u ing a mixture the bise pox ide 1 (93 mg, 0.5 mole) ell d seri no l (46 mg", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF26": {"title": "Compou nd 3f was iso lated as a brow n colour solid, yie ld 64%", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF30": {"title": "36,60.64, 61.65, 69.90, 73.77, 82.39, 110.26; MS (relative intensity): m/z 278 (M+ I, 60%)", "authors": [{"first": "", "middle": [], "last": "Nm R (c Dlod", "suffix": ""}], "year": "", "venue": "Hz, 2H), 3.88 (dd , J=3. 8 and 5.9 Hz", "link": null}, "BIBREF31": {"title": "Compound 4f was isolated as a brown sol id, yield 36%", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF34": {"title": "m/z 278 (M + I, 20% ), 246 (90%)", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF35": {"title": "Dihyd roxypropyl)-3,4, S,6-tetrahydroxyazepane Sf. Co mpound Sf was prepared analogously to compound Sa usin g azepane 3f (277 mg, 1.0 mmole) and trifluoroacetic acid (80%, 2 mL). Co mpound Sf was isolated as a brown viscous I iquid", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF38": {"title": "-Dihyd roxypropyl)-3,4, S,6-tetrahydroxyazepane 6f. Compound 6f was prepared analogously to compound 6a using azepane 4f (5 2 mg, 1.87 mmo les) and trifluoroacetic acid (80%, 4 mL). Co mpound 6f was isolated as a brown syrupy liquid", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF41": {"title": "MS (relative intensity): mlz 238 (M + I, 60% )", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF42": {"title": "References I (a) Look G C. Fotsch C H & Won g C H, Acc ('hem Res", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF43": {"title": "Win chester 13 & Fleet G W J, Glycobiology, 1992.2. 199 and rcf", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF44": {"title": "609. (b) Elbein 1\\ D", "authors": [{"first": "J", "middle": [], "last": "Ilodgso N", "suffix": ""}, {"first": "Bio", "middle": [], "last": "Technology", "suffix": ""}], "year": 1991, "venue": "Annll Rev Biochem", "link": null}, "BIBREF54": {"title": "37 /\\, 1989, 722 . (c) Spearm an M A", "authors": [{"first": "K", "middle": [], "last": "Ts", "suffix": ""}, {"first": "/\\", "middle": [], "last": "Uno", "suffix": ""}, {"first": "C", "middle": [], "last": "Shimada S &amp; Imokan", "suffix": ""}, {"first": "C", "middle": [], "last": "Res", "suffix": ""}], "year": 1987, "venue": "Jamicson J C & Wri ght J A, bpI Cell Res", "link": null}, "BIBREF56": {"title": "237. 1988. 128 and ref", "authors": [{"first": "S", "middle": [], "last": "Iinrii", "suffix": ""}, {"first": ";", "middle": [], "last": "Fukase", "suffix": ""}, {"first": "T", "middle": [], "last": "Matsuo", "suffix": ""}, {"first": "Y", "middle": [], "last": "Kamcda", "suffix": ""}, {"first": "K ; Cet G W J", "middle": [], "last": "I\\san O N &amp; Matsui", "suffix": ""}, {"first": "A", "middle": [], "last": "Ka Rpass", "suffix": ""}, {"first": "A D", "middle": [], "last": "Raymond", "suffix": ""}, {"first": "L", "middle": ["E"], "last": "Fellows", "suffix": ""}, {"first": "A S", "middle": [], "last": "Tyms", "suffix": ""}, {"first": "S", "middle": [], "last": "Peterson", "suffix": ""}, {"first": "S", "middle": ["K"], "last": "Namgoong", "suffix": ""}, {"first": "N", "middle": ["O"], "last": "Ramsden", "suffix": ""}, {"first": "P", "middle": ["W"], "last": "Smith", "suffix": ""}, {"first": "J C", "middle": [], "last": "Son", "suffix": ""}, {"first": "F", "middle": [], "last": "Wil Son", "suffix": ""}, {"first": "", "middle": [], "last": "Witt Y D R", "suffix": ""}, {"first": "G", "middle": [], "last": "Jacob", "suffix": ""}, {"first": "T W", "middle": [], "last": "Rademacher", "suffix": ""}], "year": "", "venue": "J Med Chem", "link": null}, "BIBREF57": {"title": "For Five-membered ring aza slIgars", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF58": {"title": "Takaoka Y & Wong C 1-1 . 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{"paper_id": "10703719", "_pdf_hash": "44ef0956cf49d3d8e15df264874a1e5bc609f447", "abstract": [], "body_text": [{"section": "", "text": "To the Editor:", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "We are grateful for the interest and comments by Neri et al 1 on our article, 2 and we appreciate the opportunity to respond. We agree with the authors that the finding of an association between fractures and higher bone mineral density (BMD) is not clinically useful. The importance of this finding is more to emphasize the point that the association between T scores and fracture risk is unclear in patients with cystic fibrosis (CF). It may be erroneous to assume that the data from postmenopausal women applies to those with CF. At our institution, the dual energy x-ray absorptiometry report states the fracture risk based on the T score, and that this may be misinterpreted, especially for caregivers who are unfamiliar with CF-related bone disease. Based on this report, bisphosphonates may be prescribed for CF patients with osteoporosis; however, the ability of these drugs to decrease fracture risk has not been studied. Bisphosphonates seem to increase BMD in CF patients, 3, 4 but whether this translates into fracture prevention is unclear. To initiate the long-term use of a drug in a population of young premenopausal patients, which potentially may have effects on fetal development, must be considered carefully.", "cite_spans": [{"start": 984, "end": 986, "text": "3,", "ref_id": "BIBREF3"}, {"start": 987, "end": 988, "text": "4", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "", "text": "Neri et al 1 recognized the importance of developing a tool to evaluate the risk of fractures in CF patients, which, we agree, is much needed. Using World Health Organization criteria, 5 36% of the subjects in our no-fracture group had osteopenia and 9% had osteoporosis. Within the fracture group, 25% had osteopenia and none had osteoporosis. However, it is unclear how knowing this breakdown helps clinicians assess fracture risk, given the paradoxical findings of our study. The more important question is whether or not a different modality for evaluating BMD in CF can identify those patients who are at high risk for fracture based on an abnormal test result. DEXA may not be the appropriate tool for this population. Hopefully, future studies will help to clarify these issues.", "cite_spans": [], "ref_spans": []}, {"section": "Anne Stephenson, MD St. Michael's Hospital Toronto, ON, Canada", "text": "The author has reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). ", "cite_spans": [], "ref_spans": []}, {"section": "Cost Analysis of Intensive Glycemic Control in Critically Ill Adult Patients", "text": "To the Editor:", "cite_spans": [], "ref_spans": []}, {"section": "Cost Analysis of Intensive Glycemic Control in Critically Ill Adult Patients", "text": "We congratulate Krinsley and Jones 1,2 for their impressive improvement in patient survival, which was attributed to tight glucose regulation. Surprisingly, the intensification of therapy led to decreased costs, mainly due to shorter ICU and hospital stays. Fortunately, this finding has already been confirmed. 3 However, they found 1,2 a greater improvement in mortality than did van den Berghe et al 4 in a key study. Moreover, in patients who were more comparable with the patients studied by Krinsley, 1 and Krinsley and Jones, 2 they found no significant improvement in mortality in the intention-to-treat analysis, although a tighter upper limit of 110 mg/dL was used instead of 140 mg/dL. 5 We wonder whether other factors might have influenced the findings. In a before-and-after study, subtle changes in policy or patient characteristics can easily influence outcome without apparent changes in APACHE (acute physiology and chronic health evaluation) II score or diagnostic groups. The obviously very comprehensive database should allow further analyses. It might be worthwhile to check for factors known to influence patient outcome. We would suggest checking the following: medical staff availability; nursing staff availability; nurse/patient ratio; bed occupancy ratio; rate of referred patients; availability of daily rounds; hospital admission and discharge protocols; the introduction of ventilatory protocols; and the introduction of early goal-directed therapy. This might moderate the effect of glucose regulation, putting it more in line with the results of van den Berghe et al. 4 Otherwise, the effect on mortality of a single measure seems incredibly high.", "cite_spans": [{"start": 312, "end": 313, "text": "3", "ref_id": "BIBREF3"}, {"start": 697, "end": 698, "text": "5", "ref_id": "BIBREF5"}, {"start": 1601, "end": 1602, "text": "4", "ref_id": "BIBREF4"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Intensive and Respiratory Care, PO 30.001, Groningen 9700 RB, the Netherlands; e-mail: j.g.zijlstra@ int.umcg", "authors": [{"first": "Jan", "middle": ["G"], "last": "Zijlstra", "suffix": ""}, {"first": "Phd", "middle": [], "last": "", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF1": {"title": "Effect of an intensive glucose management protocol on the mortality of critically ill adult patients", "authors": [{"first": "J", "middle": ["S"], "last": "Krinsley", "suffix": ""}], "year": 2004, "venue": "Mayo Clin Proc", "link": "26461557"}, "BIBREF2": {"title": "Cost analysis of intensive glycemic control in critically ill adult patients", "authors": [{"first": "J", "middle": ["S"], "last": "Krinsley", "suffix": ""}, {"first": "R", "middle": ["L"], "last": "Jones", "suffix": ""}], "year": 2006, "venue": "Chest", "link": null}, "BIBREF3": {"title": "Analysis of healthcare resource utilization with intensive insulin therapy in critically ill patients", "authors": [{"first": "G", "middle": [], "last": "Van Den Berghe", "suffix": ""}, {"first": "P", "middle": ["J"], "last": "Wouters", "suffix": ""}, {"first": "K", "middle": [], "last": "Kesteloot", "suffix": ""}], "year": 2006, "venue": "Crit Care Med", "link": "36962281"}, "BIBREF4": {"title": "Intensive insulin therapy in the critically ill patients", "authors": [{"first": "G", "middle": [], "last": "Van Den Berghe", "suffix": ""}, {"first": "P", "middle": [], "last": "Wouters", "suffix": ""}, {"first": "F", "middle": [], "last": "Weekers", "suffix": ""}], "year": 2001, "venue": "N Engl J Med", "link": "28565783"}, "BIBREF5": {"title": "Intensive insulin therapy in the medical ICU", "authors": [{"first": "G", "middle": [], "last": "Van Den Berghe", "suffix": ""}, {"first": "Wilmer", "middle": ["A"], "last": "Hermans", "suffix": ""}, {"first": "G", "middle": [], "last": "", "suffix": ""}], "year": 2006, "venue": "N Engl J Med", "link": "75157569"}, "BIBREF6": {"title": "Ciclesonide, a Novel Inhaled Steroid, Does Not Affect Hypothalamic-Pituitary-Adrenal Axis Function in Patients With Moderate-to-Severe Persistent Asthma", "authors": [{"first": "", "middle": [], "last": "Szefler", "suffix": ""}], "year": 2005, "venue": "Chest", "link": "19091617"}}, "ref_entries": {"FIGREF0": {"text": "Stephenson A, Jamal S, Dowdell T, et al. Prevalence of vertebral fractures in adults with cystic fibrosis and their relationship to bone mineral density. Chest 2006; 130:539 - 544 2 Kanis JA, Melton LJ III, Christiansen C, et al. Perspective: the diagnosis of osteoporosis. J Bone Miner Res 1994; 9:1137-1142 3 Orens JB, Estenne M, Arcasoy S, et al. International guide- lines for the selection of lung transplant candidates: 2006 update-a consensus report from the Pulmonary Scientific Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 2006; 25:745-755", "type": "figure"}, "TABREF0": {"text": "Correspondence to: Anne Stephenson, MD, St. Michael's Hospi-References 1 Neri AS, Lori I, Taccetti G, et al. Alteration of bone mineral density in cystic fibrosis adults. Chest 2006; 130:1952-1953 2 Stephenson A, Jamal S, Dowdell T, et al. Prevalence of vertebral fractures in adults with cystic fibrosis and their", "type": "table"}}}
{"paper_id": "10703788", "_pdf_hash": "f3390170567351a1a1b051898238ea964c97f90f", "abstract": [], "body_text": [], "bib_entries": {"BIBREF4": {"title": "Facilitative Glucose Transporters", "authors": [{"first": "E", "middle": ["G"], "last": "Saravolac", "suffix": ""}, {"first": "G", "middle": ["D"], "last": "Holman", "suffix": ""}], "year": 1997, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "10703791", "_pdf_hash": "3fedb850cffb5bac660f8398e3e5bfc17871254f", "abstract": [{"section": "Abstract", "text": "The transverse tubular system (TTS) of skeletal muscle fibers represents the morphological basis for the inward spread of conduction of the electrical signal that triggers muscle contraction. A historical account of the main steps contributing to the elucidation of the structure and function of the TTS has been presented by Huxley (1971) .", "cite_spans": [{"start": 326, "end": 339, "text": "Huxley (1971)", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Abstract", "text": "While the localization of the TTS and its association with the sarcoplasmic reticulum (SR) is well documented, there is still a need further to develop our knowledge of the morphology of the connection between the TTS and the plasma membrane. It is generally believed that the TTS opens directly to the extracellular space and that there is continuity between its membrane and the sarcolemma. However, direct observation of such a connection has been clearly shown only for the myotome of fish (Franzini-Arrrrstrong and Porter, 1964). In other muscle fibers, only indirect evidence of the connection has been provided by experiments showing penetration of extracellular tracers into the TTS. These extracellular markers were also observed inside another membranebounded compartment consisting of round profiles named \"caveolae\" (Yamada, 1955) or \"pinocytotic vesicles\" t (Ashurst, 1969) .", "cite_spans": [{"start": 828, "end": 842, "text": "(Yamada, 1955)", "ref_id": "BIBREF14"}, {"start": 871, "end": 886, "text": "(Ashurst, 1969)", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Abstract", "text": "The present study deals with the communication between the TTS, caveolae, and plasma membrane (Peachey, 1965; Ezerman and Ishikawa, 1967; Schiaffino and Margreth, 1968; and Rayns et al., 1968) . A detailed study of the caveolae compartment was undertaken with ruthenium red as an electron-dense tracer. As a result of this study, we propose that in certain species the caveolae compartment represents the transitional region in the connection between the TTS and the sarcolemma.", "cite_spans": [{"start": 110, "end": 137, "text": "Ezerman and Ishikawa, 1967;", "ref_id": "BIBREF2"}, {"start": 169, "end": 192, "text": "and Rayns et al., 1968)", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Abstract", "text": "~The term \"pinocytotic vesicles\" is inadequate for this membrane-bounded compartment, because in adult fibers the round profiles are permanently open to the outside and exclusively located under the sarcolemma.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Experiments were done on the semitendinosus muscle of the frog Rana pipiens. The muscles of both legs were removed and kept in frog Ringer's solution with l0 mg/liter of d-tubocurarine, until they were transferred to a chamber for dissection. A bundle of about four to eight fibers was dissected from the muscle at room temperature, stretched 1.2 times its slack length, and fixed.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Fixation was carried out in 3% glutaraldehyde-H202 in 0.1 M phosphate buffer, pH 7.4 (Peracchia and Mittler, 1972). Postfixation was done with I% osmium tetroxide in 0. I M sodium cacodylate buffer, pH 7.3. The samples were dehydrated in alcohol, passed through propylene oxide, and embedded in Epon 812.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Thin sections were cut with an LKB Ultramicrotome by use of a diamond knife. The sections were supported on 200 mesh carbon-coated grids and double stained with uranyl acetate and lead citrate. Observations were made with an AE1-6B electron microscope at 80 kV. Some grids were examined with a Philips EM 300 electron microscope equipped with a tilting and rotation stage. Tilting series (from -36 ~ to +36 ~ ) were performed.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Different concentrations of ruthenium red (100, 200, and 300 parts per million) were added to the osmium tetroxide solution at room temperature (Luft, 1971), Ruthenium red was used as an extracellular tracer because it heavily stains the basement lamina as well as the lumen of caveolae and transverse tubules.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "In other experiments, after postfixation in osmium tetroxide, the samples were washed five times in 0.1 M sodium acetate (pH 5.5) and block stained with I% uranyl acetate prepared in the same buffer. The samples were left in this solution overnight at room temperature.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "RESULTS", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "The transverse tubular system (TTS) of skeletal muscle fibers represents the morphological basis for the inward spread of conduction of the electrical signal that triggers muscle contraction. A historical account of the main steps contributing to the elucidation of the structure and function of the TTS has been presented by Huxley (1971) .", "cite_spans": [{"start": 326, "end": 339, "text": "Huxley (1971)", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "", "text": "While the localization of the TTS and its association with the sarcoplasmic reticulum (SR) is well documented, there is still a need further to develop our knowledge of the morphology of the connection between the TTS and the plasma membrane. It is generally believed that the TTS opens directly to the extracellular space and that there is continuity between its membrane and the sarcolemma. However, direct observation of such a connection has been clearly shown only for the myotome of fish (Franzini-Arrrrstrong and Porter, 1964) . In other muscle fibers, only indirect evidence of the connection has been provided by experiments showing penetration of extracellular tracers into the TTS. These extracellular markers were also observed inside another membranebounded compartment consisting of round profiles named \"caveolae\" (Yamada, 1955) or \"pinocytotic vesicles\" t (Ashurst, 1969) .", "cite_spans": [{"start": 829, "end": 843, "text": "(Yamada, 1955)", "ref_id": "BIBREF14"}, {"start": 872, "end": 887, "text": "(Ashurst, 1969)", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "", "text": "The present study deals with the communication between the TTS, caveolae, and plasma membrane (Peachey, 1965; Ezerman and Ishikawa, 1967; Schiaffino and Margreth, 1968; and Rayns et al., 1968) . A detailed study of the caveolae compartment was undertaken with ruthenium red as an electron-dense tracer. As a result of this study, we propose that in certain species the caveolae compartment represents the transitional region in the connection between the TTS and the sarcolemma.", "cite_spans": [{"start": 110, "end": 137, "text": "Ezerman and Ishikawa, 1967;", "ref_id": "BIBREF2"}, {"start": 169, "end": 192, "text": "and Rayns et al., 1968)", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "", "text": "~The term \"pinocytotic vesicles\" is inadequate for this membrane-bounded compartment, because in adult fibers the round profiles are permanently open to the outside and exclusively located under the sarcolemma.", "cite_spans": [], "ref_spans": []}, {"section": "MATERIALS AND METHODS", "text": "Experiments were done on the semitendinosus muscle of the frog Rana pipiens. The muscles of both legs were removed and kept in frog Ringer's solution with l0 mg/liter of d-tubocurarine, until they were transferred to a chamber for dissection. A bundle of about four to eight fibers was dissected from the muscle at room temperature, stretched 1.2 times its slack length, and fixed.", "cite_spans": [], "ref_spans": []}, {"section": "MATERIALS AND METHODS", "text": "Fixation was carried out in 3% glutaraldehyde-H202 in 0.1 M phosphate buffer, pH 7.4 (Peracchia and Mittler, 1972) . Postfixation was done with I% osmium tetroxide in 0. I M sodium cacodylate buffer, pH 7.3. The samples were dehydrated in alcohol, passed through propylene oxide, and embedded in Epon 812.", "cite_spans": [], "ref_spans": []}, {"section": "MATERIALS AND METHODS", "text": "Thin sections were cut with an LKB Ultramicrotome by use of a diamond knife. The sections were supported on 200 mesh carbon-coated grids and double stained with uranyl acetate and lead citrate. Observations were made with an AE1-6B electron microscope at 80 kV. Some grids were examined with a Philips EM 300 electron microscope equipped with a tilting and rotation stage. Tilting series (from -36 ~ to +36 ~ ) were performed.", "cite_spans": [], "ref_spans": []}, {"section": "MATERIALS AND METHODS", "text": "Different concentrations of ruthenium red (100, 200, and 300 parts per million) were added to the osmium tetroxide solution at room temperature (Luft, 1971) , Ruthenium red was used as an extracellular tracer because it heavily stains the basement lamina as well as the lumen of caveolae and transverse tubules.", "cite_spans": [], "ref_spans": []}, {"section": "MATERIALS AND METHODS", "text": "In other experiments, after postfixation in osmium tetroxide, the samples were washed five times in 0.1 M sodium acetate (pH 5.5) and block stained with I% uranyl acetate prepared in the same buffer. The samples were left in this solution overnight at room temperature.", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "The Caveolae Compartment", "text": "The term caveola defines a round or slightly flattened membrane-limited profile about 100 nm in diameter, located below the sarcolemma of the muscle fiber.", "cite_spans": [], "ref_spans": []}, {"section": "The Caveolae Compartment", "text": "In Iogitudinal sections (Fig. l) the caveolae are observed closely associated with the plasma mem-brane and aligned in a single row. Each row is made up of a group of 7-15 adjacent caveolae located mainly at the I band, but also spreading over the other bands of the sarcomere. In transverse sections (Fig. 2 ) similar groups of caveolae are observed, along the perimeter of the fiber, at the I band. However, scattered caveolae are also present, as shown in Fig. 2 (small arrows).", "cite_spans": [], "ref_spans": []}, {"section": "The Caveolae Compartment", "text": "As indicated by the presence of ruthenium red in the lumen of caveolae, the caveolae compartment communicated with the extracellular space. The extension of the communication can be inferred by noticing that at least 90% of the caveolae observed were filled with the tracer. A direct observation of such a communication is shown in Fig. 3 . The plasma membrane and the caveolae membranes are continuous via a narrow channel about 17 nm in diameter by 25 nm in length.", "cite_spans": [], "ref_spans": []}, {"section": "The Caveolae Compartment", "text": "In longitudinal and transverse views, the caveolae appear as \"+vesicles\"; however, about 25% of adjacent caveolae counted in this study were continuous with other caveolae through narrow stalks. As an example of these connections, Fig. 4 (arrow) shows a profile, 240 nm in length and 90 nm in width, of approximately twice the length of a single caveola.", "cite_spans": [], "ref_spans": []}, {"section": "The Caveolae Compartment", "text": "Besides their connection to the extracellular space and their fusion to adjacent caveolae, some caveolae are also continuous with a narrow, tortuous tubular profile oriented parallel to the fiber surface. Even though this tubule may represent another type of communication between caveolae, it is also possible that it is part of the T system of the fiber (Figs. 5, 6 ), free of its association with the SR.", "cite_spans": [], "ref_spans": []}, {"section": "Caveolae at the Myotendon Junction", "text": "At the myotendon junction the muscle fiber is divided into numerous finger-shaped projections (Hanak and Bock, 1971) . While maintaining the same characteristics with regard to shape, diameter, and connection to the extracellular space, the caveolae display a different arrangement within these projections. As shown in Fig. 7 , fusion between adjacent caveolae and their continuity with deformed tubular elements are observed more often in this region (arrow, Fig. 7) .", "cite_spans": [], "ref_spans": []}, {"section": "Distribution of the Caveolae with Respect to the Sarcomere", "text": "The typical pattern of distribution of caveolae with respect to the bands of the sarcomere is seen in Figs. 1 and 2 . In longitudinal sections, discrete groups of caveolae are centered at the I band, but also spread over the other bands of the sarcomere (Fig. 8) . In transverse sections, discrete groups of caveolae were also found facing the I band. This pattern suggests a preferential distribution of caveolae at the I band. In order further to examine this possibility we performed an analysis of the density of caveolae at each band of the sarcomere.", "cite_spans": [], "ref_spans": []}, {"section": "Distribution of the Caveolae with Respect to the Sarcomere", "text": "The histogram in Fig. 8 shows that the largest density of caveolae is associated with the sarcoiemma facing the I band. An estimate of the average density of caveolae over the fiber surface, as obtained from thin sections, is about 3 \u2022 l0 s caveolae/cm 2. This value does not include the caveolae located at the myotendon junction. Although the calculated density of caveolae is only a rough approximation, the number of caveolae is clearly severaifold larger than the number of '+sensitive spots\" per unit of surface area (Huxley and Taylor, 1958) .", "cite_spans": [{"start": 523, "end": 548, "text": "(Huxley and Taylor, 1958)", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Association of the T Tubule with Caveolae", "text": "Figs. 5 and 6 show that the caveolae are continuous with tubules below the plasma membrane. In order to investigate the possibility that these tubular profiles are part of the T system, we studied the morphology of the triads as they approach the surface of the fiber.", "cite_spans": [], "ref_spans": []}, {"section": "Association of the T Tubule with Caveolae", "text": "The triads, located deep inside the cytoplasm, display the organization previously described in the literature (Revel, 1962; Porter and Palade, 1957; Peachey, 1965; Franzini-Armstrong, 1970) . These triads are comprised of a tubulous central element and two flattened cisternae as lateral elements. The membrane of the triads displays the unit membrane pattern and are about 7 nm thick (Robertson, 1959) . The cytoplasmic leaflets of both unit membranes are separated by a gap about 10 nm wide, which is crossed by particles (\"feet\") of 16 to 18 nm diameter, spaced about 30 nm center-to-center (Franzini-Armstrong, 1970) .", "cite_spans": [{"start": 165, "end": 190, "text": "Franzini-Armstrong, 1970)", "ref_id": "BIBREF3"}, {"start": 595, "end": 621, "text": "(Franzini-Armstrong, 1970)", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Association of the T Tubule with Caveolae", "text": "Where the triads approach the surface of the fiber the characteristics described above are maintained, except that the complete triad moves away from its close alignment with the Z line (Fig. 9) . At about 150 200 nm from the sarcolemma, the array of particles connecting both cytoplasmic leaflets is lost. In this region, the T tubule opens into a round or slightly flattened profile, about 100 nm in diameter, similar to a caveola (Fig. 9) .", "cite_spans": [], "ref_spans": []}, {"section": "Association of the T Tubule with Caveolae", "text": "We have observed 20 \"face views\" of triads near FIGURE 7 Longitudinal section of a muscle fiber at the myotendon junction, block-stained with uranyl acetate. Note the caveolae apparently located deep in the cytoplasm of the fiber. The arrow points to a connection between a deformed tubule and a caveola.", "cite_spans": [], "ref_spans": []}, {"section": "Association of the T Tubule with Caveolae", "text": "\u2022 60,000.", "cite_spans": [], "ref_spans": []}, {"section": "Association of the T Tubule with Caveolae", "text": "FIGURE I Longitudinal section of two muscle fibers block-stained with ruthenium red. The arrow points to areas of high density of caveolae at both sides of the Z line. Note the spread of caveolae over the other bands of the sarcomere, x 25,000.", "cite_spans": [], "ref_spans": []}, {"section": "Association of the T Tubule with Caveolae", "text": "FIGURE 2 Transverse section of muscle fibers block-stained with ruthenium red. The large arrow points to a group of caveolae and the smaller arrows to areas where caveolae are scattered between the myofilaments. x 32,000.", "cite_spans": [], "ref_spans": []}, {"section": "Association of the T Tubule with Caveolae", "text": "FIGURE 3 Electron micrograph that shows the continuity between the caveolae membrane and the plasma membrane (arrow). Note the heavy deposits of ruthenium red in the basement lamina and in the lumen of the caveolae, x 52,000.", "cite_spans": [], "ref_spans": []}, {"section": "Association of the T Tubule with Caveolae", "text": "FIGURE 4 Longitudinal section of a muscle fiber. Note the elongated profile derived from the fusion between two adjacent caveolae, x 52,000.", "cite_spans": [], "ref_spans": []}, {"section": "Association of the T Tubule with Caveolae", "text": "FIGURE 5 Longitudinal section of a muscle fiber. At the I band a caveola is continuous with a thin tubule. x IO0,O00. cles (previously described for the triads) up to 2 4 nm from the plasma membrane.", "cite_spans": [], "ref_spans": []}, {"section": "D I S C U S S I O N", "text": "It was suggested several years ago (Robertson, 1956 ; and for a complete historical background see Huxley, 1971 ) that the TTS present in the fiber cytoplasm may be the anatomical basis for the inward spread of the electrical signal that triggers the muscle contraction. ,Through the following years, morphologists tried to support this possibility by showing continuity between the plasma membrane and the tubule membrane. However, after years of careful analysis of the fiber surface, success has been reached only in a surprisingly small number of cases (Franzini-Armstrong and Porter, 1964; Birks, 1965; Walker and Schrodt, 1965; Hoyle et al., 1966; Page, 1968; and Ashhurst, 1969 ). An inevitable conclusion of these studies is that the T tubules very infrequently open \"directly\" to the outside.", "cite_spans": [{"start": 35, "end": 51, "text": "(Robertson, 1956", "ref_id": "BIBREF10"}, {"start": 99, "end": 111, "text": "Huxley, 1971", "ref_id": "BIBREF7"}, {"start": 595, "end": 607, "text": "Birks, 1965;", "ref_id": "BIBREF1"}, {"start": 634, "end": 653, "text": "Hoyle et al., 1966;", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "D I S C U S S I O N", "text": "FIGURE 9 Triad region close to the surface of the fiber. Note that the main characteristics of the triad observed in Fig. 12 are maintained. However, the triad moves away from the Z line and then loses the particles associated with the cytoplasmic leaflets. Z, Z line; ES, extracellular space; SR, terminal cisternae of sarcoplasmic reticulum. This electron micrograph was selected from a tilting series.", "cite_spans": [], "ref_spans": []}, {"section": "D I S C U S S I O N", "text": "\u2022 200,000.", "cite_spans": [], "ref_spans": []}, {"section": "D I S C U S S I O N", "text": "The description of caveolae presented in this study may help to clarify the exact morphology of the connection between the TTS and the plasma membrane. It is clear from our results that T tubules can be seen opening to caveolae. We have found that at least 85% of the T tubules, in the intricate subsarcolemmal region, open to caveolae. Furthermore, other results obtained with extracellular tracers show that at least 90% of the caveolae open to the extracellular space and, very frequently, caveolae can be seen fusing among themselves. These observations suggest the following pattern of communication of the TTS with the outside: T tubules run in association with the SR as far as the subsarcolemmai region where they communicate with caveolae, which may also fuse to each other, and then the caveolae open to the extracellular space. That is, the caveolae seem to be the \"openings\" of the TTS of the semitendinosus muscle fibers.", "cite_spans": [], "ref_spans": []}, {"section": "D I S C U S S I O N", "text": "In order for the caveolae to be the morphological representation of the openings of the TTS, they must be distributed preferentially in relation to the bands of the sarcomere. The localization and frequency of the openings of the T tubules to the surface of the fiber have been inferred from the results of Huxley and Taylor (1958) on \"sensitive spots.\" 2 Huxley and Taylor found sensitive spots only when the pipette (2-#m tip diameter) overlapped the Z line of the sarcomeres of semitendinosus fibers. In agreement with these results we have shown that the highest density of caveolae occurs at the I band of the sarcomere. In other skeletal muscle fibers, where the triads face the junction between the A and I bands of the sarcomere, the largest density of caveolae also face the A-I junction (Rayns et al., 1968) . Therefore, the highest density of caveolae seems to occur where the openings of the T tubules have been localized.", "cite_spans": [{"start": 307, "end": 331, "text": "Huxley and Taylor (1958)", "ref_id": "BIBREF8"}, {"start": 797, "end": 817, "text": "(Rayns et al., 1968)", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "D I S C U S S I O N", "text": "An independent piece of evidence concerning the morphological meaning of caveolae is found in the studies of differentiation of the T system (Ezerman and Ishikawa, 1967; Ishikawa, 1968) . These studies suggest that caveolae are the first step in the development of the T tubules from the plasma membrane, in unmatured cultured muscle cells, supporting our conclusion that caveolae are part of the TTS.", "cite_spans": [{"start": 141, "end": 169, "text": "(Ezerman and Ishikawa, 1967;", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "D I S C U S S I O N", "text": "In general, the results reported in this paper are A sensitive spot is defined as the surface region where a localized reduction of membrane potential is able to induce a local contraction (Huxley, 1971) . consistent with the idea that caveolae are the openings of the TTS. However, one point on which we would like to make some comments is the number of caveolae communicating with each T tubule.", "cite_spans": [{"start": 189, "end": 203, "text": "(Huxley, 1971)", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "D I S C U S S I O N", "text": "Our estimate of the number of caveolae gives a ratio of about 100 caveolae per sensitive spot. This surprisingly high ratio and the very high number of caveolae filled with the tracer (at least 90%), leads to the question of whether or not all the caveolae present in the subsarcolemmal region are continuous with the T tubules. A definitive answer cannot be given yet. However, our observations of a high number of interconnected caveolae at the I band strongly suggest that several caveolae are continuous with each T tubule, i.e. each T tubule may have several small openings to the outside.", "cite_spans": [], "ref_spans": []}, {"section": "D I S C U S S I O N", "text": "Our results, as well as those reported in the literature on the morphology of the caveolae compartment, are consistent with the proposition that caveolae represent the openings of the T tubules to the extracellular space.", "cite_spans": [], "ref_spans": []}, {"section": "SUMMARY", "text": "In frog skeletal muscle the region between the T system and the sarcolemma contains single rows of round profiles named caveolae. The largest number of caveolae occur at the I band although caveolae are spread over the rest of the sarcomere. Caveolae are continuous with the extracellular space, with adjacent caveolae, and with the T tubules.", "cite_spans": [], "ref_spans": []}, {"section": "SUMMARY", "text": "These morphological characteristics lead us to propose the caveolae compartment as the opening of the T system to the extracellular space.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "The fine structure of pigeon breast muscle", "authors": [{"first": "D", "middle": ["E"], "last": "Ashurst", "suffix": ""}], "year": 1969, "venue": "Tissue Cell", "link": null}, "BIBREF1": {"title": "The sarcoplasmic reticulum of twitch fibres in the frog sartorius muscle. Muscle. 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{"paper_id": "10704355", "_pdf_hash": "94bffc34879cce6b98c7f214c95ad4ec90a21341", "abstract": [], "body_text": [{"section": "", "text": "T he Effort-Reward Imbalance (ERI) model is a theoretical model originating from medical sociology that explains how psychosocial working conditions can affect health and illness. 1, 2 The model postulates that a lack of reciprocity between \"costs\" and \"gains\" (spending high efforts while receiving low rewards) produces emotional distress that affects both mental and physical health. Effort includes dealing with quantitative workload and time pressure, whereas rewards encompass monetary gratification, career opportunities, esteem, respect, and job security.", "cite_spans": [{"start": 180, "end": 182, "text": "1,", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "", "text": "Prospective studies have demonstrated that ERI increases the risk of several disease outcomes, 3, 4 including cardiovascular disease 5, 6 and mental ill health. [7] [8] [9] [10] Several cross-sectional studies [11] [12] [13] [14] [15] [16] and three prospective studies [17] [18] [19] have shown that ERI also predicts the onset of long-term sickness absence (LTSA). In the prospective studies, ERI predicted LTSA among British civil servants, 17 Finnish public sector employees, 18 and Belgian teachers. 19 To the best of our knowledge, no prospective study has yet investigated whether ERI predicts LTSA in a representative sample of a national workforce.", "cite_spans": [{"start": 95, "end": 97, "text": "3,", "ref_id": "BIBREF3"}, {"start": 133, "end": 135, "text": "5,", "ref_id": "BIBREF5"}, {"start": 161, "end": 164, "text": "[7]", "ref_id": "BIBREF7"}, {"start": 165, "end": 168, "text": "[8]", "ref_id": "BIBREF8"}, {"start": 169, "end": 172, "text": "[9]", "ref_id": "BIBREF9"}, {"start": 173, "end": 177, "text": "[10]", "ref_id": "BIBREF10"}, {"start": 210, "end": 214, "text": "[11]", "ref_id": "BIBREF11"}, {"start": 215, "end": 219, "text": "[12]", "ref_id": "BIBREF12"}, {"start": 220, "end": 224, "text": "[13]", "ref_id": "BIBREF13"}, {"start": 225, "end": 229, "text": "[14]", "ref_id": "BIBREF14"}, {"start": 230, "end": 234, "text": "[15]", "ref_id": "BIBREF15"}, {"start": 235, "end": 239, "text": "[16]", "ref_id": "BIBREF16"}, {"start": 270, "end": 274, "text": "[17]", "ref_id": "BIBREF17"}, {"start": 275, "end": 279, "text": "[18]", "ref_id": "BIBREF18"}, {"start": 280, "end": 284, "text": "[19]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "", "text": "The paucity of prospective studies about ERI and risk of LTSA is surprising because the ERI model might be well-suited for predicting LTSA. There are at least two pathways through which ERI could increase the risk of LTSA. First, ERI might increase risk of onset of ill health, such as cardiovascular disease 5, 6 or depression, [7] [8] [9] [10] which will increase risk of LTSA. Second, employees experiencing a high-cost/low-gain situation at work may be inclined to change this imbalance by reducing their effort, which could be achieved by sickness absence. In this case, sickness absence would not be a consequence of ill health but a coping strategy to deal with adverse psychosocial working conditions. 20 In this article, we examine whether ERI predicts onset of LTSA in a representative sample of the Danish workforce. LTSA is assessed by a national register, allowing us to perform time-to-event analyses and avoid common method bias. We hypothesize that high ERI predicts increased risk of LTSA in the cohort and that the two components (high efforts and low reward) are also associated with an increased risk of LTSA.", "cite_spans": [{"start": 309, "end": 311, "text": "5,", "ref_id": "BIBREF5"}, {"start": 329, "end": 332, "text": "[7]", "ref_id": "BIBREF7"}, {"start": 333, "end": 336, "text": "[8]", "ref_id": "BIBREF8"}, {"start": 337, "end": 340, "text": "[9]", "ref_id": "BIBREF9"}, {"start": 341, "end": 345, "text": "[10]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "METHODS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Study Design and Population", "text": "This study is based on survey data of ERI from the Danish Work Environment Cohort Study (DWECS) in 2000 and register data of LTSA from the Danish Register for Evaluation of Marginalisation (DREAM). After the participants filled in the DWECS survey, they were observed for the next 12 months in DREAM. Records were linked by the unique participants' personal identification number from the central population register. Detailed descriptions of the two data sets and their linkage in work environment studies on sickness absence are published elsewhere. [21] [22] [23] DWECS is a longitudinal study on work and health in the Danish working population, initiated in 1990. 21 In 2000, a representative sample of 11,437 Danish residents was approached, of which 8583 (75%) responded to the survey. Among the respondents, 5016 were gainfully employed at the time of the survey. We have shown in a previous analysis that the sample of the gainfully employed respondents was representative for the Danish workforce with regard to sex and age. 21 There were indications that employees from the city of Copenhagen were somewhat less likely to participate in DWECS compared with employees from other Danish regions. 21 We excluded 147 participants with missing values on key variables. Furthermore, we excluded 94 participants with onset of LTSA during the first 2 weeks of follow-up. This was because several of these participants might have already been ill during the DWECS baseline survey and that their ill health could have affected their responses in the survey. The resulting final study sample consisted of 4775 employees. Mean age was 40 years (range, 18 to 69 years) and 48% were women. Table 1 gives a detailed description of the study sample.", "cite_spans": [{"start": 552, "end": 556, "text": "[21]", "ref_id": "BIBREF21"}, {"start": 557, "end": 561, "text": "[22]", "ref_id": "BIBREF22"}, {"start": 562, "end": 566, "text": "[23]", "ref_id": "BIBREF23"}], "ref_spans": [{"start": 1687, "end": 1694, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Definition and Measurement of ERI", "text": "Because DWECS does not include the original ERI questionnaire, we assessed effort and reward with proxy measures. A detailed report on the construction of these proxy measures, the wording of each item, and the calculation of the scores for effort, reward, and the ERI ratio is published elsewhere. 24 In brief, we measured effort with four items (eg, not having time to complete all work tasks) and rewards with seven items. The seven reward items included all the three dimensions of the reward concept in accordance with Siegrist et al, 2 that is, two financial and status items (prospects for future; appropriateness of salary), three esteem items (recognition and appreciation by management; help and support from colleagues; help and support from supervisors), and two job security items (worried about becoming unemployed; worried about involuntarily transferred to another job). In accordance with the literature, we calculated an effort and reward scale by summing up the respective items and then constructed an \"effort-reward imbalance ratio\" by dividing the effort score by the reward score. ", "cite_spans": [], "ref_spans": []}, {"section": "Definition and Measurement of LTSA", "text": "We defined onset of LTSA as the first record of a sicknessabsence period that lasted 3 weeks or more in DREAM. In Denmark, employers are obliged to finance sickness-absence benefits for the first 21 days of absence (before June 2008, it was the first 15 days). 25 When the absence period exceeds 21 days, the employer is eligible for sickness benefit compensation from the municipality and the compensation is recorded in DREAM. From this point on, the municipality also becomes responsible for managing and evaluating the sickness-absence process and for initiating actions that might help the sickness-absence beneficiary to return to work. For these reasons, we regarded 21 days as a meaningful cutoff point for defining LTSA in a Danish context. DREAM contains weekly updated information on all social transfer payments in Denmark, including granted sickness-absence benefits since 1982. 22, 23 Under specific circumstances, for example, if the sick-listed employee is registered with a chronic disease or if the Copyright \u00a9 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.", "cite_spans": [{"start": 892, "end": 895, "text": "22,", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "Definition and Measurement of LTSA", "text": "workplace has contracted an insurance policy, the municipality pays sickness-benefit compensation already from the first day of absence. Unfortunately, the available data did not allow us to differentiate between beneficiaries who received the usual sickness-absence benefits from those who received benefits under those specific circumstances. Hence, although the vast majority of cases entered the analyses after a sickness-absence period of at least 3 weeks, a small minority of cases might have been on sickness absence for a shorter time period.", "cite_spans": [], "ref_spans": []}, {"section": "Measurement of Covariates", "text": "We recorded age, sex, cohabitation, age of children living at home, current smoking, alcohol consumption, leisure-time physical activity, body mass index, occupational grade, mental health, and LTSA within the last 12 months before baseline. Age and sex were retrieved from the central population register, LTSA within the last 12 months was retrieved from the DREAM register, and the other variables were retrieved from self-report in DWECS. Occupational grade was assessed on the basis of information about job title, occupational position, and education. Mental health was measured with the MHI-5 scale of the 36-item short-form health survey, 26 which ranges from 0 to 100 points, with higher scores indicating better mental health. More detailed descriptions of the covariates are published elsewhere. 21, 24, [27] [28] [29] An overview of the baseline distribution of the covariates in the whole study sample and in participants who became cases of LTSA during follow-up is shown in Table 1 .", "cite_spans": [{"start": 807, "end": 810, "text": "21,", "ref_id": "BIBREF21"}, {"start": 811, "end": 814, "text": "24,", "ref_id": "BIBREF24"}, {"start": 815, "end": 819, "text": "[27]", "ref_id": "BIBREF27"}, {"start": 820, "end": 824, "text": "[28]", "ref_id": "BIBREF28"}, {"start": 825, "end": 829, "text": "[29]", "ref_id": "BIBREF29"}], "ref_spans": [{"start": 989, "end": 996, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Measurement of Covariates", "text": "In addition to these covariates, we also measured physical workload with an index combining five items on (1) sitting at work (reversed), (2) kneeling and squatting, (3) pushing and pulling, (4) carrying and lifting load, and (5) weight of the load that is carried or lifted. This index has been recommended in an earlier analysis by Burr et al. 29 Because physical workload is also considered as an element of effort at work in the original ERI questionnaire, 2 we did not adjust for this covariate in the main analyses but analyzed its potential confounding effect separately.", "cite_spans": [], "ref_spans": []}, {"section": "Statistical Analysis", "text": "We calculated crude and adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the prospective association of a one-SD increase of the ERIratio at baseline with time to onset of LTSA during the 12-month follow-up. Participants were observed until onset of LTSA, censoring due to emigration or death, or end of follow-up, whichever came first. We incrementally adjusted the HRs: in model 1, we adjusted the HRs for sociodemographic variables (age, sex, cohabitation, children at home), and health behaviors (smoking, alcohol consumption, physical activity, and body mass index); model 2 was further adjusted for occupational grade; model 3 was further adjusted for mental health and previous LTSA.", "cite_spans": [], "ref_spans": []}, {"section": "Statistical Analysis", "text": "In supplementary analyses, we used ERI as a categorical variable (ERI ratio divided into quartiles) and stratified analyses by sex and occupational grade. Finally, we examined the separate contribution of effort and reward to LTSA by calculating HR and 95% CI of LTSA for the effort scale, the reward scale, and each single effort and reward item.", "cite_spans": [], "ref_spans": []}, {"section": "Statistical Analysis", "text": "All analyses were conducted with the Stata/SE 12.1 statistical software (StataCorp LP, College Station, TX). Possible violations of the proportional hazard assumption were examined by Schoenfeld residuals.", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "During the 12-month follow-up, 375 participants (7.9%) had an episode of LTSA, 42 (0.9%) were censored due to emigration or death, and 4358 (91.3%) completed the follow-up period without event or censoring. Mean time to onset of LTSA was 26.4 weeks (SD, 15.6) with a median time of 27 weeks. Table 2 shows the crude and multivariate analyses on the prospective association between ERI at baseline and onset of LTSA. ERI did not predict LTSA in any statistical model. In the fully adjusted model, the HR of LTSA for a one-SD increase on the ERI ratio was 1.03 (95% CI, 0.93-1.15). When we used ERI as a categorical variable (quartiles of the ERI ratio) instead of the continuous score, results were similar (data not shown). Adding the physical workload index to the analyses affected the HR only marginally (data not shown).", "cite_spans": [], "ref_spans": [{"start": 292, "end": 299, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "ERI and Onset of LTSA", "text": "Among the covariates, female sex, current smoking, lower occupational grade, and previous LTSA predicted LTSA in the fully adjusted model. Occupational grade showed a strong gradual association with risk of LTSA, that is, the lower the occupational grade, the higher the HR of LTSA. When we analyzed the association between ERI and LTSA stratified by sex, we found similar results as in the main analysis. In the fully adjusted model, the HR of LTSA for a one-SD increase on the ERI ratio was 1.01 (95% CI, 0.88-1.16) among women and 1.08 (95% CI, 0.92-1.27) among men (data not shown in table). Stratification by occupational grade also did not yield any statistically significant result (data not shown). Table 3 shows the HR of LTSA with regard to the effort scale, the reward scale, the three reward subdimensions, and the single effort and reward items adjusted for covariates.", "cite_spans": [], "ref_spans": [{"start": 707, "end": 714, "text": "Table 3", "ref_id": "TABREF2"}]}, {"section": "Effort, Reward, and Onset of LTSA", "text": "The effort scale and the four single effort items were not related to risk of LTSA. A one-SD increase on the reward scale, however, predicted onset of LTSA with an HR of 1.14 (95% CI, 1.03-1.26). Of the three reward subdimensions, a decrease in the dimension \"financial and status reward\" (HR, 1.12; 95% CI, 1.04-1.20) and in its item \"appropriateness of salary\" (HR, 1.20; 95% CI, 1.05-1.38) were statistically significant predictors of LTSA. Adding the physical workload index to the analyses affected the HR only marginally and did not affect the statistical significance of any association (data not shown).", "cite_spans": [], "ref_spans": []}, {"section": "Effort, Reward, and Onset of LTSA", "text": "Postestimation tests showed that the proportional hazard assumption was fulfilled in all analyses.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "We hypothesized that ERI at work predicts onset of LTSA in this representative sample of the Danish workforce. This hypothesis was rejected. There was no association between ERI and LTSA, neither in the crude nor in the adjusted analysis. When we analyzed effort and reward separately, we noted that effort was not related to LTSA. Low reward at work, however, predicted risk of LTSA, as hypothesized. In particular, the reward dimension of low \"financial and status reward\" contributed to risk of LTSA.", "cite_spans": [], "ref_spans": []}, {"section": "Comparison With Earlier Studies", "text": "The results of this study are incongruent with earlier analyses on ERI and health outcomes from the same cohort, which showed that ERI predicted a decline in self-rated health 24 and the onset of severe depressive symptoms 10 after a 5-year follow-up. Both poor self-rated health 30 and severe depressive symptoms 31, 32 are known to predict LTSA and it is therefore surprising that ERI predicted these two health outcomes but not LTSA in this cohort.", "cite_spans": [{"start": 314, "end": 317, "text": "31,", "ref_id": "BIBREF31"}], "ref_spans": []}, {"section": "Comparison With Earlier Studies", "text": "Moreover, our results are in disagreement with three earlier prospective studies that showed an association between ERI and LTSA. In the British Whitehall II Study, ERI assessed with six proxy measures for effort and 10 proxy measures for reward predicted LTSA-defined as absence spells of 8 days or more-in male and female civil servants after adjustment for age, occupational grade, physical illness, and long-standing illness. 17 In the Finnish 10-Town Study, ERI assessed with one proxy measure for effort and three proxy measures for reward predicted LTSA-defined as absence In a Belgian study, ERI assessed with six effort and 11 reward items from the original ERI questionnaire 2 predicted LTSA-defined as absence spells of 4 days or more-in school teachers after adjustment for sex and family situation. 19 Possible explanations for the disagreement of our results with the previous findings are differences in the assessment of ERI, the assessment of LTSA, the study population, and contextual factors. Our assessment of ERI was more comprehensive than the one used in the 10-Town Study,because we covered all the three dimensions of the reward concept. On the contrary, the teacher study measured not only occurrence of exposure, as we did, but also appraisal of the exposure by the participants. With regard to LTSA, we defined this as an absence spell of 21 days or more; whereas, in the previous studies, the criterion for LTSA was already fulfilled after spells of 4 days or more (10-Town Study and teacher study) and 8 days or more (Whitehall II Study), respectively. Furthermore, the study populations of all the three previous studies were public sector employees, whereas our study population included employees from both the public and the private sector. Finally, our results might be explained by contextual factors, such as differences in the sickness-absence legislations and practices in the different countries. 25 In line with our results, Lund et al 33 have previously reported that high rewards protected against very-long-term sickness absence of 8 weeks or more in the DWECS cohort. Nevertheless, the reward scale used by Lund et al 33 was not constructed according to the conceptualization in the ERI model. It included only three items, two of the items we also used in the present study (acknowledgement and appreciation by management and job prospects) and one additional item on acknowledgement and appreciation by society.", "cite_spans": [], "ref_spans": []}, {"section": "The Role of Occupational Grade", "text": "Occupational grade was a strong predictor of LTSA. Compared with the reference group of high-grade white-collar workers, all other groups had a statistically significantly increased risk of LTSA. There was a clear indication of a dose-response association between decreasing occupational grade and increasing risk of LTSA. This is in line with previous research on another Danish workforce sample that also reported a strong occupational gradient in risk of LTSA. 34 Earlier, we reported that the association between ERI and risk of severe depressive symptoms was stronger among employees at lower occupational grade. 10 We therefore considered occupational grade as an effect modifier and conducted additional analyses stratified by occupational grade. Nevertheless, these stratified analyses did not yield any substantially different results and did not indicate effect modification by occupational grade.", "cite_spans": [], "ref_spans": []}, {"section": "Strengths and Weaknesses of the Study", "text": "The strengths of the study are the prospective design and the use of a representative cohort of a national workforce. Consequently, the results are not restricted to specific industries or occupational groups but can be generalized to the Danish workforce.", "cite_spans": [], "ref_spans": []}, {"section": "Strengths and Weaknesses of the Study", "text": "Another strength of the study is the use of a national register on sickness-absence payments to assess LTSA. This allowed us to follow-up with all participants and to perform time-to-event analyses. DREAM has been extensively used for sickness-absence research in Denmark and the validity of the register for research use is well documented. 22, 23 The ERI model is a well-established theory for defining adverse psychosocial working conditions. In our study, we assessed ERI by proxy measures because the original ERI questionnaire was not available in the study. We have previously shown that these proxy measures predicted health outcomes, 10, 24, 27 and therefore considered the ERI measure as valid operationalization of adverse psychosocial work environment exposures. Nevertheless, we acknowledge that the items and the response scales are not identical to those in the original ERI questionnaire. In particular, the response scales differed substantially. In the original ERI questionnaire, participants are asked to assess the occurrence or nonoccurrence of the exposure and to further assess the extent to which they felt distressed by the exposure. 2 In our study, we only asked the participants to rate the frequency of the exposure and did not assess their distress level. 24 Hence, in the original ERI questionnaire, both occurrence of the exposure and psychological reaction to the exposure are measured, whereas our measurement was restricted to the occurrence of the exposure.", "cite_spans": [{"start": 342, "end": 345, "text": "22,", "ref_id": "BIBREF22"}, {"start": 643, "end": 646, "text": "10,", "ref_id": "BIBREF10"}, {"start": 647, "end": 650, "text": "24,", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Strengths and Weaknesses of the Study", "text": "As in other studies on ERI, we measured ERI and its components by self-report. Self-reported psychosocial exposure measures have many advantages, but they have the major disadvantage that they might be biased by negative effect or other personal characteristics. 35 As the ERI model defines both effort and reward as individual appraisals of these constructs, developing non-self-reported measures might not be feasible. Thus, we tried to account for bias by adjusting the analyses for mental health at baseline.", "cite_spans": [], "ref_spans": []}, {"section": "Strengths and Weaknesses of the Study", "text": "The DREAM database does not include information about diagnosis. Therefore, we could only analyze LTSA in general and not cause-specific LTSA. This prevented us from analyzing whether ERI might have different effects on LTSA due to different causes, for example, due to cardiovascular disease, mental disorders, or musculoskeletal disorders.", "cite_spans": [], "ref_spans": []}, {"section": "CONCLUSIONS", "text": "We conclude that self-reported ERI did not predict LTSA in a representative sample of the Danish workforce. 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Unauthorized reproduction of this article is prohibited.", "type": "figure"}, "FIGREF2": {"text": "Copyright \u00a9 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.", "type": "figure"}, "TABREF0": {"text": "Baseline Characteristics of the Whole Study Sample and of Participants With Onset of LTSA During Follow-Up", "type": "table"}, "TABREF1": {"text": "ERI at Baseline and Onset of LTSA During 12-Month Follow-Up", "type": "table"}, "TABREF2": {"text": "Association", "type": "table"}}}
{"paper_id": "10704476", "_pdf_hash": "b7462fb72657ab22d8b4f6a85185961dc8f2d613", "abstract": [{"section": "Abstract", "text": "We report on the preliminary determination of the visual orbit of the double-lined spectroscopic binary system BY Draconis with data obtained by the Palomar Testbed Interferometer in 1999. BY Dra is a nearly equal-mass double-lined binary system whose spectroscopic orbit is well known. We have estimated the visual orbit of BY Dra from our interferometric visibility data fit both separately and in conjunction with archival radial velocity data. Our BY Dra orbit is in good agreement with the spectroscopic results. Due to the orbit's face-on orientation, the physical parameters implied by a combined fit to our visibility data and radial velocity data do not yet result in precise component masses and a system distance, but with continued interferometric monitoring we hope to improve the mass estimates to better than 10% determinations.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "BY Draconis (HDE 234677, Gl 719) is a well-studied nearby (\u223c 15 pc), multiple stellar system containing at least three objects. The A and B components form a short-period (6 d) late-type (K6 Ve -K7 Vvar) binary system, whose spectroscopic orbit is well known (Bopp & Evans 1973, hereafter BE73; Vogt & Fekel 1979, hereafter VF79; and Lucke & Mayor 1980, hereafter LM80) . BY Dra is the prototype of a class of late-type flare stars characterized by photometric variability due to star spots, rapid rotation, and Ca II H and K emission lines. Like the BY Dra system itself, a large fraction (> 85%, Bopp & Fekel 1977 , Bopp et al. 1980 ) of BY Dra stars are known to be in short-period binary orbits. The rapid rotation of BY Dra A (period 3.83 d) that gives rise to the spotting and photometric variability is consistent with pseudosynchronus rotation with the A -B orbital motion (Hut 1981 , Hall 1986 ), but pseudosynchronization is disputed by Glebocki & Stawikowski (1995 , 1997 who assert asynchronous rotation and roughly 30 \u2022 misalignment of the orbital/rotational angular momentum vectors.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Despite the fact that the BY Dra A and B components are nearly equal mass, the system exhibits a significant brightness asymmetry in spectroscopic studies (VF79, LM80). VF79", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "1 Infrared Processing and Analysis Center, California Institute of Technology 2 Jet Propulsion Laboratory, California Institute of Technology 3 Geology and Planetary Sciences, California Institute of Technology attributes this to the hypothesis that A and B components of BY Dra are pre-main sequence objects (VF79, Bopp et al. 1980) , and are still in the contraction phase. VF79 argues for physical sizes of the A component in the range of 0.9 -1.4 R \u2299 , based primarily on rotation period and v sin i considerations. LM80 concur with the A component physical size argument from their v sin i measurements, estimating a 1.2 R \u2299 size for a sin i \u2248 0.5 (presuming rotation/orbit spin alignment with pseudosynchronization, and our orbital inclination from Table 2 ). However, they continue by pointing out that if the A component macroturbulance were significantly larger than solar, then the v sin i measurements and the component diameters they are based on are biased high. If the pre-main sequence interpretation is correct, the BY Dra components are additionally interesting as an examples of the transition region between pre and zero-age main sequence states.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "BY Dra was detected as a hierachical triple system through common proper motion measurements of a BY Dra C component by Zuckerman et al. (1997) ; they find the C component separated by 17\" from the A -B pair. Zuckerman's photometry on the C component is consistent with an M5 main-sequence interpretation (V -K \u2248 6.2); assuming all three stars are coeval this clearly poses problems for the VF79 pre-main sequence hypothesis for the A and B components. At a projected physical separation of approximately 260 AU from the A -B binary, the putative low-mass C component would have negligible dynamical influence on the A -B binary motion. Further, the Hipparcos catalog (ESA 1997) implies the presence of at least one additional component as it lists BY Dra as having a circular photocentric orbital solution with 114 d period. This 114 d period is previously unreported in spectroscopic studies, and if correct it is difficult to understand why this motion was not previously detected.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Herein we report on a preliminary determination of the BY Dra A -B system visual orbit from near-infrared, long-baseline interferometric measurements taken with the Palomar Testbed Interferometer (PTI). PTI is a 110-m H (1.6\u00b5m) and K-band (2.2 \u00b5m) interferometer located at Palomar Observatory, and described in detail elsewhere (Colavita et al. 1999) . PTI has a minimum fringe spacing of roughly 4 milliarcseconds (10 \u22123 arcseconds, mas) in K-band at the sky position of BY Dra, allowing resolution of the A -B binary system.", "cite_spans": [], "ref_spans": []}, {"section": "Observations", "text": "The interferometric observable used for these measurements is the fringe contrast or visibility (squared, V 2 ) of an observed brightness distribution on the sky. The reader is refered to one of the previous papers in this series (Boden et al. 1999a , Boden et al. 1999b , Boden et al. 2000 for descriptions of the V 2 observables for binary stars.", "cite_spans": [], "ref_spans": []}, {"section": "Observations", "text": "BY Dra was observed in conjunction with objects in our calibrator list ( Table 1 : PTI BY Dra Calibration Objects Considered in our Analysis. The relevant parameters for our two calibration objects are summarized. The apparent diameter values are determined from effective temperature and bolometric flux estimates based on archival broad-band photometry, and visibility measurements with PTI.", "cite_spans": [], "ref_spans": [{"start": 73, "end": 80, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Observations", "text": "multiple times during each of these nights, and each observation, or scan, was approximately 130 sec long. For each scan we computed a mean V 2 value from the scan data, and the error in the V 2 estimate from the rms internal scatter. BY Dra was always observed in combination with one or more calibration sources within \u223c 10 \u2022 on the sky. Table 1 lists the relevant physical parameters for the calibration objects. We have calibrated the V 2 data by methods discussed in Boden et al. (1998) . Our 1999 observations of BY Dra result in 67 calibrated visibility measurements (50 in K-band, 17 in H-band). One notable aspect of our BY Dra observations is that its high declination (51 \u2022 ) relative to our Palomar site (33 \u2022 latitude) puts it at the extreme Northern edge of the delay line range on our N-S baseline (Colavita et al. 1999 ), implying extremely limited u \u2212 v coverage on BY Dra. To our PTI visibilities we have added 44 double-lined radial velocity measurments: 14 from BE73, seven from VF79, and 23 CORAVEL measurements from LM80.", "cite_spans": [{"start": 472, "end": 491, "text": "Boden et al. (1998)", "ref_id": "BIBREF2"}], "ref_spans": [{"start": 340, "end": 347, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Orbit Determination", "text": "As in previous papers in this series (Boden et al. 1999a , Boden et al. 1999b , Boden et al. 2000 ) the estimation of the BY Dra visual orbit is made by fitting a Keplerian orbit model directly to the calibrated (narrow-band and synthetic wide-band) V 2 and RV data on BY Dra; because of the limited u \u2212 v coverage in our data derivation of intermediate separation vector models is impossible. The fit is non-linear in the Keplerian orbital elements, and is therefore performed by non-linear least-squares methods with a parallel exhaustive search strategy to determine the global minimum in the chi-squared manifold. The reader is refered to the previous papers for futher details on our orbit estimation procedures. Figure 1 depicts the relative visual orbit of the BY Dra system, with the primary component rendered at the origin, and the secondary component rendered at periastron. We have indicated the phase coverage of our V 2 data on the relative orbit with heavy lines; our data samples most phases of the orbit well, leading to a reliable orbit determination. The apparent inclination is very near the estimate given by VF79 based on the primary rotation period, assumed size, and assumption of parallel orbital/rotational angular momentum alignment. The orbit is seen approximately 30 \u2022 from a face-on perspective, which makes physical parameter determination difficult ( \u00a75). Figure 2 illustrates comparisons between our PTI V 2 and archival RV data and our orbit model. In Figure 2a six consecutive nights of K-band visibility data and visibility predictions from the best-fit model are shown, inset with fit residuals along the bottom. That there are only 1 -3 data points in each of the nights follows from the brief time each night that BY Dra is simultaneously within both delay and zenith angle limits. Figure 2b gives the phased archival RV data and model predictions, inset with a histogram of RV fit residuals. The fit quality is consistent with previous PTI orbit analyses.", "cite_spans": [], "ref_spans": [{"start": 718, "end": 726, "text": "Figure 1", "ref_id": "FIGREF1"}]}, {"section": "Orbit Determination", "text": "Spectroscopic orbit parameters (from VF79 and LM80) and our visual and spectroscopic orbit parameters of the BY Dra system are summarized in Table 2 . We give the results of separate fits to only our V 2 data (our \"V 2 -only Fit\" solution), and a simultaneous fit to our V 2 data and the archival double-lined radial velocities -both with component diameters constrained as noted above. All uncertainties in parameters are quoted at the one sigma level. We see good statistical agreement between all the derived orbital parameters with the exception of the LM80 period estimate.", "cite_spans": [], "ref_spans": []}, {"section": "Comparisons With Hipparcos Model", "text": "The Hipparcos catalog lists a circular photocentric orbital solution for BY Dra with a 114 day period (ESA 1997) , presumably in addition to the well-established 6 d period A -B motion. As noted above it is difficult to reconcile this hypothesis with the quality of the existing short-period spectroscopic orbit solutions from VF79 and LM80. However if the A -B system indeed did have a companion with this period, unlike BY Dra C it would lie within PTI's 1\" primary beam, and if sufficiently luminous it would bias the visibility measurements used in our BY Dra A -B visual orbit model. We see no indications of this in our orbital solutions; the quality of our BY Dra visual orbit solution is consistent with our results on other systems. But it remains possible we have misinterpreted our V 2 data in the binary star model fit, and we are motivated to consider the 114-d periodicity hypothesis in the archival RV data.", "cite_spans": [], "ref_spans": []}, {"section": "Comparisons With Hipparcos Model", "text": "We note that the Hipparcos model is a photocentric orbit, and therefore calls for the A -B system to exhibit a reflex motion with radius \u2265 0.05 AU at the putative distance of BY Dra. The 114-d orbit hypothesis is at high inclination (113 \u2022 ), and therefore would produce a radial velocity semi-amplitude for the A -B system barycenter \u2265 3.95 km s \u22121 . This value is large compared to fit residuals observed by VF79 and LM80 in their spectroscopic orbital solutions (and by ourselves in the joint fit with our visibilities; Table 2), suggesting the 114-d motion hypothesis is unlikely.", "cite_spans": [], "ref_spans": []}, {"section": "Comparisons With Hipparcos Model", "text": "To quantify this issue we have considered Lomb-Scargle periodogram analyses of the LM80 BY Dra radial velocity data. We have chosen to use the LM80 data because it is the more precise sample, yielding an rms residual of roughly 0.5 km s \u22121 in our A -B orbit analysis. Figure 3 gives Table 2 : Orbital Parameters for BY Dra. Summarized here are the apparent orbital parameters for the BY Dra system as determined by VF79, LM80, and PTI. We give two separate fits to our data, with and without including archival double-lined radial velocities in the fit. Quantities given in italics are constrained to the listed values in our model fits. We have quoted the longitude of the ascending node parameter (\u2126) as the angle between local East and the orbital line of nodes measured positive in the direction of local North. Due to the degeneracy in our V 2 observable there is a 180 \u2022 ambiguity in \u2126; by convention we quote it in the interval of [0:180). We quote mean absolute V 2 and RV residuals in the fits, |R V 2 | and |R RV | respectively.", "cite_spans": [], "ref_spans": [{"start": 268, "end": 276, "text": "Figure 3", "ref_id": "FIGREF2"}]}, {"section": "Comparisons With Hipparcos Model", "text": "periodograms of the LM80 primary and secondary radial velocity data. First, Figure 3a gives a periodogram of the primary and secondary RV data, with probability of false alarm levels (P f a ) as noted. As expected, both component lines exhibit a significant periodicity at the observed A -B orbit frequency of approximately (6 d) \u22121 (indicated by vertical line). In the same plot we sample the frequency of the 114-d orbit hypothesis, and no comparable periodicity is evident on the scale of the A -B motion.", "cite_spans": [], "ref_spans": [{"start": 76, "end": 85, "text": "Figure 3a", "ref_id": "FIGREF2"}]}, {"section": "Comparisons With Hipparcos Model", "text": "Presuming the 114-d motion hypothesis might be superimposed on the 6-d A -B orbit, in Figure 3b we give a periodogram of the LM80 primary and secondary RV fit residuals to the 6-d hypothesis fit. In Figure 3b we have adjusted to range of the periodogram to finely sample the frequency range around the (114 d) \u22121 hypothesis (indicated by vertical line). No significant periodicity is noted at this or any other frequency. The LM80 RV dataset spans roughly 400 days, so a 4 km s \u22121 amplitude periodicity in this dataset should have been evident in our analysis. Given these considerations, it seems unlikely that our V 2 measurements and A -B orbit model are affected by the presence of a third luminous body.", "cite_spans": [], "ref_spans": [{"start": 86, "end": 95, "text": "Figure 3b", "ref_id": "FIGREF2"}, {"start": 199, "end": 208, "text": "Figure 3b", "ref_id": "FIGREF2"}]}, {"section": "Discussion", "text": "The combination of the double-lined spectroscopic orbit and relative visual orbit allow us to estimate the BY Dra A -B component masses and system distance. However, because of the nearly face-on geometry of the A -B orbit, the accuracy of our inclination estimate, and consequently the component mass estimates and system distance estimate, is relatively poor. The low-inclination geometry is particularly difficult for astrometric studies because the astrometric observable (V 2 in this case) becomes highly insensitive to small changes in the inclination Euler angle. Table 3 lists the physical parameters we estimate from our Full-Fit orbit solution. The mass estimates are in a reasonable range for stars of this type but are formally crude -roughly 24% 1-\u03c3 uncertainties, as is the system distance estimate -roughly 8% 1-\u03c3. In both cases the dominant error is the inclination; to improve these mass and distance estimates by a factor of two we must improve the inclination estimate by a factor of two. The orbital parallax with its large error is in 1-\u03c3 agreement with the Hipparcos triginometric determination of 60.9 \u00b1 0.75 mas, but we note that the Hipparcos solution was derived jointly with the 3 mas, 114-d orbital hypothesis that we believe to be suspect ( \u00a74). Table 3 also gives component absolute magnitudes and V -K color indices derived from archival broad-band photometry, our H and K component relative magnitudes, the LM80 V relative magnitude, and our system distance estimate. The component color indices are unaffected by errors in the system distance, and seem to be in good agreement with the color indices expected from stars in this mass range and the classical spectral typing of the BY Dra system. The absolute magnitudes are somewhat uncertain from the relatively poor distance estimate, but suggest a modest discrepancy with the mass-luminosity models of Baraffe et al (1998, BCAH98) . As depicted in Figure 4 , both components appear roughly 0.5 -1 mag brighter at V and K than the BCAH98 models evaluated at our model masses would predict. The cause for this discrepancy could be abnormally large component sizes suggested by VF79, or the component masses are underestimated in our analysis. Clearly we need to improve our orbit model so as to further constrain the BY Dra component parameters.", "cite_spans": [], "ref_spans": [{"start": 1933, "end": 1941, "text": "Figure 4", "ref_id": "FIGREF3"}]}, {"section": "Discussion", "text": "To assess the VF79 component size/pre-main sequence hypothesis, the most interesting measurement of the BY Dra A -B system would be unequivocal measurements of the component diameters. Unfortunately our V 2 data are as yet insufficient to determine these diameters independently. Canonical sizes of 1.0 R \u2299 and 0.8 R \u2299 (indicated by model effective temperatures and our IR flux ratios) yield angular diameters of approximately 0.6 and 0.5 mas for the A and B components respectively. At these sizes neither the H nor K-band fringe spacings of PTI sufficiently resolve the components to independently determine component sizes. Consequently we have constrained our orbital solutions to these 0.6 and 0.5 mas model values. Our data does in fact prefer the slightly smaller primary component diameter to the larger 1.2 R \u2299 size implied by VF79 and LM80 v sin i and rotational period measurements. However either primary model diameter is possible with the expected systematic V 2 calibration errors. Additional data we will collect in the coming year (see below) may well place interesting upper limits on the component sizes, but unambiguous resolution of the BY Dra A and B components will have to wait for a longer baseline infrared interferometer; most likely the CHARA array currently under construction on Mt. Wilson 4", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "The prospects for improving the BY Dra orbital model in general, and the orbital inclination estimate in particular are reasonable. To acheive 10% mass determinations on the BY Dra components we will need to reduce the inclination uncertainty to approximately 1.5 \u2022 , which implies a rough quadrupling of the PTI visibility data on BY Dra, or an improvement of our V 2 measurement precision by a factor of two on a data set of similar size to that already collected. Both are plausible; PTI is expected to be in normal operation for at least another season, and hardware upgrades to the PTI fringe camera are planned and should provide significant improvements in sensitivity. , superimposing low mass objects from Henry & McCarthy (1993) and Andersen (1990) and BCAH98 solar-metalicity model tracks at ages of 10 9 , 10 8 , and 10 7 yrs. While our mass determinations are currently too crude to be definitive, both components appear over-luminous compared to the BCAH98 models, and it is difficult to reconcile the deviations with age effects. 3.019 \u00b1 0.039 3.598 \u00b1 0.061 Table 3 : Physical Parameters for BY Dra. Summarized here are the physical parameters for the BY Dra A -B system as derived primarily from the Full-Fit solution orbital parameters in Table  2 . Quantities listed in italics (i.e. the component diameters, see text discussion) are constrained to the listed values in our model fits.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF2": {"title": "Proc. SPIE", "authors": [{"first": "A", "middle": [], "last": "Boden", "suffix": ""}], "year": 1998, "venue": "", "link": null}, "BIBREF10": {"title": "The Hipparcos and Tycho Catalogues", "authors": [], "year": "", "venue": "ESA 1997", "link": null}}, "ref_entries": {"FIGREF1": {"text": "Fig. 1.-Visual Orbit of BY Dra. The relative visual orbit model of BY Dra is shown, with the primary and secondary objects rendered at T 0 (periastron). The heavy lines along the relative orbit indicate areas where we have orbital phase coverage in our PTI data (they are not separation vector estimates); our data samples most phases of the orbit well, leading to a reliable orbit determination. Component diameter values are estimated (see discussion in \u00a7 5), and are rendered to scale.", "type": "figure"}, "FIGREF2": {"text": "Fig. 3.-Lomb -Scargle Periodograms on LM80 BY Dra Radial Velocity Data. To assess the 114-d orbit hypothesis for an additional companion to the BY Dra A -B system we have performed Lomb -Scargle periodogram analysis on double-lined BY Dra data from LM80. Top: standard periodograms on primary and secondary RV data from the LM80 dataset. Statistically significant response is seen at the well-known 6 d A -B period (vertical line). Bottom: Low-frequency periodogram of the residuals of the LM80 data to the best-fit A -B orbit model. No significant response is evident at the putative 114 d period (vertical line).", "type": "figure"}, "FIGREF3": {"text": "Fig. 4.-BY Dra Components in Mass/Luminosity Space. Here we give the positions of the A and B BY Dra components in observable Mass/M V (upper pannel) and Mass/M K (lower pannel) spaces (an emulation of Figure 3 from BCAH98), superimposing low mass objects from Henry & McCarthy (1993) and Andersen (1990) and BCAH98 solar-metalicity model tracks at ages of 10 9 , 10 8 , and 10 7 yrs. While our mass determinations are currently too crude to be definitive, both components appear over-luminous compared to the BCAH98 models, and it is difficult to reconcile the deviations with age effects.", "type": "figure"}, "TABREF0": {"text": "by PTI in K-band (\u03bb \u223c 2.2\u00b5m) on 21 nights between 23 June 1999 and 21 October 1999, covering roughly 20 periods of the system. Additionally, BY Dra was observed by PTI in H-band (\u03bb \u223c 1.6\u00b5m) on 13 September, 2 October, and 20 October 1999. BY Dra, along with calibration objects, was observed", "type": "table"}, "TABREF2": {"text": "System Distance (pc) 15.2 \u00b1 1.2 \u03c0 orb (mas) 65.8 \u00b1 5.4 Model Diameter (mas) 0.60 (\u00b1 0.06) 0.50 (\u00b1 0.05)", "type": "table"}}}
{"paper_id": "10704612", "_pdf_hash": "f3eba87228705f431b565fda0bfc46b9aa51c35a", "abstract": [], "body_text": [{"section": "Introduction", "text": "Signals of 1/ f noise type are widely observed in biomedical engineering, ranging from heart rate to DNA and protein, see, for example, , just to cite a few. Predicting such a type of signals is desired in the field [38] [39] [40] [41] [42] [43] . A fundamental issue in this regard is whether a biomedical signal of 1/ f noise type to be predicted is predicable or not.", "cite_spans": [{"start": 216, "end": 220, "text": "[38]", "ref_id": "BIBREF37"}, {"start": 221, "end": 225, "text": "[39]", "ref_id": "BIBREF38"}, {"start": 226, "end": 230, "text": "[40]", "ref_id": "BIBREF39"}, {"start": 231, "end": 235, "text": "[41]", "ref_id": "BIBREF40"}, {"start": 236, "end": 240, "text": "[42]", "ref_id": "BIBREF41"}, {"start": 241, "end": 245, "text": "[43]", "ref_id": "BIBREF42"}], "ref_spans": []}, {"section": "Introduction", "text": "The predictability of signals of non-1/ f noise type is well studied [44] [45] [46] [47] [48] . However, the predictability of 1/ f noise is rarely reported, to our best knowledge. Since many phenomena in biomedical engineering are characterized by 1/ f noise , the predictability issue of 1/ f noise is worth investigating.", "cite_spans": [{"start": 69, "end": 73, "text": "[44]", "ref_id": "BIBREF43"}, {"start": 74, "end": 78, "text": "[45]", "ref_id": "BIBREF44"}, {"start": 79, "end": 83, "text": "[46]", "ref_id": "BIBREF45"}, {"start": 84, "end": 88, "text": "[47]", "ref_id": "BIBREF46"}, {"start": 89, "end": 93, "text": "[48]", "ref_id": "BIBREF47"}], "ref_spans": []}, {"section": "Introduction", "text": "Note that minimizing the mean square error (MSE) of prediction is a commonly used criterion in both theory and practical techniques of prediction, see, for example, [49] [50] [51] [52] [53] [54] [55] [56] [57] [58] [59] [60] [61] [62] [63] [64] [65] [66] [67] [68] . Therefore, a sufficient condition for a biomedical signal x(t) to be predictable is that the variance of its predication error exists. If the variance of the predication error does not exist, on the contrary, it may be difficult to be predicted if not unpredictable. In the case of a signal being bandlimited, the variance of its predication error is generally finite. Consequently, it may be minimized and it is predictable. However, that is not always the case for biomedical signals of 1/ f noise type. Let x(t) be a biomedical signal in the class of 1/ f noise. Then, its PDF is heavy-tailed, and it is LRD, see, for example, Adler et al. [69] , Samorodnitsky and Taqqu [70] , Mandelbrot [71] , Li and Zhao [72] . Due to that, here and below, the terms, 1/ f noise, LRD random function, and heavy-tailed random function are interchangeable.", "cite_spans": [{"start": 165, "end": 169, "text": "[49]", "ref_id": "BIBREF48"}, {"start": 170, "end": 174, "text": "[50]", "ref_id": "BIBREF49"}, {"start": 175, "end": 179, "text": "[51]", "ref_id": "BIBREF50"}, {"start": 180, "end": 184, "text": "[52]", "ref_id": "BIBREF51"}, {"start": 185, "end": 189, "text": "[53]", "ref_id": "BIBREF52"}, {"start": 190, "end": 194, "text": "[54]", "ref_id": "BIBREF53"}, {"start": 195, "end": 199, "text": "[55]", "ref_id": "BIBREF54"}, {"start": 200, "end": 204, "text": "[56]", "ref_id": "BIBREF55"}, {"start": 205, "end": 209, "text": "[57]", "ref_id": "BIBREF56"}, {"start": 210, "end": 214, "text": "[58]", "ref_id": "BIBREF57"}, {"start": 215, "end": 219, "text": "[59]", "ref_id": "BIBREF58"}, {"start": 220, "end": 224, "text": "[60]", "ref_id": "BIBREF59"}, {"start": 225, "end": 229, "text": "[61]", "ref_id": "BIBREF60"}, {"start": 230, "end": 234, "text": "[62]", "ref_id": "BIBREF61"}, {"start": 235, "end": 239, "text": "[63]", "ref_id": "BIBREF62"}, {"start": 240, "end": 244, "text": "[64]", "ref_id": "BIBREF63"}, {"start": 245, "end": 249, "text": "[65]", "ref_id": "BIBREF64"}, {"start": 250, "end": 254, "text": "[66]", "ref_id": "BIBREF65"}, {"start": 255, "end": 259, "text": "[67]", "ref_id": "BIBREF66"}, {"start": 260, "end": 264, "text": "[68]", "ref_id": "BIBREF67"}, {"start": 910, "end": 914, "text": "[69]", "ref_id": "BIBREF68"}, {"start": 941, "end": 945, "text": "[70]", "ref_id": "BIBREF69"}, {"start": 959, "end": 963, "text": "[71]", "ref_id": "BIBREF70"}, {"start": 978, "end": 982, "text": "[72]", "ref_id": "BIBREF71"}], "ref_spans": []}, {"section": "Introduction", "text": "Let p(x) be the PDF of a biomedical signal x(t) of 1/ f noise type. Then, its variance is expressed by", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "where \u03bc x is the mean of x(t) if it exists. Recall that a prediction error is a random function as we shall soon mention below. Therefore, whether the prediction error is of 1/ f noise, or equivalently, heavy-tailed, turns to be a crucial issue we need studying. We aim at, in this research, exhibiting that prediction error of 1/ f noise is heavy-tailed and accordingly is of 1/ f noise. Thus, generally speaking, the variance of a prediction error of a biomedical signal x(t) of 1/ f noise type may not exist or large. That is a reason why predicting biomedical signals of 1/ f noise type is difficult.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The rest of this paper is organized as follows. Heavytailed prediction errors occurring in the prediction of biomedical signals of 1/ f noise type are explained in Section 2. Discussions are in Section 3, which is followed by con-clusions.", "cite_spans": [], "ref_spans": []}, {"section": "Prediction Errors of 1/ f Noise Type", "text": "We use x(n) to represent a biomedical signal in the discrete case for n \u2208 N, where N is the set of natural numbers. Let x N (n) be a given sample of x(n) for n = 0, 1, . . . , N \u2212 1. ", "cite_spans": [], "ref_spans": []}, {"section": "Prediction Errors of 1/ f Noise Type", "text": "where \u03bc e is the mean of e(m). Let P be the operator of a predictor. Then,", "cite_spans": [], "ref_spans": []}, {"section": "Prediction Errors of 1/ f Noise Type", "text": "A natural requirement in terms of P is that Denote by p Pareto (e) the PDF of the Pareto distribution. Then [73] , it is in the form", "cite_spans": [{"start": 108, "end": 112, "text": "[73]", "ref_id": "BIBREF72"}], "ref_spans": []}, {"section": "Prediction Errors of 1/ f Noise Type", "text": "where e \u2265 b, a > 0, and b > 0. The mean and variance of e(m) are, respectively, expressed by", "cite_spans": [], "ref_spans": []}, {"section": "Prediction Errors of 1/ f Noise Type", "text": "The Proof. Let r xx (k) be the autocorrelation function (ACF) of x(n). Then,", "cite_spans": [], "ref_spans": []}, {"section": "Prediction Errors of 1/ f Noise Type", "text": "where k is lag and E the mean operator. Let r MM (k) be the ACF of x M (m). Then,", "cite_spans": [], "ref_spans": []}, {"section": "Prediction Errors of 1/ f Noise Type", "text": "Let r ee (k) be the ACF of e(m). Then,", "cite_spans": [], "ref_spans": []}, {"section": "Prediction Errors of 1/ f Noise Type", "text": "Note that", "cite_spans": [], "ref_spans": []}, {"section": "Prediction Errors of 1/ f Noise Type", "text": "In the above expression, r Mx (k) is the cross-correlation between x M (m) and x(m). On the other side, r xM (k) is the cross-correlation between x(m) and x M (m). Since r Mx (k) = r xM (k), we have", "cite_spans": [], "ref_spans": []}, {"section": "Prediction Errors of 1/ f Noise Type", "text": "Recall that x(m) is 1/ f noise. Thus, it is heavy-tailed and hence LRD. Consequently, for a constant c 1 > 0, we have", "cite_spans": [], "ref_spans": []}, {"section": "Prediction Errors of 1/ f Noise Type", "text": "On the other hand, the predicted series x M (m) is LRD. Thus, for a constant c 2 > 0, the following holds:", "cite_spans": [], "ref_spans": []}, {"section": "Prediction Errors of 1/ f Noise Type", "text": "In (11), if r xM (k) is summable, that is, it decays faster than r x (k) or r M (k), it may be ignored for k \u2192 \u221e. In this case, r ee (k) is still non-summable. In fact, one has", "cite_spans": [], "ref_spans": []}, {"section": "Prediction Errors of 1/ f Noise Type", "text": "Computational and Mathematical Methods in Medicine   3 On the other side, when r xM (k) is non-summable, r e (k) is non-summable too. In any case, we may write r ee (k) by", "cite_spans": [], "ref_spans": []}, {"section": "Prediction Errors of 1/ f Noise Type", "text": "Therefore, the prediction error e(m) is LRD. Its PDF p(e) is heavy-tailed according to the Taqqu's law. Following [72] , therefore, e(m) is a 1/ f noise. This completes the proof.", "cite_spans": [{"start": 114, "end": 118, "text": "[72]", "ref_id": "BIBREF71"}], "ref_spans": []}, {"section": "Discussions", "text": "The present result implies that cautions are needed for dealing with predication errors of biomedical signals of 1/ f noise type. In fact, if specific biomedical signals are in the class of 1/ f noise, the variances of their prediction errors may not exist or large [72] . Tucker and Garway-Heath used to state that their prediction errors with either prediction model they used are large [74] . The result in this paper may in a way provide their research with an explanation. Due to the fact that a biomedical signal may be of 1/ f noise, PDF estimation is suggested as a preparatory stage for prediction. As a matter of fact, if a PDF estimation of biomedical signal is light-tailed, its variance of prediction error exists. On the contrary, the variance of the prediction error may not exist. In the latter case, special techniques have to be considered [75] [76] [77] [78] . For instance, weighting prediction error may be a technique necessarily to be taken into account, which is suggested in the domain of generalized functions over the Schwartz distributions [79] .", "cite_spans": [{"start": 266, "end": 270, "text": "[72]", "ref_id": "BIBREF71"}, {"start": 389, "end": 393, "text": "[74]", "ref_id": "BIBREF73"}, {"start": 858, "end": 862, "text": "[75]", "ref_id": "BIBREF74"}, {"start": 863, "end": 867, "text": "[76]", "ref_id": "BIBREF75"}, {"start": 868, "end": 872, "text": "[77]", "ref_id": "BIBREF76"}, {"start": 873, "end": 877, "text": "[78]", "ref_id": "BIBREF77"}, {"start": 1068, "end": 1072, "text": "[79]", "ref_id": "BIBREF78"}], "ref_spans": []}, {"section": "Conclusions", "text": "We have explained that the prediction error e(m) in predicting biomedical signals of 1/ f noise type is usually LRD. This implies that its PDF p(e) is heavy-tailed and 1/ f noise. Consequently, Var[e(m)] may in general be large. 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"venue": "Lecture Notes in Physics", "link": "60693661"}, "BIBREF77": {"title": "Mean square prediction error for long-memory processes", "authors": [{"first": "L", "middle": [], "last": "Bisaglia", "suffix": ""}, {"first": "S", "middle": [], "last": "Bordignon", "suffix": ""}], "year": 2002, "venue": "Statistical Papers", "link": "122886340"}, "BIBREF78": {"title": "On the predictability of long-range dependent series", "authors": [{"first": "M", "middle": [], "last": "Li", "suffix": ""}, {"first": "J.-Y.", "middle": [], "last": "Li", "suffix": ""}], "year": 2010, "venue": "Mathematical Problems in Engineering", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Denote by x M (m) the predicted values of x(n) for m = N, N + 1, N + M \u2212 1. Then, the prediction error denoted by e(m) is given by e(m) =uses the given sample of x(n) for n = N, N + 1, . . . , 2N \u2212 1 to obtain the predictions denoted by x M (m) for m = 2N, 2N + 1, 2N + M \u2212 1, the error is usually different from (2), which implies that the error e(m) is a random variable. Denote by p(e) the PDF of e(m). Then, its variance is expressed by Var[e(m)] = N+M\u22121 m=N e \u2212 \u03bc e 2 p(e),", "type": "figure"}, "FIGREF1": {"text": ", Var[e(m)] may not exist, making the prediction of biomedical signals of 1/ f noise type difficult with the way of minimizing Var[e(m)].", "type": "figure"}, "TABREF1": {"text": "is heavy tailed. In a certain cases, Var[e(m)] may not exist. To explain the latter, we assume that e(m) follows a type of heavy-tailed distribution called the Pareto distribution.", "type": "table"}, "TABREF2": {"text": "Note that the situation that Var[e(m)] does not exist may not occur if e(m) is light-tailed. Therefore, the question in this regard is whether e(m) is heavy-tailed if a biomedical signal x(n) is of 1/ f noise. The answer to that question is affirmative. We explain it below. Theorem 1. Let x(n) be a biomedical signal of 1/ f noise type to be predicted. Then, its prediction error is heavy-tailed. Consequently, it is of 1/ f noise.", "type": "table"}}}
{"paper_id": "10704774", "_pdf_hash": "058c556f93ffec697499f86ca54b8c242eba3c10", "abstract": [{"section": "Abstract", "text": "High-Q traveling-wave-resonators can enter a regime in which even minute scattering amplitudes associated with either bulk or surface imperfections can drive the system into the so-called strong modal coupling regime. Resonators that enter this regime have their coupling properties radically altered and can mimic a narrowband ref lector. We experimentally confirm recently predicted deviations from criticality in such strongly coupled systems. Observations of resonators that had Q . Here we experimentally confirm these predictions, using high-Q \u0351.10 8 \u0352 microsphere resonators coupled to fiber-optic tapered waveguides. The long photon lifetimes of high-Q microsphere resonators make possible a counterintuitive effect in which minute scattering gives rise to a regime of strong modal coupling. In this regime scattering into the oppositely oriented mode is the dominant scattering process. Resonances are significantly split, and severe deviations of the critical coupling point occur. We show and observe that in certain regimes the TWR acts as a narrow-bandwidth ref lector, causing a strongly ref lected signal and vanishing waveguide transmission.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "In the case of a slowly varying field amplitude the degenerate modes of a TWR-waveguide system can be described by a simple coupled harmonic oscillator model, equivalent to that presented in Refs. 2 and 3:", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "where a is the amplitude of the CCW and CW modes of the resonator and s denotes the input f ield \u0351jsj 2 is the input pump power). The excitation frequency is detuned by Dv with respect to resonance frequency v 0 of the initially degenerate modes and t is the total lifetime of photons in the resonator, which is related to the quality factor by Q vt. Coupling coeff icient k denotes the coupling of the input wave to the CW mode of the resonator. The relation k p 1\u035et ex associates the coupling coefficient with a corresponding lifetime, such that 1\u035et 1\u035et ex 1 1\u035et 0 . The mutual coupling of the CCW and the CW modes is described by a (scattering) lifetime, g. The coupling of the resonator modes to the waveguide gives rise to a transmitted \u0351t\u0352 and a ref lected \u0351r\u0352 f ield:", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "In a microsphere TWR, Rayleigh scattering from surface inhomogenities or density f luctuations will transfer power from the initially excited mode to all the confined and radiative modes of the resonator. The scattering to all modes other than the CW and CCW modes is included in the overall effective loss, given through the intrinsic lifetime, t 0 . The eigenmodes are symmetric and antisymmetric superpositions of the original CW and CCW modes centered about new eigenfrequencies v v 0 6 1\u035e2g (which have a linewidth of 1\u035et). Modifications to the resonator coupling physics can be described in terms of the normalized mode-coupling parameter G \u03f5 t 0 \u035eg. In addition, we introduce the normalized coupling coefficient K \u03f5 t 0 \u035et ex to facilitate the discussion.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "We experimentally observed the frequency splitting of a TWR mode in a tapered fiber-coupled 4 microsphere resonator. Because of the high-Q (typically exceeding 10 8 ), resonances frequently occur as doublets, because only minute scattering is required for easily observable mode splitting.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "In our experiments, the presence of the waveguide made a negligible contribution to the overall scattering, and distributed scattering centers that are intrinsic to the resonator or to its surface dominated. As evidence of this we found that the splitting frequency increased only slightly (less than 5%) while the taper -sphere gap decreased.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "The inset of Fig. 1 is a photograph of a microsphere (diameter, \u03f370 mm) coupled to a tapered fiber. The taper is attached to a 20-nm-resolution positioning stage to adjust the taper-sphere gap, which permits accurate control of external lifetime t ex . A 1.55-mm tunable laser source is used to excite a whispering gallery mode of the resonator. The laser is scanned repeatedly through a scan range that contains the resonance doublet. In our experiments, the transmission \u0351T \u03f5 jt\u035esj ", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "The splitting of degenerate levels in the presence of coupling is a general principle in physics; the formation of energy bands in semiconductors (level repulsion) can be attributed to this principle, as can the splitting of atomic levels in the presence of LS coupling. An optical analog of this effect can be encountered in traveling-wave resonators (TWRs). Each mode possesses a natural twofold degeneracy, which results from the two possible directions of propagation, clockwise (CW) and counterclockwise (CCW). 1 Lifting of the degeneracy can occur when a fraction of the mode energy is scattered into the oppositely oriented mode. The consequences of degeneracy lifting by distributed scattering were theoretically investigated recently. 2 Here we experimentally confirm these predictions, using high-Q \u0351.10 8 \u0352 microsphere resonators coupled to fiber-optic tapered waveguides. The long photon lifetimes of high-Q microsphere resonators make possible a counterintuitive effect in which minute scattering gives rise to a regime of strong modal coupling. In this regime scattering into the oppositely oriented mode is the dominant scattering process. Resonances are significantly split, and severe deviations of the critical coupling point occur. We show and observe that in certain regimes the TWR acts as a narrow-bandwidth ref lector, causing a strongly ref lected signal and vanishing waveguide transmission.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "In the case of a slowly varying field amplitude the degenerate modes of a TWR-waveguide system can be described by a simple coupled harmonic oscillator model, equivalent to that presented in Refs. 2 and 3:", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "where a is the amplitude of the CCW and CW modes of the resonator and s denotes the input f ield \u0351jsj 2 is the input pump power). The excitation frequency is detuned by Dv with respect to resonance frequency v 0 of the initially degenerate modes and t is the total lifetime of photons in the resonator, which is related to the quality factor by Q vt. Coupling coeff icient k denotes the coupling of the input wave to the CW mode of the resonator. The relation k p 1\u035et ex associates the coupling coefficient with a corresponding lifetime, such that 1\u035et 1\u035et ex 1 1\u035et 0 . The mutual coupling of the CCW and the CW modes is described by a (scattering) lifetime, g. The coupling of the resonator modes to the waveguide gives rise to a transmitted \u0351t\u0352 and a ref lected \u0351r\u0352 f ield:", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "In a microsphere TWR, Rayleigh scattering from surface inhomogenities or density f luctuations will transfer power from the initially excited mode to all the confined and radiative modes of the resonator. The scattering to all modes other than the CW and CCW modes is included in the overall effective loss, given through the intrinsic lifetime, t 0 . The eigenmodes are symmetric and antisymmetric superpositions of the original CW and CCW modes centered about new eigenfrequencies v v 0 6 1\u035e2g (which have a linewidth of 1\u035et). Modifications to the resonator coupling physics can be described in terms of the normalized mode-coupling parameter G \u03f5 t 0 \u035eg. In addition, we introduce the normalized coupling coefficient K \u03f5 t 0 \u035et ex to facilitate the discussion.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "We experimentally observed the frequency splitting of a TWR mode in a tapered fiber-coupled 4 microsphere resonator. Because of the high-Q (typically exceeding 10 8 ), resonances frequently occur as doublets, because only minute scattering is required for easily observable mode splitting. 5 In our experiments, the presence of the waveguide made a negligible contribution to the overall scattering, and distributed scattering centers that are intrinsic to the resonator or to its surface dominated. As evidence of this we found that the splitting frequency increased only slightly (less than 5%) while the taper -sphere gap decreased.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "The inset of Fig. 1 is a photograph of a microsphere (diameter, \u03f370 mm) coupled to a tapered fiber. The taper is attached to a 20-nm-resolution positioning stage to adjust the taper-sphere gap, which permits accurate control of external lifetime t ex . A 1.55-mm tunable laser source is used to excite a whispering gallery mode of the resonator. The laser is scanned repeatedly through a scan range that contains the resonance doublet. In our experiments, the transmission \u0351T \u03f5 jt\u035esj ref lection spectra were simultaneously fitted to the coupled oscillator model of Eqs. (1) and (2), and the model parameters were inferred. Figure 1 shows a resonance doublet for a 70-mm sphere \u0351Q 0 1.2 3 10 8 \u0352 with a resonance splitting that corresponds to G 10.", "cite_spans": [], "ref_spans": [{"start": 13, "end": 19, "text": "Fig. 1", "ref_id": "FIGREF0"}, {"start": 624, "end": 632, "text": "Figure 1", "ref_id": "FIGREF0"}]}, {"section": "", "text": "An ideal TWR (characterized by G 0) allows electromagnetic energy carried by a waveguide to be completely transferred to the resonant mode, a property that in the optical and microwave domains is termed critical coupling. Figure 2 shows power transmission and ref lection as a function of external coupling for symmetric excitation \u0351Dv 0\u0352 of a resonator mode. In the absence of scattering \u0351G 0, corresponding to the dotted-dashed curve in Fig. 2 ) the critical point, the point where the waveguide transmission vanishes, occurs at K 1. The fact that the critical coupling point coincides with the point of maximum circulating power is due to the unidirectionality of an ideal traveling-wave resonator. The forward input mode of the waveguide is coupled to only one (CCW or CW) mode of the resonator. In the presence of backscattering, unidirectionality is lost, drastically altering the coupling properties. The modif ications are particularly interesting in the regime of strong modal coupling \u0351G . . 1\u0352. Even in this regime the condition for critical coupling, vanishing transmission \u0351T 0\u0352, can be achieved for Dv 0, as can be seen from Fig. 2 . However, it is not possible to obtain vanishing transmission for the true eigenfrequencies, v v 0 6 1\u035e2g. The point of zero transmission is accompanied by a maximum ref lected signal, which occurs for", "cite_spans": [], "ref_spans": [{"start": 222, "end": 230, "text": "Figure 2", "ref_id": "FIGREF1"}, {"start": 439, "end": 445, "text": "Fig. 2", "ref_id": "FIGREF1"}, {"start": 1139, "end": 1145, "text": "Fig. 2", "ref_id": "FIGREF1"}]}, {"section": "", "text": "This expression shows that a significant shift of the critical point \u0351K 1 without modal coupling) is possible in the strong-coupling regime. The experimental data presented in Fig. 2 were obtained for a mode that exhibited a modal coupling of G 10 and Q 0 1.2 3 10 8 . The observed maximum backref lection was 84%, which agrees very well with the theory predicted maximum (see Fig. 3 ). In addition, the points of maximum backref lection and zero forward transmission were correctly predicted by theory. For reference, the dashed -dotted curve in Fig. 2 gives the case of an ideal TWR characterized by no modal coupling \u0351G 0\u0352. The solid curve in Fig. 2 is a f it obtained by use of a constant splitting frequency and a constant intrinsic lifetime. The theoretical fit shows excellent agreement with the experimental data, despite the fact that the splitting frequency was found to vary slightly as a function of resonator loading.", "cite_spans": [], "ref_spans": [{"start": 176, "end": 182, "text": "Fig. 2", "ref_id": "FIGREF1"}, {"start": 377, "end": 383, "text": "Fig. 3", "ref_id": "FIGREF2"}, {"start": 547, "end": 553, "text": "Fig. 2", "ref_id": "FIGREF1"}, {"start": 646, "end": 652, "text": "Fig. 2", "ref_id": "FIGREF1"}]}, {"section": "", "text": "The maximum ref lection is observed at the critical point and is given by", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "The ref lection asymptotically approaches unity in the limit of large G, with all incoming power coupled back into the direction of the source. We experimentally verified this functional dependence, as is shown in Fig. 3 . The inset of Fig. 3 illustrates that in the strong-modal-coupling regime the TWR behaves as a frequency-selective ref lector. The highest intermode coupling of G 31 was observed in a sphere with a diameter of 30 mm. This large modal coupling implies that the probability for scattering a photon into the oppositely oriented mode was 31 times higher than the probability of a photon's being lost (absorbed or scattered into nonresonant modes). This surprisingly eff icient coupling process can be understood qualitatively if one considers the spatial distribution of the mode in the microsphere. Only light that is scattered into an angular segment that exceeds the mode's cutoff angle is lost 2 ; all the remaining light is channeled back into the CW and CCW propagating Note that the doublet structure is masked, because the lifetime of the mode is of the same order as the lifetime of the modal coupling process. However, the doublet structure is still evident in the spectrum, causing a f lattened frequency response at resonance. modes, thereby inducing modal coupling. Because the ratio of modal volume (approximately quadratic in radius) to sphere volume increases for smaller spheres, the modal coupling is expected to increase as well. This result is in agreement with our experimental findings, as the largest intermode coupling of G \u0d20 30 was generally observed only in spheres with diameters of less than approximately 40 mm. We studied the origin of the scattering amplitudes that cause strong modal coupling by analyzing the sphere's surface about the equatorial plane, using scanning-electron imaging. We found that, for spheres with large intermode coupling, small, localized, and randomly distributed surface defects, which had subwavelength dimensions (typically hundreds of nanometers), were present, whereas in spheres that exhibited negligible mode splitting these defects were absent.", "cite_spans": [], "ref_spans": [{"start": 214, "end": 220, "text": "Fig. 3", "ref_id": "FIGREF2"}, {"start": 236, "end": 242, "text": "Fig. 3", "ref_id": "FIGREF2"}]}, {"section": "", "text": "It is important to note that the critical coupling point in the presence of scattering does not correspond to the point of maximum circulating power. In fact, maximum circulating power occurs with finite transmission. We theoretically investigated the shift of the point of maximum power transfer when one of the new eigenmodes, v v 0 6 1\u035e2g, was excited; and we determined that the largest shift occurs for a modal coupling of G 1.5, where it shifts to K 1.52. Interestingly, in the case of large modal coupling \u0351G . .1\u0352 the maximum power transfer condition approaches the condition K 1, as was the case for weak or no modal coupling \u0351G 0\u0352. The condition K 1 has the special property of corresponding to transmission and ref lection of equal amplitude. In addition, the circulating power is reduced in the presence of modal coupling. Def ining a power reduction factor C for the total circulating power, and assuming that one of the new eigenfrequencies v v 0 6 1\u035e2g is excited, we can write C as", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "The first term on the right-hand side of Eq. (5) is the power contributed by the CW mode, and the second term is the power in the CCW direction. In the limit of no scattering \u0351G 0\u0352, one obtains the ideal circulating power, whereas for large scattering the amount is reduced by a factor of 2.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "In conclusion, we have experimentally confirmed modified coupling properties in the presence of large modal coupling. We observed a shift in the critical coupling point, and a strong ref lected signal. The extent to which the resonator properties are altered depend on normalized modal coupling parameter G. Backref lection as large as 94% was observed, suggesting the use of TWRs as narrowband ref lectors. The resultant modifications of criticality and circulating power are important in cavity QED and nonlinear optical experiments. 8, 9 In addition, the results are potentially important in design considerations for resonator-based optical telecom devices. Finally, it was recently demonstrated that it is possible to couple a sharp tip to a whispering-gallery mode without degrading the Q factor of the mode. 10 This result combined with the observation of large intermode coupling, as shown in this Letter, suggests that a tip can in principle leave intact the Q factor while inducing a signif icant amount of intermode coupling.", "cite_spans": [{"start": 539, "end": 540, "text": "9", "ref_id": "BIBREF8"}], "ref_spans": []}], "bib_entries": {"BIBREF2": {"title": "Waves and Fields in Optoelectronics", "authors": [{"first": "H", "middle": [], "last": "Haus", "suffix": ""}], "year": 1984, "venue": "", "link": "109690023"}, "BIBREF5": {"title": "The doublet structure is not completely symmetric because the associated orthogonal pair of standing waves probes different regions of the sphere's surface", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF6": {"title": "The resonator-waveguide distance with respect to the critical point is DX~ln K", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF8": {"title": "Optical Processes in Microcavities", "authors": [{"first": "R", "middle": ["K"], "last": "Chang", "suffix": ""}, {"first": "A", "middle": ["J"], "last": "Campillo", "suffix": ""}], "year": 1996, "venue": "", "link": "136548377"}}, "ref_entries": {"FIGREF0": {"text": "Fig. 1. Spectral transmission \u0351T \u03f5 jt\u035esj 2 \u0352 and ref lection \u0351R \u03f5 jr\u035esj 2 \u0352 properties 6 of a 70-mm sphere with Q 0 1.2 3 10 8 and a modal coupling of G 10. Solid curve, f it from the model from Eqs. (1). Inset, microsphere coupled to a tapered fiber.", "type": "figure"}, "FIGREF1": {"text": "Fig. 2. Transmission (stars) and ref lection (diamonds) behavior for symmetric Dv 0 excitation relative to K (Ref. 7) for a mode with Q 0 1.2 3 10 8 and a modal coupling of G 10. Solid curve, a theoretical f it with the model from Eqs. (1) and (2). The minimum T 0 occurs at K \u0d20 G and is accompanied by a maximum backref lection of 84%. Dotteddashed curve, transmission for an ideal TWR in the absence of backscattering, where critical coupling occurs for K 1.", "type": "figure"}, "FIGREF2": {"text": "Fig. 3. Experimentally observed and theoretically determined ref lection at the critical point as a function of modal coupling G. Inset, transmission and ref lection at the T 0 point for a mode with G 31. In this case 94% of the optical power is ref lected. Note that the doublet structure is masked, because the lifetime of the mode is of the same order as the lifetime of the modal coupling process. However, the doublet structure is still evident in the spectrum, causing a f lattened frequency response at resonance.", "type": "figure"}}}
{"paper_id": "10705023", "_pdf_hash": "7552af3028fc38a043ff895a25a9680343c7e30d", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Security requirements, risks and recommendations for small enterprise and home-office environments", "authors": [{"first": "D", "middle": [], "last": "Spinellis", "suffix": ""}, {"first": "S", "middle": [], "last": "Kokolakis", "suffix": ""}, {"first": "S", "middle": [], "last": "Gritzalls", "suffix": ""}], "year": 1999, "venue": "Information Management & Computer Security", "link": "6396337"}, "BIBREF1": {"title": "Beyond technology -The human factor in business systems", "authors": [{"first": "Christine", "middle": ["M"], "last": "Orshesky", "suffix": ""}], "year": 2003, "venue": "Journal of Business Strategy", "link": "154135233"}, "BIBREF2": {"title": "Securing Small Business Computer Networks:An Examination of Primary Security , Information Systems Security, The (ISC) 2 Journal, Friday", "authors": [{"first": "Gokhan", "middle": 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{"paper_id": "10705133", "_pdf_hash": "5d8f32298232a0e5e2826a63b33719b73dda3b5c", "abstract": [{"section": "Abstract", "text": "The blood-air barrier in the lung consists of the alveolar epithelium, the underlying capillary endothelium, their basement membranes and the interstitial space between the cell layers. Little is known about the interactions between the alveolar and the blood compartment. The aim of the present study was to gain first insights into the possible interplay between these two neighboured cell layers. We established an in ", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "Original publication in: Neuhaus et al., Differentiation 84 (2012) 294-304.; http://dx.doi. org/10.1016/j.diff.2012.08.006 -7 -tissue flasks and sterile-filtered before usage. The terms ST1, ST1-cond., D3 and D3-cond. are used in the text for fresh or conditioned (cond.) growth medium of the corresponding cells (ST1=HPMEC-ST1.6R, D3=hCMEC/D3). H441 cells were used between passages 56-76, HPMEC-ST1.6R between passages 30-37 and hCMEC/D3", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "between passages 17-34.", "cite_spans": [], "ref_spans": []}, {"section": "Transwell model experiments", "text": "For Transwell insert experiments H441 cells were seeded at a cell density of 23,000 cells/cm 2 onto collagen-I (0.01%, C7661, Sigma) coated 6-well inserts (353090, BD, Heidelberg, Germany, pore size 0,4 \u00b5m, PVDF, transparent, apical volume 2 ml, basolateral volume 3 ml). Medium was renewed every 2-3 days. After five days of culture it was started to add dexamethasone (10, 100, 300 or 1000 nmol/l) to the apical side with every medium change in a ratio of 1:1000 of the appropriate ethanolic stock solution. In order to assess the development of the barrier properties the transepithelial electrical resistance (TEER) was determined using a WPI device with chopstick electrodes (World Presicion Instruments, Berlin, Germany) as previously published (Neuhaus et al., 2008) . In addition to the TEER measurement, transport studies with the paracellular marker fluorescein were undertaken. 10 \u00b5mol/l fluorescein was added in the apical compartment to begin the transport studies. 300 \u00b5l samples were taken after 15, 45, 105, 165 and 225 minutes from the basolateral side and were replaced after each sampling step with 300 \u00b5l fresh, prewarmed H441 medium to maintain the same hydrostatic pressure conditions during the entire transport experiment. Fluorescence of samples, stock solution and supernatants of the apical compartment after the end of the experiment (90 \u00b5l/well in a black 96-well plate from GreinerBioone) were measured with a Tecan GeniosPro (excitation Original publication in: Neuhaus et al., Differentiation 84 (2012) 294-304.; http://dx.doi.org/10.1016 /j.diff.2012 -8 -wavelength: 485 nm; emission wavelength: 535 nm). Calculation of the permeability coefficients was accomplished according the clearance principle as previously published (Neuhaus et al., 2008) and described in the supplementary file in detail. In order to ease the comparison between different experiments, the permeability coefficient values of the control experiments were set to 100% and the other results within the same experiment were normalized to the 100% of the control experiment.", "cite_spans": [{"start": 751, "end": 773, "text": "(Neuhaus et al., 2008)", "ref_id": "BIBREF3"}, {"start": 1758, "end": 1780, "text": "(Neuhaus et al., 2008)", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "mRNA analysis", "text": "mRNA analysis is described in the supplementary file in detail. In brief. mRNA of cells grown on Transwell inserts was isolated with a Nucleospin-RNAII Kit (Macherey Nagel, D\u00fcren, Germany) according to the manufacturer's instructions.", "cite_spans": [], "ref_spans": []}, {"section": "mRNA analysis", "text": "RNA concentrations were determined by means of a Nanodrop ND 2000 spectrophotometer (FisherScientific, Schwerte, Germany , where Ct is the threshold cycle value. For the qualitative proof of the presence of tight junctional proteins cDNA samples were amplified with a 2720 Thermal Cycler (Applied Biosystems) and amplification products were separated on a 2 % agarose gel in TAE-buffer with a peqGOLD 50 bp DNA-ladder (PEQLAB Biotechnologie GmbH, Erlangen, Germany) as marker at 90 V for half an hour. Bands were then visualised by UV-excited ethidium bromide using an ImageMaster VDS (Pharmacia Biotech).", "cite_spans": [], "ref_spans": []}, {"section": "Western blotting", "text": "Western blotting analysis is described in the supplementary file in detail. In brief,", "cite_spans": [], "ref_spans": []}, {"section": "Western blotting", "text": "H441 cells cultured on 6-well inserts were scraped in RIPA buffer on ice. Density values of the single tight junction protein bands were calculated with the software Alpha View and were related to the appropriate \u03b2-actin bands.", "cite_spans": [], "ref_spans": []}, {"section": "Immunofluorescence microscopy", "text": "Immunofluorescence microscopy was carried out as published recently (Neuhaus et al., 2008) and is described in the supplementary file in detail.", "cite_spans": [{"start": 68, "end": 90, "text": "(Neuhaus et al., 2008)", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Data analysis", "text": "Data are presented as means\u00b1SD. The statistical significance between culture conditions was determined by a t-test utilizing SigmaStat3.5 software. In case of test failure on normality or equality of variance of the used data set, a Mann-Whitney Rank Sum Test was carried out. A probability value less than 0.05 was considered statistically significant.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Dexamethasone influences tightness of the barrier in a concentration dependent manner", "text": "After five days of culture of H441 cells onto 6-well Transwell inserts, the surface was approximately 80% confluent and dexamethasone was added apically in different Original publication in: Neuhaus et al., Differentiation 84 (2012) with the low mRNA expression of claudin-5, only for claudin-5 it was not able to present a continuous tight junction network over the entire H441 cell layer.", "cite_spans": [], "ref_spans": []}, {"section": "Dexamethasone modulates expression of ATI markers caveolin-1 and RAGE as well as of ATII marker SP-B", "text": "One major aim was to generate a model consisting of cells expressing ATI as well as ATII markers in order to mimic both types of alveolar epithelial cells in one model.", "cite_spans": [], "ref_spans": []}, {"section": "Dexamethasone modulates expression of ATI markers caveolin-1 and RAGE as well as of ATII marker SP-B", "text": "Therefore, the expression of mRNA for the ATI markers, caveolin-1 and RAGE, as well as the ATII marker, SP-B, was examined in the presence and absence of dexamethasone by qPCR. For this, H441 cells were grown on Transwell inserts as before for the TEER-experiments and were lysed for mRNA analysis on days 7 and 15. ATI markers caveolin-1 and RAGE were regulated in a similar manner. As shown in figure 2A , mRNA expression of caveolin-1 as well as RAGE did not change significantly on day 7 after apical addition of 10 or 100 nmol/l dexamethasone on day 5, but was significantly decreased to 0.37-fold (caveolin-1, 10 nmol/l dexamethasone, p<0.05) or to 0.64-fold (RAGE, 10 nmol/l dexamethasone, p<0.05) on day 15 in comparison to the non-treated control of day 7. Interestingly, the treatment of H441 cells with 100 nmol/l dexamethasone revealed a statistically significant increase of caveolin-1 (p<0.05) and RAGE (p<0.05) mRNA expression compared to the 10", "cite_spans": [], "ref_spans": [{"start": 396, "end": 405, "text": "figure 2A", "ref_id": "FIGREF0"}]}, {"section": "Dexamethasone modulates expression of ATI markers caveolin-1 and RAGE as well as of ATII marker SP-B", "text": "Original publication in: Neuhaus et al., Differentiation 84 (2012) with 100 nmol/l dexamethasone were generated. As shown in figure 2B , pictures demonstrate the presence of caveolin-1, RAGE and SP-B in H441 cells grown on", "cite_spans": [], "ref_spans": [{"start": 125, "end": 134, "text": "figure 2B", "ref_id": "FIGREF0"}]}, {"section": "Dexamethasone modulates expression of ATI markers caveolin-1 and RAGE as well as of ATII marker SP-B", "text": "Transwell inserts for 15 days also on the protein level. Caveolin-1 was found at the cell boarders, whereas RAGE and SP-B were recognizable in the cytosol.", "cite_spans": [], "ref_spans": []}, {"section": "Soluble factors derived from lung endothelial cells enhance, but from brain endothelial cells decrease the tightness of the alveolar epithelial barrier", "text": "In order to study the effects of soluble factors derived from the lung endothelial cell line HPMEC-ST1.6R, H441 cells were seeded on the apical side of the Transwell inserts. In the apical compartment H441 cells were fed with H441 growth medium as before, whereas different growth media were added in the basolateral side during the entire cultivation. The effects of ST1-medium, conditioned ST1-medium, D3-medium medium derived from the human blood-brain barrier cell line hCMEC/D3 decreased TEER to 44.1 \u00b1 9.7 %, which was significantly different from both H441 and fresh D3 medium (both p<0.01).", "cite_spans": [], "ref_spans": []}, {"section": "Soluble factors derived from lung endothelial cells enhance, but from brain endothelial cells decrease the tightness of the alveolar epithelial barrier", "text": "In order to support TEER data, additional permeability experiments with the paracellular marker fluorescein were carried out. Calculated permeability coefficients were between 0.22-3.35 \u00b5m/min. To facilitate data comparability, permeability coefficients obtained across cell layers grown in H441 medium in both compartments were set to 100 % and the others were related to them. Basolaterally added ST1 medium decreased fluorescein permeability to 85.3 \u00b1 4.7 %, which was further decreased by conditioned ST1 medium to 61.1 \u00b1 1.5 %. These differences were statistically significant (ST1 vs In order to confirm mRNA data and to include possible non-genomic effects on the tight junction molecules, the expression of the proteins was also analyzed by western blotting. The influence of growth media on the protein expression of claudin-1 and claudin-3 was similar to the effects onto the mRNA expression as well as on TEER.", "cite_spans": [], "ref_spans": []}, {"section": "Soluble factors derived from lung endothelial cells enhance, but from brain endothelial cells decrease the tightness of the alveolar epithelial barrier", "text": "However, only the differences of samples treated with conditioned D3-medium (claudin-1: 46.7 \u00b1 0.05 %; claudin-3: 68.9 \u00b1 0.06 %) exhibited a statistically significant reduction in comparison to the fresh D3 medium (claudin-1: 91.1 \u00b1 0.08 %; claudin-3: 144 \u00b1 29.9 %) as well as to the H441-medium (p<0.05, mean \u00b1 SD, n=3). In the case of claudin-4 no significant difference was detected on the protein Original publication in: Neuhaus et al., Differentiation 84 (2012) ", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "The alveolar epithelial barrier function is involved in different pulmonary physiology processes, such as fluid homeostasis, defence mechanisms and gas exchange. Also in pulmonary disease the alveolar epithelial barrier has been shown to play a central role (Godfrey, 1997; Matthay, 1994) . (2007) , who analyzed the claudin expression patterns of rat lungs after chronic alcohol ingestion. Claudin-1 and -3 were reduced in lung tissue, whereas claudin-4 was unchanged. Also concordant to our results, they found no changes of claudin-5", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "mRNA, but reported changes of claudin-5 on the protein level. This confirmed our assumption that claudin-5 is regulated on the posttranscriptional level. Up-regulation of claudin-5 was reported in alveolar epithelial cell layers with increased tightness (Wang et al., 2003) . Since the basal expression of claudin-5 in our H441-cells is quite", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Original publication in: Neuhaus et al., Differentiation 84 (2012) 294-304.; http://dx.doi.org/10.1016 /j.diff.2012 -21 -low in comparison to claudin-1,-3 and -4, a significant regulation of claudin-5 is maybe connected with a significant change in barrier functionality. In this context, we were able to observe a distinct up-regulation of the claudin-5 network of H441-layers fed basolaterally with fresh ST1-medium by immunofluorescence microscopy (see supplementary file, figure 1 ). With regard to the ATI and ATII markers, no direct correlation was found between changes of the barrier tightness and the expression of caveolin-1, RAGE or SP-B. Notably, caveolin-1 and SP-B were regulated in a similar manner, whereas RAGE expression decreased due to addition of conditioned endothelial medium independent from the tissue origin. These data showed that the two ATI markers caveolin-1 and RAGE reacted differently on the endothelial factors in our model suggesting differences in their usability as ATI markers. This was concordant to the classification of ATI markers by McElroy and Kaspar (2004) . They added caveolin-1 to the group of ATI selective proteins, but RAGE only to the ATI selective/associated markers, since mRNA of RAGE was also detected in ATII cells (McElroy and Kaspar, 2004) . -31 -normalized to data obtained from H441 cell layers grown in H441-medium which were set to 1 and are presented as means \u00b1 SD (n=3). Statistically significant differences are marked by * (p<0.05, t-test) in comparison to the according fresh medium ST1 or D3. 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H441 means conventional H441 growth medium, ST1 and D3 are the fresh growth media for HPMEC-ST1.6R and hCMEC/D3 cells, whereas ST1-cond. and D3-cond", "authors": [{"first": "", "middle": [], "last": "Sp-B", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF21": {"title": "One representative western blot out of three with similar results is shown. Data are normalized to data obtained from H441 cell layers grown in H441-medium which were set to 1 and are presented as means \u00b1 SD", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF22": {"title": "Statistically significant differences are marked by # (p<0.05, t-test) in comparison to", "authors": [], "year": "", "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Tight junction proteins claudin-1,-3,-4,-5, occludin and ZO-1 are expressed in the alveolar epithelium in vitro model In order to investigate the presence of some main tight junctional proteins in our model, mRNA analysis of claudin-1, claudin-3, claudin-4, claudin-5, occludin and ZO-1 of H441 samples of day 15 treated with 100 nmol/l dexamethasone (apical addition) was accomplished. PCR products separated on an agarose gel confirmed the presence of all analyzed tight junctional molecules, but the band of claudin-5 was very weak indicating low expression (figure 1B). Thus, qPCR with GAPDH as endogenous control was carried out in order to rank the abundances of the tight junctional proteins which were then related to claudin-1. Claudin-4 was the most abundant (7-fold) tight junctional protein, followed by occludin (4-fold), ZO-1 (1.24- fold), claudin-1 (1-fold) and claudin-3 (0.46-fold). Confirming the agarose gel resultconfirm the presence of tight junction proteins on the protein level, immunofluorescence images of H441 cells (day 15) treated with 100 nmol/l dexamethasone were generated. As shown in figure 1C, pictures demonstrate the presence of claudin-1, claudin-3, claudin-4, claudin-5, occludin and ZO-1 in H441 cells grown on Transwell inserts for 15 days also on the protein level. In concordance", "type": "figure"}, "FIGREF1": {"text": "D3-medium were studied in comparison to the original H441 medium. Conditioned ST1-medium was obtained from lung endothelial cell line HPMEC-ST1.6R, conditioned D3-medium from human brain microvascular cell line hCMEM/D3, whereas ST1 and D3-medium represent the fresh, unconsumed growth media. It was decided to add 100 nmol/l dexamethasone to the apical side beginning on day 5 in order to obtain cell layers with a distinct barrier (ATI cell feature), but also a maximum of SP-B expression (ATII cell feature). Highest tightness of H441 cell layers was achieved after 15 days of culture (figure 1A), thus data comparison focused on this time point.", "type": "figure"}, "FIGREF2": {"text": "Figure 3 depicts the influence of the different growth media on TEER and", "type": "figure"}, "FIGREF3": {"text": "Alterations of the expression patterns of claudins accord with tightness changes of the alveolar barrier In order to investigate the functional changes of the tightness on the molecular level the expression of claudin-1, -3, -4 and -5 were analyzed. The changes of mRNA expression of claudin-1 and -3 matched well to the observed TEER values (Figure 4). mRNA expression of claudin-4 was interestingly increased by both conditioned media (ST-1 cond.: 1.28 \u00b1 0.19 -fold; D3 cond.: 1.48 \u00b1 0.11-fold) and were statistically significant in comparison to their corresponding fresh media. In the case of claudin-5 no significant changes were detected.", "type": "figure"}, "FIGREF4": {"text": "Clinical studies have highlighted the importance of this intact barrier function to clinical outcomes (Maniatis et al., 2008; Ware and Matthay, 2000, 2001). Since the microenvironment (neighbouring cells, basal matrix) of biological barriers in mammalian organisms can regulate the barrier's functionality in a significant manner, we aimed at investigating the influence of the lung endothelium on the alveolar epithelium in an in vitro model. Up to now, only few in vitro models based on stable cell lines of the alveolar epithelium are established, which consist of cells expressing either type I or type II markers and form a tight barrier (Hermanns et al., 2004, 2009, 2010). Currently, only two promising cell lines are available to model the alveolar epithelium, namely A549 and NCI H441. Several reports showed that cell line A549 is useful as a type II cell model. However, attempts to transdifferentiate them into type I cells and build up a sufficient barrier have failed until now (Hermanns et al., 2004). In case of H441 cells, recent publications showed that treatment of H441 cells with dexamethasone leads to the upregulation of the type-2 marker, SP-B, to dome formation, to a tight barrier and an increase of the expression of tight junctional molecule claudin-4 (Hermanns et al., 2004; Ladenburger et al., 2010; Shlyonsky et al., 2005). Consequently, we decided to establish an alveolar cell culture model based on human cell line H441 and to use this model to study the influence of soluble factors derived from lung as well as from brain endothelial cells.in order to validate this cell culture model the influence of dexamethasone on the barrier (TEER) and on the expression of caveolin-1, RAGE (type-1 markers) and SP-B (type-2 marker) was investigated. It was known from other studies with primary alveolar type II cells as well as cell lines that addition of dexamethasone or hydrocortisone was necessary to form a barrier (Daugherty et al., 2004; Hermanns et al., 2004; Hermanns et al., 2009; Steimer et al., 2007). To our best knowledge, we are the first to present data showing that the tightness of the H441 barrier is dependent on the dexamethasone concentration. This seems to be important considering the fact that reseachers applied dexamethasone in a rather wide concentration range (50 nmol/l -1 \u00b5mol/l) for their H441 studies (Hermanns et al., 2010; Shlyonsky et al., 2005). One major aim of the establishment of the H441-model was to generate tight cell layers which at the same time possess type I and type II markers. Previous studies showed that H441 layers treated with dexamethasone were able to exhibit several properties of the alveolar epithelium such as apical villi, laminar as well as multivesicular bodies, type-2 marker TTF-1 as well as epithelial marker E-cadherin (Hermanns et al., 2004, 2010). Thus, we have decided to concentrate on the analysis of the markers caveolin- 1, RAGE and SP-B in order to present relevant, but also novel data of H441 cells concerning the presence of both cell types within the H441 Transwell model. Ladenburger et al. (2010) showed recently that dexamethasone was able to increase SP-B in H441 cells significantly. This was concordant with our results where dexamethasone increased SP-B in a concentration dependent manner, whereas caveolin-1 and RAGE expression was not altered compared to the untreated samples on day 7. Interestingly, immunofluoresence microscopy of double-stainings against caveolin-1 and SP-B showed cells expressing caveolin-1 but not SP-B at the same time confirming the presence of two differentially differentiated cell types in theprotein level and that the marker expression can be regulated by dexamethasone. With regard to the tightness of the established H441-Transwell model, TEER values indicated that the chosen culture conditions resulted in a distinct barrier which is associated on the molecular level with the presence of tight junctional proteins. For the alveolar epithelium the presence of claudin-1,-3,-4,-5,-7 and 18 were reported (Daugherty et al., 2004; Kaarteenaho et al., 2010; Koval et al., 2010; Wang et al., 2003). Claudins are important for a stable barrier of the alveolar epithelium in health as well as in disease (Capaldo and Nusrat, 2009; Coyne et al., 2002; Crosby and Waters, 2010; Daugherty et al., 2004; Godfrey et al., 1993; Lecuona et al., 1999; Soini, 2011; Wray et al., 2009). We have analyzed the presence of ZO-1, occludin, claudin-1,-3,-4 and -5 on the mRNA as well as on the protein level in our established H441-model. In case of ZO-1 and occludin, their presence was already shown for H441 layers (Hermanns et al., 2004, 2010; Shlyonsky et al., 2005), whereas the analysis of claudin expression was carried out for the first time. In comparison to claudin-1,-3 and -4, the expression of claudin-5 was very weak in our model. Claudin- 1 is relative specific for type I cells (Daugherty et al., 2004), whereas claudin-3 and claudin-4 were found mainly in type II pneumocytes (Kaarteenaho-Wiik and Soini, 2009). In human lung development claudin-5 was only weakly expressed in the lung epithelium during the pseudoglandular and the canalicular phase observed by immunofluorescence microscopy. In the later phases (saccular and alveolar) claudin-5 was not longer detected and only found in the surrounding lung microvasculaturedevelopmental stages. These facts supported our data and demonstrate that our model mimics several properties of the alveolar epithelium including both type I and type II cells of the alveolar epithelium. After establishment and characterisation of our H441-model the influence of conditioned endothelial growth media on its barrier properties was investigated. Recently, it was shown that co-cultures of primary type II cells as well as of H441- layers with either primary lung endothelial cells or the endothelial cell line ISO-HAS- I resulted in significantly increased tightness indicated by an increase of TEER and ZO-1 localisation (Hermanns et al., 2009, 2010). In our case, application of conditioned medium of HPMEC-ST1.6R cells to the basolateral compartment increased the tightness of the H441-layers shown by TEER values and fluorescein permeability. On the contrary, conditioned medium of human brain endothelial cells hCMEC/D3 decreased the tightness of H441-layers significantly confirming tissue- specific effects. To link these observations on the functional level to the molecular level mRNA as well as protein expression of claudin-1,-3,-4 and -5 and the alveolar cell type markers (caveolin-1, RAGE, SP-B) were quantified by qPCR and western blotting. Interestingly, almost the same results to ours were found by Fernandez et al.", "type": "figure"}, "FIGREF5": {"text": "In summary, after validation of the H441-cell culture as an alveolar epithelium model consisting of cells expressing either ATI or ATII markers, it was shown for the first time that soluble factors of lung endothelial cells (HPMEC-ST1.6R) enhance the barrier of the alveolar epithelium. Furthermore, this functional improvement of the barrier was linked with the quantitative expression of claudins on the mRNA as well as on the protein level. Moreover, soluble factors of brain endothelial cells (hCMEC/D3) disrupted the barrier's integrity proving tissue-specific effects of endothelial cells. With regard to the clinical context, influencing the alveolar permeability by manipulation of the claudin expression may be a future target in the treatment of different lung diseases (Soini, 2011).", "type": "figure"}, "FIGREF6": {"text": "Figure Captions", "type": "figure"}, "FIGREF7": {"text": "Fig. 1. Concentration dependent influence of dexamethasone on the time courses of", "type": "figure"}, "FIGREF8": {"text": "Fig. 2. Concentration dependent influence of dexamethasone on the mRNA", "type": "figure"}, "FIGREF9": {"text": "Fig. 3. Influence of soluble factors from lung and brain endothelial cells on the barrier", "type": "figure"}, "FIGREF10": {"text": "Fig. 4. Influence of soluble factors from lung and brain endothelial cells on the", "type": "figure"}, "FIGREF11": {"text": "Fig. 5. Influence of soluble factors from lung and brain endothelial cells on the", "type": "figure"}, "FIGREF12": {"text": "Fig. 6. Influence of soluble factors from lung and brain endothelial cells on the", "type": "figure"}, "TABREF0": {"text": "). 1 \u00b5g total RNA per sample were reversely transcribed to 20 \u00b5l cDNA by means of the high capacity cDNA-kit", "type": "table"}, "TABREF1": {"text": "SP-B and caveolin-1 analysis were loaded onto 15% SDS-PAGE gels. After gel electrophoresis proteins were immunoblotted onto PVDF membranes by means of a semi-dry blotter. Membranes were blocked with 5% milk powder in PBS for 1 hour and primary antibodies were applied in 0.5% BSA/PBS solution at 4\u00b0C over night.", "type": "table"}, "TABREF3": {"text": "In case of cell type 2 marker SP-B, dexamethasone induced SP-B expression very significantly in a concentration dependent manner. For example, 10 nmol/l dexamethasone increased SP-B expression on day 7 7.9-fold (p<0.05). which was further increased by 100 nmol/l to 107.8-fold (p<0.05). On day 15 SP-B mRNA expression of dexamethasone treated samples was still higher than on day 7 without dexamethasone, but decreased in comparison to day 7 dexamethasone treated samples. In detail, H441-cells treated with 10 nmol/l dexamethasone revealed a 2.3- fold SP-B expression and 100 nmol/l dexamethasone application still increased SP-B expression 16-fold in comparison to the 7 days old untreated cell samples (p<0.05). In order to confirm the presence of type 1 and type 2 cell markers caveolin-1, RAGE and SP-B on the protein level immunofluorescence images of H441 cells (day 15) treated", "type": "table"}, "TABREF4": {"text": "ST1 cond.: p<0.01) and confirmed TEER data that soluble factors secreted from lung endothelial cells maintain or even enhance the barrier in our alveolar epithelium in vitro model. In concordance to the TEER data, application of conditioned D3 medium", "type": "table"}}}
{"paper_id": "10705452", "_pdf_hash": "9217c3d7fa41aa9d2980c3a0075d5b7de513422f", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "An Introduction to Nonlinear Boundary Value Problems", "authors": [{"first": "S", "middle": [], "last": "Bernfeld", "suffix": ""}, {"first": "V", "middle": [], "last": "Lakshmikantham", "suffix": ""}], "year": 1974, "venue": "", "link": "117836936"}, "BIBREF2": {"title": "The Cauchy problem for fuzzy differential equations", "authors": [{"first": "O", "middle": [], "last": "Kaleva", "suffix": ""}], "year": 1990, "venue": "Fuzzy Sets and Systems", "link": "120112342"}, "BIBREF4": {"title": "A new concept unifying Lyapunov and orbital stabilities", "authors": [{"first": "V", "middle": [], "last": "Lakshmikantham", "suffix": ""}, {"first": "S", "middle": [], "last": "Leela", "suffix": ""}], "year": "", "venue": "Communications in Applied Analysis", "link": null}, "BIBREF5": {"title": "Stability theory of fuzzy differential equations via differential inequalities", "authors": [{"first": "V", "middle": [], "last": "Lakshmikantham", "suffix": ""}, {"first": "S", "middle": [], "last": "Leela", "suffix": ""}], "year": 1999, "venue": "Math. Inequalities and Appl", "link": "123730666"}, "BIBREF6": {"title": "Stability Analysis of Nonlinear System", "authors": [{"first": "V", "middle": [], "last": "Lakshmikantham", "suffix": ""}, {"first": "S", "middle": [], "last": "Leela", "suffix": ""}, {"first": "A", "middle": ["A"], "last": "Martynyuk", "suffix": ""}], "year": 1989, "venue": "", "link": "122437763"}, "BIBREF7": {"title": "Basic properties of solutions of fuzzy differential equations", "authors": [{"first": "V", "middle": [], "last": "Lakshmikantham", "suffix": ""}, {"first": "R", "middle": [], "last": "Mohapatra", "suffix": ""}], "year": 2001, "venue": "Nonlinear Studies", "link": "123505695"}, "BIBREF8": {"title": "The meaning of stability", "authors": [{"first": "J", "middle": ["L"], "last": "Massera", "suffix": ""}], "year": 1964, "venue": "Bol. Fac. Ing. Montevideo", "link": null}, "BIBREF9": {"title": "The Cauchy problem for fuzzy differential equations. Fuzzy Sets and Systems", "authors": [{"first": "J", "middle": ["J"], "last": "Nieto", "suffix": ""}], "year": "", "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "10705528", "_pdf_hash": "7946e1ae76d9c36ca21afc0e73afdb83eaccb026", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "United Nations Department of Economic and Social Affairs. 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{"paper_id": "10705819", "_pdf_hash": "4759165db65a6f44dfae80c07d357da45f08f6f6", "abstract": [{"section": "Abstract", "text": "Current clinical guidelines for managing type 2 diabetes do not differentiate based on patient-specific factors. We present a data-driven algorithm for personalized diabetes management that improves health outcomes relative to the standard of care.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "We modeled outcomes under 13 pharmacological therapies based on electronic medical records from 1999 to 2014 for 10,806 patients with type 2 diabetes from Boston Medical Center. For each patient visit, we analyzed the range of outcomes under alternative care using a k-nearest neighbor approach. The neighbors were chosen to maximize similarity on individual patient characteristics and medical history that were most predictive of health outcomes. The recommendation algorithm prescribes the regimen with best predicted outcome if the expected improvement from switching regimens exceeds a threshold. We evaluated the effect of recommendations on matched patient outcomes from unseen data.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Among the 48,140 patient visits in the test set, the algorithm's recommendation mirrored the observed standard of care in 68.2% of visits. For patient visits in which the algorithmic recommendation differed from the standard of care, the mean posttreatment glycated hemoglobin A 1c (HbA 1c ) under the algorithm was lower than standard of care by 0.44 6 0.03% (4.8 6 0.3 mmol/mol) (P < 0.001), from 8.37% under the standard of care to 7.93% under our algorithm (68.0 to 63.2 mmol/mol).", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "A personalized approach to diabetes management yielded substantial improvements in HbA 1c outcomes relative to the standard of care. Our prototyped dashboard visualizing the recommendation algorithm can be used by providers to inform diabetes care and improve outcomes.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Type 2 diabetes is typically managed through healthy eating, physical activity, oral medication, and/or insulin injections. Although there are evidence-based clinical guidelines for glycemic control (1), how to choose among pharmacological therapies to maximize effectiveness for a given patient is not well understood. There has been growing interest in using clinical evidence to understand the effects of treatments in different populations with type 2 diabetes. In a joint statement from", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "Diabetes highlighted the need for a patientcentered approach to diabetes management (2) . The need for an individualized approach is especially pressing given the variety of disease symptoms, comorbid conditions, pharmacological treatments, individual treatment histories, and other individual characteristics that may inform treatment (3) .", "cite_spans": [{"start": 336, "end": 339, "text": "(3)", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "", "text": "Evidence suggests that the response to blood glucose regulation agents can differ among population subgroups. A post hoc secondary analysis found that African American adults with prediabetes responded better to metformin than Caucasian adults with prediabetes (4) . Another study recommended less aggressive treatments for older patients, as they were more likely to experience severe consequences from hypoglycemia (5) . These studies each provide valuable insights with respect to a single subgroup or treatment, but do not offer a decision rule for the general population that providers can easily apply in practice.", "cite_spans": [{"start": 261, "end": 264, "text": "(4)", "ref_id": "BIBREF4"}, {"start": 417, "end": 420, "text": "(5)", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "", "text": "Tailoring glycemic management for specific subpopulations can be critical. Among patients with chronic kidney disease, contraindication to metformin needs to be taken into consideration when prescribing medication (6) . Separate glycated hemoglobin A 1c (HbA 1c ) goals may be needed for subgroups or individuals differentiated by age, comorbidities, and other clinical characteristics (3) . A personalized treatment recommendation using a quantitative approach could readily incorporate different glycemic targets and contraindications and thus allow for more systematic management of subgroups.", "cite_spans": [{"start": 214, "end": 217, "text": "(6)", "ref_id": "BIBREF6"}, {"start": 386, "end": 389, "text": "(3)", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "", "text": "We provide an algorithm that generates a personalized type 2 diabetes treatment recommendation for any given patient based on evidence from historical outcomes of similar patients drawn from an electronic medical records (EMR) database. EMR analysis allows for pinpoint comparisons of effectiveness because of the abundance of clinical evidence from multiple treatment options administered to a diverse population over long-term patient clinical histories. EMR data combine the large sample sizes found in some insurance claims databases with the depth of longitudinal clinical evidence typically found in clinical trials. One caveat is that EMR data are not controlled via randomization.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "Our methodological approach applies machine learning techniques and causal inference to make personalized recommendations based on comparative effectiveness among subpopulations in the EMR database. Machine learning techniques have been increasingly adopted in health care, along with many other fields (7-9). Our novel approach leverages the power of analytics and abundant data in the EMR system to improve quality of care.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "The recommendations are personalized by patient characteristics, including age, sex, race, BMI, treatment history, and diabetes progression. We evaluate the effectiveness of the personalized treatment recommendations against the current standard of care by estimating patients' counterfactual outcomes from historical outcomes of similar patients in the EMR database. We develop a prototype clinical support dashboard that provides evidence for the algorithm's recommendations and could guide providers in caring for patients with type 2 diabetes in a personalized manner.", "cite_spans": [], "ref_spans": []}, {"section": "RESEARCH DESIGN AND METHODS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Analytic Overview", "text": "We modeled outcomes for patients with type 2 diabetes based on EMR data. We divided each patient's medical history into distinct lines of therapy, each characterized by a particular drug monotherapy or combination therapy. Within each line of therapy, we considered patient visits occurring every 100 days. At each visit, the provider decides whether to proceed with the patient's current line of therapy or to recommend an alternative regimen. We developed a nonparametric prescriptive algorithm that provides personalized treatment recommendations. For each patient visit, we used k-nearest neighbor (kNN) regression (10) to predict the potential HbA 1c outcome under each treatment alternative. The nearest neighbors were chosen to control for confounding that may be present in nonrandomized data (11) and to maximize similarity on the patient characteristics that were most predictive of outcomes. The algorithm then prescribed the regimen with best predicted outcome, provided the predicted improvement relative to the patient's current regimen exceeded a confidence threshold. The outcome metric was the average HbA 1c measurement 75 to 200 days after the visit date. The effect of the prescriptive algorithm was evaluated by comparing the expected HbA 1c outcome under our recommended therapy to the observed outcome under the standard of care (ground-truth) therapy, according to a commonly used matching approach (12). We conducted additional simulations to ensure that the results were robust to training models on different datasets and using alternative predictive modeling techniques.", "cite_spans": [{"start": 619, "end": 623, "text": "(10)", "ref_id": "BIBREF10"}, {"start": 801, "end": 805, "text": "(11)", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "Data", "text": "Through a partnership with Boston Medical Center (BMC), an academic medical center in Boston, MA, we obtained EMR for . For each patient, we had access to demographic data, including date of birth, sex, and race/ethnicity, and to all BMC EMR data, including a history of drug prescriptions and measurements of height, weight, BMI, and HbA 1c , as well as creatinine levels (Table 1) . Neither the size of the population nor the proportion with good glycemic control changed substantially over the course of the study.", "cite_spans": [], "ref_spans": [{"start": 373, "end": 382, "text": "(Table 1)", "ref_id": "TABREF1"}]}, {"section": "Interpreting Individual Medical Histories", "text": "We divided each patient's medical history into distinct lines of therapy, each characterized by a particular drug regimen ( Supplementary Fig. 1 ). Within each line of therapy, we considered patient visits occurring every 100 days, corresponding to the life cycle of a red blood cell (13) . These patient visits provided the basis for our definition of patient outcomes.", "cite_spans": [{"start": 284, "end": 288, "text": "(13)", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Lines of Therapy", "text": "We developed an algorithm to define precisely when each line of therapy ends and the next line begins according to when the combination of drugs prescribed to the patient changes in the EMR data. Each line of therapy was characterized by a unique drug regimen, defined to include all blood glucose regulation agents prescribed to the patient within the first 6 months after starting that line of therapy.", "cite_spans": [], "ref_spans": []}, {"section": "Lines of Therapy", "text": "Regimens were defined as combinations of drugs from one or more drug classes. The drug classes we considered were metformin, insulin, and other blood glucose regulation agents; the other agents included sulfonylureas, thiazolidinediones, dipeptidyl peptidase 4 inhibitors, meglitinides, a-glucosidase inhibitors, glucagon-like peptide 1 agonists, and other antihyperglycemic agents. If a sufficient number of HbA 1c observations existed during a period in which no drugs were prescribed, we defined the patient's line of therapy as \"NoRx.\" We considered 13 possible regimen types (Table 1) . A combination of drug classes was included as a regimen type if it was observed in a sufficient number of patient visits.", "cite_spans": [], "ref_spans": [{"start": 580, "end": 589, "text": "(Table 1)", "ref_id": "TABREF1"}]}, {"section": "Lines of Therapy", "text": "We determined that a patient's current line of therapy had ended whenever the patient's drug regimen changed in some way, such as when one or more drugs were added to or removed from the drug regimen, or when the phase was interrupted by a period of at least 500 days with no new prescriptions, in which case the subsequent line of therapy was determined to be NoRx. This definition of end date for each line of therapy intends to capture the period when the patient was experiencing the effect of the drug regimen.", "cite_spans": [], "ref_spans": []}, {"section": "Patient Visits", "text": "Within each line of therapy, we considered patient visits occurring every 100 days, beginning with the visit at which that regimen was initiated and continuing until no later than 80 days prior to the start of the subsequent regimen. There were 48,140 unique patient visits in our dataset (Table 1) . At each visit, we defined a set of visit-specific patient characteristics, including the current line of therapy (i.e., therapy given during the 100 days immediately preceding the current visit) and recent HbA 1c and BMI history. The outcome was measured as average HbA 1c 75 to 200 days after the visit. This effect period was chosen to allow for a complete red blood cell life cycle to elapse before measuring the effect of a drug therapy.", "cite_spans": [], "ref_spans": [{"start": 289, "end": 298, "text": "(Table 1)", "ref_id": "TABREF1"}]}, {"section": "Patient Visits", "text": "We defined the standard of care for each visit as the drug regimen that was administered. For 16.3% of visits, the provider prescribed an adjustment to the current line of therapy; in the other 83.7%, the provider's prescription was to continue the current regimen.", "cite_spans": [], "ref_spans": []}, {"section": "Prescriptive Algorithm", "text": "Our novel prescriptive algorithm considers a menu of available treatment options, including the patient's current treatment; uses kNN regression models to predict potential outcomes under each option; rejects any noncurrent treatment option with predicted outcome above a prespecified HbA 1c threshold; and chooses the remaining option with best predicted outcome. The menu of options for a given patient could be determined by the provider, accounting for contraindications and other preferences, such as not using intensive control for elderly patients or patients with a history of severe hypoglycemia.", "cite_spans": [], "ref_spans": []}, {"section": "Prescriptive Algorithm", "text": "For the purposes of this analysis, the menu of options for each patient was chosen relative to the intensity and composition of the patient's current treatment regimen. Specifically, the algorithm considered only regimens that represented an incremental addition or subtraction of a drug, or substitution of a drug of comparable intensity; metformin and insulin were considered to be of the lowest and highest intensity, Data are mean (SD) unless otherwise indicated. *Sample statistics are calculated across all patient visits. Individual patients with longer medical histories may be overrepresented in the sample. \u2020Individuals may have a current prescription for both metformin and insulin. \u2021A patient was considered to be contraindicated to metformin when current serum level of creatinine was .1.5 mg/dL.", "cite_spans": [], "ref_spans": []}, {"section": "Prescriptive Algorithm", "text": "respectively. Patients with serum creatinine levels .1.5 mg/dL (6), a sign of kidney disease, were not offered metforminbased regimens. The menu options used in our analysis, differentiated by current treatment, are depicted in Fig. 1 ; by definition, the algorithm never recommended metformin-based therapies for patients with the contraindication described above.", "cite_spans": [], "ref_spans": []}, {"section": "Prescriptive Algorithm", "text": "For each patient visit, the outcomes predicted by kNN under each treatment were compared. Our algorithm selected the treatment with the best predicted HbA 1c outcome subject to the condition that this best predicted outcome improve upon the predicted outcome under the patient's current treatment by at least some threshold d. We chose the optimal threshold value of 0.8% by testing the algorithm on a single test set, using values of d ranging from 0 to 1.5%. Increasing the threshold d causes the algorithm to recommend switching for fewer patients, but the mean benefit among those who switch increases. Above a certain threshold, the recommendation fits to noise in the training data and does not provide better mean benefits in the testing set. The optimal threshold balances these concerns.", "cite_spans": [], "ref_spans": []}, {"section": "Prescriptive Algorithm", "text": "kNN regression is a nonparametric, instance-based algorithm that makes predictions by averaging the outcomes for the subset of observations most similar to the target as defined by some distance metric (10) . To predict potential outcomes under each regimen, we used a kNN regression based on a treatmentspecific weighted Euclidean distance across normalized patient and visitspecific factors. The weights were derived by training a separate ordinary least squares linear regression model for each treatment regimen and using the magnitudes of the regression coefficients (Supplementary Table 1 ). This weighted distance improves upon classical kNN by selecting neighbors based on the factors most predictive of HbA 1c outcome, rather than weighting all factors equally.", "cite_spans": [{"start": 202, "end": 206, "text": "(10)", "ref_id": "BIBREF10"}], "ref_spans": [{"start": 587, "end": 594, "text": "Table 1", "ref_id": "TABREF1"}]}, {"section": "Prescriptive Algorithm", "text": "We considered factors from the following categories: demographic information, medical history, and treatment history. Specifically, the demographic factors used in the model were age, sex, and race. The medical history factors were days since first diabetes diagnosis, the Figure 1 -HbA 1c benefit of prescriptive algorithm for patients switching regimens. Each cell in the figure represents patients for whom the prescriptive algorithm recommended switching from the regimen on the vertical axis to the regimen on the horizontal axis. The color in each cell indicates the mean HbA 1c benefit (%) of the prescriptive algorithm for patients in that cell, with red indicating benefits of the algorithm and blue indicating worsening relative to standard of care. Each cell is labeled with the number of patients who made that switch; cells labeled with a dash were not on the menu of options provided to patients currently on a given regimen. Patients with serum creatinine levels .1.5 mg/dL were not considered for metformin-based regimens and therefore are never assigned by the algorithm to columns with metformin-based regimens. patient's average serum creatinine level in the previous year, the patient's past two HbA 1c and most recent BMI observations up to and including the current visit, the patient's average, median, 25th percentile, and 75th percentile HbA 1c and BMI in the 1,000-day period up to and including the current visit, and the patient's frequency of HbA 1c measurements. The treatment history factors were the number of regimens the patient had tried, the number of visits since starting the current regimen, whether or not the patient had been previously prescribed metformin, and the patient's current regimen.", "cite_spans": [], "ref_spans": []}, {"section": "Prescriptive Algorithm", "text": "The prediction step of our algorithm is best illustrated through an example. Suppose we would like to estimate a patient's potential outcome under metformin monotherapy. To identify the importance of each factor in predicting outcomes, we used patient visits in which metformin monotherapy was prescribed to train an ordinary least squares regression on normalized values of each patient factor listed above. The most predictive factors were: the patient's most recent HbA 1c measurement (regression coefficient magnitude 0.22), whether the patient was currently prescribed insulin (0.11), the patient's mean BMI over the past 1,000 days (0.11), and several other HbA 1c and BMI measurements (coefficient magnitudes ranging from 0.03 to 0.10) (see Supplementary Table 1 for full details). To estimate the patient's potential outcome, we used the coefficient magnitudes to weight the Euclidean distance between this patient visit and each patient visit in which metformin monotherapy was prescribed. Thus, for any choice of k, we could rank the k closest neighbors from this treatment group. This procedure was repeated for each therapy in the patient's menu of treatment options.", "cite_spans": [], "ref_spans": [{"start": 748, "end": 769, "text": "Supplementary Table 1", "ref_id": "TABREF1"}]}, {"section": "Prescriptive Algorithm", "text": "Intuitively, the number of neighbors k used to estimate posttreatment HbA 1c levels should increase with the size of the dataset. For each treatment t, we found the value k \u00c3 t that minimized the root mean square error of the kNN predictions on a subset of the data not used to evaluate the algorithm. We regressed k \u00c3 t on ffiffiffiffi n t p and thus derived the dependence function k \u00c3 t \u00bc 0:34 ffiffiffiffi n t p , which was used to select k in the prescriptive algorithm.", "cite_spans": [], "ref_spans": []}, {"section": "Prescriptive Algorithm", "text": "To verify the accuracy of the kNN HbA 1c predictions, we evaluated the R 2 metric. Positive values of R 2 suggest patient characteristics are predictive of future HbA 1c . For comparison, we evaluated the predictive accuracy of least absolute shrinkage and selection operator (LASSO) regression (14) and random forest (15), two state-of-the-art machine-learning methods used widely because of their high prediction accuracy. We used the predictions from these models in two alternative prescriptive algorithms.", "cite_spans": [{"start": 295, "end": 299, "text": "(14)", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Model Evaluation", "text": "To evaluate the performance of the kNNbased prescriptive model, we tested the algorithm's recommendations on a set of patient data that had not been used when training the models.", "cite_spans": [], "ref_spans": []}, {"section": "Model Evaluation", "text": "Because counterfactual treatment effects are not observable, we used the weighted matching approach embedded in the kNN regression to impute potential outcomes, an approach commonly used for causal inference in observational studies when randomization is unavailable (12). For each visit, we applied our prescriptive algorithm to recommend a therapy. If that recommendation matched the prescribed standard of care therapy, we observed the true effect from the therapy. Otherwise, the outcome was imputed by averaging the outcomes of the most similar patient visits at which the recommended therapy was administered; these similar visits were chosen from a test set not used for training, and the number of neighbors k \u00c3 t was selected to fit the size of the test set. This estimated outcome was compared with the true outcome under standard of care at the given patient visit.", "cite_spans": [], "ref_spans": []}, {"section": "Model Evaluation", "text": "Our hypothesis was that the average predicted HbA 1c outcome after applying our prescriptive algorithm would be less than that observed from administering standard of care, resulting in a net average improvement in outcomes.", "cite_spans": [], "ref_spans": []}, {"section": "Sensitivity Analysis", "text": "To ensure the evaluation of our algorithm was not sensitive to the particular random split of the database into training and test data, we evaluated the effectiveness of our algorithm (with fixed threshold d \u00bc 0:8) under additional random splittings of the data.", "cite_spans": [], "ref_spans": []}, {"section": "Software", "text": "All analyses were performed in R 3.3.0 (16).", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "The R 2 of the kNN predictions on unseen data ranged from 0.20 to 0.54 depending on the regimen (Supplementary Table 2 ). The strongest models were for insulin monotherapy, metformin monotherapy, metformin plus insulin, and multidrug ($3) therapies. The R 2 values from the LASSO and random forest models ranged from 0.24 to 0.53. The predictive power was similar across the three methods.", "cite_spans": [], "ref_spans": [{"start": 111, "end": 118, "text": "Table 2", "ref_id": "TABREF2"}]}, {"section": "RESULTS", "text": "The performance of the prescriptive algorithm is summarized in Table 2 . The mean HbA 1c outcome after treatment was 0.14% lower under the prescriptive algorithm than under the standard of care In our analysis, the mean difference in HbA 1c was more negative than the median because of a left-skewed distribution. Some patients received particularly large benefits from using the prescriptive algorithm, which had an outsize effect on the mean but did not affect the median. Fig. 1 depicts the number of patients for whom the prescriptive algorithm recommended switching from a given current line of therapy to a given new line of therapy, along with the mean reduction in HbA 1c for patient visits in each category. Among trajectories with at least 300 patients, the largest benefit of the algorithm was achieved through personalized recommendations for 7,564 patients currently on insulin monotherapy to switch to monotherapy with metformin or another blood glucose regulation agent. However, for the vast majority of patients currently on insulin-based regimens, the algorithm recommends that those patients continue with that therapy. Among the 7,564 patient visits, those who were recommended to switch from insulin were on average younger (mean 52.9 vs. 61.4 years of age) and had substantially higher average HbA 1c (11.0 vs. 8.0% or 97 vs. 64 mmol/mol).", "cite_spans": [], "ref_spans": [{"start": 63, "end": 70, "text": "Table 2", "ref_id": "TABREF2"}]}, {"section": "RESULTS", "text": "The performance of the prescriptive algorithm in specific patient subgroups is summarized in Supplementary Table 3 .", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "The overall mean HbA 1c outcome using the prescriptive algorithm was 0.14% (1.5 mmol/mol) lower than standard of care for both male and female patients. The benefit of using the algorithm was 0.14% (1.5 mmol/mol) for black patients (29,120 visits), 0.09% (1.0 mmol/mol) for white patients (7,444 visits), 0.22% (2.4 mmol/mol) for Hispanic patients (6,732 visits), and 0.11% (1.2 mmol/mol) for all other patients (4,844 visits). The benefit of the algorithm was 0.20% (2.2 mmol/mol) for patients ,60 years of age and 0.08% (0.9 mmol/mol) for patients aged $60 years or older. The benefit was 0.20% (2.2 mmol/mol) for patients with poor glycemic control (i.e., current HbA 1c .7.0% [53 mmol/mol]) as compared with 0.05% (0.4 mmol/mol) for those with good glycemic control.", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "Our methodology motivates a provider dashboard that would report information on the demographics, medical history, and response to treatment for patients similar to an index patient. A prototype dashboard visualization for one sample patient visit is shown in Fig. 2 . The dashboard would include the patient's demographic and health information along with visualizations of the patient's treatment history and HbA 1c progression. In addition, the dashboard would display the mean, SD, and full distribution of HbA 1c outcomes among the k \u00c3 t nearest neighbors who received each treatment in the menu of options. Based on this evidence, the dashboard would display a treatment recommendation. The provider would have the ability to override this recommendation given any special management needs of the patient. For instance, if the patient is elderly and the distribution of HbA 1c outcomes indicates that the recommended therapy has an elevated risk of hypoglycemia, the provider may opt for an alternative treatment.", "cite_spans": [], "ref_spans": [{"start": 260, "end": 266, "text": "Fig. 2", "ref_id": "FIGREF0"}]}, {"section": "RESULTS", "text": "The overall mean HbA 1c outcome using the LASSO-based prescriptive algorithm was lower by 0.13 6 0.01% (1.4 6 0.1 mmol/mol; P , 0.001) compared with the mean standard of care outcome. The benefit from using the random forestbased prescriptive algorithm relative to standard of care was 0.07 6 0.01% (0.8 6 0.1 mmol/mol; P , 0.001).", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "In the sensitivity analyses, under three alternate random splittings of the dataset, the overall mean benefit of using the prescriptive algorithm compared with standard of care ranged from 0.11 to 0.15% (1.2-1.6 mmol/mol; P , 0.001 in all instances).", "cite_spans": [], "ref_spans": []}, {"section": "CONCLUSIONS", "text": "To our knowledge, we present the first prescriptive method for personalized type 2 diabetes care. Using historical data from a large EMR database, this novel prescriptive method resulted in an average HbA 1c benefit of 0.44% (4.8 mmol/mol) at each doctor's visit for which the algorithm's recommendation differed from standard of care.", "cite_spans": [], "ref_spans": []}, {"section": "CONCLUSIONS", "text": "Our method incorporates patientspecific demographic and medical history data to determine the best course of treatment. Compared with other machine-learning methods considered, the kNN prescriptive approach is highly interpretable and flexible in clinical applications. The novelty of our approach is in personalizing the decision-making process by incorporating patient-specific factors. This method can easily accommodate alternative disease-management approaches within specific subpopulations, such as patients with chronic kidney disease and elderly patients. We believe this personalization is the primary driver of benefit relative to standard of care.", "cite_spans": [], "ref_spans": []}, {"section": "CONCLUSIONS", "text": "In practice, the algorithm can be integrated into existing EMR systems to dynamically suggest personalized treatment paths for each patient based on historical records. The algorithm ingests and analyzes EMR data and generates recommendations. An intuitive, interactive dashboard summarizes the evidence for the recommendation, including the expected distribution of outcomes under alternative treatments (Fig. 2) .", "cite_spans": [], "ref_spans": [{"start": 405, "end": 413, "text": "(Fig. 2)", "ref_id": "FIGREF0"}]}, {"section": "CONCLUSIONS", "text": "Because of the nature of retrospective data from existing EMR, this study has several limitations. Patients were not randomized into treatment groups. Although our matching methodology controls for several confounding factors that could explain differences in treatment effects, we can only estimate counterfactual outcomes. EMR data do not include socioeconomic factors or patient preferences that may be important in treatment decisions. Becaue of a lack of sufficient data, glucagon-like peptide 1 agonists were not considered as a separate drug class. If more data were available, we could further differentiate regimen types beyond the 13 we include in this analysis. In addition, the study population from BMC may not be representative of the U.S. population as a whole.", "cite_spans": [], "ref_spans": []}, {"section": "CONCLUSIONS", "text": "With EMR medication-order data alone, we cannot be certain whether a prescribed medication was filled or taken and cannot know precisely when the medication was stopped. Although this data quality issue could hamper attempts to make drug efficacy comparisons, our analysis aims to address the question of which drugs to prescribe under real-world scenarios. We optimize for an outcome that takes into account unobserved factors such as nonadherence. For instance, if nonadherence is more prevalent among patients prescribed insulin than other regimens, this perspective may explain why, in our study population, the algorithm recommends insulin less often than it is prescribed in clinical practice.", "cite_spans": [], "ref_spans": []}, {"section": "CONCLUSIONS", "text": "Our method can be extended to be more flexible and comprehensive. Currently, the prescriptive algorithm does not support individualized glycemic targets; we assume that a lower glycemic level is always preferred. The study currently optimizes only for a single health outcome; a more comprehensive algorithm would consider adverse event outcomes as well.", "cite_spans": [], "ref_spans": []}, {"section": "CONCLUSIONS", "text": "Despite these limitations, the study establishes strong evidence of the benefit of individualizing diabetes care. The success of this data-driven approach invites further testing using datasets from other hospital and care settings. Testing the prescriptive algorithm in a clinical trial setting would provide even stronger evidence of clinical effectiveness. As large-scale genomic data become more widely available, the algorithm could readily incorporate such data to reach the full potential of personalized medicine in type 2 diabetes.", "cite_spans": [], "ref_spans": []}, {"section": "CONCLUSIONS", "text": "In this study, we developed a novel data-driven prescriptive algorithm for type 2 diabetes that improves significantly on the standard of care when tested on patient-level EMR data from a large medical center. Our work is a key step toward a fully patient-centered approach to diabetes management.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for glycemic control", "authors": [{"first": "H", "middle": ["W"], "last": "Rodbard", "suffix": ""}, {"first": "P", "middle": ["S"], "last": "Jellinger", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Davidson", "suffix": ""}], "year": 2009, "venue": "Endocr Pract", "link": null}, "BIBREF2": {"title": "Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)", "authors": [{"first": "", "middle": [], "last": "European", "suffix": ""}], "year": 2012, "venue": "Diabetes Care", "link": null}, "BIBREF3": {"title": "Personalized diabetes management: Moving from algorithmic to individualized therapy", "authors": [{"first": "S", "middle": [], "last": "Subramanian", "suffix": ""}, {"first": "I", "middle": ["B"], "last": "Hirsch", "suffix": ""}], "year": 2014, "venue": "Diabetes Spectr", "link": "46462849"}, "BIBREF4": {"title": "More effective glycaemic control by metformin in African Americans than in Whites in the prediabetic population", "authors": [{"first": "C", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "R", "middle": [], "last": "Zhang", "suffix": ""}], "year": 2015, "venue": "Diabetes Metab", "link": "41906775"}, "BIBREF5": {"title": "Individualizing glycemic targets in type 2 diabetes mellitus: implications of recent clinical trials", "authors": [{"first": "F", "middle": [], "last": "Ismail-Beigi", "suffix": ""}, {"first": "E", "middle": [], "last": "Moghissi", "suffix": ""}, {"first": "M", "middle": [], "last": "Tiktin", "suffix": ""}, {"first": "I", "middle": ["B"], "last": "Hirsch", "suffix": ""}, {"first": "S", "middle": ["E"], "last": "Inzucchi", "suffix": ""}, {"first": "S", "middle": [], "last": "Genuth", "suffix": ""}], "year": 2011, "venue": "Ann Intern Med", "link": "22937846"}, "BIBREF6": {"title": "Use of metformin in the setting of mild-to-moderate renal insufficiency", "authors": [{"first": "K", "middle": ["J"], "last": "Lipska", "suffix": ""}, {"first": "C", "middle": ["J"], "last": "Bailey", "suffix": ""}, {"first": "S", "middle": ["E"], "last": "Inzucchi", "suffix": ""}], "year": 2011, "venue": "Diabetes Care", "link": "2569901"}, "BIBREF7": {"title": "Machine learning: Trends, perspectives, and prospects", "authors": [{"first": "M", "middle": ["I"], "last": "Jordan", "suffix": ""}, {"first": "T", "middle": ["M"], "last": "Mitchell", "suffix": ""}], "year": 2015, "venue": "Science", "link": "677218"}, "BIBREF8": {"title": "From predictive to prescriptive analytics", "authors": [{"first": "D", "middle": [], "last": "Bertsimas", "suffix": ""}, {"first": "N", "middle": [], "last": "Kallus", "suffix": ""}], "year": 2015, "venue": "", "link": null}, "BIBREF9": {"title": "The Analytics Edge. 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This figure visualizes how the prescriptive algorithm can be used by providers for a single patient. A: Displays the algorithm's treatment recommendation along with the predicted posttreatment HbA 1c under that treatment. B: Depicts the mean, SD, and full distribution of posttreatment HbA 1c outcomes for the k \u00c3 t most similar patient visits in the data set for each of the six regimens on this patient's menu of options. In each subpanel in panel B, the posttreatment HbA 1c level is on the horizontal axis, and the number of visits is on the vertical axis. The table in panel C presents basic information about the patient's demographic and medical history. D: Depicts the history of diabetes progression and treatment for the patient, with date along the horizontal axis. The vertical axis of the top subpanel indicates various drug classes; the vertical axis of the bottom subpanel depicts HbA 1c percentage.", "type": "figure"}, "TABREF0": {"text": "1.1 million patients from 1999 to 2014. In this dataset, 10,806 patients met all of the following inclusion criteria:", "type": "table"}, "TABREF1": {"text": "Demographics, medical history, and treatment history of patients (N = 10,806)", "type": "table"}, "TABREF2": {"text": "Performance of prescriptive algorithms", "type": "table"}}}
{"paper_id": "10705898", "_pdf_hash": "06960c60d7740b1372e83869587a2062c1664a80", "abstract": [{"section": "Abstract", "text": "Let M = (E, I) be a matroid. A k-truncation of M is a matroid M \u2032 = (E, I \u2032 ) such that for any A \u2286 E, A \u2208 I \u2032 if and only if |A| \u2264 k and A \u2208 I. Given a linear representation of M we consider the problem of finding a linear representation of the k-truncation of this matroid. This problem can be abstracted out to the following problem on matrices. Let M be a n \u00d7 m matrix over a field F. A rank k-truncation of the matrix M is a k\u00d7m matrix M k (over F or a related field) such that for every subset I \u2286 {1, . . . , m} of size at most k, the set of columns corresponding to I in M has rank |I| if and only if the corresponding set of columns in M k has rank |I|. Finding rank k-truncation of matrices is a common way to obtain a linear representation of k-truncation of linear matroids, which has many algorithmic applications. A common way to compute a rank k-truncation of a n \u00d7 m matrix is to multiply the matrix with a random k \u00d7 n matrix (with the entries from a field of an appropriate size), yielding a simple randomized algorithm. So a natural question is whether it possible to obtain a rank k-truncation of a matrix, deterministically. In this paper we settle this question for matrices over any finite field or the field of rationals (Q). We show that given a matrix M over a field F we can compute a k-truncation M k over the ring F[X] in deterministic polynomial time.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Our algorithms are based on the properties of the classical Wronskian determinant and the folded Wronskian determinant, which was recently introduced by Guruswami and Kopparty [ FOCS, 2013 ]. The folded wronskian determinant was originally defined using a primitive element of the field. We prove that one can relax this to require only an element of \"polynomially large order\". This then allows our algorithms to work over any finite field. This is our main technical contribution and we believe that it will be useful in other applications.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "One of our motivations for studying k-truncation of matroids stems from the efficient computation of \"representative families for linear matroids\". As an application we show that, given a representation of any linear matroid, we can compute representative families deterministically. This includes many important classes of matroids such as graphic matroids, co-graphic matroids, partition matroids and others. Our result derandomizes many parameterized algorithms, including an algorithm for computing \u2113-Matroid Intersection.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "A rank k-truncation of a n \u00d7 m matrix M , is a k \u00d7 m matrix M k such that for every subset I \u2286 {1, . . . , m} of size at most k, the set of columns corresponding to I in M has rank |I| if and only of the corresponding set of columns in M k has rank |I|. We can think of finding a rank k-truncation of a matrix as a dimension reduction problem such that linear independence among all sets of columns of size at most k is preserved. This problem is a variant of the more general dimensionality reduction problem, which is a basic problem in many areas of computer science such as machine learning, data compression, information processing and others. In dimensionality reduction, we are given a collection of points (vectors) in a high dimensional space, and the objective is to map these points to points in a space of small dimension while preserving some property of the original collection of points. For an example, one could consider the problem of reducing the dimension of the space, while preserving the pairwise distance, for a given collection of points. Using the Johnson-Lindenstrauss Lemma this can be done approximately for any collection of m points, while reducing the dimension of the space to O(log m).", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "In this work, we study dimensionality reduction under the constraint that linear independence of any subcollection of size up to k of the given set of vectors is preserved. The motivation for this problem comes from Matroid theory and its algorithmic applications. For any matroid M = (E, I), a k-truncation of M is a matroid M \u2032 = (E, I \u2032 ) such that for any A \u2286 E, A \u2208 I \u2032 if and only if |A| \u2264 k and A \u2208 I. Given a linear representation of a matroid M = (E, I) of rank n over a universe of size m (which has a representation matrix M of dimension n \u00d7 m), the problem of finding a linear representation of the k-truncation of the matriod M = (E, I), is precisely the dimensionality reduction problem on the matrix M . Here the objective is to map the set of column vectors of M (which lie in a space of dimension n) to vectors in a space of dimension k such that, any set S of column vectors of M with |S| \u2264 k are linearly independent if and only if the corresponding set of vectors in the k-dimensional vector space are linearly independent.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "A common way to obtain a rank k-truncation of a matrix M , is to left-multiply M by a random matrix of dimension k \u00d7 n (with entries from a field of an appropriate size). Then using the Schwartz-Zippel Lemma one can show that, the product matrix is a k-truncation of the matrix M with high probability. This raises a natural question of whether there is a deterministic algorithm for computing k-truncation of a matrix. In this paper we settle this question by giving a polynomial time deterministic algorithm to solve this problem. In particular we have the following theorem. Theorem 1.1. Let F = F p \u2113 be a finite field or F = Q. Let M be a n \u00d7 m matrix over F of rank n. Given a number k \u2264 n, we can compute a matrix M k over the field F(X) such that it is a representation of the k-truncation of M . Furthermore, given M k , we can test whether a given set of \u2113 columns in M k are linearly independent in O(n 2 k 3 ) field operations.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "We further show that for many fields, the k-truncation matrix can be represented over a finite degree extension.", "cite_spans": [], "ref_spans": []}, {"section": "Tools and Techniques.", "text": "The main tool used in this work, is the Wronskian determinant and its characterization of the linear independence of a set of polynomials. Given a polynomial P j (X) and a number \u2113, define Y \u2113 j = (P j (X), P", "cite_spans": [], "ref_spans": []}, {"section": "Tools and Techniques.", "text": "j (X), . . . , P (\u2113\u22121) j (X)) T . Here, P (i) j (X) is the i-th formal derivative of P (X). Formally, the Wronskian matrix of a set of polynomials P 1 (X), . . . , P k (X) is defined as the k \u00d7 k matrix W (P 1 , . . . ,", "cite_spans": [], "ref_spans": []}, {"section": "Tools and Techniques.", "text": "Recall that to get a k-truncation of a linear matriod, we need to map a set of vectors from F n to K k such that linear independence of any subset of the given vectors of size at most k is preserved. We associate with each vector, a polynomial whose coefficients are the entries of the vector. A known mathematical result states that a set of polynomials P 1 (X), . . . , P k (X) \u2208 F[X] are linearly independent over F if and only if the corresponding Wronskian determinant det(W (P 1 , . . . , P k )) \u2261 0 in F[X] [4, 10, 18] . However, this requires that the underlying field be Q (or R, C), or that it is a finite field whose characteristic is strictly larger than the maximum degree of P 1 (X), . . . , P k (X).", "cite_spans": [{"start": 514, "end": 517, "text": "[4,", "ref_id": "BIBREF3"}, {"start": 518, "end": 521, "text": "10,", "ref_id": "BIBREF9"}, {"start": 522, "end": 525, "text": "18]", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "Tools and Techniques.", "text": "For fields of small characteristic, we use the notion of \u03b1-folded Wronskian, which was introduced by Guruswami and Kopparty [13] in the context of subspace design, with applications in coding theory. Let F be a finite field and \u03b1 be an element of F. Given a polynomial P j (X) \u2208 F[X] and a number \u2113, define Z \u2113 j = (P j (X), P j (\u03b1X), . . . , P j (\u03b1 \u2113\u22121 X)) T . Formally, the \u03b1-folded Wronskian matrix of a family of polynomials P 1 (X), . . . , P k (X) is defined as the k \u00d7 k matrix W \u03b1 (P 1 , . . . , P k ) = [Z k 1 , . . . , Z k k ]. Let P 1 (X), . . . , P k (X) be a family of polynomials of degree at most n \u2212 1. Guruswami and Kopparty [13] showed that if \u03b1 is a primitive element of the field F and |F| > n then P 1 (X), . . . , P k (X) are linearly independent over F if and only if \u03b1-folded Wronskian determinant det(W \u03b1 (P 1 , . . . , P k )) \u2261 0 in F [X] . However, to use \u03b1-folded Wronskians in algorithmic applications we need to find a primitive element of the finite field. Still, computing a primitive element of large finite field is a non-trivial problem and no deterministic polynomial time algorithms are known in general. To overcome this difficulty, we prove that one can relax the requirement on \u03b1 such that it only needs to be an element of polynomially large order in F. In particular we prove the following theorem.", "cite_spans": [{"start": 124, "end": 128, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 642, "end": 646, "text": "[13]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Tools and Techniques.", "text": "Given a n \u00d7 m matrix M over F and a positive integer k our algorithm for finding a k-truncation of M proceeds as follows. To a column C i of M we associate a polynomial P i (X) whose coefficients are the entries of C i . That is, if", "cite_spans": [], "ref_spans": []}, {"section": "Tools and Techniques.", "text": "If the characteristic of the field F is strictly larger than n or F = Q then we return", "cite_spans": [], "ref_spans": []}, {"section": "Tools and Techniques.", "text": "In other cases we first compute an \u03b1 \u2208 F of order larger than (n \u2212 1)(k \u2212 1) and", "cite_spans": [], "ref_spans": []}, {"section": "Tools and Techniques.", "text": ". We then use Theorem 1.2 and properties of Wronskian determinant to prove the correctness of our algorithm. Observe that when M is a representation of a linear matroid then M k is a representation of it's k-truncation. Further, each entry of M k is a polynomial of degree at most n \u2212 1 in F[X]. Thus, testing whether a set of columns of size at most k is independent, reduces to testing whether a determinant polynomial of degree at most (n \u2212 1)k is identically zero or not. This is easily done by evaluating the determinant at (n \u2212 1)k + 1 points in F and testing if it is zero at all those points.", "cite_spans": [], "ref_spans": []}, {"section": "Tools and Techniques.", "text": "Applications. Matroid theory has found many algorithmic applications, starting from the characterization of greedy algorithms, to designing fixed parameter tractable (FPT) algorithms and kernelization algorithms. Recently the notion of representative families over linear matroids was used in designing fast FPT, as well as kernelization algorithm for several problems [6, 8, 15, 14, 17, 12, 21] . Let us introduce this notion more formally. Let M = (E, I) be a matroid and let S = {S 1 , . . . , S t } be a family of subsets of E of size p. A subfamily S \u2286 S is q-representative for S if for every set Y \u2286 E of size at most q, if there is a set X \u2208 S disjoint from Y with X \u222a Y \u2208 I, then there is a set X \u2208 S disjoint from Y and X \u222a Y \u2208 I. In other words, if a set Y of size at most q can be extended to an independent set of size |Y | + p by adding a subset from S, then it also can be extended to an independent set of size |Y | + p by adding a subset from S as well. The Two-Families Theorem of Bollob\u00e1s [3] for extremal set systems and its generalization to subspaces of a vector space of Lov\u00e1sz [16] (see also [9] ) imply that every family of sets of size p has a q-representative family with at most p+q p sets. Recently, Fomin et. al. [8] gave an efficient randomized algorithm to compute a representative family of size p+q p in a linear matroid of rank n > p + q. This algorithm starts by computing a randomized p + q-truncation of the given linear matroid and then computes a q-representative family over the truncated matroid deterministically. Therefore one of our motivations to study the k-truncation problem was to find an efficient deterministic computation of a representative family in a linear matroid. Formally, we have the following theorem. Theorem 1.3. Let M = (E, I) be a linear matroid of rank n and let S = {S 1 , . . . , S t } be a p-family of independent sets. Let A be a n \u00d7 |E| matrix representing M over a field F, where F = F p \u2113 or F is Q. Then there are deterministic algorithms computing S \u2286 q rep S as follows.", "cite_spans": [{"start": 369, "end": 372, "text": "[6,", "ref_id": "BIBREF5"}, {"start": 373, "end": 375, "text": "8,", "ref_id": "BIBREF7"}, {"start": 376, "end": 379, "text": "15,", "ref_id": "BIBREF14"}, {"start": 380, "end": 383, "text": "14,", "ref_id": "BIBREF13"}, {"start": 384, "end": 387, "text": "17,", "ref_id": "BIBREF16"}, {"start": 388, "end": 391, "text": "12,", "ref_id": "BIBREF11"}, {"start": 392, "end": 395, "text": "21]", "ref_id": "BIBREF20"}, {"start": 1008, "end": 1011, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 1101, "end": 1105, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 1116, "end": 1119, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 1243, "end": 1246, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "A family S of size", "text": ", operations over F.", "cite_spans": [], "ref_spans": []}, {"section": "A family S of size np", "text": "As a corollary of the above theorem, we obtain a deterministic FPT algorithm \u2113-Matroid Intersection, derandomizing the algorithm of Marx [17] . Using our results one can compute, in deterministic polynomial time, the k-truncation of graphic and co-graphic matroids, which has important applications in graph algorithms.", "cite_spans": [{"start": 137, "end": 141, "text": "[17]", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Preliminaries", "text": "In this section we give various definitions and notions which we make use of in the paper. We use the following notations: [n] = {1, . . . , n} and", "cite_spans": [], "ref_spans": []}, {"section": "Fields and Polynomials", "text": "In this section we review some definitions and properties of fields. We refer to any graduate text on algebra for more details. The cardinality or the size of a field is called its order. It is well known that rational numbers Q and real numbers R are fields of infinite order. For every prime number p and a positive integer \u2113, there exists a finite field of order p \u2113 . For a prime number p, the set {0, 1, . . . , p \u2212 1} with addition and multiplication modulo p forms a field, which we denote by F p . Such fields are known as prime fields. Let F be a finite field and F[X] be the ring of polynomials in X over F. For the ring F[X] we can define a field F(X) which is called the field of fractions of F[X] as follows. The elements of F(X) are of the form P (X)/Q(X) where P (X), Q(X) \u2208 F[X] and Q(X) is not a zero polynomial. The addition and multiplication operations from F[X] are extended to F(X) in the usual way. The degree of a polynomial P (X) \u2208 F(X) is the highest exponent on indeterminate X with a nonzero coefficient in P (X). We will use F[X] <n to denote the set the polynomials in F[X] of degree < n.", "cite_spans": [], "ref_spans": []}, {"section": "Fields and Polynomials", "text": "For a field F, we use + F and \u00d7 F to denote the addition and multiplication operations. (Often we write a + b and ab when the context is clear.) The characteristic of a field, denoted by char(F), is defined as least integer m such that m i=1 1 = 0. For fields such as R where there is no such m, the characteristic is defined to be 0. For a finite field F = F p \u2113 , let F * = F \\ {0}. This is called the multiplicative group of F which is a cyclic group and has a generator \u03b1 \u2208 F * . Every element of F * can be written as \u03b1 i for some number i. The element \u03b1 is called a primitive element of the field F. We say that an element \u03b2 \u2208 F has order r, if r is the least integer such that \u03b2 r = 1.", "cite_spans": [], "ref_spans": []}, {"section": "Fields and Polynomials", "text": "is also a field. It is of order |F| \u2113 and characteristic of K is equal to the characteristic of F. We call K a field extension of F of degree \u2113. All finite fields are obtained as extensions of prime fields, and for any prime p and positive integer \u2113 there is exactly one finite field of order p \u2113 up to isomorphism. For a matrix A = (a ij ) over a field F, the row set and the column set are denoted by R(A) and C(A) respectively. For I \u2286 R(A) and J \u2286 C(A), A[I, J] = a ij | i \u2208 I, j \u2208 J means the submatrix (or minor) of A with the row set I and the column set J. The matrix is said to have dimension n \u00d7 m if it has n rows and m columns. For a matrix A (or a vector v) by A T (or v T ) we denoted its transpose. Note that each column of a matrix is a vector over the field F. The rank of a matrix is the cardinality of the maximum sized collection of columns which are linearly independent. Equivalently, the rank of a matrix is the maximum number k such that there is a k \u00d7 k submatrix whose determinant is non-zero. We can use the definition of rank of a matrix to certify the linear independence of a set of vectors. A collection of n vectors v 1 , v 2 , . . . , v n are linearly independent if and only if the matrix M formed by v 1 , v 2 , . . . , v n as column vectors have rank n. Determinant of a n \u00d7 n matrix A is denoted by det(A) and is defined as", "cite_spans": [], "ref_spans": []}, {"section": "Vectors and Matrices", "text": "Here, S n is the set of all permutations of {1, . . . , n} and sgn(\u03c3) denotes the signature of the permutation \u03c3.", "cite_spans": [], "ref_spans": []}, {"section": "Vectors and Matrices", "text": "Throughout the paper we use \u03c9 to denote the matrix multiplication exponent. The current best known bound on \u03c9 < 2.373 [25] . We use e to denote the base of natural logarithm.", "cite_spans": [{"start": 118, "end": 122, "text": "[25]", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Matroids", "text": "In the next few subsections we give definitions related to matroids. For a broader overview on matroids we refer to [20] .", "cite_spans": [{"start": 116, "end": 120, "text": "[20]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "Matroids", "text": ", where E is a ground set and I is a family of subsets (called independent sets) of E, is a matroid if it satisfies the following conditions:", "cite_spans": [], "ref_spans": []}, {"section": "Matroids", "text": "(I3) If A, B \u2208 I and |A| < |B|, then there is e \u2208 (B \\ A) such that A \u222a {e} \u2208 I.", "cite_spans": [], "ref_spans": []}, {"section": "Matroids", "text": "The axiom (I2) is also called the hereditary property and a pair (E, I) satisfying only (I2) is called hereditary family. An inclusion wise maximal set of I is called a basis of the matroid. Using axiom (I3) it is easy to show that all the bases of a matroid have the same size. This size is called the rank of the matroid M , and is denoted by rank(M ).", "cite_spans": [], "ref_spans": []}, {"section": "Linear Matroids and Representable Matroids", "text": "Let A be a matrix over an arbitrary field F and let E be the set of columns of A. For A, we define matroid M = (E, I) as follows. A set X \u2286 E is independent (that is X \u2208 I) if the corresponding columns are linearly independent over F. The matroids that can be defined by such a construction are called linear matroids, and if a matroid can be defined by a matrix A over a field F, then we say that the matroid is representable over F. That is, a matroid M = (E, I) of rank d is representable over a field F if there exist vectors in F d corresponding to the elements such that linearly independent sets of vectors correspond to independent sets of the matroid. A matroid M = (E, I) is called representable or linear if it is representable over some field F and the corresponding matrix is called the representation matrix of M .", "cite_spans": [], "ref_spans": []}, {"section": "Truncation of a Matroid.", "text": "The t-truncation of a matroid M = (E, I) is a matroid M \u2032 = (E, I \u2032 ) such that S \u2286 E is independent in M \u2032 if and only if |S| \u2264 t and S is independent in M (that is S \u2208 I). ", "cite_spans": [], "ref_spans": []}, {"section": "Derivatives", "text": "Recall the definition of the formal derivative d dx of a function over R. We denote the k-th formal derivative of a function f by f (k) . We can extend this notion to finite fields. Let F be a finite field and let F[X] be the ring of polynomials in X over F. Let P \u2208 F[X] be a polynomial of degree n \u2212 1, i.e. P = n\u22121 i=0 a i X i where a i \u2208 F. Then we define the formal derivative of as", "cite_spans": [], "ref_spans": []}, {"section": "Derivatives", "text": "We can extend this definition to the k-th formal derivative of P as P (k) = (P (k\u22121) ) \u2032 . Note that higher derivtives are defined iteratively using lower derivatives, thus they are also called iterated formal derivatives.", "cite_spans": [], "ref_spans": []}, {"section": "Derivatives", "text": "Formal derivatives continue to carry many of their properties in R to finite fields F. However not all properties carry through. For example, in F 3 [X] the polynomial P (X) = X 3 has all derivatives 0. To remedy such problems, we require the notion of Hasse Derivatives. For a polynomial P (X) \u2208 F[X], the i-th Hasse derivative D i (P ) is defined as the coefficient of Z i in P (X + Z).", "cite_spans": [], "ref_spans": []}, {"section": "Derivatives", "text": "We note some important properties of Hasse derivatives and how they relate to formal derivatives. We refer to [5] and [11] for details.", "cite_spans": [{"start": 110, "end": 113, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 118, "end": 122, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Lemma 2.3. Let F be a finite field of characteristic p, P, Q \u2208 F[x]", "text": ". Then the following holds :", "cite_spans": [], "ref_spans": []}, {"section": "Let k be some number and let", "text": "In particular D 0 (P ) = f and D 1 (P ) = P (1) .", "cite_spans": [{"start": 44, "end": 47, "text": "(1)", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Let k be some number and let", "text": "Observe that the second statement in the above lemma shows that the value of k-th hasse derivatives and k-th formal derivatives differ only by a multiplicative value whenever k! is non-zero in F. In particular when k < p, (the characteristic of the field F) then k! is always non-zero in F. In our setting this is always the case.", "cite_spans": [], "ref_spans": []}, {"section": "Matroid Truncation", "text": "In this section we give our one of the main results. We start with an introduction to our tools and then we give two results that give rank k-truncation of the given matrix M .", "cite_spans": [], "ref_spans": []}, {"section": "Tools and Techniques", "text": "In this subsection we collect some known results, definitions and derive some new connections among them that will be central to our results. We also prove one of the main technical contribution of the paper in this subsection (Theorem 3.4).", "cite_spans": [], "ref_spans": []}, {"section": "Polynomials and Vectors", "text": "Let F be a field. The set of polynomials", "cite_spans": [], "ref_spans": []}, {"section": "Polynomials and Vectors", "text": "Otherwise they are said to be linearly dependent.", "cite_spans": [], "ref_spans": []}, {"section": "Polynomials and Vectors", "text": ". We define the vector v corresponding to the polynomial P (X) as follows:", "cite_spans": [], "ref_spans": []}, {"section": "Polynomials and Vectors", "text": "given a vector v of length n over F, we define the polynomial P (X) in F[X] corresponding to the vector v as follows:", "cite_spans": [], "ref_spans": []}, {"section": "Polynomials and Vectors", "text": "The next lemma will be key to several proofs later. We first prove the forward direction of the proof. For a contradiction, assume that v 1 , . . . , v k are linearly dependent. Then there exists a 1 , . . . , a k \u2208 F, not all zeros, such that", "cite_spans": [], "ref_spans": []}, {"section": "Polynomials and Vectors", "text": "Summing over all these expressions we get", "cite_spans": [], "ref_spans": []}, {"section": "Polynomials and Vectors", "text": "This completes the proof in the forward direction.", "cite_spans": [], "ref_spans": []}, {"section": "Polynomials and Vectors", "text": "Next we prove the reverse direction of the lemma. To the contrary assume that P 1 (X), . . . , P k (X) are linearly dependent. Then there exists a 1 , . . . , a k \u2208 F, not all zeros, such that", "cite_spans": [], "ref_spans": []}, {"section": "Polynomials and Vectors", "text": "This implies that for each j \u2208 {1, . . . , n}, the coefficients of We will use this claim to view the column vectors of a matrix M over a field F as elements in the ring F[X] and in the field of fractions F(X). We shall then use properties of polynomials to deduce properties of these column vectors and vice versa.", "cite_spans": [], "ref_spans": []}, {"section": "Wronskian", "text": "Let F be a field with characteristic at least n. Consider a collection of polynomials P 1 (X), . . . , P k (X) from F[X] of degree at most n \u2212 1. We define the following matrix, called the Wronskian, of P 1 (X), . . . , P k (X) as follows.", "cite_spans": [], "ref_spans": []}, {"section": "Wronskian", "text": "Note that, the determinant of the above matrix actually yields a polynomial. For our purpose we will need the following well known result.", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 3.2 ([4, 10, 18]). Let F be a field and P", "text": "The notion of Wronskian dates back to 1812 [18] . We refer to [4, 10] for some recent variations and proofs. The switch between usual derivatives and Hasse derivatives multiplies the Wronskian determinant by a constant, which is non-zero as long as n < char(F), and thus this criterion works with both notions. Observe that the Wronskian determinant is a polynomial of degree at most nk in F[X]. Thus to test if such a polynomial (of degree d) is identically zero, we only need to evaluate it at d + 1 arbitrary points of the field F, and check if it is zero at all those points.", "cite_spans": [{"start": 43, "end": 47, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 62, "end": 65, "text": "[4,", "ref_id": "BIBREF3"}, {"start": 66, "end": 69, "text": "10]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Folded Wronskian", "text": "The above definition of Wronskian requires us to compute derivatives of degree (n \u2212 1) polynomials. As noted earlier, they are well defined only if the underlying field has characteristic greater than or equal to n. However, we might have matrix over fields of small characteristic. For these kind of fields, we have the notion of Folded Wronskian which was recently introduced by Guruswami and Kopparty in the context of subspace design [13] .", "cite_spans": [{"start": 438, "end": 442, "text": "[13]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Folded Wronskian", "text": "Consider a collection of polynomials P 1 (X), . . . , P k (X) from F[X] of degree at most (n \u2212 1). Further, let F be of order at least n + 1, and \u03b1 be an element of F * . We define the the \u03b1-folded Wronskian, of P 1 (X), . . . , P k (X) as follows.", "cite_spans": [], "ref_spans": []}, {"section": "Folded Wronskian", "text": "As before, the determinant of the above matrix is a polynomial of degree at most nk in F[X]. It is important to note that Guruswami and Kopparty used the above notion of \u03b1-folded Wronskian only for those \u03b1 that are primitive element of F. In particualr, they proved the following result about \u03b1-folded Wronskians [13, Lemma 12] .", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 3.3 ([13])", "text": ". Let F be a field of order > n, \u03b1 be a primitive element of F and let", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 3.3 ([13])", "text": "Theorem 3.3 requires a primitive element \u03b1 of the underlying field F. However, finding a primitive element in a finite field is a non-trivial problem and currently there are no deterministic polynomial time algorithm known for this problem. To overcome this difficulty, we prove a generalization of Theorem 3.3. We relax the requirement that \u03b1 must be a primitive element of the field F and only require that \u03b1 be an element of sufficiently large order. Finding an element of large order is slightly easier task than finding a primitive element of a finite field F. We will see that for our purpose this will be sufficient. This result will be our main technical tool. The proof for next theorem is very different than the one for Theorem 3.3. Theorem 3.3 crucially uses the fact that \u03b1 is a primitive element. This is used to define an irreducible polynomial which is key to the arguments used in [13, Lemma 12] . We do not see ways to make the arguments used for the proof of Theorem 3.3 to go through for our case. Our theorem is as follows.", "cite_spans": [{"start": 898, "end": 902, "text": "[13,", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Theorem 3.3 ([13])", "text": "In what follows we build towards the proof of Theorem 3.4. For the sake of brevity, we use W \u03b1 to denote the matrix W \u03b1 (P 1 , . . . , P k ). We use the notation", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 3.3 ([13])", "text": "Observe that W \u03b1 is a matrix over the field F(X), with entries from the ring F[X]. When we talk about linear independence of", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 3.3 ([13])", "text": ", the underlying field is F(X). We recall the following well known lemma about non-zero determinant of a square matrix and the linear independence of it's columns. The next lemma will prove the reverse direction of Theorem 3.4.", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 3.3 ([13])", "text": "That is, the columns of W \u03b1 are linearly dependent over F \u2286 F(X). Therefore by Lemma 3.5 the polynomial det(W \u03b1 ) is identically zero. That is, det(W \u03b1 ) \u2261 0. This completes the proof.", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 3.3 ([13])", "text": "The next lemma will be used in the forward direction of the proof.", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 3.7. Let A(X) and B(X) be non zero polynomials in", "text": "Case 1: We first assume that b 0 = 0. Later we will show how all other cases reduce to this. Let", "cite_spans": [], "ref_spans": []}, {"section": "S A,B (X) = A(X)B(\u03b2X) \u2212 A(\u03b2X)B(X).", "text": "Since S A,B (X) \u2261 0 we have that for all t \u2208 {0, 1, . . . , 2\u2113}, the coefficients of X t in S A,B (X) is zero. Our proof is based on the following claim. Thus we assume that i \u2265 2 and by induction hypothesis the claim holds for j \u2208 {1, . . . , i \u2212 1}. Now, consider the coefficients of", "cite_spans": [], "ref_spans": []}, {"section": "S A,B (X) = A(X)B(\u03b2X) \u2212 A(\u03b2X)B(X).", "text": "By our assumption we know that", "cite_spans": [], "ref_spans": []}, {"section": "S A,B (X) = A(X)B(\u03b2X) \u2212 A(\u03b2X)B(X).", "text": "Consider the term \u03b2 j (a i\u2212j b j \u2212 a j b i\u2212j ) for 0 < j < i. By induction hypothesis, one of the following statement is true.", "cite_spans": [], "ref_spans": []}, {"section": "S A,B (X) = A(X)B(\u03b2X) \u2212 A(\u03b2X)B(X).", "text": "\u2022 a j = b j = 0", "cite_spans": [], "ref_spans": []}, {"section": "S A,B (X) = A(X)B(\u03b2X) \u2212 A(\u03b2X)B(X).", "text": "In all the three cases the term ", "cite_spans": [], "ref_spans": []}, {"section": "S A,B (X) = A(X)B(\u03b2X) \u2212 A(\u03b2X)B(X).", "text": "Thus A 1 (X)B 1 (\u03b2X) \u2212 A 1 (\u03b2X)B 1 (X) \u2261 0. So by applying Case 1 with A 1 (X) and B 1 (X), we get A 1 (X) = \u03bbB 1 (X) where 0 = \u03bb \u2208 F. This implies that A(X) = \u03bb \u22121 B(X) where 0 = \u03bb \u22121 \u2208 F. The next lemma will be useful in showing the forward direction of Theorem 3.4.", "cite_spans": [], "ref_spans": []}, {"section": "S A,B (X) = A(X)B(\u03b2X) \u2212 A(\u03b2X)B(X).", "text": "Lemma 3.9. Let P 1 (X), . . . , P k (X) be a set of polynomials from F[X] <n and \u03b1 be an element of order", "cite_spans": [], "ref_spans": []}, {"section": "S A,B (X) = A(X)B(\u03b2X) \u2212 A(\u03b2X)B(X).", "text": "Proof. We prove the lemma using induction on k -the number of polynomials. For k = 1, W \u03b1 = [P 1 (X)] and the lemma vacuously holds. Form now on we assume that k \u2265 2 and that the lemma holds for all t < k. Recall that Z i denotes the i-th column of the matrix W \u03b1 . We first give the proof for the case when there is a subset of columns of Z 1 , . . . , Z k , of size < k that are linearly dependent over F(X). Let {i 1 , . . . , i t } \u2282 {1, . . . , k} of size at most k \u2212 1, such that Z i 1 , . . . , Z it are linearly dependent. Thus, there exists \u03b4 1 (X), . . . , \u03b4 t (X) \u2208 F(X), not all equal to zero polynomial in F(X), such that", "cite_spans": [], "ref_spans": []}, {"section": "S A,B (X) = A(X)B(\u03b2X) \u2212 A(\u03b2X)B(X).", "text": ". . , Z \u2032 it are also linearly dependent over F(X). Consider W \u03b1 (P i 1 , . . . , P it ) . This is a t \u00d7 t matrix with columns", "cite_spans": [], "ref_spans": [{"start": 65, "end": 88, "text": "(P i 1 , . . . , P it )", "ref_id": "FIGREF0"}]}, {"section": "S A,B (X) = A(X)B(\u03b2X) \u2212 A(\u03b2X)B(X).", "text": ". . , Z \u2032 it are linearly dependent, by Lemma 3.5, det(W \u03b1 (P i 1 , . . . , P it )) \u2261 0. By induction hypothesis, this implies that P i 1 (X), . . . , P it (X) are linearly dependent over F and thus P 1 (X), . . . , P k (X) are linearly dependent over F. So from now on we assume that for any subset {i 1 , . . . , i t } \u2282 {1, . . . , k} of size at most k \u2212 1, Z i 1 , . . . , Z it are linearly independent and det(W \u03b1 (P i 1 , . . . , P it )) \u2261 0.", "cite_spans": [], "ref_spans": [{"start": 59, "end": 69, "text": "(P i 1 , .", "ref_id": "FIGREF0"}, {"start": 419, "end": 429, "text": "(P i 1 , .", "ref_id": "FIGREF0"}]}, {"section": "S A,B (X) = A(X)B(\u03b2X) \u2212 A(\u03b2X)B(X).", "text": "Next we prove the claim that if", "cite_spans": [], "ref_spans": []}, {"section": "S A,B (X) = A(X)B(\u03b2X) \u2212 A(\u03b2X)B(X).", "text": "are linearly dependent then we can choose the polynomials \u03b4 i (X) in F(X) which satisfy certain desirable properties.", "cite_spans": [], "ref_spans": []}, {"section": "S A,B (X) = A(X)B(\u03b2X) \u2212 A(\u03b2X)B(X).", "text": "Proof. For all i \u2208 {1, . . . , k}, define", "cite_spans": [], "ref_spans": []}, {"section": "S A,B (X) = A(X)B(\u03b2X) \u2212 A(\u03b2X)B(X).", "text": "because by assumption det(W \u03b1 (P 1 , . . . , P k )) \u2261 0. Now consider the matrix W j obtained by replacing the first row of W \u03b1 (P 1 , . . . , P k ) with j th row of W \u03b1 (P 1 , . . . , P k ). That is,", "cite_spans": [], "ref_spans": []}, {"section": "S A,B (X) = A(X)B(\u03b2X) \u2212 A(\u03b2X)B(X).", "text": "Note that for any j \u2208 {2, . . . , k},", "cite_spans": [], "ref_spans": []}, {"section": "S A,B (X) = A(X)B(\u03b2X) \u2212 A(\u03b2X)B(X).", "text": "Since we are in the case where for any subset {i 1 , . . . , i t } \u2282 {1, . . . , k} of size at most k \u2212 1, Z i 1 , . . . , Z it are linearly independent we have that det(W \u03b1 (P 1 , . . . , P i\u22121 , P i+1 , . . . , P k )) \u2261 0.", "cite_spans": [], "ref_spans": []}, {"section": "This implies that", "text": "and the degree of \u03b4 i (X) is at most (n \u2212 1)(k \u2212 1) for all i \u2208 {1, . . . , k}. This completes the proof of the claim.", "cite_spans": [], "ref_spans": []}, {"section": "This implies that", "text": "From now on we work with the collection {\u03b4 i (X)} k i=1 provided by Claim 3.10. We have the following expression.", "cite_spans": [], "ref_spans": []}, {"section": "This implies that", "text": "This implies that for each j \u2208 {0, . . . , k \u2212 1}, we have", "cite_spans": [], "ref_spans": []}, {"section": "This implies that", "text": "By rearranging Equation 1 and absorbing the negative sign into \u03b4 k (X) we get", "cite_spans": [], "ref_spans": []}, {"section": "This implies that", "text": "Substitute \u03b1X for X in Equation 2 for all j \u2208 {0, . . . , k \u2212 2} we get", "cite_spans": [], "ref_spans": []}, {"section": "This implies that", "text": "Substitute the value of P k (\u03b1 j+1 X) from Equation 2 into Equation 3, we get that for all j \u2208 {0, 1, . . . , k \u2212 2}", "cite_spans": [], "ref_spans": []}, {"section": "This implies that", "text": "Thus for each j \u2208 {0, 1, . . . , k \u2212 2} we have", "cite_spans": [], "ref_spans": []}, {"section": "This implies that", "text": "Substitute \u03b2X for X in Equation 5 , where", "cite_spans": [], "ref_spans": []}, {"section": "This implies that", "text": "Let Z \u2032 i be the column vector corresponding to Z i in the matrix W \u03b1 (P 1 , . . . , P k ) restricted to the first k \u2212 1 rows. Then from Equation 6 we get that for all j \u2208 {0, 1, . . . , k \u2212 2}", "cite_spans": [], "ref_spans": []}, {"section": "This implies that", "text": "Consider the (k \u2212 1)", "cite_spans": [], "ref_spans": []}, {"section": "This implies that", "text": ". By the case of proof we are currently dealing, we have that W \u03b1 (P 1 (X), P 2 (X), . . . , P k\u22121 (X)) has a non-zero determinant. In other words, the vectors Z \u2032 1 , . . . , Z \u2032 k\u22121 are linearly independent over F(X). This implies that for all i \u2208 {1, . . . , k \u2212 1},", "cite_spans": [], "ref_spans": []}, {"section": "This implies that", "text": "Observe that \u03b4 i (X), i \u2208 {1, . . . , k}, are non-zero polynomials in F[X] of degree at most (n\u22121)(k\u22121). Furthermore, the order of \u03b2 is > (n \u2212 1)(k \u2212 1), and thus by applying Lemma 3.7 we get that \u03b4 i (X) = \u03bb i \u03b4 k (X) for all i \u2208 {1, . . . , k \u2212 1} where 0 = \u03bb i \u2208 F. Now by simplifying we get the following expressions", "cite_spans": [], "ref_spans": []}, {"section": "This implies that", "text": "Hence P 1 (X), . . . P k (X) are linearly dependent over F. This completes the proof of the lemma.", "cite_spans": [], "ref_spans": []}, {"section": "This implies that", "text": "Combining Lemmata 3.6 and 3.9, we get the proof of Theorem 3.4. We can get the following corrollary from Theorems 3.3 and 3.4. ", "cite_spans": [], "ref_spans": []}, {"section": ". , P k (X) are linearly independent over F if and only if the \u03b1-folded", "text": "Wronskian determinant det(W \u03b1 (P 1 , . . . , P k )) \u2261 0 in F[X].", "cite_spans": [], "ref_spans": []}, {"section": "Finding irreducible polynomials and elements of large order", "text": "Whenever we will need to use folded Wronskians, we will also need to get hold of a primitive element or an element of large order of an appropriate field. We start by reviewing some known algorithms for finding irreducible polynomials over finite fields. Note that for a finite field of order p \u2113 , the field operations can be done in time (\u2113 log p) O(1) . And for an infinite field, the field operations will require (log N ) O(1) where N is the size of the largest value handled by the algorithm. Typically we will provide an upper bound on N when the need arises. A result by Shoup [22, Theorem 4.1]) allows us to find an irreducible polynomial of degree r over F p \u2113 in time polynomial in p, \u2113 and d. Adleman and Lenstra [1, Theorem 2] gave an algorithm that allows us to compute an irreducible polynomial of degree at least r over a prime field F p in time polynomial in log p and r.", "cite_spans": [], "ref_spans": []}, {"section": "Lemma 3.12 ([1, 22]). (Finding Irreducible Polynomials)", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "There is an algorithm that given prime p and r, it can compute an irreducible polynomial", "text": "where c is a constant.", "cite_spans": [], "ref_spans": []}, {"section": "For q = p \u2113 and an integer r, we can compute an irreducible polynomial of", "text": "Next we consider a few algorithms for finding primitive elements in finite fields. For fields of large order but small characteristic, we have the following lemma, which follows from the results of Shparlinski [23] and also from the results of Shoup [24] . Lemma 3.13 ([23, 24] ). Let F = F p \u2113 be a finite field. Then we can compute a set S \u2282 F, containing a primitive element, of size poly(p, \u2113) in time poly(p, \u2113).", "cite_spans": [{"start": 210, "end": 214, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 250, "end": 254, "text": "[24]", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "For q = p \u2113 and an integer r, we can compute an irreducible polynomial of", "text": "We use Lemma 3.13 to get the following result that allows us to find elements of sufficiently large order in a finite field or a primitive element in a field of small size.", "cite_spans": [], "ref_spans": []}, {"section": "For q = p \u2113 and an integer r, we can compute an irreducible polynomial of", "text": "Lemma 3.14. Let F = F p \u2113 be a finite field. Given a number n such that n < p \u2113 , we can compute an element of F of order greater than n in poly(p, \u2113, n) time. Furthermore, we can find a primitive element in F in time |F| O(1) .", "cite_spans": [], "ref_spans": []}, {"section": "For q = p \u2113 and an integer r, we can compute an irreducible polynomial of", "text": "Proof. We begin by applying Lemma 3.13 to the field F and obtain a set S of size poly(p, \u2113). This takes time poly(p, \u2113). Then for each element \u03b1 \u2208 S we compute the set G \u03b1 = {\u03b1 i | i = 1, 2, . . . , n+1}. If for any \u03b1, |G \u03b1 | = n + 1, then we return this as the required element of order greater than n. Since the set S contains at least one primitive element of F, we will find some \u03b1 in this step. Note this this step too takes poly(p, \u2113, n) time.", "cite_spans": [], "ref_spans": []}, {"section": "For q = p \u2113 and an integer r, we can compute an irreducible polynomial of", "text": "To prove the second statement of the lemma do as follows. For each element \u03b1 \u2208 S, consider the set", "cite_spans": [], "ref_spans": []}, {"section": "For q = p \u2113 and an integer r, we can compute an irreducible polynomial of", "text": "Since the set S contains at least one primitive element of F, we will find some \u03b1 in this step. Note this this step can be done in time |F| O(1) . This completes the proof of this lemma.", "cite_spans": [], "ref_spans": []}, {"section": "For q = p \u2113 and an integer r, we can compute an irreducible polynomial of", "text": "When given a small field, the following lemma allows us to increase the size of the field as well as find a primitive element in the larger field. Lemma 3.15. Given a field F = F p \u2113 and a number n such that p \u2113 < n, we can find an extension K of F such that n < |K| < n 2 and a primitive element \u03b1 of K in time n O(1) .", "cite_spans": [], "ref_spans": []}, {"section": "For q = p \u2113 and an integer r, we can compute an irreducible polynomial of", "text": "Proof. Let r be smallest number such that p \u2113r > n. But then p \u2113r/2 < n. Therefore we have that p \u2113r < n 2 . Next we find an extension of F of degree r, by finding an irreducible polynomial over F of degree r using Lemma 3.12 in time polynomial in p, \u2113, r, which is n O(1) . Then we can use Lemma 3.14 to compute a primitive element of K. Since |K| < n 2 , this can be done in time n O(1) . This completes the proof of this lemma.", "cite_spans": [], "ref_spans": []}, {"section": "Deterministic Truncation of Matrices", "text": "In this section we look at algorithms for computing k-truncation of matrices. We consider matrices over the set of rational numbers Q or over some finite field F. Therefore, we are given as input a matrix M of rank n over a field F. Let p be the characteristic of the field F and N denote the size of the input in bits. The following theorem, gives us an algorithm to compute the truncation of a matrix using the classical wronskian, over an appropriate field. We shall refer to this as the classical wronskian method of truncation. Proof. Let F[X] be the ring of polynomials in X over F and let F(X) be the corresponding field of fractions. Let C 1 , . . . , C m denote the columns of M . Observe that we have a polynomial P i (X) corresponding to the column C i of degree at most n \u2212 1, and by Lemma 3.1 we have that C i 1 , . . . , C i \u2113 are linearly independent over F if and only if P i 1 (X), . . . , P i \u2113 (X) are linearly independent over F. Further note that P i lies in F[X] and thus also in F(X). Let D i be the vector (P i (X), P . We shall show that M I has rank \u2113 by showing that there is a \u2113 \u00d7 \u2113 submatrix whose determinant is a non-zero polynomial. Let P i 1 (X), . . . , P i \u2113 (X) be the polynomials corresponding to the vectors C i 1 , . . . , C i \u2113 . By Lemma 3.1 we have that P i 1 (X), . . . , P i \u2113 (X) are linearly independent over F. Then by Theorem 3.2, the (\u2113 \u00d7 \u2113) matrix formed by the column vectors (P i j (X), P Lemma 3.16 is useful in obtaining k-truncation of matrices which entries are either from the filed of large characteristic or from Q. The following lemma allows us to find truncations in fields of small characteristic which have large order. We however require a primitive element or an element of high order of such a field to compute the truncation. In the next lemma we demand a lower bound on the size of the field as we need an element of certain order. We will later see how to remove this requirement from the statement of the next lemma. Proof. Let F[X] be the ring of polynomials in X over F and let F(X) be the corresponding field of fractions. Let C 1 , . . . , C m denote the columns of M . Observe that we have a polynomial P i (X) corresponding to the column C i of degree at most n\u22121, and by Lemma 3.1 we have that C i 1 , . . . , C i \u2113 are linearly independent over F if and only if P i 1 (X), . . . , P i \u2113 (X) are linearly independent over F.", "cite_spans": [], "ref_spans": []}, {"section": "Further note that P i (X) lies in F[X] (and also in F(X)).", "text": "Let D i be the vector (", "cite_spans": [], "ref_spans": []}, {"section": "Further note that P i (X) lies in F[X] (and also in F(X)).", "text": "Observe that the entries of D i are polynomials of degree at most n \u2212 1 and are elements of F[X]. Let us define the matrix M k to be the (k \u00d7 m) matrix whose columns are the vectors D T i , and note that M k is a matrix with entries from F[X] \u2286 F(X). We will show that M k is a desired k-truncation of the matrix M .", "cite_spans": [], "ref_spans": []}, {"section": "Further note that P i (X) lies in F[X] (and also in F(X)).", "text": "Let I \u2286 {1, . . . , m} such that |I| = \u2113 \u2264 k. Let C i 1 , . . . , C i \u2113 be a linearly independent set of columns of the matrix M over F, where I = {i 1 , . . . , i . We shall show that M I has rank \u2113 by showing that there is a \u2113 \u00d7 \u2113 submatrix whose determinant is a non-zero polynomial. Let P i 1 (X), . . . , P i \u2113 (X) be the polynomials corresponding to the vectors C i 1 , . . . , C i \u2113 . By Lemma 3.1 we have that P i 1 (X), . . . , P i \u2113 (X) are linearly independent over F. Then by Theorem 3.4, the (\u2113 \u00d7 \u2113) matrix formed by the column vectors", "cite_spans": [], "ref_spans": [{"start": 46, "end": 59, "text": "Let C i 1 , .", "ref_id": "FIGREF0"}, {"start": 137, "end": 163, "text": "where I = {i 1 , . . . , i", "ref_id": "FIGREF0"}, {"start": 360, "end": 377, "text": "vectors C i 1 , .", "ref_id": "FIGREF0"}]}, {"section": "Further note that P i (X) lies in F[X] (and also in F(X)).", "text": ". But note that this matrix is a submatrix of M I . Therefore M I has rank \u2113 in F(X). Therefore the vectors D i 1 , . . . , D i \u2113 are linearly independent in F(X). This completes the proof of the forward direction.", "cite_spans": [], "ref_spans": []}, {"section": "Further note that P i (X) lies in F[X] (and also in F(X)).", "text": "Let I \u2286 {1, . . . , m} such that |I| = \u2113 \u2264 k and let", "cite_spans": [], "ref_spans": []}, {"section": "Further note that P i (X) lies in F[X] (and also in F(X)).", "text": "be linearly independent in M k over F(X), where I = {i 1 , . . . , i \u2113 }. We will show that the corresponding set of columns C i 1 , . . . , C i \u2113 are also linearly independent over F. For a contradiction assume that C i 1 , . . . , C i \u2113 are linearly dependent over F. Let P i 1 (X), . . . , P i \u2113 (X) be the polynomials in F[X] corresponding to these vectors. Then by Lemma 3.1 we have that P i 1 (X), . . . , P i \u2113 (X) are linearly dependent over F So there is a tuple", "cite_spans": [], "ref_spans": []}, {"section": "Further note that P i (X) lies in F[X] (and also in F(X)).", "text": "Note that F is a subfield of F(X) and by the above, we have that In Lemma 3.17 we require that \u03b1 be an element of order at least (n \u2212 1)(k \u2212 1) + 1. This implies that the order of the field F must be at least (n \u2212 1)(k \u2212 1)+ 1. We can ensure these requirements by preprocessing the input before invoking the Lemma 3.17. Formally, we show the following lemma. Proof. We distinguish two cases by comparing the values of p \u2113 and n.", "cite_spans": [], "ref_spans": []}, {"section": "Further note that P i (X) lies in F[X] (and also in F(X)).", "text": "Case 1: p \u2113 \u2264 nk + 1. In this case we use Lemma 3.15 to obtain an extension K of F of size at most (nk + 1) 2 , and a primitive element \u03b1 of K in polynomial time.", "cite_spans": [], "ref_spans": []}, {"section": "Further note that P i (X) lies in F[X] (and also in F(X)).", "text": "Case 2: nk + 1 < p \u2113 . In this case we set K = F and and use Lemma 3.14 to find an element of order at least nk, in time poly(p, \u2113, nk).", "cite_spans": [], "ref_spans": []}, {"section": "Further note that P i (X) lies in F[X] (and also in F(X)).", "text": "Observe that F is a subfield of K, M is also a matrix over K. Thus, any set of linearly dependent columns over F continue to be linearly dependent over K. Similarly, linearly independent columns continue to be linearly independent. This completes the proof of this lemma.", "cite_spans": [], "ref_spans": []}, {"section": "Further note that P i (X) lies in F[X] (and also in F(X)).", "text": "Next we show a result that allows us to find basis of matrices with entries from F[X]. Proof. Let S \u2286 F * be a set of size (n \u2212 1)m + 1 and for every \u03b1 \u2208 S, let M (\u03b1) be the matrix obtained by substituting \u03b1 for X in the polynomials in matrix M . Now we compute the minimum weight column basis C(\u03b1) in M (\u03b1) for all \u03b1 \u2208 S. Let \u2113 = max{|C(\u03b1)| | \u03b1 \u2208 S}. Among all the column basis of size \u2113, let C(\u03b6) be a minimum weighted column basis for some \u03b6 \u2208 S. Let C \u2032 be the columns in M corresponding to C(\u03b6). We will prove that C \u2032 is a minimum weighted column basis of M . Towards this we start with the following claim. Proof. Let r \u2264 m be the rank of M . Thus, we know that there exists a submatrix W of M of dimension r \u00d7 r such that det(W ) is a non-zero polynomial. The degree of the polynomial det(W (X)) \u2264 (n \u2212 1) \u00d7 r \u2264 (n \u2212 1)m. Thus, we know that it has at-most (n \u2212 1)m roots. Hence, when we evaluate det(W (X)) on set S of size more than (n \u2212 1)m, there exists at least one element in S, say \u03b2, such that det(W (\u03b2)) = 0. Thus, the rank of M is upper bounded by the rank of M (\u03b2) and hence upper bounded by the maximum of the rank of matrices M (\u03b1), \u03b1 \u2208 S.", "cite_spans": [], "ref_spans": []}, {"section": "Further note that P i (X) lies in F[X] (and also in F(X)).", "text": "As before let r \u2264 \u2113 be the rank of M . Let \u03b1 be an arbitrary element of S. Observe that for any submatrix Z of dimension r \u2032 \u00d7 r \u2032 , r \u2032 > r we have that det(Z(X)) \u2261 0. Thus, for any \u03b1, the determinant of the corresponding submatrix of M (\u03b1) is also 0. This implies that for any \u03b1, the rank of M (\u03b1) is at most r. This completes the proof. The proof follows from the arguments similar to the ones used in proving reverse direction of Claim 3.20. Let r \u2264 m be the rank of M and let C * be a minimum weight column basis of M . Thus, we know that there exists a submatrix W of M of dimension r \u00d7 r such that det(W ) is a non-zero polynomial. The degree of the polynomial det(W (X)) \u2264 (n \u2212 1) \u00d7 r \u2264 (n \u2212 1)m. Thus, we know that it has at most (n \u2212 1)r roots. Hence, when we evaluate det(W (X)) on set S of size more than (n \u2212 1)r, there exists at least one element in S, say \u03b2, such that det(W (\u03b2)) = 0 and the set of columns C * is linearly independent in M (\u03b2). Using Claim 3.21 and the fact that C * is linearly independent in both M (\u03b2) and M , we can conclude that C * is a column basis for M (\u03b2).", "cite_spans": [], "ref_spans": []}, {"section": "Further note that P i (X) lies in F[X] (and also in F(X)).", "text": "We can obtain any M (\u03b1) with at most O(nmt) field operations in F. Furthermore, we can compute minimum weight column basis of M (\u03b1) in O(tm \u03c9\u22121 ) field operations [2] . Hence the total number of field operations over F is bounded by O(m 2 n 2 t + m \u03c9 nt).", "cite_spans": [{"start": 163, "end": 166, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Further note that P i (X) lies in F[X] (and also in F(X)).", "text": "Finally, we combine Lemma 3.16, Lemma 3.18 and Lemma 3.17 to obtain the following theorem. Proof. We first consider the case when the characteristic of the field F is 0, or if the characteristic p of the finite field is strictly larger than n (char(F) > n). In this case we apply Lemma 3.16 to obtain a matrix M k over F(X) which is a k-truncation of M . We now consider the case when F is a finite field and char(F) < n. First apply Lemma 3.18 to ensure that the order of the field F is greater than (n \u2212 1)(k \u2212 1) + 1 and to obtain an element of order at least (n \u2212 1)(k \u2212 1) + 1 in the field F. Of course by doing this, we have gone to an extension of K of F of size at least (n \u2212 1)(k \u2212 1) + 1. However, for brevity of presentation we will assume that the input is given over such an extension. We then apply Lemma 3.17 to obtain a matrix M k over F(X) which is a representation of the k-truncation of the matrix M . One should notice that in fact This completes the description of M k in all the cases.", "cite_spans": [], "ref_spans": []}, {"section": "Further note that P i (X) lies in F[X] (and also in F(X)).", "text": "Let ", "cite_spans": [], "ref_spans": []}, {"section": "Representating the truncation over a finite field", "text": "In Theorem 3.22, the representation M k is over the field F(X). However, in some cases this matrix can also be viewed as a representation over a finite extension of F of sufficiently large degree. That is, if F = F p \u2113 is a finite field then M k can be given over F p \u2113 \u2032 where \u2113 \u2032 \u2265 nk\u2113. Formally we have the following lemma. Proof. Let M k be the matrix returned by Theorem 3.22. Next we show how we can view the entries in M k over a finite extension of F. Consider any extension K of F of degree r \u2265 nk.", "cite_spans": [], "ref_spans": []}, {"section": "Representating the truncation over a finite field", "text": "r(X) , where r(X) is a irreducible polynomial in F[X] of degree r. Recall that each entry of M k is a polynomial in F[X] of degree at most n \u2212 1 and therefore they are present in K. Further the determinant of any k \u00d7 k submatrix of M k is identically zero in K if and only if it is identically zero in F(X). This follows from the fact that the determinant is a polynomial of degree at most (n \u2212 1)k and therefore is also present in K. Thus M k is a representation over K.", "cite_spans": [], "ref_spans": []}, {"section": "Representating the truncation over a finite field", "text": "To specify the field K we need to compute the irreducible polynomial r(X). If F is a prime field, i.e. F = F p , then we can compute the polynomial r(X) using the first part of Lemma 3.12. And if p = N O(1) we can use the second part of Lemma 3.12 to compute r(X). Thus we have a well defined k-truncation of M over the finite field K =", "cite_spans": [], "ref_spans": []}, {"section": "F[X]", "text": "r(X) . Furthermore, if degree of r(X) is nk then K is isomorphic to F p nk\u2113 . This completes the proof of this theorem.", "cite_spans": [], "ref_spans": []}, {"section": "Application to Computation of Representative Families", "text": "In this section we give deterministic algorithms to compute representative families of a linear matroid, given its representation matrix. We start with the definition of a q-representative family.", "cite_spans": [], "ref_spans": []}, {"section": "Application to Computation of Representative Families", "text": "Definition 4.1 (q-Representative Family). Given a matroid M = (E, I) and a family S of subsets of E, we say that a subfamily S \u2286 S is q-representative for S if the following holds: for every set Y \u2286 E of size at most q, if there is a set X \u2208 S disjoint from Y with X \u222a Y \u2208 I, then there is a set X \u2208 S disjoint from Y with X \u222a Y \u2208 I. If\u015c \u2286 S is q-representative for S we write S \u2286 q rep S.", "cite_spans": [], "ref_spans": []}, {"section": "Application to Computation of Representative Families", "text": "In other words if some independent set in S can be extended to a larger independent set by q new elements, then there is a set in S that can be extended by the same q elements. We say that a family S = {S 1 , . . . , S t } of sets is a p-family if each set in S is of size p. In [7, 8] Let p + q = k. Fomin et al. [8, Theorem 3 .1] first gave a deterministic algorithm for computing q-representative of a p-family of indpendent sets if the rank of the corresponding matroid is p + q. To prove Theorem 4.4 one first computes the representation matrix of a k-truncation of M = (E, I). This step returns a representation of a k-truncation of M = (E, I) with a high probability. Given this matrix, one applies [8, Theorem 3.1] and arrive at Theorem 4.4. In this section we design a deterministic algorithm for computing q-representative even if the underlying linear matroid has unbounded rank, using deterministic truncation of linear matroids.", "cite_spans": [{"start": 279, "end": 282, "text": "[7,", "ref_id": "BIBREF6"}, {"start": 283, "end": 285, "text": "8]", "ref_id": "BIBREF7"}, {"start": 314, "end": 317, "text": "[8,", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Application to Computation of Representative Families", "text": "Observe that the representation given by Theorem 3.22 is over F(X). For the purpose of computing q-representative of a p-family of independent sets we need to find a set of linearly independent columns over a matrix withe entries from F[X]. However, deterministic algorithms to compute basis of matrices over F[X] is not as fast as compare to the algorithms where we do not need to do symbolic computation. We start with a lemma that allows us to find a set of linearly independent columns of a matrix over F[X] quickly; though the size of the set returned by the algorithm given by the lemma could be slightly larger than the basis of the given matrix. The following lemma enables us to find a small size spanning set of vectors over F(X). Proof. The main idea is to do a \"gaussian elimination\" in M , but only over the subfield F of F(X). Let C i be a column of the matrix M . It is a vector of length m over F[X] <n and it's entries are polynomials P ji (X), where j \u2208 {1, . . . , m}. Observe that P ji (X) is a polynomial of degree n \u2212 1 with coefficients from F. Let v ji denote the vector of length n corresponding to the polynomial P ji (X). Consider the column vector v i formed by concatenating each v ji in order from j = 1 to m. That is, v i = (v 1i , . . . , v mi ) T . This vector has length nm and has entries from F. Let N be the matrix where columns correspond to column vectors v i . Note that N is a matrix over F of dimension nm \u00d7 t and the time taken to compute N is O(tnm). For each column v i of N we define it's weight to be w(C i ). We now do a gaussian elimination in N over F and compute a minimum weight set of column vectors S \u2032 , which spans N . Observe that |S \u2032 | \u2264 nm and time taken to compute S \u2032 is O(t(nm) \u03c9\u22121 ) [2] . Let S be the set of column vectors in M corresponding to the column vectors in S \u2032 . We return S as a nice spanning set of column vectors in M . Now we show the correctness of the above algorithm. We first show that S is a spanning set of M . Let v 1 , . . . , v |S| be the set of vectors in S and let v d be some column vector in N . Then C and of C 1 , . . . , C |S| . Towards our claim we need to show that P jd (X) = |S| i=1 a i P ji (X). But since v dj and {v ij | j \u2208 {1, . . . , m}} are the collection of vectors corresponding to P jd (X) and {P ji (X) | j \u2208 {1, . . . , m}}, the claim follows.", "cite_spans": [{"start": 1747, "end": 1750, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": [{"start": 2093, "end": 2109, "text": "C and of C 1 , .", "ref_id": "FIGREF0"}]}, {"section": "Application to Computation of Representative Families", "text": "Next we show that S is indeed a nice spanning set. Since S is a spanning set of M we have that any column C d = C i \u2208S \u03bb i C i , \u03bb i \u2208 F. Let C j \u2208 S be such that \u03bb j = 0 and w(C j ) > w(C d ). In fact one can prove Theorem 4.4 for a \"weighted notion of representative family\" (see [8] for more details), for which we would need to compute nice spanning set. It will appear in an extended version of the paper.", "cite_spans": [{"start": 282, "end": 285, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Applications", "text": "Marx [17] gave algorithms for several problems based on matroid optimization. The main theorem in his work is Theorem 1.1 [17] on which most applications of [17] are based. The proof of the theorem uses an algorithm to find representative sets as a black box. Applying our algorithm (Theorem 4.4 of this paper) instead gives a deterministic version of Theorem 1.1 of [17] . Finally, we mention another application from [17] which we believe could be useful to obtain single exponential time parameterized and exact algorithms. ", "cite_spans": [{"start": 5, "end": 9, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 122, "end": 126, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 157, "end": 161, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 367, "end": 371, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 419, "end": 423, "text": "[17]", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Conclusions", "text": "In this paper we give the first deterministic algorithm to compute a k-truncation of linear matroids over any finite field or the field Q. Our algorithms were based on the properties of the Wronskian determinant and the \u03b1-folded Wronskian determinant, where \u03b1 is an element of polynomially large order in the field F. We believe that our results on the \u03b1-folded Wronskian will be useful in other contexts. We conclude with a few related open problems.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "\u2022 Our algorithm produces a representation of the truncation over the ring F[X] when the input field is F. However when F is large enough, then one can obtain a randomized representation of the truncation over F itself. It is an interesting problem to compute the representation over F deterministically.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "\u2022 In many cases, when the field F is nice enough, we can represent the truncation over a finite degree extension of the input field F. It would be interesting to extend this to all finite field.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "\u2022 Finally, finding a deterministic representation of Transversal matroids and Gammoids, remain an interesting open problem in Matroid Theory. 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Then P 1 (X), . . . , P k (X) are linearly independent over F if and only if v 1 , v 2 , . . . , v k are linearly independent over F. Proof. For i \u2208 {1 . . . k}, let v i = (c i1 , . . . , c in ) and let P i (X) = n j=1 c ij x j\u22121 be the polynomial corresponding to v i .", "type": "figure"}, "FIGREF1": {"text": "ij is the j-th entry of the vector v i for all i and j, we have k i=1 a i v i = 0. Thus the vectors v 1 , . . . , v k are linearly dependent, a contradiction to the given assumption. This completes this proof.", "type": "figure"}, "FIGREF2": {"text": "Let M be a n \u00d7 n over a field F. Then det(M ) = 0 if and only if the columns of M are linearly independent over F.", "type": "figure"}, "FIGREF3": {"text": "For all i \u2208 {1, . . . \u2113}, either a i b i = a 0 b 0 , or a i = b i = 0. Proof. We prove the claim using induction on i. For i = 1, consider the coefficient of X in S A,B (X). The coefficient of X in S A,B (X) is (\u03b2 \u2212 1)(a 0 b 1 \u2212 a 1 b 0 ). Since the order of \u03b2 is > \u2113, (\u03b2 \u2212 1) = 0. This implies (a 0 b 1 \u2212 a 1 b 0 ) = 0. So if b 1 = 0, then a 1 = 0 (because b 0 = 0) and if b 1", "type": "figure"}, "FIGREF4": {"text": "zero. Therefore the coefficient of X i simplifies to, (\u03b2 i \u2212 1)(a 0 b i \u2212 a i b 0 ) and we get (\u03b2 i \u2212 1)(a 0 b i \u2212 a i b 0 ) = 0. Since the order of \u03b2 is > \u2113, (\u03b2 i \u2212 1) = 0. This implies (a 0 b i \u2212 a i b 0 ) = 0. So if b i = 0, then a i = 0 (because b 0 = 0) and if b iF. Thus a i = \u03bbb i . Therefore A(X) = \u03bbB(X). Since A(X) \u2261 0, \u03bb = 0. Case 2: Suppose b 0 = 0 and a 0 = 0. Then let A 1 (X) = B(X) and B 1 (X) = A(X). Since A(X)B(\u03b2X) \u2212 A(\u03b2X)B(X) \u2261 0, we have that", "type": "figure"}, "FIGREF5": {"text": "Suppose b 0 = 0 and a 0 = 0. Let r be the least integer such that either a r = 0 or b r = 0. Then let A(X) = X r A 2 (X) and B(X) = X r B 2 (X). Since A(X)B(\u03b2X) \u2212 A(\u03b2X)B(X) \u2261 0, we have that A 2 (X)B 2 (\u03b2X)\u2212A 2 (\u03b2X)B 2 (X) \u2261 0. Note that the coefficient of X 0 is non zero in at least one of the polynomials A 2 (X) or B 2 (X). Furthermore, A 2 (X), B 2 (X) \u2261 0. Thus, if the coefficient of B 2 (X) is non-zero then we are in Case 1 else we are in Case 2. This completes the proof of the lemma.", "type": "figure"}, "FIGREF6": {"text": "Let F be a field of size > n, \u03b1 be either a primitive element or an element of F of order > (n \u2212 1)(k \u2212 1) and let P 1 (X), . . . , P k (X) be a set of polynomials from F[X] <n . Then P 1 (X), . .", "type": "figure"}, "FIGREF7": {"text": "Let M be a n\u00d7m matrix of rank n over a field F, where F is either Q or char(F) > n. Then we can compute a k \u00d7 m matrix M k of rank k over the field F(X) which is a k-truncation of the matrix M in O(mnk) field operations.", "type": "figure"}, "FIGREF8": {"text": "X)) of length k with entries from F[X] (and also in F(X)). Note that the entries of D i are polynomials of degree at most n \u2212 1. Let us define the matrix M k to be the (k \u00d7 m) matrix whose columns are D T i , and note that M k is a matrix with entries from F[X]. We will show that indeed M k is a desired k-truncation of the matrix M . Let I \u2286 {1, . . . , m} such that |I| = \u2113 \u2264 k. Let C i 1 , . . . , C i \u2113 be a linearly independent set of columns of the matrix M over F, where I = {i 1 , . . . , i \u2113 }. We will show that the columns D T i 1 , . . . , D T i \u2113 are linearly independent in M k over F(X). Consider the k \u00d7 \u2113 matrix M I whose column are the vectors D T i 1 , . . . , D T i \u2113", "type": "figure"}, "FIGREF9": {"text": "is a non-zero determinant in F[X]. But note that this matrix is a submatrix of M I . Therefore M I has rank \u2113 in F(X). Therefore the vectors D T i 1 , . . . , D T i \u2113 are linearly independent in F(X). This completes the proof of the forward direction. Let I \u2286 {1, . . . , m} such that |I| = \u2113 \u2264 k and let D T i 1 , . . . , D T i \u2113 be linearly independent in M k over F(X), where I = {i 1 , . . . , i \u2113 }. We will show that the corresponding set of columns C i 1 , . . . , C i \u2113 are also linearly independent over F. For a contradiction assume that C i 1 , . . . , C i \u2113 are linearly dependent over F. Let P i 1 (X), . . . , P i \u2113 (X) be the polynomials in F[X] corresponding to these vectors. Then by Lemma 3.1 we have that P i 1 (X), . . . , P i \u2113 (X) are linearly dependent over F. So there is a tuple a i 1 , . . . , a i \u2113 of values of F such that \u2113 j=1 a i j P i j (X) = 0. Therefore, for any d \u2208 {1, . . . , \u2113 \u2212 1}, we have that \u2113 j=1 a i j P (d) i j (X) = 0. Now let D T i 1 , . . . , D T i \u2113 be the column vectors of M k corresponding to C i 1 , . . . , C i \u2113 . Note that F is a subfield of F(X) and by the above, we have that \u2113 j=1 a i j D i j = 0. Thus D T i 1 , . . . , D T i \u2113 are linearly dependent in M k over F(X), a contradiction to our assumption. Thus we have shown that for any {i 1 , . . . , i \u2113 } \u2286 {1, . . . , m} such that \u2113 \u2264 k, C i 1 , . . . , C i \u2113 are linearly independent over F if and only if D i 1 , . . . , D i \u2113 are linearly independent over F(X). To estimate the running time, observe that for each C i we can compute D i in O(kn) field operations and thus we can compute M k in O(mnk) field operations. This completes the proof of this lemma.", "type": "figure"}, "FIGREF10": {"text": "Let F be a finite field and \u03b1 be an element of F of order at least (n \u2212 1)(k \u2212 1) + 1. Let M be a (n \u00d7 m) matrix of rank n over a field F. Then we can compute a (k \u00d7 m) matrix M k of rank k over the field F(X) which is a k-truncation of the matrix M in O(mnk) field operations.", "type": "figure"}, "FIGREF11": {"text": "\u2113 }. We will show that D T i 1 , . . . , D T i \u2113 are linearly independent in M k over F(X). Consider the k \u00d7 \u2113 matrix M I whose columns are the vectors D T i 1 , . . . , D T i \u2113", "type": "figure"}, "FIGREF12": {"text": "\u2113 j=1 a i j D i j = 0. Thus D T i 1 , . . . , D T i \u2113 are linearly dependent in M k over F(X), a contradiction to our assumption. Thus we have shown that for any {i 1 , . . . , i \u2113 } \u2286 {1, . . . , m} such that \u2113 \u2264 k, C i 1 , . . . , C i \u2113 are linearly independent over F if and only if D i 1 , . . . , D i \u2113 are linearly independent over F(X). To estimate the running time, observe that for each C i we can compute D i in O(kn) field operations and thus we can compute M k in O(mnk) field operations. This completes the proof of this lemma.", "type": "figure"}, "FIGREF13": {"text": "Let M be a matrix of dimension n \u00d7 m over a finite field F, and of rank n. Let F = F p \u2113 where p < n. Then in polynomial time we can find an extension field K of order at least nk + 1 and an element \u03b1 of K of order at least nk + 1, such that M is a matrix over K with the same linear independence relationships between it's columns as before.", "type": "figure"}, "FIGREF14": {"text": "Let M be a m\u00d7t matrix with entries from F[X] <n and let m \u2264 t. Let w : C(M ) \u2192 R + be a weight function. Then we can compute minimum weight column basis of M in O(m 2 n 2 t + m \u03c9 nt) field operations in F", "type": "figure"}, "FIGREF15": {"text": "The rank of M is the maximum of the rank of matrices M (\u03b1), \u03b1 \u2208 S.", "type": "figure"}, "FIGREF16": {"text": "20 implies that \u2113 = max{|C(\u03b1)| | \u03b1 \u2208 S} is equal to the rank of M . Our next claim is following. Claim 3.21. For any \u03b1 \u2208 S, and C \u2286 C(M (\u03b1)), if C is linearly independent in M (\u03b1) then C is also linearly independent in M .", "type": "figure"}, "FIGREF17": {"text": "Theorem 3.22 (Theorem 1.1, restated). Let F = F p \u2113 be a finite field or F = Q. Let M be a n \u00d7 m matrix over F of rank n. Given a number k \u2264 n, we can compute a matrix M k over the field F(X) such that it is a representation of the k-truncation of M . Furthermore, given M k , we can test whether a given set of \u2113 columns in M k are linearly independent in O(n 2 k 3 ) field operations.", "type": "figure"}, "FIGREF18": {"text": "Let M be a n\u00d7m matrix over F of rank n, k \u2264 n be a positive integer and N be the size of the input matrix. If F = F p be a prime field or F = F p \u2113 where p = N O(1) , then in polynomial time we can find a k-truncation M k of M over a finite extension K of F where K = F p nk\u2113 .", "type": "figure"}, "FIGREF19": {"text": "Let W = {v 1 , . . . , v m } be a set of vectors over F and w : W \u2192 R + . We say that S \u2286 W is a spanning set, if every v \u2208 W can be written as linear combination of vectors in S with coefficients from F. We say that S is a nice spanning set of W , if S is a spanning set and for any z \u2208 W if z = v\u2208S \u03bb v v, and 0 = \u03bb v \u2208 F then we have w(v) \u2264 w(z).", "type": "figure"}, "FIGREF20": {"text": "Let F be a field and let M \u2208 F[X] m\u00d7t be a matrix over F[X] <n and let w : C(M ) \u2192 R + be a weight function. Then we can find a nice spanning set S of C(M ) of size at most nm with at most O(t(nm) \u03c9\u22121 ) field operations.", "type": "figure"}, "FIGREF21": {"text": "where a i \u2208 F. In particular for any j \u2208 {1, . . . , m} we have v jd = |S| i=1 a i v ji . Let C 1 , . . . , C |S| be the column vectors corresponding to v 1 , . . . , v |S| and let C d be the column vector corresponding to v d . We claim that C d = |S| i=1 a i C i . Consider the j-the entry of the column vector", "type": "figure"}, "FIGREF22": {"text": "Let v d and v j be the vectors corresponding to C d and C j respectively. We have that v d = v i \u2208S \u03bb i v i , which implies v j = \u03bb \u22121 j v d \u2212 v i \u2208S,v i =v j \u03bb \u22121 j \u03bb i v i . But this implies that S * = (S \\ {v j }) \u222a {v d } is a spanning set of N , and w(S * ) < w(S), which is a contradiction. Thus we have that for every column vector C \u2208 M if C = C i \u2208S \u03bb i C i and 0 = \u03bb i \u2208 F, then w(C i ) \u2264 w(C). This completes the proof.", "type": "figure"}, "FIGREF23": {"text": "Let M = (E, I) be a linear matroid where the ground set is partitioned into blocks of size \u2113. Given a linear representation A M of M , it can be determined in O(2 \u03c9k\u2113 ||A M || O(1) ) time whether there is an independent set that is the union of k blocks. (||A M || denotes the length of A M in the input.)", "type": "figure"}, "FIGREF24": {"text": "\u2113-Matroid Intersection Parameter: k Input: Let M 1 = (E, I 1 ), . . . , M 1 = (E, I \u2113 ) be matroids on the same ground set E given by their representations A M 1 , . . . , A M \u2113 over the same field F and a positive integer k. Question: Does there exist k element set that is independent in each M i (X \u2208 I 1 \u2229 . . . \u2229 I \u2113 )? Using Theorem 1.1 of [17], Marx [17] gave a randomized algorithm for \u2113-Matroid Intersec- tion. By using Proposition 4.5 instead we get the following result.", "type": "figure"}, "FIGREF25": {"text": "Proposition 4.6. \u2113-Matroid Intersection can be solved in O(2 \u03c9k\u2113 ||A M || O(1) ) time.", "type": "figure"}, "TABREF0": {"text": "A vector v over a field F is an array of values from F. A collection of vectors {v 1 , v 2 , . . . , v k } are said to be linearly dependent if there exist values a 1 , a 2 , . . . , a k , not all zeros, from F such that k i=1 a i v i = 0. Otherwise these vectors are called linearly independent.", "type": "table"}, "TABREF1": {"text": "Proposition 2.2 ([17, Proposition 3.7]). Given a matroid M with a representation A over a finite field F and an integer t, a representation of the t-truncation M \u2032 can be found in randomized polynomial time.", "type": "table"}, "TABREF2": {"text": ". . . , D i \u2113 be a set of columns of the matrix M k over F, where I = {i 1 , . . . , i \u2113 }. Furthermore, by M I we denote the k \u00d7 \u2113 submatrix of M k containing the columns D i 1 , . . . , D i \u2113 . To test whether these columns are linearly independent, we can apply Lemma 3.19 on M T I and see the size of column basis of M T I is \u2113 or not. This takes time O(\u2113 2 n 2", "type": "table"}, "TABREF3": {"text": "the following theorem is proved. See [7, Theorem 4]. Theorem 4.2 ([7, 8]). Let M = (E, I) be a linear matroid and let S = {S 1 , . . . , S t } be a p- family of independent sets. Then there exists S \u2286 q rep S of size p+q p . Furthermore, given a representation A M of M over a field F, there is a randomized algorithm computing S \u2286 q rep S in O p+q p tp \u03c9 + t", "type": "table"}}}
{"paper_id": "10706137", "_pdf_hash": "3819b3691611d59e55826cc76e7a590ccafa889f", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Liver abscess in adults: ten years experience in a UK centre", "authors": [{"first": "A", "middle": ["H"], "last": "Mohsen", "suffix": ""}, {"first": "S", "middle": ["T"], "last": "Green", "suffix": ""}, {"first": "R", "middle": ["C"], "last": "Read", "suffix": ""}, {"first": "M", "middle": ["W"], "last": "Mckendrick", "suffix": ""}], "year": 2002, "venue": "QJM", "link": "23397333"}, "BIBREF1": {"title": "Pyogenic liver abscess: recent trends in aetiology and mortality", "authors": [{"first": "J", "middle": [], "last": "Rahimian", "suffix": ""}, {"first": "T", "middle": [], "last": "Wilson", "suffix": ""}, {"first": "V", "middle": [], "last": "Oram", "suffix": ""}, {"first": "R", "middle": ["S"], "last": "Holzman", "suffix": ""}], "year": 2004, "venue": "Clin Infect Dis", "link": "39721730"}, "BIBREF2": {"title": "Pyogenic liver abscess: a retrospective analysis of 107 patients during a 3-year period", "authors": [{"first": "C", "middle": [], "last": "Khee-Siang", "suffix": ""}, {"first": "C", "middle": [], "last": "Chin-Ming", "suffix": ""}, {"first": "C", "middle": [], "last": "Kuo-Chen", "suffix": ""}, {"first": "H", "middle": [], "last": "Ching-Cheng", "suffix": ""}, {"first": "Hung-Jung", "middle": [], "last": "", "suffix": ""}, {"first": "L", "middle": [], "last": "", "suffix": ""}, {"first": "Wen-Liang", "middle": [], "last": "", "suffix": ""}, {"first": "Y", "middle": [], "last": "", "suffix": ""}], "year": 2005, "venue": "Jpn J Infect Dis", "link": "17634330"}, "BIBREF5": {"title": "Pantoea peritonitis in a patient receiving chronic ambulatory peritoneal dialysis", "authors": [{"first": "P", "middle": ["S"], "last": "Lim", "suffix": ""}, {"first": "S", "middle": ["L"], "last": "Chen", "suffix": ""}, {"first": "C", "middle": ["Y"], "last": "Tsai", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Pai", "suffix": ""}], "year": 2006, "venue": "Nephrology (Carlton)", "link": null}, "BIBREF6": {"title": "Abdominal computed tomography showing liver abscess", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF7": {"title": "The spectrum of myositis and rhabdomyolysis associated with bacterial infection", "authors": [{"first": "G", "middle": ["F"], "last": "Falasca", "suffix": ""}, {"first": "A", "middle": ["J"], "last": "Reginato", "suffix": ""}], "year": 1994, "venue": "J Rheumatol", "link": "29266928"}, "BIBREF8": {"title": "Infectious agents associated with myopathies", "authors": [{"first": "S", "middle": ["R"], "last": "Ytterberg", "suffix": ""}], "year": 1996, "venue": "Curr Opin Rheumatol", "link": "20337188"}, "BIBREF9": {"title": "Bacterial pyomyositis in the United States", "authors": [{"first": "N", "middle": ["F"], "last": "Crum", "suffix": ""}], "year": 2004, "venue": "Am J Med", "link": "25814547"}, "BIBREF10": {"title": "Rhabdomyolysis: a review", "authors": [{"first": "J", "middle": ["D"], "last": "Warren", "suffix": ""}, {"first": "P", "middle": ["C"], "last": "Blumbergs", "suffix": ""}, {"first": "P", "middle": ["D"], "last": "Thompson", "suffix": ""}], "year": 2002, "venue": "Muscle Nerve", "link": "8731940"}, "BIBREF12": {"title": "Clinical perspectives of statin-induced rhabdomyolysis", "authors": [{"first": "K", "middle": ["A"], "last": "Antons", "suffix": ""}, {"first": "C", "middle": ["D"], "last": "Williams", "suffix": ""}, {"first": "S", "middle": ["K"], "last": "Baker", "suffix": ""}, {"first": "P", "middle": ["S"], "last": "Phillips", "suffix": ""}], "year": 2006, "venue": "Am J Med", "link": "15974038"}, "BIBREF13": {"title": "Rhabdomyolysis of infectious and noninfectious causes", "authors": [{"first": "J", "middle": ["R"], "last": "Blanco", "suffix": ""}, {"first": "M", "middle": [], "last": "Zabalza", "suffix": ""}, {"first": "J", "middle": [], "last": "Salcedo", "suffix": ""}, {"first": "L", "middle": [], "last": "Echeverria", "suffix": ""}, {"first": "A", "middle": [], "last": "Garcia", "suffix": ""}, {"first": "M", "middle": [], "last": "Vallejo", "suffix": ""}], "year": 2002, "venue": "South Med J", "link": "46103275"}, "BIBREF14": {"title": "Rhabdomyolysis: an evaluation of 475 hospitalized patients", "authors": [{"first": "G", "middle": [], "last": "Melli", "suffix": ""}, {"first": "V", "middle": [], "last": "Chaudhry", "suffix": ""}, {"first": "D", "middle": ["R"], "last": "Cornblath", "suffix": ""}], "year": 2005, "venue": "Medicine (Baltimore)", "link": "46230270"}}, "ref_entries": {}}
{"paper_id": "10706587", "_pdf_hash": "92a6b74f6dbae6201543946900f8cd392d005f68", "abstract": [], "body_text": [{"section": "Case Presentation", "text": "Mrs. T.R.M. is a 37-yr-old Egyptian woman who presented with a history of shortness of breath, palpitations, and recurrent syncope that had lasted three days.", "cite_spans": [], "ref_spans": []}, {"section": "Case Presentation", "text": "The patient has been thyrotoxic for the last 10 years with erratic follow-up appointments and poor adherence to her treatment program.", "cite_spans": [], "ref_spans": []}, {"section": "Case Presentation", "text": "At presentation, she had progressive shortness of breath that had been occurring for the past 3 days and was associated with palpitations that she perceived as slow and heavy.", "cite_spans": [], "ref_spans": []}, {"section": "Case Presentation", "text": "She reported recurrent, unprovoked syncopal attacks that coincided with her palpitations. She had no history of chest pain or ankle oedema.", "cite_spans": [], "ref_spans": []}, {"section": "Case Presentation", "text": "In a review of systems, she reported diarrhoea associated with colicky abdominal pain and fever.", "cite_spans": [], "ref_spans": []}, {"section": "Case Presentation", "text": "The patient is a housewife who has had six pregnancies, the most recent of which was in 2008. The mode of delivery was a lower segment Cesarean section due to a twin pregnancy that had been complicated by placenta previa and antepartum hemorrhage.", "cite_spans": [], "ref_spans": []}, {"section": "Case Presentation", "text": "The remainder of her obstetric history was significant, including two abortions and two intrauterine deaths. Her first pregnancy was uneventful.", "cite_spans": [], "ref_spans": []}, {"section": "Case Presentation", "text": "She justified her noncompliance with antithyroid medications by relating these drugs to her complicated obstetric history.", "cite_spans": [], "ref_spans": []}, {"section": "Case Presentation", "text": "On examination, she was apprehensive, restless, mildly icteric, and had a low-grade fever.", "cite_spans": [], "ref_spans": []}, {"section": "Case Presentation", "text": "Her blood pressure was 140/80 mmHg, and she had a heart rate of 54 beats/min.", "cite_spans": [], "ref_spans": []}, {"section": "Case Presentation", "text": "Her extremities were moist, and she was sweating excessively.", "cite_spans": [], "ref_spans": []}, {"section": "Case Presentation", "text": "She had a diffuse goitre with bruit. Thyrotoxicosis-related eye signs, such as lid retraction and lid lag, were evident.", "cite_spans": [], "ref_spans": []}, {"section": "Case Presentation", "text": "Cannon A waves were visible in her jugular venous pressure (JVP).", "cite_spans": [], "ref_spans": []}, {"section": "Case Presentation", "text": "Auscultation of the precordium demonstrated audible heart sounds with variable S1 intensity.", "cite_spans": [], "ref_spans": []}, {"section": "Case Presentation", "text": "Her lungs were clear, and she was not experiencing congestive heart failure.", "cite_spans": [], "ref_spans": []}, {"section": "Case Presentation", "text": "The abdominal examination was unremarkable except for diffuse, mild tenderness, and active bowel sounds.", "cite_spans": [], "ref_spans": []}, {"section": "Case Presentation", "text": "The basic metabolic workup is shown in the Table 1 .", "cite_spans": [], "ref_spans": [{"start": 43, "end": 50, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Case Presentation", "text": "The septic workup and autoimmune profile were normal. Her electrocardiogram showed complete heart block with narrow QRS complexes ( Figure 1 ).", "cite_spans": [], "ref_spans": [{"start": 132, "end": 140, "text": "Figure 1", "ref_id": "FIGREF0"}]}, {"section": "Case Presentation", "text": "The echocardiogram showed preserved left ventricular systolic function with no valvular lesions. She was admitted to the cardiac care unit for closer monitoring. She consented to transvenous temporary pacing in the event that it was required.", "cite_spans": [], "ref_spans": []}, {"section": "Case Presentation", "text": "Antithyroid medications, in the form of propylthiouracil (PTU) with parenteral steroid therapy, were initiated.", "cite_spans": [], "ref_spans": []}, {"section": "Case Presentation", "text": "The patient remained hemodynamically stable, and by the third day of antithyroid medication, her heart rhythm transited into second degree AV block ( Figure 2) ; by the fifth day of medication, she was in first-degree atrioventricular block AV block (Figure 3 ). She was discharged seven days after admission. Her antithyroid medications were upgraded, and the steroids were tapered.", "cite_spans": [], "ref_spans": [{"start": 150, "end": 159, "text": "Figure 2)", "ref_id": "FIGREF1"}, {"start": 250, "end": 259, "text": "(Figure 3", "ref_id": "FIGREF2"}]}, {"section": "Case Presentation", "text": "At the follow-up appointment, her holter monitor showed normal sinus rhythms with physiological heart rate variability, and she was in an euthyroid state (Figure 4 ).", "cite_spans": [], "ref_spans": []}, {"section": "Case Presentation", "text": "Due to her nonadherence to medications, she was offered iodine ablation of her thyroid, which she adamantly resisted.", "cite_spans": [], "ref_spans": []}, {"section": "Case Presentation", "text": "The patient continued to figure prescribed medications and remained euthyroid for two months.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Thyrotoxicosis is known to cause tachyarrhythmia, the leading example of which is atrial fibrillation [1] . A hyperthyroid status complicated by high-grade atrioventricular block (AV) has been well documented in the literature [2] [3] [4] [5] [6] [7] [8] [9] [10] . Its rarity renders it more difficult to recognize in daily practice. Because the treatment of hyperthyroidism includes a betablocking agent, recognizing high-grade atrioventricular block is critical before subjecting patients with concomitant bradyarrhythmia to the hazardous effects of betablockers. Syncopal attacks are an indication of such a diagnosis in the context of thyrotoxicosis [2, 3, 5, 10] .", "cite_spans": [{"start": 102, "end": 105, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 227, "end": 230, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 231, "end": 234, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 235, "end": 238, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 239, "end": 242, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 243, "end": 246, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 247, "end": 250, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 251, "end": 254, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 255, "end": 258, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 259, "end": 263, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 655, "end": 658, "text": "[2,", "ref_id": "BIBREF1"}, {"start": 659, "end": 661, "text": "3,", "ref_id": "BIBREF2"}, {"start": 662, "end": 664, "text": "5,", "ref_id": "BIBREF4"}, {"start": 665, "end": 668, "text": "10]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Discussion", "text": "The collective evidence from the sporadic reported cases suggests that any part of the cardiac conduction system is vulnerable to the effects of high thyroxin [11] [12] [13] .", "cite_spans": [{"start": 159, "end": 163, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 164, "end": 168, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 169, "end": 173, "text": "[13]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Discussion", "text": "The effects of high thyroxin can manifest as sick sinus syndrome, sinoatrial block, or various degrees of AV block [11] [12] [13] .", "cite_spans": [{"start": 115, "end": 119, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 120, "end": 124, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 125, "end": 129, "text": "[13]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Discussion", "text": "Case Reports in Endocrinology The data in the literature that address the pathogenesis of high-grade AV block in the context of hyperthyroidism are primarily speculative. The positive chronotropic effect of thyroxin is well known; however, its negative dromotropic action is not widely recognized. The presence of interstitial inflammation in the AV node, the His-bundle and its branches, which are associated with the typical ECG changes in hyperthyroidism, is well recognized [9] .", "cite_spans": [{"start": 478, "end": 481, "text": "[9]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Discussion", "text": "Focal inflammation of the myocardium is reported in patients subjected to high levels of thyroxin [14] .", "cite_spans": [{"start": 98, "end": 102, "text": "[14]", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Discussion", "text": "In our patient, the collective thyrotoxic signs and symptoms indicated the possibility of an impending thyroid storm. Ho et al. have previously reported the coexistence of thyroid storm with high-grade AV block [7] . In other words, a high-grade AV block can be a manifestation of severe thyrotoxicosis. Despite the sporadic existence of similar cases in the literature, at least 5 of the reviewed cases were either frank or impending thyroid storms [3, [6] [7] [8] [9] .", "cite_spans": [{"start": 211, "end": 214, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 450, "end": 453, "text": "[3,", "ref_id": "BIBREF2"}, {"start": 454, "end": 457, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 458, "end": 461, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 462, "end": 465, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 466, "end": 469, "text": "[9]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Discussion", "text": "It may be worth considering high-grade AV block, which is a life-threatening emergency, to be one of the cardiovascular markers of a thyroid storm [15] .", "cite_spans": [{"start": 147, "end": 151, "text": "[15]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Discussion", "text": "However, it has to be emphasized that in such a scenario, the treatment is identical to a severe thyrotoxic crisis, with the exception of avoiding beta-blocking agents. The mainstays of treatment are antithyroid medication with steroid therapy and monitoring the cardiac rhythm by telemetry. Temporary pacing is rarely indicated unless there is hemodynamic instability, and cardiac electrophysiology has no role in acute management [3, 6] .", "cite_spans": [{"start": 432, "end": 435, "text": "[3,", "ref_id": "BIBREF2"}, {"start": 436, "end": 438, "text": "6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Discussion", "text": "For cases in which the hyperthyroidism is intractable or the patient is poor complaint, thyroid iodine ablation or subtotal thyroidectomy are long-term alternatives [16] .", "cite_spans": [{"start": 165, "end": 169, "text": "[16]", "ref_id": "BIBREF15"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "The thyroid and the heart", "authors": [{"first": "R", "middle": [], "last": "Polikar", "suffix": ""}, {"first": "A", "middle": ["G"], "last": "Burger", "suffix": ""}, {"first": "U", "middle": [], "last": "Scherrer", "suffix": ""}, {"first": "P", "middle": [], "last": "Nicod", "suffix": ""}], "year": 1993, "venue": "Circulation", "link": 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and complete heart block", "authors": [{"first": "S", "middle": ["C"], "last": "Ho", "suffix": ""}, {"first": "P", "middle": ["H K"], "last": "Eng", "suffix": ""}, {"first": "Z", "middle": ["P"], "last": "Ding", "suffix": ""}, {"first": "A", "middle": ["C K"], "last": "Fok", "suffix": ""}, {"first": "D", "middle": ["H C"], "last": "Khoo", "suffix": ""}], "year": 1998, "venue": "Annals of the Academy of Medicine Singapore", "link": "28777602"}, "BIBREF7": {"title": "Unusual presentation of thyrotoxicosis as complete heart block and renal failure: a case report", "authors": [{"first": "S", "middle": [], "last": "Krishnamoorthy", "suffix": ""}, {"first": "R", "middle": [], "last": "Narain", "suffix": ""}, {"first": "J", "middle": [], "last": "Creamer", "suffix": ""}], "year": 2009, "venue": "Journal of Medical Case Reports", "link": "17130258"}, "BIBREF8": {"title": "Inflammation of the cardiac conduction system in a case of hyperthyroidism", "authors": [{"first": "C", "middle": [], 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"TABREF0": {"text": "Results of blood investigations done during patient's admission.", "type": "table"}}}
{"paper_id": "10707187", "_pdf_hash": "aa012afbfb343db837f8796ac0b507c990832d7b", "abstract": [{"section": "Abstract", "text": "Background: Hepatitis B virus (HBV) is a major cause of chronic liver diseases, and frequently results in hepatitis, cirrhosis, and ultimately hepatocellular carcinoma. The role of HCV in associations with insulin signaling has been elucidated. However, the pathogenesis of HBV-associated insulin signaling remains to be clearly characterized. Therefore, we have attempted to determine the mechanisms underlying the HBV-associated impairment of insulin signaling.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "An estimated 2 billion people worldwide are currently infected with the hepatitis B virus (HBV), which results in chronic hepatitis, cirrhosis, and in certain instances, hepatocellular carcinoma (HCC) [1, 2] . Among the four proteins originating from the HBV genome, such as the polymerase, surface, core, and HBx proteins, hepatitis B virus X, a small 154-amino acid protein, is a multifunctional regulator which modulates a variety of host processes via interaction with virus and host factors [3, 4] . Previous reports have demonstrated that HBx proteins induce the expression of lipid synthesis-related genes and inflammation in transgenic mice [5, 6, 7] . Generally, hepatic steatosis, the accumulation of lipid in the hepatocytes, has negative effects on liver functions, which may be resulted or caused by inflammation. NFkB is activated in the hepatocytes and cytokines including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-a), and interleukin-1 beta (IL-1b) are overproduced in fatty liver. These proinflammatory cytokines can participate in the attenuation of insulin signaling [8, 9, 10] .", "cite_spans": [{"start": 201, "end": 204, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 205, "end": 207, "text": "2]", "ref_id": "BIBREF1"}, {"start": 496, "end": 499, "text": "[3,", "ref_id": "BIBREF2"}, {"start": 500, "end": 502, "text": "4]", "ref_id": "BIBREF3"}, {"start": 649, "end": 652, "text": "[5,", "ref_id": "BIBREF4"}, {"start": 653, "end": 655, "text": "6,", "ref_id": "BIBREF5"}, {"start": 656, "end": 658, "text": "7]", "ref_id": "BIBREF6"}, {"start": 1099, "end": 1102, "text": "[8,", "ref_id": "BIBREF7"}, {"start": 1103, "end": 1105, "text": "9,", "ref_id": "BIBREF8"}, {"start": 1106, "end": 1109, "text": "10]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Introduction", "text": "Insulin signaling is mediated by a complex, highly integrated network, which controls several processes. In the response of insulin, insulin receptor (IR) phosphorylates insulin receptor substrate (IRS) proteins, which are linked to the activation of two main signaling pathways: the phosphatidylinositol 3-kinase (PI3K)-Akt/protein kinase B (PKB) pathway, which is responsible for the majority of the metabolic actions of insulin, and the Rasmitogen-activated protein kinase (MAPK) pathway, which regulates the expression of some genes and cooperates with the PI3K pathway to control cell growth and differentiation [11] . In the liver, insulin is involved in a number of actions responsible for glucose control and lipid metabolism. In relations with glucose metabolism in liver, insulin regulates the glucose concentration by inhibiting hepatic glucose production and stimulating glycogen synthesis. On a molecular level, increased hepatic glucose production is regulated by insulin, which can inhibit the expression of key gluconeogenic enzymes, phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) in normal states. Also, insulin is a strong activator of the lipogenic pathway through activation of lipogenic transcription factors, such as SREBP-1 and ChREBP [12] .", "cite_spans": [{"start": 617, "end": 621, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 1288, "end": 1292, "text": "[12]", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "Introduction", "text": "Suppressor of cytokine signaling (SOCS) proteins and cytokineinducible SRC homology 2 (SH2)-domain-containing (CIS) proteins constitute a family of intracellular proteins that play major roles in immune cell proliferation, differentiation, migration, and modulation of immune responses [13, 14] . A mechanism for interleukin-6 signaling in the liver has been previously proposed, which involved the activation of signal transducer and activator of transcription 3 (STAT3) and the subsequent induction of SOCS, a negative regulator of cytokine signaling [15, 16, 17] . Activated STATs are translocated to the nucleus where they bind to STAT response elements (SREs) on target genes to regulate transcription. SOCS3 is a direct target of this signaling cascade, and acts in a negative feedback loop to inhibit STAT phosphorylation at the receptor complex [18] . In the recent report, hepatic SOCS3 is a mediator of insulin resistance in the liver; however, the hepatocyte-specific SOCS3-deficient mice promote systemic insulin resistance by mimicking chronic inflammation [19] . Generally, the induction of SOCS proteins inhibits insulin signaling via several distinct mechanisms, including direct interference with insulin receptor activation, the blockage of IRS activation, and the induction of proteasomemediated IRS degradation [20, 21] .", "cite_spans": [{"start": 286, "end": 290, "text": "[13,", "ref_id": "BIBREF12"}, {"start": 291, "end": 294, "text": "14]", "ref_id": "BIBREF13"}, {"start": 553, "end": 557, "text": "[15,", "ref_id": "BIBREF14"}, {"start": 558, "end": 561, "text": "16,", "ref_id": "BIBREF15"}, {"start": 562, "end": 565, "text": "17]", "ref_id": "BIBREF16"}, {"start": 853, "end": 857, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 1070, "end": 1074, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 1331, "end": 1335, "text": "[20,", "ref_id": "BIBREF19"}, {"start": 1336, "end": 1339, "text": "21]", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Introduction", "text": "Although recent evidence suggests that chronic hepatitis C is associated with increased risk of development of insulin resistance [22] , the studies linking HBV to insulin resistance or diabetes were less identified. However, some reports demonstrated their relationship. Custro et al. examined that incidence of diabetes mellitus in adults with CHB is four time higher than that in the general population [23] . Also, patients with chronic hepatitis have impaired glucose metabolism with hyperinsulinemia and insulin resistance [24] . In another point of view, a report defined that a high frequency of HBV infection is identified in diabetes patients [25] . Based on previous studies, we hypothesize that HBx-induced lipid accumulation and inflammation in the liver can negatively effect on hepatic insulin signaling. In this study, we have characterized the components of the insulin signaling cascades in the context of HBx protein expression. Herein, we demonstrate that the level of IRS1 is concomitantly downregulated in HBx-expressing liver tissues and cells via the persistent induction of SOCS3 proteins. We also examine that STAT3 is activated in HBx protein expression and C/EBPa and STAT3 can increase the SOCS3 expression in the transcriptional level. Furthermore, we present evidence suggesting that HBx interferes with the activation of insulin signaling, thereby resulting in the inhibition of the activities of insulin, including gluconeogenic gene expression. This may clarify the molecular mechanisms by which HBx expression is associated with the hepatic insulin signaling.", "cite_spans": [{"start": 130, "end": 134, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 406, "end": 410, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 529, "end": 533, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 653, "end": 657, "text": "[25]", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Methods", "text": "Plasmids, reagents, and antibodies pcDNA3/6myc/SOCS3 were a generous gift from Dr. Akihiko Yoshimura [26] . pGL3B/SOCS3 promoter, pSUPER/GFP control, and pSUPER/SOCS3 were generously provided by Dr. Fred Schaper [27] , HBV 1.2-mer wild-type and HBx null mutant vectors derived from the HBV ayw subtype were kindly provided by Dr. Wang-Shick Ryu [28, 29] . m67-Luc construct (high-affinity binding site for Stats followed by the luciferase gene) was kindly provided from Dr. Jacqueline Bromberg [30] . pcDNA3/HA/HBx derived from HBV adr subtype, pGL3B/PEPCK promoter, and pCMX1/C/EBPa were previously described [6, 31, 32] .", "cite_spans": [{"start": 101, "end": 105, "text": "[26]", "ref_id": "BIBREF25"}, {"start": 212, "end": 216, "text": "[27]", "ref_id": "BIBREF26"}, {"start": 345, "end": 349, "text": "[28,", "ref_id": "BIBREF27"}, {"start": 350, "end": 353, "text": "29]", "ref_id": "BIBREF28"}, {"start": 494, "end": 498, "text": "[30]", "ref_id": "BIBREF29"}, {"start": 610, "end": 613, "text": "[6,", "ref_id": "BIBREF5"}, {"start": 614, "end": 617, "text": "31,", "ref_id": "BIBREF30"}, {"start": 618, "end": 621, "text": "32]", "ref_id": "BIBREF31"}], "ref_spans": []}, {"section": "Methods", "text": "The transfection reagents PolyFect and JetPEI were purchased from QIAGEN and Polyplus-transfection, respectively. All other reagents were purchased from Sigma. The antibodies against IRS1 (sc-559), Myc (sc-789), C/EBPa (sc-61), Akt1/2 (sc-8312), and SOCS3 (sc-9023) were purchased from Santa Cruz Biotechnology, INC. and Actin (A2066), HBx (MAB8419), HA (1 867 423), Phospho-Akt (Ser473) (#9271), PI3K-p85 (#4292), Phospho-PI3K-p85 (Tyr458) (#4228), STAT3 (#9132), Phospho-STAT3 (Tyr705) (#9131), Phospho-Tyr (#9411), Phospho-IRS1 (Ser307) (07-247), and Insulin receptor b (07-724) antibody were obtained from Sigma, Chemicon, Roche, Cell Signaling, and Upstate, respectively.", "cite_spans": [], "ref_spans": []}, {"section": "Cell culture, transient transfection, and stable transfection", "text": "HepG2 cell lines were maintained in DMEM-10% fetal bovine serum (Gibco BRL). Transient transfections were conducted using PolyFect or JetPEI reagents of cell cultures in 24-well culture plates with the indicated reporter plasmids, then cotransfected with mammalian expression vectors. Expression vectors were maintained at constant total amounts via the addition of empty vectors. Relative luciferase activities were assessed by luciferin (BD Biosciences). HepG2/HA and HepG2/HA/HBx stable transfectants were as previously described [6, 7] , and maintained in DMEM-10% FBS containing 200 mg/ml of G418.", "cite_spans": [{"start": 533, "end": 536, "text": "[6,", "ref_id": "BIBREF5"}, {"start": 537, "end": 539, "text": "7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Cell culture, transient transfection, and stable transfection", "text": "RNA isolation, reverse transcriptase-polymerase chain reaction, and quantitative real-time PCR Total RNA from HepG2 cells was prepared using TRIzol (Invitrogen) in accordance with the manufacturer's recommendations. The cDNA was synthesized from 2 mg of total RNA with Moloney murine leukemia virus (MMLV) Reverse Transcriptase (Promega) with a random hexamer (Cosmo, Korea) at 37uC for 1 hour. A 1/25 th aliquot of the cDNA was subjected to PCR amplification using gene-specific primers (Table 1) . Real-time PCR was performed with an SYBR Green I LightCycler-based real-time PCR assay (Roche Applied Science). The reaction mixtures were prepared using LightCycler Fast Start DNA master mixture for SYBR Green I, 0.5 mM of each primer, 4 mM MgCl 2 . All PCR conditions and primers optimized to produce a single product of the correct base pair size.", "cite_spans": [], "ref_spans": [{"start": 488, "end": 497, "text": "(Table 1)", "ref_id": "TABREF0"}]}, {"section": "Immunohistochemistry", "text": "The liver tissues of wild-type and HBx-transgenic mice derived from the HBV adr subtype genome were kindly provided from Dr. Je Kyung Seong. The production of HBx-transgenic mice has already been reported [6, 7, 33] . The liver tissues were fixed in 4% formaldehyde. In brief, the paraffin-embedded tissue sections were deparaffinized and hydrated with distilled water. Immunohistochemical staining was conducted using a DAB system (Zymed Laboratories INC.) in accordance with the manufacturer's instructions. The anti-IRS1 and SOCS3 antibodies were diluted to 1:100 with blocking buffer. As a negative control, the primary antibody was replaced with normal immunoglobulin.", "cite_spans": [{"start": 205, "end": 208, "text": "[6,", "ref_id": "BIBREF5"}, {"start": 209, "end": 211, "text": "7,", "ref_id": "BIBREF6"}, {"start": 212, "end": 215, "text": "33]", "ref_id": "BIBREF32"}], "ref_spans": []}, {"section": "Chromatin immunoprecipitation assay", "text": "ChIP assays were conducted as described by the manufacturer (Upstate Biotechnology, Lake Placid, NY) with some modifications. The chromatin solutions were sonicated and incubated with anti-C/EBPa or control IgG, then rotated overnight at 4uC. Chromatin DNA was purified and subjected to PCR analysis. In order to amplify the human SOCS3 promoter regions harboring C/EBPs binding sites, the following primer sets were utilized; sense: 59-CTC GCG GCC CGC CCT CGG-39, antisense: 59-GCT GCG TGC GGG GCC GAA GC-39. After amplification, the PCR products were resolved on 1.5% agarose gel and visualized via ethidium bromide staining.", "cite_spans": [], "ref_spans": []}, {"section": "Coimmunoprecipitation", "text": "The cells were lysed via the addition of radioimmunoprecipitation assay (RIPA) buffer, then incubated for 10 minutes on ice and then scraped into microcentrifuge tubes. After 15 minutes of centrifugation, an aliquot of the lysates was removed for Western blotting, and the remainder was immunoprecipitated overnight with 1.5 mg anti-C/EBPa, anti-HA, anti-STAT3, and anti-IRS1, and 40 ml of protein G or A-Sepharose (50% suspension). Lysates and immunoprecipitates were then separated via SDS-PAGE and transferred onto PVDF membranes for blotting. The proteins were detected using horseradish peroxidase-conjugated secondary antibodies and visualized via chemiluminescence.", "cite_spans": [], "ref_spans": []}, {"section": "Statistical analysis", "text": "Statistical analyses were conducted via unpaired or paired t tests, as appropriate. All data were expressed as the means 6 SD. P values of ,0.05 were considered to be significant.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "HBx induces degradation of insulin receptor substrate 1 via the ubiquitin-proteasome pathway", "text": "In order to assess the effects of HBx on IRS1 in the liver, we assessed the expression of IRS1 protein using immunoblotting and immunohistochemistry, and determined that IRS1 was significantly downregulated in the liver tissues of 9 and 15-month-old transgenic mice ( Figure 1A and 1C). The phosphorylation of Ser307 of IRS1, which is located in the phosphotyrosine binding (PTB) domain, has been correlated with negative regulation of insulin signalling [11, 34] . Its phosphorylation of IRS1 can inhibit insulin-stimulated tyrosine phosphorylation of IRS1 and block interactions with the insulin receptor and inhibit insulin action [35] . We noted that the Ser307 phosphorylation levels of IRS1 proteins were higher in the HBx-transgenic mice than in the controls, even though total IRS1 protein levels were reduced. However, protein expressions of IRb were not reduced. We detected no differences in the mRNA levels of IRS1 of the transgenic mice in the RT-PCR ( Figure 1A ) and quantitative real-time PCR ( Figure 1B ).", "cite_spans": [{"start": 455, "end": 459, "text": "[11,", "ref_id": "BIBREF10"}, {"start": 460, "end": 463, "text": "34]", "ref_id": "BIBREF33"}, {"start": 634, "end": 638, "text": "[35]", "ref_id": "BIBREF34"}], "ref_spans": [{"start": 268, "end": 277, "text": "Figure 1A", "ref_id": "FIGREF0"}, {"start": 966, "end": 975, "text": "Figure 1A", "ref_id": "FIGREF0"}, {"start": 1011, "end": 1020, "text": "Figure 1B", "ref_id": "FIGREF0"}]}, {"section": "HBx induces degradation of insulin receptor substrate 1 via the ubiquitin-proteasome pathway", "text": "As shown in Figure 1D , western blot analysis consistently demonstrated that the levels of IRS1 protein in three independent HBx-stable transfectants were lower than in the parental cell lines. We observed no differences in the mRNA levels of IRS1 in the HBx-stable transfectants in RT-PCR (left) and quantitative realtime PCR (right). We surmised that the expression level of the HBx induced by a strong promoter in the transfection system is assured to be greater than the physiological level expressed during chronic HBV infection [7, 28, 36] . In consideration of this concern, we assessed the effects of a modest level of HBx expression from a HBV replicon, a greater-than-genome-length construct (1.2-mer). As shown in Figure 1E , the transfection of the wild-type HBV 1.2-mer (WT) in HepG2 cells resulted in the abrogation of IRS1 protein levels, whereas the transfection of the HBx-null mutant (X 2 ) of HBV 1.2-mer did not reduce its expression as compared to the wild-type. Furthermore, the ectopically expressed HBx could recover the suppression of the HBx-null mutant (X 2 ) of HBV 1.2-mer in IRS1 protein expression. The mRNA levels of IRS1 were unchanged in the replicon-transfected cells. The transient transfection of HBx into HepG2 cells induced a significant suppression of protein levels of IRS1 in a dose-dependent manner. However, a proteasome inhibitor, MG132, recovered the IRS1 protein level in HBx-transfected cells and mRNA levels of IRS1 were not changed ( Figure 1F ). We subsequently attempted to determine whether IRS1 was ubiquitinated for protein degradation in HBx-transfected cells. HBx promoted the ubiquitination of IRS1, particularly in the treatment of MG132 ( Figure 1G ). These results support the notion that HBx can downregulate IRS1 proteins in both the liver of transgenic mice and hepatoma cell lines expressing the HBx proteins.", "cite_spans": [{"start": 534, "end": 537, "text": "[7,", "ref_id": "BIBREF6"}, {"start": 538, "end": 541, "text": "28,", "ref_id": "BIBREF27"}, {"start": 542, "end": 545, "text": "36]", "ref_id": "BIBREF35"}], "ref_spans": [{"start": 12, "end": 21, "text": "Figure 1D", "ref_id": "FIGREF0"}, {"start": 725, "end": 734, "text": "Figure 1E", "ref_id": "FIGREF0"}, {"start": 1484, "end": 1493, "text": "Figure 1F", "ref_id": "FIGREF0"}, {"start": 1699, "end": 1708, "text": "Figure 1G", "ref_id": "FIGREF0"}]}, {"section": "HBx induces SOCS3 expression", "text": "Because previous reports have revealed a mechanism by which the action of insulin is inhibited as the result of the increased ubiquitination and degradation of IRS1 via SOCS1 and SOCS3 [20] , we first evaluated the expression levels of SOCS1 and SOCS3 proteins in the transgenic mice and HBx-transfected cells. Although levels of SOCS1 protein and mRNA were not induced, SOCS3 protein and mRNA levels were significantly higher in the HBx-transgenic mice, particularly in the 9 and 15-month stages, as compared to the control mice (Figure 2A and 2B) . The results of immunohistochemisty demonstrated that the levels of SOCS3 protein were induced in the 9 and 15-month-old transgenic mice ( Figure 2C ). Furthermore, SOCS3 mRNA levels significantly trended toward an increase in stable cells expressing the HBx proteins, and these results were consistent with the protein level observed in the immunoblotting results ( Figure 2D ). We then evaluated the induction of SOCS3 mRNA and protein levels in cells transiently transfected with HBx. As shown in Figure 2E , cells transfected with HBx evidenced a statistically significant induction of their mRNA levels as compared to control cells that were transfected with empty vectors. The protein level of SOCS3 was also upregulated in the HBx-expressing cells. The mRNA induction in quantitative real-time PCR was confirmed for SOCS3 expression in stabley or transiently HBx expression cells ( Figure 2F ). Taken together, these results suggest that the expression of SOCS3 can be regulated by HBx proteins.", "cite_spans": [{"start": 185, "end": 189, "text": "[20]", "ref_id": "BIBREF19"}], "ref_spans": [{"start": 530, "end": 548, "text": "(Figure 2A and 2B)", "ref_id": "FIGREF1"}, {"start": 689, "end": 698, "text": "Figure 2C", "ref_id": "FIGREF1"}, {"start": 917, "end": 926, "text": "Figure 2D", "ref_id": "FIGREF1"}, {"start": 1050, "end": 1059, "text": "Figure 2E", "ref_id": "FIGREF1"}, {"start": 1439, "end": 1448, "text": "Figure 2F", "ref_id": "FIGREF1"}]}, {"section": "HBx enhances SOCS3-induced IRS1 protein degradation", "text": "As noted above, the SOCS3 proteins have been previously reported to induce the proteasome-dependent degradation of IRS1, and HBx may result in the induction of SOCS3 mRNA and protein expression. In order to determine whether HBx-induced SOCS3 expressions result in the reduction of IRS1 protein levels, we cotransfected the SOCS3 expression vector into HBx-stable cell lines. As shown in Figure 3A , the further downregulation of IRS1 was observed in the coexpression of SOCS3 proteins. Furthermore, we attempted to determine whether RNAi against SOCS3 could markedly recover IRS1 protein levels ( Figure 3B) , and the polyubiquitination of IRS1 was barely observed in the coexpression of HBx and RNAi for SOCS3 (data not shown). These data indicate that HBx promotes the SOCS3-mediated downregulation of the IRS1 protein. ", "cite_spans": [], "ref_spans": [{"start": 388, "end": 397, "text": "Figure 3A", "ref_id": "FIGREF2"}, {"start": 598, "end": 608, "text": "Figure 3B)", "ref_id": "FIGREF2"}]}, {"section": "C/EBPa regulates HBx-induced SOCS3 expression", "text": "Based on the data for increasing the mRNA levels of SOCS3 by HBx, we further investigated the mechanisms for regulating SOCS3 expression by HBx. We conducted a functional analysis of the activation of the SOCS3 promoter. The structure of the SOCS3 gene has been previously determined [37] . The putative response elements present on the SOCS3 promoter are provided in Figure 4A . Using the 'MOTIF' database analysis program to identify any consensus sequences in the 59-flanking region of this gene, we identified putative binding sites for several transcription factors, including C/EBPs. Compared to the mock-transfected cells, transfection with the HBx plasmid augmented the luciferase activity of the SOCS3 promoter over two folds, indicating that the induction of SOCS3 in response to HBx is mediated through the transcriptional activation of the SOCS3 gene. In order to investigate the possible involvement of transcription factors or coactivators with HBx on this promoter, we cotransfected HBx and transcription factors/coactivators, such as SREBP-1a, SREBP-1c, C/EBPa, CBP, p300, and PGC-1a, into HepG2 cells. In particular, C/EBPa increased both the basal and HBxcotransfected luciferase expression of this promoter ( Figure 4B ). Other transcriptional regulators did not induce the HBx-mediated transactivation of the SOCS3 promoter (data not shown). ChIP assays were conducted in order to further evaluate the binding of C/EBPa to this promoter. C/EBPa bound on this promoter and HBx expression increased its binding to the promoter ( Figure 4C) .", "cite_spans": [{"start": 284, "end": 288, "text": "[37]", "ref_id": "BIBREF36"}], "ref_spans": [{"start": 368, "end": 377, "text": "Figure 4A", "ref_id": "FIGREF3"}, {"start": 1228, "end": 1237, "text": "Figure 4B", "ref_id": "FIGREF3"}, {"start": 1547, "end": 1557, "text": "Figure 4C)", "ref_id": "FIGREF3"}]}, {"section": "C/EBPa regulates HBx-induced SOCS3 expression", "text": "In order to assess the potential in vivo interaction between endogenous C/EBPa and HBx proteins involved with SOCS3 expression, HepG2 cells were transfected with HA-tagged HBx gene, and anti-C/EBPa immunoprecipitation was conducted, followed by immunoblotting with anti-HA antibody. As shown in Figure 4D , HBx proteins interacted with C/EBPa via anti-HA antibody immunoprecipitation (left). And the interaction with HBx and C/EBPa was also refined using anti-HA immunoprecipitation, followed by Western blotting with antibody against C/EBPa (right). These results suggest that the functional synergism of HBx and C/EBPa by interaction of both proteins can induce the SOCS3 expression. Transfection of C/EBPa into HBx-expressed stable cells induced a marked increase in the protein and the mRNA levels of SOCS3 ( Figure 4E, F) . The mRNA induction in quantitative real-time PCR was confirmed for SOCS3 expression ( Figure 4G) .", "cite_spans": [], "ref_spans": [{"start": 295, "end": 304, "text": "Figure 4D", "ref_id": "FIGREF3"}, {"start": 813, "end": 826, "text": "Figure 4E, F)", "ref_id": "FIGREF3"}, {"start": 915, "end": 925, "text": "Figure 4G)", "ref_id": "FIGREF3"}]}, {"section": "C/EBPa regulates HBx-induced SOCS3 expression", "text": "In an effort to examine whether HBx performs a function in SOCS3 gene expression by C/EBPa, we attempted to knockdown of C/EBPa using specific siRNA for C/EBPa. As shown in Figure 4H , siC/EBPa-transfected cells did not induce SOCS3 promoter activity, even in the transfection cells of HBx. Also, the protein levels of SOCS3 were confirmed using Western blotting ( Figure 4I ). The siC/EBPa-transfected cells did not augment the protein expression of SOCS3 and the expression levels of IRS1 were increased noteworthily. As shown in Figure 4J and 4K, the mRNA levels of SOCS3 in the RT-PCR and quantitative realtime PCR was also not increased by HBx in the siC/EBPatransfected cells. These results showed that the association of C/ EBPa and HBx is required for the induction of SOCS3 expression via the efficient recruitment of this promoter.", "cite_spans": [], "ref_spans": [{"start": 173, "end": 182, "text": "Figure 4H", "ref_id": "FIGREF3"}, {"start": 365, "end": 374, "text": "Figure 4I", "ref_id": "FIGREF3"}, {"start": 532, "end": 541, "text": "Figure 4J", "ref_id": "FIGREF3"}]}, {"section": "HBx-activated STAT3 is involved in SOCS3 expression", "text": "The tyrosine phosphorylation and activation of STATs results in the upregulation of STAT target genes, including three families of inhibitory proteins, the protein inhibitors of activated STATs (PIAS), the SH2-containing phosphatase (SHP), and SOCSs [38, 39] . Also, previous reports have shown that HBx is capable of activating STAT3 via some mechanisms [40, 41] . We attempted to determine whether HBx proteins were responsible for the activation of STAT3 in our HBx-transgenic mice and cell lines, given by the phosphorylation at Tyr705 [42, 43] . The highest levels of Tyr705 phosphorylation of STAT3 were detected in 15-monthold HBx-transgenic mice ( Figure 5A ) and forced HBx expression also increased STAT3 phosphorylation in the stable and transient transfectants ( Figures 5B and 5C ). To further substantiate our results, we examined whether HBx proteins promote activation of STAT3 transcription factor. Transient transfection of the m67-Luc construct, a reporter gene with STAT3 DNA binding sites [30] , into HepG2 cells with or without HBx was used to test transcriptional activation by HBx-induced STAT3 phosphorylation. Upon induction of tyrosine phosphorylation of STAT3 by HBx expression, transcriptional stimulation by wild type (WT)-STAT3 became evident and a further increase transcription was also achieved by constitutive active (CA)-STAT3 (STAT3-C, which is dimerized by cysteine-cysteine residues instead of pY-SH2 interactions [30] ) constructs). However, dominant negative (DN, Tyr705 mutated with Phe) STAT3 significantly decreased the HBx-induced STAT3 (WT or CA) activation ( Figure 5D ).", "cite_spans": [{"start": 250, "end": 254, "text": "[38,", "ref_id": "BIBREF37"}, {"start": 255, "end": 258, "text": "39]", "ref_id": "BIBREF38"}, {"start": 355, "end": 359, "text": "[40,", "ref_id": "BIBREF39"}, {"start": 360, "end": 363, "text": "41]", "ref_id": "BIBREF40"}, {"start": 540, "end": 544, "text": "[42,", "ref_id": "BIBREF41"}, {"start": 545, "end": 548, "text": "43]", "ref_id": "BIBREF42"}, {"start": 1010, "end": 1014, "text": "[30]", "ref_id": "BIBREF29"}, {"start": 1453, "end": 1457, "text": "[30]", "ref_id": "BIBREF29"}], "ref_spans": [{"start": 656, "end": 665, "text": "Figure 5A", "ref_id": "FIGREF4"}, {"start": 775, "end": 792, "text": "Figures 5B and 5C", "ref_id": "FIGREF4"}, {"start": 1606, "end": 1615, "text": "Figure 5D", "ref_id": "FIGREF4"}]}, {"section": "HBx-activated STAT3 is involved in SOCS3 expression", "text": "The immunoprecipitation of STAT3 and subsequent Western blot analysis showed that the STAT3 interacted with HBx. Consistent with the enhanced phosphorylation of STAT3 in the presence of HBx proteins, DN-STAT3 markedly disrupted the interaction of these proteins ( Figure 5E ). This result suggests that the activation of STAT3 by interaction with HBx proteins can induced the SOCS3 expression. Also, we subsequently detected the correlation between C/EBPa and STAT3 with regard to the expression of SOCS3. As shown in Figure 5F , the promoter activities of SOCS3 were higher in the cotransfection of HBx, C/EBPa, and STAT3 (WT and CA). The cotransfection of DN-STAT3 impaired the activation of the SOCS3 promoter. These results consistently indicate that HBx-induced C/ EBPa and STAT3 activation may be an upstream regulator of SOCS3 expression.", "cite_spans": [], "ref_spans": [{"start": 264, "end": 273, "text": "Figure 5E", "ref_id": "FIGREF4"}, {"start": 518, "end": 527, "text": "Figure 5F", "ref_id": "FIGREF4"}]}, {"section": "HBx attenuates hepatic insulin signaling", "text": "In order to confirm that HBx-induced IRS1 downregulation resulted in the impairment of insulin signaling, HBx-constitutive expressing HepG2 cells were treated with insulin in concentrations from 0 to 1000 nM for 1 hour, and the phosphorylation of p85 subunit of PI3K (Tyr458) and Akt (Ser473) were evaluated. The insulin-induced phosphorylation of the p85 subunit of PI3K and Akt were detected in HepG2 cells transfected with empty vector, even though the concentration of insulin was lower. However, lower levels of the phosphorylation of these proteins were detected in the HBx-expressing cells ( Figure 6A ). Total levels of PI3K-p85 and Akt remained unchanged by insulin treatment. We also observed that HBx-transfected cells were induced a significant decrease in the phosphorylation of p85 and Akt in response to insulin treatment in the time-dependent manner, compared to mock-transfeced cells ( Figure 6B) .", "cite_spans": [], "ref_spans": [{"start": 599, "end": 608, "text": "Figure 6A", "ref_id": "FIGREF5"}, {"start": 903, "end": 913, "text": "Figure 6B)", "ref_id": "FIGREF5"}]}, {"section": "HBx attenuates hepatic insulin signaling", "text": "Furthermore, we assessed the tyrosine phosphorylation levels of IRS1 immunoprecipitates in the stable transfectants of HBx genes. Mostly, insulin-induced tyrosine phosphorylation of IRS1 can positively regulate the insulin signaling, in opposition to phosphorylation on Ser307 ( Figure 1A ) [44] . As expected, the levels of IRS1 tyrosine phosphorylation were reduced in the HBxexpressing cells treated with insulin, as compared to the control vector-transfected cells ( Figure 6C ).", "cite_spans": [{"start": 291, "end": 295, "text": "[44]", "ref_id": "BIBREF43"}], "ref_spans": [{"start": 279, "end": 288, "text": "Figure 1A", "ref_id": "FIGREF0"}, {"start": 471, "end": 480, "text": "Figure 6C", "ref_id": "FIGREF5"}]}, {"section": "HBx disrupts insulin-induced PEPCK and G6Pase downregulation", "text": "Insulin reduces gluconeogenesis via the specific transcriptional inhibition of PEPCK and G6Pase [45] . Thus, we attempted to determine whether the attenuation of insulin signaling by HBx disrupts the actions of insulin with regard to the suppression of PEPCK and G6Pase expression. It was noted that the overexpression of HBx and SOCS3 proteins enhanced the promoter activity of PEPCK and G6Pase ( Figure 7A) . Furthermore, as shown in Figure 7B , although insulin attenuated the expression of the PEPCK and G6Pase genes, HBx inhibited the insulin-induced suppression of the promoter activity of these genes. We also verified the mRNA levels of these genes in the RT-PCR and quantitative real-time PCR (Figure 7C and 7D) . Additionally, we observed that RNAi against SOCS3 could not induce PEPCK and G6Pase promoter activity in the presence of HBx ( Figure 7E ) and confirmed the mRNA levels of PEPCK and G6Pase in the RT-PCR ( Figure 7F ) and quantitative real-time PCR ( Figure 7G ).", "cite_spans": [{"start": 96, "end": 100, "text": "[45]", "ref_id": "BIBREF44"}], "ref_spans": [{"start": 398, "end": 408, "text": "Figure 7A)", "ref_id": "FIGREF6"}, {"start": 436, "end": 445, "text": "Figure 7B", "ref_id": "FIGREF6"}, {"start": 702, "end": 720, "text": "(Figure 7C and 7D)", "ref_id": "FIGREF6"}, {"start": 850, "end": 859, "text": "Figure 7E", "ref_id": "FIGREF6"}, {"start": 928, "end": 937, "text": "Figure 7F", "ref_id": "FIGREF6"}, {"start": 973, "end": 982, "text": "Figure 7G", "ref_id": "FIGREF6"}]}, {"section": "HBx disrupts insulin-induced PEPCK and G6Pase downregulation", "text": "Collectively, these results demonstrate that HBx induces decreased insulin signaling, resulting in the inhibition of gluconeogenesis in hepatocytes.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "As it has been estimated that approximately 53% of HCC cases worldwide are associated with HBV, research into HBV infection has been focused principally on the pathogenesis of HCC. However, it is possible that the deregulation of a number of metabolic components in HBV-infected livers may contribute to the pathogenesis of advanced liver diseases. Among the four proteins that originate from the HBV genome, such as polymerase, surface, core, and HBx proteins, HBx is reported to be associated with HBV-related pathogenesis [46] . Previous reports have demonstrated that HBx proteins induce fatty liver diseases via regulating of the expression of lipid synthesis-related genes in transgenic mice and hepatic cells [5, 6] , and hepatic inflammation is observed frequently in HBx-transgenic mice [6] . Some reports are demonstrated that patients with HBV infection show an association between steatosis and insulin resistance, with its clinical concomitants of obesity, hyperglycemia, and hypertriglyceridemia [47] .", "cite_spans": [{"start": 525, "end": 529, "text": "[46]", "ref_id": "BIBREF45"}, {"start": 716, "end": 719, "text": "[5,", "ref_id": "BIBREF4"}, {"start": 720, "end": 722, "text": "6]", "ref_id": "BIBREF5"}, {"start": 796, "end": 799, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 1010, "end": 1014, "text": "[47]", "ref_id": "BIBREF46"}], "ref_spans": []}, {"section": "Discussion", "text": "HBV should be considered to exert synergistic effects with chronic inflammation [48] . Proinflammatory proteins, including TNF-a, IL-6, and IL-1b, appear to participate in the induction and maintenance of the subacute inflammatory state associated with the accumulation of fat. We also noted that the mRNA levels of TNF-a, IL-6, IL-1b, cyclooxygenase-2 (COX-2), C-reactive protein (CRP), and matrix metalloproteinase-9 (MMP-9) expression were increased in the presence of HBx (data not shown). Presumably, HBx-mediated fat accumulation may be associated with the increased production of these cytokines in response to viral hepatic infections or inflammation. Therefore, it could need to identify the relationship with chronic HBV infection, inflammation, and inflammation-related liver dysfunction, such as disruption of insulin signaling. Collectively, based on the fact that HBV, especially HBx proteins, induces hepatic steatosis and inflammation, we examined the possible association with HBx and insulin signaling.", "cite_spans": [{"start": 80, "end": 84, "text": "[48]", "ref_id": "BIBREF47"}], "ref_spans": []}, {"section": "Discussion", "text": "The SOCS proteins are the most thoroughly studied inhibitors of Jak/STAT signaling pathway and include 8 members (cytokine inducible SH2 domain protein -CIS and SOCS 1 to 7), which are expressed at low levels in unstimulated cells. After cell activation, their expression increases, thereby inhibiting activated STATs [13, 26, 49] . In this study, we showed that HBx-induced C/EBPa and STAT3 activation was accompanied resulting in SOCS3 expressions were elevated. Also, given our observations that HBx activates the STAT3-SOCS3 regulatory pathway via cooperation with C/EBPa, the activation of this pathway is resulted in HBxinduced IRS1 degradation. As IRS proteins constitute a critical link in hepatic insulin signaling, the reduced expression of IRS proteins in the liver may result in inhibition of insulin signaling [50] .", "cite_spans": [{"start": 318, "end": 322, "text": "[13,", "ref_id": "BIBREF12"}, {"start": 323, "end": 326, "text": "26,", "ref_id": "BIBREF25"}, {"start": 327, "end": 330, "text": "49]", "ref_id": "BIBREF48"}, {"start": 823, "end": 827, "text": "[50]", "ref_id": "BIBREF49"}], "ref_spans": []}, {"section": "Discussion", "text": "Compared with HCV infection, the association between HBV infection, insulin signaling, and its complications have been less clearly identified. The recent report was demonstrated that in patients with HBV infection, the relationship between host characteristics such as obesity and type 2 diabetes and HBV infection was determined [47] . It was reported that obesity and diabetes are predictors of HCC risk, possible depending on HBV infection status [51] . In this study, we suggest the molecular mechanisms resulting in the suppression of insulin signaling by HBx proteins. However, future research may be required to demonstrate the physiological significance of the disruption of insulin signaling by HBV infection, especially HBx expression, and host and/or external factors. Additionally, it is possible that HBxinduced cellular stress, such as mitochondrial dysfunction, oxidative stress, and endoplasmic reticulum stress, can be associated with inhibition of insulin signaling. Studies might also be necessary to explain a number of mechanisms, which can be associated with liver dysfunctions.", "cite_spans": [{"start": 331, "end": 335, "text": "[47]", "ref_id": "BIBREF46"}, {"start": 451, "end": 455, "text": "[51]", "ref_id": "BIBREF50"}], "ref_spans": []}, {"section": "Discussion", "text": "In conclusion, our data indicate that HBx proteins are able to augment SOCS3 expression and decrease IRS1 proteins, thereby causing impairments of hepatic insulin signaling and inhibition of hepatic insulin action. 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HBx decreases IRS1 expression. (A) The effects of HBx protein on IRS1 expression in wild-type and HBx-transgenic mice. Proteins in liver extracts from control and HBx-transgenic mice were immunoblotted with anti-IRS1, anti-phospho-IRS1 (Ser307), anti-IRb, anti-HBx, and anti-Actin antibodies. Total RNA was isolated from liver tissues, and the levels of IRS1, HBx, and b-actin mRNA were identified by RT-PCR. (B) The IRS1 mRNA expression in wild-type and HBx-transgenic mice. Total RNA was extracted from liver tissues, and the levels of IRS1 mRNA were determined by quantitative real-time PCR. The data were normalized relative to the GAPDH mRNA. (C) Left; Immunohistochemistry of IRS1 in livers of wild-type and HBx-transgenic mice. Right; isotype controls of immunohistochemistry for IRS1 antibodies. (D) The effect of HBx protein on IRS1 expression in HepG2/ HA/HBx stable cells. HepG2 cell extracts stably transfected with HA-tagged HBx protein were immunoblotted with the IRS1 antibody. Total RNA was also isolated from Mock or HBx stable cells and subjected to RT-PCR analysis (left) or quantitative real-time PCR (right) with primers for IRS1. (E) The effect of the HBV replicon on IRS1 protein expression. HepG2 cells were transfected with the 1.2-mer replicon (a greater-than-genome-length) construct, a wild-type (WT) or HBx-null mutant (X 2 ), and HBx. Total cell extracts were subjected to Western blot analysis with IRS1 antibodies and total RNA was isolated from the replicon-transfected cells, and the levels of IRS1, HBx, and GAPDH mRNA were identified by RT-PCR (upper) or quantitative real-time PCR (bottom). The data were normalized relative to the GAPDH mRNA. (F) The effect of HBx on IRS1 protein expression in HepG2 cells. HA-tagged HBx protein was transiently expressed for indicated concentrations in HepG2 cells. 48 hours after transfection, MG132 (25 mM) was added for 2 hours. Total RNA was isolated from the cells, and the levels of IRS1, HBx, and GAPDH mRNA were identified by RT-PCR (upper) or quantitative real-time PCR (bottom). The data were normalized relative to the GAPDH mRNA. (G) The identification of ubiquitinated IRS1 by HBx proteins. HA-tagged ubiquitin was expressed in Mock or HBx stable cells in the treatment of MG132, or not expressed. Whole-cell lysates were immunoprecipitated with IRS1 antibodies and immunoblotted with HA antibodies. doi:10.1371/journal.pone.0008649.g001", "type": "figure"}, "FIGREF1": {"text": "Figure 2. HBx increases SOCS3 expression. (A) The protein and mRNA expression of SOCS3 in wild-type and HBx-transgenic mice in a stagespecific manner. The liver tissues of control mice and HBx homozygous transgenic mice were immunoblotted with anti-SOCS3 antibody. (B) The SOCS3 mRNA expression in wild-type and HBx-transgenic mice. Total RNA was extracted from liver tissues, and the levels of SOCS3 mRNA were determined by quantitative real-time PCR. The data were normalized relative to the GAPDH mRNA. (C) Left; Immunohistochemistry of SOCS3 in the livers of wild-type and HBx-transgenic mice. Right; isotype controls of immunohistochemistry for SOCS3 antibodies. (D) The effect of HBx protein on SOCS3 protein and mRNA expression in stable cell lines. HepG2 cell extracts stably expressing HA-tagged HBx protein were immunoblotted with the SOCS3 antibody (left). Total RNA was also isolated from HBx-constitutive expressing cells and subjected to RT-PCR analysis with primers for SOCS3 (right). (E) The protein and mRNA expression of SOCS3 in transiently HBx-transfected cells. HA-tagged HBx were transiently expressed in HepG2 cells. (F) The mRNA expression of SOCS3 in stable cells (left) or transiently HBx-transfected cells (right). The levels of SOCS3 mRNA were examined by quantitative real-time PCR. The data were normalized relative to the GAPDH mRNA. doi:10.1371/journal.pone.0008649.g002", "type": "figure"}, "FIGREF2": {"text": "Figure 3. SOCS3 is required for HBx-induced IRS1 protein expression. (A) The degradation of IRS1 by cooperation between HBx and SOCS3. Top; Mock and HBx-constitutively expressing HepG2 cells were transiently transfected with Myc-tagged SOCS3. 48 hours after transfection, the cell extracts were immunoblotted with the IRS1-specific antibodies. Bottom; Image analysis of IRS1 protein expression by densitometry. (B) The effect of HBx and SOCS3 siRNA on IRS1 protein expression. Top; Mock and HBx-constitutive expressing HepG2 cells were transiently transfected with pSUPER/ GFP control or pSUPER/SOCS3. The cell extracts were immunoblotted with the IRS1-specific antibodies. Bottom; Image analysis of IRS1 protein expression by densitometry. Values were expressed as the means 6 SD. *P,0.05 and **P,0.01 compared with indicated controls. doi:10.1371/journal.pone.0008649.g003", "type": "figure"}, "FIGREF3": {"text": "Figure 4. C/EBPa enhances HBx-induced SOCS3 expression. (A) Schematic representation of the transcriptional response elements on the murine SOCS3 promoter, showing a distal SRE (295 to 287), a proximal SRE (271 to 264), an AP1 element (2105 to 299), a FoxO motif (2103 to 95), a GC-rich region (258 to 252), and a putative C/EBPs binding site (298 to 284). (B) The effects of HBx and C/EBPa on SOCS3 promoter activity. HepG2 cells were transfected with SOCS3 reporter construct, HBx, and C/EBPa as indicated for 48 hr, after which the ratio of reporter activities was utilized to measure the promoter activity of SOCS3. *P,0.0001 compared with C/EBPa transfectants. (C) ChIP analysis on the SOCS3 promoter. HepG2 cells were transfected with expression vectors for HBx and C/EBPa as indicated and harvested for ChIP analysis with anti-C/EBPa antibody, or control IgG. The precipitated genomic fragments were amplified using primers flanking the C/EBPs binding sites on human SOCS3 promoters. Genomic DNA from total chromatin lysates was included as an input control. The precipitates were confirmed using quantitative real-time PCR. (D) The interaction between HBx and C/EBPa by coimmunoprecipitation. HA-tagged HBx was transiently expressed in HepG2 cells. Proteins in lysates were immunoprecipitated (IP) and immunoblotted (IB) with the indicated antibodies. (E) The induction of SOCS3 protein expression by HBx and C/EBPa. The C/EBPa protein was transiently expressed for 48 hr in Mock and stably HBx-transfected cells. Whole HepG2 cell extracts stably expressing HAtagged HBx protein were immunoblotted with the SOCS3-specific antibody. (F), (G) The mRNA expression of SOCS3 by HBx and C/EBPa in RT-PCR (F) or quantitative real-time PCR (G). (H) The effect of C/EBPa knockdown on HBx-induced SOCS3 promoter activity. *P,0.0001 compared with the indicated control. (I) The expression of SOCS3 proteins by HBx in the C/EBPa knockdown system. Whole cell lysates were immunoblotted with indicated antibodies. (J). (K) The expression of SOCS3 mRNA by HBx in the C/EBPa knockdown system. Total RNA was extracted from the cells, and the levels of SOCS3 mRNA were determined via RT-PCR (J) and quantitative real-time PCR (K). doi:10.1371/journal.pone.0008649.g004", "type": "figure"}, "FIGREF4": {"text": "Figure 5. STAT3 activation is associated with HBx-induced SOCS3 expression. (A) The activation of STAT3 via HBx-induced tyrosine phosphorylation. Proteins in liver extracts from control and HBx-transgenic mice were immunoblotted with anti-STAT3 and anti-phospho-STAT3 (Tyr705) antibodies. (B), (C) The effect of HBx protein on STAT3 phosphorylation in HepG2 cells. HepG2 cell extracts stably (B) and transiently (C) transfected with HBx were immunoblotted with the STAT3 and phosphor-STAT3 (Tyr705) specific antibodies. (D) Transactivation of STAT3 by HBx expression. The m67-Luc (150 ng) was cotransfected into HepG2 cell with the eukaryotic expression vectors for the wild type (WT), constitutive active (CA), or dominant negative (DN) construct for STAT3 with or without HBx expression vectors. The luciferase activity was measured and the values are expressed as the means 6 s.d. for at least four independent experiments. (E) The activation of STAT3 via interaction with HBx proteins. HA-tagged HBx and dominant negative STAT3 constructs were transfected into HepG2 cells. Proteins in lysates were immunoprecipitated with anti-STAT3 and immunoblotted with anti-STAT3 and anti-HA. (F) Luciferase activity of SOCS3 promoter dependent on the expression of HBx, C/EBPa, and STAT3 (WT, CA, and/or DN). The values were expressed as the means 6 SD. *P,0.05 and **P,0.0001 compared with the indicated controls. doi:10.1371/journal.pone.0008649.g005", "type": "figure"}, "FIGREF5": {"text": "Figure 6. HBx disturbs insulin signaling in hepatic cells. (A) The effect of HBx on the insulin-induced phosphorylation of the p85 subunit of PI3K and Akt in the dose-response manner. Control and HBx-expressed stable cells were incubated in the presence of insulin for 60 minutes. Whole cell lysates were subjected to immunoblotting for phosphor-p85 (Tyr458) and phosphor-Akt (Ser473). (B) The effect of HBs on the insulin-treated phosphorylation of p85 and Akt in the time-course manner. Control and HBx stable cells were treated in the presence of 100 nM insulin for indicated times. Total cell lysates were examined to Western blotting for phosphor-p85 (Tyr458) and phosphor-Akt (Ser473). (C) The effect of HBx on the insulin-stimulated tyrosine phosphorylation of IRS1. Mock and HBx-expressed stable cells were treated for 60 minutes in the presence of 100 nM insulin. From the total cell extracts, IRS1 proteins were immunoprecipitated (IP), corresponding with the anti-IRS1 antibody, followed by immunoblotting with anti-phosphotyrosine antibody. doi:10.1371/journal.pone.0008649.g006", "type": "figure"}, "FIGREF6": {"text": "Figure 7. HBx suppresses insulin-inhibitory expression of gluconeogenic genes. (A) The promoter activity of PEPCK and G6Pase by HBx and SOCS3. HepG2 cells were transfected with two promoters of PEPCK (left) and G6Pase (right) and expression vectors of HBx, and SOCS3. (B) The inhibition of insulin-mediated promoter activity of PEPCK and G6Pase by HBx proteins. HepG2 cells were transiently transfected with PEPCK (left) or G6Pase (right) promoter construct and HBx in the presence or absence of insulin (100 nM). Luciferase assay was conducted to assess the promoter activity of PEPCK and G6Pase, and the error bars represent the standard deviation. *P,0.05 and **P,0.005 compared with indicated controls. (C), (D) Control and HBx stable cells were incubated for 1 h in the presence of insulin (100 nM). Total RNA was also isolated and subjected to RT-PCR analysis (C) or quantitative real-time PCR (D) with primers for PEPCK and G6Pase. b-Actin or GAPDH expression served as a control. (E) The promoter activity of PEPCK and G6Pase by HBx and RNAi against SOCS3 in the presence of insulin. HepG2 cells were transiently transfected with PEPCK (left) or G6Pase (right) promoter construct and HBx and/or RNAi for SOCS3 in the presence of insulin (100 nM). Luciferase assay was conducted to assess the promoter activity of PEPCK and G6Pase. (F), (G) The mRNA expression of PEPCK and G6Pase by HBx and/or siSOCS3 in treatments of insulin. Total RNA was isolated and subjected to RT-PCR (F) or quantitative real-time PCR (G). doi:10.1371/journal.pone.0008649.g007", "type": "figure"}, "TABREF0": {"text": "Primers for the RT-PCR amplification.", "type": "table"}}}
{"paper_id": "10707287", "_pdf_hash": "af544daafc63e599cea2f2ca46153ccf977b59eb", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "10707905", "_pdf_hash": "af3794a564876cd956b0fefd4f8a61e9a61e4911", "abstract": [], "body_text": [{"section": "INTRODUCTION", "text": "The treatment of any of a wide variety of cells with vincristine or vinblastine results in the dissolution of cytoplasmic microtubules and the formation of both 90-100 A filaments and ordered arrays of hexagonally packed, circular structures (1) (2) (3) (4) . These ordered structures have been named \"microtubular crystals\" (2, 3) , and this nomenclature will be followed here with the awareness that conclusive evidence of true crystalline order is lacking.", "cite_spans": [{"start": 242, "end": 245, "text": "(1)", "ref_id": "BIBREF0"}, {"start": 246, "end": 249, "text": "(2)", "ref_id": "BIBREF1"}, {"start": 250, "end": 253, "text": "(3)", "ref_id": "BIBREF2"}, {"start": 254, "end": 257, "text": "(4)", "ref_id": "BIBREF3"}, {"start": 325, "end": 328, "text": "(2,", "ref_id": "BIBREF1"}, {"start": 329, "end": 331, "text": "3)", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "Ultracentrifugal studies by Weisenberg and Timasheff (5) revealed a vinblastine-induced aggregation of purified microtubule subunit protein. Vinblastine selectively and quantitatively precipitates microtubule protein from supernatants of cell and tissue homogenates, if adequate concentrations of vinblastine and magnesium are used (6, 7) .", "cite_spans": [{"start": 332, "end": 335, "text": "(6,", "ref_id": "BIBREF5"}, {"start": 336, "end": 338, "text": "7)", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "Electron microscopic studies of vinblastineprecipitated microtubule protein were previously reported from this laboratory (8) . These studies on embedded, sectioned material revealed ordered acriform arrays of ladder-like structures with \"rungs\" spaced approximately 300 A apart surrounding circular profiles with a diameter on the order of 360 A . On the basis of this sectioned material it was not possible to ascertain what relationship, if any, existed between the vinblastine-induced precipitated microtubule protein in vitro and the vinblastine-induced microtubular crystals seen in vivo .", "cite_spans": [{"start": 122, "end": 125, "text": "(8)", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "The negative contrast studies which we now report demonstrate the remarkable similarity between the structures induced by vinblastine in vitro and in vivo. In addition, the three-dimensional structure of the former is clarified, and the results are extrapolated to the latter .", "cite_spans": [], "ref_spans": []}, {"section": "B R I E F N O T E S MATERIALS AND METHODS", "text": "Microtubule protein was purified from pig brain by using the method of Weisenberg, Borisy, and Taylor (9) . The final ammonium sulfate pellet was resuspended in a 0.01 ms phosphate buffer containing 0 .01 mI MgCl and 10-4 me guanosine-5'-triphosphate (phos-Mg-GTP) at pH 6.5 . Protein concentration varied from 2 to 5 mg/ml . The purified protein ran as a single band on a 7 .5% polyacrylamide gel electrophoresis after the samples had been denatured in 8 M urea, reduced, and alkylated as previously described (9, 12) .", "cite_spans": [{"start": 102, "end": 105, "text": "(9)", "ref_id": "BIBREF8"}, {"start": 511, "end": 514, "text": "(9,", "ref_id": "BIBREF8"}, {"start": 515, "end": 518, "text": "12)", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "B R I E F N O T E S MATERIALS AND METHODS", "text": "Crystals were grown by dialysis of microtubule protein solutions against Phos-Mg-GTP with 10 -4 M vinblastine sulfate for periods of up to 18 hr . At the end of the dialysis a whitish precipitate was present . Previous work has demonstrated the complete precipitation of all microtubule protein and all the colchicine-binding activity by this procedure (6) . Suspensions of the precipitate were used for negative contrast examination with the electron microscope . Occasional samples were sonicated with a Branson sonicator (Branson Instruments, Inc ., Stanford, Conn .) at settings varying from 1 to 3 for periods of up to 15 sec . The samples were immersed in an ice bath during this procedure .", "cite_spans": [{"start": 353, "end": 356, "text": "(6)", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "B R I E F N O T E S MATERIALS AND METHODS", "text": "Thin layers of the suspensions were applied to 400-mesh collodion-carbon-coated grids, and staining was then carried out by dropwise application of 0 .3-0 .5 ml of 2% uranyl acetate in deionized water . The grids were then blotted on filter paper and allowed to dry in air . Specimens were examined in Siemens IA and Hitachi HS-8-1 electron microscopes calibrated against a carbon replica grid . Plates were measured directly on a Nikon Shadowgraph optical comparator (Nikon Inc ., Instrument Div ., New York) .", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "The precipitate is composed of large, closely packed arrays of rings in hexagonal apposition ( Fig. 1) . Smaller structures consisting of single rings or individual helical structures are also seen frequently (Fig. 2) . Helices are also seen frequently at the periphery of the larger arrays and often appear to spiral out from the ringlike structures (Fig . 3) .", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "Each ring has an inner diameter of 280 A and a wall width of 70-80 A, for a total diameter of 420-440 A (Figs . 1-3) . The total wall thickness dividing two rings is 140 A with some overlap of the individual walls seen in the majority of rings studied (Fig . 2) . The helices, which are studied more readily in mildly sonicated preparations (Figs. 4, 5) , are wound from a strand of 70-80 A diameter, a dimension identical with that of the wall thickness of an individual ring . The distance between turns of the helix is approximately 250 A, though considerable variation is found in this dimension .", "cite_spans": [], "ref_spans": [{"start": 341, "end": 353, "text": "(Figs. 4, 5)", "ref_id": "FIGREF0"}]}, {"section": "RESULTS", "text": "The walls of the rings and the helical strands reveal a triple density appearance with two, light, outer bands surrounding a central, faintly crossstriated, dark band (Figs . 2, 4) . At higher magnification (Fig . 6) this pattern gives the appearance of globules with an electron-opaque core. Each band in this triple density pattern is 20-30 A in width, and the center-to-center spacing of the dark electron-opaque units is 45-50 A .", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "The helices often appear to be a series of loops (Fig . 3) on a vertical spine rather than a corkscrew of uniform pitch . Due to the distortion inherent in the drying' of material on the grids, this problem could not be further resolved . Small pieces of linearly assembled subunits were often FIGURE 1 Negative contrast image of vinblastine-induced microtubule crystal . Appearance is that of hexagonally packed rings. Areas suggestive of helical structure are observed (arrows) . X 100,000. FIGURE 2 Individual rings and helix as are often seen . The adjacent rings overlap slightly at their junction . The walls of both the rings and the helix show triple density appearance with a suggestion of crossstriation . X 100,000 . FIGURE 3 Periphery of a microtubular crystal demonstrating helices arising from the regions of circular structure . In the lower portion of the figure, helices of both corkscrew and loop conformation can be seen . X 180,000. FIGURE 4 Gently sonicated crystal showing beaded or triple density appearance of strand forming the helix. Background shows isolated rings and pieces of helices. X 100,000. seen in the background of both sonicated and unsonicated preparations, but long linear filaments such as have been reported in vivo were never seen (I) . Crystals were readily redissolved by dialysis against Phos-Mg-GTP . The protein could be precipitated again with identical morphology by readdition of vinblastine . Essentially similar results were obtained with vincristine. No structures were identifiable after addition of colchicine or griseofulvin at concentrations of 10-s M to microtubule protein solutions . The vinblastineinduced assembly was not affected by 10 -4 M colchicine, podophyllotoxin, or griseofulvin . The removal of GTP from the dialysis medium also has no effect on the formation of these crystals .", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "Preliminary studies on the binding of vinblastine to the precipitate are in progress, and a combination of colorimetric and thin-layer chromatography techniques is being utilized . Current results indicate that vinblastine in the free base form is bound to the protein, but quantitative results are not yet available . These results are consistent with the radioautographic localization of tritiated vinblastine over microtubular crystals in vivo reported by Malawista et al . (16) . No bound GTP was detected in the crystals . DISCUSSION The similarity in appearance between the crystals formed in vitro by the dialysis of microtubule protein against vinblastine and those formed by the treatment of cells with vinblastine and vincristine is striking . However, it is now apparent, in vitro, that the closely packed arrays of circular profiles are in reality helices viewed on-end, and that the crystal is assembled in much the same manner as a bedspring . The identification of a helical structure suggests that the ladderlike assemblies seen on pelleted and sectioned in vitro material (8) are helices seen in side view . Sectioned crystals, whether produced in vivo or in vitro, have smaller dimensions than those seen in unfixed, FIGURE 6 Detail of wall structure demonstrating elliptical beaded subunits (arrowheads) . Wall width is 80 A and the center-to-center subunit spacing is 50 A . Negative contrast . X 350,000 . negative contrast preparations . Reported inner diameters of the circular elements in sectioned material range from 200 to 260 A (3, 4, 8, 10 ), compared to 280 A in the negatively stained material . A similar difference exists with regard to the total wall between adjacent elements which measures 80-100 A in sectioned material compared to 140 A in the negatively stained crystals . The reported outer diameter of the sectioned material ranges from 280 to 380 A compared to 420 to 440 A in the crystals described here (3, 8, 10) . These differences are probably the result of the dehydration of the sectioned preparations . Dehydration may also account for the fact that the profiles in the negative contrast preparations are circular while in sectioned material they often appear to be hexagonal (3) .", "cite_spans": [{"start": 477, "end": 481, "text": "(16)", "ref_id": "BIBREF15"}, {"start": 1089, "end": 1092, "text": "(8)", "ref_id": "BIBREF7"}, {"start": 1947, "end": 1950, "text": "(3,", "ref_id": "BIBREF2"}, {"start": 1951, "end": 1953, "text": "8,", "ref_id": "BIBREF7"}, {"start": 1954, "end": 1957, "text": "10)", "ref_id": "BIBREF9"}, {"start": 2226, "end": 2229, "text": "(3)", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "RESULTS", "text": "The pattern of linearly arranged dots which has been reported in longitudinal sections of in vivo crystals might be the result of a fortuitous section through an array of side-by-side helices along their long axes. This is further supported by the fact that adjacent rows of dots are out of register, as would be required if the section passed through the loops of the helix (3) . Alternatively, the dots could represent a section through the tips of the helical turns . In either case the spacing would be of approximately the correct dimension .", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "High resolution studies of the wall structure reveal a pattern compatible with a linear array of globular subunits . This pattern might also be interpreted as a helical bifilar assembly, though the former explanation is more consistent with established hydrodynamic and chemical data on this protein (9, 11, 12) . It is of interest that the subunits appear to be ellipitical or rectangular with their long axes oriented at right angles to the direction of assembly, rather than spherical . This same phenomenon was reported by Ledbetter and Porter (13) in high resolution studies of the subunits in normal microtubules, and it is also apparent in similar work by Phillips (14) . It is likely that this asymmetry is due to a heavier deposition of stain along the free inner and outer surfaces of the tubules and of the helical elements and to the less ready access of stain to the surfaces where subunit-subunit contacts are formed . The subunits appear to have a core in which stain is deposited in the negative contrast preparations . Similar conformations have been seen in positively stained sections of microtubules where the core appears electron lucent (13, 14) .", "cite_spans": [{"start": 300, "end": 303, "text": "(9,", "ref_id": "BIBREF8"}, {"start": 304, "end": 307, "text": "11,", "ref_id": "BIBREF10"}, {"start": 308, "end": 311, "text": "12)", "ref_id": "BIBREF11"}, {"start": 548, "end": 552, "text": "(13)", "ref_id": "BIBREF12"}, {"start": 672, "end": 676, "text": "(14)", "ref_id": "BIBREF13"}, {"start": 1159, "end": 1163, "text": "(13,", "ref_id": "BIBREF12"}, {"start": 1164, "end": 1167, "text": "14)", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "RESULTS", "text": "Tilney and Porter (15) have reported the formation of abnormally large, 360 A diameter tubules in Actinosphaerium in which the normal microtubules have been depolymerized by exposure to cold . These tubules were seen to have cross-striations which ran at 45\u00b0angles to the long axis . In view of the work reported here, it is likely that these abnormally large microtubules are actually single helical strands.", "cite_spans": [], "ref_spans": []}, {"section": "SUMMARY", "text": "Negative contrast studies have shown the similarity between vinblastine-induced microtubule crystals in vivo and the structures formed by vinblastineinduced self-assembly of microtubule subunits in vitro . These structures are seen to be arrays of helices arranged in a bedspring-like array . The subunits strongly resemble those of the normal microtubule .", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Effects of mitotic spindle inhibitors on neurotubules and neurofilaments in anterior horn cells", "authors": [{"first": "H", "middle": [], "last": "Wisniewski", "suffix": ""}, {"first": "M", "middle": ["L"], "last": "Shelanski", "suffix": ""}, {"first": "R", "middle": ["D"], "last": "Terry", "suffix": ""}], "year": 1968, "venue": "J. 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{"paper_id": "10707951", "_pdf_hash": "60c08018597e66c758e0396c4c29dd8cd3eabafb", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "denote the set of jobs (from among J i", "authors": [], "year": "", "venue": "J i+1", "link": null}, "BIBREF1": {"title": "Divide the m-torus into m=d i many d i -subtorii across the entire interval 0; T]; line up jobs in JS( ) over each interval such that no job is scheduled on two d i -sub-torii", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF2": {"title": "2 JS( )g and let I 2 = f 0 : 0 is a -interval on right of T 0 and J i 2 JS( 0 )g. Obviously, number of intervals in I 1 and I 2 are equal. Now we can think of a one-to-one function from I 1 to I 2 . Consider an interval in I 1 and the corresponding 0 in I 2 . Since the profile P(i ? 1) is stair-like, number of d i -subtorii over in S 0 ? S(i ? 1) is at least as many as over 0 . Thus, since J i is over 0 and not over , there is at least a d i -subtorus over which is either an empty interval or occupied by", "authors": [], "year": "", "venue": "Let T 0 = T ? t i . Divide the schedule S 0 into two parts: left and right of T 0 . Let I 1 = f : is a -interval on left of T 0 and J i", "link": null}, "BIBREF3": {"title": "If Step 2 is used to schedule J i on S(i ? 1) to produce S(i), J i is scheduled on subtorus A = a 1 ; a 1 + d i ? 1] from f 1 to f 1 + t i = . In this case, T 0 > f 1 and > f 1 . For each in T 0 ; T] in S 0 , we interchange J i in its d i -subtorus with jobs in A", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF4": {"title": "Because A extends from f 1 to T in S 0 ? S(i ? 1), the swapping can always be done", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF5": {"title": "If Step 3 is used to schedule J i on S(i ? 1) to produce S(i), J i is scheduled entirely on subtorus A = a j ; a j + d i ? 1] from time f j to time f j + t i =", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF6": {"title": "S 0 , we just interchange J i in its d i -subtorus with jobs in A", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF7": {"title": "If Step 4 is used to schedule J i on S(i ? 1) to produce S(i), J i is scheduled on subtorus A from time f j to T and on subtorus B = a j+1", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF8": {"title": "An o(n log n) feasibility algorithm for preemptive scheduling of n independent jobs on a hypercube", "authors": [{"first": "M", "middle": [], "last": "Ahuja", "suffix": ""}, {"first": "Y", "middle": [], "last": "Zhu", "suffix": ""}, {"first": ";", "middle": ["S"], "last": "Borkar", "suffix": ""}, {"first": "R", "middle": [], "last": "Cohn", "suffix": ""}, {"first": "G", "middle": [], "last": "Cox", "suffix": ""}, {"first": "S", "middle": [], "last": "Gleason", "suffix": ""}, {"first": "T", "middle": [], "last": "Gross", "suffix": ""}, {"first": "H", "middle": ["T"], "last": "Kung", "suffix": ""}, {"first": "B", "middle": [], "last": "Moore", "suffix": ""}, {"first": "M", "middle": [], "last": "Lam", "suffix": ""}, {"first": "C", "middle": [], "last": "Peterson", "suffix": ""}, {"first": "J", "middle": [], "last": "Pieper", "suffix": ""}, {"first": "L", "middle": [], "last": "Rankin", "suffix": ""}, {"first": "P", "middle": ["S"], "last": "Tseng", "suffix": ""}, {"first": "J", "middle": [], "last": "Sutton", "suffix": ""}, {"first": "J", "middle": [], "last": "Urbanski", "suffix": ""}, {"first": "J", "middle": [], "last": "Webb", "suffix": ""}], "year": 1988, "venue": "Proceedings of Supercomputing '88", "link": "30749329"}, "BIBREF9": {"title": "Horizons of Parallel Computation", "authors": [{"first": "G", "middle": [], "last": "Bilardi", "suffix": ""}, {"first": "F", "middle": ["P"], "last": "Preprata", "suffix": ""}], "year": 1995, "venue": "J. of Parallel and Distributed Computing", "link": "2820816"}, "BIBREF10": {"title": "Inc. 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{"paper_id": "10708205", "_pdf_hash": "982074e709c3f9367b8460dd3854a3992c2cdfa3", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Applying artificial intelligence to virtual reality: Intelligent virtual environments", "authors": [{"first": "Michael", "middle": [], "last": "Luck", "suffix": ""}, {"first": "Ruth", "middle": [], "last": "Aylett", "suffix": ""}], "year": 2000, "venue": "Applied Artificial Intelligence", "link": "18317038"}, "BIBREF1": {"title": "Lessons from research on interaction with virtual environments", "authors": [{"first": "Jes\u00fas", "middle": [], "last": "Ib\u00e1\u00f1ez", "suffix": ""}, {"first": "Carlos", "middle": [], "last": "Delgado-Mata", "suffix": ""}], "year": 2011, "venue": "Journal of Network and Computer Applications", "link": "29553000"}, "BIBREF2": {"title": "MAM5: Multi-agent model for intelligent virtual environments", "authors": [{"first": "A", "middle": [], "last": "Barella", "suffix": ""}, {"first": "A", "middle": [], "last": "Ricci", "suffix": ""}, {"first": "O", "middle": [], "last": "Boissier", "suffix": ""}, {"first": "C", "middle": [], "last": "Carrascosa", "suffix": ""}], "year": 2012, "venue": "10th European Workshop on Multi-Agent Systems (EUMAS 2012)", "link": null}, "BIBREF3": {"title": "Developing adaptive agents situated in intelligent virtual environments", "authors": [{"first": "J", "middle": ["A"], "last": "Rincon", "suffix": ""}, {"first": "Emilia", "middle": [], "last": "Garcia", "suffix": ""}, {"first": "V", "middle": [], "last": "Julian", "suffix": ""}, {"first": "C", "middle": [], "last": "Carrascosa", "suffix": ""}], "year": 2014, "venue": "Hybrid Artificial Intelligence Systems", "link": "31896481"}, "BIBREF4": {"title": "Give Agents their Artifacts\": The A&A Approach for Engineering Working Environments in MAS", "authors": [{"first": "Alessandro", "middle": [], "last": "Ricci", "suffix": ""}, {"first": "Mirko", "middle": [], "last": "Viroli", "suffix": ""}, {"first": "Andrea", "middle": [], "last": "Omicini", "suffix": ""}], "year": 2007, "venue": "6th International Joint Conference \"Autonomous Agents & Multi-Agent Systems\" (AAMAS 2007)", "link": "14781373"}}, "ref_entries": {}}
{"paper_id": "10708760", "_pdf_hash": "46f0dc9125dc6f78f6ee492dda5c2b78b96c15ae", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "A Practical Approach to Wrist Pulse Segmentation and Singleperiod Average Waveform Estimation", "authors": [{"first": "C", "middle": [], "last": "Xia", "suffix": ""}, {"first": "Y", "middle": [], "last": "Li", "suffix": ""}, {"first": "J", "middle": [], "last": "Yan", "suffix": ""}, {"first": "Y", "middle": [], "last": "Wang", "suffix": ""}, {"first": "H", "middle": [], "last": "Yan", "suffix": ""}, {"first": "R", "middle": [], "last": "Guo", "suffix": ""}, {"first": "F", "middle": [], "last": "Li", "suffix": ""}], "year": 2008, "venue": "BioMedical Engineering and Informatics", "link": "9908727"}, "BIBREF1": {"title": "Outlier Pulse Detection and Feature Extraction for Wrist Pulse Analysis", "authors": [{"first": "B", "middle": [], "last": "Thakker", "suffix": ""}, {"first": "A", "middle": ["L"], "last": "Vyas", "suffix": ""}], "year": 2009, "venue": "World Academy of Science, Engineering & Technology", "link": "14012990"}, "BIBREF2": {"title": "Theory and Applications of the Harmonic Analysis of Arterial Pressure Pulse Waves", "authors": [{"first": "Y", "middle": ["Y L"], "last": "Wang", "suffix": ""}, {"first": "T", "middle": ["L"], "last": "Hsu", "suffix": ""}, {"first": "M", "middle": ["Y"], "last": "Jan", "suffix": ""}, {"first": "W", "middle": ["K"], "last": "Wang", "suffix": ""}], "year": 2010, "venue": "Journal of Medical and Biological Engineering", "link": "31237483"}, "BIBREF3": {"title": "Spectrum Analysis of Human Pulse", "authors": [{"first": "C", "middle": ["T"], "last": "Lee", "suffix": ""}, {"first": "L", "middle": ["Y"], "last": "Wei", "suffix": ""}], "year": 1983, "venue": "IEEE Transactions on Biomedical Engineering", "link": "17524540"}, "BIBREF4": {"title": "Wavelet-based cascaded adaptive filter for removing baseline drift in pulse waveforms", "authors": [{"first": "X", "middle": [], "last": "Lisheng", "suffix": ""}, {"first": "D", "middle": [], "last": "Zhang", "suffix": ""}, {"first": "W", "middle": [], "last": "Kuanquan", "suffix": ""}], "year": 2005, "venue": "IEEE Transactions on Biomedical Engineering", "link": "6897442"}, "BIBREF5": {"title": "Wavelet decomposition and feature extraction from pulse signals of the radial artery", "authors": [{"first": "M", "middle": [], "last": "Sareen", "suffix": ""}, {"first": "P", "middle": [], "last": "Abhinav", "suffix": ""}, {"first": "S", "middle": [], "last": "Prakash", "suffix": ""}, {"first": "", "middle": [], "last": "Anand", "suffix": ""}], "year": 2008, "venue": "2008 International Conference on Advanced Computer Theory and Engineering", "link": "17247199"}, "BIBREF6": {"title": "Pulse differences and 3D pulse mapping in TPNI displacements", "authors": [{"first": "C", "middle": ["S"], "last": "Hu", "suffix": ""}, {"first": "Y", "middle": ["F"], "last": "Chung", "suffix": ""}, {"first": "C", "middle": ["H"], "last": "Luo", "suffix": ""}, {"first": "C", "middle": ["C"], "last": "Yeh", "suffix": ""}, {"first": "X", "middle": ["C"], "last": "Si", "suffix": ""}], "year": 2011, "venue": "2011 4th International Conference on Biomedical Engineering and Informatics (BMEI)", "link": "18229621"}, "BIBREF7": {"title": "Temporal and Spatial Properties of Arterial Pulsation Measurement Using Pressure Sensor Array", "authors": [{"first": "C", "middle": ["S"], "last": "Hu", "suffix": ""}, {"first": "Y", "middle": ["F"], "last": "Chung", "suffix": ""}, {"first": "C", "middle": ["C"], "last": "Yeh", "suffix": ""}, {"first": "C", "middle": ["H"], "last": "Luo", "suffix": ""}], "year": 2012, "venue": "Evidence-Based Complementary and Alternative Medicine", "link": "10900224"}, "BIBREF8": {"title": "Possibility of quantifying TCM finger-reading sensations: I. BiSensing Pulse Diagnosis Instrument", "authors": [{"first": "C", "middle": ["H"], "last": "Luo", "suffix": ""}, {"first": "Y", "middle": ["F"], "last": "Chung", "suffix": ""}, {"first": "C", "middle": ["S"], "last": "Hu", "suffix": ""}, {"first": "C", "middle": ["C"], "last": "Yeh", "suffix": ""}, {"first": "X", "middle": ["C"], "last": "Si", "suffix": ""}, {"first": "D", "middle": ["H"], "last": "Feng", "suffix": ""}, {"first": "Y", "middle": ["C"], "last": "Lee", "suffix": ""}, {"first": "S", "middle": ["I"], "last": "Huang", "suffix": ""}, {"first": "S", "middle": ["M"], "last": "Yeh", "suffix": ""}, {"first": "C", "middle": ["H"], "last": "Liang", "suffix": ""}], "year": 2012, "venue": "European Journal of Integrative Medicine", "link": "72826262"}, "BIBREF9": {"title": "Discrete-Time Signal Processing", "authors": [{"first": "A", "middle": ["V"], "last": "Oppenheim", "suffix": ""}, {"first": "R", "middle": ["W"], "last": "Schafer", "suffix": ""}], "year": 2009, "venue": "", "link": "63180999"}}, "ref_entries": {}}
{"paper_id": "10708925", "_pdf_hash": "44bf021b2435a58ebc468075fca163803943a82a", "abstract": [{"section": "Abstract", "text": "Abstract: In addition to deoxynivalenol (DON), acetylated derivatives, i.e., 3-acetyl and 15-acetyldexynivalenol (or 3/15ADON), are present in cereals leading to exposure to these mycotoxins. Animal and human studies suggest that 3/15ADON are converted into DON after their ingestion through hydrolysis of the acetyl moiety, the site(s) of such deacetylation being still uncharacterized. We used in vitro and ex vivo approaches to study the deacetylation of 3/15ADON by enzymes and cells/tissues present on their way from the food matrix to the blood in humans. We found that luminal deacetylation by digestive enzymes and bacteria is limited. Using human cells, tissues and S9 fractions, we were able to demonstrate that small intestine and liver possess strong deacetylation capacity compared to colon and kidneys. Interestingly, in most cases, deacetylation was more efficient for 3ADON than 15ADON. Although we initially thought that carboxylesterases (CES) could be responsible for the deacetylation of 3/15ADON, the use of pure human CES1/2 and of CES inhibitor demonstrated that CES are not involved. Taken together, our original model system allowed us to identify the small intestine and the liver as the main site of deacetylation of ingested 3/15ADON in humans.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Mycotoxins are secondary metabolites produced by various molds infecting plants and crops and belonging chiefly to Aspergillus, Penicillium or Fusarium species [1] [2] [3] [4] [5] . Among the large number of existing mycotoxins (i.e., more than 350 [6] ) some, such as deoxynivalenol (DON), have attracted special attention due to their prevalence and toxicity [7, 8] . DON belongs to a family of mycotoxins called trichothecenes. Trichothecenes are small sesquiterpenoids with an epoxide group at position 12-13 that is involved in their toxic effect through their binding to ribosomes. This binding causes a ribotoxic effect characterized by the activation of various protein kinases, the modulation of gene www.mdpi.com/journal/toxins expression, leading eventually to alteration of cell functions and cell toxicity [8] [9] [10] . Thus, exposure to DON is associated to alterations of the intestinal, immune, and brain cell functions in animals and humans [8, [10] [11] [12] [13] [14] [15] [16] . In addition to native/unmodified mycotoxins, food and feeds also contain mycotoxin derivatives that may represent a risk for animals and humans, their metabolic fate and toxicity being not always characterized [4, [17] [18] [19] . Although new molecules are regularly described, the major derivatives of DON present in food and feed correspond to fungal (i.e., the acetylated derivatives: 3-and 15-acetylDON or 3ADON and 15ADON) and plant (i.e., 3-O-glucoside-DON or D3G) derivatives [17, 19] . 3/15ADON ( Figure 1 ) are precursors in the synthesis of DON [20] and are thus found in food as a mixture with DON. Indeed, like DON, 3/15ADON have a high prevalence in cereals (87% and 73% of positive samples for 3ADON and 15ADON, respectively) with contamination levels ranging from 300 to 1000 \u00b5g/kg leading to daily exposure of animals and humans to 3/15ADON [21] [22] [23] . Although in vivo and in vitro experiments have demonstrated that 3/15ADON could be absorbed by the intestinal epithelium, oral exposures of chickens, rats and pigs to 3/15ADON only result in DON and/or detoxification products of DON (i.e., the 3/15-glucuronic acid conjugates of DON and the de-epoxide form of DON, i.e., DOM-1) being present in their blood suggesting a pre-systemic and/or systemic deacetylation [21, [24] [25] [26] [27] [28] . to DON is associated to alterations of the intestinal, immune, and brain cell functions in animals and humans [8, [10] [11] [12] [13] [14] [15] [16] . In addition to native/unmodified mycotoxins, food and feeds also contain mycotoxin derivatives that may represent a risk for animals and humans, their metabolic fate and toxicity being not always characterized [4, [17] [18] [19] . Although new molecules are regularly described, the major derivatives of DON present in food and feed correspond to fungal (i.e., the acetylated derivatives: 3-and 15-acetylDON or 3ADON and 15ADON) and plant (i.e., 3-O-glucoside-DON or D3G) derivatives [17, 19] . 3/15ADON (Figure 1 ) are precursors in the synthesis of DON [20] and are thus found in food as a mixture with DON. Indeed, like DON, 3/15ADON have a high prevalence in cereals (87% and 73% of positive samples for 3ADON and 15ADON, respectively) with contamination levels ranging from 300 to 1000 \u03bcg/kg leading to daily exposure of animals and humans to 3/15ADON [21] [22] [23] . Although in vivo and in vitro experiments have demonstrated that 3/15ADON could be absorbed by the intestinal epithelium, oral exposures of chickens, rats and pigs to 3/15ADON only result in DON and/or detoxification products of DON (i.e., the 3/15-glucuronic acid conjugates of DON and the de-epoxide form of DON, i.e., DOM-1) being present in their blood suggesting a pre-systemic and/or systemic deacetylation [21, [24] [25] [26] [27] [28] . Broekaert et al. [21] elegantly showed that both oral and intravenous (i.v) exposures of pigs to 3-or 15ADON resulted in their complete transformation into DON, demonstrating that pre-systemic and systemic deacetylation may occur in parallel. Interestingly, the authors also demonstrated that traces of 15ADON are present in the blood of chickens after oral or i.v treatment, suggesting that, at least in chickens, contrarily to 3ADON, 15ADON may partially resist deacetylation [21] . Broekaert et al. [21] elegantly showed that both oral and intravenous (i.v) exposures of pigs to 3-or 15ADON resulted in their complete transformation into DON, demonstrating that pre-systemic and systemic deacetylation may occur in parallel. Interestingly, the authors also demonstrated that traces of 15ADON are present in the blood of chickens after oral or i.v treatment, suggesting that, at least in chickens, contrarily to 3ADON, 15ADON may partially resist deacetylation [21] .", "cite_spans": [{"start": 164, "end": 167, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 168, "end": 171, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 172, "end": 175, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 176, "end": 179, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 249, "end": 252, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 361, "end": 364, "text": "[7,", "ref_id": "BIBREF6"}, {"start": 365, "end": 367, "text": "8]", "ref_id": "BIBREF7"}, {"start": 819, "end": 822, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 823, "end": 826, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 827, "end": 831, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 959, "end": 962, "text": "[8,", "ref_id": "BIBREF7"}, {"start": 963, "end": 967, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 968, "end": 972, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 973, "end": 977, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 978, "end": 982, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 983, "end": 987, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 988, "end": 992, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 993, "end": 997, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 1210, "end": 1213, "text": "[4,", "ref_id": "BIBREF3"}, {"start": 1214, "end": 1218, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 1219, "end": 1223, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 1224, "end": 1228, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 1484, "end": 1488, "text": "[17,", "ref_id": "BIBREF16"}, {"start": 1489, "end": 1492, "text": "19]", "ref_id": "BIBREF18"}, {"start": 1556, "end": 1560, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 1858, "end": 1862, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 1863, "end": 1867, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 1868, "end": 1872, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 2288, "end": 2292, "text": "[21,", "ref_id": "BIBREF20"}, {"start": 2293, "end": 2297, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 2298, "end": 2302, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 2303, "end": 2307, "text": "[26]", "ref_id": "BIBREF25"}, {"start": 2308, "end": 2312, "text": "[27]", "ref_id": "BIBREF26"}, {"start": 2313, "end": 2317, "text": "[28]", "ref_id": "BIBREF27"}, {"start": 2430, "end": 2433, "text": "[8,", "ref_id": "BIBREF7"}, {"start": 2434, "end": 2438, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 2439, "end": 2443, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 2444, "end": 2448, "text": "[12]", "ref_id": "BIBREF11"}, {"start": 2449, "end": 2453, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 2454, "end": 2458, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 2459, "end": 2463, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 2464, "end": 2468, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 2681, "end": 2684, "text": "[4,", "ref_id": "BIBREF3"}, {"start": 2685, "end": 2689, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 2690, "end": 2694, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 2695, "end": 2699, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 2955, "end": 2959, "text": "[17,", "ref_id": "BIBREF16"}, {"start": 2960, "end": 2963, "text": "19]", "ref_id": "BIBREF18"}, {"start": 3026, "end": 3030, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 3328, "end": 3332, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 3333, "end": 3337, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 3338, "end": 3342, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 3758, "end": 3762, "text": "[21,", "ref_id": "BIBREF20"}, {"start": 3763, "end": 3767, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 3768, "end": 3772, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 3773, "end": 3777, "text": "[26]", "ref_id": "BIBREF25"}, {"start": 3778, "end": 3782, "text": "[27]", "ref_id": "BIBREF26"}, {"start": 3783, "end": 3787, "text": "[28]", "ref_id": "BIBREF27"}, {"start": 3807, "end": 3811, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 4268, "end": 4272, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 4292, "end": 4296, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 4753, "end": 4757, "text": "[21]", "ref_id": "BIBREF20"}], "ref_spans": [{"start": 1506, "end": 1514, "text": "Figure 1", "ref_id": "FIGREF2"}, {"start": 2975, "end": 2984, "text": "(Figure 1", "ref_id": "FIGREF2"}]}, {"section": "Introduction", "text": "The different hypotheses explaining the pre-systemic and/or systemic deacetylation of 3/15ADON are represented in Figure 2 . The different hypotheses explaining the pre-systemic and/or systemic deacetylation of 3/15ADON are represented in Figure 2 . (2) IEC may be able to absorb 3/15ADON and to convert them in DON intracellularly, resulting in only DON being released in the portal vein linking the gut to the liver. (3) Part or all of intestinally absorbed 3/15ADON may reach the liver through the portal vein and may be subjected to hepatic deacetylation before release into the hepatic veins and the systemic blood circulation. (4) Although highly unlikely based on experimental results, part or all of the intestinally absorbed 3/15ADON may reach intact the systemic blood and be converted into DON in the kidneys (or others tissues). None of these hypotheses exclude the others, and a mix of them is possible.", "cite_spans": [], "ref_spans": [{"start": 114, "end": 122, "text": "Figure 2", "ref_id": "FIGREF4"}, {"start": 239, "end": 247, "text": "Figure 2", "ref_id": "FIGREF4"}]}, {"section": "Introduction", "text": "The first hypothesis is that 3/15ADON may not be directly absorbed by intestinal epithelial cells (IEC) and require deacetylation by gut bacteria or by luminal intestinal enzymes prior to their The first hypothesis is that 3/15ADON may not be directly absorbed by intestinal epithelial cells (IEC) and require deacetylation by gut bacteria or by luminal intestinal enzymes prior to their absorption. This hypothesis seems highly unlikely since it is known that: (i) in monogastric animals (such as humans, rats and pigs) most of the absorption of DON (and 3/15ADON) occurs fast (less than an hour) at the level of the duodenum and jejunum, where only few bacteria are present; and (ii) in vitro experiments have shown that 3/15ADON could efficiently be absorbed by the IEC [8, 21, 25] . Thus, it seems more plausible that without the need of a luminal deacetylation, 3/15ADON are absorbed by the IEC. Absorbed 3/15ADON may be then deacetylated intracellularly by the IEC that possess intracellular carboxylesterase (i.e., CES2) [8, [29] [30] [31] potentially able to transform 3/15ADON in DON before its release into the blood. Alternatively, as suggested by the in vivo study conducted in pigs and chickens showing that i.v injection resulted in a fast and complete transformation of 3-and 15ADON into DON, deacetylation may take place in the liver and/or the kidneys [21] . In that case, part or all of the intestinally absorbed 3/15ADON may cross intact the intestinal wall and reach the liver where they may be deacetylated by the hepatic carboxylesterase (i.e., CES1) [8, [29] [30] [31] and/or the kidneys that, like the intestine, express a high level of CES2 [30, 31] .", "cite_spans": [{"start": 773, "end": 776, "text": "[8,", "ref_id": "BIBREF7"}, {"start": 777, "end": 780, "text": "21,", "ref_id": "BIBREF20"}, {"start": 781, "end": 784, "text": "25]", "ref_id": "BIBREF24"}, {"start": 1028, "end": 1031, "text": "[8,", "ref_id": "BIBREF7"}, {"start": 1032, "end": 1036, "text": "[29]", "ref_id": "BIBREF28"}, {"start": 1037, "end": 1041, "text": "[30]", "ref_id": "BIBREF29"}, {"start": 1369, "end": 1373, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 1573, "end": 1576, "text": "[8,", "ref_id": "BIBREF7"}, {"start": 1577, "end": 1581, "text": "[29]", "ref_id": "BIBREF28"}, {"start": 1582, "end": 1586, "text": "[30]", "ref_id": "BIBREF29"}, {"start": 1666, "end": 1670, "text": "[30,", "ref_id": "BIBREF29"}], "ref_spans": []}, {"section": "Introduction", "text": "Although not proved, the absence of 3-and 15ADON in human blood and urine suggests that humans, like pigs, are able to completely transform 3/15ADON into DON either through pre-systemic and/or systemic mechanisms [8] .", "cite_spans": [{"start": 213, "end": 216, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Introduction", "text": "To test this hypothesis, in the present work, we used in vitro and ex vivo approaches to evaluate the deacetylation activity of the different enzymes, bacteria and cells/tissues present in humans on the way from the food matrix to the systemic blood in order to estimate the role played by each of them in the transformation of 3/15ADON into DON. Our original model systems allowed us to identify the small intestinal and hepatic epithelium as the main sites of 3/15ADON deacetylation in humans.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Luminal Digestive Enzymes and Fecal Bacteria Possess Limited Activity on 3/15ADON", "text": "We first evaluated the capacity of secreted digestive enzymes present in the upper part of the intestinal tract to deacetylate 3/15ADON. Results showed that pepsin and pancreatic enzymes (pancreatin, trypsin, lipase) possessed very limited activity on 3-and 15ADON (around 10%-15% of deacetylation after 210-270 min incubation at 37\u02ddC) ( Figure 3 ). Increasing further the incubation time did not significantly improve the deacetylation, only 15%-20% of the initial concentration of 3/15ADON (100 \u00b5M) being hydrolyzed after 24 h of incubation at 37\u02ddC (data not shown). Similarly, fecal bacteria obtained from human donors displayed no activity on 15ADON and limited activity on 3ADON with only 22.6%\u02d815.9% of deacetylation after 6 h incubation ( Figure 4 ).", "cite_spans": [], "ref_spans": [{"start": 338, "end": 346, "text": "Figure 3", "ref_id": "FIGREF6"}, {"start": 746, "end": 754, "text": "Figure 4", "ref_id": "FIGREF8"}]}, {"section": "Luminal Digestive Enzymes and Fecal Bacteria Possess Limited Activity on 3/15ADON", "text": "As initially demonstrated by Sundst\u00f8l Eriksen and Pettersson [32] , 48 h incubation with human fecal bacteria resulted in a higher deacetylation, with 82.1%\u02d821.9% and 14.9%\u02d83.2% of deacetylation for 3ADON and 15ADON, respectively. Overall, the specific activity of 3ADON deacetylation by secreted digestive enzymes and fecal bacteria was comprised between 24 and 57 pmol\u00a8min\u00b41\u00a8mg\u00b41 based on 3ADON disappearance and between 20 and 37 pmol\u00a8min\u00b41\u00a8mg\u00b41 based on the appearance of DON. The intervals for 15ADON were 6-94 pmol\u00a8min\u00b41\u00a8mg\u00b41 and 14-99 pmol\u00a8min\u00b41\u00a8mg\u00b41 based on 15ADON disappearance and DON formation, respectively. ", "cite_spans": [{"start": 61, "end": 65, "text": "[32]", "ref_id": "BIBREF31"}], "ref_spans": []}, {"section": "Small Intestinal and Hepatic Human Cells Display Stronger Deacetylation Activity on 3/15ADON Than Colonic or Renal Cells", "text": "We then tested the deacetylation activity of human cell lines classically used to mimic the small intestine (Caco-2 cells), the colon (T84 cells), the liver (HepG2 cells) or the kidney (A498 cells). Results showed that Caco-2 and HepG2 cells were able to efficiently deacetylate 3ADON with 69.1% \u00b1 14.3% and 52.1% \u00b1 4.5% of 3ADON being deacetylated after 6 h incubation with Caco-2 and HepG2 cells, respectively ( Figure 5 ). Interestingly, the activity of these cells on 15ADON was much lower, only 22.4% \u00b1 5.5% and 16.8% \u00b1 2.4% of 15ADON being deacetylated after 6 h incubation with Caco-2 and HepG2 cells, respectively. T84 and A498 cells displayed very limited activity on 3-and 15ADON, with only 13%-16% and 0%-5% deacetylation after 6 h incubation with T84 and A498 cells, respectively.", "cite_spans": [], "ref_spans": [{"start": 414, "end": 422, "text": "Figure 5", "ref_id": "FIGREF10"}]}, {"section": "Small Intestinal and Hepatic Human Cells Display Stronger Deacetylation Activity on 3/15ADON Than Colonic or Renal Cells", "text": "Based on the disappearance of 3ADON, specific activities were found to be equal to 479, 902, 80 and 79 pmol\u2022min \u22121 \u2022mg \u22121 for Caco-2, HepG2, T84 and A498 cells, respectively. In the case of 15ADON, based on disappearance rates, specific activities were found to be equal to 152, 295, 98 and 0.4 pmol\u2022min \u22121 \u2022mg \u22121 for Caco-2, HepG2, T84 and A498 cells, respectively. Similar results were obtained if the specific activities were determined based on the appearance of DON. Thus, human small intestinal and hepatic cells were 6 to 11-times more active on 3ADON than colonic and renal cells. The difference between the cell lines was lower in the case of 15ADON, with small intestinal and hepatic cells being 1.5 to 3-times more active than colonic cells, while renal cells were virtually inactive on 15ADON. ", "cite_spans": [], "ref_spans": []}, {"section": "Small Intestinal and Hepatic Human Cells Display Stronger Deacetylation Activity on 3/15ADON Than Colonic or Renal Cells", "text": "We then tested the deacetylation activity of human cell lines classically used to mimic the small intestine (Caco-2 cells), the colon (T84 cells), the liver (HepG2 cells) or the kidney (A498 cells). Results showed that Caco-2 and HepG2 cells were able to efficiently deacetylate 3ADON with 69.1%\u02d814.3% and 52.1%\u02d84.5% of 3ADON being deacetylated after 6 h incubation with Caco-2 and HepG2 cells, respectively ( Figure 5 ). Interestingly, the activity of these cells on 15ADON was much lower, only 22.4%\u02d85.5% and 16.8%\u02d82.4% of 15ADON being deacetylated after 6 h incubation with Caco-2 and HepG2 cells, respectively. T84 and A498 cells displayed very limited activity on 3-and 15ADON, with only 13%-16% and 0%-5% deacetylation after 6 h incubation with T84 and A498 cells, respectively.", "cite_spans": [], "ref_spans": [{"start": 410, "end": 418, "text": "Figure 5", "ref_id": "FIGREF10"}]}, {"section": "Small Intestinal and Hepatic Human Cells Display Stronger Deacetylation Activity on 3/15ADON Than Colonic or Renal Cells", "text": "Based on the disappearance of 3ADON, specific activities were found to be equal to 479, 902, 80 and 79 pmol\u00a8min\u00b41\u00a8mg\u00b41 for Caco-2, HepG2, T84 and A498 cells, respectively. In the case of 15ADON, based on disappearance rates, specific activities were found to be equal to 152, 295, 98 and 0.4 pmol\u00a8min\u00b41\u00a8mg\u00b41 for Caco-2, HepG2, T84 and A498 cells, respectively. Similar results were obtained if the specific activities were determined based on the appearance of DON. Thus, human small intestinal and hepatic cells were 6 to 11-times more active on 3ADON than colonic and renal cells. The difference between the cell lines was lower in the case of 15ADON, with small intestinal and hepatic cells being 1.5 to 3-times more active than colonic cells, while renal cells were virtually inactive on 15ADON. In order to confirm the observations made with human cell lines, we tested the activity of human tissue explants obtained from human intestinal and hepatic resections. Regarding 3ADON, we found stronger activity of small intestinal and hepatic tissues compared to colonic one, with 67.3% \u00b1 13.8%, 54.6% \u00b1 15.4% and 4.2% \u00b1 3.1% of deacetylation after 6 h incubation with small intestinal, hepatic and colonic explants, respectively ( Figure 6 ). As observed with the human cell lines, deacetylation activity of the human tissues were lower on 15ADON, with 17.2% \u00b1 13.4%, 24.6% \u00b1 2.8% and 0.2% \u00b1 1.2% of deacetylation after 6 h incubation with small intestinal, hepatic and colonic In order to confirm the observations made with human cell lines, we tested the activity of human tissue explants obtained from human intestinal and hepatic resections. Regarding 3ADON, we found stronger activity of small intestinal and hepatic tissues compared to colonic one, with 67.3%\u02d813.8%, 54.6%\u02d815.4% and 4.2%\u02d83.1% of deacetylation after 6 h incubation with small intestinal, hepatic and colonic explants, respectively ( Figure 6 ). As observed with the human cell lines, deacetylation activity of the human tissues were lower on 15ADON, with 17.2%\u02d813.4%, 24.6%\u02d82.8% and 0.2%\u02d81.2% of deacetylation after 6 h incubation with small intestinal, hepatic and colonic explants, respectively.", "cite_spans": [], "ref_spans": [{"start": 1233, "end": 1241, "text": "Figure 6", "ref_id": "FIGREF12"}, {"start": 1907, "end": 1915, "text": "Figure 6", "ref_id": "FIGREF12"}]}, {"section": "Small Intestinal and Hepatic Human Cells Display Stronger Deacetylation Activity on 3/15ADON Than Colonic or Renal Cells", "text": "Based on the disappearance of 3ADON, specific activities of 714, 338 and 22.5 pmol\u00a8min\u00b41\u00a8mg\u00b41 were found for hepatic, small intestinal and colonic explants, respectively. For 15ADON deacetylation, specific activities were 330, 85 and 4.5 pmol\u00a8min\u00b41\u00a8mg\u00b41 for hepatic, small intestinal and colonic explants, respectively. explants, respectively. Based on the disappearance of 3ADON, specific activities of 714, 338 and 22.5 pmol\u2022min \u22121 \u2022mg \u22121 were found for hepatic, small intestinal and colonic explants, respectively. For 15ADON deacetylation, specific activities were 330, 85 and 4.5 pmol\u2022min \u22121 \u2022mg \u22121 for hepatic, small intestinal and colonic explants, respectively. ", "cite_spans": [], "ref_spans": []}, {"section": "The Deacetylation Activity Is Present in the S9 Fractions But Is Not Due to CES1 or CES2", "text": "Next, we evaluated the activity of commercial pooled S9 fractions obtained from human small intestine, liver and kidneys on 3-and 15ADON. Results found with S9 fractions corroborated data obtained with human cells and tissues ( Figure 7 ). Only small intestinal and liver S9 fractions had significant activity on 3/15ADON, whereas renal S9 fraction had minor activity, if any. ", "cite_spans": [], "ref_spans": [{"start": 228, "end": 236, "text": "Figure 7", "ref_id": "FIGREF14"}]}, {"section": "The Deacetylation Activity Is Present in the S9 Fractions But Is Not Due to CES1 or CES2", "text": "Next, we evaluated the activity of commercial pooled S9 fractions obtained from human small intestine, liver and kidneys on 3-and 15ADON. Results found with S9 fractions corroborated data obtained with human cells and tissues ( Figure 7 ). Only small intestinal and liver S9 fractions had significant activity on 3/15ADON, whereas renal S9 fraction had minor activity, if any. Then, we evaluated the involvement of CES in 3/15ADON deacetylation. We first tested the involvement of CES in 3/15ADON deacetylation using benzil, a pan inhibitor of CES [31] . We measured the deacetylation activity of S9 fractions and human cells in the presence of benzil (100 \u03bcM). Results showed that benzil had only limited inhibitory effect on the conversion of 3/15ADON into DON by S9 fractions, i.e., 8% to 24% inhibition (Table 1) . Once again, deacetylation activity of S9 fractions on 3ADON was largely higher than the activity on 15ADON with specific activities of 1250; 1791 and 33 pmol\u00a8min\u00b41\u00a8mg\u00b41 and 166; 208 and 16 pmol\u00a8min\u00b41\u00a8mg\u00b41 for intestinal, hepatic and renal S9 fractions on 3ADON and 15ADON, respectively.", "cite_spans": [], "ref_spans": [{"start": 228, "end": 236, "text": "Figure 7", "ref_id": "FIGREF14"}, {"start": 807, "end": 816, "text": "(Table 1)", "ref_id": "TABREF1"}]}, {"section": "The Deacetylation Activity Is Present in the S9 Fractions But Is Not Due to CES1 or CES2", "text": "Then, we evaluated the involvement of CES in 3/15ADON deacetylation. We first tested the involvement of CES in 3/15ADON deacetylation using benzil, a pan inhibitor of CES [31] . We measured the deacetylation activity of S9 fractions and human cells in the presence of benzil (100 \u00b5M). Results showed that benzil had only limited inhibitory effect on the conversion of 3/15ADON into DON by S9 fractions, i.e., 8% to 24% inhibition (Table 1) . Similarly, benzil (at 100 \u00b5M) caused a limited and none significant inhibition (i.e., 10%-20%) of the deacetylation of 3/15ADON by human cell lines (data not shown). To confirm that CES were actually inhibited by benzil, we monitored the activity of cells and S9 fractions on para-nitrophenyl acetate (pNPA), a chromogenic substrate of CES. Results showed that cell lines and S9 fractions were all able to efficiently cleave pNPA, confirming that high levels of CES were present even in the cells and S9 fractions with limited activity on 3/15ADON (i.e., A498 and T84 cells and renal S9 fraction) ( Table 2) . Importantly, benzil at 100 \u00b5M caused a dramatic inhibition of the deacetylation of pNPA ranging from 83% to 96% inhibition depending of the system tested confirming its ability to inhibit CES activity (Table 2 ). Finally, we tested the activity of commercial recombinant human CES1 and CES2 on 3/15ADON. Although recombinant CES1 and CES2 displayed strong benzil-sensitive activity on pNPA (Table 2) , we failed at observing any deacetylation activity of these enzymes on 3/15ADON, even after 24 h of incubation of 3/15ADON with 5 \u00b5g/mL of CES1/2 (data not shown).", "cite_spans": [], "ref_spans": [{"start": 430, "end": 439, "text": "(Table 1)", "ref_id": "TABREF1"}, {"start": 1041, "end": 1049, "text": "Table 2)", "ref_id": "TABREF3"}, {"start": 1253, "end": 1261, "text": "(Table 2", "ref_id": "TABREF3"}, {"start": 1442, "end": 1451, "text": "(Table 2)", "ref_id": "TABREF3"}]}, {"section": "Discussion", "text": "Numerous studies conducted in animals have shown that, although 3/15ADON are able to cross intact the gut wall, their ingestion does not lead to their presence into the systemic blood [21, [26] [27] [28] . Similarly, although humans are daily exposed to 3/15ADON through contaminated food, analysis of human blood and urine failed at detecting 3/15ADON [8] . These two observations suggest that, once ingested, 3/15ADON are subjected to pre-systemic and/or systemic deacetylation, the site(s) of such deacetylation remaining unknown until now. In the present study, using original models, we were able to identify precisely the organs responsible for the deacetylation of 3/15ADON in humans. Table 3 summarizes the specific deacetylation activities of enzymes, cells and tissues used in this study based either on the kinetics of 3/15ADN disappearance or DON appearance.", "cite_spans": [{"start": 184, "end": 188, "text": "[21,", "ref_id": "BIBREF20"}, {"start": 189, "end": 193, "text": "[26]", "ref_id": "BIBREF25"}, {"start": 194, "end": 198, "text": "[27]", "ref_id": "BIBREF26"}, {"start": 199, "end": 203, "text": "[28]", "ref_id": "BIBREF27"}, {"start": 353, "end": 356, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": [{"start": 692, "end": 699, "text": "Table 3", "ref_id": "TABREF4"}]}, {"section": "Discussion", "text": "Based on data of Table 3 , Figure 8 proposes an overview of the hydrolytic fate of 3/15-acetyl-deoxynivalenol in humans, with the contribution of each compartment considering that total 3/15-ADON deacetylation activity is the sum of specific activities of digestive enzymes, fecal bacteria, small intestinal, hepatic and colonic tissues. Table 3 , we were able to assess the respective implication of enzymes, cells and tissues, expressed as percentage of total activity, in the deacetylation of 3-and 15ADON in humans, the contribution of each compartment being calculated considering that total 3/15-ADON deacetylation activity is the sum of specific activities of digestive enzymes, fecal bacteria, small intestinal, hepatic and colonic tissues.", "cite_spans": [], "ref_spans": [{"start": 17, "end": 24, "text": "Table 3", "ref_id": "TABREF4"}, {"start": 27, "end": 35, "text": "Figure 8", "ref_id": "FIGREF16"}, {"start": 338, "end": 345, "text": "Table 3", "ref_id": "TABREF4"}]}, {"section": "Discussion", "text": "Our results showed that pepsin has 3% and 7% of total deacetylation capacity for 3-and 15ADON, respectively and that pancreatic enzymes display higher deacetylation activity with 10% and 26% of deacetylation of 3-and 15ADON, respectively. In accordance with previous publication Figure 8 . Overview of deacetylation of 3/15ADON in humans. Based on specific activities calculated in Table 3 , we were able to assess the respective implication of enzymes, cells and tissues, expressed as percentage of total activity, in the deacetylation of 3-and 15ADON in humans, the contribution of each compartment being calculated considering that total 3/15-ADON deacetylation activity is the sum of specific activities of digestive enzymes, fecal bacteria, small intestinal, hepatic and colonic tissues.", "cite_spans": [], "ref_spans": [{"start": 279, "end": 287, "text": "Figure 8", "ref_id": "FIGREF16"}, {"start": 382, "end": 389, "text": "Table 3", "ref_id": "TABREF4"}]}, {"section": "Discussion", "text": "Our results showed that pepsin has 3% and 7% of total deacetylation capacity for 3-and 15ADON, respectively and that pancreatic enzymes display higher deacetylation activity with 10% and 26% of deacetylation of 3-and 15ADON, respectively. In accordance with previous publication showing 78%\u02d830% deacetylation of 3ADON after 48 h incubation [32] , we confirmed that human fecal bacteria are able to deacetylate 3/15ADON. However, based on specific activity, this bacterial deacetylation is very limited and only accounts for 2.6% and 0.9% of total deacetylation of 3-and 15ADON, respectively. Taken together, our results show that the intestinal luminal events play a minor role in the deacetylation of 3/15ADON accounting for 16% and 34% of deacetylation of 3-and 15ADON, more than two thirds of 3/15ADON being able to enter/cross the intestinal epithelial cells.", "cite_spans": [{"start": 340, "end": 344, "text": "[32]", "ref_id": "BIBREF31"}], "ref_spans": []}, {"section": "Discussion", "text": "We find that once 3/15ADON are absorbed, the small intestine and the liver are the two major sites of 3/15ADON deacetylation, with 26% and 56% of 3ADON and 13% and 52% of 15ADON being hydrolyzed by small intestinal and hepatic tissues, respectively, colonic and renal cells playing limited roles in 3/15ADON deacetylation. Our demonstration of a strong deacetylation capacity of the liver compared to kidneys indicates that the hepatic conversion is responsible for the observed conversion of 3/15ADON into DON after i.v exposure of pigs and chickens [21] . Interestingly, although Caco-2 and T84 cells both originate from colonic adenocarcinoma, Caco-2 cells possess higher activity on 3/15ADON than T84 cells confirming, if needed, that Caco-2 cells are a valuable model of small intestinal epithelium.", "cite_spans": [{"start": 551, "end": 555, "text": "[21]", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Discussion", "text": "We observed that deacetylation of 3ADON is higher than the one of 15ADON in Caco-2, HepG2, intestinal, colonic and liver explants, and the corresponding S9 fractions, as well as in colonic bacteria and A498 cells. However, no such discrimination between 3ADON and 15ADON is observed with the digestive enzymes, T84 cells and renal S9 fraction. Interestingly, preferential deacetylation of 3ADON compared to 15ADON has also been reported in HepG2 by others [33] , in plant cells [34, 35] and in vivo with chickens since exposure to 15ADON, but not 3ADON, results in some acetylated form being detected into their blood [21] . At this stage, the reason of this selectivity remains unknown but could rely on an easier access and/or higher affinity of 3ADON compared to 15ADON for the catalytic site of the enzyme(s) responsible of their deacetylation.", "cite_spans": [{"start": 456, "end": 460, "text": "[33]", "ref_id": "BIBREF32"}, {"start": 478, "end": 482, "text": "[34,", "ref_id": "BIBREF33"}, {"start": 483, "end": 486, "text": "35]", "ref_id": "BIBREF34"}, {"start": 618, "end": 622, "text": "[21]", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Discussion", "text": "We tried to identify the enzyme(s) present in human intestinal and hepatic cells that are responsible for the deacetylation of 3/15ADON. Initially, based on the nature of the chemical modification, we thought that carboxylesterases may be responsible [8] . Surprisingly, our results clearly demonstrate that CES are not responsible for the deacetylation of 3/15ADON by human cells. First, although they possess strong CES activity as mentioned in the literature [29] [30] [31] and demonstrated with the chromogenic CES substrate para-nitrophenyl acetate (pNPA), human colonic and renal cell lines (T84 and A498 cells), human colonic explants and renal S9 fractions have no or low deacetylation activity on 3/15ADON. In addition, benzil (at 100 \u00b5M), a pan inhibitor of CES [31] , strongly inhibits CES activity on pNPA (85%-96% inhibition) but moderately inhibits 3/15ADON deacetylation (8%-24% inhibition). Finally, recombinant human CES1 and CES2 were unable to cause the deacetylation of 3/15ADON confirming that these CES are not involved. Although not tested, a role of other CES such as CES3 is highly unlikely since benzil is known to inhibit all type of CES and that CES3 is present not only in hepatic but also in colonic cells that weakly hydrolyze 3/15ADON according to our results [36] . Work is underway to identify the enzyme(s) present in small intestinal and hepatic epithelial cells responsible for 3/15ADON deacetylation. Once these enzyme(s) are identified, we will potentially be able to understand the biochemical reason(s) of the preferential deacetylation of 3ADON compared to 15ADON.", "cite_spans": [{"start": 251, "end": 254, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 462, "end": 466, "text": "[29]", "ref_id": "BIBREF28"}, {"start": 467, "end": 471, "text": "[30]", "ref_id": "BIBREF29"}, {"start": 1292, "end": 1296, "text": "[36]", "ref_id": "BIBREF35"}], "ref_spans": []}, {"section": "Discussion", "text": "In conclusion, we were able to precisely quantify the role played by the different enzymes, cells and organs in the deacetylation of 3-and 15ADON by humans and to identify the small intestinal and hepatic epithelium as major site of deacetylation of acetylated derivatives of DON. In addition to answer a specific question regarding the deacetylation of 3/15ADON in humans, this study demonstrates the high value of our original model system to evaluate and predict the fate of any contaminants present in human food.", "cite_spans": [], "ref_spans": []}, {"section": "Materials and Methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Materials", "text": "Human cell lines (A498, Caco-2, HepG2, and T84) were from ATCC (Molsheim, France). Culture medium, sterile PBS (Phosphate buffer saline) and culture supplements (antibiotics, serum, trypsin-EDTA solution) were from Thermo Fisher Scientific (Illkirch, France). Cell culture plastics were from Dominique Dutscher (Saint-Maximin-la-Sainte-Baume, France). DON, 3ADON and 15ADON were from Romer labs (Tulln, Austria). Pooled S9 fractions from human small intestine, liver and kidneys were from Xenotech (Kansas City, KS, USA). Recombinant human CES1 and CES2 were from R&D Systems (Minneapolis, MN, USA). All others reagents were from Sigma-Aldrich (Saint-Quentin Fallavier, France).", "cite_spans": [], "ref_spans": []}, {"section": "Cell Culture", "text": "A498, Caco-2, T84 and HepG2 cells were used as models of human renal, small intestinal, colonic and hepatic cells, respectively. Cells were routinely grown in culture media (Dulbecco's Modified Eagle Medium (DMEM), DMEM:F12 mixture and Minimum Essential Media (MEM) for A498/Caco-2, T84 and HepG2 cells, respectively) supplemented with 10% fetal calf serum and 1% antibiotics (streptomycin-penicillin solution). Cells were grown in 25 cm 2 ventilated flask maintained at 37\u02ddC in a 5% CO 2 incubator. Cells were routinely passed using trypsin-EDTA solution. For deacetylation experiments, cells were seeded onto 6-well plates at an initial density of 200,000 cells/cm 2 . HepG2 and A498 were used 3-4 days post-seeding when confluence was reached. Caco-2 and T84 cells were let to differentiate for 10-14 days post-seeding before being used. In all cases, cells were washed three times with sterile phosphate buffer saline PBS ++ (PBS containing 100 mg/L of calcium and magnesium salts) before deacetylation assay.", "cite_spans": [], "ref_spans": []}, {"section": "Preparation of Human Intestinal and Hepatic Explants", "text": "Human tissue samples were obtained from patients undergoing surgery at the Hospital Nord of Marseille, unit of general and gastrointestinal surgery according to a collaborative \"clinical transfer\" project. The procedures were approved by the French ethic committee (CODECOH n\u02ddDC-2011-1319). Patients were from both genders (six men, three women), 31-74 years of age, all of European origin. All patients agree to use their tissues for research purposes. Samples were taken from macroscopically unaffected area as identified by the surgeon for intestinal samples or the pathologist for liver resections. Diagnoses leading to surgery were carcinoma for intestine or liver. After resection, the specimens were placed in ice-cold non-sterile Krebs solution implemented and transferred to the school of medicine on the same campus within 5 min, composition of the Krebs solution being previously described [37] . The tissues were rinsed several times and maintained in oxygenated Krebs during 1 h for recovery before final dissection. Intestinal and hepatic resections were extensively washed and maintained in ice-cold culture media containing 1% streptomycin/penicillin solution and 50 \u00b5g/mL gentamycin. Tissues were cleaned from vascular vessels and conjunctive tissue using forceps under binocular microscope. In case of intestinal resection, muscularis and plexus were removed and only epithelial layer was kept. Intestinal and hepatic explants (wet weight of 20-30 mg) were then isolated from the cleaned resections using surgical punch (diameter of 0.5 cm 2 ). All these operations were achieved in less than 3 h after the resections were obtained from the surgery unit. Finally, the explants were washed 3 times with PBS ++ and transferred into 6-well plates before being used for deacetylation assay.", "cite_spans": [{"start": 901, "end": 905, "text": "[37]", "ref_id": "BIBREF36"}], "ref_spans": []}, {"section": "Preparation of Human Fecal Bacteria", "text": "The whole procedure involving fecal bacteria (including the use of fecal bacteria for the deacetylation assay) was performed in an anaerobic cabinet (Coy Laboratory Products, Grass Lake, MI, USA). Human fecal bacteria were isolated from three volunteers (men) working in the department, 40-50 years of age. Stools were collected fresh in a sterile container and were immediately introduced into the anaerobic cabinet. Feces samples were taken by pushing a cut-off disposal 1 mL pipette tip into the inner part of the stools. Samples were then mechanically suspended in 9 mL of degassed PBS ++ . Homogenates were allowed to decant for ten minutes to eliminate insoluble matter, and supernatants (1 mL aliquots) were transferred to sterile Eppendorf tubes and used for deacetylation assay.", "cite_spans": [], "ref_spans": []}, {"section": "Deacetylation Assay", "text": "Stock solutions of DON, 3ADON and 15ADON at 2 mg/mL were prepared in absolute ethanol and stored at\u00b420\u02ddC. For deacetylation assay, 3-or 15ADON were incubated with cells, explants, bacteria or digestive enzymes after being diluted in PBS ++ at a final concentration of 100 \u00b5M. PBS ++ solution containing only ethanol (at 1.5% final concentration) or DON (at 100 \u00b5M) were used in parallel as negative and positive control, respectively. For cells and explants, deacetylation assay take place in 6-well plates, wells being filled with 2 mL of PBS ++ containing either ethanol, DON, 3-or 15ADON. For fecal bacteria and digestive enzyme assay, deacetylation assay was conducted in 2 mL Eppendorf tubes filled with 1.5 mL of PBS ++ containing either ethanol, DON, 3-or 15ADON. In vitro intestinal digestion by luminal enzymes was performed using porcine enzymes from Sigma-Aldrich and physiological conditions [38] . Briefly, 3-or 15ADON were incubated with pepsin (at 1.6 mg/mL corresponding to 900 U/mL), trypsin (at 0.35 mg/mL corresponding to 6000 U/mL), pancreatic lipase (at 0.75 mg/mL corresponding to 18 U/mL) or pancreatin (at 1.23 mg/mL, lipase activity >10 U/mL, protease activity >100 U/mL, amylase activity >100 U/mL). Except for pepsin for which the digestion was conducted in HCl solution at 10 mM (pH 2.3), in vitro digestion was performed in PBS ++ (pH 7.4). Finally, deacetylation assay was also performed with commercial pooled S9 fractions from human liver, small intestine and kidneys as well as with pure recombinant human CES1 and CES2. S9 fractions and CES1/2 were used at 0.1 mg/mL and 5 \u00b5g/mL (corresponding to CES activity >20 U/mL), respectively. In all cases, aliquots of the reaction solution were collected immediately (i.e., \"time zero\" sample) or after the indicated time period at 37\u02ddC and analyzed by HPLC. In order to normalize the results obtained with the different cells, tissues and enzymes and to express the deacetylation activity as specific activity (pmol of 3/15ADON hydrolyzed (or pmol of DON formed) per min and per mg of protein), protein contents were measured using the Lowry's procedure [39] and bovine serum albumin as a reference as previously described [40, 41] . In all cases, the experiments were conducted in triplicate (n = 3).", "cite_spans": [{"start": 904, "end": 908, "text": "[38]", "ref_id": "BIBREF37"}, {"start": 2132, "end": 2136, "text": "[39]", "ref_id": "BIBREF38"}, {"start": 2201, "end": 2205, "text": "[40,", "ref_id": "BIBREF39"}, {"start": 2206, "end": 2209, "text": "41]", "ref_id": "BIBREF40"}], "ref_spans": []}, {"section": "HPLC Analysis", "text": "Deacetylation was monitoring both in term of disappearance of 3-or 15ADON and formation of DON. Measurement of DON, 3ADON and 15ADON concentrations was performed by reversed-phase HPLC using Waters Alliance System equipped with a Waters 2690 XE separation module and a Waters 996 photodiode array detector (Waters, Saint Quentin Falavier, France). The separation was achieved by mean of a LiChroCart column (125 mm\u02c64 mm) packed with 5 \u00b5m RP-18 Purospher gel (Merck, Darmstadt, Germany) and equipped with a LiChroCart precolumn (4 mm\u02c64 mm) packed with the same material (Merck). The precolumn and column were placed in room temperature. The elution procedure was carried out at 0.7 mL\u00a8min\u00b41 by a methanol-water solvent, using the following conditions: 40% methanol during 2 min followed by an increase in methanol to 50% at 2.1 min. The detection wavelength was set at 237 nm allowing the best signal/baseline ratio for simultaneous detection of the three DON forms in the incubation mediums. Under these conditions, DON and 3/15ADON were clearly separated, the retention time being around 2.7 min and 5.7 min, for DON and 3/15ADON, respectively ( Figure 9 ). Quantification was based on calibration with the corresponding standard using Millinium Software (Waters, Saint Quentin Falavier, France). ", "cite_spans": [], "ref_spans": [{"start": 1147, "end": 1155, "text": "Figure 9", "ref_id": "FIGREF17"}]}, {"section": "Measurement of Carboxylesterases (CES) Activity", "text": "Carboxylesterase activity was measured using the chromogenic substrate para-nitrophenyl acetate (pNPA). Briefly, cells, explants, S9 fractions or recombinant CES1/2 were incubated with 1 mM of pNPA diluted in PBS ++ at 37 \u00b0C. Color development due to the formation of para-nitrophenol (pNP) was recorded using optical density measurement at 405 nm over time. The amount of pNP formed was calculated using its extinction coefficient (18,000 M \u22121 \u2022cm \u22121 ). 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Nutr", "link": "29658229"}, "BIBREF37": {"title": "Interaction of curcumin with phosphocasein micelles processed or not by dynamic high-pressure", "authors": [{"first": "A", "middle": [], "last": "Benzaria", "suffix": ""}, {"first": "M", "middle": [], "last": "Maresca", "suffix": ""}, {"first": "N", "middle": [], "last": "Taieb", "suffix": ""}, {"first": "E", "middle": [], "last": "Dumay", "suffix": ""}], "year": 2013, "venue": "Food Chem", "link": "38014022"}, "BIBREF38": {"title": "Protein measurement with Folin phenol reagent", "authors": [{"first": "O", "middle": ["H"], "last": "Lowry", "suffix": ""}, {"first": "N", "middle": ["J"], "last": "Rosebrough", "suffix": ""}, {"first": "A", "middle": ["L"], "last": "Farr", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Randall", "suffix": ""}], "year": 1951, "venue": "J. Biol. 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Biomed. Sci", "link": "8536136"}}, "ref_entries": {"FIGREF0": {"text": "2016, 8, 232; doi:10.3390/toxins8080232", "type": "figure"}, "FIGREF2": {"text": "Figure 1. Chemical structure of DON (deoxynivalenol), 3ADON (3-acetyldeoxynivalenol) and 15ADON (15-acetyldeoxynivalenol). Green circles indicate the acetyl group on carbon 3 or 15 in 3-and 15ADON, respectively. Structures were drawn using ChemSpider 2D Image software.", "type": "figure"}, "FIGREF3": {"text": "Figure 1. Chemical structure of DON (deoxynivalenol), 3ADON (3-acetyldeoxynivalenol) and 15ADON (15-acetyldeoxynivalenol). Green circles indicate the acetyl group on carbon 3 or 15 in 3-and 15ADON, respectively. Structures were drawn using ChemSpider 2D Image software.", "type": "figure"}, "FIGREF4": {"text": "Figure 2. Current hypotheses regarding the deacetylation of ingested 3/15ADON. As described in the text, four hypotheses could explain animal results showing the absence of systemic 3/15ADON in case of oral exposure. (1) 3/15ADON may not be absorbed directly by intestinal epithelial cells (IEC), requiring their luminal transformation (by digestive enzymes and/or bacteria) prior to cross the intestinal wall. (2) IEC may be able to absorb 3/15ADON and to convert them in DON intracellularly, resulting in only DON being released in the portal vein linking the gut to the liver. (3) Part or all of intestinally absorbed 3/15ADON may reach the liver through the portal vein and may be subjected to hepatic deacetylation before release into the hepatic veins and the systemic blood circulation. (4) Although highly unlikely based on experimental results, part or all of the intestinally absorbed 3/15ADON may reach intact the systemic blood and be converted into DON in the kidneys (or others tissues). None of these hypotheses exclude the others, and a mix of them is possible.", "type": "figure"}, "FIGREF5": {"text": "Figure 2. Current hypotheses regarding the deacetylation of ingested 3/15ADON. As described in the text, four hypotheses could explain animal results showing the absence of systemic 3/15ADON in case of oral exposure. (1) 3/15ADON may not be absorbed directly by intestinal epithelial cells (IEC), requiring their luminal transformation (by digestive enzymes and/or bacteria) prior to cross the intestinal wall. (2) IEC may be able to absorb 3/15ADON and to convert them in DON intracellularly, resulting in only DON being released in the portal vein linking the gut to the liver. (3) Part or all of intestinally absorbed 3/15ADON may reach the liver through the portal vein and may be subjected to hepatic deacetylation before release into the hepatic veins and the systemic blood circulation. (4) Although highly unlikely based on experimental results, part or all of the intestinally absorbed 3/15ADON may reach intact the systemic blood and be converted into DON in the kidneys (or others tissues). None of these hypotheses exclude the others, and a mix of them is possible.", "type": "figure"}, "FIGREF6": {"text": "Figure 3. Luminal digestive enzymes possess minor activity on 3/15ADON. 3-or 15ADON (initially 100 \u03bcM) were incubated with pepsin, lipase, trypsin or pancreatin as explained in the Materials and Methods. Deacetylation of 3/15ADON and formation of DON were monitored using High Performance Liquid Chromatography (HPLC). Closed and open blue circles correspond to 3ADON disappearance and DON formation from 3ADON, respectively. Closed and open red squares correspond to 15ADON disappearance and DON formation from 15ADON, respectively (n = 3). Results are expressed as means \u00b1 S.D.", "type": "figure"}, "FIGREF7": {"text": "Figure 3. Luminal digestive enzymes possess minor activity on 3/15ADON. 3-or 15ADON (initially 100 \u00b5M) were incubated with pepsin, lipase, trypsin or pancreatin as explained in the Materials and Methods. Deacetylation of 3/15ADON and formation of DON were monitored using High Performance Liquid Chromatography (HPLC). Closed and open blue circles correspond to 3ADON disappearance and DON formation from 3ADON, respectively. Closed and open red squares correspond to 15ADON disappearance and DON formation from 15ADON, respectively (n = 3). Results are expressed as means\u02d8S.D.", "type": "figure"}, "FIGREF8": {"text": "Figure 4. Deacetylation of 3/15ADON by human fecal bacteria. 3-or 15ADON (initially 100 \u03bcM) were incubated with human fecal bacteria as explained in the Materials and Methods. Deacetylation of 3/15ADON and formation of DON were monitored using HPLC. The symbols are the same as in Figure 3 (n = 3). Results are expressed as means \u00b1 S.D.", "type": "figure"}, "FIGREF9": {"text": "Figure 4. Deacetylation of 3/15ADON by human fecal bacteria. 3-or 15ADON (initially 100 \u00b5M) were incubated with human fecal bacteria as explained in the Materials and Methods. Deacetylation of 3/15ADON and formation of DON were monitored using HPLC. The symbols are the same as in Figure 3 (n = 3). Results are expressed as means\u02d8S.D.", "type": "figure"}, "FIGREF10": {"text": "Figure 5. Deacetylation of 3/15ADON by human cell lines. 3-or 15ADON (initially 100 \u03bcM) were incubated with human cell lines as explained in the Materials and Methods. Deacetylation of 3/15ADON and formation of DON were monitored using HPLC. The symbols are the same as in Figure 3 (n = 3). Results are expressed as means \u00b1 S.D.", "type": "figure"}, "FIGREF11": {"text": "Figure 5. Deacetylation of 3/15ADON by human cell lines. 3-or 15ADON (initially 100 \u00b5M) were incubated with human cell lines as explained in the Materials and Methods. Deacetylation of 3/15ADON and formation of DON were monitored using HPLC. The symbols are the same as in Figure 3 (n = 3). Results are expressed as means\u02d8S.D.", "type": "figure"}, "FIGREF12": {"text": "Figure 6. Deacetylation of 3/15ADON by human explants. 3-or 15ADON (initially 100 \u03bcM) were incubated with human explants as explained in the Materials and Methods. Deacetylation of 3/15ADON and formation of DON were monitored using HPLC. The symbols are the same as in Figure 3 (n = 3). Results are expressed as means \u00b1 S.D.", "type": "figure"}, "FIGREF13": {"text": "Figure 6. Deacetylation of 3/15ADON by human explants. 3-or 15ADON (initially 100 \u00b5M) were incubated with human explants as explained in the Materials and Methods. Deacetylation of 3/15ADON and formation of DON were monitored using HPLC. The symbols are the same as in Figure 3 (n = 3). Results are expressed as means\u02d8S.D.", "type": "figure"}, "FIGREF14": {"text": "Figure 7. Deacetylation of 3/15ADON by human S9 fractions. 3-or 15ADON (initially 100 \u03bcM) were incubated with human S9 fractions as explained in the Materials and Methods. The symbols are the same as in Figure 3 (n = 3). Results are expressed as means \u00b1 S.D.", "type": "figure"}, "FIGREF15": {"text": "Figure 7. Deacetylation of 3/15ADON by human S9 fractions. 3-or 15ADON (initially 100 \u00b5M) were incubated with human S9 fractions as explained in the Materials and Methods. The symbols are the same as in Figure 3 (n = 3). Results are expressed as means\u02d8S.D.", "type": "figure"}, "FIGREF16": {"text": "Figure 8. Overview of deacetylation of 3/15ADON in humans. Based on specific activities calculated in Table 3, we were able to assess the respective implication of enzymes, cells and tissues, expressed as percentage of total activity, in the deacetylation of 3-and 15ADON in humans, the contribution of each compartment being calculated considering that total 3/15-ADON deacetylation activity is the sum of specific activities of digestive enzymes, fecal bacteria, small intestinal, hepatic and colonic tissues.", "type": "figure"}, "FIGREF17": {"text": "Figure 9. Example of HPLC analysis of the deacetylation of 3-and 15ADON. 3-or 15ADON (initially 100 \u03bcM) were incubated with HepG2 cells for 0, 1, 3 or 6 h. At the end of the incubation period, aliquots of media were analyzed using HPLC as explained in Materials and Methods. DON and 3/15ADON were clearly separated with retention times of 2.7 and 5.7 min, respectively.", "type": "figure"}, "TABREF1": {"text": "Effect of benzil (100 \u03bcM) on the deacetylation activity of S9 fraction on 3/15ADON. Specific activities were calculated from deacetylation kinetics and are expressed as pmol of 3/15ADON hydrolyzed (or DON formed) per minute and per mg of protein (n = 3). Results are expressed as means \u00b1 S.D.", "type": "table"}, "TABREF2": {"text": "Effect of benzil (100 \u00b5M) on the deacetylation activity of S9 fraction on 3/15ADON. Specific activities were calculated from deacetylation kinetics and are expressed as pmol of 3/15ADON hydrolyzed (or DON formed) per minute and per mg of protein (n = 3). Results are expressed as means\u02d8S.D.", "type": "table"}, "TABREF3": {"text": "Effect", "type": "table"}, "TABREF4": {"text": "Specific activity of digestive enzymes, fecal bacteria, cell lines, explants and S9 fractions on 3/15ADON. Specific activities were calculated from deacetylation kinetics and are expressed as pmol of 3/15ADON that disappeared (or pmol of DON formed) per minute and per mg of protein (n = 3). In the case of pepsin, the rate of formation of DON was not determined (ND) due to the presence of a contamination peak (present in the pepsin solution) at the retention time of DON. Results are expressed as means\u02d8S.D.contamination peak (present in the pepsin solution) at the retention time of DON. Results are expressed as means \u00b1 S.D.", "type": "table"}}}
{"paper_id": "10708991", "_pdf_hash": "79519d414394ee1164b4109736e8316ebab6ac56", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Draft report on an ACM SIGGRAPH Curriculum for Visualization", "authors": [{"first": "", "middle": [], "last": "Domik G", "suffix": ""}], "year": 2003, "venue": "", "link": null}, "BIBREF1": {"title": "Highly interactive web-based courseware", "authors": [{"first": "", "middle": [], "last": "Hanisch F", "suffix": ""}, {"first": "", "middle": [], "last": "Strasser W", "suffix": ""}], "year": 2002, "venue": "Proc. of CGE02 -Eurographics/SIGGRAPH Workshop on Computer Graphics Education", "link": null}, "BIBREF2": {"title": "Adaptability and interoperability in the field of highly interactive web-based courseware", "authors": [{"first": "", "middle": [], "last": "Hanisch F", "suffix": ""}, {"first": "", "middle": [], "last": "Strasser W", "suffix": ""}], "year": 2003, "venue": "Computer & Graphics", "link": "28317782"}, "BIBREF3": {"title": "OpenGL Programming Guide: The Official Guide to Learning OpenGL, Version 1.2, third ed", "authors": [{"first": "", "middle": [], "last": "Opengl Architecture Review", "suffix": ""}, {"first": "", "middle": [], "last": "Board", "suffix": ""}, {"first": "M", "middle": [], "last": "Woo", "suffix": ""}, {"first": "J", "middle": [], "last": "Neider", "suffix": ""}, {"first": "", "middle": [], "last": "Davis T", "suffix": ""}, {"first": "", "middle": [], "last": "Shreiner D", "suffix": ""}], "year": 1999, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "10709065", "_pdf_hash": "caa711a0d51f34c0338177de01250e74ea82cc91", "abstract": [], "body_text": [], "bib_entries": {"BIBREF1": {"title": "Estudio sobre evaluaci\u00f3n de la usabilidad m\u00f3vil y propuesta de un m\u00e9todo para tests de usabilidad cuantitativos basado en t\u00e9cnicas de eyetracking", "authors": [{"first": "Cuadrat", "middle": [], "last": "Seix", "suffix": ""}, {"first": "C", "middle": [], "last": "", "suffix": ""}], "year": 2012, "venue": "", "link": null}, "BIBREF2": {"title": "Usabilidad en aplicaciones m\u00f3viles", "authors": [{"first": "J", "middle": [], "last": "Enriquez", "suffix": ""}, {"first": "S", "middle": [], "last": "Casas", "suffix": ""}], "year": 2014, "venue": "Informes Cient\u00edficos-T\u00e9cnicos UNPA", "link": null}, "BIBREF3": {"title": "Aplicaci\u00f3n de criterios de usabilidad en sitios web: consejos y pautas para una correcta interpretaci\u00f3n", "authors": [{"first": "D", "middle": [], "last": "Maniega-Legarda", "suffix": ""}], "year": 2006, "venue": "Observatorio TIC: REBIUN Red de Bibliotecas Universitarias", "link": null}, "BIBREF4": {"title": "Calidad de software e ingenier\u00eda de usabilidad", "authors": [{"first": "M", "middle": ["A"], "last": "Mascheroni", "suffix": ""}, {"first": "C", "middle": ["L"], "last": "Greiner", "suffix": ""}, {"first": "R", "middle": ["H"], "last": "Petris", "suffix": ""}, {"first": "G", "middle": ["N"], "last": "Dapozo", "suffix": ""}, {"first": "", "middle": [], "last": "Estayno", "suffix": ""}], "year": 2012, "venue": "XIV Workshop de Investigadores en Ciencias de la Computaci\u00f3n", "link": null}, "BIBREF5": {"title": "Human factors for informatics usability", "authors": [{"first": "Brian", "middle": [], "last": "Shackel", "suffix": ""}, {"first": "Simon", "middle": ["J"], "last": "Richardson", "suffix": ""}], "year": "", "venue": "", "link": "60896808"}, "BIBREF6": {"title": "Ergonomic requirements for office work with visual display terminals (VDTs) --Part 11: Guidance on usability", "authors": [], "year": 1998, "venue": "", "link": null}, "BIBREF7": {"title": "10 Usability Heuristics for User Interface Design", "authors": [{"first": "J", "middle": [], "last": "Nielsen", "suffix": ""}], "year": 1995, "venue": "", "link": null}, "BIBREF8": {"title": "Systems and software engineering --Systems and software Quality Requirements and Evaluation (SQuaRE) --System and software quality models", "authors": [{"first": "", "middle": [], "last": "Iso/Iec", "suffix": ""}], "year": 2011, "venue": "", "link": null}, "BIBREF9": {"title": "Calidad de sistemas de informaci\u00f3n", "authors": [{"first": "M", "middle": [], "last": "Piattini", "suffix": ""}, {"first": "F", "middle": [], "last": "Garc\u00eda", "suffix": ""}, {"first": "I", "middle": [], "last": "Garc\u00eda", "suffix": ""}, {"first": "F", "middle": [], "last": "Pino", "suffix": ""}], "year": 2011, "venue": "", "link": null}, "BIBREF10": {"title": "Simplemente pregunta: Integraci\u00f3n de la accesibilidad en el dise\u00f1o", "authors": [{"first": "S", "middle": [], "last": "Henry", "suffix": ""}], "year": 2008, "venue": "", "link": null}, "BIBREF11": {"title": "Generacion de interfaces usables para dispositivos moviles", "authors": [{"first": "E", "middle": [], "last": "Castillo", "suffix": ""}], "year": 2005, "venue": "", "link": null}, "BIBREF12": {"title": "C\u00f3mo implementar un laboratorio de usabilidad de bajo coste", "authors": [{"first": "E", "middle": [], "last": "Parham", "suffix": ""}], "year": 2013, "venue": "", "link": null}, "BIBREF20": {"title": "Aplicaci\u00f3n e Importancia de las pruebas de usabilidad en los Estudios de Videojuegos y Materiales Audiovisuales", "authors": [{"first": "H", "middle": ["L"], "last": "Regueiferos", "suffix": ""}], "year": 2016, "venue": "", "link": null}, "BIBREF21": {"title": "La psicolog\u00eda de los objetos cotidianos", "authors": [{"first": "Donald", "middle": ["A"], "last": "Norman", "suffix": ""}], "year": 1998, "venue": "", "link": null}, "BIBREF22": {"title": "Dise\u00f1ando apps para m\u00f3viles", "authors": [{"first": "J", "middle": [], "last": "Cuello", "suffix": ""}, {"first": "J", "middle": [], "last": "Vittone", "suffix": ""}], "year": 2013, "venue": "", "link": null}, "BIBREF23": {"title": "Why You Only Need to Test with 5 Users\". (2000) Fig. 5. Tasks realization analysis by task", "authors": [{"first": "Jakob", "middle": [], "last": "Nielsen", "suffix": ""}], "year": "", "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "10709432", "_pdf_hash": "7947ec8dcd5009dfada063dbf08be96e07aa59be", "abstract": [], "body_text": [], "bib_entries": {"BIBREF1": {"title": "Elecro-and Magnetooptics of Liquid Crystals", "authors": [{"first": "L", "middle": ["M"], "last": "Blinov", "suffix": ""}], "year": 1978, "venue": "", "link": null}, "BIBREF2": {"title": "Liquid Crystals in Optoelectronics", "authors": [{"first": "V", "middle": ["A"], "last": "Tsvetkov", "suffix": ""}, {"first": "M", "middle": ["F"], "last": "Grebenkin", "suffix": ""}], "year": 1979, "venue": "In: Ed. S.I.Zhdanov, Liquid Crystals", "link": null}}, "ref_entries": {}}
{"paper_id": "10709630", "_pdf_hash": "17b9cd571f04b7ac2936583ecc382ae56767c126", "abstract": [{"section": "Abstract", "text": "The H i content of galaxies in the Eridanus group is studied using the GMRT observations and the HIPASS data. A significant H i deficiency up to a factor of 2 \u2212 3 is observed in galaxies in the high galaxy density regions. The H i deficiency in galaxies is observed to be directly correlated with the local projected galaxy density, and inversely correlated with the line-of-sight radial velocity. Furthermore, galaxies with larger optical diameters are predominantly in the lower galaxy density regions. It is suggested that the H i deficiency in Eridanus is due to tidal interactions. In some galaxies, evidences of tidal interactions are seen. An important implication is that significant evolution of galaxies can take place in the group environment. In the hierarchical way of formation of clusters via mergers of groups, a fraction of the observed H i deficiency in clusters could have originated in groups. The co-existence of S0's and severely H i deficient galaxies in the Eridanus group suggests that galaxy harassment is likely to be an effective mechanism for transforming spirals to S0's.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Spiral galaxies in the cores of clusters are known to be H i deficient compared to their field counterparts (Davies & Lewis 1973 , Giovanelli & Haynes 1985 , Cayatte et al. 1990 , Bravo-Alfaro et al. 2000 , Solanes et al. 2001 ). Several gas-removal mechanisms have been proposed to explain the H i deficiency in cluster galaxies. There are convincing results from both the simulations and the observations that ram-pressure stripping (cf. Gunn & Gott 1972) is effective in galaxies which have crossed the high intra cluster medium (ICM) density region near the core of the cluster (Vollmer et al. 2001 , van Gorkom 2003 . \"Galaxy harassment\" can also affect outer regions of the disk as a result of repetitive fast encounters of galaxies in clusters (Moore et al. 1998 ). There can be other scenarios where galaxies can become gas deficient, e.g., thermal evaporation and viscous stripping (Cowie & Songaila 1977 , Nulsen 1982 , Sarazin 1988 , and \"galaxy starvation\" where hot gas in the halos of galaxies is stripped. It is believed that halos contain a reservoir of hot gas, which sustains star formation in galaxies over their present ages (Larson et al. 1980) .", "cite_spans": [{"start": 603, "end": 620, "text": ", van Gorkom 2003", "ref_id": "BIBREF28"}, {"start": 928, "end": 942, "text": ", Sarazin 1988", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Introduction", "text": "Often one or more processes have been shown to be working in individual cases. There are no strong arguments for any of these processes to be globally effective in clusters. Cayatte et al (1990) showed that the H i deficiency in Virgo galaxies can be understood by a combination of ram-pressure stripping and transport processes. However, there are several inconsistencies. Magri et al. (1988) showed that no single gas-removal process can be justified consistently in any cluster. Further uncertainties arise since some of the parameters driving these mechanisms are not known well, e.g., thermal conductivity of the ICM, amount of hot gas in halos etc. It is also not clear that all severely H i deficient galaxies have crossed the core as required for rampressure to be effective. Contrary to what is expected from ram-pressure stripping, the low mass spirals and dwarfs are indistinguishable from the massive spirals in terms of H i deficiency (Hoffman et al. 1988 ). Valluri & Jog (1991) observed in Virgo and some other rich clusters that galaxies with medium to large optical sizes tend to be more severely H i deficient compared to smaller galaxies in terms of both the fractional number and the amount of gas lost. This behavior is contrary to that expected from ram-pressure stripping or transport processes, however, consistent with that expected if tidal interactions were responsible for the gas deficiency. The exact mechanism responsible for H i deficiency in clusters is still uncertain. These difficulties have led one to speculate that cluster galaxies were perhaps H i deficient even before they fell into the cluster. Such a speculation is motivated by the hierarchical theory of structure formation where clusters build up via mergers of small groups. Groups of galaxies therefore provide an opportunity to trace early evolution of galaxies.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Several clusters have been imaged in H i . However, only limited H i data exist for large groups. Previous studies on groups were mainly aimed at Hickson Compact Groups (HCG's), which usually have less than 10 galaxies packed in a small volume . For instance, Verdes-Montenegro et al. (2001) imaged several HCG's in H i and found a significant H i deficiency in the galaxies. To our knowledge, the only large group studied in H i is Ursa-Major, which is rich in spirals, and has a few S0's and no ellipticals. Verheijen (2001) showed that there is no H i deficiency in the Ursa-Major galaxies. The environment in the Ursa-Major group is similar to that in the field. The H i data for groups in which the environment is intermediate between field and cluster is lacking. Here, we present an H i study of the Eridanus group which appears to be an intermediate system between a loose group like Ursamajor and a cluster like Fornax or Virgo. The properties of the Eridanus group are described in detail in Omar & Dwarakanath (2004; hereafter paper-I) . The Eridanus group has a significant population of S0's (paper-I). The origin of S0's has been the subject of much debate. Usually the population of S0's is enhanced in clusters where galaxy density is high. There are two hypotheses for the formation of S0's, one is \"Nature\" where it is believed that S0's were formed as such, and the other is \"Nurture\" (evolution) according to which these galaxies are transformed spirals. The presence of enhanced population of S0's in the Eridanus group indicates that significant evolution of galaxies has perhaps already happened in the group. In the present study, H i content of galaxies in the Eridanus group is analysed. The aim is to identify the galaxy evolution processes in the group environment. Both the GMRT data and the HIPASS (HI Parkes All Sky Survey) data are used. The details of the GMRT observations, data reduction and analyses are presented in paper-I and Omar (2004) . Some new results based on follow-up VLA observations are also presented here.", "cite_spans": [{"start": 510, "end": 526, "text": "Verheijen (2001)", "ref_id": "BIBREF30"}], "ref_spans": []}, {"section": "The Eridanus group", "text": "The Eridanus group was identified as a moderate size cluster in a large scale filamentary structure near cz \u223c 1500 km s \u22121 in the Southern Sky Redshift Survey (SSRS; da Costa et al. 1988 ). This filamentary structure, which is the most prominent in the southern sky, extends for more than 20 Mpc. The Fornax cluster and the Dorado group of galaxies are also part of this structure. Eridanus has \u223c 200 galaxies distributed over \u223c 10 Mpc region. The properties of the group are described in detail in paper-I. The distance to the group is estimated as \u223c 23 \u00b1 2 Mpc. The group appears to be made of different sub-groups which have different morphological mix. One of the sub-group, NGC 1407 (cf. Willmer et al. 1989) , has a population mix of (E+S0's) and (Sp+Irr's) in the ratios of 70% & 30% respectively, which is quite similar to those found in clusters. The overall population mix in the Eridanus group is 30% (E+S0) & 70% (Sp +Irr). These sub-groups often have their brightest member as an elliptical or an S0. The brightest member in the entire group is a luminous (L B \u223c 4\u00d710 10 L \u2299 ) elliptical galaxy with diffuse X-ray emission (L \u00d7;0.1\u22122.0keV \u223c 2 \u00d7 10 41 erg s \u22121 ) surrounding it. Diffuse x-ray emission(L \u00d7;0.1\u22122.0keV \u223c 7 \u00d7 10 40 erg s \u22121 ) is also seen around another elliptical galaxy NGC 1395 which belongs to another sub- group. There is no appreciable difference in the velocities over which the early types and the late types are distributed. This is contrary to that seen in Virgo, Coma and several nearby Abell clusters where spirals have much flatter velocity distribution while E/S0's have nearly a Gaussian distribution in velocity (Binggeli et al. 1987 , Colless & Dunn 1996 , Biviano et al. 2002 3. The H i content A total of 57 galaxies in the Eridanus group were observed with the GMRT in the H i 21 cm-line. The details of the observations and the data analyses are described in paper-I. The H i detections were made for 31 galaxies. It was noticed that the H i flux densities of some large (dia. > 6 \u2032 ) galaxies were underestimated by the GMRT observations presumably due to inadequate sampling of the short (u, v) spacings. In the present study, the H i masses for such galaxies were replaced by those obtained from the HIPASS data (Meyer et al. 2004 ). In addition, HIPASS data were used for galaxies in the Eridanus region not observed by the GMRT. The final sample consisted of a total of 63 H i detected galaxies of different morphological types. The H i sample is described in Appendix-A.", "cite_spans": [], "ref_spans": []}, {"section": "The Eridanus group", "text": "The H i masses of galaxies in the field environment are observed to be correlated with their Hubble types and optical diameters D opt (e.g., Haynes & Giovanelli 1984 , hereaf ter HG84). The H i deficiency (cf. HG84) for a galaxy of a given type can be estimated by comparing log(M H i /D 2 opt ) of the galaxy with that observed for field galaxies. In the present study, the ratio log(M H i /D 2 opt ) for each Eridanus galaxy is compared with the mean value of the ratio log(M H i /D 2 opt ) obtained by HG84 for isolated galaxies of similar types. A significant positive difference between the two ratios indicates", "cite_spans": [], "ref_spans": []}, {"section": "The Eridanus group", "text": ". It should be noted that this deficiency parameter is distance independent. The optical diameters of galaxies used in HG84 were from the the Upsala General Catalog (UGC). The optical diameters of galaxies in the Eridanus group are from the Third Reference Catalog of Galaxies (RC3; de Vaucouleurs et al. 1991) . The optical diameters in RC3 are at 25 mag arc sec \u22122 in the Bband. To convert the RC3 diameters or D 25 to D opt consistent with the UGC diameters, the conversion relation obtained by Paturel et al. (1991) was used. This relation predicts that the D opt (UGC) is about 1.09 times the D 25 .", "cite_spans": [{"start": 286, "end": 310, "text": "Vaucouleurs et al. 1991)", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "The Eridanus group", "text": "A histogram of the H i deficiency for the Eridanus galaxies is plotted in Fig. 1 . The H i deficiency is independent of the morphological type of the galaxies. It can be seen that although the distribution peaks at zero deficiency, there are more galaxies with positive differences. Some H i rich galaxies (def. < \u22120.5) are also seen in Fig. 1 . These turn out to be interacting pairs, and hence the H i masses are likely to be overestimated. Figure 3. (Lower panel) All galaxies in the Eridanus group. The early type galaxies (E+S0) are marked as filled circles and late type galaxies (Sp+Irr) are marked as crosses. (Upper panel) Galaxies with H i deficiency greater than 0.3. It can be seen that severely H i deficient galaxies and early type galaxies are confined to the regions of higher galaxy densities. diameter 1.0 Mpc. It can be seen that in higher galaxy density (> 10 Mpc \u22122 ) regions, majority of galaxies are H i deficient while in the lower galaxy density regions both normal and deficient galaxies are present. Galaxies are H i deficient up to a factor of 2 \u2212 3 (\u223c 0.3 \u2212 0.5 in log units) in these plots. The correlation between the projected galaxy density and H i deficiency can also be seen in Fig. 3 where the locations of all identified group members (lower panel) and the locations of galaxies deficient by more than a factor of two are plotted (top panel). It is evident that severely H i deficient galaxies and the early type galaxies are confined to the regions of higher galaxy densities. The H i deficiency also shows a strong inverse correlation with the line-of-sight radial velocities (w.r.t. the systemic velocity of the group) of galaxies in the group (Fig. 4) . All of these information are used in the next section to identify the gas-removal mechanism active in the group.", "cite_spans": [], "ref_spans": [{"start": 74, "end": 80, "text": "Fig. 1", "ref_id": "FIGREF0"}, {"start": 337, "end": 343, "text": "Fig. 1", "ref_id": "FIGREF0"}, {"start": 1684, "end": 1692, "text": "(Fig. 4)", "ref_id": "FIGREF3"}]}, {"section": "The gas-removal processes", "text": "Several gas-removal mechanisms have been discussed in the literature to explain the H i deficiency in cluster galaxies. These mechanisms are rampressure stripping, transport processes (thermal conduction, and viscous and turbulent stripping), galaxy harassment (tidal interactions), and galaxy strangulation etc. All these mechanisms are expected to show some correlation of the H i deficiency with the properties of the cluster-environment and of the galaxies. For instance, ram-pressure stripping will be more effective for galaxies with higher radial velocities in the group. The trend observed in Fig. 4 is opposite to that expected if ram-pressure stripping were globally effective in the Eridanus group. It can be shown that for galaxies in the Eridanus group the ram-pressure is one to two orders of magnitude lower than that in the cores of clusters (Omar 2004) . This implies that ram-pressure stripping is of a little importance in the Eridanus group.", "cite_spans": [], "ref_spans": [{"start": 601, "end": 607, "text": "Fig. 4", "ref_id": "FIGREF3"}]}, {"section": "The gas-removal processes", "text": "The direct correlation of deficiency with the local projected galaxy density, and the inverse correlation with the line-of-sight radial velocity suggest that the H i deficiency in Eridanus galaxies is due to tidal interactions. Galaxies in higher galaxy density regions will have higher probability of tidal encounters. Therefore, a direct correlation of deficiency with the local projected galaxy density is expected. Further, the perturbation due to tidal interactions are expected to be maximum for slow encounters. In the Eridanus group where the velocity distribution of galaxies is peaked near the mean velocity of the group (paper-I) and falls off nearly as a Gaussian at higher relative velocities, galaxies having nearly zero radial velocities in the group will have a higher probability of interacting with a companion having a lower velocity difference. Therefore, the inverse correlation of H i deficiency with the line-of-sight radial velocity is qualitatively understood. The presence of a wider distribution of deficiency near the zero radial velocity is likely to be due to projection effects. Galaxies with higher radial velocities but moving nearly perpendicular to the line-of-sight will have almost zero line-of-sight radial velocities. Therefore, some discordant points are expected near zero velocity in Fig. 4 . Tidal forces will affect both the gas and the stars in galaxies. In contrast, ram-pressure affects only the gas. If the H i deficiency in the Eridanus group is indeed due to tidal interactions, some observational signatures of the same should be seen in both the stellar and the H i disks. The tidal interactions often produce gaseous and stellar tidal tails extending to large distances in the IGM. Some of the gas and the stars will be lost from the galaxy to the IGM in this process. It will be difficult to detect this low column density tidal debris in the IGM except for those associated with recent events where the column densities could still be detectable. However, repeated tidal encounters in the high galaxy density regions will shrink the optical sizes of galaxies. Fig. 5 indicates that the Eridanus galaxies with larger optical sizes are predominantly in the lower galaxy density regions. This trend is further indicative of the scenario of tidal interactions being effective in the Eridanus group.", "cite_spans": [], "ref_spans": [{"start": 1326, "end": 1332, "text": "Fig. 4", "ref_id": "FIGREF3"}, {"start": 2115, "end": 2121, "text": "Fig. 5", "ref_id": "FIGREF4"}]}, {"section": "The gas-removal processes", "text": "It is worthwhile to discuss an important effect while estimating H i deficiency using the M H i /D 2 opt parameter. Since both D opt and M H i are reduced as a result of tidal encounters, the H i gas loss inferred from this deficiency parameter will be a lower limit. In the absence of detailed sim- ulations of repetitive tidal encounters in a group environment, such effects are hard to quantify.", "cite_spans": [], "ref_spans": []}, {"section": "The morphological peculiarities of the Eridanus galaxies", "text": "Some galaxies in the Eridanus group show tidal tails and other peculiarities like H i extending out of the disk, H i warps, asymmetric H i disks, shrunken or fragmented H i disks, kinematical or H i lopsidedness etc. Tidal interactions can produce long tails of gas and stars, and deformations in the disks of galaxies. Some representative examples of these peculiarities are shown in Figs. 6 & 7, and are discussed below.", "cite_spans": [], "ref_spans": []}, {"section": "Shrunken H i disks", "text": "ESO 549-G 002 and NGC 1422 show shrunken H i disks. Both of these galaxies are H i deficient, and are in a region with a galaxy density \u223c 20 Mpc \u22122 . The H i deficiencies for ESO 549-G 002 and NGC 1422 are 0.67 and 0.44 respectively. ESO 549-G 002 has a faint stellar envelop in the outer region and has an irregular optical morphology in the inner region. NGC 1422 is an edge-on galaxy with a prominent dust lane. It has an H i morphology similar to that seen in ram-pressure stripped galaxies in clusters where gas from the outer regions is preferentially removed. As it has been argued that the ram-pressure is not much effective in the Eridanus group, it indicates Figure 6 . GMRT H i column density contours overlaid upon the optical DSS grayscale images of Eridanus galaxies which show peculiar H i morphologies (see Sect. 5 for details). The contours levels increase in units of N H i = 2X10 20 cm \u22122 . The first contour is at N H i = 10 20 cm \u22122 . Figure 7 . GMRT H i column density contours overlaid upon the optical DSS grayscale images of Eridanus galaxies which have clearly visible tidal tails in optical.", "cite_spans": [], "ref_spans": []}, {"section": "Shrunken H i disks", "text": "that highly shrunken H i disk in NGC 1422 is due to some other reasons. Moreover, no tidal features are seen either in optical or in H i . The origin of shrunken H i disk in NGC 1422 therefore remains elusive. Fig. 6 ) This extra-planar gas is seen in the form of wisps and small plumes of gas. It appears that this phenomena is often seen in the edge-on galaxies since the extra-planar gas will be easier to detect in these systems. It may be possible that other galaxies also have such features. The extra-planar gas might be quite common in galaxies. H i warps can be noticed in ESO 548-G 021 and NGC 1414.", "cite_spans": [], "ref_spans": []}, {"section": "Extra-planar gas & warps", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Some galaxies in the Eridanus group show H i extending out of the disk (see ESO 482-G 013, IC 1952, ESO 548-G 065, ESO 549-G 035 in", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Asymmetric H i disks", "text": "NGC 1309 and UGCA 068 have asymmetric H i disks. These two galaxies have normal H i content. One side of the galaxy appears more diffuse than the opposite side. These two galaxies also show kinematical asymmetries (Paper-I). NGC 1309 has a warp in the outer region. UGCA 068 shows asymmetry in the rotation curve. We speculate that such features could be due to retrograde tidal encounters. The retrograde encounter described by Toomre & Toomre (1972) does not pull out stars (the gas will respond in the same way) but can cause both morphological and kinematical asymmetries.", "cite_spans": [], "ref_spans": []}, {"section": "Peculiar H i disks", "text": "The H i disks of ESO 482-G 035 and NGC 1415 are seen to be very peculiar. Both are early type disk galaxies, and it is not common to see fully developed H i disks in such galaxies. It is likely that the detected H i is in a ring rather than being in a fully developed disk. NGC 1415 is an S0/a galaxy with a faint optical ring in the outer regions where most of the H i is seen in isolated clouds. The inclination of the ring is mis-aligned with the inner disk by more than 20 \u2022 . The H i disk of NGC 1390 is bent in an arc shape. Some diffuse nebulosity is visible toward the west of this galaxy.", "cite_spans": [], "ref_spans": []}, {"section": "Polar ring galaxy", "text": "ESO 548 -G 036 (S?) has the position angle of the H i disk inferred from H i kinematics almost normal to the position angle of the optical isophotes. The optical body resembles an S0 galaxy with a dust lane normal to the major axis of the main body. It is suggested that this is a polar ring galaxy. Polar rings are believed to be due to recent accretion of gas from tidal encounters. IC 1953, an H i rich galaxy at a projected separation of \u223c 50 kpc, is likely to be the companion.", "cite_spans": [], "ref_spans": []}, {"section": "Tidal tails", "text": "Either gaseous or stellar tidal features are seen in NGC 1359, NGC 1385, and NGC 1482 (Fig. 7) . The H i tidal tail and some isolated H i features in the vicinity can be seen in NGC 1359. Both NGC 1385 and NGC 1482 are farinfrared luminous galaxies, and undergoing intense star forming activities. NGC 1385 has highly asymmetric diffuse stellar envelop, however no gaseous tidal tail is seen. NGC 1482 (S0/a) appears to have an H i ring coincident with the dust ring seen in the optical image. The apparent central H i hole in NGC 1482 is due to H i absorption against the radio emission. Stellar tidal features can be seen in NGC 1482. Follow up VLA H i observations on these galaxies were carried out aimed at detecting any low column density tidal debris. The details are given in the next section.", "cite_spans": [], "ref_spans": []}, {"section": "Follow-up VLA observations", "text": "Although several peculiarities are seen in both the optical and the GMRT H i images of Eridanus galaxies, no tidal debris in H i were detected in the GMRT images. It is expected that tidal debris will have low column density gas which could have been missed in the GMRT images due to its limited sensitivity to the extended emission. Follow-up VLA observations were, therefore, carried out in its D-configuration which is most sensitive to the extended low column density emission. The observations were carried out on galaxies having one or more close neighbors or on galaxies which showed tidal features in optical. The details of the observations are given in Tab. 1. The observations were carried out in the D-north-C (DnC) hybrid configuration which gives a nearly symmetric synthesised beam for sources in the southern hemisphere. The data were analysed following the standard procedures using AIPS (Astronomical Image Processing System) developed by the National Radio Astronomy Observatory. The flux density scale is based on the standard VLA calibrator 0137+331. Observations were carried out in two polarizations. Fields 2 and 3 (cf. Tab. 1) were observed in the 4IF correlator mode at two different centre frequencies in the two IFs each of bandwidth 3.125 MHz with sufficient overlap so that the total usable bandwidth after stitching the two IFs was \u223c 5 MHz. Other fields were observed in the 2IF correlator mode with 3.125 MHz of bandwidth. The velocity resolution was \u223c 10.4 km s \u22121 for fields 2 and 3, and \u223c 5.2 km s \u22121 for the other fields. The H i emission was searched by eye in the channel images. The H i moment maps were constructed using the AIPS task MOMNT. Field 1 (NGC 1482; Fig. 8 ) and field 6 (NGC 1359; Fig. 9) show extended H i tails previously un- 5, 2, 3, 4, 6, 8, 12, 16, 24, 32 \u00d710 19 cm \u22122 . Faint stellar streamers can be seen around NGC 1482.", "cite_spans": [], "ref_spans": [{"start": 1701, "end": 1707, "text": "Fig. 8", "ref_id": "FIGREF6"}, {"start": 1733, "end": 1740, "text": "Fig. 9)", "ref_id": "FIGREF7"}]}, {"section": "Follow-up VLA observations", "text": "detected in the GMRT images. The H i images of other galaxies are almost identical to those obtained from the GMRT. Both NGC 1482 and NGC 1359 are in the sub-groups of which they are the brightest members. Both galaxies show tidal features in their optical images. It appears that NGC 1482 has interacted with NGC 1481. NGC 1359 has two nearest neighbors, but H i streamers do not connect them. It appears that NGC 1359 has undergone multiple interactions as there are two different H i streamers or tails, one toward the north-east and the other toward the west winding toward the south. An understanding of the H i morphologies in these galaxies requires detailed N-body simulations. Nevertheless, these H i detections indicate that tidal interactions are effective in the Eridanus group. 5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, 64, 96, 128 \u00d710 19 cm \u22122 . Stellar tidal tail can be seen in NGC 1359. The approximate directions of the velocity gradients in the two tidal features are marked.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Galaxies in the Eridanus group are H i deficient up to a factor of 2 \u2212 3 compared to their field counterparts. The direct correlation of the H i deficiency with the local galaxy density, and the inverse correlation of the H i deficiency with the line-of-sight radial velocities of galaxies suggest that the deficiency is due to tidal interactions. Since the H i deficiency of the Eridanus galaxies is observed in all types of galaxies, the correlation of the H i deficiency with the local galaxy density can not be just a manifestation of the densitymorphology relation. Although Eridanus appears as a loose group, it has significant sub-grouping. These sub-groups have regions of higher galaxy densities where H i deficient galaxies are seen. A Galaxy moving with a radial velocity of \u223c 240 km s \u22121 (velocity dispersion of the galaxies in the group) can cross a linear distance of \u223c 1 Mpc (typical extents of the sub-groups) in \u223c 5 Gyr (typical ages of the galaxies). The higher galaxy density and the relatively short crossing time in the sub-groups enhance the chances of encounters between the galaxies. Therefore, it appears that the sub-grouping is playing an important role in producing the H i deficiency. Further, the inverse correlation of deficiency with the radial velocity indicates that it is necessary for a galaxy to interact with another galaxy with smaller velocity difference to make the tidal encounters effective.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "The observed H i deficiency in a loose group like Eridanus has some interesting implications for the evolution of galaxies. Galaxies in clusters are known to be H i deficient up to a factor of 10. However, the reasons for such large deficiencies are not completely understood. If clusters form as mergers of groups as expected in a hierarchical Universe, a fraction of the H i deficiency seen in cluster galaxies might have originated in the group environment. In other words, clusters are built with galaxies, some of them are already H i deficient. This implication is particularly important for simulations which try to match the observed H i deficiency in cluster galaxies with what can be produced by ram-pressure stripping in the cluster environment (e.g., Vollmer et al. 2001) . Tidal interactions will become less effective in removing matter from galaxies in a cluster environment as encounters will be relatively fast. However, increased frequency of encounters in clusters due to higher galaxy density may actually affect the outer regions of galaxies as envisaged by the process of \"galaxy harassment\". Therefore, it is possible that tidal interactions play an important role in the evolution of galaxies in both the group and the cluster environments.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "The origin of S0's in high galaxy density regions is not understood. Whether S0's are due to some evolutionary processes driven by the environment (\"N urture\") or due to the result of natural processes of galaxy formation (\"N ature\") is being debated. Several co-workers (Poggianti et al. 1999 , Dressler et al. 1997 , Fasano et al. 2000 found in observations of clusters at intermediate redshifts (z \u223c 0.1 \u2212 0.3) that the fraction of S0's tends to grow at the expense of the spiral population as the redshift decreases. These observations support the \"N urture\" scenario. Several mechanisms have been proposed for the transformation of spirals into S0's, e.g., ram-pressure stripping, galaxy harassment, strangulation. The present observations in the Eridanus group indicate that both the severely H i deficient galaxies and the S0's are found in the higher galaxy density regions in the Eridanus group. It may be an indication that both the H i deficient and the S0 galaxies originated through similar processes. Since the ram-pressure is not playing any major role in the Eridanus group, the S0's in Eridanus are produced by some other process. Tidal interactions appear to be a favorable mechanism for transformation of spirals into S0's in the wake of the current understanding of the Eridanus group from this study.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "The H i deficiency observed in the Eridanus galaxies is consistent with the H i deficiency seen in other low velocity dispersion groups and clusters, viz., the Hickson Compact groups (Verdes-Montenegro et al. 2001 ) and the Fornax cluster (Schroder et al. 2001) . Mulchaey (2000) observed that groups of galaxies are filled with the metal-enriched intra-group medium with average metallicity \u223c 0.3. While other mechanisms can also enrich the intragroup medium with metals, gas lost from the galaxies via tidal interactions will have some contribution to the metal content of the intra-group medium. The environment in the Eridanus group is intermediate between that in a loose group like the Ursa-Major and a cluster like the Fornax or the Virgo (paper-I). The Ursa-Major has a few S0's and the H i contents of spirals are similar to the field spirals. However, the Eridanus group which has relatively large velocity dispersion, relatively large fraction of S0's, shows significant H i deficiency. Willmer et al. (1989) indicated that the Eridanus group is in its early phase of cluster formation. If all these results are combined, it appears that the Eridanus group is indeed in an initial phase of cluster formation where physical conditions in the group are favorable for driving the galaxy evolution.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "\u2022 The galaxies in the Eridanus group are H i deficient up to a factor of 2 \u2212 3. The H i deficiency is inversely correlated with the line-of-sight radial velocity, and directly correlated with the local projected galaxy density.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "\u2022 The H i deficiency in the Eridanus group is likely to be due to tidal interactions.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "\u2022 The optical diameters of galaxies are observed to be reduced in the high galaxy density regions indicating the effectiveness of tidal interactions in the Eridanus group.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "\u2022 If clusters are built via mergers of groups, a fraction of the H i deficiency in cluster galaxies might have been produced in the group environment.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "\u2022 The co-existence of S0's and H i deficient galaxies in the Eridanus group suggests that tidal interactions may be an effective mechanism for transforming spirals to S0's.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "\u2022 The environment in the Eridanus group is intermediate between the field and a cluster. Nevertheless, conditions are favorable for driving galaxy evolution in the Eridanus group. ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF8": {"title": "Third Reference Catalogue of Bright Galaxies", "authors": [{"first": "", "middle": [], "last": "De Vaucouleurs", "suffix": ""}], "year": 1991, "venue": "", "link": "123587344"}, "BIBREF23": {"title": "X-ray emission from clusters of galaxies", "authors": [{"first": "C", "middle": ["L"], "last": "Sarazin", "suffix": ""}], "year": 1988, "venue": "Cambridge Astrph. Series", "link": "14127056"}, "BIBREF28": {"title": "clusters of galaxies: Probes of cosmological structure and galaxy formation", "authors": [{"first": "J", "middle": ["H"], "last": "Van Gorkom", "suffix": ""}], "year": 2003, "venue": "", "link": null}, "BIBREF30": {"title": "gas and galaxy evolution", "authors": [{"first": "M", "middle": ["A"], "last": "Verheijen", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Hibbard", "suffix": ""}], "year": 2001, "venue": "", "link": "116963228"}, "BIBREF33": {"title": "The H i detected galaxies", "authors": [{"first": "A", "middle": [], "last": "Table", "suffix": ""}], "year": "", "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Figure 1. Histogram of the H i deficiency in the Eridanus galaxies.", "type": "figure"}, "FIGREF1": {"text": "Figure 2. H i deficiency vs the local projected galaxy density. The Spearman Rank-Order Correlation Coefficient test shows that the correlation is significant at > 99%.", "type": "figure"}, "FIGREF2": {"text": "shows the H i deficiency plotted against the local projected galaxy density. The projected galaxy density is estimated within a circular region of", "type": "figure"}, "FIGREF3": {"text": "Figure 4. H i deficiency is plotted against the line-of-sight radial velocities (w.r.t. the systemic velocity of the group) of galaxies in the group. The Spearman RankOrder Correlation Coefficient test shows that the correlation is significant at > 99.9% for velocities > 100 km s \u22121 .", "type": "figure"}, "FIGREF4": {"text": "Figure 5. The optical disk diameters plotted against the local projected galaxy density.", "type": "figure"}, "FIGREF5": {"text": "Notes -(a) The bandwidth of each IF was 3.125 MHz. (b) Fields 1, 4, 5 and 6 were observed in 2 IFs with 128 channels in each IF. Fields 2 and 3 were observed in 4 IFs with 64 channels in each IF. The total integration time was \u223c 3.2 hrs for the fields 1, 2, 3, and 4 and \u223c 1.6 for fields 5 and 6.", "type": "figure"}, "FIGREF6": {"text": "Figure 8. Contours of the VLA H i image of NGC 1482 overlaid upon the optical image from DSS. The contours are at N H i = 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32 \u00d710 19 cm \u22122 . Faint stellar streamers can be seen around NGC 1482.", "type": "figure"}, "FIGREF7": {"text": "Figure 9. Contours of the VLA H i image of NGC 1359 overlaid upon the optical image from DSS. The contours are at N H i = 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 32, 48, 64, 96, 128 \u00d710 19 cm \u22122 . Stellar tidal tail can be seen in NGC 1359. The approximate directions of the velocity gradients in the two tidal features are marked.", "type": "figure"}, "TABREF0": {"text": "VLA D-config. observations", "type": "table"}, "TABREF1": {"text": "The H i detected galaxies", "type": "table"}}}
{"paper_id": "10709656", "_pdf_hash": "3e85442e8d9521121bfce719477225b4a1a40247", "abstract": [], "body_text": [{"section": "", "text": "", "cite_spans": [], "ref_spans": []}], "bib_entries": {}, "ref_entries": {"TABREF0": {"text": "S. M. K., and JANES, J. M. (1965): Diffuse PigmentedA. G., and HORN, R. C., Jun. (1951): Giant Cell Tumors of Tendon Sheath Origin. A Consideration of Bone Involvement and Report of Two Cases with Extensive Bone Destruction. Annals of Surgery, 133,374.H. L., LICHTENSTEIN, L., and SUTRO, C. J. (1941): PigmentedLEWIS, R. W. (1947):Springfield, Illinois:Charles C.BoletIn y trahajos de Ia Sociedad argentina de ortopedIa y traumatologIa,", "type": "table"}}}
{"paper_id": "10709750", "_pdf_hash": "569483965c2364fc301d3c269941da02243cdb87", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "of analytical methods and the interpretation of results", "authors": [], "year": 2002, "venue": "Official J", "link": null}, "BIBREF1": {"title": "amending Decision 2002/657/EC as regards the setting of minimum required performance limits (MRPLs) for certain residues in food of animal origin", "authors": [], "year": 2003, "venue": "Official J", "link": null}, "BIBREF6": {"title": "Turnipseed", "authors": [{"first": "A", "middle": ["P"], "last": "Pfenning", "suffix": ""}, {"first": "J", "middle": ["E"], "last": "Roybal", "suffix": ""}, {"first": "H", "middle": ["S"], "last": "Rupp", "suffix": ""}, {"first": "S", "middle": ["B S A"], "last": "Gonzales", "suffix": ""}, {"first": "J", "middle": ["A"], "last": "Harlbut", "suffix": ""}], "year": 2000, "venue": "J. Assoc. Off. Anal. Chem. Int", "link": null}, "BIBREF7": {"title": "Annexure IV and 1430/94", "authors": [], "year": 1990, "venue": "European Community Regulations", "link": null}, "BIBREF8": {"title": "implementing Council Directive 96/23/EC concerning the Fig. 4. HPLC-MS-MS chromatograms of blank milk sample (a, b) and milk sample spiked with 40 ng/kg CAP", "authors": [], "year": 2002, "venue": "", "link": null}, "BIBREF21": {"title": "Optimizuotas efektyviosios skys\u010di\u0173 chromatografijos-dvigubos masi\u0173 spektrometrijos metodas chloramfenikoliui piene nustatyti. Chloramfenikolis i\u0161 pieno m\u0117gini\u0173 ekstrahuojamas etilo acetatu, ekstraktas i\u0161garinamas, skied\u017eiamas vandeniu, papildomai i\u0161valomas ekstrahuojant anglies tetrachlorido", "authors": [{"first": "Vytautas", "middle": [], "last": "Tamo\u0161i\u016bnas", "suffix": ""}, {"first": "Julijonas", "middle": [], "last": "Petraitis", "suffix": ""}, {"first": "Audrius", "middle": [], "last": "Padarauskas", "suffix": ""}, {"first": "Chloramfenikolio Nustatymas Piene Skys\u010di\u0173 Chromatografijos-Dvigubos Masi\u0173 Spektrometrijos", "middle": [], "last": "Metodu", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF22": {"title": "I\u0161matuotos pagrindin\u0117s analizin\u0117s charakteristikos: kalibracin\u0117 kreiv\u0117 yra tiesin\u0117 chloramfenikolio koncentracij\u0173 intervale 0.02-1.0 \u00b5g/kg; koreliacijos koeficientas -0,995; sprendimo riba -0,050 \u00b5g/kg; aptikimo geba -0,066 \u00b5g/kg. Vidutin\u0117s chloramfenikolio standartini\u0173 pried\u0173 (0,1-0,45 \u00b5g/kg) piene i\u0161gavos siekia 86-92%", "authors": [], "year": "", "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "188183918", "_pdf_hash": "69da58d0ca5f6a9869f7fe5ad702cb217121a2d9", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "188187490", "_pdf_hash": "facfad8d811b54d4c545c7b90b2877964e447fff", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
{"paper_id": "188189079", "_pdf_hash": "453153cd6944d425ebb8fb3992aa5396d75ab645", "abstract": [{"section": "Abstract", "text": "The objective of this research is to improve the students' learning outcomes and liveliness through the application of Mind Mapping model in learning web programming. The problems in this research are the existence of a class that still uses the conventional methods, and the value of the students' learning outcomes and liveliness is still under completeness. The research adopted a mixed research method, comprises pre-test/post-test and observation data collection. The data used in this research is through assessment test with cognitive aspects of the pre-test. While to assess the aspects of students' affective, psychomotor, and liveliness is using observation sheets. After the implementation of two cycles of study, the performance assessment indicated the increase in four aspects of learning namely cognitive, affective, psychomotor, and liveliness. The novelty of this research is the use of liveliness as the parameter of classroom action research. This contributes to the three conventional parameters of learning in Bloom Taxonomy.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION", "text": "Entering the global era, Indonesia must be able to compete with other countries, both in products, services and in the preparation of human resources. Vocational education as one of the sub-systems of national education is expected to prepare and develop human resources that can work professionally in the field, as well as competitive in the world of work [22] . The course of vocational education, however, faced the challenges related to the rapid changes in employment including the negative stigma of vocational graduates that inhibit the progress of training itself. The availability of facilities and infrastructure, the burden of study is growing, study time is dense, and other problems that demanded immediately addressed in the midst of this globalization. An alternative learning method, therefore, is needed that can help students in learning. According to Sujana [21] , teachers undertake the teaching methods tend to carry out the instruction conventionally. Such classroom condition drives the student to be passively attending the class. In contrast, teachers should be actively delivering instruction during the class hours.", "cite_spans": [{"start": 358, "end": 362, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 878, "end": 882, "text": "[21]", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "The Mind Map is a way of noting the creative, effective, and quite literally would be \"mapped\" human's thoughts [3] . Mind mapping methods can be used as a means of fitting to make learning methods because, with the methods, a student can take notes with full color. Researchers employ mind mapping learning model as it is appropriate for learning and widely used in various fields of research. Parikh [17] , for instance, revealed that mind mapping techniques are more effective than the traditional method. Mind mapping is conceived to have a better ability to memorize than regular way of text writing [14] . Moreover, Liu [15] advocates that Mind Mapping potentially promote teaching efficiency and improve students' ability of practical application. Students tend to cultivate a good habit of thought, aiming at the application of mind mapping in learning.", "cite_spans": [{"start": 112, "end": 115, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 402, "end": 406, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 605, "end": 609, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 626, "end": 630, "text": "[15]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "Despite Mind mapping has been applied in various fields of research, the application of Mind Mapping to increase students' performance and liveliness has not been adequately elaborated. Few if any, delved deeper on the benefits of Mind Mapping as suggested by Buzan [4] . This research contributes to knowledge and literature by investigating two aspects of Buzan's proposed benefits of implementing mind mapping namely the liberating rules, and fun and memorable learning.", "cite_spans": [], "ref_spans": []}, {"section": "LITERATURE REVIEW", "text": "Tony Buzan suggested the conception of Mind Mapping Method in the early 1970s. Tony Buzan in his book [4] . \"Smart Book Mind Map,\" advocated that Mind Mapping be a creative, effective, and way of mapping the human's thoughts. According to Caroline Edward [10] , Mind Mapping is the depicted as the most effective and efficient way to enter, store and extract data from or to the brain. This system works according to the natural workings of our brains, to optimize the overall potential and capacity of the human brain. A similar thought was suggested by Melvin L. Silberman [20] . He conceived that mind mapping is a creative way for students to record what they have learned, generate ideas, or a new task decision. By using this method, students are expected to understand the material first before recording in the form of Mind Mapping. Students can write and decorate by their creations. From some of the above sources can be interpreted by way of mind mapping is a recording technique that can map the creative and effective mind and unite the potential work of the brain either the right brain hemisphere or the left hemisphere in the person", "cite_spans": [{"start": 102, "end": 105, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 255, "end": 259, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 575, "end": 579, "text": "[20]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "LITERATURE REVIEW", "text": "The mind mapping can be applied to numerous area of practices, for example, in the design of health data management system [5] . Mind mapping is believed to improve the visualization of ideas for a better health data management system. Mind mapping also excels in conceptualizing constructivist learning in technical disciplines [18] . The practice of making collective mind maps using the initial word structure has a positive impact on the quality of learning among the community of learners. The application of mind mapping in a higher education indicated a significant improvement in the students' learning outcomes in comparison to students attending lecture class. Another example of the use of mind mapping in education is in the automotive electrical course [12] . A quasi-experimental study indicated that the mind mapping method is believed to be the driver for a higher performance of the students.", "cite_spans": [{"start": 123, "end": 126, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 329, "end": 333, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 766, "end": 770, "text": "[12]", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "LITERATURE REVIEW", "text": "Mind mapping benefits users in several ways. The first advantage is the direct value derived by teachers during learning processes [16] . Mind mapping allows student be conveniently capturing their thought as it is facilitating the development. It works well both collaboratively or during the individual learning [1] . Mind mapping is beneficial for creative processes such as writing [24] . Students participating in an open-ended questionnaire research responded that mind mapping helps them organize their ideas effectively. Topic comprehension and their writing were improved to the extent that they can be easily articulating ideas.", "cite_spans": [{"start": 131, "end": 135, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 314, "end": 317, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 386, "end": 390, "text": "[24]", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "RESEARCH METHODS", "text": "A mixed method research was conducted involved 35 high school students. The quantitative aspect of research employed a pre-test/post-test design of a web programming course. The qualitative technique of data collection, on the other hand, carried out by observing student's behavior during the course. Triangulation of data was exercised by the variety of data collection technique and the types of data collected from multiple sources. Quantitative information in the form of a cognitive test instrument validated its contents with the how to make a lattice and the validity of the test by the teacher. Data analysis technique used in this research is a qualitative and descriptive method to calculate its data using quantitative methods of evidence obtained in the form of test results.", "cite_spans": [], "ref_spans": []}, {"section": "RESEARCH METHODS", "text": "Research performance indicators are the success criteria or targets to be achieved by a given action. The performance of the research is indicated by the increase in the score and the liveliness of the learners by more than 70%. Learners learn thoroughly if the stated value of the results of the study of cognitive, affective, and psychomotor respectively has reached the Minimum Exhaustiveness Criteria (MEC). The MEC of the learning outcome of cognitive, psychomotor, affective domain and the liveliness of the classroom are 75. Each cycle consists of four stages of activity, i.e., planning, implementation, observation, and reflection. It complied with Dwitagama and Kusumah's [8] model of Classroom Action Research that was similar to Kemmis & Taggart's model. It comprises four components, namely: action plan (planning), action (acting), observation (observing), and reflection (reflecting). All four elements constitute one cycle of activities. According to Daryanto [6] , a class action research should be enumerated starting from planning, implementation of the measure, observation, and evaluation of analysis and reflection which encompasses the cycles the action. He argued that the number of cycles perform depend on the satisfaction of researchers, but should be more than one cycle and a minimum of two cycles of action. The cycle is depicted in Figure  1 . ", "cite_spans": [{"start": 682, "end": 685, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": [{"start": 1363, "end": 1372, "text": "Figure  1", "ref_id": "FIGREF0"}]}, {"section": "RESULTS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Evaluation of the Affective Outcome", "text": "A comparison of the average results of affective learners observation for each cycle can be seen in Table II . Table III depicted the percentage of cognitive learning outcomes that tend to increase in every cycle. In the percentage of completeness of the cognitive learning outcomes before the application of the method was 45.71%. While it was measured before the application of the Mind Mapping, the cognitive observation score was 70.08.", "cite_spans": [], "ref_spans": [{"start": 100, "end": 108, "text": "Table II", "ref_id": "TABREF0"}, {"start": 111, "end": 120, "text": "Table III", "ref_id": "TABREF0"}]}, {"section": "Evaluation of the Affective Outcome", "text": "After the application of the Mind Mapping learning model, the percentage of cognitive completeness learning outcomes, the learner experience increases over cycles as of 66.67% in the Cycle I to 85.71% in Cycle II. The average value inclined steeply by 7.11 points from cycle I to cycle II. It is indicated the significant improvement of the cognitive learning outcomes after the implementation of the Mind Mapping model. Table IV . ", "cite_spans": [], "ref_spans": [{"start": 421, "end": 429, "text": "Table IV", "ref_id": "TABREF0"}]}, {"section": "The Evaluation of Psychomotor Observation Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "A comparison of the average results of observation Psychomotor learners among cycles is depicted in", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "The Evaluation of Liveliness Observation Result", "text": "A comparison of the average the results of observation Liveliness learners in each cycle can be seen in Table V . Based on Table V , it can be seen that the percentage of learners' learning outcome the liveliness are always increasing in each cycle. The percentage of completeness learning outcomes the liveliness of the learners on the stage of Pre-cycle that is, before the application of the model of learning Mind Mapping is 37.14%, and the average results of observation before the application of the learning model the liveliness of Mind Mapping is 65.59.", "cite_spans": [], "ref_spans": [{"start": 104, "end": 111, "text": "Table V", "ref_id": "TABREF4"}, {"start": 123, "end": 130, "text": "Table V", "ref_id": "TABREF4"}]}, {"section": "The Evaluation of Liveliness Observation Result", "text": "After the application of the Mind Mapping learning model, the percentage of learners' liveliness learning outcome rose by 7.14% from cycle to cycle. So does the aggregate average value was increasing from 73.09 in Cycle I to 84.26 in Cycle II. It is evident that the application of Mind Mapping learning model improves the learner's psychomotor learning outcomes.", "cite_spans": [], "ref_spans": []}, {"section": "The Comparison of the Learning Completeness Between Cycles", "text": "Based on the data obtained from the research, a comparison of the percentage of each learning cycle's completeness of the cognitive, affective, psychomotor, and liveliness aspects of the learners are represented in Table VI. A completeness comparison of the percentage of each learning cycle in the realm of cognitive, affective, psychomotor, and liveliness of the learners are represented in diagrams of the stem as depicted in Figure 2 . ", "cite_spans": [], "ref_spans": [{"start": 215, "end": 224, "text": "Table VI.", "ref_id": "TABREF0"}, {"start": 429, "end": 437, "text": "Figure 2", "ref_id": "FIGREF1"}]}, {"section": "DISCUSSION", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Conditions of Prior Learning Mind Mapping", "text": "The analysis of data indicated that student's the liveliness was relatively low at 37.14%. Specific to the Minimum Exhaustive Completeness score, only 54.29% of students did not meet the criteria of 75 score. Prior to the implementation of Mind Mapping method, lecture was the main instruction applied in Web Programming class. Students were not encouraged to be actively asking questions, discuss, and collaborate, as well as exploring new concept or knowledge. Learners tend to become the object during course delivery. They have to listen and become the recipient of the instructions. As it is in a learning phase [9] , teachers should prepare for the appropriate learning technique during the learning phase.", "cite_spans": [{"start": 617, "end": 620, "text": "[9]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Conditions of Prior Learning Mind Mapping", "text": "Having said the description, the Web Programming course providers are supposed to alter the learning method offered in the class. Mind mapping model was expected for the nature of students' involvement during the learning. The application of the model is expected to improve the results of the study and the liveliness of the learners in the learning in the classroom.", "cite_spans": [], "ref_spans": []}, {"section": "Post-Implementation Condition", "text": "After a given learning Mind Mapping method next learners are given pre-test to find out the capabilities of the end learners. From post-test, obtained the average value After applying the learning Mind mapping method, students are invited to understand the matter by noting the use of colored ballpoint pen. It is in line with [2] that states that the mind map is a simple way to explore information from inside and outside the student's brain. The teacher together with students is digging material from experiments, discussions, book sources, and delivery of the teachers themselves.", "cite_spans": [{"start": 327, "end": 330, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Post-Implementation Condition", "text": "All material obtained through such activities and then poured in the student's Mind Mapping. Students are provided with a white paper Folio plain and wide range of colored ballpoint pen. As a result, the white paper students filled with scribbles and drawings from the material presented. The interesting thing is the result of Mind Mapping different students with one another. Mind Mapping results in the form of colors, lines, images, is the interpretation of the results of the work of the students in the shape of the right brain of the imagination, colors, and dimensions [3] . This shows that students can make their mind maps based on materials they received from various sources.", "cite_spans": [{"start": 577, "end": 580, "text": "[3]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Post-Implementation Condition", "text": "On cycle I students implement the learning done by teachers in methods of Mind Mapping. Learners engage in activities with teachers asking, but only certain students and not all learners engage actively. Other students attend dutifully in early learning activities. In the next minute, students began a rowdy and chatted with other students. This can be caused because students are not involved actively in the learning activities. Sagala [19] , noted that the learning experience is an activity, the students noted herself meaningful patterns from the new knowledge, and not just given by the teacher.", "cite_spans": [{"start": 439, "end": 443, "text": "[19]", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Post-Implementation Condition", "text": "The completeness percentage results of a study on cycle II, good learning results of completeness the realm of affective, psychomotor, cognitive, or may have already reached \u2265 70%. So that, the performance indicators (success) research already achieved. Based on the results of observation and cognitive tests on stage Pre-cycle, cycles I and II cycles, then it can be concluded that the application of the model of efficiency of mapping the Mind learning on subjects Web programming can enhance the learning outcome of students of class X RPL C SMK Negeri 2 Karanganyar.", "cite_spans": [], "ref_spans": []}, {"section": "Influences the application of Mind Mapping against Learning Outcomes and Students' liveliness", "text": "This research aims to know the effect of Mind Mapping against learning results and the liveliness of the students. The initial conditions are relatively low because the learners receive regular learning research done before, namely teachers delivering informatively without involving the role of students to delve information deeper. Hamalik [11] argued that the regular learning activities focusing on the intellectual development through learning memories about things that have been read and the tasks have been carried out by the teacher.", "cite_spans": [{"start": 342, "end": 346, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Influences the application of Mind Mapping against Learning Outcomes and Students' liveliness", "text": "Make Mind Mapping lets students use their abilities to think they made a map of the material obtained from various sources such as books, experiment, experience, and material from the teacher. According to Jensen Mind Mapping is the perfect method to illustrate the theme of learning to the students [13] . Mind Mapping can also be interpreted as a way to make the record that is not boring to use words, lines, and color images. Apply Mind Mapping is more fun because students get creative with pictures, lines, colors and all that is on their mind. Through the activities make Mind Mapping, the role of students are also involved in digging up information subject matter.", "cite_spans": [{"start": 300, "end": 304, "text": "[13]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Influences the application of Mind Mapping against Learning Outcomes and Students' liveliness", "text": "Learning by applying methods of Mind Mapping is more influential significantly to cognitive learning results than lecturing method and accounting learning faqs. Mind mapping was introduced as a culturally relevant pedagogy aims to improve the experience of teaching and learning in general education, environmental science class for most Language learners Emirates United Kingdom (ELL) [23] .", "cite_spans": [{"start": 386, "end": 390, "text": "[23]", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "Influences the application of Mind Mapping against Learning Outcomes and Students' liveliness", "text": "Mind Mapping results of students on average are in the categories above the value of the MEC compared records always, Mind Mapping has more appeal because of the mix of colors, lines; images make the students learn as in the atmosphere of the play. Relevant to De Porter and Hernacki's opinion that that mind mapping is fun because it combines the creativity and imagination of students are not limited to, more fun when compared to make notes [7] .", "cite_spans": [{"start": 444, "end": 447, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "CONCLUSIONS", "text": "Based on the results of the research action class that is implemented, then the conclusions that can be drawn using the learning mind mapping methods can improve the results of the study and liveliness of the students. Increasing student learning outcomes and the Liveliness can be proven with increasing the value of the average students in the learning process with mind mapping methods, namely: the average value of affective aspects of 42.86%, increases cognitive aspects of increased 37.14%, increase in psychomotor aspect 37.15%, aspects of liveliness on increased 51.43%. 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(Alih bahasa: Narulita Yusron). yogyakarta: Pustaka Pelajar", "authors": [{"first": "E", "middle": [], "last": "Jensen", "suffix": ""}], "year": 2008, "venue": "", "link": null}, "BIBREF13": {"title": "Effectiveness of Mind Mapping Technique in Information Retrieval Among Medical College Students in Puducherry-A Pilot Study", "authors": [{"first": "M", "middle": [], "last": "Kalyanasundaram", "suffix": ""}, {"first": "S", "middle": ["B"], "last": "Abraham", "suffix": ""}, {"first": "D", "middle": [], "last": "Ramachandran", "suffix": ""}, {"first": "V", "middle": [], "last": "Jayaseelan", "suffix": ""}, {"first": "J", "middle": [], "last": "Bazroy", "suffix": ""}, {"first": "Z", "middle": [], "last": "Singh", "suffix": ""}, {"first": "A", "middle": ["J"], "last": "Purty", "suffix": ""}], "year": 2017, "venue": "Indian Journal of Community Medicine : Official Publication of Indian Association of Preventive & Social Medicine", "link": "13259697"}, "BIBREF14": {"title": "Application of Mind Mapping Method in College English Vocabulary Teaching", "authors": [{"first": "G", "middle": [], "last": "Liu", "suffix": ""}], "year": 2016, "venue": "", "link": "59584036"}, "BIBREF15": {"title": "Penggunaan Mind Map sebagai Instrumen Penilaian Hasil Belajar Siswa pada Pembelajaran Konsep Sistem Reproduksi di SMPN 1 Anyar", "authors": [{"first": "F", "middle": [], "last": "Noviyanti", "suffix": ""}], "year": 2007, "venue": "", "link": null}, "BIBREF16": {"title": "Effectiveness of Teaching through Mind Mapping Technique", "authors": [{"first": "N", "middle": ["D"], "last": "Parikh", "suffix": ""}], "year": 2016, "venue": "The International Journal of Indian Psychology", "link": null}, "BIBREF17": {"title": "Using Mind maps for the Measurement and Improvement of Learning Quality", "authors": [{"first": "C", "middle": [], "last": "Radix", "suffix": ""}, {"first": "A", "middle": [], "last": "Abdool", "suffix": ""}], "year": 2013, "venue": "Caribbean Teaching Scholar", "link": "60534761"}, "BIBREF18": {"title": "Kemampuan Profesional Guru dan Tenaga Kependidikan", "authors": [{"first": "S", "middle": [], "last": "Sagala", "suffix": ""}], "year": 2010, "venue": "", "link": null}, "BIBREF19": {"title": "Active Learning: 101 Cara Belajar Siswa Aktif", "authors": [{"first": "M", "middle": ["L"], "last": "Silberman", "suffix": ""}], "year": 2013, "venue": "", "link": null}, "BIBREF20": {"title": "Penilaian Hasil Proses Belajar Mengajar. Bandung: PT Remaja Rosdakarya", "authors": [{"first": "N", "middle": [], "last": "Sujana", "suffix": ""}], "year": 2009, "venue": "", "link": null}, "BIBREF21": {"title": "Permasalahan dan alternatif kebijakan peningkatan relevansi pendidikan", "authors": [{"first": "A", "middle": [], "last": "Suryadi", "suffix": ""}], "year": 2010, "venue": "", "link": null}, "BIBREF22": {"title": "A Preliminary study on the use of Mind Mapping as a Visual-Learning Strategy, in General Education Science classes for Arabic speakers in the United Arab Emirates", "authors": [{"first": "K", "middle": [], "last": "Wilson", "suffix": ""}, {"first": "E", "middle": [], "last": "Copeland Solas", "suffix": ""}, {"first": "N", "middle": [], "last": "Guthrie-Dixon", "suffix": ""}], "year": 2016, "venue": "Journal of the Scholarship of Teaching and Learning", "link": "52906542"}, "BIBREF23": {"title": "The Use of Mind Mapping Strategy in Malaysian University English Test ( MUET ) Writing", "authors": [{"first": "M", "middle": [], "last": "Yunus", "suffix": ""}, {"first": "C", "middle": ["H"], "last": "Chien", "suffix": ""}], "year": 2016, "venue": "", "link": "45284502"}}, "ref_entries": {"FIGREF0": {"text": "Figure 1. Classroom Action Research Procedures (derived from Dwitagama and Kusumah [8])", "type": "figure"}, "FIGREF1": {"text": "Figure 2 The Proportion of Learning Completeness of Each Cycle.", "type": "figure"}, "FIGREF2": {"text": "Figure 2 indicates the dynamic of each learning aspects over cycles. According to data analysis, the increase of liveliness achievement is of the highest value. It increases by 22.86% in Cycle 1 and from 65.71% to 88.57% in Cycle 1 and Cycle 2 respectively. Therefore, in this research liveliness is the best predictor for the impact of Mind Mapping learning model in web programming course.", "type": "figure"}, "FIGREF3": {"text": "aspects of 66.67% in cycle I and cycled II 82.85%. Post-test results indicate the completeness value obtained has been increased.", "type": "figure"}, "TABREF0": {"text": "", "type": "table"}, "TABREF1": {"text": "THE EVALUATION OF AFFECTIVE OBSERVATION OUTCOME No.Table II indicated the proportion of affective learning outcomes that tend to increase in every cycle. The percentage of completeness of the affective learning outcomes during the pre-cycle was 42.86%. While tt was measured before the application of Mind Mapping, the average value was 66.43. After the application of the Mind Mapping learning model, the percentage of affective completeness learning outcomes, learner experience increases over cycles as of 65.71% in the Cycle I to 85.71% in Cycle II. The average value rose by 3.13 points from cycle I to cycle II. It is concluded that the application of Mind Mapping model improves learners' affective learning outcomes.", "type": "table"}, "TABREF2": {"text": "THE EVALUATION OF PSYCHOMOTOR OBSERVATION RESULTS. No. The Achievement of Psychomotor Learning", "type": "table"}, "TABREF3": {"text": "depicts the result of psychomotor learning outcomes that tend to increase in every cycle. The completeness of the psychomotor learning outcomes prior to the application of Mind Mapping was 51.42%. While the average value of the psychomotor was 73.74 After the application of the Mind Mapping learning model, the psychomotor learning outcome rose by 20% from cycle to cycle. So does the aggregate average value was increasing from 73.88 in Cycle I to 79.18 in Cycles II. It is evident that the application of Mind Mapping learning model improves the learner's psychomotor learning outcomes.", "type": "table"}, "TABREF4": {"text": "THE EVALUATION OF LIVELINESS OBSERVATION RESULT No. The Achievement of The Learning Results of Liveliness Pre-cycle", "type": "table"}, "TABREF5": {"text": "THE COMPARISON OF LEARNING COMPLETENESS ACROSS CYCLES", "type": "table"}}}
{"paper_id": "17430138", "_pdf_hash": "1b02a853d81fba2e907623d5aaa906051d8c8ad7", "abstract": [{"section": "Abstract", "text": "Polycyclic aromatic hydrocarbons (PAHs) are of global environmental concern because they cause many health problems including cancer and inflammation of tissue in humans. Plants are important in removing PAHs from the atmosphere; yet, information on the physiology, cell and molecular biology, and biochemistry of PAH stress responses in plants is lacking. The PAH stress response was studied in Arabidopsis (Arabidopsis thaliana) exposed to the three-ring aromatic compound, phenanthrene. Morphological symptoms of PAH stress were growth reduction of the root and shoot, deformed trichomes, reduced root hairs, chlorosis, late flowering, and the appearance of white spots, which later developed into necrotic lesions. At the tissue and cellular levels, plants experienced oxidative stress. This was indicated by localized H 2 O 2 production and cell death, which were detected using 3, 39-diaminobenzidine and trypan blue staining, respectively. Gas chromatography-mass spectrometry and fluorescence spectrometry analyses showed that phenanthrene is internalized by the plant. Gene expression of the cell wall-loosening protein expansin was repressed, whereas gene expression of the pathogenesis related protein PR1 was induced in response to PAH exposure. These findings show that (i) Arabidopsis takes up phenanthrene, suggesting possible degradation in plants, (ii) a PAH response in plants and animals may share similar stress mechanisms, since in animal cells detoxification of PAHs also results in oxidative stress, and (iii) plant specific defence mechanisms contribute to PAH stress response in Arabidopsis.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "With increasing environmental pollution and anthropological disturbances to ecosystems, the study of abiotic stress responses in plants has become ever more important in agriculture, forest management, and ecosystem restoration strategies. Ozone, for instance, has been shown to compromise forest and crop species leading to reduced yields (Preston and Tingey, 1988; Heagle, 1989; Pell et al., 1997) , whereas organic pollutants accumulate in vegetation (Simonich and Hites, 1994; reviewed in Pilot-Smits, 2005) and can cause health problems (reviewed in Harvey, 1991; Pitot and Dragan, 1996) . Some of the best studied abiotic stress inducers include heavy metals, ozone, UV light, salinity, and drought. Experimentation on the toxicology and physiology of abiotic stress inducers has resulted in significant advances in environmental protection and agriculture.", "cite_spans": [{"start": 340, "end": 366, "text": "(Preston and Tingey, 1988;", "ref_id": "BIBREF43"}, {"start": 367, "end": 380, "text": "Heagle, 1989;", "ref_id": "BIBREF22"}, {"start": 381, "end": 399, "text": "Pell et al., 1997)", "ref_id": "BIBREF39"}, {"start": 454, "end": 480, "text": "(Simonich and Hites, 1994;", "ref_id": "BIBREF53"}, {"start": 555, "end": 568, "text": "Harvey, 1991;", "ref_id": "BIBREF21"}, {"start": 569, "end": 592, "text": "Pitot and Dragan, 1996)", "ref_id": "BIBREF41"}], "ref_spans": []}, {"section": "Introduction", "text": "For example, studies on metal toxicity in plants have led to the identification of transport proteins. This has advanced bioremediation of metal-contaminated soil environments, where some plants have been shown to internalize toxic elements such as cadmium (Salt et al., 1995) , arsenic (Ma et al., 2001) , and nickel (Kr\u00e4mer et al., 2000) . The molecular knowledge of uptake, transformation, and storage of toxic metals and their derivatives in plants have led to promising biotechnological applications (Bizily et al., 2000; Mej\u00e1re and B\u00fclow, 2001; Dhankher et al., 2002; Song et al., 2003) . In addition, studies of ozone-induced stress have shown that oxidative stress leads to cell death (reviewed in Rao and Davis, 2001) . The necrosis of tissues involves salicylic acid (SA), jasmonic acid (JA), and ethylene signalling processes (Rao et al., 2000 (Rao et al., , 2002 Vahala et al., 2003) . Moreover, common signalling molecules have been identified for abiotic and biotic stress pathways. For instance, mitogen-activated protein kinases (MAPKs) mediate responses to both ozone and pathogen exposure (Sharma et al., 1996; Samuel et al., 2000; Kovtun et al., 2000; reviewed in Rao and Davis, 2001; Vranova et al., 2002) .", "cite_spans": [{"start": 257, "end": 276, "text": "(Salt et al., 1995)", "ref_id": "BIBREF48"}, {"start": 287, "end": 304, "text": "(Ma et al., 2001)", "ref_id": "BIBREF34"}, {"start": 318, "end": 339, "text": "(Kr\u00e4mer et al., 2000)", "ref_id": "BIBREF30"}, {"start": 505, "end": 526, "text": "(Bizily et al., 2000;", "ref_id": "BIBREF5"}, {"start": 551, "end": 573, "text": "Dhankher et al., 2002;", "ref_id": "BIBREF16"}, {"start": 574, "end": 592, "text": "Song et al., 2003)", "ref_id": "BIBREF56"}, {"start": 706, "end": 726, "text": "Rao and Davis, 2001)", "ref_id": "BIBREF44"}, {"start": 837, "end": 854, "text": "(Rao et al., 2000", "ref_id": "BIBREF45"}, {"start": 855, "end": 874, "text": "(Rao et al., , 2002", "ref_id": "BIBREF46"}, {"start": 875, "end": 895, "text": "Vahala et al., 2003)", "ref_id": "BIBREF60"}, {"start": 1107, "end": 1128, "text": "(Sharma et al., 1996;", "ref_id": "BIBREF52"}, {"start": 1129, "end": 1149, "text": "Samuel et al., 2000;", "ref_id": "BIBREF50"}, {"start": 1150, "end": 1170, "text": "Kovtun et al., 2000;", "ref_id": "BIBREF29"}], "ref_spans": []}, {"section": "Introduction", "text": "The hazardous pollutants polycyclic aromatic hydrocarbons (PAHs) are poorly studied stress inducers. PAHs consist of two or more benzene rings, which make these molecules highly persistent in the environment. Examples include naphthalene, phenanthrene, benz [a] anthracene, and benz [a] pyrene, which contain 2-5 aromatic rings, respectively. Many PAHs in the environment are by-products in petroleum-based manufacturing; they are present in coal tar, asphalt, tyres, and other oil-containing products and are released into the environment during incomplete combustion, and through oil spills, for instance (Committee on In Situ Bioremediation, 1993). In animals, PAHs have a broad impact on health. They interact with DNA resulting in mutations and cancer, benz [a] pyrene being one of the most toxic and carcinogenic compounds known (Harvey, 1991; Anonymous, 2002) . In animal cells PAHs are transformed by oxidases and reductases (Burczynski et al., 1999; Burchiel and Luster, 2001) . PAH metabolism generates reactive electrophilic metabolites, which are the actual carcinogenic compounds that cause DNA damage (Wang et al., 2002) . Furthermore, PAHs trigger the production of reactive oxygen species and cell death in animal cells (Flowers et al., 1997; Burcyznski et al., 1999; Hiura et al., 1999) .", "cite_spans": [{"start": 835, "end": 849, "text": "(Harvey, 1991;", "ref_id": "BIBREF21"}, {"start": 850, "end": 866, "text": "Anonymous, 2002)", "ref_id": "BIBREF1"}, {"start": 933, "end": 958, "text": "(Burczynski et al., 1999;", "ref_id": "BIBREF7"}, {"start": 959, "end": 985, "text": "Burchiel and Luster, 2001)", "ref_id": "BIBREF6"}, {"start": 1115, "end": 1134, "text": "(Wang et al., 2002)", "ref_id": "BIBREF63"}, {"start": 1236, "end": 1258, "text": "(Flowers et al., 1997;", "ref_id": "BIBREF17"}, {"start": 1284, "end": 1303, "text": "Hiura et al., 1999)", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Introduction", "text": "Various trees (such as poplar and jack pine; Rentz et al., 2003) , grasses (rye, oat, wheat, and maize; Aprill and Sims, 1990 ) and other agricultural crops (sunflower, soybean, pea, canola, and carrot; Wild and Jones, 1992; Liste and Alexander, 2000) have been shown to tolerate crude oil pollutants in soil . As in the hyperaccumulation and detoxification of heavy metals, most elaborate approaches for organic pollutant removal include genetic engineering of plants specifically to target the contaminant. Promising results have been obtained with plants expressing bacterial enzymes to detoxify trinitrotoluene (Hannink et al., 2001) , or overexpressing a plant enzyme to degrade trichlorphenol and other phenolic compounds (Wang et al., 2004) . Such innovative work in plants has become possible only after decades of research on bacterial degradation of organics, which has led to identifying strains capable of using aromatic compounds as carbon sources, isolating their biodegrading genes, and engineering bacterial species with the appropriate genes for their introduction into contaminated sites (Sisler and Zobell, 1947; Treccani et al., 1954; reviewed in Pieper and Reineke, 2000) .", "cite_spans": [{"start": 45, "end": 64, "text": "Rentz et al., 2003)", "ref_id": "BIBREF47"}, {"start": 104, "end": 125, "text": "Aprill and Sims, 1990", "ref_id": "BIBREF2"}, {"start": 203, "end": 224, "text": "Wild and Jones, 1992;", "ref_id": "BIBREF65"}, {"start": 225, "end": 251, "text": "Liste and Alexander, 2000)", "ref_id": "BIBREF33"}, {"start": 615, "end": 637, "text": "(Hannink et al., 2001)", "ref_id": "BIBREF19"}, {"start": 728, "end": 747, "text": "(Wang et al., 2004)", "ref_id": "BIBREF62"}, {"start": 1106, "end": 1131, "text": "(Sisler and Zobell, 1947;", "ref_id": "BIBREF54"}, {"start": 1132, "end": 1154, "text": "Treccani et al., 1954;", "ref_id": "BIBREF59"}], "ref_spans": []}, {"section": "Introduction", "text": "In contrast to micro-organisms and animals, little is known about the cellular and molecular mechanisms of how plants take up, respond to, and degrade PAHs (Cobbett and Meagher, 2002; Harvey et al., 2002) . Generally, xenobiotic detoxification in plants involves transformation, conjugation for example with glucose or glutathione, and sequestration in the vacuole or cell wall (McCutcheon and Schnoor, 2003) . Some PAHs like benz[a]pyrene (Sandermann et al., 1984) and fluoranthene (Kolb and Harms, 2000) have been shown to be metabolized in cell cultures of different plant species. Because of the high hydrophobicity of PAHs, they are generally assumed to be tightly bound to soil particles and hardly bioavailable (Pilon-Smits, 2005) , but some studies indicate that plants do take up PAHs from soil (Samsoe-Petersen et al., 2002; Kuhn et al., 2004) . However, the plant genes responsible for PAH uptake, degradation, and conjugation are largely unknown. Mechanisms of the PAH toxicity to plants are poorly understood, and the phytotoxicity appears to vary depending on the particular PAH and plant species (Wittig et al., 2003; Baek et al., 2004) . In addition to degradation and detoxification, molecular knowledge about the stress response and defence mechanisms involved is required for finding ways to support plant tolerance towards PAHs. Presently, it is not clear to what extent PAH exposure triggers stress signalling pathways common to other abiotic or biotic stresses in plants, and whether signalling components specific to PAH stress exist.", "cite_spans": [{"start": 156, "end": 183, "text": "(Cobbett and Meagher, 2002;", "ref_id": "BIBREF10"}, {"start": 184, "end": 204, "text": "Harvey et al., 2002)", "ref_id": "BIBREF20"}, {"start": 378, "end": 408, "text": "(McCutcheon and Schnoor, 2003)", "ref_id": "BIBREF34"}, {"start": 440, "end": 465, "text": "(Sandermann et al., 1984)", "ref_id": "BIBREF51"}, {"start": 483, "end": 505, "text": "(Kolb and Harms, 2000)", "ref_id": "BIBREF28"}, {"start": 804, "end": 834, "text": "(Samsoe-Petersen et al., 2002;", "ref_id": "BIBREF49"}, {"start": 835, "end": 853, "text": "Kuhn et al., 2004)", "ref_id": "BIBREF31"}, {"start": 1111, "end": 1132, "text": "(Wittig et al., 2003;", "ref_id": "BIBREF66"}, {"start": 1133, "end": 1151, "text": "Baek et al., 2004)", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Introduction", "text": "The objective of this study was to investigate the physiological, cellular, and molecular details of PAH stress responses in Arabidopsis (Arabidopsis thaliana). Because many PAHs are reminiscent of plant hormones and secondary metabolites, plants treated with phenanthrene were expected to internalize the model PAH and exhibit altered growth, morphology, and gene expression. Investigations on the stress response were also expected to provide insights into plant PAH monitoring, degradation and stress signalling mechanisms.", "cite_spans": [], "ref_spans": []}, {"section": "Materials and methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Plants and growth conditions", "text": "Seeds from Arabidopsis thaliana ecotype Columbia plants were used in most experiments. For tissue-specific localization of the glutathione-S-transferase expression, seeds from the AtGSTF2 promoter::bglucuronidase reporter plant line (GSTF2::GUS) were used (Smith et al., 2003) . The construct contains 1050 bp of the GSTF2 (At4g02520) promoter fused to the b-glucuronidase (GUS) ORF in the binary vector pBI101 (Smith et al., 2003) . Seeds were surfacesterilized and stratified at 4 8C for 3 d. For control plants, which were grown without the presence of phenanthrene, square Petri dishes containing solid growth medium were prepared with half-strength Murashige and Skoog (MS) medium supplemented with 1.5% w/v sucrose and 0.9% w/v phytoagar, pH 5.7. Phenanthrene has an octanol:water distribution coefficient, log K ow , of 4.45-4.57, reflecting its high hydrophobicity. With water solubility of 1-1.6 mg l \u00ff1 it is practically insoluble in water. Therefore, special care was taken in preparing growth medium with the PAH. Phenanthrene containing Petri dishes were prepared by adding 7.5-175 ll of 100 mM phenanthrene in methanol to aliquots of 35 ml of MS medium to achieve concentrations of 0.05-0.75 mM phenanthrene. The aliquots were autoclaved, mixed well while hot, and poured into Petri dishes. Seeds were sown in the Petri dishes, which were then incubated vertically under long-day conditions (16/8 h photoperiod at approximately 130 lmol photons m \u00ff2 s \u00ff1 at 2361 8C day and night) for 7-35 d as indicated in the text. Plants were observed under a Zeiss 2000-C dissection microscope equipped with an Olympus 340 digital camera.", "cite_spans": [{"start": 256, "end": 276, "text": "(Smith et al., 2003)", "ref_id": "BIBREF55"}, {"start": 411, "end": 431, "text": "(Smith et al., 2003)", "ref_id": "BIBREF55"}], "ref_spans": []}, {"section": "Histochemistry and ion leakage", "text": "Trypan blue staining of dead cells was performed as described by Belenghi et al. (2003) . Staining for the presence of H 2 O 2 by the DAB uptake method was performed as described by Thordal-Christensen et al. (1997) . GUS-staining was performed as described by Jefferson et al. (1987) . For all histochemical methods whole plants, shoots or detached leaves were taken and photographed under a Zeiss 2000-C dissecting microscope equipped with an Olympus 340 digital camera before and after staining. Per treatment at least six plants were stained with each method. To quantify cell death, relative ion leakage was determined by a method modified from Vahala et al. (2003) . Shoots of 26-d-old plants were rinsed twice in double distilled (dd) water and placed in 10 ml of dd water. After 20 h of incubation at room temperature ion leakage was measured with a conductivity meter (YSI Model 35, Yellow Springs Instrument Co. Inc., OH). Samples were autoclaved to kill tissue and conductivity was measured again to determine total ion content. Ion leakage was expressed as the percentage of total ion content. Per treatment at least three samples consisting of 3-10 plants each were measured.", "cite_spans": [{"start": 65, "end": 87, "text": "Belenghi et al. (2003)", "ref_id": "BIBREF4"}, {"start": 182, "end": 215, "text": "Thordal-Christensen et al. (1997)", "ref_id": "BIBREF58"}, {"start": 261, "end": 284, "text": "Jefferson et al. (1987)", "ref_id": "BIBREF24"}, {"start": 650, "end": 670, "text": "Vahala et al. (2003)", "ref_id": "BIBREF60"}], "ref_spans": []}, {"section": "RT-PCR", "text": "Gene expression was analysed in 21-d-old plants grown on 0 or 0.25 mM phenanthrene by applying the reverse transcriptase-polymerase chain reaction (RT-PCR). Total RNA from whole plants was isolated using the RNeasy Plant Mini Kit (Qiagen USA). First-strand cDNA was synthesized using SuperscriptII protocol (Invitrogen). Following primers were used in the PCR: elongation initiation factor 4A (EIF4A; At3g13920), 59-CTCTCGCAATCTTCGCTCTTCTCTTT-39 and 59-TTCTCAAAAC-CATAAGCATAAATACCC-39; actin 7 (ACT7; At5g09810), 59-GGTCGTCCTAGGCACACTGGTG-39 and 59-ACAATACCGGTTGTACGACCAC-39; expansin 8 (EXP8; At2g40610), 59-ATGGGCGGAGCTTGTGGCTATG-39 and 59-AC-CTCAGCAATATGCAGCCACG-39; pathogenesis related protein 1 (PR1; At2g14610), 59-GCAGACTCATACACTCTGGTGG-39 and 59-ACTCCATTGCACGTGTTCGCAG-39; glutathione-S-transferase F2 (GSTF2; At4g02520), 59-TCGACCCAGTGGCTTCAAAGC-39 and 59-TTGGGCAATGAGAAAGCC-39. PCR reactions were carried out by Taq Polymerase (Invitrogen) with following program: an initial 2 min at 94 8C followed by 25 cycles of 1 min at 94 8C, 50 s at 58.0, 59.1, or 61.0 8C (annealing temperatures for EIF4A/ACT7, PR1, and EXP8/GSTF2, respectively), 1 min at 72 8C; and a final extension of 4 min at 72 8C. Gene expression was analysed in two independently grown, harvested, and extracted sets of samples (biological replicates) of 5-10 plants each and the results were similar.", "cite_spans": [], "ref_spans": []}, {"section": "Spectrofluorometric and gas chromatography-mass spectrometry (GC-MS) analyses", "text": "Extracts were prepared from 30 d old control and phenanthrene treated plants. Shoot and root tissues from 12 to 24 plants were separated for analysis. 0.125-0.541 g of tissue was quickly washed twice in hexane to remove residual phenanthrene, frozen in liquid nitrogen, ground to fine powder with a mortar and pestle, and extracted with dichloromethane:methanol (9:1, v/v). Extracts were passed through a Na 2 SO 4 column to remove water. Extracts were excited at 337 nm, and then emission scanned using a PTI QM-1 spectrofluorometer (Photon Technology International Inc.). For the GC-MS, extracts were concentrated into approximately 100 ll and analysed with a Finnigan Voyager Gas Chromatography-Mass Spectrometer. The GC was equipped with a split/splitless injector and an AS800 auto-sampler. One ll of concentrated samples was injected into the column and aromatic compounds were separated using a DB-5MS 3030.25 mm fused silica column (J&W Scientific) programmed from 50 8C to 300 8C at the rate of 6 8C min \u00ff1 and held at 300 8C for 10 min. Helium was used as a carrier gas and the flow rate was set at 1 ml min \u00ff1 . The mass spectrum was scanned from 50-600 nm in the Electron Ionization (EI) mode (70 eV). Phenanthrene was identified based on the retention time and ion m/z ratio of authentic PAH mixed standard (Sigma). Analyses were carried out for two independent biological replicates and the results were similar.", "cite_spans": [], "ref_spans": []}, {"section": "Fluorescence microscopy", "text": "The leaves from plants growing at 0, 0.25, or 0.5 mM phenanthrene were mounted on a slide glass with glycerol and viewed under an Olympus BX60 compound microscope with an U-MWU cube (excitation filter BA420), and photographed with an Olympus 340 digital camera.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Arabidopsis stress response to phenanthrene", "text": "To characterize plant responses to a PAH, Arabidopsis was grown on phenanthrene containing medium under sterile conditions. Phenanthrene-treated plants exhibited many stress characteristics, such as reduction of root growth and reduction in size and number of leaves (Fig. 1) . Root hair development was drastically inhibited (Fig. 1C-F ). Trichomes were deformed and reduced in size and number (Fig. 2E, F) . Between 0.05 mM and 0.25 mM phenanthrene, the severity of the stress symptoms increased with concentration. Plants grown on 0.25, 0.5, or 0.75 mM phenanthrene appeared equally stressed, indicating a saturation of the response. Concentrations higher than 1.0 mM were excessively toxic and killed the plants after 30 d of growth.", "cite_spans": [], "ref_spans": [{"start": 267, "end": 275, "text": "(Fig. 1)", "ref_id": "FIGREF0"}, {"start": 326, "end": 336, "text": "(Fig. 1C-F", "ref_id": "FIGREF0"}, {"start": 395, "end": 407, "text": "(Fig. 2E, F)", "ref_id": "FIGREF1"}]}, {"section": "Arabidopsis stress response to phenanthrene", "text": "When Arabidopsis was grown on phenanthrene concentrations higher than 0.05 mM, plants exhibited white spots, which developed into necrotic lesions (Fig. 2B, D-H) . Note in Fig. 2D the glossy, compact, slightly upward curved leaves, which were typical for plants grown on phenanthrene. The white spots were most prominent in leaves, starting in cotyledons (Fig. 2B ), but were also present on the hypocotyl, flowers, and stems.", "cite_spans": [], "ref_spans": [{"start": 147, "end": 161, "text": "(Fig. 2B, D-H)", "ref_id": "FIGREF1"}, {"start": 172, "end": 179, "text": "Fig. 2D", "ref_id": "FIGREF1"}, {"start": 355, "end": 363, "text": "(Fig. 2B", "ref_id": "FIGREF1"}]}, {"section": "Arabidopsis stress response to phenanthrene", "text": "Necrotic lesions are a symptom of a hypersensitive response (HR) in an avirulent plant-pathogen interaction, in which plant defence mechanisms include local cell death to restrict the spread of the pathogen (Lamb and Dixon, 1997) . Therefore, an attempt was made to find out if there were further parallels to an HR. Firstly, to determine whether the white spots and necrotic looking patches contained dead cells, trypan blue staining was used. Phenanthrene-exposed plants exhibited blue spots indicating dye accumulation in dead cells (Fig. 3D, E) . The frequency and size of the cell death events and lesions on leaves were dependent on the phenanthrene concentration in the medium, and the duration of exposure (data not shown). When plants were initially grown without phenanthrene for 8 d, and then transferred to medium containing 0.25, 0.5, or 0.75 mM phenanthrene, dead cells were detected as early as 6 h after the start of exposure. After 12 h of exposure, 50% of the plants exhibited cell death. At this time point, white spots became visible under the dissection microscope. Figure 3C , D show a leaf 48 h after transfer to 0.5 mM phenanthrene. Blue spots indicating dead cells in Fig. 3D co-localize with white spots in Fig. 3C , which shows the same leaf before staining. In addition, conductance measurements indicated increased ion leakage at higher phenanthrene concentrations (Fig. 3F) , strengthening the hypothesis that plants were experiencing cell death as a result of phenanthrene exposure.", "cite_spans": [{"start": 207, "end": 229, "text": "(Lamb and Dixon, 1997)", "ref_id": "BIBREF32"}], "ref_spans": [{"start": 536, "end": 548, "text": "(Fig. 3D, E)", "ref_id": "FIGREF2"}, {"start": 1087, "end": 1096, "text": "Figure 3C", "ref_id": "FIGREF2"}, {"start": 1193, "end": 1200, "text": "Fig. 3D", "ref_id": "FIGREF2"}, {"start": 1233, "end": 1240, "text": "Fig. 3C", "ref_id": "FIGREF2"}, {"start": 1394, "end": 1403, "text": "(Fig. 3F)", "ref_id": "FIGREF2"}]}, {"section": "Arabidopsis stress response to phenanthrene", "text": "In an HR, reactive oxygen species (ROS) such as hydrogen peroxide are known to mediate cell death in exposed tissues (Lamb and Dixon, 1997) . Therefore H 2 O 2 production was analysed in phenanthrene-treated plants using the 3,39-diaminobenzidine (DAB) uptake method. Polymerization of DAB, visible as a brown precipitate in the presence of H 2 O 2 , was detected in leaves (Fig. 4C, H, J,  K) . Notably, like cell death, H 2 O 2 production co-localized with white and necrotic spots, where present (Fig. 4I, J) . Figure 5 summarizes the time-course of H 2 O 2 production and cell death after transferring 8-d-old plants from control medium (0 mM phenanthrene) to 0.25, 0.5, or 0.75 mM phenanthrene-containing environments. Because the frequency of the symptoms did not differ between the phenanthrene concentrations 0.25, 0.5, and 0.75 mM, the data from those plants were pooled at each time point (Fig.  5B) . Phenanthrene-exposed plants started developing symptoms after 3-6 h of exposure, and the number of plants exhibiting symptoms increased with time. After 48 h of phenanthrene exposure 85% of the analysed plants exhibited white spots, dead cells, and H 2 O 2 production (Fig. 5B) . No white spots were found in the plants that were transferred to 0 mM phenanthrene (Fig. 5A) . Positive DAB reaction in some plants at 3, 18, and 24 h after transfer to the 0 mM phenanthrene can be attributed to plant damage during transfer, because wounding also induces H 2 O 2 production (Orozco-Cardenas and Ryan, 1999). After 48 h, no H 2 O 2 production was detected in plants not treated with phenanthrene, indicating that plants had completely recovered from the transfer.", "cite_spans": [{"start": 117, "end": 139, "text": "(Lamb and Dixon, 1997)", "ref_id": "BIBREF32"}], "ref_spans": [{"start": 374, "end": 393, "text": "(Fig. 4C, H, J,  K)", "ref_id": "FIGREF3"}, {"start": 499, "end": 511, "text": "(Fig. 4I, J)", "ref_id": "FIGREF3"}, {"start": 514, "end": 522, "text": "Figure 5", "ref_id": "FIGREF4"}, {"start": 899, "end": 909, "text": "(Fig.  5B)", "ref_id": "FIGREF4"}, {"start": 1180, "end": 1189, "text": "(Fig. 5B)", "ref_id": "FIGREF4"}, {"start": 1275, "end": 1284, "text": "(Fig. 5A)", "ref_id": "FIGREF4"}]}, {"section": "Arabidopsis stress response to phenanthrene", "text": "To reveal phenanthrene-induced changes in gene expression, reverse-transcription (RT) PCR experiments were carried out for selected genes in 21-d-old plants. The expression levels of the translation elongation initiation factor (EIF4A) and actin (ACT7) genes, which were used as a control for overall gene expression levels, were similar in plants grown on 0 mM and 0.25 mM phenanthrene (Fig. 6 ). Gene expression of expansin (EXP8) was examined because expansins have known roles in cell wall loosening and cell enlargement (Keller and Cosgrove, 1995; O'Malley and Lynn, 2000) . In phenanthrene-treated plants the transcript levels of EXP8 were reduced (Fig. 6 ). To identify a signalling pathway possibly involved in the phenanthrene response, gene expression levels were analysed of the pathogenesis related protein 1 (PR1), a SA-dependent marker gene in defence pathways and the HR (Alvarez et al., 1998; Klessig et al., 2000) , and the glutathione-S-transferase (GST) gene GSTF2, which is known to be induced by ethylene, auxin, SA, paraquat, and sulphydryl compounds (Smith et al., 2003) . Phenanthrene-exposed plants showed an increase in mRNA steady-state levels for PR1, but not for GSTF2 (Fig.  6) . However, tissue-specific expression analysis using the GSTF2::GUS reporter line (Smith et al., 2003) showed localized induction of GSTF2 in leaves of 14-d-old phenanthrene-treated plants (Fig. 7B) . These spatial expression patterns in leaves of GSTF2::GUS are reminiscent of H 2 O 2 and trypan blue staining patterns observed in phenanthrene-exposed plants (Figs 3, 4) . , 3, 6, 12, 18, 24 , and 48 h after transfer, 12 and 36 plants, on media without and with phenanthrene, respectively, were visually inspected for the presence of white spots using a dissection microscope. Afterwards, half of the plants from each treatment was stained with trypan blue to detect dead cells and the other half was stained with DAB to detect H 2 O 2 production. Because at each time point each plant was examined for the presence of white spots and for dead cells or for H 2 O 2 production, the number of observations is n=24 (A, control) and n=72 (B, phenanthrene exposure). The number of plants exhibiting stress symptoms when exposed to phenanthrene (B) increased monotonically over the seven time points. The probability that such an increase occurred by chance is (permutation test) 1/5040=0.0002.", "cite_spans": [{"start": 525, "end": 552, "text": "(Keller and Cosgrove, 1995;", "ref_id": "BIBREF26"}, {"start": 553, "end": 577, "text": "O'Malley and Lynn, 2000)", "ref_id": "BIBREF37"}, {"start": 886, "end": 908, "text": "(Alvarez et al., 1998;", "ref_id": "BIBREF0"}, {"start": 909, "end": 930, "text": "Klessig et al., 2000)", "ref_id": "BIBREF27"}, {"start": 1073, "end": 1093, "text": "(Smith et al., 2003)", "ref_id": "BIBREF55"}, {"start": 1290, "end": 1310, "text": "(Smith et al., 2003)", "ref_id": "BIBREF55"}], "ref_spans": [{"start": 387, "end": 394, "text": "(Fig. 6", "ref_id": "FIGREF5"}, {"start": 654, "end": 661, "text": "(Fig. 6", "ref_id": "FIGREF5"}, {"start": 1198, "end": 1207, "text": "(Fig.  6)", "ref_id": "FIGREF5"}, {"start": 1397, "end": 1406, "text": "(Fig. 7B)", "ref_id": "FIGREF6"}, {"start": 1568, "end": 1579, "text": "(Figs 3, 4)", "ref_id": "FIGREF2"}]}, {"section": "Phenanthrene is internalized by Arabidopsis", "text": "To verify that the observed responses to phenanthrene were due to its internalization, PAH uptake was analysed by gas chromatography and mass spectrometry (GC-MS), and fluorescence spectroscopy.", "cite_spans": [], "ref_spans": []}, {"section": "Phenanthrene is internalized by Arabidopsis", "text": "The total ion chromatograms presented in Fig. 8A and B provide evidence for phenanthrene uptake in Arabidopsis. The chromatograms of extracts from control (A) and phenanthrene-treated plants (B) show different patterns reflecting changes in the levels of many chemical compounds. In extracts from plants grown on 0.5 mM phenanthrene, the elution peak at 26.39 min, with a mass to charge (m/z) ratio of 178, (Fig. 8B) , was identified as phenanthrene. No such peak was detected in extracts of control plants (Fig. 8A) . Both root and leaf extracts contained phenanthrene (root data not shown).", "cite_spans": [], "ref_spans": [{"start": 41, "end": 48, "text": "Fig. 8A", "ref_id": "FIGREF7"}, {"start": 407, "end": 416, "text": "(Fig. 8B)", "ref_id": "FIGREF7"}, {"start": 507, "end": 516, "text": "(Fig. 8A)", "ref_id": "FIGREF7"}]}, {"section": "Phenanthrene is internalized by Arabidopsis", "text": "Because phenanthrene, like other PAHs, is fluorescent when exposed to UV light and has a specific spectral emission signature, it can be detected using fluorescence spectroscopy (Dabestani and Ivanov, 1999) . Phenanthrene in hexane has emission peaks at 347, 356, 364, and 374 nm after an excitation at 337 nm. Analysing fluorescence spectra of plant extracts, supporting evidence was obtained that phenanthrene is internalized by Arabidopsis (Fig. 8C,   D ). Both root and leaf extracts from phenanthrene-exposed plants exhibited emission spectra identical to the phenanthrene standard (root data not shown).", "cite_spans": [{"start": 178, "end": 206, "text": "(Dabestani and Ivanov, 1999)", "ref_id": "BIBREF14"}], "ref_spans": [{"start": 443, "end": 456, "text": "(Fig. 8C,   D", "ref_id": "FIGREF7"}]}, {"section": "Phenanthrene is internalized by Arabidopsis", "text": "To determine if phenanthrene could be detected in plant tissue in vivo, plants grown in the presence or absence of phenanthrene were analysed using a fluorescence microscope. In 3-d-old seedlings no special fluorescence was detected, not even at the high concentration of 0.5 mM phenanthrene. From 7 d on, a clear difference in the fluorescence between control and phenanthrene-treated samples was observed (Fig. 9) . In cotyledons of 7-d-old control plants, no notable fluorescence beyond the red autofluorescence of chlorophyll was seen (Fig. 9B) . Some distinct, bright fluorescent spots were seen in the cotyledons of plants grown on 0.05 mM phenanthrene (not shown), and many more fluorescent spots were observed in the 0.5 mM phenanthrene treatment (Fig. 9D) . In the 14-and 21-d-old plants grown on phenanthrene, fluorescence in true leaves was predominantly connected with trichomes (Fig. 9F, H , J, L, N, P). Particularly in young leaves, the fluorescence was always located in trichomes. Larger fluorescent patches developed with time, and were often centred on a collapsing trichome (Fig. 9L, N, P) . Notably, the specific fluorescence, together with H 2 O 2 production Representative images of ethidium bromide-stained agarose gels showing relative mRNA levels for EIF4A, ACT7, EXP8, PR1, and GSTF2 are presented. Relative expression levels of EIF4A, ACT7, EXP8, PR1, and GSTF2 on 0.25 mM phenanthrene as compared to 0 mM phenanthrene were 0.9560.046, 0.9360.073, 0.276 0.111, 4.8162.853, and 1.0260.049, respectively (mean 6standard error of mean calculated using image analysis software Image J; n=2). For each PCR reaction with the gene specific primers 2 ll of the cDNA were taken, and 6 lLl of the PCR reaction was loaded on the gel. and cell death, was also observed in phenanthrene-treated leaves, which did not yet contain visible necrotic lesions (i.e. plants treated with a low concentration of phenanthrene or for a short period of time), indicating that these events precede lesion formation.", "cite_spans": [], "ref_spans": [{"start": 407, "end": 415, "text": "(Fig. 9)", "ref_id": "FIGREF8"}, {"start": 539, "end": 548, "text": "(Fig. 9B)", "ref_id": "FIGREF8"}, {"start": 755, "end": 764, "text": "(Fig. 9D)", "ref_id": "FIGREF8"}, {"start": 891, "end": 902, "text": "(Fig. 9F, H", "ref_id": "FIGREF8"}, {"start": 1094, "end": 1109, "text": "(Fig. 9L, N, P)", "ref_id": "FIGREF8"}]}, {"section": "Discussion", "text": "Despite the recognized importance of abiotic stresses in plants, little is known about the PAH stress responses and the mediating cellular signals. This report extensively documents the toxic nature of PAHs to plant growth. In addition, the experiments presented provide a foundation for PAH phytoremediation research in a genetically and molecularly tractable system such as Arabidopsis. In phytoremediation, plants, together with their associated microorganisms, are employed for decontamination (Cunningham and Ow, 1996) . Phytoremediation has more public approval, and is far more cost-efficient in soil remediation compared with soil removal and incineration or disposal into landfills, or chemical extraction from removed soil (PilonSmits, 2005) , adding an economic interest to studying stress responses to organic pollutants.", "cite_spans": [{"start": 498, "end": 523, "text": "(Cunningham and Ow, 1996)", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Discussion", "text": "One prerequisite for using Arabidopsis as a model plant for PAH phytoremediation is that it takes up the compound under study. The GC-MS and fluorescence spectrometric analyses clearly show this to happen (Fig. 8) . Present fluorescence microscopic analyses suggest that phenanthrene, or some phenanthrene derivative(s) accumulates in white spots seen under the dissection microscope (compare Figs 2, 9) . Furthermore, the fluorescent spots (Fig. 9D, F , L, N, P) are reminiscent of the cell death patterns detected by trypan blue staining (Fig. 3D, E) , suggesting that the accumulation locally causes cell death. While similar fluorescence observations have not been reported for plants growing on other abiotic stress inducers, it cannot be excluded that the fluorescence is due to endogenous fluorescent molecules that may be produced in response to PAH exposure as in wounding or in the HR. However, in the HR, fluorescent phenolic compounds are deposited in layers at or in the cell wall (Mellersh and Heath, 2001) , while the fluorescence in the phenanthrene-treated plants is mostly in patches, seemingly inside the cytoplasm (e.g. Fig. 9J ). The uptake of organic xenobiotics into the plant cell is often mediated by an ABC transport protein (Cobbett and Meagher, 2002) , although simple diffusion is also thought possible (Pilon-Smits, 2005) . Based on the hydrophobicity of the molecule, phenanthrene may passively penetrate the plasmalemma of root and shoot cells without any carrier. This view is supported by the observations of Wild et al. (2004) , who traced the movement of anthracene (also a three-ring PAH) in maize leaves using twophoton excitation microscopy. The authors showed that anthracene, applied as droplets on leaves, formed focused nests on the leaf surface, from which it diffused into the cytoplasm within 72 h. Moreover, from experiments with two medium layers (bottom with, and top without, phenanthrene) and multiple cell Petri dishes (some cells with, some without phenanthrene), it is known that phenanthrene can enter Arabidopsis both through direct contact with the tissue and from the air (details not shown).", "cite_spans": [{"start": 994, "end": 1020, "text": "(Mellersh and Heath, 2001)", "ref_id": "BIBREF36"}, {"start": 1251, "end": 1278, "text": "(Cobbett and Meagher, 2002)", "ref_id": "BIBREF10"}, {"start": 1543, "end": 1561, "text": "Wild et al. (2004)", "ref_id": "BIBREF64"}], "ref_spans": [{"start": 205, "end": 213, "text": "(Fig. 8)", "ref_id": "FIGREF7"}, {"start": 393, "end": 403, "text": "Figs 2, 9)", "ref_id": "FIGREF1"}, {"start": 441, "end": 452, "text": "(Fig. 9D, F", "ref_id": "FIGREF8"}, {"start": 540, "end": 552, "text": "(Fig. 3D, E)", "ref_id": "FIGREF2"}, {"start": 1140, "end": 1147, "text": "Fig. 9J", "ref_id": "FIGREF8"}]}, {"section": "Discussion", "text": "Based on the observations presented here, the development of the white spots/lesions typically starts at trichomes (Fig. 9F, H, J) . After a certain amount of PAH accumulation in the trichome, it seems to diffuse to the base of the cell, and spread into the adjacent cells of the trichome basement (Fig. 9L) . Finally, the trichome collapses (Fig. 9N) . It is unclear if trichomes act as entering points for the PAH, 'combing' phenanthrene from the air, or if they import the PAH coming from other cell types and tissues. Notably, in these experiments trichomes never stained with trypan blue. Possibly, the trichome cells remain alive until they suddenly collapse. These observations corroborate the special role in detoxification that has been designated to trichomes in some previous studies: Trichomes of Brassica juncea accumulate cadmium (Salt et al., 1995) , and Arabidopsis trichomes contain at least 300-fold increased glutathione concentrations compared with other epidermal cells, suggesting that trichomes may function as an efficient site of xenobiotic conjugation (Gutierrez-Alcala et al., 2000) . Trichome-specific engineering with PAH-degrading enzymes may be one strategy for future phytoremediation. Many microbial PAH biodegrading enzymes are mono-and dioxygenases (Cerniglia, 1997; Kanaly and Harayama, 2000) ; and, therefore, it is tantalizing to think that plants with increased levels of particular mono-or dioxygenases, especially in trichomes, will show increased tolerance and transform PAHs to non-toxic intermediate compounds.", "cite_spans": [{"start": 844, "end": 863, "text": "(Salt et al., 1995)", "ref_id": "BIBREF48"}, {"start": 1078, "end": 1109, "text": "(Gutierrez-Alcala et al., 2000)", "ref_id": "BIBREF18"}, {"start": 1284, "end": 1301, "text": "(Cerniglia, 1997;", "ref_id": "BIBREF8"}, {"start": 1302, "end": 1328, "text": "Kanaly and Harayama, 2000)", "ref_id": "BIBREF25"}], "ref_spans": [{"start": 115, "end": 130, "text": "(Fig. 9F, H, J)", "ref_id": "FIGREF8"}, {"start": 298, "end": 307, "text": "(Fig. 9L)", "ref_id": "FIGREF8"}, {"start": 342, "end": 351, "text": "(Fig. 9N)", "ref_id": "FIGREF8"}]}, {"section": "Discussion", "text": "In animal cells, PAH metabolism causes oxidative stress (Burchiel and Luster, 2001) . In this regard, plant and animal cells respond similarly to PAH exposure, as shown by the production of H 2 O 2 (Fig. 4) and localized cell death (Fig. 3) in Arabidopsis. On the other hand, in plant defence against pathogenic organisms (Lamb and Dixon, 1997; Chamnongpol et al., 1998) , or ozone exposure (Rao et al., 2000) , programmed cell death is also mediated by local increases in ROS levels. The origin of H 2 O 2 under phenanthrene exposure remains unclear. It remains to be determined whether a NADPH oxidase generates the H 2 O 2 or it comes from the oxidation of PAHs. In addition, it is unclear whether SA potentiates H 2 O 2 generation as has been reported in plant defence responses.", "cite_spans": [{"start": 56, "end": 83, "text": "(Burchiel and Luster, 2001)", "ref_id": "BIBREF6"}, {"start": 322, "end": 344, "text": "(Lamb and Dixon, 1997;", "ref_id": "BIBREF32"}, {"start": 345, "end": 370, "text": "Chamnongpol et al., 1998)", "ref_id": "BIBREF9"}, {"start": 391, "end": 409, "text": "(Rao et al., 2000)", "ref_id": "BIBREF45"}], "ref_spans": [{"start": 198, "end": 206, "text": "(Fig. 4)", "ref_id": "FIGREF3"}, {"start": 232, "end": 240, "text": "(Fig. 3)", "ref_id": "FIGREF2"}]}, {"section": "Discussion", "text": "PAH exposure does not induce a general shut down of metabolic activities, because the expression levels of housekeeping genes were not affected by phenanthrene treatment (Fig. 6) , rather the response is more specific. The small size of plants grown on phenanthrene may be attributed to a decrease in cell division or cell expansion rate, or both. However, experiments with plants expressing the CyclinB1;1::GUS reporter, which enables an analysis of cell division (Col\u00f3n-Carmona et al., 1999) , indicate that spatio-temporal patterns of mitotic activity are not affected by phenanthrene (data not shown). The reduction in expansin expression suggests that growth reduction may largely be due to an inhibition of cell enlargement. However, because EXP8 may be expressed at higher levels in floral organs compared with leaves (http://mpss.udel. edu/at/GeneAnalysis.php?featureName=AT2G40610), the reduced expression levels of the gene may partly be explained by the delayed flowering of phenanthrene-treated plants ( Figs 1G, 2C, D) . The delay in flowering is remarkable, since most abiotic stress situations usually tend to accelerate flowering. An analysis of hormone levels may provide an explanation for this response.", "cite_spans": [{"start": 465, "end": 493, "text": "(Col\u00f3n-Carmona et al., 1999)", "ref_id": "BIBREF11"}], "ref_spans": [{"start": 170, "end": 178, "text": "(Fig. 6)", "ref_id": "FIGREF5"}, {"start": 1016, "end": 1031, "text": "Figs 1G, 2C, D)", "ref_id": "FIGREF0"}]}, {"section": "Discussion", "text": "Currently, it is unclear how PAH stress relates to other abiotic or biotic stresses. It is exciting that the marker gene of the systemic acquired resistance, PR1, is induced in phenanthrene-exposed plants (Fig. 6) . The induction of PR1 is regulated by SA, which mediates defence responses against biotrophic pathogens (Thomma et al., 1998) . However, the extent of defence gene activation upon PAH exposure remains to be determined. Results from a genome-wide analysis will provide insight into the activation of stress signalling pathways and the involvement of other hormones. Studying the crosstalk between phenanthrene stress, disease resistance, and oxidative stress pathways is important since it may be a major factor in any PAH phytoremediation strategy. For example, plants overexpressing the enzyme NahG from Pseudomonas, an enzyme in the naphthalene metabolic pathway, which converts SA to catechol, accumulate little SA and are more susceptible to pathogens (Delaney et al., 1994) . To understand the crosstalk between signalling pathways of PAH and other environmental stresses, it will be interesting to study the PAH responses of nahG over-expressing, or SA overproducing plants, as well as Arabidopsis mutants affected in the production or perception of other hormones.", "cite_spans": [{"start": 319, "end": 340, "text": "(Thomma et al., 1998)", "ref_id": "BIBREF57"}, {"start": 971, "end": 993, "text": "(Delaney et al., 1994)", "ref_id": "BIBREF15"}], "ref_spans": [{"start": 205, "end": 213, "text": "(Fig. 6)", "ref_id": "FIGREF5"}]}, {"section": "Discussion", "text": "In conclusion, novel and conventional stress responses to phenanthrene, an organic environmental pollutant, have been identified. Integrating these data into signalling and metabolic pathways, and applying these models towards PAH phytoremediation will expand the knowledge surrounding abiotic stress responses. The genomic tools available for Arabidopsis offer an excellent basis to screen for genes relevant in PAH phytoremediation. 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(G) Shoots of 28-d-old plants grown on 0, 0.05, 0.1, 0.25, or 0.5 mM phenanthrene (from left to right). Scale bars 10 mm.", "type": "figure"}, "FIGREF1": {"text": "Fig. 2. Phenanthrene causes white spots and necrotic lesions on leaves. Arabidopsis was grown on medium supplemented with 0-0.5 mM phenanthrene under long days at 23 8C. (A, B) 7-d-old seedlings grown on 0 (A) or 0.5 mM (B) phenanthrene. (C, D) 21-d-old plants grown on 0 (C) or 0.25 mM (D) phenanthrene. Inset in (C) shows a trichome on a plant grown on 0 mM phenanthrene. (E-H) Leaves of plants grown on 0.5 mM phenanthrene for 21 (G), 31 (E, F), or 34 d (H). Scale bars 1 mm, except 100 lm in (C, inset) and in (F).", "type": "figure"}, "FIGREF2": {"text": "Fig. 3. Phenanthrene exposure promotes cell death. (A-D) Arabidopsis was grown on medium without phenanthrene under long days at 23 8C for 8 d before transfer to 0 (A, B) or 0.5 mM (C, D) phenanthrene for 48 h. Leaves were photographed before (A, C) and after (B, D) staining with trypan blue. (E) Leaf of a plant grown continuously on 0.5 mM phenanthrene for 60 d before staining with trypan blue. Dark blue spots in (D) and (E) indicate dye accumulation in dead cells. (F) Ion leakage (as the percentage of total ion content) into distilled water during 20 h of incubation at room temperature from in 26-d-old plants grown on 0-0.5 mM phenanthrene. Data points show mean 6standard deviation; n=4 for 0, 0.05, and 0.1 mM phenanthrene, n=3 for 0.25 and 0.5 mM phenanthrene. Scale bars in (A-E) 1 mm.", "type": "figure"}, "FIGREF3": {"text": "Fig. 4. Phenanthrene exposure promotes H 2 O 2 production. Arabidopsis was grown on medium supplemented with 0-0.75 mM phenanthrene under long days at 23 8C. H 2 O 2 was visualized by the DAB uptake method (A, C, G, H, J, K). Brown spots show polymerization of DAB in the presence of H 2 O 2 . Representative plants (B, D, E, F) or the leaf to be stained (I) were photographed prior to DAB staining. (A-D) 7-d-old seedlings grown on 0 (A, B) or 0.5 mM (C, D) phenanthrene. (E-H) 17-dold plants grown on 0 (E, G) or 0.5 mM (F, H) phenanthrene. (I-K) A leaf from a plant transferred to 0.75 mM phenanthrene for 48 h after 8 d of growth on 0 mM phenanthrene. The leaf was photographed before (I) and after the staining (J). (K) Detail from (J) at higher magnification. Scale bars 1 mm except 100 lm in (K).", "type": "figure"}, "FIGREF4": {"text": "Fig. 5. The number of plants showings lesions (white bars), H 2 O 2 production (black bars), and cell death (hatched bars) in leaves increases with the time of phenanthrene exposure. (A) Control plants, grown in the absence of phenanthrene; (B) plants treated with phenanthrene. A total of 336 plants were grown on medium without phenanthrene under long days at 23 8C for 8 d. Then 84 and 252 plants were transferred to media without and with phenanthrene, respectively. At 0, 3, 6, 12, 18, 24, and 48 h after transfer, 12 and 36 plants, on media without and with phenanthrene, respectively, were visually inspected for the presence of white spots using a dissection microscope. Afterwards, half of the plants from each treatment was stained with trypan blue to detect dead cells and the other half was stained with DAB to detect H 2 O 2 production. Because at each time point each plant was examined for the presence of white spots and for dead cells or for H 2 O 2 production, the number of observations is n=24 (A, control) and n=72 (B, phenanthrene exposure). The number of plants exhibiting stress symptoms when exposed to phenanthrene (B) increased monotonically over the seven time points. The probability that such an increase occurred by chance is (permutation test) 1/5040=0.0002.", "type": "figure"}, "FIGREF5": {"text": "Fig. 6. Phenanthrene exposure affects gene expression. Total RNA was isolated from 21-d-old plants grown on 0 or 0.25 mM phenanthrene and used for RT-PCR experiments. Representative images of ethidium bromide-stained agarose gels showing relative mRNA levels for EIF4A, ACT7, EXP8, PR1, and GSTF2 are presented. Relative expression levels of EIF4A, ACT7, EXP8, PR1, and GSTF2 on 0.25 mM phenanthrene as compared to 0 mM phenanthrene were 0.9560.046, 0.9360.073, 0.276 0.111, 4.8162.853, and 1.0260.049, respectively (mean 6standard error of mean calculated using image analysis software Image J; n=2). For each PCR reaction with the gene specific primers 2 ll of the cDNA were taken, and 6 lLl of the PCR reaction was loaded on the gel.", "type": "figure"}, "FIGREF6": {"text": "Fig. 7. Phenanthrene exposure induces localized GSTF2::GUS expression in leaves. GSTF2::GUS transgenic Arabidopsis plants were grown for 14 d on medium supplemented with 0 (A) or 0.25 (B) mM phenanthrene under long days at 23 8C. Plants were stained for 18 h in GUS staining buffer containing 2 mM 5-bromo-4-chloro-3-indolyl-b-D-glucuronide. Scale bars 1 mm.", "type": "figure"}, "FIGREF7": {"text": "Fig. 8. Phenanthrene is found in root and leaf tissue. (A, B) Total ion chromatograms obtained with gas chromatography-mass spectrometry (GC-MS) analysis of leaf extracts from plants grown on 0 (A) or 0.5 mM (B) phenanthrene. Leaves were washed in hexane before freezing in liquid nitrogen. Ground tissue samples were extracted in dichloromethane:methanol (9:1, v/v) and analysed by GC-MS. The peak with the retention time of 26.39 min in (B) represents phenanthrene. Insets in (A)", "type": "figure"}, "FIGREF8": {"text": "Fig. 9. Phenanthrene-grown plants exhibit specific fluorescence. Arabidopsis was grown for 7-28 d on medium supplemented with 0, 0.25, or 0.5 mM phenanthrene and observed at weekly intervals. Leaves were viewed with a compound microscope under bright field or UV illumination and images were captured with a digital camera. Two consecutive images (A, B, C, D etc) show the same site under bright field and UV illumination, respectively. (A-D) Cotyledons of 7-d-old plants on 0 (A, B) or 0.5 mM (C, D) phenanthrene. (E, F) Leaves of 14-d-ld plants on 0.5 mM phenanthrene. (G-N) Leaves of 21-d-old plants on 0.25 mM phenanthrene. Images show different stages of fluorescence accumulation in a trichome and spot formation. (O, P) Leaves of 28-d-old plants on 0.5 mM phenanthrene. Scale bars 10 lm, except 100 lm in (E), (F), (O), and (P).", "type": "figure"}}}
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{"paper_id": "17431143", "_pdf_hash": "10b1671805e6118394e9078c1549ac312d2b1bbc", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Information extraction and automatic markup for xml documents", "authors": [{"first": "M", "middle": [], "last": "Abolhassani", "suffix": ""}, {"first": "N", "middle": [], "last": "Fuhr", "suffix": ""}, {"first": "N", "middle": [], "last": "G\u00f6vert", "suffix": ""}], "year": 2003, "venue": "Intelligent Search on XML Data", "link": "16475718"}, "BIBREF1": {"title": "Enriching very large ontologies using the www", "authors": [{"first": "E", "middle": [], "last": "Agirre", "suffix": ""}, {"first": "O", "middle": [], "last": "Ansa", "suffix": ""}, {"first": "E.-H", "middle": [], "last": "Hovy", "suffix": ""}, {"first": "D", "middle": [], "last": "Mart\u00ecnez", "suffix": ""}], "year": 2000, "venue": "ECAI Workshop on Ontology Learning", "link": "59687"}, "BIBREF2": {"title": "Lia-ismart at the trec 2011 entity track: Entity list completion using contextual unsupervised scores for candidate entities ranking", "authors": [{"first": "L", "middle": [], "last": "Bonnefoy", "suffix": ""}, {"first": "P", "middle": [], "last": "Bellot", "suffix": ""}], "year": 2011, "venue": "TREC", "link": "3020863"}, "BIBREF3": {"title": "A simple named entity extractor using adaboost", "authors": [{"first": "X", "middle": [], "last": "Carreras", "suffix": ""}, {"first": "L", "middle": [], "last": "S M Arque", "suffix": ""}, {"first": "L", "middle": [], "last": "Padro", "suffix": ""}], "year": 2003, "venue": "Proceedings of CoNLL-2003", "link": "12022794"}, "BIBREF4": {"title": "Cat\u00e9gorisation des noms propres : une\u00e9tude en corpus", "authors": [{"first": "B", "middle": [], "last": "Daille", "suffix": ""}, {"first": "N", "middle": [], "last": "Fourour", "suffix": ""}, {"first": "N", "middle": [], "last": "Morin", "suffix": ""}], "year": 2000, "venue": "chapter Cahiers de Grammaire", "link": null}, "BIBREF5": {"title": "Exploiting shallow linguistic information for relation extraction from biomedical literature", "authors": [{"first": "C", "middle": [], "last": "Giuliano", "suffix": ""}, {"first": "A", "middle": [], "last": "Lavelli", "suffix": ""}, {"first": "L", "middle": [], "last": "Romano", "suffix": ""}], "year": 2006, "venue": "Proceedings of the 11th Conference of the European Chapter of the Association for Computational Linguistics", "link": "6825083"}, "BIBREF6": {"title": "Explorations in Automatic Thesaurus Discovery", "authors": [{"first": "G", "middle": [], "last": "Grefenstette", "suffix": ""}], "year": 1994, "venue": "", "link": "59167516"}, "BIBREF7": {"title": "Using Term-Matching Algorithms for the Annotation of Geo-services", "authors": [{"first": "M", "middle": [], "last": "Gr\u010dar", "suffix": ""}, {"first": "E", "middle": [], "last": "Klien", "suffix": ""}, {"first": "B", "middle": [], "last": "Novak ; Dunja", "suffix": ""}, {"first": "Marco", "middle": [], "last": "Mladeni\u010d", "suffix": ""}, {"first": "Giovanni", "middle": [], "last": "Gemmis", "suffix": ""}, {"first": "Myra", "middle": [], "last": "Semeraro", "suffix": ""}, {"first": "Gerd", "middle": [], "last": "Spiliopoulou", "suffix": ""}, {"first": "", "middle": [], "last": "Stumme", "suffix": ""}], "year": 2009, "venue": "Knowledge Discovery Enhanced with Semantic and Social Information", "link": null}, "BIBREF8": {"title": "Text categorization with suport vector machines: Learning with many relevant features", "authors": [{"first": "T", "middle": [], "last": "Joachims", "suffix": ""}], "year": 1998, "venue": "ECML", "link": "2427083"}, "BIBREF9": {"title": "Associating spatial patterns to text-units for summarizing geographic information", "authors": [{"first": "J", "middle": [], "last": "Lesbegueries", "suffix": ""}, {"first": "C", "middle": [], "last": "Sallaberry", "suffix": ""}, {"first": "M", "middle": [], "last": "Gaio", "suffix": ""}], "year": 2006, "venue": "Proceedings of ACM SIGIR 2006. 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{"paper_id": "17431167", "_pdf_hash": "a04262498eb967afc076f48f831f98854d4db405", "abstract": [], "body_text": [{"section": "InTRODUcTIOn", "text": "Wegener's Granulomatosis (WG), also known as granulomatosis with polyangiitis is a systemic small-vessel vasculitides associated with anti-neutrophil cytoplasmic antibodies (AncA).\u00b9 WG is an uncommon and severe granulomatous necrotizing vasculitis, which affects the upper and lower respiratory tracts and kidneys.\u00b2 It can present with multiple pulmonary and renal lesions, including pulmonary nodule, cavitary lung lesions, fibrosis, and a rapidly progressive crescentic glomerulonephritis of the kidney.\u00b9,\u00b3 Gastrointestinal (GI) manifestations of WG are uncommon and gastric in-", "cite_spans": [], "ref_spans": []}, {"section": "ABSTRAcT", "text": "Wegener's granulomatosis is an uncommon inflammatory disease that manifests as vasculitis, granulomatosis, and necrosis. It usually involves the upper and lower respiratory tracts and kidneys. Although it may essentially involve any organ, gastrointestinal (GI) involvement is notably uncommon.", "cite_spans": [], "ref_spans": []}, {"section": "ABSTRAcT", "text": "A 20-year-old male patient presented with epigastric pain, vomiting, hematemesis, and melena. On physical examination, he was pale. There was no abdominal tenderness or organomegaly. Upper GI endoscopy revealed dark blue-colored infiltrative lesions in prepyloric area. Evaluation of the biopsy sample showed mononuclear cell infiltration in the submucosal area, hyperplastic polyp, and chronic gastritis. High dose proton pump inhibitor and adjunctive supportive measures were given but no change in the follow-up endoscopy was detected. During hospital course, he developed intermittent fever and serum creatinine elevation. 12 days after admission, he developed dyspnea, tachypnea, and painful swelling of metacarpophalangeal joints, and maculopapular rash in extensor surface of the right forearm. chest radiography showed pulmonary infiltration. Serum c-ANCA titer was strongly positive and skin biopsy revealed leukocytoclastic vasculitis. The patient received methylprednisolone pulse, which resulted in complete recovery of symptoms and gastric lesion. Upper Gastrointestinal Bleeding volvement is rare and non-specific. A review of literature showed only two cases in whom gastric involvement, as massive and frequent gastric hemorrhages were the presenting features. [4] [5] [6] cASE REPORT", "cite_spans": [{"start": 1277, "end": 1280, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 1281, "end": 1284, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 1285, "end": 1288, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "ABSTRAcT", "text": "A 20-year-old white male patient presented with epigastric pain, vomiting, hematemesis, and melena since 10 days prior to the admission. He had the history of recurrent sinusitis and frequent ibuprofen consumption. There was no other significant medical history and he was not an active smoker. He was conscious with stable vital signs, had nasal speech and no scleral icterus. Examination of neck, ears, and nose showed purulent post-nasal discharge. Heart, lung, and abdominal examinations were not remarkable. Upper GI endoscopy revealed blue black colored necrotic infiltrative lesions in prepyloric area (about 5 cm long). The biopsy revealed focal mononuclear cell infiltration in the mucosal area associated with active gastritis. There was no vasculitis or granuloma and also no organism was identified on Giemsa staining (figure 1).", "cite_spans": [], "ref_spans": []}, {"section": "ABSTRAcT", "text": "High dose proton pump inhibitor and adjunctive supportive measures were given but the patient had recurrent hematemesis. no visible changes in repeated endoscopies were detected. During the hospital course, he developed intermittent fever and elevation of serum creatinine. Serum hemoglobin level demonstrated decreasing pattern and two units of packed cells were transfused. In 12 days after admission, dyspnea-tachypnea, and painful swelling of metacarpophalangeal joints, and maculopapular rash in extensor surface of the right forearm were developed.", "cite_spans": [], "ref_spans": []}, {"section": "ABSTRAcT", "text": "On physical examination, pericardial friction rub, bilateral decreased breathing sounds, and basilar fine crackle were detected. chest radiography and high resolution computed tomography of the lung revealed high normal heart shadow, bilateral basilar alveolar opacities, and bilateral pleural effusions (figure 2). Echocardiography revealed pericardial effusion. Urinalysis revealed many dysmorphic RBcs without RBc casts and 8-10 WBcs/hpf. Serum creatinine level rose from 1 to 3.3 mg/dL. Leukocytosis (20700) with PMn dominancy was detected. After taking appropriate culture specimen, antibiotic was administered without any response. Other laboratory investigations showed the following data: serologic tests for hepatitis B, hepatitis c, and human immunodeficiency viruses showed negative results, electrolyte profile, and antinuclear antibodies were normal, c-reactive protein was 2+, and serum c-AncA (antineutrophil cytoplasmic antibody) titer was strongly positive (455.5). A biopsy of skin revealed leukocytoclastic vasculitis.", "cite_spans": [], "ref_spans": []}, {"section": "ABSTRAcT", "text": "According to clinical course and mentioned paraclinical findings diagnosis of WG was made on and treatment with methylprednisolone pulse 1000 mg daily was started. The patient showed clinical improvement and gradual disease resolution. Five days later, upper GI endoscopy A B showed significant improvement (figure 3). Treatment was continued by prescribing cyclophosphamide monthly pulse. Gastric lesion was completely healed and GI bleeding did not recur after 6 months follow-up. All pulmonary, renal, articular, and skin lesions were recovered.", "cite_spans": [], "ref_spans": []}, {"section": "DIScUSSIOn", "text": "Most patients with WG show multisystemic disease in clinical course. 7 However, GI involvement is very uncommon and is usually detected in autopsy studies. 8 Involvement of the GI tract in WG is relatively rare and usually occurs several years after the onset of initial symptoms and its treatment. 9, 10 A large prospective study of 158 patients with WG showed no gastrointestinal involvement throughout the course of disease. 1 The small bowel is the most common site involved by WG. 12, 13 clinically, gastrointestinal WG mimics inflammatory and infectious bowel diseases.", "cite_spans": [{"start": 69, "end": 70, "text": "7", "ref_id": "BIBREF6"}, {"start": 156, "end": 157, "text": "8", "ref_id": "BIBREF7"}, {"start": 299, "end": 301, "text": "9,", "ref_id": "BIBREF8"}, {"start": 302, "end": 304, "text": "10", "ref_id": "BIBREF9"}, {"start": 428, "end": 429, "text": "1", "ref_id": "BIBREF0"}, {"start": 486, "end": 489, "text": "12,", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "DIScUSSIOn", "text": "14 WG may mimic crohn's disease with granulomatous gastritis or ileitis, 15, 16 Inflammatory ileocolitis with hemorrhage, gangrenous cholecystitis, and bowel infarction, which have been reported earlier. 17 Furthermore, three patients with esophageal involvement were reported. A patient whose initial presentation of WG was odynophagia secondary to esophageal vasculitis was described in whom multiple punched out ulcerations in the esophagus were detected, which resolved by standard therapy for systemic WG. 18 In 1990, the American college of Rheumatology (ACR) established the criteria for the classification of WG as follows: (1) nasal or oral manifestation (painful or painless oral ulcers or purulent or bloody nasal discharge) (2) Abnormal chest radiography showing nodules, fixed infiltrates, or cavities (3) Abnormal urinary sediment (microscopic hematuria with or without red cell casts) and (4) Granulomatous inflammation on biopsy of an artery or perivascular area. Patients should have at least 2 of these 4 criteria to be labeled as having WG. 19 The diagnosis of WG was based on the clinical manifestations, imaging studies showing progressive multisystem involvements especially renal, and upper and lower respiratory tracts, skin biopsy, and presence of high titer of c-AncA. The diagnosis was further supported in our patient by mild leukocytosis and normocytic normochromic anemia. Presence of c-AncA or PR3-ANCA by immunofluorescence is recognized as a reliable and valuable diagnostic tool with high specificity in the absence of histopathological evaluation for the diagnosis of WG and is extremely helpful in differentiating WG from other diseases. 20 Occasionally, patients with infections, neoplasms, inflammatory bowel disease, sclerosing cholangitis, and other rheumatologic diseases develop AncA, but these are predominantly perinuclear AncAs (p-AncA) or exhibit an atypical staining pattern. 21 Our patient had a long history of recurrent sinusitis, which may represent a slowly progressive mild WG. He fulfilled three ACR criteria for diagnosis of WG. In addition, the diagnosis was further supported by mild leukocytosis and normocytic normochromic anemia and high titer of c-AncA.", "cite_spans": [{"start": 73, "end": 76, "text": "15,", "ref_id": "BIBREF14"}, {"start": 77, "end": 79, "text": "16", "ref_id": "BIBREF15"}, {"start": 204, "end": 206, "text": "17", "ref_id": "BIBREF16"}, {"start": 511, "end": 513, "text": "18", "ref_id": "BIBREF17"}, {"start": 1060, "end": 1062, "text": "19", "ref_id": "BIBREF18"}, {"start": 1674, "end": 1676, "text": "20", "ref_id": "BIBREF19"}, {"start": 1923, "end": 1925, "text": "21", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "DIScUSSIOn", "text": "The histological proof of necrotizing vasculitis is dependent on the depth of the biopsy and therefore, can be easily missed. 22 In our patient, stomach lesion appearance was not typical for peptic ulcer or tumoral mass. It was a blue black necrotic lesion and the biopsy was not diagnostic. Treatment was initiated with pulse of steroid and cyclophosphamide, according to the clinical course and laboratory findings especially high titer of c-ANCA. Response to treatment was achieved in short-term. Immunosuppressive therapy combined with routine antiulcer treatment has been shown very effective in repairing ulcerative lesions. 23 Application of aggressive immunotherapy in this disease is justified because survival in patients with untreated WG is extremely poor. 24 In conclusion, upper GI bleeding may be the first presenting feature of WG. considering this fact can lead to an early diagnosis and treatment, thereby to avoid unnecessary surgery and potential mortality.", "cite_spans": [{"start": 126, "end": 128, "text": "22", "ref_id": "BIBREF21"}, {"start": 631, "end": 633, "text": "23", "ref_id": "BIBREF22"}, {"start": 769, "end": 771, "text": "24", "ref_id": "BIBREF23"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Revisiting the classification of clinical phenotypes of anti-neutrophil cytoplasmic antibody-associated vasculitis: a cluster analysis", "authors": [{"first": "A", "middle": [], "last": "Mahr", "suffix": ""}, {"first": "S", "middle": [], "last": 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{"paper_id": "17431209", "_pdf_hash": "7f522b6992c0347c8c2dd82e2978bcb46b1084f7", "abstract": [{"section": "Abstract", "text": "The hierarchy in the Yukawa couplings may be the result of a gauged horizontal U (1) H symmetry. If the mixed anomalies of the Standard Model gauge group with U (1) H are cancelled by a Green-Schwarz mechanism, a relation between the gauge couplings, the Yukawa couplings and the \u00b5-term arises. Assuming that at a high energy scale g ", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "4/95", "text": "A possible intriguing relation between hierarchies in the fermion Yukawa couplings and unification of gauge couplings has been recently proposed by Bin\u00e9truy and Ramond [BR] [1] and by Ib\u00e1\u00f1ez and Ross [2] . The relation arises if anomalies of a gauged horizontal U (1) H symmetry are cancelled by a Green-Schwarz mechanism [3] . One of the basic assumptions of BR was that the \u00b5-term in the superpotential is neutral under U (1) H . In this work, we investigate the more general case, namely that the \u00b5-term carries an arbitrary charge. We point out that if we take that, at a high scale, (a) the gauge couplings satisfy", "cite_spans": [], "ref_spans": []}, {"section": "4/95", "text": "and (b) the fermion masses satisfy", "cite_spans": [], "ref_spans": []}, {"section": "4/95", "text": "(where \u03bb \u223c 0.2 is the small breaking parameter of U (1) H ), then the horizontal symmetry solves the \u00b5-problem with", "cite_spans": [], "ref_spans": []}, {"section": "4/95", "text": "We work in the framework of Supersymmetry and", "cite_spans": [], "ref_spans": []}, {"section": "4/95", "text": "gauge symmetry. We now list the assumptions that lead to our results. (We also show that some of the assumptions made by BR are actually not necessary for their result.)", "cite_spans": [], "ref_spans": []}, {"section": "4/95", "text": "1. The smallness and hierarchy among the Yukawa couplings is a result of a horizontal U (1) H symmetry that is broken by a single small parameter \u03bb(\u223c 0.2) whose charge under U (1) H is defined to be -1.", "cite_spans": [], "ref_spans": []}, {"section": "1", "text": "It follows that the order of magnitude of the various Yukawa couplings,", "cite_spans": [], "ref_spans": []}, {"section": "1", "text": "1 The parameter \u03bb is the ratio between the VEV of a SM-singlet scalar field that carries charge -1 under U (1) H and a somewhat higher scale where the information about U (1) H breaking is communicated to the light fermions [4] .", "cite_spans": [], "ref_spans": []}, {"section": "1", "text": "can be estimated by the following selection rules [5] :", "cite_spans": [], "ref_spans": []}, {"section": "1", "text": "The zeros, corresponding to negative charges, are a result of the holomorphy of the superpotential [5] . If there are no zero eigenvalues (as experimentally known for quarks and leptons, with the possible exception of", "cite_spans": [], "ref_spans": []}, {"section": "1", "text": "Note that (6) requires neither that third generation fermions acquire masses without horizontal suppression, nor that all excess charges in \u03bb This allows one to calculate the mixed anomalies", "cite_spans": [], "ref_spans": []}, {"section": "1", "text": "Y factors in the SM gauge group) in terms of the H-charges carried by the MSSM fields only. Explicitly [1] :", "cite_spans": [], "ref_spans": []}, {"section": "1", "text": "2 The fields required by the Froggatt-Nielsen mechanism [4] are either SM-singlets or in vector representations, consistent with this assumption.", "cite_spans": [], "ref_spans": []}, {"section": "1", "text": "determinants of the fermion mass matrices, the VEVs of the Higgs doublets and the sum of Higgs charges", "cite_spans": [], "ref_spans": []}, {"section": "1", "text": "These are", "cite_spans": [], "ref_spans": []}, {"section": "1", "text": "The reason that there are only two independent relations is that the Yukawa couplings", "cite_spans": [], "ref_spans": []}, {"section": "1", "text": "The Yukawa sector has yet another accidental symmetry, U (1) X , with X(", "cite_spans": [], "ref_spans": []}, {"section": "1", "text": "and all other supermultiplets carrying X = 0. One combination of the anomalies is U (1) X invariant and should, therefore, appear in an H(\u03c6)-independent relation. Indeed, dividing (10) by (9), we get", "cite_spans": [], "ref_spans": []}, {"section": "1", "text": "The LHS of this relation can be estimated to be < \u223c O(m s m c ) (assuming approximate geometrical hierarchies and det", "cite_spans": [], "ref_spans": []}, {"section": "1", "text": "the mixed anomalies cannot vanish simultaneously. This conclusion is independent of H(\u03c6).", "cite_spans": [], "ref_spans": []}, {"section": "1", "text": "If U (1) H is a local symmetry, there should exist a mechanism to cancel these anomalies.", "cite_spans": [], "ref_spans": []}, {"section": "1", "text": "3. The mixed anomalies are cancelled by a Green-Schwarz mechanism [7] , with Im(S) playing the role of the U (1) H axion (S stands for the dilaton supermultiplet).", "cite_spans": [], "ref_spans": []}, {"section": "This is possible only if [3]", "text": "where k i are the Kac-Moody levels and \u03b4 GS is a constant that gives the transformation law of the axion under U (1) H . In general, k 2 and k 3 are integers and k 1 is a rational number.", "cite_spans": [], "ref_spans": []}, {"section": "This is possible only if [3]", "text": "The gauge couplings for the SM gauge group are given (at the string scale) by", "cite_spans": [], "ref_spans": []}, {"section": "This is possible only if [3]", "text": "We can then relate the mixed anomalies to the gauge couplings:", "cite_spans": [], "ref_spans": []}, {"section": "This is possible only if [3]", "text": "We next turn our attention to another relation that results from (9) and (10) and is independent of \u03c6 u , \u03c6 d :", "cite_spans": [], "ref_spans": []}, {"section": "This is possible only if [3]", "text": "Using (14) we can rewrite (15) as", "cite_spans": [], "ref_spans": []}, {"section": "This is possible only if [3]", "text": "Before proceeding with the analysis of (16), we would like to discuss the relation between H(\u03c6) and the \u00b5-problem. H(\u03c6) is the horizontal charge carried by the \u00b5 term in the superpotential,", "cite_spans": [], "ref_spans": []}, {"section": "This is possible only if [3]", "text": "The \u00b5-term is special in that it can come from two sources: it may arise from the high energy superpotential, in which case it is holomorphic and its natural scale is unknown (but most likely \u223c M P l ); or it may arise from the K\u00e4hler potential, in which case it is not holomorphic and its natural scale is the SUSY breaking scale [8] . In other words, the selection rule for \u00b5 is", "cite_spans": [], "ref_spans": []}, {"section": "This is possible only if [3]", "text": "where\u03bc is the unknown natural scale of \u00b5 (most likely\u03bc \u223c M P l ). This suggests that the horizontal symmetry may actually solve the \u00b5-problem: if the charge carried by the \u00b5-term is negative, then it cannot come from the superpotential and its natural scale is m 3/2 . Note, however, that the charge cannot be too negative, because \u00b5 \u226a m 3/2 is phenomenologically unacceptable. With \u03bb \u223c 0.2, we can allow H(\u03c6) = \u22121, which would give \u00b5/m 3/2 \u223c \u03bb. We conclude that a continuous horizontal symmetry can solve the \u00b5-problem. The solution requires an almost unique choice of charge, namely that the \u00b5-term carries one negative unit of the horizontal charge.", "cite_spans": [], "ref_spans": []}, {"section": "This is possible only if [3]", "text": "Eq. (18) gives a new interpretation of (16); it is a relation between Yukawa couplings, the gauge couplings and the \u00b5-term. For example, if H(\u03c6) < 0, (16) can be rewritten as", "cite_spans": [], "ref_spans": []}, {"section": "This is possible only if [3]", "text": "BR made the following further three assumptions:", "cite_spans": [], "ref_spans": []}, {"section": "This is possible only if [3]", "text": "Then (16) leads to the interesting result sin", "cite_spans": [], "ref_spans": []}, {"section": "This is possible only if [3]", "text": ", in perfect agreement with extrapolated phenomenology. The weakest assumption in this derivation is that of H(\u03c6) = 0 which is just the rather arbitrary ansatz that \u00b5 is unsuppressed relative to\u03bc (which is unknown).", "cite_spans": [], "ref_spans": []}, {"section": "This is possible only if [3]", "text": "The way in which we will proceed is to use the extrapolated phenomenology to make assumptions about the gauge couplings and the Yukawa couplings and find the consequences for H(\u03c6) and the \u00b5-term. Specifically, we make the following assumptions, which are based on running the various gauge and Yukawa couplings to the high scale:", "cite_spans": [], "ref_spans": []}, {"section": "This is possible only if [3]", "text": "4. At the string scale, the gauge couplings satisfy ", "cite_spans": [], "ref_spans": []}, {"section": "This is possible only if [3]", "text": "which is just the right value to solve the \u00b5-problem (see (19))", "cite_spans": [], "ref_spans": []}, {"section": "This is possible only if [3]", "text": "To summarize: if anomalies in a gauged horizontal U (1) symmetry are cancelled by a GS mechanism, then interesting relations among gauge couplings, Yukawa couplings and the \u00b5 term arise. The values of the gauge and Yukawa couplings, when extrapolated from their measured low energy values, imply that the scale of the \u00b5 term is below (but not far below) the SUSY breaking scale.", "cite_spans": [], "ref_spans": []}, {"section": "This is possible only if [3]", "text": "While this paper was in writing, we received a preprint by Dudas, Pokorski and Savoy [9] that also investigates the general H(\u03c6) case.", "cite_spans": [{"start": 85, "end": 88, "text": "[9]", "ref_id": "BIBREF9"}], "ref_spans": []}], "bib_entries": {"BIBREF5": {"title": "hep-ph/9403203, to appear in the Proc. of the Yukawa Couplings and the Origins of Mass Workshop", "authors": [{"first": "See", "middle": ["T"], "last": "For A Recent Review", "suffix": ""}, {"first": "Y", "middle": [], "last": "Banks", "suffix": ""}, {"first": "N", "middle": [], "last": "Nir", "suffix": ""}, {"first": "", "middle": [], "last": "Seiberg", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF9": {"title": "SPhT Saclay T95/027", "authors": [{"first": "E", "middle": [], "last": "Dudas", "suffix": ""}, {"first": "S", "middle": [], "last": "Pokorski", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Savoy", "suffix": ""}], "year": 1995, "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "(m e m \u00b5 m \u03c4 )/(m d m s m b ) \u223c \u03bb (where \u03bb is of the order of the Cabibbo angle), the U (1) H symmetry solves the \u00b5-problem with \u00b5 \u223c \u03bbm 3/2 .", "type": "figure"}, "FIGREF1": {"text": "ij are positive (two assumptions made by BR). It only requires that all fermion masses are non-zero, and so it holds in any phenomenologically acceptable model. 2. The only fields that are in chiral representations of U (1) H and transform non- trivially under the SM gauge group are the MSSM supermultiplets.", "type": "figure"}}}
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Explanation of Program Designs", "authors": [{"first": "M", "middle": [], "last": "Moriconi", "suffix": ""}, {"first": "D", "middle": ["F"], "last": "Hare", "suffix": ""}], "year": 1985, "venue": "Proc. of ACM SIGPLAN '85 Symp. on Language Issues in Programming Environments", "link": "14078547"}, "BIBREF34": {"title": "The Pegasys System: Pictures as Formal Documentation of Large Programs", "authors": [{"first": "M", "middle": [], "last": "Moriconi", "suffix": ""}, {"first": "D", "middle": ["F"], "last": "Hare", "suffix": ""}], "year": 1986, "venue": "TPLS", "link": "11142089"}, "BIBREF35": {"title": "On Proving Inductive Properties of Abstract Data Types", "authors": [{"first": "D", "middle": ["R"], "last": "Musser", "suffix": ""}], "year": 1980, "venue": "", "link": "13820406"}, "BIBREF36": {"title": "Abstract Data Type Specification in the AFFIRM system", "authors": [{"first": "D", "middle": ["R"], "last": "Musser", "suffix": ""}], "year": 1980, "venue": "", "link": "14053393"}, 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{"paper_id": "17431301", "_pdf_hash": "304992365558645b71b801b4ecc7c8872559fa68", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "A Two Stage Recognition Scheme for Handwritten Tamil Characters", "authors": [{"first": "U", "middle": [], "last": "Bhattacharya", "suffix": ""}, {"first": "S", "middle": ["K"], "last": "Ghosh", "suffix": ""}, {"first": "S", "middle": ["K"], "last": "Parui", "suffix": ""}], "year": 2007, "venue": "Ninth International Conference on Document Analysis and Recognition", "link": "62593015"}, "BIBREF1": {"title": "Neural network based offline Tamil handwritten char-acter recognition system", "authors": [{"first": "J", "middle": [], "last": "Sutha", "suffix": ""}, {"first": "N", "middle": [], "last": "Ramaraj", "suffix": ""}], "year": 2007, "venue": "Proceedings of ICCIMA07", "link": "7890989"}, "BIBREF2": {"title": "An attempt to recognize handwritten Tamil character using Kohonen SOM", "authors": [{"first": "R", "middle": ["I"], "last": "Gandhi", "suffix": ""}, {"first": "K", "middle": [], "last": "Iyakutti", "suffix": ""}], "year": 2009, "venue": "Int. J. Advanced Network. Appl", "link": null}, "BIBREF3": {"title": "Performance Comparison of Different Image Sizes for Recognizing Unconstrained Handwritten Tamil Characters using SVM", "authors": [{"first": "N", "middle": [], "last": "Shanthi", "suffix": ""}, {"first": "K", "middle": [], "last": "Duraiswamy", "suffix": ""}], "year": 2007, "venue": "Journal of Computer Science", "link": "17470340"}, "BIBREF4": {"title": "Character recognition using Dempster-Shafer theory combining different distance measurement methods", "authors": [{"first": "T", "middle": [], "last": "Sitamahalakshmi", "suffix": ""}, {"first": "V", "middle": [], "last": "Babu", "suffix": ""}, {"first": "M", "middle": [], "last": "Jagadeesh", "suffix": ""}], "year": 2010, "venue": "Int.J. Engin. Sci. Technol", "link": "17337165"}, "BIBREF5": {"title": "Classification and identification of Telugu handwritten characters extracted from palm leaves using decision tree approach", "authors": [{"first": "P", "middle": ["N"], "last": "Sastry", "suffix": ""}, {"first": "R", "middle": [], "last": "Krishnan", "suffix": ""}, {"first": "Ram", "middle": [], "last": "", "suffix": ""}, {"first": "B", "middle": [], "last": "", "suffix": ""}], "year": 2010, "venue": "J. Applied Engn. Sci", "link": "111037034"}, "BIBREF6": {"title": "Isolated Telugu Palm Leaf Character Recognition Using Radon Transform-A Novel Approach", "authors": [{"first": "Ramakrishnan", "middle": [], "last": "Panyam Narahari Sastry", "suffix": ""}, {"first": "", "middle": [], "last": "Krishnan", "suffix": ""}], "year": "", "venue": "2012 World Congress on Information and Commmunication Technologies", "link": null}, "BIBREF7": {"title": "Recognition of isolated handwritten Kannada vowels", "authors": [{"first": "S", "middle": ["K"], "last": "Sangame", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Ramteke", "suffix": ""}, {"first": "Rajkumar", "middle": [], "last": "Benne", "suffix": ""}], "year": 2009, "venue": "Advances in Computational Research", "link": "113600801"}, "BIBREF8": {"title": "Using Moments Features from Gabor Directional Images for Kannada Handwriting Character Recognition", "authors": [{"first": "M", "middle": [], "last": "L R Ragha", "suffix": ""}, {"first": "", "middle": [], "last": "Sasikumar", "suffix": ""}], "year": "", "venue": "International Conference and Workshop on Emerging Trends in Technology (ICWET 2010) TCET", "link": "10222666"}, "BIBREF9": {"title": "Probabilistic neural network based approach for handwritten character recognition", "authors": [{"first": "V", "middle": ["N. 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National conf. on Innovations in IT", "link": null}, "BIBREF12": {"title": "Discrete Curve Evolution Based Skeleton Pruning for Character Recognition", "authors": [{"first": "P", "middle": [], "last": "Binu", "suffix": ""}, {"first": "Babu", "middle": [], "last": "Chacko", "suffix": ""}, {"first": "P", "middle": [], "last": "Anto", "suffix": ""}], "year": 2009, "venue": "Seventh International Conference on Advances in Pattern Recognition", "link": "21114057"}, "BIBREF13": {"title": "A differential chain code histogram based approach for offline Malayalam character recognition", "authors": [{"first": "Anitha", "middle": [], "last": "Mary", "suffix": ""}, {"first": "M", "middle": ["O"], "last": "Chacko", "suffix": ""}, {"first": "P", "middle": ["M"], "last": "Dhanya", "suffix": ""}], "year": 2014, "venue": "International Conference on Communication and Computing (ICC-2014)", "link": null}, "BIBREF14": {"title": "Offline Malayalam Character Recognition Using Global and Local Features", "authors": [{"first": "Anitha", "middle": [], "last": "Mary", "suffix": ""}, {"first": "M", "middle": ["O"], "last": "Chacko", "suffix": ""}, {"first": "P", "middle": ["M"], "last": "Dhanya", "suffix": ""}], "year": 2014, "venue": "Proceedings of the Second International Conference on Emerging Research in Computing, Information, Communication and Applications", "link": null}, "BIBREF15": {"title": "Combining Classifiers for Offline Malayalam Character Recognition Emerging ICT for Bridging the Future", "authors": [{"first": "Anitha", "middle": [], "last": "Mary", "suffix": ""}, {"first": "M", "middle": ["O"], "last": "Chacko", "suffix": ""}, {"first": "P", "middle": ["M"], "last": "Dhanya", "suffix": ""}], "year": 2015, "venue": "Advances in Intelligent Systems and Computing", "link": null}, "BIBREF16": {"title": "Offline Handwritten Malayalam Recognition Based on Chain Code Histogram", "authors": [{"first": "Jomy", "middle": [], "last": "John", "suffix": ""}, {"first": "K", "middle": ["V"], "last": "Pramod", "suffix": ""}, {"first": "Kannan", "middle": [], "last": "Balakrishnan", "suffix": ""}], "year": 2011, "venue": "Proceedings of ICETECT", "link": null}}, "ref_entries": {}}
{"paper_id": "17431904", "_pdf_hash": "6ebbb82da3009ea769466b1e363f4aec969fece9", "abstract": [{"section": "Abstract", "text": "The paper presents a description of the dynamic properties of cohesive material, namely silty clays, obtained by using one of the applied seismology methods, the bender elements technique. The authors' aim was to present the dynamics of a porous medium, in particular an extremely important passage of seismic waves that travel through the bulk of a medium. Nowadays, the application of the bender element (BE) technique to measure, e.g., small strain shear stiffness of soils in the laboratory is well recognized, since it allows for reliable and relatively economical shear wave velocity measurements during various laboratory experiments. However, the accurate estimation of arrival time during BE tests is in many cases unclear. Two different interpretation procedures (from the time domain) of BE tests in order to measure travel times of waves were examined. Those values were then used to calculate shear and compression wave velocities and elastic moduli. Results showed that the dynamic parameters obtained by the start-to-start method were always slightly larger (up to about 20%) than those obtained using the peak-to-peak one. It was found that the peak-to-peak method led to more scattered results in comparison to the start-to-start method. Moreover, the influence of the excitation frequency, the mean effective stress and the unloading process on the dynamic properties of the tested material was studied. In addition, the obtained results highlighted the importance of initial signal frequency and the necessity to choose an appropriate range of frequencies to measure the shear wave velocity in clayey soils.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "The determination of seismic velocities, as well as the elasticity modulus and structural properties of porous materials plays an extremely important role in the development of various engineering projects [1] . The small strain and elastic moduli, such as the shear modulus (G max ) and Young's modulus (E max ), are key parameters during, for example, the site response analysis of an earthquake, the design of machine foundations and soil dynamics problems [2] . Burland et al. [3] even emphasized the significance of G max in static deformation analysis of geotechnical problems. Usually, the above-mentioned elastic modulus of soil deposits is measured in situ by means of so-called seismic exploration [4] . In order to evaluate the shear modulus (G) or Young's modulus (E) values in the laboratory, triaxial or torsional shear testing machines, which employ what is generally known as the static loading methods [5] , are applied. Other kinds of evaluation methods, commonly referred to as vibration test methods, are those relying on applying wave motions to the test specimens and then observing their behavior during the resonance, including free oscillation time. A great example is a resonant column apparatus. Apart from this, there are also pulse transmission techniques, which include the ultrasonic pulse test, bender element (BE), etc. They allow calculating G max at small strains on the basis of the wave velocity [6] .", "cite_spans": [{"start": 206, "end": 209, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 460, "end": 463, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 481, "end": 484, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 708, "end": 711, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 919, "end": 922, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 1433, "end": 1436, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Introduction", "text": "Some of the laboratory tests and field studies, such as cross-hole seismic [7, 8] , down-hole seismic [9] , suspension logging [10] , seismic cone [11] , seismic flat dilatometer [12] and spectral analysis of seismic waves [13] , are indirect tests [14] . Compared to direct tests, the indirect tests enable measuring quantities different from the more desired ones and relate them to each other through mathematical relationships. Seismic techniques are classified as indirect testing methods for small strain stiffness [7] . They yield profiles of wave propagation velocity. When we assume that the behavior of the material is linear-elastic, this means that elastic stiffness relates to wave propagation velocity following the equations below:", "cite_spans": [{"start": 75, "end": 78, "text": "[7,", "ref_id": "BIBREF6"}, {"start": 79, "end": 81, "text": "8]", "ref_id": "BIBREF7"}, {"start": 102, "end": 105, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 127, "end": 131, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 147, "end": 151, "text": "[11]", "ref_id": "BIBREF11"}, {"start": 179, "end": 183, "text": "[12]", "ref_id": "BIBREF12"}, {"start": 223, "end": 227, "text": "[13]", "ref_id": "BIBREF13"}, {"start": 249, "end": 253, "text": "[14]", "ref_id": "BIBREF14"}, {"start": 521, "end": 524, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Introduction", "text": "where \u03c5 P is the propagation velocity of pressure, which might as well be called a primary (P-) wave velocity, \u03c5 S is the propagation velocity of shear or the secondary (S-) wave and \u03bb and G are Lame's constants (another term for G is the shear modulus). For engineers, it is more convenient to express Lame's constant as a function of Young's modulus and Poisson's ratio in accordance with these equations:", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "\u03bb \" \u03bdE p1`\u03bdqp1\u00b42\u03bdq (4) Figure 1 illustrates the particle motion in P-and S-waves.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Appl. Sci. 2016, 6, 49 2 of 21 commonly referred to as vibration test methods, are those relying on applying wave motions to the test specimens and then observing their behavior during the resonance, including free oscillation time. A great example is a resonant column apparatus. Apart from this, there are also pulse transmission techniques, which include the ultrasonic pulse test, bender element (BE), etc. They allow calculating Gmax at small strains on the basis of the wave velocity [6] . Some of the laboratory tests and field studies, such as cross-hole seismic [7, 8] , down-hole seismic [9] , suspension logging [10] , seismic cone [11] , seismic flat dilatometer [12] and spectral analysis of seismic waves [13] , are indirect tests [14] . Compared to direct tests, the indirect tests enable measuring quantities different from the more desired ones and relate them to each other through mathematical relationships. Seismic techniques are classified as indirect testing methods for small strain stiffness [7] . They yield profiles of wave propagation velocity. When we assume that the behavior of the material is linear-elastic, this means that elastic stiffness relates to wave propagation velocity following the equations below:", "cite_spans": [{"start": 490, "end": 493, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 571, "end": 574, "text": "[7,", "ref_id": "BIBREF6"}, {"start": 575, "end": 577, "text": "8]", "ref_id": "BIBREF7"}, {"start": 598, "end": 601, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 623, "end": 627, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 643, "end": 647, "text": "[11]", "ref_id": "BIBREF11"}, {"start": 675, "end": 679, "text": "[12]", "ref_id": "BIBREF12"}, {"start": 719, "end": 723, "text": "[13]", "ref_id": "BIBREF13"}, {"start": 745, "end": 749, "text": "[14]", "ref_id": "BIBREF14"}, {"start": 1017, "end": 1020, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Introduction", "text": "where \u03c5P is the propagation velocity of pressure, which might as well be called a primary (P-) wave velocity, \u03c5S is the propagation velocity of shear or the secondary (S-) wave and \u03bb and G are Lame's constants (another term for G is the shear modulus). For engineers, it is more convenient to express Lame's constant as a function of Young's modulus and Poisson's ratio in accordance with these equations:", "cite_spans": [], "ref_spans": []}, {"section": "2(1 )", "text": "\u03bb (1 )(1 2 ) E \u03bd = + \u03bd \u2212 \u03bd (4) Figure 1 illustrates the particle motion in P-and S-waves. Figure 1 . P-wave (top) and S-wave (bottom) particle motion. The particle motion in P-waves is longitudinal, while in S-waves, it is transverse. The particle motion vector in the plane perpendicular to the direction of propagation is referred to as polarization (only in the case of S-waves) [8] .", "cite_spans": [{"start": 382, "end": 385, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "2(1 )", "text": "Over the years, bender elements have become increasingly popular in order to determine the S-wave velocity [9, 10] through experiments. Nowadays, they are commonly available [11, 12] . Bender elements consist of two sheets produced from piezoceramic plates, which are rigidly bonded, to a center brass shim or stainless steel plate. Because of their piezoelectric properties, they are capable of converting mechanical excitation into electrical output and vice versa. When excited by an Figure 1 . P-wave (top) and S-wave (bottom) particle motion. The particle motion in P-waves is longitudinal, while in S-waves, it is transverse. The particle motion vector in the plane perpendicular to the direction of propagation is referred to as polarization (only in the case of S-waves) [8] .", "cite_spans": [{"start": 107, "end": 110, "text": "[9,", "ref_id": "BIBREF8"}, {"start": 111, "end": 114, "text": "10]", "ref_id": "BIBREF9"}, {"start": 174, "end": 178, "text": "[11,", "ref_id": "BIBREF11"}, {"start": 179, "end": 182, "text": "12]", "ref_id": "BIBREF12"}, {"start": 779, "end": 782, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "2(1 )", "text": "Over the years, bender elements have become increasingly popular in order to determine the S-wave velocity [9, 10] through experiments. Nowadays, they are commonly available [11, 12] . Bender elements consist of two sheets produced from piezoceramic plates, which are rigidly bonded, to a center brass shim or stainless steel plate. Because of their piezoelectric properties, they are capable of converting mechanical excitation into electrical output and vice versa. When excited by an input voltage, the bender element changes its shape, which is accompanied by mechanical excitation. Because of this fact, it acts as a signal transmitter. Being subjected to mechanical excitation causes the emission of an electrical output by another bender element, which is, in this way, acting as a signal receiver [9] .", "cite_spans": [{"start": 107, "end": 110, "text": "[9,", "ref_id": "BIBREF8"}, {"start": 111, "end": 114, "text": "10]", "ref_id": "BIBREF9"}, {"start": 174, "end": 178, "text": "[11,", "ref_id": "BIBREF11"}, {"start": 179, "end": 182, "text": "12]", "ref_id": "BIBREF12"}, {"start": 805, "end": 808, "text": "[9]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "2(1 )", "text": "The first person to use piezoceramic elements bonded to shear plates was probably Lawrence [13, 14] . His idea was to measure the velocity of the shear wave in materials, such as clay and sand. In 1978, Shirley [15] proposed the introduction of piezoceramic bender elements to determine S-wave velocity in the laboratory. Other scientists, like Dyvik and Madshus [16] , described the incorporation of BE for geotechnical laboratory testing in the 1980s.", "cite_spans": [{"start": 91, "end": 95, "text": "[13,", "ref_id": "BIBREF13"}, {"start": 96, "end": 99, "text": "14]", "ref_id": "BIBREF14"}, {"start": 211, "end": 215, "text": "[15]", "ref_id": "BIBREF15"}, {"start": 363, "end": 367, "text": "[16]", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "2(1 )", "text": "The appeal of the BE technique lies in its apparent simplicity: one of the transducers is excited at one end of a specimen by a single pulse excitation, and the second, located at the other end of a specimen, is receiving it. The time required for this process can be simply read off from an oscilloscope. On the basis of this value, shear wave velocity can be obtained [17] . Therefore, BEs are an inexpensive and versatile solution, which can be used for laboratory seismic measurement. Furthermore, their capabilities of monitoring the process of stiffening with effective stresses, namely cementation, load stabilization, curing or consolidation, are particularly appealing [18] . However, there is a critical drawback connected with a BE test that contributes to many errors, namely the determination of the travel time. A number of researchers, including Viggiani and Atkinson (1995) , attempted to use various methods in order to find the arrival time in order to reduce the degree of subjectivity [19] . In 2005, Lee and Santamarina [20] , as well as Leong et al. [21] reported a method of travel time determination, by performing a bender element test. Nevertheless, there are still some differences between the first arrival of the S-wave and the preferred input wave. Therefore, the BE technique still needs to be verified with respect to how reliable it is, when it comes to calculation of the arrival time [2, 22] .", "cite_spans": [{"start": 370, "end": 374, "text": "[17]", "ref_id": "BIBREF17"}, {"start": 678, "end": 682, "text": "[18]", "ref_id": "BIBREF18"}, {"start": 861, "end": 889, "text": "Viggiani and Atkinson (1995)", "ref_id": "BIBREF20"}, {"start": 1005, "end": 1009, "text": "[19]", "ref_id": "BIBREF20"}, {"start": 1041, "end": 1045, "text": "[20]", "ref_id": "BIBREF21"}, {"start": 1072, "end": 1076, "text": "[21]", "ref_id": "BIBREF22"}, {"start": 1419, "end": 1422, "text": "[2,", "ref_id": "BIBREF1"}, {"start": 1423, "end": 1426, "text": "22]", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "2(1 )", "text": "The intention of the authors of this paper was to recognize the dynamic characteristics of the cohesive medium through the performance of the BE tests on this material, i.e., clayey soil, obtained from the area of Warsaw, the capital of Poland, at various effective confining pressures under saturated conditions. Two methods, namely peak-to-peak and start-to-start, were used to determine the travel time using the BE technique. The \u03c5 S was calculated on this basis. Subsequently, shear modulus (G) was obtained using the value of shear wave velocity. Additionally, the authors used piezoceramic elements to determine compression wave velocity (\u03c5 P ). Furthermore, they tried to evaluate the values of dynamic Poisson's ratio (\u03bd d ). The dynamic Poisson's ratio of soil deposits is a matter that has attracted rather little attention so far [23] . Nevertheless, it significantly affects stresses, strains, wave propagation characteristics in a mass of soils and other important types of soil deposit behavior during dynamic excitation [4] . In this paper, \u03bd d was calculated from the results of measurements of longitudinal and shear wave velocities in seismic exploration and then used to establish Young's modulus (E). The authors also studied the possible impact of unloading on the received values of elastic modulus.", "cite_spans": [{"start": 842, "end": 846, "text": "[23]", "ref_id": "BIBREF24"}, {"start": 1036, "end": 1039, "text": "[4]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Methods and Materials", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Test Equipment", "text": "For the experiments, the authors employed a Stokoe fixed-free type of resonant column, manufactured in 2009 by the British company GDS Instruments Ltd, with its office in Hook, Hampshire, U.K. A detailed description of this device is contained in the authors' other publications [24, 25] and will not be discussed in this paper. The BEs, produced as well by GDS Instruments Ltd in 2009, were installed in the above-mentioned resonant column apparatus. The GDS bender elements are made from piezoelectric ceramic bimorphs. Two sheets are bonded together with a metal shim in between them. Excitation voltage is used to produce a displacement in the source transducer, resulting in a wave being sent through the sample. This wave generates a displacement in the receiver, which induces a voltage that can be measured.", "cite_spans": [{"start": 279, "end": 283, "text": "[24,", "ref_id": "BIBREF25"}, {"start": 284, "end": 287, "text": "25]", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "Test Equipment", "text": "The GDS bender elements come in the form of an insert that can be mounted in a top cap or a pedestal ( Figure 2 ). This makes them easy to replace and able to be used with a wide range of triaxial cells. The insert for the base pedestal is made of stainless steel, while the one for the top cap is made of titanium. This reduces the weight by half and minimizes the axial load caused by the top cap, which is cells. The insert for the base pedestal is made of stainless steel, while the one for the top cap is made of titanium. This reduces the weight by half and minimizes the axial load caused by the top cap, which is being applied to the sample. The inserts are embedded in a modified Perspex top cap and stainless steel base pedestal. At the same time, the top cap and the base pedestal are mounted on the specimen in the same way, as during a conventional triaxial test [26] . The S-wave source comprises two piezoceramic strips both polarized in the same direction. The application of an excitation voltage induces the extension of one strip and the contraction of the other, causing the strip to bend. Turning the excitation voltage in the opposite direction contributes to strips bending reversely. The two strips in the receiver are polarized in opposite directions. The P-wave source consists of two piezoceramic strips polarized conversely. When an excitation voltage is applied, strips extend simultaneously. Reversion of the excitation voltage causes the strips to contract [26] .", "cite_spans": [{"start": 876, "end": 880, "text": "[26]", "ref_id": "BIBREF27"}, {"start": 1488, "end": 1492, "text": "[26]", "ref_id": "BIBREF27"}], "ref_spans": [{"start": 103, "end": 111, "text": "Figure 2", "ref_id": "FIGREF0"}]}, {"section": "Test Equipment", "text": "In Figure 3 , the BE arrangement adopted for the presented experiments is shown. Elements are manufactured to allow both S-and P-wave testing to be performed (in opposite propagation directions) on the same sample. The software switches input gain levels (of the received signal), sets the level of the output signal voltage and controls switching between P-and S-wave modes for our combined wave type elements [26] . In the current research, bender elements were used to obtain \u03c5VH velocities, propagating in the vertical plane (index V), polarized in the horizontal (index H). When performing a bender element test, one of its most important aspects is the phase orientation of the elements. The authors always checked the relationship between the received signals with respect to the source signal. The desirable orientation was \"in-phase\". If the orientation was correct, the source and received traces were exactly \"in-line\". An example of non-desirable output is presented in Figure 4 . The source signal and the received one are not simultaneously upward. The S-wave source comprises two piezoceramic strips both polarized in the same direction. The application of an excitation voltage induces the extension of one strip and the contraction of the other, causing the strip to bend. Turning the excitation voltage in the opposite direction contributes to strips bending reversely. The two strips in the receiver are polarized in opposite directions. The P-wave source consists of two piezoceramic strips polarized conversely. When an excitation voltage is applied, strips extend simultaneously. Reversion of the excitation voltage causes the strips to contract [26] .", "cite_spans": [{"start": 411, "end": 415, "text": "[26]", "ref_id": "BIBREF27"}, {"start": 1668, "end": 1672, "text": "[26]", "ref_id": "BIBREF27"}], "ref_spans": [{"start": 3, "end": 11, "text": "Figure 3", "ref_id": "FIGREF1"}, {"start": 982, "end": 990, "text": "Figure 4", "ref_id": "FIGREF6"}]}, {"section": "Test Equipment", "text": "In Figure 3 , the BE arrangement adopted for the presented experiments is shown. Elements are manufactured to allow both S-and P-wave testing to be performed (in opposite propagation directions) on the same sample. The software switches input gain levels (of the received signal), sets the level of the output signal voltage and controls switching between P-and S-wave modes for our combined wave type elements [26] . In the current research, bender elements were used to obtain \u03c5 V H velocities, propagating in the vertical plane (index V), polarized in the horizontal (index H). When performing a bender element test, one of its most important aspects is the phase orientation of the elements. The authors always checked the relationship between the received signals with respect to the source signal. The desirable orientation was \"in-phase\". If the orientation was correct, the source and received traces were exactly \"in-line\". An example of non-desirable output is presented in Figure 4 . The source signal and the received one are not simultaneously upward. The S-wave source comprises two piezoceramic strips both polarized in the same direction. The application of an excitation voltage induces the extension of one strip and the contraction of the other, causing the strip to bend. Turning the excitation voltage in the opposite direction contributes to strips bending reversely. The two strips in the receiver are polarized in opposite directions. The P-wave source consists of two piezoceramic strips polarized conversely. When an excitation voltage is applied, strips extend simultaneously. Reversion of the excitation voltage causes the strips to contract [26] .", "cite_spans": [{"start": 411, "end": 415, "text": "[26]", "ref_id": "BIBREF27"}, {"start": 1670, "end": 1674, "text": "[26]", "ref_id": "BIBREF27"}], "ref_spans": [{"start": 3, "end": 11, "text": "Figure 3", "ref_id": "FIGREF1"}, {"start": 984, "end": 992, "text": "Figure 4", "ref_id": "FIGREF6"}]}, {"section": "Test Equipment", "text": "In Figure 3 , the BE arrangement adopted for the presented experiments is shown. Elements are manufactured to allow both S-and P-wave testing to be performed (in opposite propagation directions) on the same sample. The software switches input gain levels (of the received signal), sets the level of the output signal voltage and controls switching between P-and S-wave modes for our combined wave type elements [26] . In the current research, bender elements were used to obtain \u03c5VH velocities, propagating in the vertical plane (index V), polarized in the horizontal (index H). When performing a bender element test, one of its most important aspects is the phase orientation of the elements. The authors always checked the relationship between the received signals with respect to the source signal. The desirable orientation was \"in-phase\". If the orientation was correct, the source and received traces were exactly \"in-line\". An example of non-desirable output is presented in Figure 4 . The source signal and the received one are not simultaneously upward. ", "cite_spans": [{"start": 411, "end": 415, "text": "[26]", "ref_id": "BIBREF27"}], "ref_spans": [{"start": 3, "end": 11, "text": "Figure 3", "ref_id": "FIGREF1"}, {"start": 982, "end": 990, "text": "Figure 4", "ref_id": "FIGREF6"}]}, {"section": "Methods of Interpretation of BE Results", "text": "The BE technique has many advantages, which have been mentioned so far, but the interpretation of BE results can often be questionable [18, 22, 27] . A number of methods for the analysis of bender element results are commonly used in the time or frequency domain [17, 28] . The time domain methods are classified as direct measurements, which use plots of electrical signals versus time [19, 29] . These methods employ a time-based axis in order to identify the propagation time, hence [6] . In frequency domain approaches, on the other hand, the spectral breakdown of the signals is analyzed, and the shift in the phase angle between the trigger and response signal is calculated [19, 30] . The time domain techniques are generally simpler and more straightforward, as the travel time can be directly defined by studying the time interval between characteristic points in the transmitted and received wave traces. However, the frequency domain methods appear to be more detailed, since they employ the support of signal processing and spectrum analysis tools. Additionally, they enable automated data acquisition and processing [18] . It is important to note that no method of interpreting the BE test results is yet proven superior to the others [6, 19, 31] . Reliable determination of travel time is very significant, due to BEs being installed in laboratory equipment and their application for studying relatively small specimens, which means that the travel distance is quite small. Below, the authors briefly present the methods of determining the arrival time of the shear wave that were employed in the paper. These are further illustrated in Figure 5 . The peak-to-peak method [19, 28] is based on the assumption that the received signal bears a high resemblance to the transmitted one. The travel time may be treated as the time elapsed between ", "cite_spans": [{"start": 135, "end": 139, "text": "[18,", "ref_id": "BIBREF18"}, {"start": 140, "end": 143, "text": "22,", "ref_id": "BIBREF23"}, {"start": 144, "end": 147, "text": "27]", "ref_id": "BIBREF28"}, {"start": 263, "end": 267, "text": "[17,", "ref_id": "BIBREF17"}, {"start": 268, "end": 271, "text": "28]", "ref_id": "BIBREF29"}, {"start": 387, "end": 391, "text": "[19,", "ref_id": "BIBREF20"}, {"start": 392, "end": 395, "text": "29]", "ref_id": "BIBREF30"}, {"start": 486, "end": 489, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 681, "end": 685, "text": "[19,", "ref_id": "BIBREF20"}, {"start": 686, "end": 689, "text": "30]", "ref_id": "BIBREF31"}, {"start": 1129, "end": 1133, "text": "[18]", "ref_id": "BIBREF18"}, {"start": 1248, "end": 1251, "text": "[6,", "ref_id": "BIBREF5"}, {"start": 1252, "end": 1255, "text": "19,", "ref_id": "BIBREF20"}, {"start": 1256, "end": 1259, "text": "31]", "ref_id": "BIBREF32"}, {"start": 1686, "end": 1690, "text": "[19,", "ref_id": "BIBREF20"}, {"start": 1691, "end": 1694, "text": "28]", "ref_id": "BIBREF29"}], "ref_spans": [{"start": 1651, "end": 1659, "text": "Figure 5", "ref_id": "FIGREF7"}]}, {"section": "Methods of Interpretation of BE Results", "text": "The BE technique has many advantages, which have been mentioned so far, but the interpretation of BE results can often be questionable [18, 22, 27] . A number of methods for the analysis of bender element results are commonly used in the time or frequency domain [17, 28] . The time domain methods are classified as direct measurements, which use plots of electrical signals versus time [19, 29] . These methods employ a time-based axis in order to identify the propagation time, hence [6] . In frequency domain approaches, on the other hand, the spectral breakdown of the signals is analyzed, and the shift in the phase angle between the trigger and response signal is calculated [19, 30] . The time domain techniques are generally simpler and more straightforward, as the travel time can be directly defined by studying the time interval between characteristic points in the transmitted and received wave traces. However, the frequency domain methods appear to be more detailed, since they employ the support of signal processing and spectrum analysis tools. Additionally, they enable automated data acquisition and processing [18] . It is important to note that no method of interpreting the BE test results is yet proven superior to the others [6, 19, 31] . Reliable determination of travel time is very significant, due to BEs being installed in laboratory equipment and their application for studying relatively small specimens, which means that the travel distance is quite small. Below, the authors briefly present the methods of determining the arrival time of the shear wave that were employed in the paper. These are further illustrated in Figure 5 . ", "cite_spans": [{"start": 135, "end": 139, "text": "[18,", "ref_id": "BIBREF18"}, {"start": 140, "end": 143, "text": "22,", "ref_id": "BIBREF23"}, {"start": 144, "end": 147, "text": "27]", "ref_id": "BIBREF28"}, {"start": 263, "end": 267, "text": "[17,", "ref_id": "BIBREF17"}, {"start": 268, "end": 271, "text": "28]", "ref_id": "BIBREF29"}, {"start": 387, "end": 391, "text": "[19,", "ref_id": "BIBREF20"}, {"start": 392, "end": 395, "text": "29]", "ref_id": "BIBREF30"}, {"start": 486, "end": 489, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 681, "end": 685, "text": "[19,", "ref_id": "BIBREF20"}, {"start": 686, "end": 689, "text": "30]", "ref_id": "BIBREF31"}, {"start": 1129, "end": 1133, "text": "[18]", "ref_id": "BIBREF18"}, {"start": 1248, "end": 1251, "text": "[6,", "ref_id": "BIBREF5"}, {"start": 1252, "end": 1255, "text": "19,", "ref_id": "BIBREF20"}, {"start": 1256, "end": 1259, "text": "31]", "ref_id": "BIBREF32"}], "ref_spans": [{"start": 1651, "end": 1659, "text": "Figure 5", "ref_id": "FIGREF7"}]}, {"section": "Methods of Interpretation of BE Results", "text": "The BE technique has many advantages, which have been mentioned so far, but the interpretation of BE results can often be questionable [18, 22, 27] . A number of methods for the analysis of bender element results are commonly used in the time or frequency domain [17, 28] . The time domain methods are classified as direct measurements, which use plots of electrical signals versus time [19, 29] . These methods employ a time-based axis in order to identify the propagation time, hence [6] . In frequency domain approaches, on the other hand, the spectral breakdown of the signals is analyzed, and the shift in the phase angle between the trigger and response signal is calculated [19, 30] . The time domain techniques are generally simpler and more straightforward, as the travel time can be directly defined by studying the time interval between characteristic points in the transmitted and received wave traces. However, the frequency domain methods appear to be more detailed, since they employ the support of signal processing and spectrum analysis tools. Additionally, they enable automated data acquisition and processing [18] . It is important to note that no method of interpreting the BE test results is yet proven superior to the others [6, 19, 31] . Reliable determination of travel time is very significant, due to BEs being installed in laboratory equipment and their application for studying relatively small specimens, which means that the travel distance is quite small. Below, the authors briefly present the methods of determining the arrival time of the shear wave that were employed in the paper. These are further illustrated in Figure 5 . The peak-to-peak method [19, 28] is based on the assumption that the received signal bears a high resemblance to the transmitted one. The travel time may be treated as the time elapsed between The peak-to-peak method [19, 28] is based on the assumption that the received signal bears a high resemblance to the transmitted one. The travel time may be treated as the time elapsed between any two corresponding characteristic points in the signals. By doing this, the near field problems should be reduced. The characteristic points that are most commonly used to identify the wave travel time are the first positive peak in the input of S-wave signals and in the output [32] . In some circumstances, however, properly defining the first major peak becomes quite difficult, as the received signal has several consecutive peaks, which differ slightly in amplitude. The reliability of choosing the right first peak as the first major one can be influenced by sample geometry and size or, for example, by the energy-absorbing nature of the soil. The arriving signal is then distorted to various extents due to the increase of damping with distance. The quality of received signals significantly affects this technique [28] .", "cite_spans": [{"start": 135, "end": 139, "text": "[18,", "ref_id": "BIBREF18"}, {"start": 140, "end": 143, "text": "22,", "ref_id": "BIBREF23"}, {"start": 144, "end": 147, "text": "27]", "ref_id": "BIBREF28"}, {"start": 263, "end": 267, "text": "[17,", "ref_id": "BIBREF17"}, {"start": 268, "end": 271, "text": "28]", "ref_id": "BIBREF29"}, {"start": 387, "end": 391, "text": "[19,", "ref_id": "BIBREF20"}, {"start": 392, "end": 395, "text": "29]", "ref_id": "BIBREF30"}, {"start": 486, "end": 489, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 681, "end": 685, "text": "[19,", "ref_id": "BIBREF20"}, {"start": 686, "end": 689, "text": "30]", "ref_id": "BIBREF31"}, {"start": 1129, "end": 1133, "text": "[18]", "ref_id": "BIBREF18"}, {"start": 1248, "end": 1251, "text": "[6,", "ref_id": "BIBREF5"}, {"start": 1252, "end": 1255, "text": "19,", "ref_id": "BIBREF20"}, {"start": 1256, "end": 1259, "text": "31]", "ref_id": "BIBREF32"}, {"start": 1686, "end": 1690, "text": "[19,", "ref_id": "BIBREF20"}, {"start": 1691, "end": 1694, "text": "28]", "ref_id": "BIBREF29"}, {"start": 1879, "end": 1883, "text": "[19,", "ref_id": "BIBREF20"}, {"start": 1884, "end": 1887, "text": "28]", "ref_id": "BIBREF29"}, {"start": 2330, "end": 2334, "text": "[32]", "ref_id": "BIBREF33"}, {"start": 2874, "end": 2878, "text": "[28]", "ref_id": "BIBREF29"}], "ref_spans": [{"start": 1651, "end": 1659, "text": "Figure 5", "ref_id": "FIGREF7"}]}, {"section": "Methods of Interpretation of BE Results", "text": "The principle of the start-to-start method, also known as the visual picking method, is the acceptance of the moment, when the first major deflection of the received signal occurs, as the shear wave arrival time [19, 33] . The presented method is characterized by simplicity, which is the main reason behind its popularity. Depending on the installation and polarity of the bender elements, the first important deviation from zero amplitude may be positive or negative [28] . In many cases, it is simply a single sine pulse. This represents the start of energy transfer from the source to the soil. However, in case of the output wave signal, it is the moment when the investigated receiver begins exhibiting motion. Said moment represents the instant of the energy transfer from the soil to the receiving BE [32] .", "cite_spans": [{"start": 212, "end": 216, "text": "[19,", "ref_id": "BIBREF20"}, {"start": 217, "end": 220, "text": "33]", "ref_id": "BIBREF34"}, {"start": 469, "end": 473, "text": "[28]", "ref_id": "BIBREF29"}, {"start": 809, "end": 813, "text": "[32]", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "Methods of Interpretation of BE Results", "text": "During the bender element test, shear wave velocity is calculated from the simple measurement of propagation distance (\u2206s) and propagation time (\u2206t). Based on a number of previous works, it is generally accepted that the travel distance is the distance between the tips of two BEs [11] . There are various waveforms, for example sine and square waves, with various frequencies, that have been recommended as an excitation signal [2] .", "cite_spans": [{"start": 281, "end": 285, "text": "[11]", "ref_id": "BIBREF11"}, {"start": 429, "end": 432, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Characterization of Test Material", "text": "In order to investigate the elastic modulus of cohesive material, associated with the passage of seismic waves (an S-wave and a P-wave), silty clay (siCl) samples, from the test site located in the center of Warsaw (the capital of Poland), recognized by particle size analysis using the sieves and hydrometer methods (European Standard Eurocode 7, [34] ), were used. The description of the research area can be found in [25] . The index properties of the examined soils are summarized in Table 1 . In order to compute the fundamental indices (w P , w L ), standard test methods were employed, namely plastic limit test of soil, Casagrande liquid limit test and fall cone liquid limit test. The grain size distribution of the soil specimens is shown in Figure 6 . The proportional content of each fraction is as follows: Gr = 0%, Sa = 13%, Si = 66%, Cl = 21%. The soil used during the tests, which is of Quaternary origin, was sampled in an undisturbed state using a standard Shelby tube. All of the samples were acquired at a depth of around 6.0 m and selected cautiously with the consideration of the soil structure uniformity, their physical properties and their double phase. Tubes were pressed carefully and gently into the pre-drilled holes. Subsequently, the samples were sealed and stored in a humidity room until needed [35] . Table 1 . Basic properties of the tested soils.", "cite_spans": [{"start": 348, "end": 352, "text": "[34]", "ref_id": "BIBREF35"}, {"start": 420, "end": 424, "text": "[25]", "ref_id": "BIBREF26"}, {"start": 1328, "end": 1332, "text": "[35]", "ref_id": "BIBREF36"}], "ref_spans": [{"start": 752, "end": 760, "text": "Figure 6", "ref_id": "FIGREF14"}]}, {"section": "Parameter", "text": "Value", "cite_spans": [], "ref_spans": []}, {"section": "Parameter", "text": "17.14 w L (%) 33 .00", "cite_spans": [{"start": 14, "end": 16, "text": "33", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "Parameter", "text": "15.86", "cite_spans": [], "ref_spans": []}, {"section": "Parameter", "text": "w is the water content; w P is the plastic limit; w L is the liquid limit; I P is the plastic index; I L is the liquidity index; I C is the consistency index; and \u03c1 is the mass density.", "cite_spans": [], "ref_spans": []}, {"section": "Parameter", "text": "w is the water content; wP is the plastic limit; wL is the liquid limit; IP is the plastic index; IL is the liquidity index; IC is the consistency index; and \u03c1 is the mass density.", "cite_spans": [], "ref_spans": []}, {"section": "Figure 6.", "text": "Grain size distribution of the tested soils.", "cite_spans": [], "ref_spans": []}, {"section": "Test Setup and Procedure", "text": "The test procedure followed that of a drained isotropic resonant column test. An upright cylindrical specimen of soil, with an aspect ratio of 2:1 (length:diameter), was employed. The proportions between length and diameter were as follows: 140 mm \u00d7 70 mm. Undisturbed material was set up in the resonant column cell, then saturated by the back pressure method in order to achieve the level of full saturation and subsequently consolidated to predetermined isotropic stress levels of 30, 120, 180, 240, 360 and 410 kPa. Back pressure was increased slowly, in order to ensure the proper saturation of the sample, until Skempton's B value reached 0.84. This represents, with respect to Head [36] , the saturation level being equal to approximately 97%. During the consolidation stage, the axial deformation and volume change of the sample were measured. The back pressure was kept at a constant level of 290 kPa. At the end of each consolidation stage, seismic wave velocities were checked, in the undrained conditions, as well as using the bender elements located at the top and bottom of the soil specimen. The BE transmitter was excited with a sine pulse, whose magnitude equaled 15 V. A change of voltage applied to the transmitter caused bending and transmission of a shear wave through the sample. The receiver, located at the other end of the specimen, registered the arrival of the shear wave as a change in voltage [37] [38] [39] . For each isotropic confining pressure level, a range of input frequencies between 100 and 1 kHz was tested, in order to identify the value of greater amplification in the received signals. This value should represent the clearest output signals. In the case of some input frequencies, particularly the higher ones, compression wave velocity was measured additionally. Due to the limitations of the software and hardware (S-and P-waves were transmitted by the same piezoelectric element) provided by the GDS company, the authors were unable to conduct the measurements in the same period (T) of Sand P-waves. Hence, there is an apparent limit in the predetermined period or frequency of propagating various waves through the soil sample.", "cite_spans": [{"start": 689, "end": 693, "text": "[36]", "ref_id": "BIBREF37"}, {"start": 1422, "end": 1426, "text": "[37]", "ref_id": "BIBREF39"}, {"start": 1427, "end": 1431, "text": "[38]", "ref_id": "BIBREF41"}, {"start": 1432, "end": 1436, "text": "[39]", "ref_id": "BIBREF42"}], "ref_spans": []}, {"section": "Test Setup and Procedure", "text": "In Figure 7 , the oscilloscope data obtained during the discussed studies are shown. The input signals at different frequencies were sent under the same stress conditions. During the analysis of this figure, it appeared to the authors, that at higher frequencies, the determination of the arrival time was more precise. Changes in the input signal frequency did not produce any change of polarization in the shear waves. For all applied frequencies, the input and output signals indicated the same amount of polarization. ", "cite_spans": [], "ref_spans": [{"start": 3, "end": 11, "text": "Figure 7", "ref_id": "FIGREF15"}]}, {"section": "Test Setup and Procedure", "text": "The test procedure followed that of a drained isotropic resonant column test. An upright cylindrical specimen of soil, with an aspect ratio of 2:1 (length:diameter), was employed. The proportions between length and diameter were as follows: 140 mm\u02c670 mm. Undisturbed material was set up in the resonant column cell, then saturated by the back pressure method in order to achieve the level of full saturation and subsequently consolidated to predetermined isotropic stress levels of 30, 120, 180, 240, 360 and 410 kPa. Back pressure was increased slowly, in order to ensure the proper saturation of the sample, until Skempton's B value reached 0.84. This represents, with respect to Head [36] , the saturation level being equal to approximately 97%. During the consolidation stage, the axial deformation and volume change of the sample were measured. The back pressure was kept at a constant level of 290 kPa. At the end of each consolidation stage, seismic wave velocities were checked, in the undrained conditions, as well as using the bender elements located at the top and bottom of the soil specimen. The BE transmitter was excited with a sine pulse, whose magnitude equaled 15 V. A change of voltage applied to the transmitter caused bending and transmission of a shear wave through the sample. The receiver, located at the other end of the specimen, registered the arrival of the shear wave as a change in voltage [37] [38] [39] . For each isotropic confining pressure level, a range of input frequencies between 100 and 1 kHz was tested, in order to identify the value of greater amplification in the received signals. This value should represent the clearest output signals. In the case of some input frequencies, particularly the higher ones, compression wave velocity was measured additionally. Due to the limitations of the software and hardware (S-and P-waves were transmitted by the same piezoelectric element) provided by the GDS company, the authors were unable to conduct the measurements in the same period (T) of S-and P-waves. Hence, there is an apparent limit in the predetermined period or frequency of propagating various waves through the soil sample.", "cite_spans": [{"start": 687, "end": 691, "text": "[36]", "ref_id": "BIBREF37"}, {"start": 1420, "end": 1424, "text": "[37]", "ref_id": "BIBREF39"}, {"start": 1425, "end": 1429, "text": "[38]", "ref_id": "BIBREF41"}, {"start": 1430, "end": 1434, "text": "[39]", "ref_id": "BIBREF42"}], "ref_spans": []}, {"section": "Test Setup and Procedure", "text": "In Figure 7 , the oscilloscope data obtained during the discussed studies are shown. The input signals at different frequencies were sent under the same stress conditions. During the analysis of this figure, it appeared to the authors, that at higher frequencies, the determination of the arrival time was more precise. Changes in the input signal frequency did not produce any change of polarization in the shear waves. For all applied frequencies, the input and output signals indicated the same amount of polarization. To interpret the BE results, the authors applied two commonly-known techniques used in time domain methods, which they described in the earlier subsection. For the start-to-start method, the noise level is very significant. Leong et al. [40] verified the criteria for the improvement of the interpretation of the BE test, among which there is the signal-to-noise ratio (SNR) criterion. According to their research, the SNR should be of at least 4 dB for the receiver signal. In the authors' research, the average SNR for the start-to-start method was equal to 10.44 dB. This level of the SNR allowed picking a very reliable and comfortable wave onset. Values of the wave velocity were calculated on the basis of the tip-to-tip distance between the transmitter and the receiver bender element [41] . The shear wave velocity was evaluated from the relationship presented below [11, 42] :", "cite_spans": [{"start": 759, "end": 763, "text": "[40]", "ref_id": "BIBREF43"}, {"start": 1314, "end": 1318, "text": "[41]", "ref_id": "BIBREF44"}, {"start": 1397, "end": 1401, "text": "[11,", "ref_id": "BIBREF11"}, {"start": 1402, "end": 1405, "text": "42]", "ref_id": "BIBREF45"}], "ref_spans": [{"start": 3, "end": 11, "text": "Figure 7", "ref_id": "FIGREF15"}]}, {"section": "Test Setup and Procedure", "text": "where h is the distance between the transmitter and the receiver and t is the travel time.", "cite_spans": [], "ref_spans": []}, {"section": "Test Setup and Procedure", "text": "Finally, the unloading process was carried out. After each unloading stage, BE tests were also performed, followed by the measurement of travel times, which were determined using peak-to-peak and start-to-start interpretation procedures. To interpret the BE results, the authors applied two commonly-known techniques used in time domain methods, which they described in the earlier subsection. For the start-to-start method, the noise level is very significant. Leong et al. [40] verified the criteria for the improvement of the interpretation of the BE test, among which there is the signal-to-noise ratio (SNR) criterion. According to their research, the SNR should be of at least 4 dB for the receiver signal. In the authors' research, the average SNR for the start-to-start method was equal to 10.44 dB. This level of the SNR allowed picking a very reliable and comfortable wave onset. Values of the wave velocity were calculated on the basis of the tip-to-tip distance between the transmitter and the receiver bender element [41] . The shear wave velocity was evaluated from the relationship presented below [11, 42] :", "cite_spans": [{"start": 475, "end": 479, "text": "[40]", "ref_id": "BIBREF43"}, {"start": 1030, "end": 1034, "text": "[41]", "ref_id": "BIBREF44"}, {"start": 1113, "end": 1117, "text": "[11,", "ref_id": "BIBREF11"}, {"start": 1118, "end": 1121, "text": "42]", "ref_id": "BIBREF45"}], "ref_spans": []}, {"section": "Test Setup and Procedure", "text": "where h is the distance between the transmitter and the receiver and t is the travel time.", "cite_spans": [], "ref_spans": []}, {"section": "Test Setup and Procedure", "text": "Appl. Sci. 2016, 6, 49", "cite_spans": [], "ref_spans": []}, {"section": "Test Setup and Procedure", "text": "Finally, the unloading process was carried out. After each unloading stage, BE tests were also performed, followed by the measurement of travel times, which were determined using peak-to-peak and start-to-start interpretation procedures.", "cite_spans": [], "ref_spans": []}, {"section": "Test Setup and Procedure", "text": "BE tests were conducted to provide information on the shear (G) and Young's (E) moduli. From the S-wave velocity (\u03c5 S ), the small strain shear modulus (G max ), was determined, using the elastic wave velocity according to the equation [43, 44] :", "cite_spans": [{"start": 236, "end": 240, "text": "[43,", "ref_id": "BIBREF46"}, {"start": 241, "end": 244, "text": "44]", "ref_id": "BIBREF47"}], "ref_spans": []}, {"section": "Test Setup and Procedure", "text": "where \u03c1 is the soil mass density.", "cite_spans": [], "ref_spans": []}, {"section": "Test Setup and Procedure", "text": "By transforming Equation (3) and combining it with Equation (5), the authors estimated the value of the small strain Young's modulus (E max ) as follows [45] :", "cite_spans": [{"start": 153, "end": 157, "text": "[45]", "ref_id": "BIBREF48"}], "ref_spans": []}, {"section": "Test Setup and Procedure", "text": "where \u03bd is Poisson's ratio. According to a well-known relation [4] , Poisson's ratio is equal to:", "cite_spans": [{"start": 63, "end": 66, "text": "[4]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Results and Discussion", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Frequency Dependency", "text": "In Figures 8 and 9 the variation of the measured shear wave velocity (\u03c5 S ) with a predetermined period of propagating wave at different specified stress levels is shown. In Figure 10 , however, the equivalent plot for measured compression wave velocity (\u03c5 P ) is illustrated. The presented results are related to both procedures adopted for determining the travel time. BE tests were conducted to provide information on the shear (G) and Young's (E) moduli. From the S-wave velocity (\u03c5S), the small strain shear modulus (Gmax), was determined, using the elastic wave velocity according to the equation [43, 44] :", "cite_spans": [{"start": 603, "end": 607, "text": "[43,", "ref_id": "BIBREF46"}, {"start": 608, "end": 611, "text": "44]", "ref_id": "BIBREF47"}], "ref_spans": [{"start": 3, "end": 18, "text": "Figures 8 and 9", "ref_id": "FIGREF18"}, {"start": 174, "end": 183, "text": "Figure 10", "ref_id": "FIGREF22"}]}, {"section": "Frequency Dependency", "text": "where \u03c1 is the soil mass density. By transforming Equation (3) and combining it with Equation (5), the authors estimated the value of the small strain Young's modulus (Emax) as follows [45] :", "cite_spans": [{"start": 185, "end": 189, "text": "[45]", "ref_id": "BIBREF48"}], "ref_spans": []}, {"section": "Frequency Dependency", "text": "where \u03bd is Poisson's ratio. According to a well-known relation [4] , Poisson's ratio is equal to:", "cite_spans": [{"start": 63, "end": 66, "text": "[4]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Results and Discussion", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Frequency Dependency", "text": "In Figures 8 and 9 , the variation of the measured shear wave velocity (\u03c5S) with a predetermined period of propagating wave at different specified stress levels is shown. In Figure 10 , however, the equivalent plot for measured compression wave velocity (\u03c5P) is illustrated. The presented results are related to both procedures adopted for determining the travel time. Inspection of Figures 8 and 9 indicates that, regardless of the method used to measure the travel time, the shear wave velocities decrease with the predetermined period (T), which transfers to frequency (f). Oscillation frequency is in fact the inverse of period. The linear approximation fits accurately most of the presented data obtained using the peak-to-peak and start-to-start methods. The coefficient of determination (R 2 ) reaches high values, from 70% upwards, which shows that for the studied cohesive material, the linear regression functions explain the majority of \u03c5S variation. In general, the differences in the shear wave velocities with different frequencies are not large, from 18 to 27 m\u00b7s \u22121 and from 32 to 38 m\u00b7s \u22121 , depending on the technique used to measure the travel time. Inspection of Figures 8 and 9 indicates that, regardless of the method used to measure the travel time, the shear wave velocities decrease with the predetermined period (T), which transfers to frequency (f ). Oscillation frequency is in fact the inverse of period. The linear approximation fits accurately most of the presented data obtained using the peak-to-peak and start-to-start methods. The coefficient of determination (R 2 ) reaches high values, from 70% upwards, which shows that for the studied cohesive material, the linear regression functions explain the majority of \u03c5 S variation. In general, the differences in the shear wave velocities with different frequencies are not large, from 18 to 27 m\u00a8s\u00b41 and from 32 to 38 m\u00a8s\u00b41, depending on the technique used to measure the travel time. In said graphs, the influence of stress level (p') is visible, as well. The average effective stress level significantly affects \u03c5S. For the highest pre-set pressure, i.e., 410 kPa, the authors received the highest values of shear wave velocity, with average values around 307 m\u00b7s \u22121 (peak-to-peak method) and 319 m\u00b7s \u22121 (start-to-start method). The lowest values of \u03bdS were recorded for the smallest given stress (30 or 180 kPa), their average being around 160 m\u00b7s \u22121 (peak-to-peak method) and 246 m\u00b7s \u22121 (start-to-start method). The difference in \u03c5S decreases with the increasing pressure value.", "cite_spans": [], "ref_spans": [{"start": 3, "end": 18, "text": "Figures 8 and 9", "ref_id": "FIGREF18"}, {"start": 174, "end": 183, "text": "Figure 10", "ref_id": "FIGREF22"}, {"start": 383, "end": 398, "text": "Figures 8 and 9", "ref_id": "FIGREF18"}, {"start": 1183, "end": 1198, "text": "Figures 8 and 9", "ref_id": "FIGREF18"}]}, {"section": "Frequency Dependency", "text": "The results of the current study show also that for the period of propagation lasting up to 0.1 ms (i.e., f = 10 kHz), both selected procedures used in the time domain methods consistently produce the values of \u03c5S, which are less dependent on frequency than in the case of a larger period of wave (Figures 8 and 9 on the right). The frame in these figures indicates the highest values of shear wave velocity for each mean effective stress level. The authors suggest in this way certain frequencies at which the bender elements tests should be performed. Hence, the recommended frequency values, for which the highest shear wave velocities can be obtained, are in the range of 20 to 50 kHz. Certainly, it should be remembered that the optimum frequency of excitation depends on many factors, for example on the pressure applied in the cell during tests [46] . There is no rule at all for choosing the best wave [47] . In the literature, some authors have reported their experience with choosing a specific frequency. Brignoli et al. in 1996 [38] noted that when bender elements are measuring the samples, whose height is between 100 and 140 mm, the most interpretable output waves occur in the range from 3 to 10 kHz. Jovo\u010di\u010d et al. [33] , however, observed that with a higher frequency, the near field effect is less discernible. For stiffer materials, the required frequency must In said graphs, the influence of stress level (p') is visible, as well. The average effective stress level significantly affects \u03c5S. For the highest pre-set pressure, i.e., 410 kPa, the authors received the highest values of shear wave velocity, with average values around 307 m\u00b7s \u22121 (peak-to-peak method) and 319 m\u00b7s \u22121 (start-to-start method). The lowest values of \u03bdS were recorded for the smallest given stress (30 or 180 kPa), their average being around 160 m\u00b7s \u22121 (peak-to-peak method) and 246 m\u00b7s \u22121 (start-to-start method). The difference in \u03c5S decreases with the increasing pressure value.", "cite_spans": [{"start": 852, "end": 856, "text": "[46]", "ref_id": "BIBREF49"}, {"start": 910, "end": 914, "text": "[47]", "ref_id": "BIBREF50"}, {"start": 1040, "end": 1044, "text": "[38]", "ref_id": "BIBREF41"}, {"start": 1232, "end": 1236, "text": "[33]", "ref_id": "BIBREF34"}], "ref_spans": [{"start": 297, "end": 313, "text": "(Figures 8 and 9", "ref_id": "FIGREF18"}]}, {"section": "Frequency Dependency", "text": "The results of the current study show also that for the period of propagation lasting up to 0.1 ms (i.e., f = 10 kHz), both selected procedures used in the time domain methods consistently produce the values of \u03c5S, which are less dependent on frequency than in the case of a larger period of wave (Figures 8 and 9 on the right). The frame in these figures indicates the highest values of shear wave velocity for each mean effective stress level. The authors suggest in this way certain frequencies at which the bender elements tests should be performed. Hence, the recommended frequency values, for which the highest shear wave velocities can be obtained, are in the range of 20 to 50 kHz. Certainly, it should be remembered that the optimum frequency of excitation depends on many factors, for example on the pressure applied in the cell during tests [46] . There is no rule at all for choosing the best wave [47] . In the literature, some authors have reported their experience with choosing a specific frequency. Brignoli et al. in 1996 [38] noted that when bender elements are measuring the samples, whose height is between 100 and 140 mm, the most interpretable output waves occur in the range from 3 to 10 kHz. Jovo\u010di\u010d et al. [33] , however, observed that with a higher In said graphs, the influence of stress level (p') is visible, as well. The average effective stress level significantly affects \u03c5 S . For the highest pre-set pressure, i.e., 410 kPa, the authors received the highest values of shear wave velocity, with average values around 307 m\u00a8s\u00b41 (peak-to-peak method) and 319 m\u00a8s\u00b41 (start-to-start method). The lowest values of \u03bd S were recorded for the smallest given stress (30 or 180 kPa), their average being around 160 m\u00a8s\u00b41 (peak-to-peak method) and 246 m\u00a8s\u00b41 (start-to-start method). The difference in \u03c5 S decreases with the increasing pressure value.", "cite_spans": [{"start": 852, "end": 856, "text": "[46]", "ref_id": "BIBREF49"}, {"start": 910, "end": 914, "text": "[47]", "ref_id": "BIBREF50"}, {"start": 1040, "end": 1044, "text": "[38]", "ref_id": "BIBREF41"}, {"start": 1232, "end": 1236, "text": "[33]", "ref_id": "BIBREF34"}], "ref_spans": [{"start": 297, "end": 313, "text": "(Figures 8 and 9", "ref_id": "FIGREF18"}]}, {"section": "Frequency Dependency", "text": "The results of the current study show also that for the period of propagation lasting up to 0.1 ms (i.e., f = 10 kHz), both selected procedures used in the time domain methods consistently produce the values of \u03c5 S , which are less dependent on frequency than in the case of a larger period of wave (Figures 8 and 9 on the right). The frame in these figures indicates the highest values of shear wave velocity for each mean effective stress level. The authors suggest in this way certain frequencies at which the bender elements tests should be performed. Hence, the recommended frequency values, for which the highest shear wave velocities can be obtained, are in the range of 20 to 50 kHz. Certainly, it should be remembered that the optimum frequency of excitation depends on many factors, for example on the pressure applied in the cell during tests [46] . There is no rule at all for choosing the best wave [47] . In the literature, some authors have reported their experience with choosing a specific frequency. Brignoli et al. in 1996 [38] noted that when bender elements are measuring the samples, whose height is between 100 and 140 mm, the most interpretable output waves occur in the range from 3 to 10 kHz. Jovo\u010di\u010d et al. [33] , however, observed that with a higher frequency, the near field effect is less discernible. For stiffer materials, the required frequency must be higher than the reported 10 kHz [33] , although the problem of overshooting becomes more important. In addition to this, a high frequency wave attenuates faster than the low frequency one, provided the medium is the same. The fact that the use of a high frequency gives the clearest output signals remains undisputed.", "cite_spans": [{"start": 854, "end": 858, "text": "[46]", "ref_id": "BIBREF49"}, {"start": 912, "end": 916, "text": "[47]", "ref_id": "BIBREF50"}, {"start": 1042, "end": 1046, "text": "[38]", "ref_id": "BIBREF41"}, {"start": 1234, "end": 1238, "text": "[33]", "ref_id": "BIBREF34"}, {"start": 1418, "end": 1422, "text": "[33]", "ref_id": "BIBREF34"}], "ref_spans": [{"start": 299, "end": 315, "text": "(Figures 8 and 9", "ref_id": "FIGREF18"}]}, {"section": "Frequency Dependency", "text": "In the case of compression waves (Figure 10 ), the authors carried out research in the frequency scope of up to 10 kHz. A very large dispersion of the results and a lack of dependence of \u03c5 P on the frequency ratio, as well as on mean effective stress can be clearly noticed. The authors could not find a proper relationship of \u03c5 P vs. frequency and mean effective stress. Empirical equations expressing the variation of P-wave velocity with frequency are characterized, however, by the low coefficients of determination (R 2 ), listed in Figure 10 . In general, the differences in compression wave velocities with the different frequencies reach high values, from 54 to 110 m\u00a8s\u00b41 and from 19 to 57 m\u00a8s\u00b41, depending on the technique used to measure the travel time.", "cite_spans": [], "ref_spans": [{"start": 33, "end": 43, "text": "(Figure 10", "ref_id": "FIGREF22"}, {"start": 538, "end": 547, "text": "Figure 10", "ref_id": "FIGREF22"}]}, {"section": "Frequency Dependency", "text": "In Figures 11 and 12 the effect of excitation frequency on shear modulus ( Figure 11 ) and Young's modulus (Figure 12 ) is presented. The excitation frequencies varied from 1 to 100 kHz. The specimens were subjected to various isotropic effective confining pressures. It was observed (black frame in the figures) that the best signal, and consequently the greatest values of shear modulus (G), were received at the excitation frequency, whose values were equal 20 kHz for the peak-to-peak method ( Figure 11a ) and 50 kHz for the start-to-start method (Figure 11b ). The excitation frequency being equal to (Figure 12b ) or smaller than 50 kHz (Figure 12a ) gave the greatest values of Young's modulus (E), as well. It is worth paying attention to a decrease in the modulus values along with the decreasing frequency, although G max and E max values were not obtained for the highest frequency, as already mentioned above. The average G max value obtained from all applied values of pressure ranged from 139 MPa to 194 MPa, depending on the measurement of the travel time, while average E max was around 405 MPa and 557 MPa. In the case of the minimal dynamic properties of the studied soils, using the lowest frequencies resulted in the smallest values of G and E, with the average minimal G ranging from 116 MPa to 152 MPa and the minimal E ranging from 379 MPa to 509 MPa. be higher than the reported 10 kHz [33] , although the problem of overshooting becomes more important. In addition to this, a high frequency wave attenuates faster than the low frequency one, provided the medium is the same. The fact that the use of a high frequency gives the clearest output signals remains undisputed.", "cite_spans": [{"start": 1411, "end": 1415, "text": "[33]", "ref_id": "BIBREF34"}], "ref_spans": [{"start": 3, "end": 20, "text": "Figures 11 and 12", "ref_id": "FIGREF0"}, {"start": 75, "end": 84, "text": "Figure 11", "ref_id": "FIGREF24"}, {"start": 107, "end": 117, "text": "(Figure 12", "ref_id": "FIGREF0"}, {"start": 498, "end": 508, "text": "Figure 11a", "ref_id": "FIGREF24"}, {"start": 552, "end": 563, "text": "(Figure 11b", "ref_id": "FIGREF24"}, {"start": 607, "end": 618, "text": "(Figure 12b", "ref_id": "FIGREF0"}, {"start": 644, "end": 655, "text": "(Figure 12a", "ref_id": "FIGREF0"}]}, {"section": "Frequency Dependency", "text": "In the case of compression waves (Figure 10 ), the authors carried out research in the frequency scope of up to 10 kHz. A very large dispersion of the results and a lack of dependence of \u03c5P on the frequency ratio, as well as on mean effective stress can be clearly noticed. The authors could not find a proper relationship of \u03c5P vs. frequency and mean effective stress. Empirical equations expressing the variation of P-wave velocity with frequency are characterized, however, by the low coefficients of determination (R 2 ), listed in Figure 10 . In general, the differences in compression wave velocities with the different frequencies reach high values, from 54 to 110 m\u00b7s \u22121 and from 19 to 57 m\u00b7s \u22121 , depending on the technique used to measure the travel time.", "cite_spans": [], "ref_spans": [{"start": 33, "end": 43, "text": "(Figure 10", "ref_id": "FIGREF22"}, {"start": 536, "end": 545, "text": "Figure 10", "ref_id": "FIGREF22"}]}, {"section": "Frequency Dependency", "text": "In Figures 11 and 12 , the effect of excitation frequency on shear modulus ( Figure 11 ) and Young's modulus (Figure 12 ) is presented. The excitation frequencies varied from 1 to 100 kHz. The specimens were subjected to various isotropic effective confining pressures. It was observed (black frame in the figures) that the best signal, and consequently the greatest values of shear modulus (G), were received at the excitation frequency, whose values were equal 20 kHz for the peak-to-peak method ( Figure 11a ) and 50 kHz for the start-to-start method (Figure 11b ). The excitation frequency being equal to (Figure 12b It should be also pointed out that the values of E are arranged in some trend with increasing frequency, whereas the values of \u03c5P do not show any dependence on frequency. This may seem incorrect, because Young's modulus is relevant to the compression wave velocity, due to the motion of the particles. However, it must be remembered that the authors used the results of \u03c5P only indirectly, in order to determine the proper value of \u03bd. It should be also pointed out that the values of E are arranged in some trend with increasing frequency, whereas the values of \u03c5 P do not show any dependence on frequency. This may seem incorrect, because Young's modulus is relevant to the compression wave velocity, due to the motion of the particles. However, it must be remembered that the authors used the results of \u03c5 P only indirectly, in order to determine the proper value of \u03bd. ", "cite_spans": [], "ref_spans": [{"start": 3, "end": 20, "text": "Figures 11 and 12", "ref_id": "FIGREF0"}, {"start": 77, "end": 86, "text": "Figure 11", "ref_id": "FIGREF24"}, {"start": 109, "end": 119, "text": "(Figure 12", "ref_id": "FIGREF0"}, {"start": 500, "end": 510, "text": "Figure 11a", "ref_id": "FIGREF24"}, {"start": 554, "end": 565, "text": "(Figure 11b", "ref_id": "FIGREF24"}, {"start": 609, "end": 620, "text": "(Figure 12b", "ref_id": "FIGREF0"}]}, {"section": "The Effect of Stress Level", "text": "In Table 2 , the authors compiled the range of received S-wave and P-wave velocities after each consolidation stage. On the basis of Table 2 , it can be concluded that the values of shear wave velocity obviously increase with applied pressure. At the same time, it is visible that the differences between the shear wave velocity values and each p' amount to 20 to 30 m\u00b7s \u22121 . The values of compression wave velocity confirmed the earlier observation about the lack of dependence between \u03c5P and stress level. The typical P-wave velocity of the tested material reached the value of 1400 to 1500 m\u00b7s \u22121 for the peak-to-peak method and 1600 to 1700 m\u00b7s \u22121 for the start-to-start method. Variation of Young's modulus with frequency.", "cite_spans": [], "ref_spans": [{"start": 3, "end": 10, "text": "Table 2", "ref_id": "TABREF1"}, {"start": 133, "end": 140, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "The Effect of Stress Level", "text": "(a) Peak-to-peak method; (b) start-to-start method.", "cite_spans": [], "ref_spans": []}, {"section": "The Effect of Stress Level", "text": "In Table 2 , the authors compiled the range of received S-wave and P-wave velocities after each consolidation stage. On the basis of Table 2 , it can be concluded that the values of shear wave velocity obviously increase with applied pressure. At the same time, it is visible that the differences between the shear wave velocity values and each p' amount to 20 to 30 m\u00a8s\u00b41. The values of compression wave velocity confirmed the earlier observation about the lack of dependence between \u03c5 P and stress level. The typical P-wave velocity of the tested material reached the value of 1400 to 1500 m\u00a8s\u00b41 for the peak-to-peak method and 1600 to 1700 m\u00a8s\u00b41 for the start-to-start method. Table 2 . Seismic waves velocities for various mean effective stress levels. (a) Peak-to-peak method; (b) start-to-start method. In Table 2 , additionally, the average ratio list of seismic wave's velocities is enclosed. It is evident that the values of \u03c5 P are several times higher, when compared with \u03c5 S . The \u03c5 P /\u03c5 S velocity ratio has the variation interval ranging from 5.0 to 9.3. The authors obtained larger values of P-wave velocity than is observed in certain positions in the literature. Das and Ramana [48] , for example, reported the characteristic compression wave velocity as ranging from 1220 m\u00a8s\u00b41 to 1370 m\u00a8s\u00b41 for saturated clay, although the ratio \u03c5 P /\u03c5 S was in the range of 8.0 to 9.0, thus similar to those obtained by the authors. Gary Mavko [49] , on the other hand, in his study on Parameters That Influence Seismic Velocity mentions P-wave velocity for saturated clays as being in the range of 1100 to 2500 m\u00a8s\u00b41. Campanella and Steward [50] detailed typical speeds of longitudinal and transversal waves to a depth of 40 m. According to their research, compressive wave velocity for saturated soils may have values between 1500 and 1900 m\u00a8s\u00b41.", "cite_spans": [{"start": 1195, "end": 1199, "text": "[48]", "ref_id": "BIBREF51"}, {"start": 1448, "end": 1452, "text": "[49]", "ref_id": "BIBREF52"}, {"start": 1646, "end": 1650, "text": "[50]", "ref_id": "BIBREF53"}], "ref_spans": [{"start": 3, "end": 10, "text": "Table 2", "ref_id": "TABREF1"}, {"start": 133, "end": 140, "text": "Table 2", "ref_id": "TABREF1"}, {"start": 680, "end": 687, "text": "Table 2", "ref_id": "TABREF1"}, {"start": 812, "end": 819, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "The Effect of Stress Level", "text": "In Table 3 , the results of the average dynamic Poisson's ratio computed for each applied mean effective stress is shown. \u03bd d was determined on the basis of the relationship between S-wave and P-wave velocities (Equation (8)). The values of \u03bd d seem to be consistent with the literature [4, 51, 52] . The authors described the values of this parameter in another publication [23] , in which the results obtained for saturated clay were at the level of 0.40 to 0.50, which is similar to the value obtained during the current studies. It is interesting to note that there is no significant change in \u03bd d regarding the pressure. Variation in Poisson's ratio amounts to approximately 4% and approaches 0.5. Moreover, a number of different techniques for interpreting the BE results causes no definite difference in the values of Poisson's ratio. Based on the experiments conducted, a general trend can be observed: as far as tested clayey material is concerned, Poisson's ratios represent little appreciable change with regard to shear modulus ( Figure 13) . The values of \u03bd d were used afterwards in order to determine the dynamic modulus of elasticity (E). The effect of mean effective stress on the small strain shear modulus and on the small strain modulus of elasticity of the examined silty clays is displayed in Figures 14 and 15 . The presented data were obtained for one excitation frequency, selected on the basis of its greatest values of dynamic properties regarding the analyzed soil specimens, as described in the previous section. BE measurements show that Gmax and Emax values increase with confining pressure as a linear function. Shear modulus at small strains, which was calculated for the tested material using Equation (6), does not exceed the interval of 60 to 242 MPa, regarding the travel time measurement. The modulus of elasticity at small strains, on the other hand, varies from 178 MPa to 694 MPa. The effect of mean effective stress on the small strain shear modulus and on the small strain modulus of elasticity of the examined silty clays is displayed in Figures 14 and 15 . The presented data were obtained for one excitation frequency, selected on the basis of its greatest values of dynamic properties regarding the analyzed soil specimens, as described in the previous section. BE measurements show that G max and E max values increase with confining pressure as a linear function. Shear modulus at small strains, which was calculated for the tested material using Equation (6) The effect of mean effective stress on the small strain shear modulus and on the small strai odulus of elasticity of the examined silty clays is displayed in Figures 14 and 15 . The presente ta were obtained for one excitation frequency, selected on the basis of its greatest values o namic properties regarding the analyzed soil specimens, as described in the previous section. B easurements show that Gmax and Emax values increase with confining pressure as a linear functio ear modulus at small strains, which was calculated for the tested material using Equation (6) ", "cite_spans": [{"start": 287, "end": 290, "text": "[4,", "ref_id": "BIBREF3"}, {"start": 295, "end": 298, "text": "52]", "ref_id": "BIBREF55"}, {"start": 375, "end": 379, "text": "[23]", "ref_id": "BIBREF24"}], "ref_spans": [{"start": 1042, "end": 1052, "text": "Figure 13)", "ref_id": "FIGREF1"}, {"start": 1315, "end": 1332, "text": "Figures 14 and 15", "ref_id": "FIGREF6"}, {"start": 2082, "end": 2099, "text": "Figures 14 and 15", "ref_id": "FIGREF6"}, {"start": 2667, "end": 2684, "text": "Figures 14 and 15", "ref_id": "FIGREF6"}]}, {"section": "Comparison of Results from Different Methods", "text": "The input signals employed in all of the tests were single sinusoidal pulses with different frequencies, obtained using peak-to-peak and start-to-start methods. The amplitude of input signals in both cases was fixed at \u00b115 V. The tip-to-tip distances between the transducers were used to calculate the shear wave velocity of the samples (Equation (5)). All of the test traces were examined in the time domain, in order to obtain the travel time of the wave through the specimens.", "cite_spans": [], "ref_spans": []}, {"section": "Comparison of Results from Different Methods", "text": "In Figure 16 , S-wave velocities determined by means of the two analyzed time domain techniques are portrayed. It is clearly visible that travel time derived from the start-to-start method must be longer due to the presence of the greatest values of the shear wave velocities. The difference in the obtained values of \u03c5S between these two methods remains at the average level of 21.25 m\u00b7s \u22121 , in favor of the start-to-start method (Figure 17a ). Naturally, these spotted differences vary, depending on the mean effective stress.", "cite_spans": [], "ref_spans": [{"start": 3, "end": 12, "text": "Figure 16", "ref_id": "FIGREF14"}, {"start": 432, "end": 443, "text": "(Figure 17a", "ref_id": "FIGREF15"}]}, {"section": "Comparison of Results from Different Methods", "text": "In Figure 17b , the evolution of the shear stiffness modulus based on travel time deduced by means of the peak-to-peak and start-to-start techniques is summarized. In this comparison, the second of the aforementioned methods comes off as the better one. The average difference in stiffness of the examined cohesive material falls in the range of about 33.44 MPa. For the Emax (Figure  17c ), the discrepancy between the results of two different interpretation methods achieves a maximum percentage of about 16% (89.2 MPa). ", "cite_spans": [], "ref_spans": [{"start": 3, "end": 13, "text": "Figure 17b", "ref_id": "FIGREF15"}, {"start": 376, "end": 388, "text": "(Figure  17c", "ref_id": "FIGREF15"}]}, {"section": "Peak-toPeak", "text": "Start-toStart Figure 15 . Elastic moduli from the start-to-start method under different stress levels.", "cite_spans": [], "ref_spans": [{"start": 14, "end": 23, "text": "Figure 15", "ref_id": "FIGREF7"}]}, {"section": "Comparison of Results from Different Methods", "text": "The input signals employed in all of the tests were single sinusoidal pulses with different frequencies, obtained using peak-to-peak and start-to-start methods. The amplitude of input signals in both cases was fixed at\u02d815 V. The tip-to-tip distances between the transducers were used to calculate the shear wave velocity of the samples (Equation (5)). All of the test traces were examined in the time domain, in order to obtain the travel time of the wave through the specimens.", "cite_spans": [], "ref_spans": []}, {"section": "Comparison of Results from Different Methods", "text": "In Figure 16 , S-wave velocities determined by means of the two analyzed time domain techniques are portrayed. It is clearly visible that travel time derived from the start-to-start method must be longer due to the presence of the greatest values of the shear wave velocities. The difference in the obtained values of \u03c5 S between these two methods remains at the average level of 21.25 m\u00a8s\u00b41, in favor of the start-to-start method (Figure 17a ). Naturally, these spotted differences vary, depending on the mean effective stress. ", "cite_spans": [], "ref_spans": [{"start": 3, "end": 12, "text": "Figure 16", "ref_id": "FIGREF14"}, {"start": 431, "end": 442, "text": "(Figure 17a", "ref_id": "FIGREF15"}]}, {"section": "Comparison of Results from Different Methods", "text": "The input signals employed in all of the tests were single sinusoidal pulses with different frequencies, obtained using peak-to-peak and start-to-start methods. The amplitude of input signals in both cases was fixed at \u00b115 V. The tip-to-tip distances between the transducers were used to calculate the shear wave velocity of the samples (Equation (5)). All of the test traces were examined in the time domain, in order to obtain the travel time of the wave through the specimens.", "cite_spans": [], "ref_spans": []}, {"section": "Comparison of Results from Different Methods", "text": "In Figure 16 , S-wave velocities determined by means of the two analyzed time domain techniques are portrayed. It is clearly visible that travel time derived from the start-to-start method must be longer due to the presence of the greatest values of the shear wave velocities. The difference in the obtained values of \u03c5S between these two methods remains at the average level of 21.25 m\u00b7s \u22121 , in favor of the start-to-start method (Figure 17a ). Naturally, these spotted differences vary, depending on the mean effective stress.", "cite_spans": [], "ref_spans": [{"start": 3, "end": 12, "text": "Figure 16", "ref_id": "FIGREF14"}, {"start": 432, "end": 443, "text": "(Figure 17a", "ref_id": "FIGREF15"}]}, {"section": "Comparison of Results from Different Methods", "text": "In Figure 17b , the evolution of the shear stiffness modulus based on travel time deduced by means of the peak-to-peak and start-to-start techniques is summarized. In this comparison, the second of the aforementioned methods comes off as the better one. The average difference in stiffness of the examined cohesive material falls in the range of about 33.44 MPa. For the Emax (Figure  17c ), the discrepancy between the results of two different interpretation methods achieves a maximum percentage of about 16% (89.2 MPa). In Figure 17b , the evolution of the shear stiffness modulus based on travel time deduced by means of the peak-to-peak and start-to-start techniques is summarized. In this comparison, the second of the aforementioned methods comes off as the better one. The average difference in stiffness of the examined cohesive material falls in the range of about 33.44 MPa. For the E max (Figure 17c) , the discrepancy between the results of two different interpretation methods achieves a maximum percentage of about 16% (89.2 MPa). In conclusion, it is worth noting that in the case of the start-to-start method, the findings of \u03c5S and Gmax lie on a straight line, but of a different gradient. This observation is not reflected in the outcomes regarding Emax. The results obtained with the use of the peak-to-peak method appear to be more scattered. On the basis of Figure 17 , it can be noted that the S-S method (start-to-start method) of identification results in a relatively smaller variation, when compared to the P-P technique (peak-to-peak method). The latter method yields slightly smaller values of the dynamic parameters.", "cite_spans": [], "ref_spans": [{"start": 3, "end": 13, "text": "Figure 17b", "ref_id": "FIGREF15"}, {"start": 376, "end": 388, "text": "(Figure  17c", "ref_id": "FIGREF15"}, {"start": 526, "end": 536, "text": "Figure 17b", "ref_id": "FIGREF15"}, {"start": 900, "end": 912, "text": "(Figure 17c)", "ref_id": "FIGREF15"}, {"start": 1380, "end": 1389, "text": "Figure 17", "ref_id": "FIGREF15"}]}, {"section": "The Effect of Unloading", "text": "The aim of the current study, besides finding S-wave velocity and the small strain shear modulus when loading soil samples, was also to find \u03c5S and Gmax while unloading. The unloading process of the tested material was carried out to the pressure level of 120 kPa. In Figures 18 and 19 , the values of computed parameters from the loading and the subsequent unloading stages are presented.", "cite_spans": [], "ref_spans": [{"start": 268, "end": 285, "text": "Figures 18 and 19", "ref_id": "FIGREF18"}]}, {"section": "The Effect of Unloading", "text": "During the inspection of Figures 18 and 19 , the authors noticed that \u03c5S, unloading and consequently Gmax, unloading carry greater values than \u03c5S, loading and Gmax, loading. The variance between silty clay dynamic stiffness during loading and unloading stages falls within the range between 16.8 and 22.8 MPa. The biggest difference was obtained for the mean effective stress equal to 180 kPa, the smallest one for p' = 360 kPa. The unloading process causes the increase of the results from 8% to 16%. Thus, it should be highlighted that the unloading of soil considerably improves its stiffness. In conclusion, it is worth noting that in the case of the start-to-start method, the findings of \u03c5 S and G max lie on a straight line, but of a different gradient. This observation is not reflected in the outcomes regarding E max . The results obtained with the use of the peak-to-peak method appear to be more scattered. On the basis of Figure 17 , it can be noted that the S-S method (start-to-start method) of identification results in a relatively smaller variation, when compared to the P-P technique (peak-to-peak method). The latter method yields slightly smaller values of the dynamic parameters.", "cite_spans": [], "ref_spans": [{"start": 25, "end": 42, "text": "Figures 18 and 19", "ref_id": "FIGREF18"}, {"start": 935, "end": 944, "text": "Figure 17", "ref_id": "FIGREF15"}]}, {"section": "The Effect of Unloading", "text": "The aim of the current study, besides finding S-wave velocity and the small strain shear modulus when loading soil samples, was also to find \u03c5 S and G max while unloading. The unloading process of the tested material was carried out to the pressure level of 120 kPa. In Figures 18 and 19 the values of computed parameters from the loading and the subsequent unloading stages are presented.", "cite_spans": [], "ref_spans": [{"start": 270, "end": 287, "text": "Figures 18 and 19", "ref_id": "FIGREF18"}]}, {"section": "The Effect of Unloading", "text": "During the inspection of Figures 18 and 19 the authors noticed that \u03c5 S,unloading and consequently G max, unloading carry greater values than \u03c5 S, loading and G max, loading . The variance between silty clay dynamic stiffness during loading and unloading stages falls within the range between 16.8 and 22.8 MPa. The biggest difference was obtained for the mean effective stress equal to 180 kPa, the smallest one for p' = 360 kPa. The unloading process causes the increase of the results from 8% to 16%. Thus, it should be highlighted that the unloading of soil considerably improves its stiffness. ", "cite_spans": [], "ref_spans": [{"start": 25, "end": 42, "text": "Figures 18 and 19", "ref_id": "FIGREF18"}]}, {"section": "Conclusions", "text": "In this study, the characterization of the dynamic properties of cohesive material, namely silty clays, was inspected. The conducted experiments included the dynamic tests in the GDS Resonant Column Apparatus equipped with bender elements. The authors aimed to verify the dynamic behavior of clayey soil in connection with wave propagation produced by piezoelectric transducers. Shear wave velocity is related to the shear modulus of soil. Consequently, the measurements of the S-wave velocity provided a convenient method for determining soil stiffness. Additionally, the calculation of the P-wave velocity and, subsequently, the dynamic Poisson's ratio allowed for the examination of Young's modulus with regard to the tested cohesive material.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "The findings of this research, in line with the literature in relation to the methods of interpretation of bender element test results, indicate that, for tests with piezoelectric transducers installed in the resonant column apparatus on silty clays, both analyzed techniques used as a part of the time domain methods, i.e., peak-to-peak and start-to-start, yield similar results. They are also considered as the most comprehensive and appropriate methods to identify the travel time of the shear waves propagating through the sample. The authors, however, did not inspect any other methods, like the cross-correlation or \u03c0-point phase, but the velocities established by those methods ", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "In this study, the characterization of the dynamic properties of cohesive material, namely silty clays, was inspected. The conducted experiments included the dynamic tests in the GDS Resonant Column Apparatus equipped with bender elements. The authors aimed to verify the dynamic behavior of clayey soil in connection with wave propagation produced by piezoelectric transducers. Shear wave velocity is related to the shear modulus of soil. Consequently, the measurements of the S-wave velocity provided a convenient method for determining soil stiffness. Additionally, the calculation of the P-wave velocity and, subsequently, the dynamic Poisson's ratio allowed for the examination of Young's modulus with regard to the tested cohesive material.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "The findings of this research, in line with the literature in relation to the methods of interpretation of bender element test results, indicate that, for tests with piezoelectric transducers installed in the resonant column apparatus on silty clays, both analyzed techniques used as a part of the time domain methods, i.e., peak-to-peak and start-to-start, yield similar results. They are also considered as the most comprehensive and appropriate methods to identify the travel time of the shear waves propagating through the sample. The authors, however, did not inspect any other methods, like the cross-correlation or \u03c0-point phase, but the velocities established by those methods ", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "In this study, the characterization of the dynamic properties of cohesive material, namely silty clays, was inspected. The conducted experiments included the dynamic tests in the GDS Resonant Column Apparatus equipped with bender elements. The authors aimed to verify the dynamic behavior of clayey soil in connection with wave propagation produced by piezoelectric transducers. Shear wave velocity is related to the shear modulus of soil. Consequently, the measurements of the S-wave velocity provided a convenient method for determining soil stiffness. Additionally, the calculation of the P-wave velocity and, subsequently, the dynamic Poisson's ratio allowed for the examination of Young's modulus with regard to the tested cohesive material.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "The findings of this research, in line with the literature in relation to the methods of interpretation of bender element test results, indicate that, for tests with piezoelectric transducers installed in the resonant column apparatus on silty clays, both analyzed techniques used as a part of the time domain methods, i.e., peak-to-peak and start-to-start, yield similar results. They are also considered as the most comprehensive and appropriate methods to identify the travel time of the shear waves propagating through the sample. The authors, however, did not inspect any other methods, like the cross-correlation or \u03c0-point phase, but the velocities established by those methods are comparable to the findings from the resonant column measurements [25] . The dynamic parameters obtained by the start-to-start method were always slightly larger (up to about 20%) than those obtained using the peak-to-peak method. According to the authors, this is a consequence of the broadening of the excitation pulses after they are propagated through the sample. The lowest wavelength in the presented experiments was about 1.0 mm, which was at least 10-times bigger than the largest grain size of soil sample (that was less than or equal to 100 \u00b5m). In addition, no inhomogeneous pockets were found in the sample constitution after a destructive analysis of the material. In these conditions the macroscopic sample was expected to behave as a conducting media, and no enhanced scattering was expected at the grain boundaries. Since the studied sample was homogeneous, in terms of the wavelength, the difference between the results from the two discussed techniques can be explained by taking into account different wave velocities and different attenuations of the frequency components that constitute the excitation peaks. Although each excitation pulse used in the experiments was considered to have a well-defined frequency, in reality, the pulses are composed of a continuity of different frequencies with different amplitudes. This happens due to the finite size of the excitation pulse in the time domain, which adds additional frequencies to it. In the start-to-start method, the results were strongly influenced by the fastest travelling wave, while in the peak-to-peak method, the frequency component with the highest amplitude was the one considered. From the Figures 9 and 10 it can be clearly noticed that the wave velocity from the S-S method had an almost flat dependency as a function of frequency; however, in the P-P method, it has a change of about 20% in the frequency range experimented. This suggests that, in the S-S method, the frequency component responsible for the excitation of the detector is independent of the frequency chosen for the excitation pulse (due to the unintentional frequencies present in the excitation pulse). In certain experimental circumstances, such as during the measurements of G, the peak-to-peak method led to more scattered results, which were probably connected to the interpretation of the findings made by the authors. It must be always kept in mind, that even when using the same identification method, reading points differed with the laboratory [22] . The scatter in the S-S method was definitely smaller in comparison to another method. Presented results show and confirm observations made by previous researchers [6, 22] , acknowledging the status of the start-to-start method as the most prevalent and consistent method for the determination of travel time.", "cite_spans": [{"start": 754, "end": 758, "text": "[25]", "ref_id": "BIBREF26"}, {"start": 3198, "end": 3202, "text": "[22]", "ref_id": "BIBREF23"}, {"start": 3368, "end": 3371, "text": "[6,", "ref_id": "BIBREF5"}, {"start": 3372, "end": 3375, "text": "22]", "ref_id": "BIBREF23"}], "ref_spans": [{"start": 2364, "end": 2380, "text": "Figures 9 and 10", "ref_id": "FIGREF22"}]}, {"section": "Conclusions", "text": "With reference to the dependence of the dynamic behavior of clayey material on various factors, the following conclusions can be drawn:", "cite_spans": [], "ref_spans": []}, {"section": "\u201a", "text": "The data show that the input signal frequency, in particular frequencies, which are below the level of T = 0.1 ms, does not significantly affect the stiffness values obtained by both adopted identification methods. The decrease in frequency results in greater dependence on frequency.", "cite_spans": [], "ref_spans": []}, {"section": "\u201a", "text": "The best measurements of travel time for the tested soils were received at the frequencies of the input signal in the range of 50 to 20 kHz. In most of the considered cases, the greatest values of the dynamic parameters were obtained when the frequencies from this range were applied.", "cite_spans": [], "ref_spans": []}, {"section": "\u201a", "text": "Mean effective stress has a visible influence on the seismic wave velocities and on the elastic modulus of the examined soils.", "cite_spans": [], "ref_spans": []}, {"section": "\u201a", "text": "There are linear relationships between the mean effective stress and the small strain shear modulus and the small strain modulus of elasticity.", "cite_spans": [], "ref_spans": []}, {"section": "\u201a", "text": "The compression waves propagate through the analyzed clayey material with far larger velocities than in the case of shear waves; at certain pressure levels, these velocities can be even up to 10-times larger.", "cite_spans": [], "ref_spans": []}, {"section": "\u201a", "text": "The dynamic Poisson's ratio for the tested cohesive soils is almost constant, being approximately equal to 0.46.", "cite_spans": [], "ref_spans": []}, {"section": "\u201a", "text": "The dynamic Poisson's ratio linearly increases with the decrease of the shear modulus.", "cite_spans": [], "ref_spans": []}, {"section": "\u201a", "text": "Concerning the unloading process, it profitably affects the stiffness of silty clays. The dynamic properties rise in their values, from 8% to 16%, owing to unloading.", "cite_spans": [], "ref_spans": []}, {"section": "\u201a", "text": "Based on the results as described above, the standard procedure for the BE tests was proposed here in order to obtain appropriate test results in the present conditions. The authors discussed the important issue regarding the applied sciences, precisely the seismic research and dynamic response of porous material due to dynamic loads, such as earthquakes, traffic loads or machine vibrations. They attempted to characterize the dynamic properties of a fine-grained material, whose average porosity is approximately 0.44. This differs from the commonly-encountered in the literature dynamic characteristics of granular materials, non-cohesive soils, with a larger porosity value, described for example in [53, 54] . The authors used generally-applied laboratory tests in order to investigate a still new material, as well as to expand the knowledge of the interpretation of this new material's results.", "cite_spans": [{"start": 706, "end": 710, "text": "[53,", "ref_id": "BIBREF56"}, {"start": 711, "end": 714, "text": "54]", "ref_id": "BIBREF57"}], "ref_spans": []}, {"section": "\u201a", "text": "The acquired knowledge of the behavior of the tested material should be verified in the process of modeling, using an appropriate model, such as the one proposed in [55] .", "cite_spans": [{"start": 165, "end": 169, "text": "[55]", "ref_id": "BIBREF58"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Soil parameters which can be determined with seismic velocities", "authors": [{"first": "M", "middle": [], "last": "Salacak", "suffix": ""}, {"first": "S", "middle": ["B"], "last": "Pinar", "suffix": ""}], "year": 2012, "venue": "", "link": null}, "BIBREF1": {"title": "Measurement of small-strain shear modulus G max of dry and saturated sands by bender element, resonant column, and torsional shear tests", "authors": [{"first": "J.-U", "middle": [], "last": "Youn", "suffix": ""}, {"first": "Y.-W", "middle": [], "last": "Choo", "suffix": ""}, {"first": "D.-S", "middle": [], "last": "Kim", "suffix": ""}], "year": 2008, "venue": "Can. 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Am", "link": "27161899"}}, "ref_entries": {"FIGREF0": {"text": "Figure 2. Bender element inserts mounted in a top cap and base pedestal.", "type": "figure"}, "FIGREF1": {"text": "Figure 3. Frontal sample view with bender element (BE) arrangement and an example of the waves' path.", "type": "figure"}, "FIGREF2": {"text": "Figure 2. Bender element inserts mounted in a top cap and base pedestal.", "type": "figure"}, "FIGREF3": {"text": "Figure 2. Bender element inserts mounted in a top cap and base pedestal.", "type": "figure"}, "FIGREF4": {"text": "Figure 3. Frontal sample view with bender element (BE) arrangement and an example of the waves' path.", "type": "figure"}, "FIGREF5": {"text": "Figure 3. Frontal sample view with bender element (BE) arrangement and an example of the waves' path.", "type": "figure"}, "FIGREF6": {"text": "Figure 4. Non-desirable orientation of the top cap and base pedestal element.", "type": "figure"}, "FIGREF7": {"text": "Figure 5. Typical identification techniques of travel time in the time domain method.", "type": "figure"}, "FIGREF8": {"text": "\u0394t (peak to peak) \u0394t (start to start)", "type": "figure"}, "FIGREF9": {"text": "Figure 4. Non-desirable orientation of the top cap and base pedestal element.", "type": "figure"}, "FIGREF10": {"text": "Figure 4. Non-desirable orientation of the top cap and base pedestal element.", "type": "figure"}, "FIGREF11": {"text": "Figure 5. Typical identification techniques of travel time in the time domain method.", "type": "figure"}, "FIGREF12": {"text": "Figure 5. Typical identification techniques of travel time in the time domain method.", "type": "figure"}, "FIGREF14": {"text": "Figure 6. Grain size distribution of the tested soils.", "type": "figure"}, "FIGREF15": {"text": "Figure 7. The oscilloscope signals at various frequencies of input signals: (a) 20 kHz, (b) 10 kHz, (c) 2 kHz, (d) 1 kHz and at the same effective stress value.", "type": "figure"}, "FIGREF16": {"text": "Figure 7. The oscilloscope signals at various frequencies of input signals: (a) 20 kHz, (b) 10 kHz, (c) 2 kHz, (d) 1 kHz and at the same effective stress value.", "type": "figure"}, "FIGREF18": {"text": "Figure 8. Variation of measured \u03c5S with period: peak-to-peak method. (a) Period's range from 0 to 1 ms; (b) Period's range from 0.01 to 0.1 ms.", "type": "figure"}, "FIGREF19": {"text": "Figure 8. Variation of measured \u03c5 S with period: peak-to-peak method. (a) Period's range from 0 to 1 ms; (b) Period's range from 0.01 to 0.1 ms.", "type": "figure"}, "FIGREF20": {"text": "Figure 9. Variation of measured \u03c5S with period: start-to-start method. (a) Period's range from 0 to 1 ms; (b) Period's range from 0.01 to 0.1 ms.", "type": "figure"}, "FIGREF21": {"text": "Figure 9. Variation of measured \u03c5 S with period: start-to-start method. (a) Period's range from 0 to 1 ms; (b) Period's range from 0.01 to 0.1 ms.", "type": "figure"}, "FIGREF22": {"text": "Figure 10. Variation of measured \u03c5 P with period. (a) Peak-to-peak method; (b) start-to-start method.", "type": "figure"}, "FIGREF24": {"text": "Figure 11. Variation of dynamic stiffness with frequency. (a) Peak-to-peak method; (b) start-to-start method.", "type": "figure"}, "FIGREF25": {"text": "Figure 11. Variation of dynamic stiffness with frequency. (a) Peak-to-peak method; (b) start-to-start method.", "type": "figure"}, "FIGREF26": {"text": "Figure 12. Variation of Young's modulus with frequency. (a) Peak-to-peak method; (b) start-to-start method.", "type": "figure"}, "FIGREF27": {"text": "Figure 12. Variation of Young's modulus with frequency. (a) Peak-to-peak method; (b) start-to-start method.", "type": "figure"}, "FIGREF29": {"text": "Figure 13. Shear modulus versus dynamic Poisson's ratio. (a) Peak-to-peak method; (b) start-to-start method.", "type": "figure"}, "FIGREF30": {"text": "Figure 14. Elastic moduli from the peak-to-peak method under different stress levels.", "type": "figure"}, "FIGREF31": {"text": "Figure 13. Shear modulus versus dynamic Poisson's ratio. (a) Peak-to-peak method; (b) start-to-start method.", "type": "figure"}, "FIGREF32": {"text": ", does not exceed the interval of 60 to 242 MPa, regarding the travel time measurement. The modulus of elasticity at small strains, on the other hand, varies from 178 MPa to 694 MPa.", "type": "figure"}, "FIGREF33": {"text": "Figure 13. Shear modulus versus dynamic Poisson's ratio. (a) Peak-to-peak method; (b) start-to-start method.", "type": "figure"}, "FIGREF34": {"text": ", doe t exceed the interval of 60 to 242 MPa, regarding the travel time measurement. The modulus o sticity at small strains, on the other hand, varies from 178 MPa to 694 MPa.", "type": "figure"}, "FIGREF35": {"text": "Figure 14. Elastic moduli from the peak-to-peak method under different stress levels.", "type": "figure"}, "FIGREF37": {"text": "Figure 15. Elastic moduli from the start-to-start method under different stress levels.", "type": "figure"}, "FIGREF38": {"text": "Figure 16. Comparison of \u03c5S obtained using various methods of travel time determination.", "type": "figure"}, "FIGREF39": {"text": "Figure 16. Comparison of \u03c5 S obtained using various methods of travel time determination.", "type": "figure"}, "FIGREF40": {"text": "Figure 17. Comparison of results obtained by means of the peak-to-peak and start-to-start methods. (a) Shear wave velocity; (b) small strain shear modulus; (c) small strain Young's modulus.", "type": "figure"}, "FIGREF41": {"text": "Figure 17. Comparison of results obtained by means of the peak-to-peak and start-to-start methods. (a) Shear wave velocity; (b) small strain shear modulus; (c) small strain Young's modulus.", "type": "figure"}, "FIGREF42": {"text": "Figure 18. Shear wave velocity versus period at the loading and unloading stage.", "type": "figure"}, "FIGREF43": {"text": "Figure 19. Small strain shear modulus versus mean effective stress at the loading and unloading stage.", "type": "figure"}, "FIGREF44": {"text": "Figure 18. Shear wave velocity versus period at the loading and unloading stage.", "type": "figure"}, "FIGREF45": {"text": "Figure 19. Small strain shear modulus versus mean effective stress at the loading and unloading stage.", "type": "figure"}, "FIGREF46": {"text": "Figure 19. Small strain shear modulus versus mean effective stress at the loading and unloading stage.", "type": "figure"}, "TABREF0": {"text": "cells. The insert for the base pedestal is made of stainless steel, while the one for the top cap is made of titanium. This reduces the weight by half and minimizes the axial load caused by the top cap, which is being applied to the sample. The inserts are embedded in a modified Perspex top cap and", "type": "table"}, "TABREF1": {"text": "Seismic waves velocities for various mean effective stress levels. (a) Peak-to-peak method; (b) start-to-start method.", "type": "table"}}}
{"paper_id": "17431941", "_pdf_hash": "91399b4110861f5b2da76733700aae8793755cf0", "abstract": [{"section": "Abstract", "text": "Following my previous study of paper length vs. number of citations in astronomy (Stanek 2008) , some colleagues expressed an interest in knowing if any correlation exists between citations and the number of authors on an astronomical paper. At least naively, one would expect papers with more authors to be cited more. I test this expectation with the same sample of papers as analyzed in Stanek (2008) , selecting all (\u223c 30, 000) refereed papers from A&A, AJ, ApJ and MNRAS published between 2000 and 2004. These particular years were chosen so that the papers analyzed would not be too \"fresh\", but number of authors and length of each article could be obtained via ADS.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "There have been a number of publications analyzing citation patterns in the astronomical literature, see my previous paper for more discussion (Stanek 2008) . In that paper I addressed the question of whether longer astronomical papers are cited more (they are). Following a number of suggestions I received after posting that seminal 2 study, here I address the question of whether astronomical papers with more authors are also cited more. That this would be the case is somewhat expected, for a number of reasons, but the expected size of the effect varied quite widely among my informally polled colleagues. I therefore decided to investigate the citation vs. number of authors correlation for astronomical papers, and I found the results interesting enough to warrant this posting. In Section 2 I describe the data, namely citation and number of authors statistics for about 30,000 refereed astronomical papers published between 2000 and 2004 in ApJ, A&A, AJ and MNRAS. In Section 3 I discuss the results, and in Section 4 I conclude with some brief remarks.", "cite_spans": [], "ref_spans": []}, {"section": "Data", "text": "I used the ADS Abstract Service 3 to obtain the citations, page length and number of authors for all papers published between 2000 and 2004 (i.e., five complete years) in the four largest astronomical journals, A&A, AJ, ApJ and MNRAS.", "cite_spans": [], "ref_spans": []}, {"section": "Data", "text": "4 I start in 2000 so that page lengths will be reported for all papers and end with 2004 to allow significant time for papers to mature (or not) and obtain citations. The journals were chosen so there would be plenty of papers for statistics, with the page length being about the same for each journal. There were 12,854 ApJ (including ApJL and ApJS) papers, 9,275 A&A papers, 5,328 MNRAS papers and 2,564 AJ papers, for a total of 30,021 papers. Originally, that number was somewhat larger, but I have removed all one-page papers from the list, as these were mostly errata or editorials, usually cited 0 times. I procured these data using ADS in mid-November 2009. As this is the same sample of papers I have used in my previous study (Stanek 2008 ), but previously with citations accumulated until June 2008, I will also discuss briefly the growth of citations for the whole sample between the two studies.", "cite_spans": [], "ref_spans": []}, {"section": "Data", "text": "In Figures 1 and 2 I show the basic properties of our sample, such as the distribution of number of authors ( Fig. 1 ) and the distribution of citations (Fig. 2) . While the distributions presented in Fig. 1 are more or less the same, except for AJ having a larger fraction of papers with more authors, the distributions presented in Fig. 2 are not identical in shape.", "cite_spans": [], "ref_spans": [{"start": 3, "end": 20, "text": "Figures 1 and 2 I", "ref_id": "FIGREF0"}, {"start": 110, "end": 116, "text": "Fig. 1", "ref_id": "FIGREF0"}, {"start": 153, "end": 161, "text": "(Fig. 2)", "ref_id": "FIGREF1"}, {"start": 201, "end": 207, "text": "Fig. 1", "ref_id": "FIGREF0"}, {"start": 334, "end": 340, "text": "Fig. 2", "ref_id": "FIGREF1"}]}, {"section": "Data", "text": "The median number of authors per paper for the entire sample of \u223c 30, 000 papers is 3, with a mode of 2 authors, and only \u223c 100 papers with 50 or more authors. In the distribution of citations, \u223c 2, 3000 papers in the sample have 3 or fewer citations, while \u223c 1, 700 papers have 100 or more citations, and only 10 papers have 1,000 or more citations. Th median number of citations for the entire sample grew from 15 in June 2008 (Stanek 2008) to 19 in November 2009. I have not tried in any way to correct for or to remove self-citations. ", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "Having the number of authors and the number of citations, I can produce a CitationAuthors Diagram (hereafter: CAD), which I present in Fig. 3 . For display purposes, I have added +1 to the number of citations for each paper (\"an honorary citation\"), to avoid the log citations = \u2212\u221e problem. Also, for display purposes, I add a random variable uniformly distributed between 0 and 0.9 to both N Authors and the number of citations, otherwise all papers with the same number of authors and citations would produce only one dot in the CAD.", "cite_spans": [], "ref_spans": [{"start": 135, "end": 141, "text": "Fig. 3", "ref_id": "FIGREF2"}]}, {"section": "Results", "text": "For bins of journals articles with a given number of authors, the median number of citations is shown by large open circles. As can be seen from our CAD, these medians clearly increase with the number of authors, and range from 12 for articles with 1 author to about 50 for articles with 50 and more authors. One obvious thing to notice is that, as expected, for any given number of authors on a paper there is a very wide range in the number of citations, as seen by the 10% and 90% ranges (filled blue dots). Somewhat surprisingly, barring any ADS errors, there seem to exist papers with very many authors and very few citations.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "Since I have already shown (Stanek 2008 ) that longer papers are cited more (again, in the median sense, and as always with a large dispersion in number of citations), maybe what we are seeing in Fig. 3 is simply that having more authors also means writing more pages? However, as can be seen in Fig. 4 , that is definitely not the case, in fact the median number of pages does not seem to depend at all on the number of authors and it is always from 8 to 10 pages. Additional authors clearly do not seem to be actually contributing much in terms of additional paper length, but they are clearly adding (logarithmically) to a paper's impact. This additional impact could be simply due to more self-citations, but that is only a guess, which I have not investigated here.", "cite_spans": [], "ref_spans": [{"start": 196, "end": 202, "text": "Fig. 3", "ref_id": "FIGREF2"}, {"start": 296, "end": 302, "text": "Fig. 4", "ref_id": "FIGREF3"}]}, {"section": "Results", "text": "Finally, in Fig 5 I plot the cumulative distributions of the fraction of the total citations vs. number of authors for each of the four journals. The curves for ApJ, A&A and MNRAS are rather similar, while the cumulative curve for AJ is significantly different, meaning papers with more authors contribute a significantly larger fraction of total citations for AJ vs. the other journals. I will let the Reader amuse herself/himself by speculating on or investigating the possible reasons for this difference.", "cite_spans": [], "ref_spans": [{"start": 12, "end": 19, "text": "Fig 5 I", "ref_id": "FIGREF4"}]}, {"section": "Brief Remarks", "text": "In Stanek (2008) I concluded with some semi-humorous publishing advice, directed especially towards first-year graduate students. I stand by that advice, also because of the For bins of articles with a given number of authors, the median number of citations is shown with the large dotted circle, ranging from 12 citations for articles with 1 author to \u223c 50 median citations for articles with more than 50 authors (there are only \u223c 100 papers in that last bin). Also shown are 10% and 90% ranges in each bin. The \"best-fit\" line was fit by eye. mostly positive feedback I have received after posting that study 5 : \"I enjoyed your well written article about citations and the length of papers. Perhaps surprisingly, the longest of the \u223cN00 papers that I have written was often cited, but not much read. So perhaps one should look for ways to try to measure the impact of a paper rather than the number of times it is cited -clearly a difficult task. Perhaps the truly great papers are the ones that still get cited after many decades. It is a bit frightening to note that Zwicky's great paper on the discovery of dark matter only started to get cited a quarter of a century after it was written.\"; \"I wanted to say that I read your paper and really enjoyed it. In particular, the last section where you gave 'semi-humorous' advice. That was the best advice I've heard in a long time!\"; \"brilliant astro-ph submission! I think this will be a mandatory read for any students that want to go on to grad school.'; \"Thanks for your insightful and very funny paper on astro-ph. It made my morning.\"; but also \"Cute paper on astro-ph today, but don't you find this whole series of meta-papers to be rather cynical? You call the advice to first-year graduate students like myself 'semi-humorous,' but the message seems to be telling us how to game the system.\" I do not have enough new semi-humorous material to put in this paper, but if you send me something funny and relevant, I might add you and the advice to the paper, and perhaps together we will be cited more (logarithmically speaking). It would perhaps be of some interest to investigate how the effect found in this paper changes with time, and more generally if the statistics of number of authors has evolved in the last few decades. This might or might not be a subject of a future study.", "cite_spans": [], "ref_spans": []}, {"section": "Brief Remarks", "text": "I thank Hsiao-Wen Chen and Chris Kochanek for suggesting this particular line of inquiry. I also thank Chris Kochanek for locating all these \"the\"s and \"a\"s that I have lost, misplaced or applied randomly. I thank the people whose e-mails I am quoting (I will keep them anonymous). The data and plots presented in this paper are real, despite the (mostly intended) humorous style of writing. This paper will not be submitted to any journal.", "cite_spans": [], "ref_spans": []}], "bib_entries": {}, "ref_entries": {"FIGREF0": {"text": "Fig. 1.-Distribution of the number of authors for 30,021 A&A, AJ, ApJ, and MNRAS papers published between 2000-2004. There are about 100 papers with 50 or more authors, and there are about 3,000 papers with one author.", "type": "figure"}, "FIGREF1": {"text": "Fig. 2.-Distribution of citations for 30,021 A&A, AJ, ApJ and MNRAS papers published between 2000-2004, shown for the entire sample and for each journal separately. This is analogous figure to Fig. 2 in Stanek (2008), but with citations numbers updated for November 2009. Median number of citations for the entire sample grew from 15 in June 2008 to 19 in November 2009. There are about 1,700 papers with 100 or more citations and 10 papers with more than 1000 citations.", "type": "figure"}, "FIGREF2": {"text": "Fig. 3.-Citations vs. number of authors for our sample of 30,021 papers published in A&A, AJ, ApJ, and MNRAS between 2000-2004. For bins of articles with a given number of authors, the median number of citations is shown with the large dotted circle, ranging from 12 citations for articles with 1 author to \u223c 50 median citations for articles with more than 50 authors (there are only \u223c 100 papers in that last bin). Also shown are 10% and 90% ranges in each bin. The \"best-fit\" line was fit by eye.", "type": "figure"}, "FIGREF3": {"text": "Fig. 4.-Length of paper vs. number of authors on a paper. The median number of pages in each bin is shown with the large dotted circle.", "type": "figure"}, "FIGREF4": {"text": "Fig. 5.-Cumulative distributions of the total citations vs. number of authors for each of the four journals.", "type": "figure"}}}
{"paper_id": "17431971", "_pdf_hash": "f51d544230db748d9cd31a7b538d92bebfc930a9", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Is the Visual Cortex a Fast Clifford Algebra Quantum Compiler? A NATO Advanced Research Workshop Clifford Analysis and Its Applications", "authors": [{"first": "E", "middle": ["V"], "last": "Labunets-Rundblad", "suffix": ""}, {"first": "V", "middle": ["G"], "last": "Labunets", "suffix": ""}, {"first": "J", "middle": [], "last": "Astola", "suffix": ""}], "year": 1999, "venue": "", "link": null}, "BIBREF1": {"title": "Explicit solutions of Galois Embedding problems by means of generalized Clifford algebras", "authors": [{"first": "M", "middle": [], "last": "Vela", "suffix": ""}], "year": "", "venue": "J. Symbolic Computation", "link": "38320109"}, "BIBREF2": {"title": "On algebraic triplets", "authors": [{"first": "", "middle": [], "last": "Ch", "suffix": ""}, {"first": "", "middle": [], "last": "Greaves", "suffix": ""}], "year": "", "venue": "Proc. Irish Acad", "link": null}, "BIBREF3": {"title": "A new development on ANN in ChinaBiomimetic pattern recognition and multi weight vector neurons", "authors": [{"first": "Wang", "middle": [], "last": "Shoujue", "suffix": ""}], "year": 2003, "venue": "LECTURE NOTES IN ARTIFICIAL INTELLIGENCE", "link": null}, "BIBREF4": {"title": "Multi Camera Human Face Personal Identification System Based on Biomimetic pattern recognition", "authors": [{"first": "Wang", "middle": [], "last": "Shoujue", "suffix": ""}, {"first": "", "middle": [], "last": "Etc", "suffix": ""}], "year": 2003, "venue": "Acta Electronica Sinica", "link": "63388690"}, "BIBREF5": {"title": "Coverage in Biomimetic Pattern Recognition", "authors": [{"first": "Wenming", "middle": [], "last": "Cao", "suffix": ""}, {"first": "Guoliang", "middle": [], "last": "Zhao", "suffix": ""}], "year": 2007, "venue": "", "link": "39127442"}, "BIBREF6": {"title": "Corresponding Author", "authors": [], "year": "", "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "17432104", "_pdf_hash": "4f07351b076e4654e559d65d17d32695cda3606f", "abstract": [{"section": "Abstract", "text": "Bayer Pharmaceuticals, West Haven, Connecticut", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Background. Limited prospective data are available for elderly patients with community-acquired pneumonia (CAP). This study aimed to determine the efficacy and safety of moxifloxacin versus that of levofloxacin for the treatment of CAP in hospitalized elderly patients (age, \u044365 years).", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Methods. We conducted a prospective, double-blind, randomized, controlled trial. Eligible patients were stratified by CAP severity before randomization to receive treatment with either intravenous/oral moxifloxacin (400 mg daily) or intravenous/oral levofloxacin (500 mg daily) for 7-14 days. Clinical response at test-of-cure (the primary efficacy end point was between days 5 and 21 after completion of therapy), and clinical response during therapy (between days 3 and 5 after the start of therapy) and bacteriologic response were secondary end points.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Results. The safety population included 394 patients (195 in the moxifloxacin group and 199 in the levofloxacin group). The population eligible for clinical efficacy analysis (i.e., the clinically valid population) included 281 patients (141 in the moxifloxacin group and 140 in the levofloxacin group); 51.3% were male, and the mean age (\u202b\u05e2\u202cSD) was years. Cure rates at test-of-cure for the clinically valid population were 92.9% in the 77.4 \u202b\u05e2\u202c 7.7 moxifloxacin arm and 87.9% in the levofloxacin arm (95% confidence interval [CI], \u03ea1.9 to 11.9;", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "). Clinical P p .2 recovery by days 3-5 after the start of treatment was 97.9% in the moxifloxacin arm vs. 90.0% in the levofloxacin arm (95% CI, 1.7-14.1;", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "). In the moxifloxacin group, cure rates were 92.6% for patients with mild or P p .01 moderate CAP and 94.7% for patients with severe CAP, compared with cure rates of 88.6% and 84.6%, respectively, in the levofloxacin group ( significant). Cure rates in the moxifloxacin arm were 90.0% for patients aged P p not 65-74 years and 94.5% for patients aged \u044375 years, compared with 85.0% and 90.0%, respectively, in the levofloxacin arm ( significant). There were no statistically significant differences between the treatment groups P p not with regard to drug-related adverse events.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Conclusions. Intravenous/oral moxifloxacin therapy was efficacious and safe for hospitalized elderly patients with CAP, achieving 190% cure in all severity and age subgroups, and was associated with faster clinical recovery than intravenous/oral levofloxacin therapy, with a comparable safety profile.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "In the United States, community-acquired pneumonia (CAP) accounts for 15.6 million cases and 1 million hospitalizations annually [1] . A retrospective cohort within 18 months [4] . Accordingly, institution of appropriate antibiotic therapy is imperative for elderly patients, to prevent unnecessary morbidity and death [3, [5] [6] [7] [8] .", "cite_spans": [{"start": 129, "end": 132, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 175, "end": 178, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 319, "end": 322, "text": "[3,", "ref_id": "BIBREF2"}, {"start": 323, "end": 326, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 327, "end": 330, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 331, "end": 334, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 335, "end": 338, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "", "text": "Updated CAP treatment guidelines recommend fluoroquinolone monotherapy or b-lactam plus macrolide combination therapy for hospitalized patients with CAP [9, 10] . However, no prospective clinical trials have been published that compare fluoroquinolones in hospitalized elderly patients with CAP. Thus, the primary purpose of this study was to compare the efficacy of sequential intravenous/oral moxifloxacin therapy with levofloxacin therapy in hospitalized elderly patients aged \u044365 years with CAP. A separate publication involving this same patient population and protocol describes the primary safety variable (i.e., cardiac adverse events) [11] .", "cite_spans": [{"start": 153, "end": 156, "text": "[9,", "ref_id": "BIBREF8"}, {"start": 157, "end": 160, "text": "10]", "ref_id": "BIBREF9"}, {"start": 644, "end": 648, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "PATIENTS AND METHODS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Study design and treatment.", "text": "A prospective, randomized controlled, double-blind, double-dummy, comparative study was conducted from November 2002 to April 2004 at 47 study centers in the United States. The study was conducted in accordance with the Declaration of Helsinki, and each institution's internal review board approved the study protocol; written informed consent was obtained from each patient.", "cite_spans": [], "ref_spans": []}, {"section": "Study design and treatment.", "text": "After stratification by disease severity with the revised American Thoracic Society criteria (mild/moderate vs. severe) [10] , patients were randomly assigned to receive either intravenous moxifloxacin, 400 mg once daily, or intravenous levofloxacin, 500 mg once daily, for 7-14 days. Patients were also assigned a Pneumonia Outcome Research Team pneumonia severity index score [12] , although it was not used for stratification. For patients with a documented and/or a calculated creatinine clearance rate of 20-49 mL/min, the intravenous dose of levofloxacin therapy was a 500-mg loading dose, followed by a dosage of 250 mg once daily for 7-14 days. Treatment with moxifloxacin did not require dosage adjustment for these patients.", "cite_spans": [{"start": 120, "end": 124, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 378, "end": 382, "text": "[12]", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "Study design and treatment.", "text": "Patients could be switched to oral therapy at the investigator's discretion (moxifloxacin, 400 mg once daily, or levofloxacin, 250-500 mg once daily) after \u04432 days of intravenous therapy if they demonstrated improvement during intravenous therapy, were afebrile for \u04438 h, and could tolerate oral food, fluids, and medications without vomiting or diarrhea. Both oral medications were encapsulated for blinding.", "cite_spans": [], "ref_spans": []}, {"section": "Study design and treatment.", "text": "Patient population. The trial population included hospitalized elderly patients (age, \u044365 years) with clinical signs and symptoms of CAP, radiologically confirmed evidence of a new and/or progressive infiltrate(s), a requirement for initial parenteral therapy, and at least 2 of the following conditions: productive cough with purulent and/or mucopurulent sputum (\u044325 polymorphonuclear neutrophils per low-power field) or a change in sputum character (increased volume and/or purulence), dyspnea and/or tachypnea (respiratory rate of 120 breaths/min), rigors and/or chills, pleuritic chest pain, auscultatory findings of rales and/or crackles on pulmonary examination and/or evidence of pulmonary consolidation, fever ( ). Patients with any of the following characteristics were excluded from the study: hospitalization for 148 h before pneumonia development, end-organ damage or shock (systolic blood pressure of !90 mm Hg and diastolic blood pressure of !60 mm Hg) with need for vasopressors for 14 h, need for mechanical ventilation, implanted cardiac defibrillator, significant bradycardia (heart rate of !50 beats/min), systemic antibacterial therapy for 124 h within 7 days of enrollment unless therapy failed after receiving 172 h of a nonfluoroquinolone antibiotic, mechanical endobronchial obstruction, known or suspected active tuberculosis or endemic fungal infection, neutropenia (neutrophil count of !1000 neutrophils/mL), chronic therapy (duration of \u04432 weeks) with immunosuppressant therapy (115 mg/day of systemic prednisone or equivalent), known HIV infection (CD4 cell count of !200 cells/mm 3 ), severe hepatic insufficiency (Child-Pugh classification of C), renal impairment (serum creatinine clearance rate of !20 mL/min), uncorrected hypokalemia, known prolongation of the corrected QT interval or use of class IA or class III antiarrhythmics, previous history of tendinopathy with quinolones, or known hypersensitivity to study medications.", "cite_spans": [], "ref_spans": []}, {"section": "Study design and treatment.", "text": "Clinical and bacteriologic evaluations. Clinical signs and symptoms were evaluated before treatment (within 48 h before receipt of the first dose of study drug), during treatment (between days 3 and 5 after the start of treatment), and at the test-of-cure visit (between days 5 and 21 after the end of therapy). Sputum samples were collected before study drug was started. Cultures were performed if Gram staining revealed \u044010 squamous epithelial cells per low-power field and \u044325 leukocytes per low-power field. Additional sputum specimens were obtained from patients with clinical failure. Blood specimens were obtained at enrollment, and if results of culture were positive, samples were obtained and cultured every 48 h until results were negative. A urinary antigen test for detection of Legionella pneumophila was performed.", "cite_spans": [], "ref_spans": []}, {"section": "Study design and treatment.", "text": "Clinical and bacteriologic outcome definitions. Clinical response at the test-of-cure visit (between days 5 and 21 after the end of therapy) was the primary efficacy outcome. Secondary efficacy outcomes included clinical response during therapy (between days 3 and 5 after the start of therapy) and bacteriologic response at the test-of-cure visit.", "cite_spans": [], "ref_spans": []}, {"section": "Study design and treatment.", "text": "Patients were considered to be eligible for the clinical efficacy analysis (i.e., for enrollment in the clinically valid population) if they met the eligibility criteria, received the study drug for \u044348 h (in cases of clinical failure) or for \u04435 days (in cases of clinical cure), received no other concomitant systemic antimicrobial therapy, had a test-of-cure clinical assessment that was not indeterminate, and had \u044380% adherence with study medication. Patients who met these criteria but discontinued receiving the study drug because of an adverse event were included in the efficacy analysis. Clinical response at the test-of-cure visit was defined as cure (disappearance of acute signs and symptoms related to the infection or sufficient improvement such that additional or alternative antimicrobial therapy was not required), failure (failure to respond or insufficient improvement of the signs and symptoms of infection such that additional antimicrobial therapy was required), or indeterminate. Clinical response at the during therapy visit (between days 3 and 5 after the start of therapy) was categorized as recovery (disappearance of acute signs and symptoms related to the infection or reduction in the severity and/or number of signs and symptoms of infection), failure (as defined above), or indeterminate.", "cite_spans": [], "ref_spans": []}, {"section": "Study design and treatment.", "text": "Patients who were in the clinically valid population and had a pathogen isolated from sputum or blood culture before treatment comprised the microbiologically valid population. Bacteriologic responses during therapy and at the test-of-cure visit were defined as eradication, presumed eradication (if no sputum specimen was available because of clinical success), persistence, presumed persistence (no sputum specimen was available for patients with clinical failure), or indeterminate. Superinfection was defined as the appearance of a new pathogen in patients with clinical failure.", "cite_spans": [], "ref_spans": []}, {"section": "Study design and treatment.", "text": "Safety and tolerability assessment. The safety analysis included patients who received at least 1 dose of study drug (intention-to-treat population). Adverse events were documented up to the test-of-cure visit using Medical Dictionary for Regulatory Activities (MedDra) terminology. Treatment-emergent adverse events (i.e., regardless of their relationship to study drug) and adverse reactions leading to premature discontinuation were recorded. Each adverse event was rated by the investigator on the basis of intensity (mild, moderate, or severe) and whether it was definitely, probably, or possibly related to the study drug. Serious adverse reactions were defined as those that were fatal, were life-threatening, required hospitalization, resulted in disability, or otherwise endangered the patient and were documented up to 30 days after receipt of the final dose of study drug. Serial blood and urine samples were collected throughout the study for routine hematologic, chemistry, and coagulation evaluations and for urinalysis. Health resource utilization assessment. Data on the total duration of hospital stay, duration of intensive care unit (ICU) stay, total duration of antimicrobial therapy, and duration of intravenous therapy were collected at the test-of-cure visit.", "cite_spans": [], "ref_spans": []}, {"section": "Study design and treatment.", "text": "Statistical analysis. All statistical analyses were performed using SAS (SAS Institute) [13] . The primary efficacy objective was to show that moxifloxacin therapy was not inferior to levofloxacin therapy for the treatment of CAP, on the basis of clinical response at the test-of-cure visit for the clinically valid population. The power calculation for this end point was based on the Farrington-Manning method: assuming a clinical success rate of 90% and an eligibility of 70% for the enrolled subjects, a total of 400 enrolled patients provides 280 patients (400 ) in the clinically valid population, giving a patients \u03eb 70% power of 76% by using a D (critical difference) of \u03ea10% or a power of 90% by using a D of \u03ea15%. The Cochran-MantelHaenszel method was used to calculate 95% CIs [14] . Secondary efficacy end points included clinical outcome at other time points in the intention-to-treat and microbiologically valid populations, as well as bacteriologic outcomes.", "cite_spans": [{"start": 88, "end": 92, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 788, "end": 792, "text": "[14]", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Study design and treatment.", "text": "Logistic regression was performed to evaluate treatment effect on the primary dependent efficacy outcome variable (i.e., ). B, Clinical cure at the test-of-cure visit (i.e., primary efficacy outcome); \u2020 95% CI for difference, \u03ea1.9 to P p .01 11.9 ( ). P p .2 clinical response at the test-of-cure visit) after adjusting for risk factors, including sex, race, age, pretreatment hospitalization history, pneumonia severity index score, switch from intravenous to oral treatment, sequence of intravenous dosing, smoking history, primary residence, presence of pathogen at baseline, body mass index, infection duration, aspiration pneumonia, and health status. Multiple logistic regression was performed with only those variables with P values of !.20. Treatment effect was evaluated after adjusting for other confounding factors in the regression model from the univariate analyses. Continuous independent variables were treated as continuous, with no collapsing done for the analysis.", "cite_spans": [], "ref_spans": []}, {"section": "Study design and treatment.", "text": "Demographic and clinical characteristics at baseline, adverse events, and laboratory data were summarized using descriptive statistics, and treatment groups were compared using 1-way analysis of variance for continuous variables or x 2 analysis for categorical data.", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Patient disposition and demographic characteristics.", "text": "Of 401 patients randomly assigned to receive study therapy, 7 received no study medication. Thus, the safety population included 394 patients (figure 1). The clinically valid population included 141 patients in the moxifloxacin group and 140 patients in the levofloxacin group. Baseline demographic and clinical characteristics for the clinically valid population are summarized in table 1 and were similar between the 2 treatment groups. The clinically valid population had a mean age (\u202b\u05e2\u202cSD) of years, with 77.9 \u202b\u05e2\u202c 7.1 For the clinically valid population, the mean duration (\u202b\u05e2\u202cSD) of total antimicrobial therapy was days for the mox-10.0 \u202b\u05e2\u202c 2.7 ifloxacin arm and days for the levofloxacin arm 10.0 \u202b\u05e2\u202c 2.9 ( ). The mean duration (\u202b\u05e2\u202cSD) of intravenous therapy was P 1 .8 days for the moxifloxacin arm versus days 3.7 \u202b\u05e2\u202c 2.0 3.8 \u202b\u05e2\u202c 2.2 for levofloxacin arm ( ). The majority of patients were P p .7 switched to oral therapy on day 3 or 4 after the start of therapy (93.6% in the moxifloxacin arm vs. 88.6% in the levofloxacin arm;", "cite_spans": [], "ref_spans": []}, {"section": "Patient disposition and demographic characteristics.", "text": "). P p .2 Clinical outcomes. At the test-of-cure visit, the clinical cure rate (i.e., the primary efficacy outcome) for the clinically valid population was 92.9% for the moxifloxacin arm and 87.9% for the levofloxacin arm (95% CI, \u03ea1.9 to 11.9; ) (figure P p .2 2). At the during treatment visit (between days 3 and 5 after the start of therapy) for the clinically valid population, 97.9% of patients in the moxifloxacin arm, compared with 90.0% of patients in the levofloxacin arm, had achieved clinical recovery (95% CI, 1.7-14.1; ) (figure 2). P p .01 Univariate analysis identified the following risk factors as influences of clinical outcome (figure 3): for severe CAP, the rates of clinical cure were 94.7% in the moxifloxacin arm and 84.6% in the levofloxacin arm (95% CI, \u03ea0.12 to 0.32; P p ); for patient age, the clinical cure rates for those aged 65-.5 74 years were 90.0% in the moxifloxacin arm and 85.0% in the levofloxacin arm (95% CI, \u03ea0.09 to 0.19;", "cite_spans": [], "ref_spans": []}, {"section": "Patient disposition and demographic characteristics.", "text": "), and the P p .6 rates for those aged \u044375 years were 94.5% and 90.0%, respectively (95% CI, \u03ea0.05 to 0.14; ); and patients who P p .4 were still receiving intravenous therapy at the test-of-cure visit had lower clinical cure rates (55.6% [ ). P p .98 Safety and tolerability. The rate of treatment-emergent adverse events due to any cause was significantly higher in the moxifloxacin-treated patients ( ) (table 3) , although the P p .01 rates of drug-related and serious adverse events were similar for both treatment arms. There was no difference between treatments with regard to the rate of premature discontinuation owing to an adverse event; 17 (48.6%) of 35 of these events were considered to be drug related (10 in the moxifloxacin arm and 7 in the levofloxacin arm). Serious adverse events were reported for \u223c23% of patients in both treatment groups ( ). No clinically significant differences between treatment P p .9 groups were seen for clinical laboratory test values or vital signs.", "cite_spans": [], "ref_spans": [{"start": 406, "end": 415, "text": "(table 3)", "ref_id": "TABREF4"}]}, {"section": "Patient disposition and demographic characteristics.", "text": "There was no difference in mortality between the 2 treatment groups ( ), and the majority of deaths occurred 17 days P p .5 after receipt of the final dose of study drug. Only 6 moxifloxacin-and 3 levofloxacin-treated patients died during therapy or within the first 7 days after therapy. None of the deaths were considered to be drug related, and all were determined by the investigators to be due to the patient's comorbid diseases.", "cite_spans": [], "ref_spans": []}, {"section": "Patient disposition and demographic characteristics.", "text": "Health resource utilization. For the clinically valid population, the total duration of hospital stay (\u202b\u05e2\u202cSD) was 7.5 \u202b\u05e2\u202c days in the moxifloxacin arm and days in the 4.2 7.5 \u202b\u05e2\u202c 4.6 levofloxacin arm ( ), with a mean duration (\u202b\u05e2\u202cSD) of P p .95 days and days, respectively, for hospital stay 6.8 \u202b\u05e2\u202c 4.1 6.8 \u202b\u05e2\u202c 4.6 after the initiation of study drug treatment ( ). For pa-P p .95 tients in the ICU, the total duration of hospital stay was similar between the treatment groups. There were no differences in health resource utilization between patients with positive versus those with negative results of pretherapy bacterial cultures. ", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "In this prospective, randomized, double-blind trial involving hospitalized elderly patients with CAP, moxifloxacin-treated patients were more likely to have clinical improvement by treatment day 3-5 than were levofloxacin-treated patients. The overall clinical cure rate and bacteriologic success rates were similar between the 2 treatment groups. There was a higher incidence of adverse events due to any cause in the moxifloxacin group, although the incidence of drug-related adverse events was similar to that in the levofloxacin group. In subgroup analyses based on CAP severity and patient age, clinical cure rates in the moxifloxacin arm were consistently higher than, although not statistically significantly different from, those for levofloxacin. This trial included 394 elderly patients with a mean age (\u202b\u05e2\u202cSD) of years, 60.9% of whom were at least 75 77.4 \u202b\u05e2\u202c 7.7 years old. Most patients had concomitant comorbid conditions, including cardiac, gastrointestinal, chronic lung disease, and diabetes mellitus. More than two-thirds of patients in both groups had a pneumonia severity index score of \u04433. The pneumonia severity index score is high for this population probably because this measure is strongly influenced by age [12] .", "cite_spans": [{"start": 1234, "end": 1238, "text": "[12]", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "Clinical trials involving adults have demonstrated that moxifloxacin is effective against CAP [15] [16] [17] [18] . In very elderly patients with CAP (age, 175 years), a pooled analysis of 5 prospective, randomized, controlled trials of intravenous and oral moxifloxacin therapy found similar efficacy and adverse event rates to those observed in the current trial [19] . Comparator agents were clarithromycin and amoxicillin in the oral treatment studies and trovafloxacin, levofloxacin, and amoxicillin/ clavulanate with or without clarithromycin in the intravenous treatment studies [19] . The overall clinical success rates were 93.0% (53 of 57 patients) and 90.2% (83 of 92 patients) for the oral and intravenous moxifloxacin arms, respectively (95% CI, \u03ea3.2 to 15.9), and 86.4% (38 of 44 patients) and 83.7% (77 of 92 patients) for the oral and intravenous comparator arms, respectively (95% CI, \u03ea5.4 to 20.9) [19] .", "cite_spans": [{"start": 94, "end": 98, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 99, "end": 103, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 104, "end": 108, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 109, "end": 113, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 365, "end": 369, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 586, "end": 590, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 916, "end": 920, "text": "[19]", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "Recently, Dunbar et al. [20] reported similar efficacy and safety outcomes between 2 levofloxacin doses (500 mg vs. 750 mg, once daily) for treatment of mild or severe CAP in adult patients. However, the present study is the first comparative evaluation of 2 different fluoroquinolones in hospitalized elderly patients with CAP. The finding that moxifloxacin therapy led to a significantly more rapid clinical improvement and/or resolution of pneumonia than levofloxacin therapy in elderly patients (i.e., between days 3 and 5 after the start of therapy) may be clinically important. This end point should be considered for other CAP clinical trials because it may represent a more sensitive measure of antibiotic efficacy than assessment at the test-of-cure visit. However, it should be noted that, in the current study, there were no differences in duration of stay or duration of intravenous therapy between the 2 regimens. This could, at least in part, be due to the minimum duration of therapy (5 days) mandated by the protocol for patients to be considered for the clinically valid population, and the fact that the total duration of hospitalization in this patient population could have been influenced by other factors, including multiple comorbidities present in these patients.", "cite_spans": [{"start": 24, "end": 28, "text": "[20]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "The rate of treatment-emergent adverse events was significantly higher in the moxifloxacin arm, compared with the levofloxacin arm. However, the rates of drug-related and serious adverse events were similar for both treatment arms. It is possible that the higher rate of adverse events due to any cause was caused by high rates of underlying comorbid illness, including cardiac disease. Moxifloxacin-treated patients experienced fewer drug-related cardiac adverse events than did levofloxacin-treated patients, although this difference was not statistically significant (1.0% vs. 3.5%;", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "). Diarrhea and P ! .2 oral candidiasis were the 2 most commonly reported drugrelated adverse events in both treatment groups. There was no evidence that moxifloxacin therapy increased the risk of Clostridium difficile diarrhea in elderly patients more than levofloxacin did; there were more occurrences of C. difficile colitis in the levofloxacin arm (6 patients [3.0%]) than in the moxifloxacin arm (1 patient [0.5%]), although the difference was not statistically significant ( ). Recent publications sug-P p .1 gest that fluoroquinolones may increase the risk of C. difficile colitis [21] and may reduce the effectiveness of subsequent antimicrobial therapy [22] . One study in a long-term care facility showed that gatifloxacin therapy may be associated with a higher rate of C. difficile diarrhea than levofloxacin therapy [21] .", "cite_spans": [{"start": 588, "end": 592, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 662, "end": 666, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 829, "end": 833, "text": "[21]", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "Twenty-six patients died during the observation period; most deaths were associated with the severity of comorbid diseases. The mortality rate in this study is lower than those reported elsewhere for hospitalized patients with CAP, which range from 10% to 40% [1, 2, 7, 8] . This difference may be due to the eligibility criteria for this study, which excluded patients who required mechanical ventilation or vasopressors or who had multiorgan failure.", "cite_spans": [{"start": 260, "end": 263, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 264, "end": 266, "text": "2,", "ref_id": "BIBREF1"}, {"start": 267, "end": 269, "text": "7,", "ref_id": "BIBREF6"}, {"start": 270, "end": 272, "text": "8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "An important limitation of this study is that the etiology of CAP could not be identified in the majority of patients. Pneumococcal urine antigen testing and serologic testing for detection of atypical organisms were not performed. Thus, correlation of clinical outcomes with bacteriologic outcomes was not possible for most patients. Also, antimicrobial susceptibility data were not available for all cultured organisms. The organisms isolated most commonly were Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus, as reported by other investigators [2, 8] .", "cite_spans": [{"start": 576, "end": 579, "text": "[2,", "ref_id": "BIBREF1"}, {"start": 580, "end": 582, "text": "8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "In conclusion, sequential intravenous/oral moxifloxacin monotherapy provided significantly higher clinical recovery rates by day 3-5 after initiation of treatment and was as effective, safe, and well tolerated as intravenous/oral levofloxacin monotherapy in hospitalized elderly patients with CAP. Prospective studies are needed to identify the factors associated with duration of antibiotic therapy and hospital stay in this patient population.", "cite_spans": [], "ref_spans": []}, {"section": "MEMBERS OF THE STUDY GROUP", "text": "", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "The cost of treating community-acquired pneumonia", "authors": [{"first": "M", "middle": ["S"], "last": "Niederman", "suffix": ""}, {"first": "J", "middle": [], "last": "Mccombs", "suffix": ""}, {"first": "A", "middle": [], "last": "Unger", "suffix": ""}, {"first": "A", "middle": [], "last": "Kumar", "suffix": ""}, {"first": "R", "middle": [], "last": "Popovian", "suffix": ""}], "year": 1998, "venue": "Clin Ther", "link": "24386869"}, "BIBREF1": {"title": "The burden of community-acquired pneumonia in seniors: results of a population-based study", "authors": [{"first": "M", "middle": ["L"], "last": "Jackson", "suffix": ""}, {"first": "K", "middle": ["M"], "last": "Neuzil", "suffix": ""}, {"first": "W", "middle": ["W"], "last": "Thompson", "suffix": ""}], "year": 2004, "venue": "Clin Infect Dis", "link": "23880549"}, "BIBREF2": {"title": "Pneumonia: still the old man's friend?", "authors": [{"first": "V", "middle": [], "last": "Kaplan", "suffix": ""}, {"first": "G", "middle": [], "last": "Clermont", "suffix": ""}, {"first": "M", "middle": ["F"], "last": "Griffin", "suffix": ""}], "year": 2003, "venue": "Arch Intern Med", "link": "23429125"}, "BIBREF3": {"title": "Outcome predictors of pneumonia in elderly patients: importance of functional assessment", "authors": [{"first": "O", "middle": ["H"], "last": "Torres", "suffix": ""}, {"first": "J", "middle": [], "last": "Munoz", "suffix": ""}, {"first": "D", "middle": [], "last": "Ruiz", "suffix": ""}], "year": 2004, "venue": "J Am Geriatr Soc", "link": "72405857"}, "BIBREF4": {"title": "Pneumonia in the elderly (geriatric) population", "authors": [{"first": "J", "middle": ["P"], "last": "Janssens", "suffix": ""}], "year": 2005, "venue": "Curr Opin Pulm Med", "link": "40715205"}, "BIBREF5": {"title": "Indicators of recurrent hospitalization for pneumonia in the elderly", "authors": [{"first": "A", "middle": ["A"], "last": "El Solh", "suffix": ""}, {"first": "T", "middle": [], "last": "Brewer", "suffix": ""}, {"first": "M", "middle": [], "last": "Okada", "suffix": ""}, {"first": "O", "middle": [], "last": "Bashir", "suffix": ""}, {"first": "M", "middle": [], "last": "Gough", "suffix": ""}], "year": 2004, "venue": "J Am Geriatr Soc", "link": "30457365"}, "BIBREF6": {"title": "Prognosis and outcomes of patients with community-acquired pneumonia: a meta-analysis", "authors": [{"first": "M", "middle": ["J"], "last": "Fine", "suffix": ""}, {"first": "M", "middle": ["A"], "last": "Smith", "suffix": ""}, {"first": "C", "middle": ["A"], "last": "Carson", "suffix": ""}], "year": 1996, "venue": "JAMA", "link": "23981040"}, "BIBREF7": {"title": "Severe community-acquired pneumonia in the elderly: epidemiology and prognosis. 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Patient flow in a clinical trial of the efficacy and safety of moxifloxacin versus that of levofloxacin in the treatment of hospitalized elderly patients with community-acquired pneumonia.", "type": "figure"}, "FIGREF1": {"text": "Figure 2. Clinical outcomes for the clinically valid population: A, Clinical recovery during therapy (between days 3 and 5 after the start of treatment); *95% CI for difference, 1.7-14.1 ( ). B, Clinical cure at the test-of-cure visit (i.e., primary efficacy outcome); \u2020 95% CI for difference, \u03ea1.9 to P p .01 11.9 ( ). P p .2", "type": "figure"}, "FIGREF2": {"text": "Figure 3. Clinical cure rates at the test-of-cure visit for the clinically valid population, stratified by community-acquired pneumonia (CAP) severity (A) and age (B).", "type": "figure"}, "TABREF0": {"text": "an oral temperature of \u044338\u040aC [100.4\u040aF], a rectal temperature of \u044339\u040aC [102.2\u040aF], or a tympanic temperature of \u044338.5\u040aC [101.2\u040aF]) or hypothermia (rectal or core temperature of !35\u040aC [95.2\u040aF]), and a WBC count of \u044310,000 cells/mm 3 or \u044315% immature neutrophils (bands; regardless of peripheral WBC count) or leukopenia (total WBC count of !4500 cells/mm", "type": "table"}, "TABREF1": {"text": "Baseline demographic and medical characteristics of the clin- ically valid population in a clinical trial of the efficacy and safety of moxifloxacin versus levofloxacin for the treatment of hospitalized elderly patients with community-acquired pneumonia (CAP).NOTE. Data are no. (%) of patients, unless otherwise indicated. a According to 2001 guidelines of the American Thoracic Society (ATS) [10].", "type": "table"}, "TABREF2": {"text": "Baseline positive culture results for and most common pathogens isolated from elderly patients who received moxi- floxacin or levofloxacin for the treatment of community-acquired pneumonia (CAP).\u223c60.9% of patients aged \u044375 years. Patients in this population had a mean number of 18.8 comorbidities (18.3 in the mox- ifloxacin group and 19.3 in the levofloxacin group; ), P p .67 and the mean number of pretreatment medications was 6.0.", "type": "table"}, "TABREF3": {"text": "5 of 9 patients] in the moxifloxacin arm vs. 50.0% [8 of 16 patients] in the levoflox- acin arm). Multiple regression analysis using various combi- nations of risk factors failed to show a statistically significant higher cure rate between treatment groups.", "type": "table"}, "TABREF4": {"text": "Overview of adverse events for hospitalized elderly patients eligible who received moxifloxacin or levofloxacin for the treatment of community-acquired pneumonia.", "type": "table"}}}
{"paper_id": "17432107", "_pdf_hash": "664b2047f0649f118269a733b0acf99cf40797c7", "abstract": [{"section": "Abstract", "text": "The influence of urbanisation on physical activity and dietary changes was examined in a Papua New Guinea Highland population. Adult male and female subjects (n 56) were selected, including twenty-seven rural villagers and twenty-nine urban migrants. BMR was calculated from values measured in similar samples of Huli-speaking population, according to gender and body weight. Total daily energy expenditure (TEE) was assessed by 24 h heart rate (HR) monitoring (flex-HR method) and physical activity level (PAL) calculation was based on BMR. Energy, protein and fat intakes were measured by weighing food on a single day. Urban subjects were heavier and taller than their rural counterparts; significant differences were found in stature in men P , 0\u00b405 and body weight in women P , 0\u00b405X Urban subjects had longer sedentary periods HR # flex-HR) and shorter active periods HR . flex-HR) than rural subjects. Consequently, the former had lower TEE and PAL than the latter; significant differences were found in women (TEE, P , 0\u00b405Y PAL, P , 0\u00b401 but not in men. Total daily energy intake and TEE were well balanced (,7 %) in all groups, whereas protein and fat intakes were considerably higher in urban subjects than rural subjects. Reduced PAL and increased fat intake by urban dwellers may increase the risks of obesity and chronic degenerative diseases.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "Non-communicable diseases such as obesity, diabetes and cardiovascular disorders have long been the main health problems in developed countries, while in recent decades the prevalence of these diseases and their antecedent risk factors have rapidly increased in developing countries, known as`health transition ' (Sinnett et al. 1992; Taylor et al. 1992; Hodge et al. 1996) . These changes are caused to a large extent by Westernised dietary changes and a reduction in daily physical activity in relation to socioeconomic and living environmental conditions (King & Collins, 1989; Dowse et al. 1994; Hodge et al. 1995) .", "cite_spans": [{"start": 335, "end": 354, "text": "Taylor et al. 1992;", "ref_id": "BIBREF18"}, {"start": 355, "end": 373, "text": "Hodge et al. 1996)", "ref_id": "BIBREF9"}, {"start": 581, "end": 599, "text": "Dowse et al. 1994;", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "", "text": "Although a large number of studies have evaluated the dietary changes in various urban populations in developing countries, little is known about the physical activity levels (PAL) in these populations (Stein et al. 1988; Spurr et al. 1996) . This situation is mainly due to the difficulties in measuring energy expenditure (EE), particularly total daily energy expenditure (TEE), in free-living situations (World Health Organization/Food and Agriculture Organization/ United Nations University (FAO/WHO/UNU), 1985; Durnin, 1990) . In fact, there are only a few studies that have quantitatively compared the patterns of physical activity between urban and rural dwellers who shared the same genetic traits and cultural background (often seen in rural\u00b1urban migrants and rural residents of the same group). Such comparisons are useful for determining the effect of urbanisation.", "cite_spans": [{"start": 202, "end": 221, "text": "(Stein et al. 1988;", "ref_id": "BIBREF17"}, {"start": 222, "end": 240, "text": "Spurr et al. 1996)", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "", "text": "The subjects of this study were Huli-speaking villagers in their homeland in Papua New Guinea (PNG) Highlands and their migrants who lived in settlements (i.e. spontaneously developed residential areas) in Port Moresby, the national capital city of PNG; field work was conducted from July to September in 1994 for the former and from July to September in 1995 for the latter. We monitored the heart rate (HR) and measured the amounts of all foods consumed among adult samples of the two groups. The aims of the study were: (1) comparison of nutritional status (body weight and BMI) between rural villagers and urban migrants; (2) comparison of daily PAL between the two groups, with special interest in possible reduction of physical activity in the migrant group; (3) comparison of energy and major nutrient (protein and fat) intakes between the two groups, with special emphasis on dietary changes by urbanisation.", "cite_spans": [], "ref_spans": []}, {"section": "Subjects and methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Study populations", "text": "The Huli, one of the largest language groups in PNG, have inhabited the Tari basin located 1600 m above sea level between 142870", "cite_spans": [], "ref_spans": []}, {"section": "Study populations", "text": "H and 143830 H east longitude and between 5870 H and 6820 H south latitude in the central part of Southern Highlands Province, PNG. They have subsisted on agriculture of sweet potatoes (Ipomoea batatas) and pig husbandry (Kuchikura, 1999; Umezaki et al. 1999; Yamauchi et al. 2000) . Most migration of the Highlanders, including the Huli, to Port Moresby has progressively increased since the 1970s, particularly since the time of independence of PNG in 1975. Migrants from rural villages reside in settlements in Port Moresby by ethnic groups. The houses are built by the migrants themselves using secondhand or makeshift materials. Most of the migrants have not been able to obtain jobs in the formal sector, and thus have depended for their livelihood on income from informal sector jobs such as collection of empty bottles and selling of betel-nuts (nuts of Areca cateichu), cigarettes and/or cooked meat in markets or settlements. The major socioeconomic differences between the Huli rural and urban groups can be summarised as follows: (1) change in occupational activities from subsistence agriculture in rural villages to cash-earning work in urban settlements; (2) change in dietary pattern, represented by changes in staple foods from sweet potato and leafy greens in the former to purchased foods such as rice, tinned fish and lamb chops in the latter.", "cite_spans": [{"start": 239, "end": 259, "text": "Umezaki et al. 1999;", "ref_id": "BIBREF20"}, {"start": 260, "end": 281, "text": "Yamauchi et al. 2000)", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "Subjects", "text": "Married men and women, fifty-six in total, volunteered to participate in the present study. They included twentyseven villagers (fifteen men and twelve women) from two villages, and twenty-nine urban dwellers (fourteen men and fifteen women) from three settlements in Port Moresby. The rural subjects represented almost the entire adult populations of these two areas during the study period. The urban subjects were selected to match the age distribution of their village counterparts. All urban subjects were born and grew up in their homeland in the Tari basin. The average length of living in Port Moresby was 15 (range 0\u00b1 35) years for men and 7\u00b41 (1\u00b120) years for women. In addition, the average ages of these individuals when they migrated to Port Moresby were 21\u00b46 and 26\u00b44 years for men and women respectively. Elderly subjects over 60 years and pregnant women were not sampled due to the difficulty of conducting the step test (see p. 66). Ten lactating women (four in the rural sample and six in the urban sample) were included in the present study; there were no problems in collecting data from them and so their records were analysed without any special treatment. One of the authors (T.Y.) explained the purpose of the investigation to the participants in Tok Pisin (pidgin English, the lingua franca in PNG), with occasional assistance of interpreters.", "cite_spans": [], "ref_spans": []}, {"section": "Anthropometry", "text": "Before breakfast in the early morning, the body weight of each subject was measured using a portable scale with a precision of^0\u00b41 kg. Stature was measured to the nearest 1 mm using a portable field anthropometer (GPM, Switzerland). For rural samples, stature data were collected from twenty subjects (eleven men and nine women) who participated in the food consumption survey conducted in January 1995. Unfortunately, height was not measured in the remaining seven subjects in the HR monitoring survey conducted between July and September 1994. Their stature, however, was on average not markedly different from that of the other twenty rural subjects.", "cite_spans": [], "ref_spans": []}, {"section": "Heart rate monitoring", "text": "Using a cardio-frequency meter (Vantage XL; Polor Electro, Kempele, Finland), HR of each subject was monitored for 24 h from about 18.00 hours to the same time on the following day for most subjects, or from early morning (from 06.00 to 08.00 hours) to the same time on the following morning for some urban subjects. The HR monitoring system consisted of an electrode-belt transmitter and a wrist microcomputer receiver, which digitised and stored the recorded pulse. This system was light (,100 g) and did not disturb the subject's behaviour. The pulse was recorded at 1 min intervals and the maximum recording capacity of the system was 2020 min. Some HR profiles were excluded from analysis due to faulty electrode contact. Subsequent analysis of the HR and behavioural data indicated that transmission problems, recognised as zero or spikes, occurred during both rest and exercise and were not specific to given activities (Panter-Brick et al. 1996; Yamauchi et al. 2000) . The recordings in these short gaps were replaced with the average HR calculated from the data on either side of the gap (Leonard et al. 1995; Yamauchi et al. 2000) .", "cite_spans": [{"start": 954, "end": 975, "text": "Yamauchi et al. 2000)", "ref_id": "BIBREF22"}, {"start": 1098, "end": 1119, "text": "(Leonard et al. 1995;", "ref_id": "BIBREF11"}, {"start": 1120, "end": 1141, "text": "Yamauchi et al. 2000)", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "Heart rate monitoring", "text": "Step test", "cite_spans": [], "ref_spans": []}, {"section": "Heart rate monitoring", "text": "On the day of investigation each subject was requested to do two different step tests (stepping-1 and stepping-2) following the author's instructions in Tok Pisin or Huli language. The duration of each step test was 3 min and the height of the step was 0\u00b43 m. In stepping-1 and stepping-2 tests each subject stepped up and down at a constant pace of fifteen and thirty steps per min respectively. A metronome was used to achieve a steady-state condition for stepping exercises. The HR value in the final minute was used for analysis.", "cite_spans": [], "ref_spans": []}, {"section": "Heart rate monitoring", "text": "BMR, resting metabolic rate and energy cost of step test BMR and EE at rest (lying, sitting and standing) and during step tests were determined based on the subject's body 66 T. Yamauchi et al. weight, gender and the energy costs, which were measured in Huli-speaking individuals using the Douglas bag technique of indirect calorimetry (Douglas, 1911) on other occasions; the gender-and weight-specific BMR values used for estimation were 77\u00b48 and 70\u00b48 J/kg per min for rural (n 9) and urban (n 9) men respectively, and 75\u00b48 and 66\u00b45 J/kg per min for rural (n 7) and urban (n 8) women respectively . Resting metabolic rates were determined as the mean of energy costs measured when lying, sitting and standing (Katzmarzyk et al. 1994; Leonard et al. 1995; Murayama & Ohtsuka, 1999) .", "cite_spans": [{"start": 336, "end": 351, "text": "(Douglas, 1911)", "ref_id": "BIBREF3"}, {"start": 710, "end": 734, "text": "(Katzmarzyk et al. 1994;", "ref_id": "BIBREF11"}, {"start": 735, "end": 755, "text": "Leonard et al. 1995;", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "Heart rate monitoring", "text": "Determination of flex-heart rate points and estimation of total energy expenditure There is no standard procedure for determination of the flex-HR point which discriminates between resting and exercise HR values (Panter-Brick et al. 1996) . In the present study, we used the method described previously by our laboratory . Flex-HR was determined as the mean of the mean HR of the three resting activities (lying, sitting and standing) and the lowest HR during stepping exercise (i.e. stepping-1). The recorded HR values were then converted to energetic equivalents using each subject's EE v. HR regression line. TEE was estimated by the flex-HR method (Spurr et al. 1988; Ceesay et al. 1989 ) and EE during sleeping was assumed to equal BMR . For HR values which were equal to and below the flex-HR point (i.e.`sedentary' HR), the RMR determined as the mean EE values for lying, sitting and standing was assumed to represent their energy costs. Values above the flex-HR point (`active' HR) were converted to energy costs based on a regression line which was calibrated for each subject. The TEE was then calculated using the following formula: James et al. 1988) was also determined. The use of PAL allows comparison of individuals of different body size. PAL values are a universally accepted way of expressing EE and they help to convey an easily understandable concept (Ferro-Luzzi & Martino, 1996) .", "cite_spans": [{"start": 652, "end": 671, "text": "(Spurr et al. 1988;", "ref_id": "BIBREF16"}, {"start": 672, "end": 690, "text": "Ceesay et al. 1989", "ref_id": "BIBREF2"}, {"start": 1144, "end": 1162, "text": "James et al. 1988)", "ref_id": "BIBREF11"}, {"start": 1372, "end": 1401, "text": "(Ferro-Luzzi & Martino, 1996)", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Dietary intake", "text": "Dietary consumption was studied for each subject on the same day as HR monitoring. All foods consumed were weighed with a portable beam scale or a spring scale before cooking throughout the daytime period. In addition, the subjects were asked in the morning about the types and amounts of foods consumed during the previous night. Sweet potatoes and green leaves, which were most frequently eaten in the villages, were sampled in the Huli villages and their food compositions were determined in the laboratory in Japan. For other foodstuffs, the energy and major nutrient contents were estimated using food composition tables of Hongo & Ohtsuka (1993) and other available data for PNG and the surrounding areas (Umezaki et al. 1999) .", "cite_spans": [{"start": 629, "end": 651, "text": "Hongo & Ohtsuka (1993)", "ref_id": "BIBREF10"}, {"start": 711, "end": 732, "text": "(Umezaki et al. 1999)", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Statistical analysis", "text": "Data were expressed as means and standard deviations. Differences between groups were examined for statistical significance using the unpaired t test. P , 0\u00b405 was considered significant. Table 1 shows the number of subjects listed by age-group and their physical characteristics. Since rural subjects did not know their exact age, they were categorised into three groups (20\u00b130, 30\u00b140 and .40 years) according to the census data of the PNG Institute of Medical Research (Tari branch) and the authors' interviews. Urban women, but not men, were significantly heavier than their rural counterparts P , 0\u00b405Y while urban men were significantly taller than their rural counterparts P , 0\u00b405X BMR, TEE, PAL and the level of work classified according to PAL (WHO/FAO/UNU, 1985) are presented in Table 2 . No significant difference was found in BMR in 67 Physical activity and diet in urbanisation either sex. In men there were no significant differences in TEE or PAL. In contrast, significant differences were found in these indices in women (TEE, P , 0\u00b405Y PAL, P , 0\u00b401). According to the work levels of WHO/FAO/ UNU (1985) , PAL were moderate to heavy for rural men, moderate for urban men and women, and heavy for rural women. These results suggested that urban men and women were less active than their rural counterparts, although not significantly so for men.", "cite_spans": [], "ref_spans": [{"start": 188, "end": 195, "text": "Table 1", "ref_id": "TABREF0"}, {"start": 790, "end": 797, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "Results", "text": "Using flex-HR as the cut-off point, the recorded data (1440 min) were divided into three categories: sleeping, sedentary HR # flex and active HR . flexX The active category was further subdivided into`moderately-active' flex , HR # 1\u00b42 \u00c2 flex and`highly-active' HR . 1\u00b42 \u00c2 flex (Table 3 ). The cut-off points (i.e. 1\u00b42 \u00c2 flex) were determined by considering that the mean HR of lying down (the lowest intensity among the observed activities) was about 80 % flex-HR and the same rate (20 %) below or above the flex-HR point (i.e. 0\u00b48 or 1\u00b42 \u00c2 flex). There were considerable differences between rural subjects and urban subjects, and both men and women had a similar tendency in the pattern of their time allocation when rural subjects and urban subjects were compared. Data analysis showed that sedentary time was longer (men, P , 0\u00b405Y women, P , 0\u00b4005 and active time shorter among women P , 0\u00b4005 for urban subjects than for rural subjects. Urban men spent a shorter time sleeping (by 65 min, P , 0\u00b405 than rural men, although the sleep time was identical in rural women and urban women.", "cite_spans": [], "ref_spans": [{"start": 278, "end": 286, "text": "(Table 3", "ref_id": "TABREF2"}]}, {"section": "Results", "text": "PAL value was also divided into four categories, as described earlier, in order to compare the differences between rural and urban subjects (Fig. 1) . Specifically:", "cite_spans": [], "ref_spans": [{"start": 140, "end": 148, "text": "(Fig. 1)", "ref_id": "FIGREF0"}]}, {"section": "PAL TEEaBMRY", "text": "where PAL sle , PAL sed , PAL ACT-1 , PAL ACT-2 are the sleeping, sedentary, moderately-active and highly-active components respectively. As illustrated in Fig. 1 , the active component of PAL (sum of PAL ACT-1 and PAL ACT-2 ) was lower in urban women than in rural women P , 0\u00b405Y while the sedentary component (PAL sed ) was significantly higher in both urban men and women P , 0\u00b405X Activity profiles (24 h) were compared for each 2 h period (00.01\u00b102.00, 02.01\u00b104.00, 04.01\u00b106.00 hours, etc.), averaged minute-by-minute, to derive the physical exertion index, i.e. average HR valueaflex-HR \u00c2 100 for each 2 h period. This analysis was based on the presence of systematic and substantial gender differences in raw HR values. The average 24 h activity profiles for each sample are depicted in Fig. 2 . Considerable differences between rural and urban subjects were found in the morning in both sexes. The physical exertion index values were relatively stable throughout the day at ,100 in urban subjects, while they fluctuated throughout the day in rural subjects, showing peak values in the morning, although the levels in other periods were similar to those seen in urban subjects.", "cite_spans": [], "ref_spans": [{"start": 156, "end": 162, "text": "Fig. 1", "ref_id": "FIGREF0"}]}, {"section": "PAL TEEaBMRY", "text": "Dietary energy, protein and fat intakes and daily energy ACT-1, moderately-active subdivision of active category (flex , heart rate # 1\u00b42 times flex); ACT-2, highly-active subdivision of active category (heat rate . 1\u00b42 times flex). Mean values were significantly different from those of rural subjects: *P , 0\u00b405Y **P , 0\u00b4005Y ***P , 0\u00b40001X \u00b2 For details of subjects and procedures, see Table 1 and p. 66.", "cite_spans": [], "ref_spans": [{"start": 389, "end": 396, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "68", "text": "T. Yamauchi et al. balance (total daily energy intake TEI 2 TEE are shown in (Table 4) . No significant differences were found in TEI and TEI/BMR between rural and urban subjects for both sexes. Protein and fat intakes were, on the other hand, higher in the urban samples for both sexes, although the protein intake for women was not significantly different between the two groups. The balance between TEI and TEE was ,7 % in each group.", "cite_spans": [], "ref_spans": [{"start": 77, "end": 86, "text": "(Table 4)", "ref_id": "TABREF3"}]}, {"section": "Discussion", "text": "Differences in body size between rural and urban subjects", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Urban men and women in the present study were taller and heavier than their rural counterparts. However, no significant difference was found in BMI between the two groups because the increased body weight in urban subjects was offset by increased stature. According to another survey conducted by our laboratory using a large sample of rural villagers and urban migrants which included almost all subjects in this study (eighty-six rural men, 127 rural women, 101 urban men and thirty-nine urban women), the mean values for body weight, height and BMI were almost identical to those of the present study, although the differences between rural and urban subjects were more marked (Table 5) . Table 5 shows the data of two anthropometric surveys conducted for the same Hulispeaking group. The first was conducted in August 1995 as a part of a large study on cardiovascular risk factors of migrants in Port Moresby (Natsuhara et al. 2000) . In that study almost all adult Huli migrants who resided in five settlements in Port Moresby were invited to participate. components of daily physical activity levels (total energy expenditure/BMR; PAL) of men and women from rural and urban populations of Papua New Guinea (n 56). Mean values were significantly different between urban dwellers and rural villagers: *P , 0\u00b405X For details of subjects and procedures, see Table 1 and p. 66. Fig. 2 . Daily activity profiles of men and women from rural and urban populations of Papua New Guinea (n 56). Physical exertion index (average heart rate/flex-heart rate \u00c2 100; PEI) values were calculated for consecutive 2 h periods over 24 h. (V), Rural men; (B), urban men; (O), rural women; (\u00c2), urban women. For details of subjects and procedures, see Table 1 and p. 66.", "cite_spans": [{"start": 913, "end": 936, "text": "(Natsuhara et al. 2000)", "ref_id": "BIBREF12"}], "ref_spans": [{"start": 680, "end": 689, "text": "(Table 5)", "ref_id": "TABREF4"}, {"start": 692, "end": 699, "text": "Table 5", "ref_id": "TABREF4"}, {"start": 1360, "end": 1367, "text": "Table 1", "ref_id": "TABREF0"}, {"start": 1736, "end": 1743, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "Physical activity and diet in urbanisation", "text": "The second study was conducted in July and August 1998 with rural adults in Tari basin, including the two villages of the present study. Thus, the lack of significant difference in body weight and BMI for men and in stature and BMI for women in the present study is probably due to the small sample size. Furthermore, the finding that urban subjects who were born and raised until pubescence or adolescence in their home villages had a significantly larger body size, especially in height, suggests that well-nourished individuals had selectively migrated to the capital city (Port Moresby). It is possible, however, that a long adolescent growth spurt also contributed to the difference between the height of urban and rural groups (Heywood & Norgan, 1982; Norgan, 1995 ).", "cite_spans": [{"start": 733, "end": 757, "text": "(Heywood & Norgan, 1982;", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Physical activity and diet in urbanisation", "text": "Reduced daily physical activity level in urban subjects PAL of the subjects participating in the present study were comparable with those described by Ferro-Luzzi & Martino (1996) who reviewed fifty-five studies of about 1550 subjects in free-living conditions in more than twenty developed and developing countries. According to their study the PAL values of Third World subjects were 1\u00b484 (SD 0\u00b431) for male subjects and 1\u00b465 (SD 0\u00b417) for female subjects whereas those of Western subjects were 1\u00b474 (SD 0\u00b415) for male subjects and 1\u00b464 (SD 0\u00b418) for female subjects. Compared with Third World subjects, PAL values for rural Huli villagers were similar for men and higher for women, reflecting the gender inequality in labour commonly observed in PNG Highlands (Waddell, 1972; Strathern, 1982; Allen et al. 1995) . This factor has been discussed in detail in our recent report . For the Huli urban subjects, on the other hand, PAL values were lower than those of Third World subjects, and even Western subjects. According to the review of FerroLuzzi & Martino (1996) on Third World populations, including both subsistence and urban populations, the highest two or three PAL values for male or female subjects in urban Third World populations were similar to or lower than those of the urban migrants in the present study (for men; Philippines drivers 1\u00b464, Philippines textile mill workers 1\u00b464; for women: Guatemala urban resettled of lower socio-economic status 1\u00b458, Philippine typists 1\u00b460, Philippine housewives 1\u00b457). Thus, the lower PAL values of the Huli urban migrants are considered to reflect a general tendency that urban dwellers in developing countries are less active than those in developed countries.", "cite_spans": [{"start": 151, "end": 179, "text": "Ferro-Luzzi & Martino (1996)", "ref_id": "BIBREF5"}, {"start": 763, "end": 778, "text": "(Waddell, 1972;", "ref_id": "BIBREF21"}, {"start": 796, "end": 814, "text": "Allen et al. 1995)", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Physical activity and diet in urbanisation", "text": "What are the mechanisms of low PAL observed in urban subjects? Several studies have shown a close relationship between PAL and the percentage of time spent above the flex-HR point (Livingstone et al. 1990; Leonard et al. 1995; Murayama & Ohtsuka, 1999) . In the present study Mean values were significantly different from those of rural villagers: *P , 0\u00b405Y **P , 0\u00b401Y ***P , 0\u00b4001X \u00b2 For details of subjects and procedures, see Table 1 and p. 66. \u00b3 Surveyed in 1998 . \u00a7 Surveyed in 1995 (Natsuhara et al. 2000 . TEI, total energy intake; TEE, total energy expenditure. Mean values were significantly different from those of rural villagers: *P , 0\u00b405Y **P , 0\u00b40005Y ***P , 0\u00b40001X \u00b2 For details of subjects and procedures, see Table 1 and p. 66. \u00b3 Adjusted for lactating women (n 10). \u00a7 Energy balance TEI 2 TEEX 70 T. Yamauchi et al. there was a significant positive correlation (r 0\u00b497, P , 0\u00b40001 between PAL and the percentage of active time (HR . flex; Fig. 3 ). In fact, in urban subjects who had lower PAL than rural subjects active time decreased and sedentary time HR # flex increased (Table 3) ; consequently, the active component of PAL was reduced and sedentary component of PAL was increased in urban subjects (Fig. 1) . It was clear that the low active component of PAL in urban dwellers, due to a reduced active time, was the main factor in reducing the EE as a whole. This phenomenon is considered as the most typical effect of urbanisation from the energy viewpoint. Furthermore, in view of the progressive change in the intensity of physical activity in each sample throughout the day, considerable differences between rural and urban subjects were found in the morning in both sexes (Fig. 2) . The high levels of physical activity recorded in the morning in rural subjects reflected intensified agricultural activities, especially in women (P , 0\u00b401; Table 2 ).", "cite_spans": [{"start": 180, "end": 205, "text": "(Livingstone et al. 1990;", "ref_id": "BIBREF12"}, {"start": 206, "end": 226, "text": "Leonard et al. 1995;", "ref_id": "BIBREF11"}, {"start": 490, "end": 512, "text": "(Natsuhara et al. 2000", "ref_id": "BIBREF12"}], "ref_spans": [{"start": 431, "end": 438, "text": "Table 1", "ref_id": "TABREF0"}, {"start": 730, "end": 737, "text": "Table 1", "ref_id": "TABREF0"}, {"start": 1097, "end": 1106, "text": "(Table 3)", "ref_id": "TABREF2"}, {"start": 1226, "end": 1234, "text": "(Fig. 1)", "ref_id": "FIGREF0"}, {"start": 1873, "end": 1880, "text": "Table 2", "ref_id": "TABREF1"}]}, {"section": "Energy balance and methodological assessments", "text": "Rural subjects consumed low-protein low-fat meals containing mainly sweet potatoes and local greens. In contrast, urban subjects depended totally on purchased food such as rice, tinned fish and chicken, leading to increased intakes of protein and fat (Table 4) . Ulijaszek (1992 Ulijaszek ( , 1995 reviewed the mean energy intake and EE in non-industrialised populations. In six of twelve samples the reported energy intake was more than 1 MJ below EE, a difference that cannot be explained by possible seasonal fluctuations in work output and food availability. In the present study, a negative energy balance was noted in three of the four groups (Table 4) . Although a large negative energy balance such as that described earlier (.1 MJ/d) was not found in any group, it is possible that we have underestimated the energy intake in the present study. Under-reporting of energy intake was not likely because subjects were under observation during the daytime and all food was measured just before it was consumed. Admittedly, the observer effect cannot be completely excluded, i.e. subjects might eat less on the day of investigation because they are under constant observation. However, TEI and protein and fat intakes for rural subjects in the present study were similar to or even higher than those for twenty-eight households of a Huli-speaking sample studied using a consecutive 6 d food weighing survey (daily per capita intakes: Kuchikura, 1999) . Thus, we believe that the small negative energy balance observed in the present study was not influenced by an observer effect, the small sample size or the short observation period. In fact, TEE might have been overestimated due to overestimation of EE during the step test. In the present study, EE values during step tests were not obtained from the study subjects but were estimated using gender-andweight-specific equations for similar samples of Hulispeaking people . In that study, the net mechanical efficiency values for three levels of the step tests were compared with those for worldwide populations reported in previous studies (Katzmarzyk et al. 1996) . Net mechanical efficiencies of the Huli-speaking population (16 and 15 % for rural men and women respectively, and 17 % for both urban men and women) were comparable with those of previous studies and WHO standards (i.e. 16 %; Shephard, 1967; Shephard et al. 1968; Anderson et al. 1971) . Thus, we conclude that the EE of the step tests, and consequently TEE for present participants, are unlikely to be overestimated.", "cite_spans": [{"start": 2098, "end": 2122, "text": "(Katzmarzyk et al. 1996)", "ref_id": "BIBREF11"}, {"start": 2352, "end": 2367, "text": "Shephard, 1967;", "ref_id": "BIBREF13"}, {"start": 2390, "end": 2411, "text": "Anderson et al. 1971)", "ref_id": "BIBREF1"}], "ref_spans": [{"start": 251, "end": 260, "text": "(Table 4)", "ref_id": "TABREF3"}, {"start": 649, "end": 658, "text": "(Table 4)", "ref_id": "TABREF3"}]}, {"section": "Energy balance and methodological assessments", "text": "A further explanation of the small negative energy balance in rural subjects may be due to the fact that rural subjects from two villages (Heli and Wenani) suffered from an extended rain season during the study period, and the food intake or energy intake of Heli villagers was unusually low. This issue was discussed in detail in our previous report (Umezaki et al. 1999) . In fact, we found significant differences in energy intake between the subsamples in both rural men and women (9\u00b472 and 15\u00b404 MJ/d in Heli and Wenani men respectively, P , 0\u00b401; 8\u00b479 and 12\u00b422 MJ/d in Heli and Wenani women respectively, P , 0\u00b4005).", "cite_spans": [{"start": 351, "end": 372, "text": "(Umezaki et al. 1999)", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Energy balance and methodological assessments", "text": "The results of the food and nutrient intake survey demonstrated a well-maintained daily energy balance, especially in urban subjects. However, low TEI and TEE, which were observed in urban subjects, are considered to be risk factors for obesity and cardiovascular disorders (King & Collins, 1989; Dowse et al. 1994; Hodge et al. 1995) . For instance, Ferro-Luzzi & Martino (1996) suggested that a PAL of 1\u00b48 was the threshold for triggering such diseases. Fat intake in urban subjects, which was markedly higher than that of rural subjects, was comparable with that in subjects from a PNG coastal population (Wanigela) who migrated to a settlement in Port Moresby (men 71 g/d, women 65 g/d), and the fat consumed was reported to be predominantly saturated fat (Hodge et al. 1996) . Taking into consideration that more than 60 % of the fat intake of Fig. 3 . Correlation between daily physical activity level (total energy expenditure/BMR; PAL) and percentage of time spent being active (average heart rate . flex) for men and women from rural and urban populations of Papua New Guinea (n 56). Rural men (\u00c2) urban men (+), rural women (A), urban women (B). PAL 0\u00b4032 (%)+1\u00b4212, r 0\u00b497. For details of subjects and procedures, see Table 1 and p. 66.", "cite_spans": [{"start": 297, "end": 315, "text": "Dowse et al. 1994;", "ref_id": "BIBREF4"}, {"start": 351, "end": 379, "text": "Ferro-Luzzi & Martino (1996)", "ref_id": "BIBREF5"}, {"start": 760, "end": 779, "text": "(Hodge et al. 1996)", "ref_id": "BIBREF9"}], "ref_spans": [{"start": 1229, "end": 1236, "text": "Table 1", "ref_id": "TABREF0"}]}, {"section": "71", "text": "Physical activity and diet in urbanisation Huli migrants in Port Moresby was provided by sheep meat, butter and chicken, the fat intake pattern appears to be almost identical to that of Wanigela migrants. These findings imply that the level of EE of urban dwellers (whose energy intake was balanced), together with higher intake of saturated fat, tended to increase the risks of degenerative disorders following migration to, and settlement in, an urban environment.", "cite_spans": [], "ref_spans": []}, {"section": "71", "text": "In conclusion, lifestyle changes in urban migrants were examined in the present study by comparing their food intake and EE data with those of their rural counterparts. The effects of urbanisation on daily physical activity were evident in the considerably lower PAL in urban subjects than in rural subjects, especially in women. Large increases in protein and fat intakes were noted in urban subjects due to dietary changes from local to purchased foods. The reduction in PAL among urban dwellers, perhaps together with increased fat intake, is considered to increase the risks of obesity and chronic degenerative diseases.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "The sustainability of Papua New Guinea agricultural systems: the conceptual background", "authors": [{"first": "B", "middle": ["J"], "last": "Allen", "suffix": ""}, {"first": "R", "middle": ["M"], "last": "Bourke", "suffix": ""}, {"first": "R", "middle": ["L"], "last": "Hide", "suffix": ""}], "year": 1995, "venue": "Global Environmental Change", "link": "154340479"}, "BIBREF1": {"title": "Fundamentals of Exercise Testing", "authors": [{"first": "K", "middle": ["L"], "last": "Anderson", "suffix": ""}, {"first": "R", "middle": ["J"], "last": "Shephard", "suffix": ""}, {"first": "H", "middle": [], "last": "Denolin", "suffix": ""}, {"first": "E", "middle": [], "last": "Varnauskas", "suffix": ""}, {"first": "R", "middle": [], "last": "Masironi", "suffix": ""}], "year": 1971, "venue": "", "link": "194097193"}, "BIBREF2": {"title": "The use of heart rate monitoring in the estimation of energy expenditure: a validation study using indirect whole-body calorimetry", "authors": [{"first": "S", "middle": ["M"], "last": "Ceesay", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Prentice", "suffix": ""}, {"first": "K", "middle": ["C"], "last": "Day", "suffix": ""}, {"first": "P", "middle": ["R"], "last": "Murgatroyd", "suffix": ""}, {"first": "G", "middle": ["R"], "last": "Goldberg", "suffix": ""}, {"first": "W", "middle": [], "last": "Scott", "suffix": ""}, {"first": "G", "middle": ["B"], "last": "Spurr", "suffix": ""}], "year": 1989, "venue": "British Journal of Nutrition", "link": "12608472"}, "BIBREF3": {"title": "A method for determining the total respiratory exchange in man", "authors": [{"first": "C", "middle": ["G"], "last": "Douglas", "suffix": ""}], "year": 1911, "venue": "Journal of Physiology", "link": null}, "BIBREF4": {"title": "Extraordinary prevalence of non-insulin-dependent diabetes mellitus and bimodal plasma glucose distribution in the Wanigela people of Papua New Guinea", "authors": [{"first": "G", "middle": ["K"], "last": "Dowse", "suffix": ""}, {"first": "R", "middle": ["A"], "last": "Spark", "suffix": ""}, {"first": "B", "middle": [], "last": "Mavo", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Hodge", "suffix": ""}, {"first": "R", "middle": ["T"], "last": "Erasmus", "suffix": ""}, {"first": "M", "middle": [], "last": "Gwalimu", "suffix": ""}, {"first": "L", "middle": ["T"], "last": "Knight", "suffix": ""}, {"first": "G", "middle": [], "last": "Koki", "suffix": ""}, {"first": "P", "middle": ["Z"], "last": "Zimmet", "suffix": ""}], "year": 1990, "venue": "European Journal of Clinical Nutrition", "link": "37924887"}, "BIBREF5": {"title": "Obesity and physical activity", "authors": [{"first": "A &amp;", "middle": [], "last": "Ferro-Luzzi", "suffix": ""}, {"first": "L ; G", "middle": [], "last": "Martino", "suffix": ""}, {"first": "", "middle": [], "last": "Cardew", "suffix": ""}], "year": 1996, "venue": "The Origins and Consequences of Obesity", "link": "37334293"}, "BIBREF6": {"title": "Overnight and basal metabolic rates in men and women", "authors": [{"first": "West", "middle": [], "last": "Chichester", "suffix": ""}, {"first": ":", "middle": ["J"], "last": "Sussex", "suffix": ""}, {"first": "", "middle": [], "last": "Wiley", "suffix": ""}, {"first": "G", "middle": ["R"], "last": "Goldberg", "suffix": ""}, {"first": "A", "middle": ["M"], "last": "Prentice", "suffix": ""}, {"first": "H", "middle": ["L"], "last": "Davies", "suffix": ""}, {"first": "P", "middle": ["R"], "last": "Murgatroyd", "suffix": ""}], "year": 1988, "venue": "European Journal of Clinical Nutrition", "link": "39553283"}, "BIBREF7": {"title": "Human growth in Papua New Guinea", "authors": [{"first": "P", "middle": ["F"], "last": "Heywood", "suffix": ""}, {"first": "N", "middle": ["G"], "last": "Norgan", "suffix": ""}], "year": 1982, "venue": "Human Biology in Papua New Guinea. 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Sleep (B), sedentary (B), moderately-active (A) and highly-active (J) components of daily physical activity levels (total energy expenditure/BMR; PAL) of men and women from rural and urban populations of Papua New Guinea (n 56). Mean values were significantly different between urban dwellers and rural villagers: *P , 0\u00b405X For details of subjects and procedures, see Table 1 and p. 66.", "type": "figure"}, "TABREF0": {"text": "Age distribution and physical characteristics of the Papua New Guinea Highland subjects participating in the study (Mean values and standard deviations)NA, not available. Mean values were significantly different from those of rural subjects: *P , 0\u00b405X \u00b2 Values in parentheses are the percentage of the total number of subjects for each group. \u00b3 Mean values for eleven rural men and nine rural women.", "type": "table"}, "TABREF1": {"text": "BMR, total daily energy expenditure (TEE), physical activity level (PAL) and work level of men and women in rural and urban populations of Papua New Guinea\u00b2", "type": "table"}, "TABREF2": {"text": "Time", "type": "table"}, "TABREF3": {"text": "Extra energy and protein are recommended for lactation (WHO/FAO/UNU, 1985). In fact, Norgan et al.", "type": "table"}, "TABREF4": {"text": "Body weight, height and BMI of rural and urban men and women from a larger study population in Papua New Guinea, including", "type": "table"}, "TABREF5": {"text": "Dietary energy, protein and fat intakes and daily energy balance in men and women from rural and urban populations in Papua New Guinea\u00b2", "type": "table"}}}
{"paper_id": "17432224", "_pdf_hash": "e7d9b7d06bc1cf50323714c7a1a7927c136e956b", "abstract": [{"section": "Abstract", "text": "abstract: Sertoli cells undergo a maturation process during post-natal testicular development that leads to the adult-type Sertoli cell, which is required for spermatogenesis. Understanding Sertoli cell maturation is therefore necessary to gain insight into the underlying causes of impaired spermatogenesis and male infertility. The present study characterized the cellular and molecular differentiation of Sertoli cells in a xenograft model of mammalian testicular development. Immature rat Sertoli cells were cultured in a three-dimensional culture system to allow the formation of cord-like structures. The in vitro Sertoli cell cultures were then grafted into nude mice. Sertoli cell proliferation, morphological differentiation and mRNA expression of Sertoli cell maturation markers were evaluated in xenografts. Sertoli cell proliferation significantly decreased between 1 and 4 weeks (6.7 + 0.9 versus 1.2+ 0.1%, P , 0.001), and was maintained at low levels thereafter. Sertoli cell cord-like structures significantly decreased between 1 and 4 weeks (59.6 versus 21%, P , 0.05), whereas Sertoli cell tubules were more frequently observed after 4 weeks (13.3 versus 73.1%, P , 0.05). Furthermore, expression of androgen binding protein, transferrin and follicle stimulating hormone receptor, markers for mature Sertoli cells, was detected after 1 week of grafting and increased significantly thereafter. We conclude from these results that rat Sertoli cells continue maturation after xenografting to the physiological environment of a host. This model of in vitro tubule formation will be helpful in future investigations addressing testicular maturation in the mammalian testis.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Post-natal testicular development depends on the proliferation of immature Sertoli cells to establish the final Sertoli cell number in the adult testis, thereby determining testicular size, and ultimately spermatogenic capacity (Orth et al., 1988) . Sertoli cell numbers in rodents, non-human primates and humans are exclusively established in the pre-and peri-pubertal period when the cells are proliferating and differentiating. In the adult testis Sertoli cells are mitotically inactive in rodents as well as in rhesus monkeys and in humans (Clermont and Perey, 1957; Steinberger and Steinberger, 1971; Orth, 1982; Plant and Marshall, 2001) . Concurrent with the cessation of proliferation, Sertoli cells undergo functional maturation during puberty, leading to the adult phenotype that is required for spermatogenesis. This maturation process is characterized by changes in cell morphology and polarity, the secretion of factors supporting spermatogenesis and by the establishment of the blood-testis barrier that divides the seminiferous epithelium into a basal and an adluminal compartment (Pelliniemi et al., 1984; Lui et al., 2003) . Barrier formation is temporarily correlated with the development of a lumen within seminiferous tubules through fluid-secretion (Russell et al., 1989) . Therefore, Sertoli cell maturation is marked by the transition from testicular cords to seminiferous tubules.", "cite_spans": [{"start": 228, "end": 247, "text": "(Orth et al., 1988)", "ref_id": "BIBREF18"}, {"start": 544, "end": 570, "text": "(Clermont and Perey, 1957;", "ref_id": "BIBREF4"}, {"start": 571, "end": 605, "text": "Steinberger and Steinberger, 1971;", "ref_id": "BIBREF36"}, {"start": 606, "end": 617, "text": "Orth, 1982;", "ref_id": "BIBREF17"}, {"start": 1096, "end": 1121, "text": "(Pelliniemi et al., 1984;", "ref_id": "BIBREF22"}, {"start": 1122, "end": 1139, "text": "Lui et al., 2003)", "ref_id": "BIBREF15"}, {"start": 1270, "end": 1292, "text": "(Russell et al., 1989)", "ref_id": "BIBREF28"}], "ref_spans": []}, {"section": "Introduction", "text": "At the molecular level, functional maturation of Sertoli cells can be further characterized by the complement of genes that are up-and down-regulated during each stage of testicular development. Genes that are specifically expressed during the proliferative phase of Sertoli cell development include anti-Mullerian hormone (Amh), Gata4 and cytokeratin 18 (Krt18) . AMH suppresses female development in XY embryos upon primary sex determination, thereby allowing testicular differentiation and the development of the male phenotype. AMH is expressed in premature Sertoli cells, starting around embryonic Day 15, and continues to be expressed until the onset of puberty. AMH expression declines as meiotic germ cells appear and as Sertoli cells gain increased androgen sensitivity (Rey et al., 2003) . Postnatally, Gata4 expression in Sertoli cells peaks between 1 and 14 days and declines during testis maturation (Viger et al., 1998; Ketola et al., 1999) . The intermediate filament marker Krt18 is detectable in pre-Sertoli cells as early as embryonic Day 15, and expression continuously decreases throughout post-natal development, disappearing by 14 days after birth (Paranko et al., 1986) . Likewise, Krt18 is a robust marker for immature Sertoli cells in the pathological human testis (Steger et al., 1996 (Steger et al., , 1999 . Cytochrome p450 aromatase (Cyp19a1) catalyzes the final step of androgen aromatization into estrogens (Simpson et al., 1994) . In the rat, cytochrome p450 aromatase is first expressed in Sertoli cells during fetal and neonatal development (Sharpe et al., 2003) and expression is down-regulated after post-natal Day 10 during maturation of Sertoli cells Carpino et al., 2001; Pezzi et al., 2001) . In the adult testis, aromatase expression is mainly located to interstitial Leydig cells.", "cite_spans": [{"start": 779, "end": 797, "text": "(Rey et al., 2003)", "ref_id": "BIBREF26"}, {"start": 913, "end": 933, "text": "(Viger et al., 1998;", "ref_id": "BIBREF40"}, {"start": 934, "end": 954, "text": "Ketola et al., 1999)", "ref_id": "BIBREF12"}, {"start": 1170, "end": 1192, "text": "(Paranko et al., 1986)", "ref_id": "BIBREF19"}, {"start": 1290, "end": 1310, "text": "(Steger et al., 1996", "ref_id": "BIBREF34"}, {"start": 1311, "end": 1333, "text": "(Steger et al., , 1999", "ref_id": "BIBREF35"}, {"start": 1438, "end": 1460, "text": "(Simpson et al., 1994)", "ref_id": "BIBREF32"}, {"start": 1575, "end": 1596, "text": "(Sharpe et al., 2003)", "ref_id": "BIBREF31"}, {"start": 1689, "end": 1710, "text": "Carpino et al., 2001;", "ref_id": "BIBREF2"}, {"start": 1711, "end": 1730, "text": "Pezzi et al., 2001)", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Introduction", "text": "Adult-type Sertoli cells express transferrin (Trf), androgen binding protein (Shbg) and follicle stimulating hormone receptor (Fshr). Trf, a common marker for Sertoli cell differentiation, is present 10 days after birth and its levels continue to rise into adulthood (Skinner and Griswold, 1980; Perez-Infante et al., 1986) . Shbg is present 14 days after birth and the greatest increase in Shbg levels occurs between the second and third weeks after birth (Hagenas et al., 1975; Tindall et al., 1975; Rich et al., 1983) . FSHR levels begin to increase in number during the start of spermatogenesis, between 7 and 14 days after birth (Thanki and Steinberger, 1978) .", "cite_spans": [{"start": 267, "end": 295, "text": "(Skinner and Griswold, 1980;", "ref_id": "BIBREF33"}, {"start": 296, "end": 323, "text": "Perez-Infante et al., 1986)", "ref_id": "BIBREF23"}, {"start": 457, "end": 479, "text": "(Hagenas et al., 1975;", "ref_id": "BIBREF10"}, {"start": 480, "end": 501, "text": "Tindall et al., 1975;", "ref_id": "BIBREF39"}, {"start": 502, "end": 520, "text": "Rich et al., 1983)", "ref_id": "BIBREF27"}, {"start": 634, "end": 664, "text": "(Thanki and Steinberger, 1978)", "ref_id": "BIBREF37"}], "ref_spans": []}, {"section": "Introduction", "text": "We have recently developed a three-dimensional culture system for the de novo generation of testicular cord-like structures from single cell suspensions of rat Sertoli cells (Gassei et al., 2006) . Subsequently, in vitro derived cord-like structures morphologically differentiated into seminiferous tubule-like structures after xenografting into immunodeficient host mice. In the present study, we add to these reports a detailed analysis of the Sertoli cell maturation process during the formation of tubule-like structures in xenografts. Previously, it remained unclear whether Sertoli cells in xenografts would continue proliferation, or if Sertoli cells would cease mitotic activity and mature after grafting to the physiological environment of a host. Therefore, in this study, we analysed cell proliferation, cellular composition of xenografts and the expression of Sertoli cell maturation markers in xenografts to determine the developmental status of Sertoli cells during a time course of up to 12 weeks in host mice.", "cite_spans": [{"start": 174, "end": 195, "text": "(Gassei et al., 2006)", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Materials and Methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Sertoli cell culture", "text": "Seven-day-old CD rats were obtained from Charles River Laboratories, Inc. (Wilmington, MA, USA). All procedures were in compliance with the University of Pittsburgh Guidelines for the Care and Use of Laboratory Animals.", "cite_spans": [], "ref_spans": []}, {"section": "Sertoli cell culture", "text": "Testes from 10 rat pups per experiment were dissected, pooled and transferred to chilled Dulbecco's Minimum Essential Medium (DMEM, 4.5 g glucose/ml; Mediatech Inc., Herndon, VA, USA; No. 10-013-CV). Initial digestion was performed with 1 mg/ml collagenase I (Sigma, Saint Louis, MO, USA; No. C-2674) and 5 mg/ml DNAse (15 U/ml; Roche Applied Science, Indianapolis, IN, USA; No. 104132) in DMEM mixed 1:1 with Ham's F12 (Mediatech Inc.; and supplemented with 1% MEM non-essential amino acids (BioWhittaker Walkersville, MD, USA; No. 13-114E), 100 IU/ml Penicillin and 100 mg/ml Streptomycin (Mediatech Inc.; at 378C for 15 min. Tubule fragments were separated from interstitial and peritubular cells by sedimentation at unit gravity. A second digestion with 1 mg/ml collagenase I, 5 mg/ml DNAse and 1 mg/ml hyaluronidase (Sigma-Aldrich, St. Louis, MO, were carried out at 378C for 20 min. Cells were resuspended in culture medium [DMEM 1 g glucose/ml supplemented with 1% nonessential amino-acids (NEAA) and 1% penicillin/streptomycin], and plated on a 24-well culture plate coated with 250 ml extracellular matrix proteins (Matrigel, BD Biosciences, Bedford, MA; No. 354234; 1:1 diluted with culture medium; 10 6 cells per well), and cultured at 358C in 5% CO 2 . This standard protocol yields a single cell suspension enriched for Sertoli cells, containing residual germ cells (25%), peritubular myoid cells (15%) and Leydig cells (0.3%), as described previously .", "cite_spans": [], "ref_spans": []}, {"section": "Xenografting", "text": "Adult male nude mice (strain: nu/nu) were obtained from Charles River Laboratories and used as hosts for cell culture grafts. Castration was performed at the time of grafting. Rat Sertoli cells were injected under the dorsal skin of nude mice after 9 days of Matrigel culture. Each host received six injections of 250 ml extracellular matrix gel containing Sertoli cells under the dorsal skin. In the first study, xenografts were allowed to develop for up to 4 weeks (referred to as short-term xenografting). As the data derived from this study indicated a possibility for further changes in graft physiology with time, a second study was performed in which grafts were allowed to develop for up to 12 weeks. This second study is referred to as long-term xenografting. As the two studies each consist of a separate set of experiments, data where evaluated separately, although some of the time points overlap. Animal numbers for all groups are provided in Table I . At the time of graft removal, host mice received an intra-peritoneal injection of BrdU (100 mg/kg) and were killed 2 h later by exsanguinations under deep anaesthesia with Ketamine/Xylazine (Sigma-Aldrich, St. Louis, MO, No. K113). Xenografts were removed from the inner surface of the back skin and fixed in Bouin's fixative overnight for histology and immunohistochemistry, and then transferred to 70% (v/v) ", "cite_spans": [], "ref_spans": []}, {"section": "Immunostaining", "text": "For immunofluorescence staining, Sertoli cells were cultured in Matrigel for 9 days, incubated with BrdU for 2 h, and then isolated from Matrigel. Cell aggregates were plated on poly-L-lysin coated coverslips and fixed with 4% formalin. Paraffin sections (7 mm) of Bouin-fixed xenografts were deparaffinized and washed with Tris buffered saline (TBS) before proceeding with immunohistochemistry. Coverslips and sections blocked with TBS containing 0.5% bovine serum albumin (BSA) and 10% goat serum were incubated overnight at 48C with antibodies against bromodeoxyuridine (BrdU, Biomeda, Foster City, CA, USA; diluted 1:50 in TBS containing 0.1% BSA), a-smooth muscle actin (aSMA; peritubular myoid cell marker; Sigma no. A2547; 1:2000 dilution), and cytochrome P450 side-chain cleavage enzyme (p450scc, Leydig cell marker; Chemicon no. AB1244; 1:500). Samples stained with anti-BrdU antibody were incubated with 1 M HCl for 15 min prior to antibody incubation. Negative controls were performed in all experiments by omitting primary antibodies to ensure antibody specificity. Sections from a 7-day-old rat, adult rat or adult mouse testes served as positive controls. Slides were washed and incubated with secondary goat anti-mouse IgG (for aSMA and BrdU detection) or secondary goat anti-rabbit IgG (for p450scc), either conjugated to horseradish peroxidase or AlexaFluor-488 fluorophore. Colorimetric detection with diaminobenzidine (DAB; SigmaFast TM , Sigma No. D4168) was performed according to the manufacturer's specifications. Samples were counterstained with Mayer's hematoxylin or DAPI, depending on the experiment.", "cite_spans": [], "ref_spans": []}, {"section": "Proliferation index", "text": "BrdU labelling indices were determined by scoring BrdU-negative and BrdU-positive cells in paraffin embedded xenograft sections. At least six grafts from three or more recipients were scored per time point, and 500 cells were scored in each xenograft. In sections with fewer than 500 total cells, all cells were scored.", "cite_spans": [], "ref_spans": []}, {"section": "Proliferation index", "text": "RNA isolation and cDNA preparation RNA was obtained from freshly isolated Sertoli cells, Sertoli cell aggregates after 9 days of culture in Matrigel, or liquid nitrogen-frozen xenografts (50-150 mg tissue per sample, n \u00bc 3 for each time point) by ultracentrifugation (40 000g for 16 h at 168C) in a guanidine isothiocyanate caesium chloride (GITC/CsCl) gradient. The RNA pellet was resuspended in 0.3 M NaAcO, pH 6.0/0.1% SDS for ethanol precipitation. The RNA was treated with RNase-free DNase (Promega Madison, WI, USA; No. M6101) and subjected to reverse transcription. One microgram total RNA was used for reverse transcription in a reaction mix containing 5 mM MgCl 2 , 40 U RNasin ribonuclease inhibitor (Promega No. N2111), 0.4 mM deoxynucleotide triphosphates (Promega, No. U1330), 45 mM random hexamers (Integrated DNA Technologies, Coralville, IA, USA) and 10 U AMV reverse transcriptase (Promega, No. M5101). To control for contaminant DNA, parallel reactions were carried out without reverse transcriptase. All samples were incubated at 258C for 10 min, at 428C for 45 min and at 958C for 10 min.", "cite_spans": [], "ref_spans": []}, {"section": "RT-PCR", "text": "Sertoli cell immaturity and differentiation markers were amplified using 2 ml cDNA in a PCR mix containing 1.5 mM MgCl 2 , 0.2 mM deoxynucleotide triphosphates, 1.25 U GoTaq DNA polymerase (Promega No. M3005) and 10 mM forward and reverse primer. Parallel reactions were performed without template cDNA to control for contaminant DNA. Table II . PCR products were analysed on a 2% (w/v) agarose gel for large fragments, or a 10% (w/v) poly-acrylamide gel for small fragments (100 bp). Intensity of RT -PCR bands was quantified with ImageJ software (Abramoff et al., 2004) and data from three independent experiments were combined to a mean + standard error of the mean (SEM).", "cite_spans": [{"start": 548, "end": 571, "text": "(Abramoff et al., 2004)", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Statistical analysis", "text": "All data are presented as mean + SEM. Descriptive statistical analysis and detection of significant differences were performed using SigmaStat software (Jandel Scientific Software, San Rafael, CA, USA). Data sets were first tested for normality and equality of variances and further analyzed using One Way ANOVA. The expected level of statistical significance was P , 0.05.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Sertoli cell aggregation in vitro and expression of maturation markers", "text": "Immature Sertoli cells aggregate in three-dimensional culture systems to form cord-like structures. Confocal fluorescence microscopy revealed that Sertoli cells and peritubular myoid cells that are present in the primary cell suspension co-operate during the morphogenetic cascade (Fig. 1A) . Further, it was observed that Sertoli cells are organized in single-layer epithelia, and that most aggregates were hollow, showing a central cavity lined by smooth-muscle actin positive myoid cells. In contrast, p450-positive cells were never observed to participate in cord formation. Interestingly, neither Sertoli cells nor myoid cells appeared to be mitotically active in Matrigel cultures, as indicated by the absence of BrdU-positive S-phase cells. Analysis of Sertoli cell maturation marker expression showed that the markers of undifferentiated Sertoli cells Krt18, Gata4 and Amh were expressed in immature Sertoli cells isolated from 7-day-old rats, and expression was maintained during Matrigel culture, albeit at low levels (Fig. 1B) . Trf, Fshr and Cyp19a1, markers of mature Sertoli cells, were also found to be expressed in isolated Sertoli cells, but expression was weak or absent after 9 days of 3D culture. Finally, Shbg was not detected in isolated Sertoli cells or in Sertoli cell aggregates after Matrigel culture. In control studies using Sertoli cell mRNA from 15-day-old rats after 3 days in a conventional culture system, the expression pattern of Sertoli cell markers was as expected for this post-natal age.", "cite_spans": [], "ref_spans": []}, {"section": "Differentiation of Sertoli cell tubules after xenografting", "text": "Xenografts were recovered from 7 to 16 recipients per time point. Xenografts could be distinguished as flat to round patches of soft tissue attached to the inner side of the dorsal skin, most prominently along dorsal blood vessels. Due to the low viscosity of the Matrigel that served as vehicle for the Sertoli cells during xenografting, we found that in some recipients a higher number of grafts could be recovered than initially injected, due to the spreading of Matrigel away from the injection side, and that graft weights varied widely (Table I and Fig. 2) . Overall, graft weights significantly increased between 1 and 4 weeks during short-term xenografting, and between 4 and 10 weeks during long-term xenografting. Leukocyte infiltration into xenografts was observed in one out of five hosts after 3 weeks, two out of five hosts after 4 weeks, one out of three hosts after 8 weeks and one out of three hosts after 12 weeks.", "cite_spans": [], "ref_spans": []}, {"section": "Differentiation of Sertoli cell tubules after xenografting", "text": "Histological analysis revealed the occurrence of four Sertoli cell phenotypes, representing progressive maturation judged by the morphology and appearance of Sertoli cell aggregates. First, Sertoli cells with an immature phenotype were organized in small, round or oval groups without a pronounced basement membrane (cord-like structure, Fig. 3A) . Second, Sertoli cell tubule-like structures were characterized by a larger diameter than the cord-like structures, and the presence of a basement membrane. Peritubular myoid cells were observed aligned around tubules (Fig. 3B) . Third, Sertoli cells were observed to be aligned as a single layer epithelium. Finally, the formation of a fluid-filled lumen was observed and persisted throughout all later time points tested (Fig. 3C-F) . Semi-quantitative morphometric evaluation revealed a morphological cascade of progressive Sertoli cell tubule development. After 1 week of xenografting, cordlike structures represented the most commonly observed developmental stage (59.6 + 5.3%), but they were significantly decreased after 2 weeks (38.6 + 3.3%), 3 weeks (28.3 + 2.8%) and 4 weeks (21 + 3.7%) (n \u00bc 16 -31 grafts). In contrast, tubule-like structures were only rarely observed at 1 week (13.3 + 4.2%) and became more frequent after 2, 3 and 4 weeks (44.9 + 4.5, 61.7 + 3.6, 73.1 + 4.2%).", "cite_spans": [], "ref_spans": [{"start": 338, "end": 346, "text": "Fig. 3A)", "ref_id": "FIGREF1"}, {"start": 566, "end": 575, "text": "(Fig. 3B)", "ref_id": "FIGREF1"}, {"start": 771, "end": 782, "text": "(Fig. 3C-F)", "ref_id": "FIGREF1"}]}, {"section": "Differentiation of Sertoli cell tubules after xenografting", "text": "These data suggest a progressive maturation of Sertoli cells, leading to the development of tubule-like structures from cord-like structures. Tubules with single layered epithelia were observed in 38.4 + 5.4% of Sertoli cell cords and tubules after 1 week, and significantly increased between 2, 3 and 4 weeks (61.4 + 3.3, 71.8 + 1.8, 78.9 + 3.7%). In 2.9 + 1.16% of all structures, lumen formation was observed after 1 week. Tubules with a fluid-filled lumen were only rarely observed after 1 week (2.9 + 1.2%) and 2 weeks (7.9 + 1.5%) but were more common after 3 weeks (14.1 + 2%) and 4 weeks (19.9 + 3.4%). Finally, after 4 weeks of xenografting, Sertoli cell tubules became increasingly complex and were organized in clusters of several tubules (Fig. 3D) . Most tubules showed differentiated basement membranes and recruitment of peritubular myoid cells. Endothelial and fibroblast-like cells migrated into and resided in Matrigel residues between Sertoli cell tubules.", "cite_spans": [], "ref_spans": [{"start": 750, "end": 759, "text": "(Fig. 3D)", "ref_id": "FIGREF1"}]}, {"section": "Differentiation of Sertoli cell tubules after xenografting", "text": "Increased migration of cells from the host into the Matrigel was observed after 8 and 12 weeks ( Fig. 3E and F) . At all late time points investigated, Sertoli cell tubules were associated with extratubular cells. After 12 weeks of development in the host, some Sertoli cell tubules began to degenerate and the epithelial organization deteriorated (Fig. 3F) .", "cite_spans": [], "ref_spans": [{"start": 97, "end": 111, "text": "Fig. 3E and F)", "ref_id": "FIGREF1"}, {"start": 348, "end": 357, "text": "(Fig. 3F)", "ref_id": "FIGREF1"}]}, {"section": "Proliferation of Sertoli cells in xenografts", "text": "After 1 week of grafting, Sertoli cells in cord-like structures were actively proliferating (Fig. 4B) . The Sertoli cell labelling index (LI) for BrdU was 6.7 + 0.9%. In xenografts after 3 weeks we observed only few cells per tubule that were labelled with BrdU (Fig. 4C) , and the BrdU LI was significantly lower after 3 and 4 weeks (LI 2.2 + 0.3 and 1.2 + 0.1%, respectively) (n \u00bc 10 -24 grafts; Fig. 4D ). In xenografts after 2 and 3 weeks we also observed peritubular myoid cells occasionally labelled with BrdU. These cells were excluded Figure 1 Three-dimensional Sertoli cell culture in Matrigel.", "cite_spans": [], "ref_spans": [{"start": 92, "end": 101, "text": "(Fig. 4B)", "ref_id": "FIGREF2"}, {"start": 262, "end": 271, "text": "(Fig. 4C)", "ref_id": "FIGREF2"}, {"start": 398, "end": 405, "text": "Fig. 4D", "ref_id": "FIGREF2"}]}, {"section": "Proliferation of Sertoli cells in xenografts", "text": "(A) Sertoli cell aggregates isolated from Matrigel culture. Sequential z-axis confocal scan through a spherical aggregate stained for a-smooth muscle actin (SMA, myoid cell marker, green) and DAPI nuclear stain (blue). Sixteen planes in 2 mm intervals were taken from the top (1) to the bottom (16) of the aggregate. Scale bar \u00bc 100 mm. Peritubular cells are located at the outer and inner periphery of the aggregate (arrows). The sequential scan also reveals the hollow structure of the aggregate and epithelial-like arrangement of the SMA negative Sertoli cells (asterisks). (B) Expression of Sertoli cell maturation markers in Sertoli cells isolated from 7-day-old rats and from Sertoli cell aggregates cultured in Matrigel for 9 days prior to xenografting (ECM Day 9). Sertoli cells isolated from 15-day-old rats and cultured for 3 days were used as positive controls for PCR efficiency. Figure 2 The distribution of graft weights in xenografts after short-and long-term grafting.", "cite_spans": [], "ref_spans": []}, {"section": "Proliferation of Sertoli cells in xenografts", "text": "The median of the graft weights (black line) and lower and upper quartiles (gray box) are presented. Whiskers extend to the 5th and 95th percentile, respectively. Left: graft weights significantly increased between 1 and 4 weeks (ANOVA on ranks, n \u00bc 71-157). Right: graft weights significantly increased between 4 and 10 weeks (ANOVA on ranks, n \u00bc 46 -122). from the BrdU-LI. Consistent with this result we also observed a decrease of the BrdU-labelling during long-term xenografting. The Sertoli cell LI was significantly higher at 2 weeks (4.2 + 0.3%) than after 4, 6, 8, 10 and 12 weeks (0.62 + 0.1, 1 + 0.2, 0.7 + 0.2, 1 + 0.2, 0.8 + 0.2%, respectively; n \u00bc 5-13 grafts) (Fig. 4D) .", "cite_spans": [], "ref_spans": [{"start": 675, "end": 684, "text": "(Fig. 4D)", "ref_id": "FIGREF2"}]}, {"section": "Expression of Sertoli cell immaturity and differentiation markers in xenografts", "text": "The presence of Sertoli cell differentiation markers were assessed to determine whether populations of proliferating or differentiating Sertoli cells are present within the developing xenografts. Wt1 mRNA expression was assayed as a positive control for Sertoli cell presence and was detected at all time points tested (Figs 5 and 6). During short-term grafting, markers of less mature, proliferating Sertoli cells Gata4 and Krt18 were expressed at relative constant levels throughout the development of the xenografts (Fig. 5 ). In contrast, Amh expression was low and could only be observed sporadically (in two out of five experiments) during the first 3 weeks of grafting, and could not be detected thereafter (data not shown). Cyp19a1 expression was not observed after 1 week of xenografting, and weak expression was occasionally observed after 2 weeks (in one out of five experiments) and 4 weeks (in three out of five experiments, data not shown). The expression of differentiation markers Trf, Fshr and Shbg were observed at all time points (Fig. 5) . Overall, for the short-term xenografts mRNA levels remained low and semi-quantitative RT-PCR evaluation did not reveal statistically significant changes over the course of the study for any of the markers.", "cite_spans": [], "ref_spans": [{"start": 519, "end": 526, "text": "(Fig. 5", "ref_id": "FIGREF3"}, {"start": 1049, "end": 1057, "text": "(Fig. 5)", "ref_id": "FIGREF3"}]}, {"section": "Expression of Sertoli cell immaturity and differentiation markers in xenografts", "text": "During long-term xenografting, Krt18 and Gata4 levels remained constant at low levels during the course of the study (Fig. 6) . Interestingly, Cyp19a1 was initially absent but expression increased after 8 weeks. Similar to the results obtained during short-term grafting, Amh expression could not be detected in long-term xenografts (data not shown). In contrast, up-regulation of Trf, Fshr and Shbg expression was observed during xenografting. Trf mRNA became up-regulated after 4 weeks and significantly increased between 2, 8 and 12 weeks. Fshr expression significantly increased between 2 and 12 weeks, and Shbg expression was up-regulated between 2, 8 and 12 weeks. Overall, expression of these markers was stronger at later time points than observed during the short-term experiment.", "cite_spans": [], "ref_spans": [{"start": 117, "end": 125, "text": "(Fig. 6)", "ref_id": "FIGREF4"}]}, {"section": "Recruitment of peritubular myoid cells to xenografts", "text": "Peritubular myoid cells were identified by cytoplasmic aSMA-staining (Fig. 7) . After 1 week, only few cord-like structures were associated with aSMA-positive cells. The connective tissue capsule surrounding xenografts was also lined by myoid cells (Fig. 7C) . After 4 weeks most Sertoli cell tubules were surrounded by a thick layer of peritubular myoid cells (Fig. 7D and E) . mRNA isolated from xenografts after 1 -4 weeks was analyzed by RT -PCR (n \u00bc 3 -5). In control experiments, PCR reactions were performed on RT reactions without reverse transcriptase (2RT) and in the absence of cDNA (no DNA). Average expression levels were normalized to Ppia, and the mean (+SEM) fold change expressed relative to 1 week (scaled to 1). M \u00bc 100 bp DNA ladder. Expression of Wt1, known to be expressed in Sertoli cells at all developmental stages was detected at all time points. The expression patterns of Krt18, Gata4, Trf, Fshr and Shbg were examined. mRNA isolated from xenografts after 2 -12 weeks was analyzed by RT -PCR (n \u00bc 3). In control experiments, PCR reactions were performed on RT reactions without reverse transcriptase (2RT) and in the absence of cDNA (no DNA). Average expression levels were normalized to Ppia, and the mean (+SEM) fold change expressed relative to 2 weeks (scaled to 1). M \u00bc 100 bp DNA ladder. Expression of Wt1 was detected throughout all time points. Expression of Krt18, Gata4, Cyp19a1 Trf, Fshr and Shbg were examined. Different lower case letters indicate statistically significant changes of expression (P , 0.05).", "cite_spans": [], "ref_spans": [{"start": 69, "end": 77, "text": "(Fig. 7)", "ref_id": "FIGREF5"}, {"start": 249, "end": 258, "text": "(Fig. 7C)", "ref_id": "FIGREF5"}, {"start": 361, "end": 376, "text": "(Fig. 7D and E)", "ref_id": "FIGREF5"}]}, {"section": "Recruitment of peritubular myoid cells to xenografts", "text": "In addition, aSMA could be seen in cells that appeared to be vascular smooth muscle cells or pericytes as judged by their morphology, and therefore could be used as an indicator of vasculature distribution throughout the grafts. Further, the connective tissue capsule surrounding xenografts was covered with multi-layered myoid cells in many grafts (Fig. 7F) .", "cite_spans": [], "ref_spans": [{"start": 349, "end": 358, "text": "(Fig. 7F)", "ref_id": "FIGREF5"}]}, {"section": "Differentiation of Leydig cells in xenografts", "text": "Small groups of Leydig cells were occasionally observed in xenografts after 1 week (Fig. 8) , but the overall level of p450scc-positive cells remained low within the first 3 weeks of xenografting. After 4 weeks, Leydig cells became more abundant and were mostly located in proximity to Sertoli cell tubules (Fig. 8D) . Leydig cells were also observed in xenografts after 8 weeks (Fig. 8E ) and 12 weeks (Fig. 8F) . Although most p450scc-positive cells were located in the interstitial compartment, we also observed intratubular p450scc-positive cells after prolonged xenografting.", "cite_spans": [], "ref_spans": [{"start": 83, "end": 91, "text": "(Fig. 8)", "ref_id": "FIGREF6"}, {"start": 307, "end": 316, "text": "(Fig. 8D)", "ref_id": "FIGREF6"}, {"start": 379, "end": 387, "text": "(Fig. 8E", "ref_id": "FIGREF6"}, {"start": 403, "end": 412, "text": "(Fig. 8F)", "ref_id": "FIGREF6"}]}, {"section": "Anatomical data", "text": "Seminal vesicle weights in graft recipients decreased between 1 and 4 weeks after castration in the short-term xenografting study (75.8 + 12.5 versus 33.5 + 4.2 mg; n \u00bc 10 -15 mice). During long-term graft development, seminal vesicles further decreased between 2 and 8 weeks after castration (43.8 + 2.7 versus 20.5 + 3.2 mg; n \u00bc 6-10 mice), but remained slightly higher than the seminal vesicles weights in castrated control animals (Fig. 9) .", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "In this study we analysed Sertoli cell maturation in xenografts as a model of mammalian testicular development. We hypothesized that limited maturation of Sertoli cells in vitro is due to the lack of environmental input and can be overcome in a xenografting model. Immune rejection by the hosts in this model was rare, leading to successful growth of xenografts at all time points. The wide range of graft sizes observed could be due to the physical properties of the Matrigel vehicle. In future studies, encapsulation of Sertoli cells in alternative matrices such as alginate could improve the xenografting technique for greater reproducibility. Nevertheless, we show that Sertoli cells initiate proliferation immediately after xenografting, and that proliferation is reduced to low levels as Sertoli cell maturation is initiated. This process is complemented by the recruitment of peritubular myoid cells and Leydig cells to newly-formed seminiferous tubules. The Sertoli cell proliferation studies indicate that Sertoli cell mitosis is transiently re-established after xenografting. BrdU-labelled cells could not be detected during three-dimensional culture, although Sertoli cells isolated from rats of this age group are highly proliferative in vivo and in conventional cell culture (Orth, 1982 , Schlatt et al., 1996 . In contrast, Sertoli cells initiated mitotic activity after xenografting and proliferation was maintained at high levels within the first 3 weeks after grafting. Proliferating Sertoli cells were observed at a low level for up to 12 weeks. This is in contrast to the in vivo situation, where Sertoli cell proliferation ceases around Day 15 in the rat (Clermont and Perey, 1957; Steinberger, 1971, Orth, 1982) . These data are also correlated with the observation of immature Sertoli cell cords in xenografts throughout the study period until they start to deteriorate. Therefore, our results suggest that Sertoli cell tubules progressively differentiated in xenografts up to 12 weeks. Further, the data suggest that a heterogeneous Sertoli cell population consisting of proliferating and differentiated Sertoli cells is present in xenografts, and that Sertoli cell maturation occurs in a non-synchronized manner. This could be caused by local differences in the graft environment due to uneven vascular development. A similar effect was reported before by Rathi et al. (2008) for the maturation of immature rhesus monkey testicular grafts.", "cite_spans": [{"start": 1288, "end": 1299, "text": "(Orth, 1982", "ref_id": "BIBREF17"}, {"start": 1300, "end": 1322, "text": ", Schlatt et al., 1996", "ref_id": "BIBREF29"}, {"start": 1675, "end": 1701, "text": "(Clermont and Perey, 1957;", "ref_id": "BIBREF4"}, {"start": 2380, "end": 2399, "text": "Rathi et al. (2008)", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "Discussion", "text": "This observation is further supported by data obtained from mRNA expression studies of xenografts. Specifically, the expression of immature Sertoli cell markers Krt18 and Gata4 persisted at low levels for at least 12 weeks after xenografting. In the case of Gata4 it has been proposed that Gata4 expression remains constant in adult Sertoli cells (Imai et al., 2004) , and it was speculated that the previously reported decline of Gata4 after post-natal Day 14 might be due to a dilution effect caused by increasing numbers of germ cells. Accordingly, the absence of germ cells in this model might be accountable for the persistence of constant Gata4 mRNA in xenografts. Cyp19a1 mRNA expression increased with time, counter to the expected down-regulation during Sertoli cell differentiation. However, Cyp19a1 is also expressed in Leydig cells and germ cells in the adult testis, but is absent from peritubular myoid cells (Levallet et al., 1998; Lambard et al., 2005) . Taking into account the increasing number of Leydig cells at the later time points, it seems plausible that these cells might account for the increase in total aromatase mRNA expression in xenografts.", "cite_spans": [{"start": 347, "end": 366, "text": "(Imai et al., 2004)", "ref_id": "BIBREF11"}, {"start": 923, "end": 946, "text": "(Levallet et al., 1998;", "ref_id": "BIBREF14"}, {"start": 947, "end": 968, "text": "Lambard et al., 2005)", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Discussion", "text": "The gene expression studies further indicated that Sertoli cells matured after xenografting, in contrast to Sertoli cells during in vitro culture that showed low levels or absent expression of Trf, Fshr and Shbg. In contrast, expression of Trf, Shbg and Fshr mRNA indicated the presence of differentiated Sertoli cells. These genes have been shown to be expressed at low levels during early post-natal life and to become up-regulated as Sertoli cells mature and cease proliferation (around Day 15 post-partum in the rat). Up-regulation of these markers during long-term xenografting therefore indicates that Sertoli cells in the testis and in xenografts develop with similar kinetics.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "The importance of peritubular myoid cells for tubulogenesis becomes apparent in this study. Immunohistochemistry showed an increase in peritubular myoid cells aligned along Sertoli cell tubules with time, coinciding with the emergence of polarized Sertoli cell epithelial organization and tubule growth. The formation of a basement membrane in cooperation by Sertoli cells and peritubular myoid cells appears to be of crucial importance for continuing Sertoli cell maturation. In in vivo studies it has been shown that impaired peritubular myoid cell proliferation and differentiation during post-natal testicular development causes decreased testicular size and disturbed longitudinal growth of seminiferous tubules in the adult testis (Nurmio et al., 2007) . This is in line with observations from knock-out models that show testicular pathology due to abnormal peritubular tissue differentiation. In Dhh (desert hedgehog)-null mice, a focally absent basal lamina leads to ectopical gonocytes and apolar Sertoli cells in the adult testis (Clark et al., 2000) . Targeted deletion of Figure 9 Seminal vesicle weights of castrated graft recipients.", "cite_spans": [{"start": 737, "end": 758, "text": "(Nurmio et al., 2007)", "ref_id": "BIBREF16"}, {"start": 1040, "end": 1060, "text": "(Clark et al., 2000)", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Discussion", "text": "Seminal vesicle sizes significantly decreased between 1 and 4 weeks after castration in the short-term xenografting study (ANOVA on ranks, n \u00bc 10 -15; black line). During long-term graft development, seminal vesicles decreased between 2 and 8 weeks after castration (ANOVA on ranks, n \u00bc 6-10; dashed line). \u2020 Castrate level seminal vesicles derived from previous studies. Average SVW \u00bc 14.4 mg (+2.4, n \u00bc 16; red line).", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Dax1 (dosage-sensitive sex reversal, adrenal hypoplasia congenital, critical region on the X chromosome, gene 1) in mice results in decreased numbers of peritubular myoid cells at embryonic Day 13.5 testis (Park et al., 2005 ) and the resulting phenotype shows a disrupted basal lamina and incompletely formed testicular cords.", "cite_spans": [{"start": 206, "end": 224, "text": "(Park et al., 2005", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Discussion", "text": "It has long been speculated that precursor cells for peritubular myoid cells are among the migrating mesonephric cell population that enters the gonad during embryonic cord formation, a crucial event for testicular morphogenesis (Tilmann and Capel, 1999) . More recently it was reported that peritubular myoid cells do not enter the gonad from the mesonephros (Cool et al., 2008) , but rather are established through cell proliferation of a resident precursor cell population within the gonad. Both mechanisms were observed in our model. Firstly, peritubular myoid cells were detected in the initial cell suspension used for three-dimensional cell culture and were found to be important for in vitro morphogenesis of cord-like structures (Gassei et al., 2006) . Additionally, immunofluorescence staining for aSMA on Sertoli cell aggregates isolated from Matrigel revealed the integration of myoid cells in the cord-like structures at the time of grafting. These observations lead to the conclusion that Sertoli cells and myoid cells likewise contribute to cord-formation in vitro and in xenografts. In addition, proliferating peritubular cells were occasionally observed for up to 3 weeks in xenografts. On the other hand, myoid cells were present in grafts after 1 week, and these cells were found to be aligned along the mesenchymal capsule of xenografts, independent of Sertoli cell cords. At later time points, these cells appeared to migrate into xenografts together with fibroblast-like cells and endothelial cells. Thus, it is possible that the peritubular cells present in aggregates at the time of grafting initially differentiate and contribute to tubule differentiation. However, the increasing number of invading mesenchymal precursor cells could also be responsible for the formation of intact layers of myoid cells surrounding the Sertoli cell tubules in xenografts.", "cite_spans": [{"start": 229, "end": 254, "text": "(Tilmann and Capel, 1999)", "ref_id": "BIBREF38"}, {"start": 360, "end": 379, "text": "(Cool et al., 2008)", "ref_id": "BIBREF5"}, {"start": 738, "end": 759, "text": "(Gassei et al., 2006)", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Discussion", "text": "In vivo, steroidogenic Leydig cells reside within the interstitium. We used cytochrome p450 side-chain cleavage enzyme (p450scc), the initial and rate-limiting enzyme during androgen biosynthesis, as a marker for Leydig cells (Payne and Youngblood, 1995) to examine if they would be recruited to the interstitial compartment in xenografts. Histological analysis showed the development of interstitial compartments around 4 weeks after grafting. Within this compartment, the presence of p450scc-positive putative Leydig cells was low during the first weeks of xenografting and high at 8-12 weeks. The initial single cell suspension used for three-dimensional culture contained only a low number of Leydig cells, as previously determined . Furthermore, immunohistochemistry for p450scc on isolated Sertoli cell aggregates did not reveal the integration of Leydig cells in Sertoli cell aggregates at the time of grafting (data not shown). However, as the presence of the p450scc enzyme alone is not sufficient for androgen production, we also analysed the size of seminal vesicles from castrated host mice. As expected, seminal vesicles rapidly decreased in size after castration, but after prolonged xenografting their weights were slightly above those reported in castrated nude mice in previous studies (Schlatt et al., 2003l; Ehmcke et al., 2008) , indicating low levels of bioactive testosterone in the castrated host mice. We therefore suggest that a small population of steroidogenic Leydig cells differentiated from mesenchymal precursor cells that migrated into xenografts.", "cite_spans": [{"start": 226, "end": 254, "text": "(Payne and Youngblood, 1995)", "ref_id": "BIBREF21"}, {"start": 1327, "end": 1347, "text": "Ehmcke et al., 2008)", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Discussion", "text": "We conclude that immature Sertoli cells in xenografts continue to mature beyond the developmental state at post-natal Day 7, the day of cell isolation, and we further show that this maturation could not be achieved by in vitro culture alone. Sertoli cells in xenografts cease to proliferate and morphologically mature, and this is concurrent with the up-regulation of Fshr, Shbg and Trf. We further conclude that progressive migration of fibroblast-like cells into xenografts is crucial for the differentiation of peritubular myoid cells and Leydig cells in xenografts and the overall differentiation of a somatic testicular environment. However, seminiferous tubules in this study showed a 'Sertoli cell only' (SCO)-phenotype, and it remains unclear if these tubules would be potentially capable of maintaining spermatogonia. 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culture", "authors": [{"first": "A", "middle": [], "last": "Steinberger", "suffix": ""}, {"first": "E", "middle": [], "last": "Steinberger", "suffix": ""}], "year": 1971, "venue": "Biol Reprod", "link": "7239978"}, "BIBREF37": {"title": "Effect of age and hypophysectomy on FSH binding by rat testes", "authors": [{"first": "K", "middle": ["H"], "last": "Thanki", "suffix": ""}, {"first": "A", "middle": [], "last": "Steinberger", "suffix": ""}], "year": 1978, "venue": "Andrologia", "link": null}, "BIBREF38": {"title": "Mesonephric cell migration induces testis cord formation and Sertoli cell differentiation in the mammalian gonad", "authors": [{"first": "C", "middle": [], "last": "Tilmann", "suffix": ""}, {"first": "B", "middle": [], "last": "Capel", "suffix": ""}], "year": 1999, "venue": "Development", "link": null}, "BIBREF39": {"title": "Androgen binding protein as a biochemical marker of formation of the blood-testis barrier", "authors": [{"first": "D", "middle": ["J"], "last": "Tindall", "suffix": ""}, {"first": "R", "middle": [], "last": "Vitale", "suffix": ""}, {"first": "A", "middle": ["R"], "last": "Means", "suffix": ""}], "year": 1975, "venue": "Endocrinology", "link": "12093062"}, "BIBREF40": {"title": "Transcription factor GATA-4 is expressed in a sexually dimorphic pattern during mouse gonadal development and is a potent activator of the Mullerian inhibiting substance promoter", "authors": [{"first": "R", "middle": ["S"], "last": "Viger", "suffix": ""}, {"first": "C", "middle": [], "last": "Mertineit", "suffix": ""}, {"first": "J", "middle": ["M"], "last": "Trasler", "suffix": ""}, {"first": "M", "middle": [], "last": "Nemer", "suffix": ""}], "year": 1998, "venue": "Development", "link": "41825764"}}, "ref_entries": {"FIGREF0": {"text": "PCR conditions were as follows: 5 min at 958C (30 s at 958C, 30 s at ............................................................................................................................................................................................. Table II Oligonucleotide primer sequences for the amplification of Sertoli cell maturation", "type": "figure"}, "FIGREF1": {"text": "Figure 3 Development of seminiferous tubules in xenografts. Resin embedded sections were stained with periodic acid/Schiff's reagent for histological analysis. Scale bars \u00bc 50 mm. (A) After 1 week, small cord-like structures are present, and secretion of carbohydrate-rich basement membrane components is evident (arrow). (B) Xenograft after 2 weeks. Tubule-like structured with single-layered Sertoli cell epithelium are predominantly observed. Peritubular cells are aligned along tubules (arrows). (C) Maturation of Sertoli cells and formation of tight junctional complexes is indicated by the formation of fluid-filled lumen (asterisk, xenograft after 3 weeks). (D) Sertoli cell tubules after 4 weeks. Tubules are organized in clusters and show differentiated basement membranes and recruitment of peritubular myoid cells. Endothelial (asterisk) and fibroblast-like cell (arrow) migration into xenografts. (E) Xenograft after 8 weeks are associated with extratubular cells (arrows), resembling the interstitial compartment in vivo. (F) After 12 weeks, xenografts become fibrotic (asterisk). Sertoli cell tubules begin to degenerate and the epithelial organization deteriorates.", "type": "figure"}, "FIGREF2": {"text": "Figure 4 Proliferation of Sertoli cells in xenografts. Sertoli cells in S-phase were labelled by BrdU-incorporation and detected using an anti-BrdU primary antibody and visualized with DAB (brown precipitate in cell nucleus). Sections were counterstained with hematoxylin. Scale bars \u00bc 50 mm. (A) Positive control. In adult mouse testis, type A and B spermatogonia are the only proliferating cell types. (B) Sertoli cell cords actively proliferate in xenografts after 1 week. Inset: negative control. The same cord in an adjacent cross section that was incubated without primary antibody. No specific staining was visible in Sertoli cells in this cord. (C) Xenograft after 3 weeks. Sertoli cell proliferation decreased (arrow). Proliferating peritubular cells surrounding the Sertoli cell tubule were frequently observed (arrowhead). (D) BrdU-LI after short-term and long-term xenografting. Left panel: in the shortterm study, Sertoli cell proliferation significantly declined from Week 1 to Week 3 (P , 0.05, ANOVA on ranks, n \u00bc 10 -24 xenografts). Right panel: similarly, Sertoli cell proliferation was significantly higher at 2 weeks than in later time points (P , 0.05, ANOVA, n \u00bc 5 -13 grafts). A low proliferation rate (1%) was observed at all time points up to 12 weeks.", "type": "figure"}, "FIGREF3": {"text": "Figure 5 Expression of Sertoli cell differentiation markers during short-term grafting.", "type": "figure"}, "FIGREF4": {"text": "Figure 6 Expression of Sertoli cell differentiation markers during long-term grafting.", "type": "figure"}, "FIGREF5": {"text": "Figure 7 Development of peritubular myoid cells in xenografts. Xenografts were stained for a-smooth muscle actin (SMA, brown precipitate), a myoid and smooth muscle cell marker. Scale bars \u00bc 50 mm. (A) Positive control. A representative cross-section from a 7-day-old rat testis. Immature testicular cords are surrounded by peritubular myoid cell. (B) The same tubules as shown in A in an adjacent section that was incubated with secondary antibody only. No staining is visible in the control section. (C) Sertoli cell cord in a xenograft after 1 week. The cord is partly surrounded by peritubular myoid cells (arrow). The connective tissue capsule (c) next to the cord is aligned by myoid cells (arrow). (D) After 4 weeks, Sertoli cell tubules are surrounded by peritubular myoid cells, as indicated by positive staining for SMA. (E) Cluster of Sertoli cell tubules and intertubular compartment in a xenograft after 12 weeks. Peritubular myoid cells are located around Sertoli cell tubules. Single myoid cells or small groups are located within the inter-tubular compartment. (F) Higher magnification of the boxed area in E. The connective tissue capsule is covered with multi-layered myoid cells (asterisk). A SMApositive vascular wall cell, indicating vascularization, is shown (arrow).", "type": "figure"}, "FIGREF6": {"text": "Figure 8 Development of Leydig cells in xenografts. Paraffin embedded sections of xenografts were stained for cytochrome p450 side-chain cleavage enzyme (p450scc, Leydig cell marker, brown precipitate), and counterstained with hematoxylin. Scale bars \u00bc 50 mm. (A, B) Positive controls. Testicular cross-sections from post-natal (A) and adult (B) rats show specific staining of Leydig cells in the interstitial compartment. Insets: negative controls. The same areas as captured in A and B in adjacent sections were incubated with secondary antibody only and do not show staining for Leydig cells. (C) Small groups of p450scc positive cells were observed in xenografts after 1 week. (D) Leydig cells become more abundant in xenografts after 4 weeks, and are located close to Sertoli cell tubules. (E, F) Progressive development of Leydig cells in long-term xenografts after 8 weeks (E) and 12 weeks (F). Most p450scc-positive cells are located in the interstitial compartment. After prolonged grafting periods, p450scc-poitive cells are also observed within Sertoli cell tubules (arrows in E).", "type": "figure"}, "TABREF0": {"text": "ethanol. For preparation of mRNA, xenografts were snap-frozen in liquid nitrogen. Body weights, seminal vesicle weights, as well as graft numbers and weights were recorded for each host animal. ........................................................................................", "type": "table"}}}
{"paper_id": "17432397", "_pdf_hash": "8bd7474d7f3aa183ccc74b62155593c676e6744f", "abstract": [{"section": "Abstract", "text": "Abstract. We have used the velocity dispersion as an age indicator to constrain the ages of a large sample of main sequence Vega-like stars in order to study the lifetimes and temporal evolution of the dust disks around them. We use Hipparcos measurements to compute stellar velocities in the sky plane. The velocity dispersion of Vega-like stars is found to be systematically smaller than that of the normal main sequence field stars for all spectral types, suggesting that the main sequence dusty systems, on average, are younger than normal field stars. The debris disks seem to survive longer around late type stars as compared to early type stars. Further, we find a strong correlation between fractional dust luminosity ( f d \u2261 L dust /L \u22c6 ) and velocity dispersion of stars with dust disks. Fractional dust luminosity is found to drop off steadily with increasing stellar age from early pre-main sequence phase to late main sequence phase.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "It has been well established that the majority of pre-main sequence stars are surrounded by circumstellar disks which are analogous in their properties to the protosolar nebula before the onset of planet formation (e.g., Beckwith 1999; Mundy et al. 2000; Wilner & Lay 2000; Beckwith & Sargent 1996) . Young circumstellar disks lose most of this material due to planet formation and other disk dispersal processes by the time the central stars harbouring these disks reach the main sequence. In the standard model of planet formation, the dust grains with sizes typical of interstellar dust settle down to the disk mid-plane and stick together to grow into rocky planetesimals (e.g. Weidenschilling & Cuzzi 1993) . The disk is depleted of smaller grains and this lowers the opacity of the reprocessing disk. Planetesimals grow further to earth-like planetary bodies by coalescence and eventually accrete gas in the outer disk to form giant planets (e.g. Pollack et al. 1996) . When the disk has become sufficiently gas-free, so that it is dominated by grain dynamics, the planetary mass objects can gravitationally perturb kilometer-sized planetesimals sending them into highly eccentric orbits. Collisions between these planetesimals then replenish the disk with 'second generation dust' which is observed around many main sequence stars (e.g. Lagrange et al. 2000) . These main sequence stars with debris disks, known as 'Vega-like' stars, were first discovered by IRAS in 1983 (Aumann et al. 1984) . At least 15% of main sequence stars are surrounded by such disks (Lagrange et al. 2000) .", "cite_spans": [{"start": 221, "end": 235, "text": "Beckwith 1999;", "ref_id": "BIBREF3"}, {"start": 236, "end": 254, "text": "Mundy et al. 2000;", "ref_id": "BIBREF28"}, {"start": 255, "end": 273, "text": "Wilner & Lay 2000;", "ref_id": "BIBREF41"}, {"start": 682, "end": 711, "text": "Weidenschilling & Cuzzi 1993)", "ref_id": "BIBREF38"}, {"start": 1344, "end": 1365, "text": "Lagrange et al. 2000)", "ref_id": "BIBREF25"}, {"start": 1567, "end": 1589, "text": "(Lagrange et al. 2000)", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "Introduction", "text": "Send offprint requests to : Manoj P. Planet formation is well underway in main sequence dusty systems and the disks that we observe are the debris product of the planet formation process (Lagrange et al. 2000) . These disks are thought to be 'sign posts' of planet formation (Kenyon & Bromley 2002) . What are the lifetimes of these disks? Do disk lifetimes depend on the nature of the central star? How do these observed disks evolve with time? These questions are central to our understanding of planet formation and disk evolution. A study of the lifetimes and the temporal evolution of the dust disks should provide insight into the formation of planetary systems and disk dispersal timescales and mechanisms.", "cite_spans": [{"start": 187, "end": 209, "text": "(Lagrange et al. 2000)", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "Introduction", "text": "There have been a number of studies on the evolution of circumstellar disks around main sequence stars. Zuckerman & Becklin (1993) have found that the mass of dust in the disks declines as rapidly as (time)", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "\u22122 during the initial 3 \u00d7 10 8 yr. Similar results have been reported by Holland et al. (1998) from their SCUBA observations. There is general agreement now on the fact that the amount of dust retained in the disks decreases with increasing stellar age Lagrange et al. 2000) . However, the exact nature of this decline is not clear. Most of these studies are based on the ages of a few prototype Vega-like stars. When more stars are employed, reliable estimation of their ages poses a serious problem.", "cite_spans": [{"start": 253, "end": 274, "text": "Lagrange et al. 2000)", "ref_id": "BIBREF25"}], "ref_spans": []}, {"section": "Introduction", "text": "It is difficult to determine the ages of main sequence stars with reasonable accuracy. There have been a few attempts to estimate ages of field Vega-like stars (e.g. Lachaume et al. 1999; Song 2000; Silverstone 2000) , but the ages determined using different techniques are not always mutually consistent (Zuckerman 2001) . Recently, Spangler et al. (2001) have carried out a survey of circumstellar disks around pre-main sequence and young main sequence stars that are members of young open clusters of known ages using ISOPHOT. They found that the fractional dust luminosity f d drops off with stellar age according to the power law f d \u221d (age) \u22121.76 . This suggestion of a global power law has been contested by Decin et al. (2003) who find a spread in fractional dust luminosity at any age from the revised age estimates of their sample stars observed by ISOPHOT. , based on a physical model that they developed for the dust production in Vega-like disks, have argued that a collisional cascade with constant collision velocities leads to a power law decrease of the amount of dust seen in the debris disk with a power law index of \u22121. They add that a collisional cascade with continuous stirring can produce slopes steeper than \u22121.", "cite_spans": [{"start": 199, "end": 216, "text": "Silverstone 2000)", "ref_id": "BIBREF32"}], "ref_spans": []}, {"section": "Introduction", "text": "In this paper, we study the temporal evolution of dust disks around main sequence stars. We consider the kinematics of a large sample of Vega-like stars and use the velocity dispersion as an age indicator. It has long been known that there is a strong correlation between the random velocities and ages of stars in the Galactic disk. Velocity dispersion of stars in the solar neighborhood has been found to increase with age (Wielen 1977; Jahrei\u00df & Wielen 1983) . Observationally, velocity dispersion \u03c3 is found to grow with age at least as fast as t 0.3 and more likely t 0.5 (Wielen 1977; Binney & Tremaine 1987) . The dynamical origin of this effect is attributed to the encounters between the disk stars and the massive gas-clouds (Spitzer & Schwarzschild 1951 , 1953 and to transient spiral waves heating up the Galactic disk (Barbanis & Woltjer 1967) . Using accurate Hipparcos parallaxes and proper motions, Binney et al. (2000) and Dehnen & Binney (1998) have shown that for a coeval group of stars, the rms dispersion in transverse velocity S (in the plane of the sky), which is connected to the principal velocity dispersion by the relation", "cite_spans": [{"start": 439, "end": 461, "text": "Jahrei\u00df & Wielen 1983)", "ref_id": "BIBREF19"}, {"start": 591, "end": 614, "text": "Binney & Tremaine 1987)", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Introduction", "text": ", increases with time from 8 kms \u22121 at birth as t 1/3 . We follow this formalism and use the dispersion in transverse velocity to constrain the ages of Vega-like stars in order to study the lifetimes and temporal evolution of the dust disks.", "cite_spans": [], "ref_spans": []}, {"section": "Data", "text": "A number of recent studies give lists of Vega-like stars and candidate Vega-like stars, selected on the basis of their infrared excesses in the IRAS wave bands. Song (2000) lists 361 objects taken from different surveys and searches published in the literature. From a search of the IRAS FSC catalog, Silverstone (2000) produced a list of 191 Vega-like stars. A number of additional Vega-like objects have been discussed in Coulson et al. (1998) and Malfait et al. (1998) . We first compiled a total of 486 distinct Vega-like stars taken from these lists that had many objects in common. This large sample could have some stars that are erroneously classified as Vega-like or have uncertain associations with the IRAS sources due to the large IRAS beam size. In our study, we consider only those stars for which the positional offset between the optical star and the IRAS association is \u2264 30 \u2032\u2032 . Further, we examined the Digital Sky Survey images of the region near each Vega-like candidate to make sure that the far-infrared emission is indeed from the stellar source and not from any extended background source, for example a galaxy, near the star in the plane of the sky (e.g., Zuckerman & Song 2004) . We have eliminated those stars from our sample where an optical galaxy or an IRAS extended source was found inside or very near ( \u2264 1 \u2032 ) to the IRAS error ellipse for the point source. Alternative associations have been found for some of the proposed Vega-like stars in the literature (Sylvester & Mannings 2000; Lisse et al. 2002) . We have excluded such stars from our sample. We also exclude known pre-main sequence stars (e.g., Herbig Ae/Be stars; Th\u00e9 et al. (1994) ) and other emission-line objects from our sample. Further, we consider only stars in the spectral range between B9 and K5 -infrared excess from early B type star could be due to free-free emission (Zuckerman 2001 ) and Kgiants are known to exhibit Vega-like excesses (e.g., Plets et al. 1997; Jura 1999) . Finally, our sample contains 221 Vega-like stars for which both Hipparcos and IRAS (PSC/FSC) measurements are available.", "cite_spans": [{"start": 301, "end": 319, "text": "Silverstone (2000)", "ref_id": "BIBREF32"}], "ref_spans": []}, {"section": "Analysis", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Dustiness of Vega-like stars", "text": "A good measure of the 'dustiness' of the disks around Vega-like stars is the fractional dust luminosity f d \u2261 L dust /L \u22c6 , which represents the optical depth offered by an orbiting dust disk to ultraviolet and visual radiation (Zuckerman 2001) . We compute f d from IRAS (PSC/FSC) fluxes for the Vega-like stars in our sample using the relation (Emerson 1988). In the above equation e 12 , e 25 , e 60 , e 100 are the excess flux densities in Jy over the photospheric values in the IRAS wave bands at 12, 25, 60 and 100\u00b5m respectively, m V is the visual magnitude of the star corrected for extinction (which is generally very small, typically \u2264 0.1 mag for stars in our sample) and BC is the bolometric correction. The excess flux density in each IRAS band was estimated as follows. The photospheric 12\u00b5m magnitude was derived from the extinction-corrected V magnitude and (B-V) color of the star as discussed in Oudmaijer et al. (1992) . The photospheric magnitudes at the other bands were calculated using the relations given in Oudmaijer et al. (1992) . Photospheric magnitudes were then converted into flux densities in the IRAS bands by using the magnitude zero points listed in the IRAS catalog, and then color corrected to a photospheric SED (e.g., Silverstone 2000) . The photospheric estimates in the IRAS catalog color convention were subtracted from the corresponding non-upper limit IRAS PSC/FSC flux densities to obtain the excess flux densities e \u03bb in each of the IRAS bands.", "cite_spans": [{"start": 1257, "end": 1274, "text": "Silverstone 2000)", "ref_id": "BIBREF32"}], "ref_spans": []}, {"section": "Dustiness of Vega-like stars", "text": "In order to account for the possible inexact approximation of the photosphere, the excesses computed are considered, as in Silverstone (2000) , to be significant only if it exceeds 20% of the photospheric flux value in each of the bands. Stars with significant excess in any one of the bands are taken as 'true' Vega-like and their f d is computed as described above. Fractional dust luminosities thus computed for 181 'true' Vegalike systems agree well with earlier estimates in the literature (Backman & Gillett 1987; Song 2000; Silverstone 2000) , generally to within 10%. We find a number of stars with excesses of less than 20% of the photospheric fluxes in all the four IRAS bands. The excesses, if any, that these stars show are at a very low level. However, these stars have been classified as Vegalike stars in earlier studies in which excesses were inferred by different methods. We assign an upper limit value of 10 \u22126 for f d of these stars as the values of f d computed for them are < \u223c 10 \u22126 .", "cite_spans": [{"start": 123, "end": 141, "text": "Silverstone (2000)", "ref_id": "BIBREF32"}, {"start": 495, "end": 519, "text": "(Backman & Gillett 1987;", "ref_id": "BIBREF1"}, {"start": 531, "end": 548, "text": "Silverstone 2000)", "ref_id": "BIBREF32"}], "ref_spans": []}, {"section": "Kinematics -transverse velocities of Vega-like stars", "text": "For all the stars in our sample we have proper motions and parallaxes from the Hipparcos catalog (ESA 1997). The transverse velocity perpendicular to the line of sight relative to the solar system barycenter is then computed using the relation", "cite_spans": [], "ref_spans": []}, {"section": "Kinematics -transverse velocities of Vega-like stars", "text": "2 ) 1/2 with \u00b5 \u03b4 and \u00b5 \u03b1 cos \u03b4 being the proper motions along declination and right ascension in milliarcseconds. Errors in transverse velocities are estimated from the probable errors in parallaxes and proper motions given in the Hipparcos catalog. Transverse velocities of stars thus obtained will have solar motion reflected in them. We have corrected the velocities for solar motion using the values of U = 10.0 \u00b1 0.4 km s \u22121 , V = 5.2 \u00b1 0.6 km s \u22121 , W = 7.2 \u00b1 0.4 km s \u22121 (Binney & Merrifield 1998) for the standard solar motion. To minimize the effect of Galactic differential rotation we consider only stars within 250 pc from the Sun. Further, we include only those stars in our analysis that have a fractional error in transverse velocity less than 0.5. We have, then, 158 Vega-like stars with transverse velocities and fractional dust luminosities computed for the final analysis.", "cite_spans": [{"start": 478, "end": 504, "text": "(Binney & Merrifield 1998)", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Velocity dispersion and disk lifetimes", "text": "As discussed in \u00a71, the velocity dispersion of a group of stars is a measure of the average age of the group. Here we use transverse velocity dispersion as an age indicator to constrain the ages of the stars with dusty disks in order to study the disk lifetimes and evolution. The transverse velocity dispersion of the 158 Vega-like stars in our final sample is found to be 21.4 \u00b1 1.2 km sec \u22121 . The transverse velocity dispersion, again computed using Hipparcos measurements, of about 14 000 field stars with spectral types between B9 and K5 which are within 250 pc from the Sun and whose fractional errors in transverse velocities are less than 0.5, is computed to be 37.3 \u00b1 0.2 km sec \u22121 . The smaller velocity dispersion for Vega-like stars compared to field stars indicates, at the very outset, that the main sequence dusty systems are younger than the field stars and that the debris disk lifetimes are shorter than the main sequence lifetimes of the stars. In the following, we analyze the spectral type dependence of the velocity dispersion of Vega-like stars. (2000) is also shown on the y-axis on the right. Note that the age axis is not linear In Fig 1 we It can be seen from Fig 1 that the Vega-like stars, on average, show a lower velocity dispersion than the field stars at any given (B -V). While this trend is clearly evident on visual inspection for stars with B \u2212 V \u2265 0.3 (spectral type F0 or later), it is not as striking for stars of early spectral type, though in general, their velocity dispersions are smaller than the field stars. A two-sided two dimensional Kolomogorov-Smirnov test shows that the velocity dispersion -(B -V) relation for Vegalike stars and field stars to be different with probability 99.99%. Thus, Vega-like stars have a lower velocity dispersion than that of field stars for any given spectral type. Since a lower velocity dispersion indicates younger ages, it follows that the main sequence stars with debris disks are statistically younger than the field stars of similar spectral type. It can also be seen from Fig 1 that late type Vega-like stars have a larger velocity dispersion than early type Vega-like stars, suggesting that statistically they are older.", "cite_spans": [], "ref_spans": [{"start": 1156, "end": 1167, "text": "In Fig 1 we", "ref_id": "FIGREF1"}, {"start": 1188, "end": 1198, "text": "Fig 1 that", "ref_id": "FIGREF1"}]}, {"section": "Velocity dispersion and disk lifetimes", "text": "In order to quantify the disk lifetimes of Vega-like stars, we relate the velocity dispersion to the stellar age following the formalism of Binney et al. (2000) where the velocity dispersion for a coeval group of stars as a function of age is given by S = v 10 [(\u03c4 + \u03c4 1 )/(10Gyr + \u03c4 1 )]", "cite_spans": [], "ref_spans": []}, {"section": "Velocity dispersion and disk lifetimes", "text": "\u03b2 . In this equation, \u03c4 1 determines the random velocity of stars at birth, and v 10 and \u03b2 characterize the efficiency of stellar acceleration. Using values of \u03b2 = 1/3, v 10 = 58 km s \u22121 and \u03c4 1 = 0.03 Gyr (Binney et al. 2000) we translate velocity dispersion into age. The ages thus derived from the velocity dispersion are plotted in Fig 1 on the y-axis on the right. The figure shows Vega-like stars to be systematically younger than the field stars for all values of (B\u2212V).", "cite_spans": [], "ref_spans": [{"start": 336, "end": 344, "text": "Fig 1 on", "ref_id": "FIGREF1"}]}, {"section": "Velocity dispersion and disk lifetimes", "text": "Vega-like stars being a younger population than the field stars indicates that the lifetimes of debris disks are shorter than the main sequence lifetimes of the stars which harbour them. The debris disk may not survive for the entire lifetime of the central star. However, it is possible that this is a selection effect, as IRAS will not be able to detect low luminosity disks below its sensitivity limit. The luminosity of debris disks gradually goes down as the central stars age and eventually falls below the limit of detection. This is expected physically as the larger bodies which replenish the disk are eroded continuously and are finite in supply. We also find such a fall in fractional dust luminosity of debris disks with age as demonstrated in Fig 2  (see  \u00a74. 2). Dust debris of low optical depth f d < \u223c 10 \u22127 like that around the Sun may be present over the entire lifetimes of the main sequence stars.", "cite_spans": [], "ref_spans": [{"start": 756, "end": 772, "text": "Fig 2  (see  \u00a74.", "ref_id": "FIGREF0"}]}, {"section": "Velocity dispersion and disk lifetimes", "text": "The ages of Vega-like stars are found to range from 10 8 yr to 1 \u2212 2 Gyr with Vega-like stars of later spectral types being older on average than stars of early spectral types. Ages of early type Vega-like stars span from 10 8 yr to 4 \u2212 5 \u00d7 10 8 yr while late type Vega-like stars can be as old as 1 \u2212 2 Gyr. That main sequence dusty systems of earlier spectral type are systematically younger than the late type systems strongly suggests shorter lifetimes for debris disks around early type stars. This would mean that the temporal evolution of main sequence disks is a function of the spectral type of the central star, with debris disks surviving longer around late type stars, a conclusion also reached by Song (2001) . This is not surprising as the timescales for grain removal processes like radiation pressure ' blowout' and Poynting-Robertson drag which dominate Vegalike disks are inversely proportional to the stellar luminosity, and thus are shorter for early type stars.", "cite_spans": [], "ref_spans": []}, {"section": "Temporal evolution of dust disks", "text": "Next, we study the evolution of the 'dustiness' of circumstellar disks with age. We look for a correlation between fractional dust luminosity f d and transverse velocity dispersion S, for stars of similar f d . For this we grouped the stars into bins of a given range in dustiness ( f d ). We then computed the dispersion in transverse velocities of stars in each of these bins. The mean value of f d in each bin is then plotted against the velocity dispersion of stars in that bin as shown in Malfait et al. (1998) , and for which Hipparcos and IRAS measurements are available. As for Vega-like stars, we restrict ourselves to stars within 250 pc and with fractional errors in transverse velocities less than 0.5. We have 22 such Herbig Ae/Be stars. Their average f d is plotted against the velocity dispersion S and is represented by the filled star symbol in Fig 2. It is clear from Fig 2 that there is a systematic decrease in the dustiness ( f d ) of the disks with increasing velocity dispersion S of stars. Herbig Ae/Be stars have the velocity dispersion S smaller than that of Vega-like stars, indicating younger ages. As discussed earlier, the velocity dispersion S of stars, in general, is found to increase with stellar age as S \u221d t 1/3 (Binney et al. 2000) . The correlation between fractional dust luminosity of stars with disks and their velocity dispersion seen in Fig 2 clearly implies a steady decrease in the optical thickness of the disks with stellar age. This is consistent with the earlier findings that the amount of dust in the disks appears to decrease generally with system age.", "cite_spans": [], "ref_spans": []}, {"section": "Temporal evolution of dust disks", "text": "The stellar ages obtained from translating velocity dispersion into age using the formalism of Binney et al. (2000) are also shown in Fig 2 on the x-axis on the top. The steady drop of fractional dust luminosity with increasing stellar age is evident from the figure. There is an overall decrease in the 'dustiness' of the circumstellar disks from the early pre-main sequence phase ( a few Myr) to well up to the late main sequence phase (\u223c 1 -2 Gyr). It can also be seen from Fig 2 that We note here that the correlation that we find between f d and velocity dispersion is not because of the spectral type dependence of velocity dispersion that we discussed earlier. It should also be noted that the ages that we derive from the velocity dispersion are statistical in nature. They are the average ages appropriate for the velocity dispersion shown by the group of stars and are derived from the relation between velocity dispersion and age as given by Binney et al. (2000) . The ages obtained this way can have relatively large errors for small ages because for small ages the velocity dispersion S is a steeply rising function of age for the relation S \u221d t 1/3 .", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Of the 158 stars in our final sample for which the analysis was carried out, 107 (68%) are within 100 pc and 51 (32%) have d > 100 pc. Kalas et al. (2002) have cautioned that the far-infrared emission from some of the Vega-like stars beyond 100 pc could be thermal emission from interstellar reflection nebulosities, similar to that seen in the Pleiades, due to the chance encounters of stars with relatively dense interstellar clouds. The dust density \u03c1 of the reflection nebulosities required to account for the observed fluxes is in the range of 10 \u221224 -10 \u221223 gcm \u22123 (Kalas et al. 2002) which corresponds to a gas number density n of 10 2 -10 3 cm \u22123 . Such high densities are generally associated with molecular clouds and not with the normal interstellar HI clouds. In fact the reflection nebulosity which causes the so called 'Pleiades phenomenon' is a fragment of the Taurus-Auriga molecular cloud that has been encountered by the Pleiades in that cluster's southward motion (Herbig & Simon 2001) . Such encounters of stars with dense molecular cloud clumps in the solar neighbourhood must be rare. Of the initial sample of 79 Vega-like candidates of Kalas et al. (2002) , 72 have Hipparcos-detected distances, and of these 43 (60%) have d > 100 pc. Among the 60 stars that they have observed from this sample, only six are found to have reflection nebulosities surrounding them. We have excluded these stars from our sample. Therefore amongst the stars in our sample that have not yet been investigated for the 'Pleiades phenomenon', one would expect only a few additional objects with reflection nebulosities. Because our analysis is statistical in nature, the average trends that we derive are not expected to be affected, even if a few stars with d > 100 pc are found to be surrounded by reflection nebulosities instead of orbiting dust grains. Restricting our entire analysis to stars within 100 pc gives the same trends and does not affect the results, except for poorer number statistics.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "In Fig 2 we have plotted both Herbig Ae/Be stars and Vegalike stars together and have derived an overall decline in fractional dust luminosity with stellar age. We point out here that the pre-main sequence disks like those around Herbig Ae/Be stars and the main sequence disks are physically different. Premain sequence disks are relatively optically thick ( f d \u223c 0.1) and gas-rich and are formed from the primordial cloud core from which the star itself is born. The infrared excess that the IRAS detected in these disks is due to the re-radiation from the first generation dust grains. On the other hand, the infrared excess shown by Vega-like disks is due to the debris dust produced in the collisions between larger bodies. The debris disks are gas-poor and the disk evolution is dominated by dust dynamics. Moreover, the decline in the fractional dust luminosity in the pre-main sequence disks is primarily due to the grain growth by which smaller sub-micron sized grains get depleted in the disks thereby reducing the effective surface area of dust absorption/emission. In main sequence debris disks, where the grains causing infrared excess are continuously being replenished, the fall in f d is due to the decline in the collisional regeneration rate.", "cite_spans": [], "ref_spans": []}, {"section": "Discussion", "text": "Nevertheless, it is expected that the pre-main sequence disks gradually evolve into Vega-like disks, although it is not yet clear when exactly the secondary dust generation begins in these disks. Recent studies have suggested that in general, the lifetimes of primordial disks are only a few Myr (Haisch et al. 2001; Lada 1999) . Larger bodies like kilometer-sized planetesimals and comets, which replenish the main sequence debris disks, can also be formed within a few Myr (e.g. Beckwith et al. 2000) . Thus the transition of optically thick disks into optically thin disks is expected to take place on similar timescales. The resolution of the stellar ages derived from velocity dispersion is poor and is inadequate to address the issue of the timescale of the transition from primordial pre-main sequence disks to Vega-like disks. However, a general decline in the 'dustiness' of the disks with stellar age from the pre-main sequence phase to the late main sequence phase is clearly seen.", "cite_spans": [{"start": 317, "end": 327, "text": "Lada 1999)", "ref_id": "BIBREF24"}, {"start": 481, "end": 502, "text": "Beckwith et al. 2000)", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Discussion", "text": "The results that we obtain from our analysis are consistent with the earlier studies on the disk evolution around main sequence stars. The overall decline in the dust content of the debris disks has been reported by Zuckerman & Becklin (1993) , Holland et al. (1998) and Spangler et al. (2001) . The conclusions of Decin et al. (2003) that there are few young stars with small excesses and that a Vega-like excess is more common in young stars than in old stars are consistent with our result of Vega-like stars being younger than the field stars for all spectral types. Decin et al. (2003) also argue that at most ages, there is a spread in fractional dust luminosity of Vega-like stars. While this may be true, our results strongly suggest that there is also a general decline in the f d of the disks with stellar age. However, we are not able to fit a single power law to the fall in f d with the average stellar ages that we derive from the velocity dispersion of the stars.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "In this paper we have used velocity dispersion as an age indicator to constrain the ages of a large sample of Vega-like stars. From the statistical ages derived from the velocity dispersion, we have studied the disk lifetimes and the temporal evolution of the dust disks around main sequence stars. The conclusions of this study are summarized below.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusions", "text": "-Velocity dispersion of Vega-like stars is found to be smaller than that of main sequence field stars for all spectral types. Main sequence stars with debris disks, on average, are younger than normal field stars of similar spectral type. -The ages of Vega-like stars derived from the velocity dispersion range from 10 8 yr to 1 \u2212 2 Gyr. -Vega-like stars of later spectral types are statistically older than Vega-like stars of earlier spectral type. Debris disks seem to survive longer around late type stars as compared to early type stars. -There is a strong correlation between fractional dust luminosity and velocity dispersion of Vega-like stars. Average fractional dust luminosity f d of stars with disks decreases monotonically with increasing velocity dispersion. There is a general decline of f d with stellar age from the early premain sequence phase to the late main sequence phase. -The observed high f d , lower velocity dispersion S and the implied younger ages for Herbig Ae/Be stars are consistent with them being the progenitors of Vega-like stars.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF1": {"title": "Cool Stars, Stellar Systems and the Sun", "authors": [{"first": "D", "middle": [], "last": "Backman", "suffix": ""}, {"first": "F", "middle": ["C"], "last": "Gillett", "suffix": ""}], "year": 1987, "venue": "", "link": "117240964"}, "BIBREF3": {"title": "NATO ASIC Proc. 540: The Origin of Stars and Planetary Systems", "authors": [{"first": "S", "middle": ["V W"], "last": "Beckwith", "suffix": ""}], "year": 1999, "venue": "", "link": null}, "BIBREF4": {"title": "Protostars and Planets IV", "authors": [{"first": "S", "middle": ["V W"], "last": "Beckwith", "suffix": ""}, {"first": "T", "middle": [], "last": "Henning", "suffix": ""}, {"first": "Y", "middle": [], "last": "Nakagawa", "suffix": ""}], "year": 2000, "venue": "", "link": null}, "BIBREF7": {"title": "Galactic Astronomy", "authors": [{"first": "J", "middle": [], "last": "Binney", "suffix": ""}, {"first": "M", "middle": [], "last": "Merrifield", "suffix": ""}], "year": 1998, "venue": "", "link": null}, "BIBREF8": {"title": "Galactic dynamics", "authors": [{"first": "J", "middle": [], "last": "Binney", "suffix": ""}, {"first": "S", "middle": [], "last": "Tremaine", "suffix": ""}], "year": 1987, "venue": "", "link": "118717388"}, "BIBREF13": {"title": "NATO ASIC Proc. 241: Formation and Evolution of Low Mass Stars", "authors": [{"first": "J", "middle": ["P"], "last": "Emerson", "suffix": ""}], "year": 1988, "venue": "", "link": null}, "BIBREF14": {"title": "The Hipparcos and Tycho Catalogues", "authors": [{"first": "", "middle": [], "last": "Esa", "suffix": ""}], "year": 1997, "venue": "", "link": null}, "BIBREF19": {"title": "IAU Colloq. 76: Nearby Stars and the Stellar Luminosity Function", "authors": [{"first": "H", "middle": [], "last": "Jahrei\u00df", "suffix": ""}, {"first": "R", "middle": [], "last": "Wielen", "suffix": ""}], "year": 1983, "venue": "", "link": null}, "BIBREF24": {"title": "NATO ASIC Proc. 540: The Origin of Stars and Planetary Systems", "authors": [{"first": "E", "middle": ["A"], "last": "Lada", "suffix": ""}], "year": 1999, "venue": "", "link": null}, "BIBREF25": {"title": "Protostars and Planets IV", "authors": [{"first": "A.-M", "middle": [], "last": "Lagrange", "suffix": ""}, {"first": "D", "middle": ["E"], "last": "Backman", "suffix": ""}, {"first": "P", "middle": [], "last": "Artymowicz", "suffix": ""}], "year": 2000, "venue": "", "link": null}, "BIBREF28": {"title": "Protostars and Planets IV", "authors": [{"first": "L", "middle": ["G"], "last": "Mundy", "suffix": ""}, {"first": "L", "middle": ["W"], "last": "Looney", "suffix": ""}, {"first": "W", "middle": ["J"], "last": "Welch", "suffix": ""}], "year": 2000, "venue": "", "link": null}, "BIBREF32": {"title": "UCLA Song, I", "authors": [{"first": "M", "middle": ["D"], "last": "Silverstone", "suffix": ""}], "year": 2000, "venue": "ASP Conf. Ser", "link": null}, "BIBREF38": {"title": "Protostars and Planets III", "authors": [{"first": "S", "middle": ["J"], "last": "Weidenschilling", "suffix": ""}, {"first": "J", "middle": ["N"], "last": "Cuzzi", "suffix": ""}], "year": 1993, "venue": "", "link": null}, "BIBREF39": {"title": "Lifetimes and evolution of main sequence dust disks 7", "authors": [{"first": "P", "middle": ["H C"], "last": "Manoj", "suffix": ""}, {"first": "", "middle": [], "last": "Bhatt", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF41": {"title": "Protostars and Planets IV", "authors": [{"first": "D", "middle": ["J"], "last": "Wilner", "suffix": ""}, {"first": "O", "middle": ["P"], "last": "Lay", "suffix": ""}], "year": 2000, "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "[6.45e 12 + 2.35e 25 + 1.43e 60 + 0.55e 100 ] 10 [0.4(4.75\u2212m V \u2212BC)]", "type": "figure"}, "FIGREF1": {"text": "Fig. 1. Transverse velocity dispersion S plotted against the dereddened color (B \u2212 V) for Vega-like stars and normal field stars. Filled circles represent Vega-like stars and open squares the normal field stars. The vertical error bars are errors in velocity dispersion. The ages derived from the velocity dispersion using the formalism of Binney et al. (2000) is also shown on the y-axis on the right. Note that the age axis is not linear", "type": "figure"}, "FIGREF2": {"text": "plot the velocity dispersion of Vega-like stars against their dereddened (B\u2212V) color. The values of transverse velocity dispersion S shown in Fig 1 are for a sliding window of 30 stars plotted against the mean (B \u2212 V) for each bin. A fresh point is plotted every time six stars have left the window. We have also plotted the velocity dispersion of the field stars, computed from their Hipparcos proper motions and parallaxes in the same way as that for Vega-like stars, for comparison. The values of S plotted for field stars are for bins of 500 stars with a new point plotted when 100 stars have left the window. The error bars plotted in S are the standard deviation of dispersion in each bin which is given by \u2206S = S / \u221a (2n \u2212 2) where n is the number of stars in the bin.", "type": "figure"}, "FIGREF3": {"text": "Fig. 2. Fractional dust luminosity f d plotted against transverse velocity dispersion S for stars with circumstellar dust disks. Filled circles represent Vega-like stars. Herbig Ae/Be stars are also plotted, represented by the solid star symbol. The point with a downward arrow represents stars with f d \u2264 10 \u22126 (see text). Horizontal error bars represent errors in velocity dispersion. The ages appropriate for the velocity dispersion are also shown on the x-axis on the top. Note that the age axis is not linear", "type": "figure"}, "FIGREF4": {"text": "Fig. 3. Fractional dust luminosity f d plotted against dereddened color (B \u2212 V) for Vega-like stars", "type": "figure"}, "FIGREF5": {"text": "Such a manifestation is expected if f d has a spectral type dependence where the late type stars preferentially have lower values of f d . However, for our sample stars, we find that there is no such trend of f d with spectral type. In Fig 3 we present a plot of f d against (B \u2212 V) where it can be seen that there are as many or more early type stars with lower values of f d as there are late type stars.", "type": "figure"}}}
{"paper_id": "17432472", "_pdf_hash": "8ca27b79ed84b9a42553fddcae47769764900eca", "abstract": [], "body_text": [{"section": "INTRODUCTION", "text": "Hepatitis C virus (HCV) and human immunodeiciencyvirus(HIV)infectionsareamong thetenmajorcausesofdeathduetoinfectious diseasesworldwide.", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "1 Nowadays,therearemore than40millionHIV-infectedindividuals,30% of whom are estimated to be also infected by HCV, representing a growing public health problemworldwide. 2, 3 Coinfection rates range from 4% to 90%, depending on the type of exposure. Studies carriedoutinBrazilhaveshownacoinfection prevalence of 40%, which varies according to region, geographic differences, age, and eficiencyofexposure. 1, 3, 4, 5 TheHCVandHIVhavesimilartransmission modalities, but the eficacy of the transmission of each virus differs, and several factorsinfluencethatcoinfection.Forboth,blood exposure and injection drug use are eficient transmission forms. However, the risk of vertical and perinatal transmissions is high for HIVandrelativelylowforHCV,althoughthe risk increases twice when the mother is HIV positive. 6, 7 The sexual transmission of HCV is ineficient, and the exact risk related to different typesofsexualactivityisunknown;nevertheless,ithasbeenincreasingamongHIV-infected menwhohavesexwithmen(MSM). 8 The introduction of highly active antiretroviral therapy (HAART) has signiicantly improved life expectancy of HIV-infected patients; however, the consequences of hepatitis C have become more apparent, as a result eitherofdecompensatedcirrhosisorhepatotoxicityduetoHAART. 9, 10, 11 The interaction of those viruses has been the object of great concern, being considered oneofthemostimportantpublichealthproblemsfacedbyhealthprofessionalsandauthoritiesworldwide. 12 Thepresentstudyaimedatdeterminingthe frequencyofhepatitisCmarker(anti-HCV)in a population of HIV patients notiied in the SINAMdatabaseandcaredforattheFunda\u00e7\u00e3odeMedicina TropicaldoAmazonas(FMTAM)from2000to2007.Inaddition,italsoaimedatbetterknowingtheproileandbehaviorofthispopulation,sinceepidemiologicalstudieson HIV/HCVcoinfectioninthestateofAmazonasarescarce.", "cite_spans": [{"start": 170, "end": 172, "text": "2,", "ref_id": "BIBREF1"}, {"start": 405, "end": 407, "text": "1,", "ref_id": "BIBREF0"}, {"start": 411, "end": 413, "text": "4,", "ref_id": "BIBREF3"}, {"start": 414, "end": 415, "text": "5", "ref_id": "BIBREF4"}, {"start": 808, "end": 810, "text": "6,", "ref_id": "BIBREF5"}, {"start": 811, "end": 812, "text": "7", "ref_id": "BIBREF6"}, {"start": 1007, "end": 1008, "text": "8", "ref_id": "BIBREF7"}, {"start": 1280, "end": 1282, "text": "9,", "ref_id": "BIBREF8"}, {"start": 1283, "end": 1286, "text": "10,", "ref_id": "BIBREF9"}, {"start": 1287, "end": 1289, "text": "11", "ref_id": "BIBREF10"}, {"start": 1470, "end": 1472, "text": "12", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "MATERIAL AND METHODS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Description of the study area", "text": "This study was developed at FMTAM, a state reference center for the follow-up of HIV patients in the city of Manaus,hometoapproximately1.71millionpeopleofthe 2.8millioninhabitantsofthestateofAmazonas,71.4%of whomareinurbanareasand28.6%inruralarea. 13 The FMTAM is one of the 20 testing and counseling centers of the state of Amazonas. It comprises specialized outpatient clinics, a hospitalization unit, and laboratories equippedfordiagnosinginfectiousdiseases. ", "cite_spans": [], "ref_spans": []}, {"section": "Statistical analysis", "text": "Thesampleusedforanalysiscomprised70HIV/HCVcoinfectedpatientscaredforatFMTAMfrom2000to2007.", "cite_spans": [], "ref_spans": []}, {"section": "Statistical analysis", "text": "Datawerepresentedusingtablesandgraphsofsimple, absolute, and relative frequencies. In the analysis of quantitative variables, mean and standard deviation (SD) were calculated.DataanalysisusedtheEpi-Infosoftware,version 3.5forWindows,developedanddistributedbyCDC(www. cdc.gov/epiinfo). The 95% conidence interval (CI) was adopted.", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Origin of the coinfected population", "text": "AccordingtoSINAN,from2000to2007,thetotalnumber of AIDS cases accumulated in Brazil corresponded to 209,975 cases.", "cite_spans": [], "ref_spans": []}, {"section": "Origin of the coinfected population", "text": "14 In the Northern Region of Brazil, there were8,903cases,andinthestateofAmazonas,2,653cas-es,representing1.3%ofthetotalnumberofcasesinthe country.", "cite_spans": [], "ref_spans": []}, {"section": "Origin of the coinfected population", "text": "14 IntermsofAIDSincidence,intheBraziliannorthern region,thestateofAmazonasissecondonlytothestateof Par\u00e1.Thatpopulationhasamantowomanratioof2:1,a tendencythathasbeenkeptsince1999inthestateofAma-zonas,whileinBrazilthecurrentratiois1.5:1.", "cite_spans": [], "ref_spans": []}, {"section": "Origin of the coinfected population", "text": "14 During the period studied, 2,653 cases of AIDS were notiiedatSINAN.Ofthose,only1,582patientshadun-dergone the serologic test for hepatitis C, 70 of which testedpositive,representingafrequencyof4.42%ofHIV/ HCVcoinfectedpatientscaredforatFMTAMduringthis period.", "cite_spans": [], "ref_spans": []}, {"section": "Origin of the coinfected population", "text": "TheHBV/HCVdoubleinfectionwasidentiiedintwo patients, and the HBV/HCV/HDV triple infection was identiied in only one patient. These three patients were excludedfromthestudy.", "cite_spans": [], "ref_spans": []}, {"section": "Origin of the coinfected population", "text": "In Figure 1 , the annual curve shows an increase in coinfection cases, from 1.45% in the year 2000 to 5.03% in2007.", "cite_spans": [], "ref_spans": [{"start": 3, "end": 11, "text": "Figure 1", "ref_id": "FIGREF0"}]}, {"section": "Origin of the coinfected population", "text": "EpidemiologyofcoinfectionHIV/HCVinFMTAM ", "cite_spans": [], "ref_spans": []}, {"section": "Evolution of coinfected patients", "text": "The coinfected patients detected in the period studied showedahighdeathrate(n=24,34.3%),withmostdeaths occurringbetweentheyears2000and2003,and46(65.7%) patientswerealivebytheendofthestudyinDecember2007 (Table2).", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "The epidemiology of AIDS has changed over the years in Brazil. This epidemic has shown its strength by spreading fromthesoutheasternregiontootherregionsinthecountry.InthenorthernregionofBrazil,especiallyinthestate ofAmazonas,theepidemichasshownsocial,cultural,and geographicpeculiarities. 15 Almost ive years after its discovery,AIDS appeared in thestateofAmazonas,andtheirstnotiicationofthediseaseoccurredinApril1986,whenthenotiicationofAIDS cases in Brazil became compulsory. 16 From 1986 to 1990, AIDS was restricted to the municipality of Manaus, and, from1991,itspreadtotheinnerstate,butthecityofManausstillhasthegreatestnumberofnotiiedcases.", "cite_spans": [{"start": 289, "end": 291, "text": "15", "ref_id": "BIBREF14"}, {"start": 478, "end": 480, "text": "16", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "14 BarbieriVictoria,daSilvaVictoria,Torreset al. According to data from the Ministry of Health, the epidemicinthestateofAmazonasseemstohavehadatendency toincreasewithaprogressiveincidencerateuntil1999,and stabilization from 2000 to 2003. It began to increase again from2004,whenanimprovementinepidemiologicalsurveillancewasobservedwiththerestructurationoftheStateCoordinationofSTD/AIDSPrograminthestateofAmazonas. 14, 15 Nevertheless, the AIDS Epidemiological Surveillance systemstillsuffersfromsub-notiicationofcasesanddelay innotiications. 17, 18 ThismaybeoneoftheplausiblejustiicationsforthediscrepancyobservedbetweenthecasesnotiiedinthestateofAmazonasandtheactualmagnitudeof theepidemic,ascomparedtotherestofthecountry.", "cite_spans": [{"start": 414, "end": 417, "text": "14,", "ref_id": "BIBREF13"}, {"start": 418, "end": 420, "text": "15", "ref_id": "BIBREF14"}, {"start": 542, "end": 545, "text": "17,", "ref_id": "BIBREF16"}, {"start": 546, "end": 548, "text": "18", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "Inthepopulationstudied,apredominanceofthemale gender (72.9%) is observed, and this signiicant difference betweenmenandwomenisinaccordancewiththeindings ofotherstudiescarriedoutinBrazil, 4, 12, 17, 19 despitethetendencyofAIDStoincreaseamongwomen. 14, 20 The population affected is young, at productive age, 60.1%agedbetween25and40years,butalreadyshowing anincreaseintheagebracketascomparedwiththecasesat thebeginningoftheAIDSepidemic. Theeducationallevelexpressesdifferencesbetweenindividuals in terms of access to information, and some parameterstoreachbetterqualityinpreventionandhealthassistanceareundeniablydirectlylinkedtothesocioeconomic levelofthepopulation,whosebetterindicatorsareeducationallevel,income,andoccupation. 17 InBrazil,therewasatendencytowardsAIDSpatientshavingahighereducationallevel.In1982,almostallcaseswere among individuals with university level or complete high schoollevel,whileonly24%ofthecaseswereamongilliterate individuals.Aninversioninthistrendhasbeenobservedsince 2000,with74%ofthecasesinformingtheeducationallevel wereilliterateorhadcompletedonlymiddleschool. 21 These data are consistent with those presented in our study,inwhich80%ofthepatientsincludedhaveonlycom-pleted middle school, representing a low-income population,50%ofwhomreceiveuptooneminimumwage,20% areunemployed,andhavealoweducationallevel.", "cite_spans": [{"start": 186, "end": 188, "text": "4,", "ref_id": "BIBREF3"}, {"start": 189, "end": 192, "text": "12,", "ref_id": "BIBREF11"}, {"start": 193, "end": 196, "text": "17,", "ref_id": "BIBREF16"}, {"start": 197, "end": 199, "text": "19", "ref_id": "BIBREF18"}, {"start": 246, "end": 249, "text": "14,", "ref_id": "BIBREF13"}, {"start": 250, "end": 252, "text": "20", "ref_id": "BIBREF19"}, {"start": 727, "end": 729, "text": "17", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "Inourstudy,mostofthepatientswerebornandcame from the capital of the state of Amazonas, the city of Manaus,wherethequalityoflifeandaccesstoinformation regardingdiseasepreventionisdirectlyrelatedtotheeducationalandsocioeconomiclevel,essentialfactorsinvolved inreducingtheratesofthediseasesinquestion,especially HIVinfection.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "TheHIV/HCVcoinfectionrateofpatientscaredforat FMTAM was 2.6% (n = 70), and the world estimates, accordingtosomeauthors,haverangedfrom4%to90%,dependingontransmissionroute. 22 InBrazil,theNationalProgramofControlandPrevention ofViral Hepatitis has estimated, based on studies alreadycarriedoutinthecountrythattheprevalenceofHIV/ HCVcoinfectionrangesfrom17%to36%ofthecases,varyingindifferentregions. The high variability depends not only on the risk factorstowhichthepopulationareexposedto,butalsoonthe methodsofHCVdetection. 26 In the present study, the major risk factor found was sexual transmission, characterized by sexual promiscuity(84.3%),andSTDacquisition(47.1%)betweenheterosexual patients. This is in accordance with the studies by Szwarcwald (2000) 27 and Amaral et al. (2007), 4 who have alsoshownthepredominanceofcoinfectionamongpatients havingheterosexualintercourse(68.6%)ascomparedwith menhavingsexwithmen(MSM)(22.8%).", "cite_spans": [{"start": 171, "end": 173, "text": "22", "ref_id": "BIBREF22"}, {"start": 523, "end": 525, "text": "26", "ref_id": "BIBREF26"}, {"start": 758, "end": 760, "text": "27", "ref_id": "BIBREF27"}, {"start": 787, "end": 788, "text": "4", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "The transmission modalities of HCV and HIV are knowntobesimilar,butthetransmissioneficiencyofeach virus differs. HCV transmission is more eficient through exposure to contaminated blood or blood products, especially through the use of injection drugs. 28 In certain high riskpopulations,suchasusersofinjectiondrugs,coinfectionispresentin72%to95%ofthem. 6, 29, 30 Similarlytothenortheasternregionofthecountry,in thenorthernregion,themajordrugsknowntobeusedare cannabisandcocaine. 12, 17 TheUnitedNationshasreported Brazilasthesecondcountrywiththehighestnumberof individuals with HIV among drug users in LatinAmerica, in addition to being one of the major cocaine trafic routes. 31 A recent study carried out in the state of Pernambuco,inthenortheasternregionofBrazil,confirmsour study, also showing a low prevalence of coinfected individualsinthisstate. 25 Theauthorshavereportedthat only8.4%ofthepatientsacquireHIVinfectionthrough the use of injection drugs, differently from the southeasternandsouthernregions,whoseratesare25.8%and 30.7%,respectively.Theyhavenotfoundapositiverelationbetweencoinfectionandtheuseofinjectiondrugs, inaccordancewithourstudy,inwhichthedrug-injectionuseratewasonly21.4%. 25 Despite the small number of HIV/HCV coinfected patients(4.42%)inourstudy,theannualdistributionaccording to the frequency showed an ascending curve, ranging from1.45%intheyear2000to5.03%in2007.", "cite_spans": [{"start": 252, "end": 254, "text": "28", "ref_id": "BIBREF28"}, {"start": 353, "end": 355, "text": "6,", "ref_id": "BIBREF5"}, {"start": 356, "end": 359, "text": "29,", "ref_id": "BIBREF29"}, {"start": 360, "end": 362, "text": "30", "ref_id": "BIBREF30"}, {"start": 479, "end": 482, "text": "12,", "ref_id": "BIBREF11"}, {"start": 483, "end": 485, "text": "17", "ref_id": "BIBREF16"}, {"start": 677, "end": 679, "text": "31", "ref_id": "BIBREF31"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "SuchindingsemphasizethepossibilitythatgradualincreaseresultsfromtheimprovementinnotiicationofAIDS cases,fromtheinvestigationofhepatitiscasesinthosepatientsovertheyears,andfromthelongersurvivalofAIDS patientsduetotheuseoftheHAARTregimenintroduced in1996.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "Itisworthnotingthatthedeathsinourstudy(34.3%)occurredmainlybetweentheyears2000and2003,whenthecause ofdeathcouldnotbeattributedtothepresenceofHCV.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "Ourstudycanhaveunderestimatedtheactualprevalence ofcoinfectioninthepopulationstudiedduetotheexistence offloatationintheserologicstatusandevenseroconversion (the anti-HCV turns negative), which are 2.5 times more frequentamongHIV/HCVcoinfectedpatientsascompared withHCVmono-infectedpatients. 32 Inanti-HCVpositiveimmunosuppressedpatients,HCV RNAshouldbeinvestigated,anditspresenceconirmsthe diagnosis;however,anegativeresultdoesnotexcludeHCV infection,and,wheneversuspicionishigh,anewinvestigationshouldbeperformedinsixmonths. 33, 34 However, in some active HCV infections, HCV RNA cannot be detected. This can occur in individuals whose anti-HCVantibodylevelsarehigh,andRNAlevelsarelow. 35 Thus,HCVRNAcannotbedetectedincertainindividuals intheacutephaseofhepatitisC,butsuchindingsaretransientandachronicinfectioncandevelop. 36 The low HIV/HCV coinfection rate (4.42%) found in our study as compared to that of other regions can be attributednotonlytothesmallsizeofthesample,butalsoto thefactthatHCVinfectionanddiagnosisarestillincreasing intheregion.", "cite_spans": [{"start": 291, "end": 293, "text": "32", "ref_id": "BIBREF32"}, {"start": 526, "end": 529, "text": "33,", "ref_id": "BIBREF33"}, {"start": 687, "end": 689, "text": "35", "ref_id": "BIBREF35"}, {"start": 824, "end": 826, "text": "36", "ref_id": "BIBREF36"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "Ontheotherhand,serologicaltestsareknowntohave lower sensitivity in the immunodeiciency scenario, and polymerasechainreaction(PCR)isrequiredforconirming thediagnosis.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "The present study suggests that larger studies are required for better assessing the proile of this population and the prevalence of HIV/HCV coinfection in the state ofAmazonas.Thepresentstudyalsostressestheneedfor earlyinvestigationofhepatitisCinHIVpatientsbyusing bothserologicandmolecularmethods,becausetheliteratureemphasizestheimpactofHIVinpatientswithHCV, regardingtherapidliverdiseaseprogressionandevolution todeath.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Epidemiology of viral hepatitis and HIV co-infection", "authors": [{"first": "J", "middle": ["M"], "last": "Alter", "suffix": ""}], "year": 2006, "venue": "", "link": "47104"}, "BIBREF1": {"title": "HepatitisCandHIV-1Coinfection.GUT2002", "authors": [{"first": "", "middle": [], "last": "Mohsenah", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF3": {"title": "Epidemiologiadepacientesco-infectadosHIV/HCVatendidosnaFunda\u00e7\u00e3oSanta Casa de Miseric\u00f3rdia do Par\u00e1. 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{"FIGREF0": {"text": "Figure 1: Annual distribution according to the frequency of HIV/HCV coinfected patients cared for at FMTAM from 2000 to 2007.", "type": "figure"}, "FIGREF1": {"text": "reported a large number of individuals (89.2%) with AIDSatthatagebracket.", "type": "figure"}, "FIGREF2": {"text": "city of Recife, in the state of Pernambuco, studying the HIV/HCV coinfection have reported a low prevalence (4.1%)ascomparedwithotherstudiesintheliterature,pos- siblyduetodifferencesinriskfactorsforacquiringHCV.", "type": "figure"}, "TABREF0": {"text": "ToidentifytheHIVandHCVcoinfectedpopulationcared for at FMTAM from 2000 to 2007, the following databases wereused:theSINAN(SistemadeInforma\u00e7\u00f5esdeAgravos deNotiica\u00e7\u00e3o)database;thedatabaseoftheCoordinationof Sexually Transmitted Diseases/AIDS of the state of Amazo- nas,andthedatabaseoftheVirologyUnitofFMTAM. Wechosetostartthestudyintheyear2000duetothe lack of available data on viral hepatitis prior to that year.", "type": "table"}, "TABREF1": {"text": "Sexual orientation and risk factors Accordingtothesexualorientationofthepatientsstudied, 48(68.6%)patientswereheterosexual,16(22.8%)wereho- mosexual,andsix(8.6%)werebisexual.Fifty-nine(84.3%) patientshavereportedsexualpromiscuity,thatis,morethan two partners in six months, and that was the major risk factoranalyzed.Otherriskfactorswereasfollows:acquisi-", "type": "table"}, "TABREF2": {"text": "Distribution of HIV/HCV coinfected patients cared for at FMTAM from 2000 to 2007, according to sexual orientation, risk factors for coinfection, and outcome", "type": "table"}}}
{"paper_id": "17432478", "_pdf_hash": "2a067a37f0354b51cd6281e0f7f4ea6f27f6c6c2", "abstract": [], "body_text": [], "bib_entries": {"BIBREF0": {"title": "Base vectors containing one horizontal and one vertical bar", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF1": {"title": "Other base vectors, containing several bars and in some cases even noise", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF2": {"title": "we made decomposition of images into binary vectors by Boolean factor analysis method proposed in", "authors": [{"first": "", "middle": [], "last": "Finally", "suffix": ""}], "year": "", "venue": "", "link": null}, "BIBREF3": {"title": "6th International Conference on Computer Information Systems and Industrial Management Applications", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF4": {"title": "Computational Methods for Intelligent Information Access", "authors": [{"first": "M", "middle": [], "last": "Berry", "suffix": ""}, {"first": "S", "middle": [], "last": "Dumais", "suffix": ""}, {"first": "T", "middle": [], "last": "Letsche", "suffix": ""}], "year": 1995, "venue": "Proceedings of the 1995 ACM/IEEE Supercomputing Conference", "link": "52801363"}, "BIBREF5": {"title": "Forming sparse representations by local anti-Hebbian learning", "authors": [{"first": "P", "middle": [], "last": "F\u00f6ildi\u00e1k", "suffix": ""}], "year": 1990, "venue": "Biological Cybernetics", "link": "9855029"}, "BIBREF6": {"title": "New Neural Network Based Approach Helps to Discover Hidden Russian Parliament Votting Paterns", "authors": [{"first": "A", "middle": [], "last": "Frolov", "suffix": ""}, {"first": "D", "middle": [], "last": "H\u00fasek", "suffix": ""}, {"first": "P", "middle": [], "last": "Polyakov", "suffix": ""}, {"first": "H", "middle": [], "last": "\u0158ezankov\u00e1", "suffix": ""}], "year": 2006, "venue": "In: International Joint Conference on Neural Networks. -Madison", "link": "17955778"}, "BIBREF7": {"title": "Image Information Retrieval: An Overview of Current Research", "authors": [{"first": "A", "middle": ["A"], "last": "Goodrum", "suffix": ""}], "year": 2000, "venue": "Informing Science", "link": "8197990"}, "BIBREF8": {"title": "Computation and uses of the semidiscrete matrix decomposition", "authors": [{"first": "T", "middle": ["G"], "last": "Kolda", "suffix": ""}, {"first": "D", "middle": ["P"], "last": "O&apos;leary", "suffix": ""}], "year": 2000, "venue": "ACM Transactions on Information Processing", "link": "117180828"}, "BIBREF9": {"title": "Testing Dimension Reduction Methods for Image Retrieval", "authors": [{"first": "P", "middle": [], "last": "Moravec", "suffix": ""}, {"first": "V", "middle": [], "last": "Sn\u00e1\u0161el", "suffix": ""}], "year": 2006, "venue": "the 6th International Conference on Intelligent Systems Design and Applications (ISDA'06)", "link": "118779227"}, "BIBREF10": {"title": "Document clustering using nonnegative matrix factorization", "authors": [{"first": "F", "middle": [], "last": "Shahnaz", "suffix": ""}, {"first": "M", "middle": [], "last": "Berry", "suffix": ""}, {"first": "P", "middle": [], "last": "Pauca", "suffix": ""}, {"first": "R", "middle": [], "last": "Plemmons", "suffix": ""}], "year": 2006, "venue": "Journal on Information Processing and Management", "link": "11360438"}, "BIBREF11": {"title": "An Application of LSI and M-tree in Image Retrieval", "authors": [{"first": "T", "middle": [], "last": "Skopal", "suffix": ""}, {"first": "V", "middle": [], "last": "Sn\u00e1\u0161el", "suffix": ""}], "year": 2006, "venue": "GESTS International Transactions on Computer Science and Engineering", "link": "5592441"}, "BIBREF12": {"title": "Learning Image Components for Object Recognition", "authors": [{"first": "M", "middle": ["W"], "last": "Spratling", "suffix": ""}], "year": 2006, "venue": "Journal of Machine Learning Research", "link": "5652259"}, "BIBREF13": {"title": "Eigenfaces for recognition", "authors": [{"first": "M", "middle": [], "last": "Turk", "suffix": ""}, {"first": "A", "middle": [], "last": "Pentland", "suffix": ""}], "year": 1991, "venue": "6th International Conference on Computer Information Systems and Industrial Management Applications (CISIM'07)", "link": "26127529"}}, "ref_entries": {}}
{"paper_id": "17432688", "_pdf_hash": "8abfba675efb0e2c5496f6ff4af0363d06a06bc9", "abstract": [{"section": "Abstract", "text": "We show that the number of arithmetic operations required to calculate a dominant -eigenvector of a real symmetric or complex Hermitian n \u00d7 n matrix, when averaged over any density invariant under linear transformations that preserve the Frobenius norm, is bounded above by a polynomial in the size of the matrix. In fact, a specific upper bound is given in terms of n and . We also describe an estimate of the distance between an arbitrary complex n \u00d7 m matrix and its rank one approximation.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "We present upper bounds on the statistical complexity of dominant -eigenvector calculation. We assume exact arithmetic throughout. See Blum et al. (1989) , Smale (1985) , and Traub et al. (1988) for a general discussion of this methodology. We restrict our attention to real symmetric and complex Hermitian matrices until Section 4. However, Definitions 2.1-2.4 apply to any matrix. Analogous results for stochastic matrices can be found in Wright (1989) . Our definition of a dominant -eigenvector is a root error definition as opposed to a residual error definition:", "cite_spans": [{"start": 135, "end": 153, "text": "Blum et al. (1989)", "ref_id": "BIBREF0"}, {"start": 156, "end": 168, "text": "Smale (1985)", "ref_id": "BIBREF5"}, {"start": 175, "end": 194, "text": "Traub et al. (1988)", "ref_id": "BIBREF6"}, {"start": 441, "end": 454, "text": "Wright (1989)", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Introduction", "text": "Definition. A vector v is a dominant -eigenvector of a matrix M if there exists a dominant eigenvector w of M with the property that ||v \u2212 w|| 2 \u2264 ||v|| 2 . Whenever dominant -eigenvectors are discussed, it is assumed that 0 < \u2264 1.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "This definition is better adapted to the exact arithmetic model than to models that include error. One of the referees described the limitations of the real number model and the chosen definition of the -eigenvector as follows.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "\"[The author] assumes exact arithmetic, which makes his model easier to compute in than the usual floating point one. But his stopping criterion is quite strong, that the dominant eigenvector be computed with accuracy (in the norm sense) no matter how close \u03bb 1 and \u03bb 2 are. This is more than is asked in the usual situation, since if we compute with arithmetic with relative accuracy a , then perturbation theory implies that we expect uncertainty in the dominant eigenvector of about a /(1 \u2212 |\u03bb 2 /\u03bb 1 |). To meet the author's stopping criterion, we would need at least that a < a /(1 \u2212 |\u03bb 2 /\u03bb 1 |). Thus the work would grow at least like log a log log a log log log a , (via Sch\u00f6nhage-Strassen multiplication) where log a grows like | log | + log(\u03bb 2 /\u03bb 1 \u2212 1). This is much more pessimistic than the author's bound, which grows like log | log |, although the \u03bb 2 /\u03bb 1 dependence is similar.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "\"This may be a situation where the real number model studied by Smale and others is definitely 'too strong' to accurately model actual approximate computation, and this may be the most interesting conclusion.\"", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "The author will only add that the propagation of error inherent to the algorithm can be controlled by occasionally multiplying the iterates by the original matrix and then symmetrizing. A detailed error analysis is not include in this paper.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "We assume that the density chosen for the space of matrices is invariant under linear transformations that preserver the Frobenius norm. Examples of such densities are given in Section 1. However, as is implicit in Section 4 of Kostlan (1985) , Wishart matrices would give similar results.", "cite_spans": [{"start": 228, "end": 242, "text": "Kostlan (1985)", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Introduction", "text": "A well-known algorithm for finding dominant eigenvectors of matrices consists of repeatedly squaring a matrix, renormalizing the matrix after each squaring. See Wilkinson (1965) . In order to find an upper bound on the complexity of dominant eigenvector calculation, we need a criterion for when to terminate the algorithm. This is discussed in Section 2, and is based upon a Gerschgorin-like estimate developed in Section 4 (in particular, Corollary 4.2). The available statistical information about the eigenvalues of real symmetric and complex Hermitian n \u00d7 n matrices allows us to show that the average number of iterations required by the algorithm is O(ln n + ln | ln |). A specific upper bound is given in Theorem 3.1.", "cite_spans": [{"start": 161, "end": 177, "text": "Wilkinson (1965)", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Introduction", "text": "The average complexity of an algorithm can be misleading. For example, Theorem 9.2 of Kostlan (1985) shows that the average complexity of the power method is infinite. We thus include an estimate of the cost distribution function of the algorithm; this is, we give an upper bound on the probability that the algorithm will take more than any prescribed number of iterations to produce a dominant -eigenvector (Theorem 3.2).", "cite_spans": [{"start": 86, "end": 100, "text": "Kostlan (1985)", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Introduction", "text": "Throughout the paper, the cumulative distribution function of a random variable X, that is, Prob[X \u2264 z], is denoted by F X (z). The eigenvalues of a matrix are denoted by \u03bb i , in decreasing order of magnitude. The i-th element of the standard basis of R n or C n is denoted by e i . The Frobenius norm of a matrix M is denoted by ||M|| F .", "cite_spans": [], "ref_spans": []}, {"section": "Random Matrices", "text": "We consider densities invariant under linear transformations that preserve the Frobenius norm. For simplicity we assume that Prob[M = 0] = 0. Since we are only concerned with the ratio of the eigenvalues, all such densities give the same results. Thus, for example, our results apply to matrices uniformly distributed over the set {||M|| F \u2264 c}, for any constant c > 0. Alternately, we would consider the \u00b5 = 0 case of the two-parameter family of densities", "cite_spans": [], "ref_spans": []}, {"section": "Random Matrices", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "Random Matrices", "text": "complex Hermitian] n \u00d7 n matrices. These densities have the property of being invariant under conjugation by orthogonal [resp. unitary] matrices. For a detailed study of the properties of these matrices and their eigenvalues, see Mehta (1967) . It is easily checked that these densities are invariant under linear transformations that preserve the Frobenius norm if and only if \u00b5 = 0. Theorem 1.1 For matrices distributed as described above the cumulative distribution function of the random variable |\u03bb 1 /\u03bb 2 | satisfies", "cite_spans": [{"start": 230, "end": 242, "text": "Mehta (1967)", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Random Matrices", "text": ", and where \u03b2 = 1 for the real symmetric case and \u03b2 = 2 for the complex Hermitian case.", "cite_spans": [], "ref_spans": []}, {"section": "Random Matrices", "text": ". Proof. This is Theorem 4.3 of Kostlan (1985) . This is also equivalent to Theorem 4.4 of Kostlan (1988) , which is stated somewhat differently, and which contains a minor error -there is a division by \u221a 2 that should be a multiplication by \u221a 2. 2 Note that similar bounds may be obtained by applying the theory of volumes of tubes of real algebraic varieties.", "cite_spans": [{"start": 32, "end": 46, "text": "Kostlan (1985)", "ref_id": "BIBREF1"}, {"start": 91, "end": 105, "text": "Kostlan (1988)", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "The Algorithm", "text": "Definition 2.1 For any matrix M, define I and J by (\u2200i, j)|M IJ | \u2265 |M ij |. I and J are uniquely defined with probability one, and if they are not unique, break the tie by any method. Definition 2.4 For any matrix M, define M * to be the rank one approximation of M, that is, the closest rank one matrix to M in the Frobenius norm. M * is uniquely defined with probability one, and if it is not unique, break the tie by any method.", "cite_spans": [], "ref_spans": []}, {"section": "Note that if M is a rank one matrix", "text": "For the remainder of this section, assume M is a complex Hermitian n \u00d7 n matrix. We consider the following algorithm:", "cite_spans": [], "ref_spans": []}, {"section": "Note that if M is a rank one matrix", "text": "The algorithm will stop if |\u03bb 1 | > |\u03bb 2 |. Thus the algorithm will stop with probability one. If the algorithm has stopped, Me K is a dominant -eignevector -see Lemmas 2.1 and 2.2. In practice, norms other than the Frobenius norm are easier to calculate, but for the Frobenius norm the geometric picture is clearer.", "cite_spans": [], "ref_spans": []}, {"section": "Note that if M is a rank one matrix", "text": "Step 2 could be omitted for our purposes, but in practice it must be included to prevent under/overflow. We place the stopping criterion at the end of the iteration to simplify the iteration count. , the algorithm will stop on the current iteration.", "cite_spans": [], "ref_spans": []}, {"section": "Proof. The result follows immediately from", "text": "Proof. For \u03b4 \u2265 1 the result is trivial. For 0 < \u03b4 < 1,", "cite_spans": [], "ref_spans": []}, {"section": "Proof. The result follows immediately from", "text": "Since \u03b4 < 1 this implies that", "cite_spans": [], "ref_spans": []}, {"section": "Proof. The result follows immediately from", "text": "Theorem 2.1 For any complex Hermitian n \u00d7 n matrix the number of iterations the algorithm requires is less than or equal to", "cite_spans": [], "ref_spans": []}, {"section": "Proof. The result follows immediately from", "text": "In particular, the algorithm exhibits quadratic convergence.", "cite_spans": [], "ref_spans": []}, {"section": "Proof. The result follows immediately from", "text": "Proof. For \u03b4 = n \u22123/2 , Lemma 2.3 implies that if", "cite_spans": [], "ref_spans": []}, {"section": "Proof. The result follows immediately from", "text": "F , and therefore, by Lemman 2.2, the algorithm will stop on the current interation. So for any matrix M, and for any s \u2265 0, |\u03bb 1 /\u03bb 2 | 2 s > n 2 / implies that the algorithm will stop in at most s + 1 iterations -we must add one to s because s may not be an integer. Solve for s. Proof. We need to integrate the expression in Theorem 2.1 against the distribution function of |\u03bb 1 /\u03bb 2 |. Therefore, it suffices to bound", "cite_spans": [], "ref_spans": []}, {"section": "Proof. The result follows immediately from", "text": "from above. By Theorem 1.1, (3.1) is bounded above by", "cite_spans": [], "ref_spans": []}, {"section": "Proof. The result follows immediately from", "text": "Corollary. For real symmetric and complex Hermitian matrices, the dominant eigenvector can be estimated to any accuracy in a number of arithmetic operations that, on the average, grows slower than some polynomial of the size of the matrix.", "cite_spans": [], "ref_spans": []}, {"section": "Proof. The result follows immediately from", "text": "Proof. Each iteration of the algorithm can be performed in a number of operations that grows as a polynomial in the size of the matrix. 2 For a discussion of the complexity of matrix squaring, see Pan (1984) . Theorem 3.2 Let N be the number of iterations required by the algorithm to find a dominant -eigenvector. Then for z \u2265 1,", "cite_spans": [{"start": 197, "end": 207, "text": "Pan (1984)", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Proof. The result follows immediately from", "text": "where \u03b2 = 1 for the real symmetric case and \u03b2 = 2 for the complex Hermitian case.", "cite_spans": [], "ref_spans": []}, {"section": "Proof. The result follows immediately from", "text": "Proof. By Theorem 2.1,", "cite_spans": [], "ref_spans": []}, {"section": "Proof. The result follows immediately from", "text": "Solving for |\u03bb 1 /\u03bb 2 |, the right-hand side of (3.2) becomes Prob", "cite_spans": [], "ref_spans": []}, {"section": "Proof. The result follows immediately from", "text": "But by Theorem 1.1, this is less than or equal to 3", "cite_spans": [], "ref_spans": []}, {"section": "Proof. The result follows immediately from", "text": "Note that we could have derived Theorem 3.1 by estimating the integral", "cite_spans": [], "ref_spans": []}, {"section": "Proof. The result follows immediately from", "text": "xdF N (x), using Theorem 3.2.", "cite_spans": [], "ref_spans": []}, {"section": "An Inequality for Complex n \u00d7 m Matrices", "text": "In this section, we prove an inequality that allows us to estimate the distance between a matrix and its rank one approximation. This result relates information about the singular values of a matrix to information about its entries, and is therefore in the spirit of the Gerschgorin Circle Theorem for eigenvalues. Theorem 4.1 For any n \u00d7 m matrix M, and for any v \u2208 C m and any w \u2208 C n ,", "cite_spans": [], "ref_spans": []}, {"section": "An Inequality for Complex n \u00d7 m Matrices", "text": "Note that the left-hand side of this inequality depends only on the entries of the matrix M, while the right-hand side depends only on the singular values of M.", "cite_spans": [], "ref_spans": []}, {"section": "An Inequality for Complex n \u00d7 m Matrices", "text": "Proof. All sums appearing in this proof are single sums; the index of summation is always the first variable appearing under the summation sign. Both sides of the inequality are invariant under two-sided unitary coordinate transformations, so without loss of generality assume that M is diagonal, positive semidefinite, with singular values \u00b5 1 \u2265 \u00b7 \u00b7 \u00b7 \u2265 \u00b5 k > 0, where k is the rank of M. The desired inequality reduces to The left-hand side of (4.1) can be rewritten as But by the Cauchy-Schwartz inequality,", "cite_spans": [], "ref_spans": []}, {"section": "An Inequality for Complex n \u00d7 m Matrices", "text": "so we see that (4.2) is less than or equal to", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "On the theory of computation and complexity over the real numbers, NP-competeness, recursive functions and universal machines", "authors": [{"first": "L", "middle": [], "last": "Blum", "suffix": ""}, {"first": "M", "middle": [], "last": "Shub", "suffix": ""}, {"first": "S", "middle": [], "last": "Smale", "suffix": ""}], "year": 1989, "venue": "Bull. Amer. Math. 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{"paper_id": "17433141", "_pdf_hash": "57bad5cee5fcb417018abbe28c4414a46ba6af03", "abstract": [], "body_text": [], "bib_entries": {}, "ref_entries": {}}
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{"paper_id": "17433599", "_pdf_hash": "80585e92fc09c84be29b0f8672af696ff3e4326b", "abstract": [{"section": "Abstract", "text": "Introns are common among all eukaryotes, while only a limited number of introns are found in prokaryotes. Globin and globin-like proteins are widely distributed in nature, being found even in prokaryotes and a wide range of patterns of intron-exon have been reported in several eukaryotic globin genes. Globin genes in invertebrates show considerable variation in the positions of introns; globins can be found without introns, with only one intron or with three introns in different positions. In this work we analyzed the introns in the myoglobin gene from Biomphalaria glabrata, B. straminea and B. tenagophila. In the Biomphalaria genus, the myoglobin gene has three introns; these were amplified by PCR and analyzed by PCR-RFLP. Results showed that the size (number or nucleotides) and the nucleotide sequence of the coding gene of the myoglobin are variable in the three species. We observed the presence of size polymorphisms in intron 2 and 3; this characterizes a homozygous/heterozygous profile and it indicates the existence", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Genes 2010, 1 358 of two alleles which are different in size in each species of Biomphalaria. This polymorphism could be explored for specific identification of Biomphalaria individuals.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "In 1977, several research groups published their findings about DNA coding sequences (exons) broken by non-coding sequences (introns) in eukaryotes [1] [2] [3] . Introns are widespread among eukaryotes [4, 5] , while only a limited number of introns are found in prokaryotes.", "cite_spans": [{"start": 148, "end": 151, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 152, "end": 155, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 156, "end": 159, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 202, "end": 205, "text": "[4,", "ref_id": "BIBREF3"}, {"start": 206, "end": 208, "text": "5]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Introduction", "text": "Cavalier-Smith [6] suggested that introns were selfish DNA with no distinct cellular function, however there is much to discuss about the presence of these non-coding sequences [7] . After the ENCODE project consortium, it is known that intronic regions are transcribed in humans, indicating that protein coding loci are more transcriptionally complex than previously thought [8, 9] .", "cite_spans": [{"start": 15, "end": 18, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 177, "end": 180, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 376, "end": 379, "text": "[8,", "ref_id": "BIBREF7"}, {"start": 380, "end": 382, "text": "9]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Introduction", "text": "Independently in 1978, Doolittle [10] and Darnell [11] proposed the \"Introns-Early theory\" which states that introns are very early elements in the genome, which have been present since the eukaryote/prokaryote divergence. In the \"Introns-Late theory\" introns appeared recently in the eukaryotic genome [6, 12, 13] . A growing collection of introns has been found in different positions in some animal species while closely related species do not have the introns [14] [15] [16] [17] [18] .", "cite_spans": [{"start": 33, "end": 37, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 50, "end": 54, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 303, "end": 306, "text": "[6,", "ref_id": "BIBREF5"}, {"start": 307, "end": 310, "text": "12,", "ref_id": "BIBREF11"}, {"start": 311, "end": 314, "text": "13]", "ref_id": "BIBREF12"}, {"start": 464, "end": 468, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 469, "end": 473, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 474, "end": 478, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 479, "end": 483, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 484, "end": 488, "text": "[18]", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "Introduction", "text": "In the evolutionary history of introns, the selective stretch which modulates their evolution and the relative contribution of its eukaryotic gene loss or insertion is not understood [19] . In interpreting the evidence that a few introns may have a common position between animals, plants and fungi, one must bear in mind their evolutionary history. Comparisons of rRNA sequences support the idea that the three kingdoms of multicellular eukaryotes form monophyletic groups, which seem to have originated almost simultaneously, possibly from a common ancestor. This would also explain the conservation of the position of some introns among homologous genes within these kingdoms, without having to invoke the presence of introns in these genes from the very beginning [20] .", "cite_spans": [{"start": 183, "end": 187, "text": "[19]", "ref_id": "BIBREF18"}, {"start": 768, "end": 772, "text": "[20]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "Introduction", "text": "Many authors have attempted to interpret the distribution of intron in terms of a mixture of movement and removal of introns, but the difficulty of phase-shifting movement causes serious doubts about these interpretations. In contrast, some gene families for which phylogenies can be traced show patterns that clearly indicate intron insertions [21] .", "cite_spans": [{"start": 345, "end": 349, "text": "[21]", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Introduction", "text": "The protein coding sequences are interrupted by introns at specific points, which could be used to investigate, for instance, the evolution of protein families. The gene encoding the ancestral globin chain is assumed to be interrupted by three introns inserted in the B, E and G helices. However, the conservation of this intron pattern and the exact insertion positions of the introns during evolution is a matter of ongoing discussion [22] .", "cite_spans": [{"start": 437, "end": 441, "text": "[22]", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Introduction", "text": "Intron location and sequence may also shed light on the origin of some protein genes, for instance the polymeric globin genes occurring in mollusks and arthropods [23] . In this way introns could be used to study evolution as well as the origin, phylogeny and systematic of the Mollusca phylum. The mollusk Biomphalaria glabrata has three introns in the myoglobin gene at positions A3.2, B12.2 and G7.0; the two last ones are conserved.", "cite_spans": [{"start": 163, "end": 167, "text": "[23]", "ref_id": "BIBREF23"}], "ref_spans": []}, {"section": "Introduction", "text": "Identifying individuals from the Biomphalaria genus is a difficult task because they are very similar in morphology. Classic methodology of identification is based on comparative morphology of shells and anatomy of the reproductive organs, however there is much intra-specific variation [24] . Classic methods of identifying Biomphalaria species are important; however association with molecular techniques can result in more solid diagnostic [25] . In 1996, Vidigal and co-workers [26] showed that it is possible to distinguish B. glabrata and B. tenagophila by ribosomal gene amplification. In 1991, Knight and co-workers [27] showed intra-specific variability in B. glabrata susceptibility and resistance to Schistosoma mansoni by RFLP. These results show the efficiency of molecular techniques to identify the mollusks.", "cite_spans": [{"start": 287, "end": 291, "text": "[24]", "ref_id": "BIBREF24"}, {"start": 443, "end": 447, "text": "[25]", "ref_id": "BIBREF25"}, {"start": 482, "end": 486, "text": "[26]", "ref_id": "BIBREF26"}, {"start": 624, "end": 628, "text": "[27]", "ref_id": "BIBREF27"}], "ref_spans": []}, {"section": "Introduction", "text": "In this work, we analyze the introns of the myoglobin gene of mollusks from the Biomphalaria genus in order to evaluate their potential use for precise identification in systematic studies.", "cite_spans": [], "ref_spans": []}, {"section": "Results and Discussion", "text": "The size (in base pairs) of the amplicons of intron 1 was analyzed by polyacrylamide gel electrophoresis. All individuals of the three Biomphalaria species showed a DNA fragment of about 1,300 bp ( Figure 1) .", "cite_spans": [], "ref_spans": [{"start": 198, "end": 207, "text": "Figure 1)", "ref_id": "FIGREF0"}]}, {"section": "Results and Discussion", "text": "Amplification of intron 2 of B. straminea generated an amplicon larger than 1,300 bp, of about 1,500 bp. In B. glabrata and B. tenagophila, some individuals were observed to have a large amplicon of about 1,400 bp, and some individuals showed a smaller fragment (of about 1,300 bp for B. glabrata and about 1,200 bp for B. tenagophila), whereas some individuals showed the two fragments ( Figure 2 ).", "cite_spans": [], "ref_spans": [{"start": 389, "end": 397, "text": "Figure 2", "ref_id": "FIGREF1"}]}, {"section": "Results and Discussion", "text": "The amplification of the intron 3 presented a similar homozygous/heterozygous pattern in B. straminea. Some individuals showed an amplicon of about 1,400 bp, other individuals showed an amplicon of about 1,200 bp, and some ones showed the two amplicons. In B. glabrata, was observed one amplicon only of about 750-850 bp, and B. tenagophila showed an amplicon of about 1,300 bp ( Figure 3 ). Clear and satisfactory amplification using genomic DNA as a template is not a simple task, since nonspecific amplifications and artifacts could contaminate the true results. After obtaining the best protocol for amplification, this was repeated at least five times. The monitoring of all amplifications showed the results on the size of introns from Biomphalaria, which are described in the text; the gels presented as figures have some artifacts that do not refer to amplification of introns.", "cite_spans": [], "ref_spans": [{"start": 380, "end": 388, "text": "Figure 3", "ref_id": "FIGREF2"}]}, {"section": "Results and Discussion", "text": "The models for putative alleles from the three Biomphalaria species are shown in Figure 4 . They were built based on the nucleotide sequence of the myoglobin gene from B. glabrata deposited in data bank and sequence of the cDNA myoglobins of B. tenagophila and B. straminea that were deposited in Genbank (accession n\u00ba EF646378 and EF646379), which are very similar to B. glabrata myoglobin (>96% identity).", "cite_spans": [], "ref_spans": [{"start": 81, "end": 89, "text": "Figure 4", "ref_id": "FIGREF3"}]}, {"section": "Results and Discussion", "text": "PCR-RFLP was used to obtain rapid information about the nucleotide sequence of the myoglobin introns from Biomphalaria; for individuals who had introns of different sizes, the largest fragment was digested. In no individual from the Biomphalaria species was fragmentation of intron 1 observed by restriction enzymes. The intron 2 from B. straminea and B. tenagophila was digested by Hind III only, however it was digested in different places, generating fragments of different sizes.", "cite_spans": [], "ref_spans": []}, {"section": "Results and Discussion", "text": "Intron 3 from B. straminea was cutted by Xba I, Xho I, Bgl II and Hind III, and the same intron from B. tenagophila was cutted by Xba I and Hind III. Intron 3 from B. glabrata was not cut by any enzyme ( Figure 5 ).", "cite_spans": [], "ref_spans": [{"start": 204, "end": 212, "text": "Figure 5", "ref_id": "FIGREF4"}]}, {"section": "Results and Discussion", "text": "In 2004, Sokolova and Boulding [28] described size polymorphism in one intron of the enzyme N-aminopeptidase among individual mollusks of the Littorina genus. A similar result has been obtained in this work in the myoglobin gene of the three species of Biomphalaria mollusks. We observed that B. tenagophila, B. glabrata and B. straminea have size polymorphism in the myoglobin gene. This polymorphism, which characterizes a profile of homozygosity/heterozygosity for the introns of the myoglobin gene, had not been described for B. glabrata, whose gene has been characterized.", "cite_spans": [{"start": 31, "end": 35, "text": "[28]", "ref_id": "BIBREF28"}], "ref_spans": []}, {"section": "Results and Discussion", "text": "The first intron of B. glabrata has 1,116 bp, the second intron has 1,008 bp and third has 582 bp [18] . The difference in size observed between the cited introns of B. glabrata and those obtained in this work is due to segments of exons and/or segments of the UTR amplified together with the intron in the PCR. The same referred fragments are present in the introns of the other Biomphalaria species analyzed. The first elucidation of globin gene structure was that of the human hemoglobin \u03b1 and \u03b2 chains. These genes have two introns conserved exactly at positions B12.2 (\u03b1-helix B in the protein) and G6.3 [29] . According to Dewilde et al. [22] , the structure of the globin gene of B. glabrata contains three intron/four exon. The B. glabrata myoglobin gene contains an unprecedented \u03b1-helix intron at position A3.2 that encodes a monodomain globin. It must, therefore, be considered as a newly inserted intron.", "cite_spans": [{"start": 98, "end": 102, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 644, "end": 648, "text": "[22]", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Results and Discussion", "text": "The analyses of the amplicons of the introns from B. tenagophila and B. straminea suggest the same pattern for myoglobin gene.", "cite_spans": [], "ref_spans": []}, {"section": "Results and Discussion", "text": "The typical gene structure of three exons/two introns are found in all vertebrate globins and in most annelids [30] . The results observed in amplicons from intron 2 and 3 suggest that the studies of Biomphalaria species present a homozygous/heterozygous pattern in the second and third intron of the myoglobin gene which can be observed by its size. The polymorphisms are confined to introns 2 and 3. Perhaps, it is possible that the conservation of size in intron 1 is because this intron position is evolutionarily most recent.", "cite_spans": [{"start": 111, "end": 115, "text": "[30]", "ref_id": "BIBREF30"}], "ref_spans": []}, {"section": "Results and Discussion", "text": "The globin genes of vertebrates and plants contain, respectively, two and three introns and their insertion positions are conserved. The three intron/four exon pattern of plants is proposed to be ancestral and all other globin gene structures would be derived mainly by intron loss [31] . Several non vertebrate and protozoan globin genes have been characterized and it has become clear that the intron/exon pattern is less conserved than originally expected [32] .", "cite_spans": [{"start": 282, "end": 286, "text": "[31]", "ref_id": "BIBREF31"}, {"start": 459, "end": 463, "text": "[32]", "ref_id": "BIBREF32"}], "ref_spans": []}, {"section": "Results and Discussion", "text": "B. straminea presents a size polymorphism in the third intron of the myoglobin gene. B. tenagophila and B. glabrata contain size polymorphism in the second intron, and any of the three species showed size polymorphism in the first intron. This kind of polymorphism and the homozygous/heterozygous pattern was not shown for the myoglobin gene of B. glabrata which had been described.", "cite_spans": [], "ref_spans": []}, {"section": "Results and Discussion", "text": "Analysis of unique individuals indicates that there are two alleles of different sizes which code for myoglobins in the Biomphalaria genus. The difference is about 200 bp and each Biomphalaria specie presents polymorphism in one intron only. The smaller alleles were observed in B. glabrata and the bigger ones were observed in B. straminea. By analyzing the size it is believed that the nucleotide sequence of the myoglobin gene of the B. glabrata deposited in data bank could be the minor allele of this specie.", "cite_spans": [], "ref_spans": []}, {"section": "Results and Discussion", "text": "No differences were observed in size of the primary sequences (amino acids) of the myoglobins from the three Biomphalaria species such that the contribution of the exon to the size of the amplicons is the same for all three Biomphalaria species. The difference among the myoglobin introns from B. glabrata, B. straminea e B. tenagophila suggests a potential for using these as molecular markers to carry out the specific identification of these mollusks.", "cite_spans": [], "ref_spans": []}, {"section": "Results and Discussion", "text": "Analysis of the distribution of the possible alleles of the gene encoding myoglobin among individuals of three species of Biomphalaria do not indicated a relation to the geographical origin of the mollusks, but this relationship cannot be ruled out, since it would be necessary to analyze a larger number of individuals.", "cite_spans": [], "ref_spans": []}, {"section": "Results and Discussion", "text": "The sequencing of heterozygous genotypes with different alleles in size is a difficult task, and RFLP analysis is a way to get quick information about the nucleotide sequence [28] . Analysis by PCR-RFLP of myoglobin introns showed that introns 2 and 3 are different in the three Biomphalaria species. Intron 1 was not cut by any of the five enzymes chosen, but this does not mean that the nucleotide sequence is the same, since introns are elements that accumulate a large number of mutations during evolution [7] .", "cite_spans": [{"start": 175, "end": 179, "text": "[28]", "ref_id": "BIBREF28"}, {"start": 510, "end": 513, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Results and Discussion", "text": "The Biomphalaria genus covers organisms morphologically very similar, making their identification difficult. The classical identification is based on comparative morphology of the shells and anatomy of reproductive organs, but the enormous intraspecific variation of morphological and anatomical features commits to a specific classification. Identification may also be hampered by the small size of the specimens, whose distinctive morphological characters are not very evident [24] .", "cite_spans": [{"start": 479, "end": 483, "text": "[24]", "ref_id": "BIBREF24"}], "ref_spans": []}, {"section": "Results and Discussion", "text": "Monis [25] highlights the importance of traditional methods of identification, and suggests its association with molecular techniques for obtaining a more robust and reliable result. In 1996, Vidigal and co-workers [26] demonstrated that it is possible to specifically differentiate B. glabrata and B. tenagophila by amplification of portions of their ribosomal gene. These same authors in 2001 were able to separate the species B. glabrata, B. tenagophila and B. straminea by PCR-RFLP using the gene for ITS (internal transcribed spacer) that refers to a piece of non-functional RNA situated between structural ribosomal RNA.", "cite_spans": [{"start": 6, "end": 10, "text": "[25]", "ref_id": "BIBREF25"}, {"start": 215, "end": 219, "text": "[26]", "ref_id": "BIBREF26"}], "ref_spans": []}, {"section": "Results and Discussion", "text": "In the same context, Knight et al. [27] , using the gene for ribosomal RNA to detect size polymorphisms in restriction fragments (RFLP), were able to show intraspecific variation in B. glabrata susceptible and resistant to infection by Schistosoma mansoni. These results show the efficiency of molecular techniques in the identification of these mollusks.", "cite_spans": [{"start": 35, "end": 39, "text": "[27]", "ref_id": "BIBREF27"}], "ref_spans": []}, {"section": "Experimental Section", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Snails", "text": "B. glabrata, B. tenagophila and B. straminea from several Brazilian provinces (Table 1) belonging to Teof\u00e2nia H.D.A. Vidigal's (Laborat\u00f3rio de Malacologia e Sistem\u00e1tica Molecular/ICB/UFMG) collection were used. These individuals were collected in their habitat in the environment, thus there was no genetic cross between them. Every individual was analyzed in regard to infection by Schistosoma mansoni. After a negative result for infection, fragments from foot tissue were frozen at -80 \u00b0C. ", "cite_spans": [], "ref_spans": [{"start": 78, "end": 87, "text": "(Table 1)", "ref_id": "TABREF0"}]}, {"section": "Genomic DNA Extraction of Snails", "text": "Genomic DNA was purified from foot tissue of each individual of Biomphalaria using a DNA purification kit (Wizard Genomic DNA Purification, Promega) according to recommendations from the manufacturer. The DNA quantification and purity were analyzed by spectrophotometry at 260 and 280 nm using a UV-160A UV-Visible recording spectrophotometer (Shimadzu). The DNA quality was determined by 1% agarose gel electrophoresis. The DNA was not pooled at any step.", "cite_spans": [], "ref_spans": []}, {"section": "Amplification of the Introns from the Biomphalaria Myoglobin Gene", "text": "Amplification of the introns were performed by PCR using three sets of primers which were drafted based on nucleotide sequence from the B. glabrata myoglobin gene available in GenBank Accession Code U89283. The primers were BIO 1F and BIO 2 (Dewilde et al. 1998 ) and the other primers annealing in exon regions or in the UTR (untranslated region) to provide the complete sequence of the three introns of the myoglobin gene ( Figure 6 ). All amplifications were reproduced at least five times.", "cite_spans": [], "ref_spans": [{"start": 426, "end": 434, "text": "Figure 6", "ref_id": "FIGREF5"}]}, {"section": "Amplification of the Introns from the Biomphalaria Myoglobin Gene", "text": "Primer pair BIO 1F (forward) (5' TACTGTCACACAACCAGCCC 3') and BIO 1R (reverse) (5' GCGTTCTTTTTGCCGTCAGC 3') were used to amplify the first intron (intron 1), primers BIO 4F (5' GGCAAAAAGAACGCTGGAAT 3') and BIO 4R (5' GAGTCCGATTTTCAGGTTG 3') were used to amplify the second intron (intron 2) and primers BIO 2 and BIO 3 (5' GAGTTGGTCAGGATCCGTGG 3') were used to amplify the third intron (intron 3).", "cite_spans": [], "ref_spans": []}, {"section": "Amplification of the Introns from the Biomphalaria Myoglobin Gene", "text": "The PCR for intron 1 was performed for 30 cycles of 94 \u00b0C for 30 s, 65 \u00b0C for 60 s, 72 \u00b0C for 2 min and a final elongation step at 72 \u00b0C for 10 min. The amplification of the introns 2 and 3 used the same reaction, except for an annealing temperature of 60 \u00b0C. The amplicons were analyzed by 6% polyacrylamide gel electrophoresis with silver stain; the base pair markers \uf066X174/Hae III digested (Amersham Biosciences) and 1 kb Plus DNA ladder (Invitrogen) were applied.", "cite_spans": [], "ref_spans": []}, {"section": "PCR-RFLP", "text": "PCR-RFLP was used to analyze the similarity of the nucleotide sequence from myoglobin introns. The three introns of the myoglobin gene from three Biomphalaria species were amplified as previously described and amplicons were submitted to digestion with the restriction endonucleases Xba I, Bgl II, Xho I, Hind III and Bam HI (Invitrogen). Only intronic fragments were digested, because the aim was to observe if the nucleotide sequence of the introns differed among species of Biomphalaria. The use of the full gene (whole gene amplification) in RFLP would not allow identification of the differences (cuts) belonging to the introns and exons, and in which intron. Reactions were performed according to the manufacturer and were evaluated by 6% polyacrylamide gel electrophoresis with silver staining; the base pair marker \uf066X174/Hae III digested (Amersham Biosciences) was applied.", "cite_spans": [], "ref_spans": []}, {"section": "Conclusion", "text": "The gene encoding myoglobin from B. glabrata, B. straminea and B. tenagophila displays size polymorphisms (base pairs) in the intronic regions, featuring a profile of homozygosity/heterozygosity in this gene. Considering the difference among the introns of myoglobin from B. glabrata, B. straminea and B. tenagophila, there is the possibility of using these introns as molecular markers for specific identification of these mollusks. 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Polyacrylamide gel electrophoresis with silver stain. Amplification of intron 1 of the myoglobin gene. (A) B. glabrata; (B) B. straminea; (C) B. tenagophila. Numbers above the lane are one different individual. MW = molecular weight (base pairs) of \uf066X174/Hae III digested (Amersham Biosciences). On right: molecular weight (base pairs) of 1 kb Plus DNA ladder (Invitrogen).", "type": "figure"}, "FIGREF1": {"text": "Figure 2. Polyacrylamide gel electrophoresis with silver stain. Amplification of intron 2 of the myoglobin gene. (A) B. glabrata; (B) B. straminea; (C) B. tenagophila. Numbers above the lanes indicate one different individual. MW = molecular weight (base pairs) of \uf066X174/Hae III digested (Amersham Biosciences). Right: molecular weight (base pairs) of", "type": "figure"}, "FIGREF2": {"text": "Figure 3. Polyacrylamide gel electrophoresis with silver stain. Amplification of intron 3 of the myoglobin gene. (A) B. glabrata; (B) B. straminea; (C) B. tenagophila. Numbers above the lane are one different individual. MW = molecular weight (base pairs) of \uf066X174/Hae III digested (Amersham Biosciences). Right: molecular weight (base pairs) of", "type": "figure"}, "FIGREF3": {"text": "Figure 4. Schematic representation of the supposed alleles from (A) B. glabrata, (B) B. straminea, and (C) B. tenagophila according to amplicons obtained. Exons (white) were represented only to delimit introns (black).", "type": "figure"}, "FIGREF4": {"text": "Figure 5. Polyacrylamide gel electrophoresis with silver stain. PCR-RFLP of the amplicons of the introns from Biomphalaria myoglobin. 1. B. glabrata; 2. B. straminea; 3. B. tenagophila. MW = molecular weight (base pairs) of \uf066X174/Hae III (Amersham Biosciences). Above the lanes, restriction endonucleases are indicated.", "type": "figure"}, "FIGREF5": {"text": "Figure 6. Annealing position of the primers related to the myoglobin gene from B. glabrata (U89283.1). Solid line: Primers BIO 1F/R. Dashed line: BIO 4F/R. Grey box: BIO2/3. Tick line: Initiation and stop codon. I, II and III: introns 1, 2 and 3 respectively. Below the figure, the sequence of the primers and expected sizes of amplicons according to the gene U89283.1 are shown.", "type": "figure"}, "TABREF0": {"text": "Individuals from Biomphalaria genus distributed according to Brazilian province.Number of the individual in the collection from Vidigal, T.H.D.A.", "type": "table"}}}
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{"paper_id": "17434984", "_pdf_hash": "e10f6607ce1fb789dfed787fc813faa2e08d76b2", "abstract": [{"section": "Abstract", "text": "Summary: We qualitatively and quantitatively investigated the parathyroid glands of golden hamsters aged 6, 12, 18, 24 and 30 months. Percent area of rER in the parathyroid gland in golden hamsters at 24 months of age was significantly higher when compared to 6 and 12 months of age, and the percent area at 30 months of age was significantly higher when compared to 12 months of age, but there were no significant differences between 24 and 30 months of age. Percent area of the Golgi apparatus at 24 and 30 months of age was significantly higher when compared to 6, 12 and 18 months of age. Ultrastructurally, we believe that in the parathyroid gland of the golden hamster, synthesis and release of parathyroid hormone increase gradually from 6 to 24months of age and are maintained from 24 to 30 months of age.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Previous studies on the development of parathyroid gland (PTG) in various mammals have demonstrated ultrastructural changes in the chief cells of fetus, young and adult animals [1] [2] [3] . Emura et al. 4) reported the age-related changes in the ultrastructure of PTG in prenatal golden hamsters until 18 months after birth. It has been reported that the lifespan of the golden hamster is two to three years 5) , but there have been no studies on the precise fate of PTG in golden hamsters after age 18 months. This investigation was therefore undertaken to study the quantitative and qualitative changes to chief cells in the PTG of adult golden hamsters from age 6 to 30 months.", "cite_spans": [{"start": 177, "end": 180, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 181, "end": 184, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 185, "end": 188, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 204, "end": 206, "text": "4)", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Materials and Methods", "text": "Twenty-five male golden Syrian hamsters were classified into 5 age groups of 5 animals each. All animals were kept under automatically controlled conditions of temperature (23\u00b11\u00b0C) and humidity (50\u00b110%), with a 12-h light/dark cycle, and standard laboratory diet (CMF; Oriental Yeast Co., Tokyo, Japan) and drinking water were provided ad libitum. Under deep anesthesia with an intraperitoneal injection of sodium pentobarbital (50 mg/kg body weight), hamsters were sacrificed at 6, 12, 18, 24 and 30 months of age. Experimental protocols of this study followed the Guidelines for Animal Experiments at the School of Dentistry, Aichi-Gakuin University. PTG from animals in all groups was dissected, fixed in a mixture of 2.5% glutaraldehyde and 2% OsO 4 in Veronal acetate buffer, pH 7.4, for 1 h at 4\u00baC, followed by dehydration in a graded acetone series and embedding in Epon 812. Body weight of all animals was measured after anesthesia. Ultrathin sections were cut using a PorterBlum MT-1 ultramicrotome (SORVALL, Newtown, U.S.A.), stained with uranyl acetate and lead salts, and were examined under a JEM-1210 electron microscope (JEOL, Tokyo, Japan). In each hamster from all groups, 20 micrographs at a final magnification of 17,000 were taken at random from different regions of the PTG.", "cite_spans": [], "ref_spans": []}, {"section": "Materials and Methods", "text": "Tracing paper was placed over the micrographs and outlines of the cytoplasm, the Golgi apparatus (Golgi vesicles, Golgi vacuoles and Golgi lamellae), the cisternae of the rough endoplasmic reticulum (rER), lysosomes, large vacuolar bodies and lipid droplets were drawn. Quantitation of the areas of cytoplasm (= total cell volume minus nucleus), cytoplasmic organelles and cytoplasmic inclusions was performed with a CanoScan 9900F scanner (Canon Inc., Tokyo, Japan) interfaced to an eMac PowerPC G4 computer (Apple, Cupertino, U.S.A. ", "cite_spans": [], "ref_spans": []}, {"section": "Statistical Methods", "text": "All data are presented as means \u00b1 SEM. One-way analysis of variance (ANOVA) was used to detect significant differences among the 5 groups, and then Fisher's PLSD test was used to determine differences between pairs of means. Levels of 5% were used to establish the significance of differences.", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Body weight", "text": "Changes in body weight of golden hamsters in each of the 5 groups are shown in Table 1 . Mean body weight in the hamster at 24 months of age was significantly less than at 6 months of age, and at 30 months of age, it was significantly less than at all other ages.", "cite_spans": [], "ref_spans": [{"start": 79, "end": 86, "text": "Table 1", "ref_id": "TABREF1"}]}, {"section": "Electron microscopic findings of PTG", "text": "In the golden hamsters at all ages, the parenchyma of PTG largely consisted of chief cells, which were oval or polygonal in shape and contained abundant free ribosomes and mitochondria (Figs. 1-5). The fine structure of PTG in each group generally corresponded to previous descriptions 4, 6) .", "cite_spans": [{"start": 286, "end": 288, "text": "4,", "ref_id": "BIBREF3"}, {"start": 289, "end": 291, "text": "6)", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Electron microscopic findings of PTG", "text": "In the hamster PTG, cytoplasm of the chief cells contained well-developed Golgi apparatus consisting of small vesicles and large, dilated vacuoles with increasing age (Figs. 2-5 ). In the cytoplasm at all ages, rER was well developed, and at 30 months of age, was arranged as curvilinear whirls rather than as parallel arrays and was randomly distributed ( . Numerous lipid droplets were particularly noted at 6 months of age (Fig. 1) . Numerous secretory granules were scattered in the cytoplasm at all ages except 6 months, and after 12 months of age, numerous secretory granules were situated near the plasma membrane (Figs. 3, 4) . The tortuous course of the plasma membranes of adjacent chief cells and the enlargement of intercellular spaces containing floccular or fine particulate materials were frequently observed with advancing age (Fig. 5 ). In the PTG at 30 months of age, two unusual types of cells were observed among the chief cells: waterclear cells, which had numerous vacuoles containing a fine particulate substance and thread-like material (Fig.  6) ; and oxyphil cells, which were characterized by the presence of tightly packed, rod-shaped mitochondria with parallel lamellar cristae (Fig. 7) .", "cite_spans": [], "ref_spans": [{"start": 167, "end": 177, "text": "(Figs. 2-5", "ref_id": "FIGREF2"}, {"start": 843, "end": 850, "text": "(Fig. 5", "ref_id": "FIGREF2"}, {"start": 1061, "end": 1070, "text": "(Fig.  6)", "ref_id": "FIGREF3"}]}, {"section": "Morphometry of PTG", "text": "The results of morphometric measurements are shown in Table 2 . Table 2 shows the organellar profiles of PTG among golden hamsters in all age groups. The mean value for rER in the PTG of hamsters was significantly higher at 24 months of age than that at 6 and 12 months of age, and was significantly higher at 30 months of age than that at 12 months of age, but there were no significant differences between 24 and 30 months of age. The mean value for the Golgi apparatus was significantly higher at 24 and 30 months of age than at 6, 12 and 18 months of age. The mean value for lysosomes was markedly increased from 6 to 18 months of age and was significantly higher at 18, 24 and 30 months of age than at 6 months of age and was significantly higher at 18 months of age than at 12 months of age. The mean value for lipid droplets was significantly lower at 30 months of age than at 6 months of age. The mean value for large vacuolar bodies showed no significant differences among animals at any age. The mean value for secretory granules was significantly lower at 6 months of age than at all other ages, was significantly higher at 12 months of age than at all other ages, and was significantly higher at 18 months of age than at 30 months of age. ", "cite_spans": [], "ref_spans": [{"start": 54, "end": 61, "text": "Table 2", "ref_id": "TABREF2"}, {"start": 64, "end": 71, "text": "Table 2", "ref_id": "TABREF2"}]}, {"section": "Discussion", "text": "The rER, the site of parathyroid hormone (PTH) synthesis, the Golgi apparatus, where PTH is packaged into secretory granules, which store and transport PTH to the cell surface, and other organelles (lysosomes, lipid droplets and large vacuolar bodies) related to regulating overproduction of PTH are known to be morphological parameters associated with the functional status of chief cells 7) .", "cite_spans": [{"start": 390, "end": 392, "text": "7)", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Discussion", "text": "In the present study, the main changes in the cytoplasm of the PTG were an increase in the Golgi apparatus and rER with growth. Cytoplasm at 24 and 30 months of age showed a well-developed Golgi apparatus and rER when compared with 6 and 12 months of age. The large size of the Golgi apparatus and rER suggest an increased capacity for synthesis and packaging of PTH 8) . In addition, numerous chief cells contained numerous prosecretory granules in the Golgi areas. These findings are similar to the observation of increased in functional activity of PTG 9) .", "cite_spans": [{"start": 367, "end": 369, "text": "8)", "ref_id": "BIBREF7"}, {"start": 556, "end": 558, "text": "9)", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Discussion", "text": "It has been suggested that lysosomes in PTG increase in number with growth, and may function in the regulation of overproduced secretory granules 10) . Our findings are generally consistent with the observations described above. Emura et al. 11) demonstrated that large vacuolar bodies decrease with age and increase when the secretory activity of PTG is suppressed in response to acute hypercalcemia. One role of the large vacuolar body is the regulation of overproduction of the secretory process in Golgi areas in the suppressed PTG. In the present study, there were no significant differences among the groups with regard to large vacuolar bodies. However, additional study is required in order to clarify the origin and role of large vacuolar bodies in the PTG.", "cite_spans": [{"start": 146, "end": 149, "text": "10)", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Discussion", "text": "In the cytoplasm from 6 to 30 months of age, changes in lipid droplets showed the opposite trend as activity of the rER and Golgi apparatus. Nunenz et al. 12) noted that lipid droplets may provide the energy required for the synthesis of PTH when synthesis increases. According to Castleman and Roth 13) , lipid droplets that originate from autophagosomes 14) peak in resting chief cells and are reduced in the active state.", "cite_spans": [{"start": 155, "end": 158, "text": "12)", "ref_id": "BIBREF11"}, {"start": 300, "end": 303, "text": "13)", "ref_id": "BIBREF12"}, {"start": 356, "end": 359, "text": "14)", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Discussion", "text": "In active chief cells, secretory granules tend to increase in number and gather beneath the plasma membrane 15) . In the present study in the groups after 12 months of age, secretory granules situated near the plasma membrane were numerous when compared with those at 6 months of age, and the enlarged intercellular spaces containing material similar to the contents of secretory granules increased when compared to those at 6 months of age. These findings suggest that secretory granules in the PTG of the golden hamster may be actively discharged by an eccrine-type secretion 16) . The number of secretory granules does not correlate with the functional condition of the PTG 17) . In the present study, the number of secretory granules was highest at 12 months of age, and decreased gradually with age. Accordingly, a decrease in secretory granules in the groups after 12 months of age suggests that the intracellular transport and lysosomal digestion are more markedly stimulated than their synthesis. In this study, water-clear cells and oxyphil cells were seen in the PTG at 30 months of age. Emura et al. 18) reported the presence of water-clear cells containing 19) and in older men 20) . They are not seen consistently and their function is largely unknown; therefore, previous studies have failed to demonstrate this type of cell in the golden hamster PTG.", "cite_spans": [{"start": 108, "end": 111, "text": "15)", "ref_id": "BIBREF15"}, {"start": 578, "end": 581, "text": "16)", "ref_id": "BIBREF16"}, {"start": 677, "end": 680, "text": "17)", "ref_id": "BIBREF17"}, {"start": 1111, "end": 1114, "text": "18)", "ref_id": "BIBREF18"}, {"start": 1169, "end": 1172, "text": "19)", "ref_id": "BIBREF19"}, {"start": 1190, "end": 1193, "text": "20)", "ref_id": "BIBREF20"}], "ref_spans": []}, {"section": "Discussion", "text": "In conclusion, ultrastructurally, it appears that the synthesis and release of PTH in the PTG of the golden hamsters increase gradually from 6 to 24months of age, and are maintained from 24 to 30 months of age.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Ultrastrukturelle Untersuchungen zur Funktionellen Epithelk\u00f6rperchen 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Lysosomes and irregularly shaped heterogeneously dense bodies (lipofuscin-like bodies) gradually increased in number with age (Figs. 2-5). Large vacuolar bodies containing floccular material or vesicles were sometimes observed in the cytoplasm at all ages (Figs. 1-5)", "type": "figure"}, "FIGREF1": {"text": "Fig. 1. Parathyroid chief cells in hamsters at 6 months of age. Chief cells contain abundant free ribosomes, mitochondria, cisternae of rough endoplasmic reticulum (ER), Golgi apparatus (G), lysosomes (L), large vacuolar bodies (V), lipid droplets (LD) and secretory granules. Scale bar = 1 \u03bcm.", "type": "figure"}, "FIGREF2": {"text": "Fig. 5. Parathyroid chief cells of hamster at 30 months of age. Many well-developed cisternae of rough endoplasmic reticulum (ER) and Golgi apparatus (G) are randomly distributed. L: lysosome, V: large vacuolar body, LD: lipid droplet. Insert on the left-hand side of this panel shows the tortuous course of plasma membranes of adjacent chief cells, and the enlarged intercellular space containing floccular or fine particulate materials. Insert at the right-hand side of this panel shows curvilinear whirls of the rough endoplasmic reticulum. Scale bar = 1 \u03bcm.", "type": "figure"}, "FIGREF3": {"text": "Fig. 6. A water-clear cell of a hamster parathyroid gland at 30 months of age. Scale bar= 1\u03bcm. Fig. 7. An oxyphil cell of a hamster parathyroid gland at 30 months of age. Scale bar= 1 \u03bcm.", "type": "figure"}, "TABREF1": {"text": "Comparison of body weight between groups.", "type": "table"}, "TABREF2": {"text": "Comparison of organellar profiles on the PTG among groups.Values are means\u00b1SEM. m: month; G: the Golgi apparatus; ER: rough endoplasmic reticulum; Ly: lysosome; V: large vacuolar body; LD: lipid droplet. Values are presented as percentage of cytoplasmic areas. Value of secretory granule (SG) is presented as number of profiles per 100 \u03bcm 2 in the cytoplasm. a: p<0.05 vs. 6-month group, b: p<0.05 vs. 12-month group, c: p<0.05 vs. 18-month group, d: p<0.05 vs. 24-month group, e: p<0.05 vs. 30-month group. numerous vacuoles within the cytoplasm in the PTG of 3-to 15-month-old golden hamsters. To our knowledge, oxyphil cells have not yet been reported in hamster PTG. Oxyphil cells are characterized by numerous mitochon- dria located in the cytoplasm and believed to derive from chief cells, occurring only in older animals", "type": "table"}}}
{"paper_id": "17435012", "_pdf_hash": "619478c10cd49858d2b6ccdb9da37e850cfb6af7", "abstract": [{"section": "Abstract", "text": "who were aged \u054618 years of age and had complete blood counts, iron studies, and A1C levels. Iron deficiency was defined as at least two abnormalities including free erythrocyte protoporphyrin \u03fe70 g/dl erythrocytes, transferrin saturation \u03fd16%, or serum ferritin \u054515 g/l. Anemia was defined as hemoglobin \u03fd13.5 g/dl in men and \u03fd12.0 g/dl in women.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "RESULTS -Among women (n \u03ed 6,666), 13.7% had iron deficiency and 4.0% had iron deficiency anemia. Whereas 316 women with iron deficiency had A1C \u05465.5%, only 32 women with iron deficiency had A1C \u05466.5%. Among men (n \u03ed 3,869), only 13 had iron deficiency and A1C \u05465.5%, and only 1 had iron deficiency and A1C \u05466.5%. Among women, iron deficiency was associated with a greater odds of A1C \u05465.5% (odds ratio 1.39 [95% CI 1.11-1.73]) after adjustment for age, race/ethnicity, and waist circumference but not with a greater odds of A1C \u05466. 5% (0.79 [0.33-1.85", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "CONCLUSIONS -Iron deficiency is common among women and is associated with shifts in A1C distribution from \u03fd5.5 to \u05465.5%. Further research is needed to examine whether iron deficiency is associated with shifts at higher A1C levels.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Diabetes Care 33:780-785, 2010", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "1C is formed by the glycation of the terminal valine of the \u2424-chain of hemoglobin. It is used commonly as a screening test for diabetes in clinical practice (1) . A1C may be less susceptible than other measures of glycemia to temporary fluctuations caused by diet, physical activity, or illness as well as differences in local testing standards; as a result, an expert committee has recently endorsed an A1C \u05466.5% as diagnostic for diabetes (1) .", "cite_spans": [{"start": 157, "end": 160, "text": "(1)", "ref_id": "BIBREF0"}, {"start": 441, "end": 444, "text": "(1)", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "", "text": "Previous studies have reported that depletion of iron stores may alter the glycation rate of hemoglobin and elevate A1C concentrations, independent of glycemia (2) . Iron deficiency may be present without associated anemia (3) . Although iron deficiency is the most common nutritional deficiency (3), the clinical relevance of iron deficiency on the use of A1C as a screening test for diabetes has not been studied. Reproductive-age women are particularly vulnerable to iron deficiency, reflecting iron loss through menstruation and pregnancy. In the Third National Health and Nutrition Examination Survey (NHANES) 1988 -1994 and later NHANES waves, \u03fe11% of women had iron deficiency (3, 4) .", "cite_spans": [{"start": 160, "end": 163, "text": "(2)", "ref_id": "BIBREF1"}, {"start": 223, "end": 226, "text": "(3)", "ref_id": "BIBREF2"}, {"start": 684, "end": 687, "text": "(3,", "ref_id": "BIBREF2"}, {"start": 688, "end": 690, "text": "4)", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "", "text": "Using a recent population-based sample of U.S. adults, we examined the distribution of A1C by iron deficiency status among adults without known diabetes. We hypothesized that adults with iron deficiency would be more likely to have elevated A1C levels, even after consideration of fasting plasma glucose. We also hypothesized that any differences would persist after adjustment for other factors associated with A1C and iron deficiency, including age, race/ethnicity, and waist circumference.", "cite_spans": [], "ref_spans": []}, {"section": "RESEARCH DESIGN AND", "text": "METHODS -We used data from the NHANES 1999 -2006 conducted by the National Center for Health Statistics of the Centers for Disease Control and Prevention to assess the health and nutritional status of the U.S. population. The NHANES 1999 -2006 included a nationally representative probability sample of the U.S. civilian noninstitutionalized population, identified through a complex multistage cluster sampling design (5) . During a household interview, participants provided information on sociodemographics and health status, and physicians and health care technicians conducted a standard examination on sampled subjects within 4 weeks of the interview. For the purposes of this analysis, we included NHANES 1999 -2006 participants aged \u054618 years who had a complete blood count, iron studies, and A1C levels. We excluded individuals with known self-reported diabetes (n \u03ed 1,029) and pregnant women (n \u03ed 1,144). Con-ditions such as renal disease that shorten erythrocyte survival may proportionately decrease A1C levels and are also associated with iron deficiency, (6), but the degree of renal impairment at which anemia occurs is unclear (7) . Therefore, we also excluded participants with chronic kidney disease (n \u03ed 1,266), defined as a glomerular filtration rate (GFR) \u03fd60 ml/min per 1 , intra-assay variation was \u03fd3% for both assays, and assays correlated at 0.98, with similar values for the range of A1C examined in this analysis (9 -11). Therefore, for the purposes of this analysis, we combined the results from the two assays.", "cite_spans": [{"start": 418, "end": 421, "text": "(5)", "ref_id": "BIBREF5"}, {"start": 1142, "end": 1145, "text": "(7)", "ref_id": "BIBREF7"}, {"start": 1291, "end": 1292, "text": "1", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "RESEARCH DESIGN AND", "text": "According to analyses of 1999 -2004 NHANES data, an A1C of 5.5% has a sensitivity of 89% and a specificity of 80% compared with fasting glucose, and an A1C of 6.1% has a sensitivity of 67% and a specificity of 98% compared with fasting glucose levels \u0546126 mg/dl to detect diabetes (12) . In 2009, an expert committee endorsed A1C as a diagnostic test for diabetes (1) . For the purposes of this report, A1C was categorized in two ways. Because of the distribution of A1C values (Table 1) , we examined a cut point of \u03fd5.5 vs. \u05465.5%, and because of the expert committee recommendation, we examined a cut point of \u03fd6.5 vs. \u05466.5%.", "cite_spans": [{"start": 281, "end": 285, "text": "(12)", "ref_id": "BIBREF10"}, {"start": 364, "end": 367, "text": "(1)", "ref_id": "BIBREF0"}], "ref_spans": [{"start": 478, "end": 487, "text": "(Table 1)", "ref_id": "TABREF1"}]}, {"section": "Independent variables", "text": "Iron status may be assessed through several laboratory tests. We used the definition applied previously in the Third NHANES and the NHANES 1999 -2000 for iron deficiency, i.e., any two of the following three indexes: erythrocyte protoporphyrin levels \u03fe70 g/dl erythrocytes, ferritin \u054515 g/l, and transferrin saturation levels \u03fd16% (3). The presence of anemia was defined as an Hb level of \u03fd12.0 g/dl for women and \u03fd13.5 g/dl for men (3) .", "cite_spans": [{"start": 433, "end": 436, "text": "(3)", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "Independent variables", "text": "We controlled for several factors that could have served as confounders because of their associations with both iron deficiency and A1C, including age (13, 14) , race (13, 14) , and obesity, particularly visceral adiposity (14, 15) . In NHANES 1998 -2006, race/ethnicity was defined as non-Hispanic white, nonHispanic black, Mexican American, and other race. For the total estimates of iron deficiency, all racial/ethnic groups were combined. BMI was calculated as weight in kilograms divided by the square of height in meters, and waist circumference is reported in centimeters. In women, we also controlled for self-report of parity and hysterectomy status, as these may be associated with iron deficiency (16) and glucose tolerance (17, 18) .", "cite_spans": [{"start": 156, "end": 159, "text": "14)", "ref_id": "BIBREF12"}, {"start": 172, "end": 175, "text": "14)", "ref_id": "BIBREF12"}, {"start": 223, "end": 227, "text": "(14,", "ref_id": "BIBREF12"}, {"start": 228, "end": 231, "text": "15)", "ref_id": "BIBREF13"}, {"start": 708, "end": 712, "text": "(16)", "ref_id": "BIBREF14"}, {"start": 735, "end": 739, "text": "(17,", "ref_id": "BIBREF15"}, {"start": 740, "end": 743, "text": "18)", "ref_id": "BIBREF16"}], "ref_spans": []}, {"section": "Statistical analyses", "text": "We performed analyses using SAS for data management and SUDAAN to account for unequal probabilities of selection, planned oversampling, and the complex sample design of the NHANES (5). All analyses were stratified by sex, as anemia cut points for hemoglobin levels differ by sex. We compared categorical variables by iron deficiency status using 2 tests and continuous variables using ANOVA. We constructed several types of multivariable models. First, we compared the distribution of A1C between participants with and without iron deficiency. Of participants, 97% had A1C levels \u03fe5.5 or 5.5-6.0% (Table 1) ; therefore, we used 5.5% as a cut point in one analysis and 6.5% as a cut point in another analysis. We used multiple logistic regression models to describe the odds of having A1C levels \u05465.5 vs. \u03fd5.5% or \u05466.5 vs. \u03fd6.5% by iron deficiency status, before and after adjustment for age, race/ ethnicity, waist circumference, and, among women, parity (as a continuous variable) and hysterectomy status. Models using BMI instead of waist circumference were also constructed with similar results, so only the results using waist circumference are shown. We also calculated the predicted prevalence of an elevated A1C level according to iron deficiency status, and differences between prevalences before and after adjustment for the covariates mentioned above.", "cite_spans": [], "ref_spans": [{"start": 597, "end": 606, "text": "(Table 1)", "ref_id": "TABREF1"}]}, {"section": "Statistical analyses", "text": "We conducted several sensitivity analyses. First, we used multiple linear regression to calculate the adjusted prevalence of mean A1C levels by iron deficiency status before and after adjustment for the above factors. Because of the skewed A1C distribution, we logtransformed A1C levels but obtained similar results and, therefore, for ease of interpretation, present the analysis without log transformation. To determine whether the association between iron deficiency and A1C was independent of glycemia, we examined the subpopulation of men and women in our sample who also underwent a fasting glucose measurement (n \u03ed 2,796 women and n \u03ed 1,680 men). Approximately one-half of NHANES participants were sampled to attend the morning session. These participants were instructed to fast at least 9 h before the appointment time. Fasting plasma glucose values are available for those adults who attended the morning examination and were fasting \u05468 h. In this subpopulation, we included fasting glucose levels as a continuous covariate when we examined the association between iron deficiency and A1C levels. Because of the small number of male participants with both elevated A1C levels and iron deficiency, we performed sensitivity analyses only among women participants. In the third sensitivity analysis, we also included adults with GFR from 60 to 90 ml/min per 1.73 m 2 with microalbuminuria, resulting in an increase in sample size from 2,993 women and 1,799 men to 3,033 women and 2,044 men. Finally, we examined the subpopulation of adults with anemia to determine whether any associations were more pronounced in the subgroup of women with iron deficiency anemia, but we did not find this (results not shown).", "cite_spans": [], "ref_spans": []}, {"section": "Statistical analyses", "text": "RESULTS -Unadjusted characteristics of men and women with and without iron deficiency are shown in Table 1 . Among women (n \u03ed 6,666), 13.7% (n \u03ed 1,150) had iron deficiency, and, after consideration of sample weighting, 30% of iron-deficient women also had anemia. Among men (n \u03ed 3,869), 1.6% (n \u03ed 75) had iron deficiency, and, after consideration of sample weighting, 33% of irondeficient men also had anemia. Among women, 316 participants with iron deficiency had an A1C \u05465.5%; 32 participants with iron deficiency had an A1C \u05466.5%. Among men, 13 participants with iron deficiency had an A1C \u05465.5%, and only 1 male participant with iron deficiency had an A1C \u05466.5%.", "cite_spans": [], "ref_spans": [{"start": 99, "end": 106, "text": "Table 1", "ref_id": "TABREF1"}]}, {"section": "Statistical analyses", "text": "Characteristics of iron-deficient adults differed among men and women. Women with iron deficiency tended to be aged \u03fd50 years and were more likely to be African American or Hispanic, to be obese, and to have a greater waist circumference and were less likely to have had a hysterectomy. Men with iron deficiency tended to be aged \u054650 years and to have greater waist circumference. In the subpopulation of participants who had fasting glucose levels, iron-deficient women had slightly lower fasting glucose compared with non-iron-deficient women, but similar proportions had fasting glucose \u03fd126 mg/dl. Iron-deficient men had mean fasting glucose values similar to those of non-iron-deficient men, although no iron-deficient men had a fasting glucose \u03fd126 mg/dl. Among women, unadjusted A1C mean levels did not differ between iron-deficient and non-irondeficient adults; A1C distributions were primarily shifted from \u03fd5.5 to 5.5-5.9%. Among men, unadjusted mean A1C levels were higher in iron-deficient men compared with those for iron-sufficient men.", "cite_spans": [], "ref_spans": []}, {"section": "Statistical analyses", "text": "The odds of having an A1C \u05465.5% by iron deficiency status are shown in Table  2 . Among women, iron deficiency was associated with increased odds of an A1C \u05465.5% before and after adjustment for age and race/ethnicity, waist circumference, parity, and hysterectomy. Among men with and without iron deficiency, the odds of having an A1C \u05465.5% did not reach statistical significance after adjustment for covariates ( Table 2 ). The odds of having an A1C \u05466.5 by iron-deficiency status for women is also shown in Table 2 , with no statistically significant association, although the number of irondeficient women with A1C \u05466.5% was small. Because only one man had iron deficiency and an A1C \u05466.5%, multivariate regression was not performed. Data are n (%), weighted percentage, or means \u03ee SE adjusted for complex survey design. Percentages may not total 100 because of rounding, and percentages may differ from unweighted calculations of percentages. *P value was determined by a design-corrected 2 test or t test. Table 3 illustrates the predicted prevalence of women with an elevated A1C by iron status before and after adjustment for covariates. The difference in the predicted prevalence of an A1C \u05465.5% between women with and without iron deficiency was small although statistically significant. There was no significant difference in the predicted prevalence of an A1C \u05466.5% between women with and without iron deficiency, although again the number of women with iron deficiency and an A1C \u05466.5% was small.", "cite_spans": [], "ref_spans": [{"start": 71, "end": 79, "text": "Table  2", "ref_id": "TABREF2"}, {"start": 414, "end": 421, "text": "Table 2", "ref_id": "TABREF2"}, {"start": 509, "end": 516, "text": "Table 2", "ref_id": "TABREF2"}, {"start": 1011, "end": 1018, "text": "Table 3", "ref_id": "TABREF3"}]}, {"section": "Sensitivity analyses", "text": "Although mean A1C levels differed between women with and without iron deficiency, differences were small. The mean A1C values among iron-deficient and non-iron-deficient women were 5.33 and 5.27% after adjustment for age and race/ethnicity (P \u03ed 0.002), 5.31 and 5.27% after further adjustment for waist Data are odds ratios (95% CI). The referent group is adults who are iron-sufficient; an odds ratio \u03fe1 indicates that an iron-deficient adult has greater odds of having an elevated A1C than an iron-sufficient adult, and an odds ratio \u03fd1 indicates that an iron-deficient adult has a lower odds of having an elevated A1C than an iron-sufficient adult. *316 female participants with iron deficiency had a measured A1C \u05465.5%; 32 female participants with iron deficiency had a measured A1C \u05466.5%. \u202013 male participants with iron deficiency had a measured A1C \u05465.5%; 1 male participant with iron deficiency had a measured A1C \u05466.5%. NA, not applicable. Adjusted for above and parity, hysterectomy", "cite_spans": [], "ref_spans": []}, {"section": "Sensitivity analyses", "text": "Data are % \u03ee SE. *316 female participants with iron deficiency and 1,478 without iron deficiency had a measured A1C \u05465.5%, 13 male participants with iron deficiency and 1,178 without iron deficiency had a measured A1C \u05465.5%. \u2020P \u03fd 0.05. \u202132 female participants with iron deficiency and 102 without iron deficiency had a measured A1C \u0546 6.5%.", "cite_spans": [], "ref_spans": []}, {"section": "Sensitivity analyses", "text": "circumference (P \u03ed 0.059), and 5.32 and 5.27% after further adjustment for parity and hysterectomy (P \u03ed 0.022). The mean A1C values among iron-deficient men and non-iron-deficient men were 5.38 and 5.29% after adjustment for age and race/ethnicity (P \u03ed 0.22) and 5.29 and 5.29% after further adjustment for waist circumference (P \u03ed 0.92).", "cite_spans": [], "ref_spans": []}, {"section": "Sensitivity analyses", "text": "When we examined only women with a fasting glucose level and included fasting glucose as an adjuster, the odds of having an A1C \u05465.5% remained significant after adjustment for age, race/ ethnicity, waist circumference, parity and hysterectomy, and fasting glucose (P \u03fd 0.05). Mean A1C levels were also significantly different after adjustment for these factors (P \u03fd 0.001). When we included adults with mild renal impairment, the odds of having an A1C \u05465.5% with iron deficiency no longer remained significantly decreased after adjustment for age, race/ethnicity, waist circumference, parity, hysterectomy, and fasting glucose among women (OR 0.73, 95% CI 0.51-1.04). Among men, the odds of having an A1C \u05465.5% with iron deficiency remained nonsignificant (results not shown).", "cite_spans": [], "ref_spans": []}, {"section": "Sensitivity analyses", "text": "CONCLUSIONS -T h e o p t i m a l screening strategies for diabetes in terms of sensitivity, specificity, and cost may vary among different populations based on demographics and other risk factors for diabetes. We found that iron deficiency, a common condition among reproductive-age women, was associated with shifts in A1C distribution to higher levels, but this shift occurred primarily between \u03fd5.5 and 5.5-6.0%. Although we did not find an association between iron deficiency and shifts in A1C between \u03fd6.5 and \u05466.5%, few women and men had both iron deficiency and A1C elevations \u05466.5, and therefore conclusions regarding iron deficiency and the higher cut point are limited.", "cite_spans": [], "ref_spans": []}, {"section": "Sensitivity analyses", "text": "Previous studies of the influence of iron deficiency and glucose control have documented the high prevalence of iron deficiency in pregnancy (19) and the association with erythrocyte indexes (20) . In a premenopausal nonpregnant population, Koga et al. (20) found that red cell counts and A1C were associated in premenopausal women with otherwise normal glucose tolerance. Hashimoto et al. (19) found that A1C levels were significantly increased in the third trimester compared with earlier in pregnancy, but serum glycated albumin did not change; A1C was negatively correlated with serum ferritin and transferrin saturation, suggesting that A1C was influenced by iron stores rather than by glucose control. Furthermore, replacement with iron is associated with decreases in A1C, independent of glucose changes. Coban et al. (21) found that among nondiabetic adults with iron-deficiency anemia, the A1C was 7.4 \u03ee 0.3% before treatment and 6.2 \u03ee 0.6% after treatment. Likewise, Tarim et al. (22) found that A1C in iron-deficient patients decreased from 7.6 \u03ee 2.6 to 6.2 \u03ee 1.4% after iron therapy (P \u03fd 0.05), despite similar glucose levels. We did not find such large shifts in A1C associated with iron deficiency, either because of the population-based nature of the sample or differences in A1C assays. In addition, we did not examine pregnant patients, and the previous studies of nonpregnant patients may have included some adults with undiagnosed diabetes, as suggested by the A1C levels. In this respect, our results are similar to a subanalysis of the Diabetes Control and Complications Trial, in which comparisons of A1C and glucose associations were similar between premenopausal women and men (23) , suggesting that iron deficiency might not be influential in larger samples, although actually iron measurements were not available in that study.", "cite_spans": [{"start": 141, "end": 145, "text": "(19)", "ref_id": "BIBREF17"}, {"start": 191, "end": 195, "text": "(20)", "ref_id": "BIBREF18"}, {"start": 390, "end": 394, "text": "(19)", "ref_id": "BIBREF17"}, {"start": 825, "end": 829, "text": "(21)", "ref_id": "BIBREF19"}, {"start": 990, "end": 994, "text": "(22)", "ref_id": "BIBREF20"}, {"start": 1701, "end": 1705, "text": "(23)", "ref_id": "BIBREF21"}], "ref_spans": []}, {"section": "Sensitivity analyses", "text": "When we examined only women who underwent a fasting glucose measurement and included fasting glucose as an adjuster, iron deficiency was still associated with a greater mean level of A1C after adjustment as well as a greater odds of having an A1C \u05465.5%. When we excluded women who were likely to have undiagnosed diabetes by fasting glucose value, iron deficiency was still associated with a higher mean level of A1C after adjustment, but the increased odds of having an A1C \u05465.5% was no longer significant. When we included adults with renal impairment, the association between iron deficiency and A1C was attenuated. This result is consistent with the observation that factors contributing to shorter erythrocyte half-life such as renal disease may lower the range of A1C values and reduce the strength of the association between A1C and factors such as iron deficiency.", "cite_spans": [], "ref_spans": []}, {"section": "Sensitivity analyses", "text": "The strengths of our report include its population-based sampling frame, size, and standardized A1C measurements that accounted for factors that might alter A1C measures such as hemoglobinopathies.", "cite_spans": [], "ref_spans": []}, {"section": "Sensitivity analyses", "text": "Our study has several limitations. Iron studies may be affected by inflammation, and we have limited ability to assess such inflammation. Whereas previous studies have not shown that adjustment for C-reactive protein affected estimates of iron deficiency, it is possible that adults more prone to glucose intolerance and higher A1C levels were also prone to inflammation that was not detected. However, inflammation would be expected to raise ferritin levels so that adults with iron deficiency would be less likely to be diagnosed with iron deficiency, thus biasing estimates of association between A1C and iron deficiency to the null, and we used a low cutoff for ferritin (15 mg/dl). We were also unable to account for other factors that might affect red cell production, including malignancies and aplastic anemia. These factors might act as effect modifiers by decreasing red cell half-life and thus artificially lower A1C, thus reducing the magnitude of the association and might also act as confounders through influencing iron resorption, although we expect that these conditions were probably uncommon and would bias any associations to the null. As with any observational study, residual confounding from measurement error may account for the observed associations, and multiple testing may have contributed to chance positive findings.", "cite_spans": [], "ref_spans": []}, {"section": "Sensitivity analyses", "text": "In summary, we found that iron deficiency was common among women, this iron deficiency was not necessarily accompanied by anemia, and iron deficiency shifted the A1C slightly upward independent of fasting glucose level. However, the shift occurred at the lower end of the A1C spectrum, and we were unable to conclude whether iron deficiency affected A1C distributions at a higher cut point of \u03fd6.5 vs. \u05466.5%, a new recommended diagnostic cut point (1) . Similar relationships were observed in men, although the proportion of men with iron deficiency was fairly low, prohibiting more definitive conclusions. Although younger populations are generally at low risk for diabetes compared with older populations, the incidence and prevalence of diabetes are increasing among younger women and pregnant women with the obesity epidemic as well as advancing maternal age (24, 25) . 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Collection procedures were similar from 1999 to 2004 and be- tween 2005 and 2006", "type": "table"}, "TABREF1": {"text": "Characteristics of adults aged 18 years and older with and without iron deficiency, NHANES 1999 -2006", "type": "table"}, "TABREF2": {"text": "Odds ratios (95% CI) for iron deficiency predicting high A1C among adults aged >18 years, NHANES 1999 -2006", "type": "table"}, "TABREF3": {"text": "Predicted prevalence of elevated A1C among adults aged >18 years with and without iron deficiency", "type": "table"}}}
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{"paper_id": "17435517", "_pdf_hash": "ca3c197763a1691e3eeaebb3f0ddda06dce81049", "abstract": [], "body_text": [{"section": "INTRODUCTION", "text": "Oligonucleotide microarrays, also known as \"DNA chips\", allow for massively parallel hybridization experiments. [1] [2] [3] [4] High density chips now routinely present 100 000 and more probe sequences on their surface. 5 Gene expression profiling is the most common application for DNA chips, 6 but diagnostics, 7 SNP genotyping, 8, 9 and sequencing by hybridization are applications that have also been envisioned. 10 Since the results of experiments with DNA microarrays generate large data sets, a fair number of algorithms have been developed to aid the handling and analysis of these data. 11, 12 To review (or even fully list) them is beyond the scope of this article. However, it should be mentioned that many of them are proprietary and that their foci include visualization and quantification of data, 13 encoding biological knowledge, 14 feature extraction, 15 array size determination for sufficient specificity, 16 nonparametric statistical techniques, 17 statistical significance, 18, 19 and eliminating artifacts due to saturation. 20 To the best of our knowledge, few of the algorithms attempt to solve the problem of cross hybridization between partially matched strands 21 or mismatched probe data, 22, 23 and no publicly accessible algorithm undertakes the calculation of total hybridization equilibria.", "cite_spans": [{"start": 112, "end": 115, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 116, "end": 119, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 120, "end": 123, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 124, "end": 127, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 220, "end": 221, "text": "5", "ref_id": "BIBREF4"}, {"start": 294, "end": 295, "text": "6", "ref_id": "BIBREF5"}, {"start": 313, "end": 314, "text": "7", "ref_id": "BIBREF6"}, {"start": 331, "end": 333, "text": "8,", "ref_id": "BIBREF7"}, {"start": 334, "end": 335, "text": "9", "ref_id": "BIBREF8"}, {"start": 417, "end": 419, "text": "10", "ref_id": "BIBREF9"}, {"start": 596, "end": 599, "text": "11,", "ref_id": "BIBREF10"}, {"start": 600, "end": 602, "text": "12", "ref_id": "BIBREF11"}, {"start": 812, "end": 814, "text": "13", "ref_id": "BIBREF12"}, {"start": 846, "end": 848, "text": "14", "ref_id": "BIBREF13"}, {"start": 869, "end": 871, "text": "15", "ref_id": "BIBREF14"}, {"start": 925, "end": 927, "text": "16", "ref_id": "BIBREF15"}, {"start": 966, "end": 968, "text": "17", "ref_id": "BIBREF16"}, {"start": 995, "end": 998, "text": "18,", "ref_id": "BIBREF17"}, {"start": 999, "end": 1001, "text": "19", "ref_id": "BIBREF18"}, {"start": 1047, "end": 1049, "text": "20", "ref_id": "BIBREF19"}, {"start": 1188, "end": 1190, "text": "21", "ref_id": "BIBREF20"}, {"start": 1217, "end": 1220, "text": "22,", "ref_id": "BIBREF21"}, {"start": 1221, "end": 1223, "text": "23", "ref_id": "BIBREF22"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "In an ideal hybridization experiment, only duplexes between strands fully complementary according to the Watson-Crick base pairing rules should form, and all duplexes should have the same stability, so that signal intensities obtained from each spot can be directly translated into relative amounts of the complementary strand. Unfortunately, real life hybridization experiments suffer from several violations of these principles of an ideal chip assay. Partial complementarity between mismatched probes and target strands can lead to false positive results, and low G/Ccontent of duplexes can lead to false negative results. For a simple system, some of the errors resulting from the former violation are schematically shown in the lower part of Figure  1 . A high concentration of strands with partial complementarity to a probe can lead to strong false positive signals. Binding of strands with partial complementarity can also enhance the signal on a spot that does engage in correct hybridization, leading to an incorrectly strong signal. Unfortunately, the extent to which these signal distortions occur at a given spot cannot be settled once and for all during chip design, since it depends on the concentration of all other strands with partial complementarity to a given probe and thus varies with the composition of a sample. In traditional Southern Blots, low level false positive signals are treated as noise, and the same is true for DNA chip results without special data treatment. 24 In fact, many of the programs developed for analyzing chip experiments try to pick correct from false signals via statistical analysis 25 or defining a cutoff level below which signals cannot be interpreted. The latter measure makes the detection of low abundance mRNA (often encoding critical, low copy number proteins) impossible in experiments with large arrays.", "cite_spans": [{"start": 1496, "end": 1498, "text": "24", "ref_id": "BIBREF23"}, {"start": 1634, "end": 1636, "text": "25", "ref_id": "BIBREF24"}], "ref_spans": [{"start": 747, "end": 756, "text": "Figure  1", "ref_id": "FIGREF0"}]}, {"section": "INTRODUCTION", "text": "To deconvolute, rather than statistically sort the information gained through hybridizations on real life DNA chips, one needs to know the binding constants for the strands involved. The prediction of binding equilibria for oligonucleotide duplexes in solution 26 has become increasingly accurate in recent years. The scope of \"nearest neighbor\" predictions, i.e., predictions that do not just add increments to the total binding constant for each base pair but modulate the increment for each base pair according to what the neighboring base pair is, has been greatly expanded. Through a series of experimental studies involving UV-melting curves, calorimetry, and NMR-based structure elucidation, refined parameter sets have been generated. [27] [28] [29] [30] [31] Recently, this work has included generating parameter sets for duplexes that contain mismatches [32] [33] [34] and dangling ends. 35 The computer program HyTher, 36, 37 by Drs. Peyret and SantaLucia, Wayne State University, for example, is accessible free of charge for calculations via the Internet. It calculates, among other things, hybridization thermodynamics for any given duplex and can also perform \"primer walks\".", "cite_spans": [{"start": 261, "end": 263, "text": "26", "ref_id": "BIBREF25"}, {"start": 743, "end": 747, "text": "[27]", "ref_id": "BIBREF26"}, {"start": 748, "end": 752, "text": "[28]", "ref_id": "BIBREF27"}, {"start": 753, "end": 757, "text": "[29]", "ref_id": "BIBREF28"}, {"start": 758, "end": 762, "text": "[30]", "ref_id": "BIBREF29"}, {"start": 763, "end": 767, "text": "[31]", "ref_id": "BIBREF30"}, {"start": 864, "end": 868, "text": "[32]", "ref_id": "BIBREF31"}, {"start": 869, "end": 873, "text": "[33]", "ref_id": "BIBREF32"}, {"start": 874, "end": 878, "text": "[34]", "ref_id": "BIBREF33"}, {"start": 898, "end": 900, "text": "35", "ref_id": "BIBREF34"}, {"start": 930, "end": 933, "text": "36,", "ref_id": "BIBREF35"}, {"start": 934, "end": 936, "text": "37", "ref_id": "BIBREF36"}], "ref_spans": []}, {"section": "INTRODUCTION", "text": "We have an interest in base pairing fidelity and chemical approaches to improving it, particularly at the termini of duplexes. So-called \"molecular caps\" have been generated that, when covalently appended to the terminus of a hybridization probe, increase base pairing fidelity for the terminal and penultimate base pair. 38, 39 Further, we have taken the molecular cap approach to custom-made oligonucleotide arrays. 40 When performing hybridization experiments in solution, we noticed that mismatches at the termini of short duplexes (which are more sensitive to mismatches than longer duplexes) induced melting point depressions as small as 1.9\u00b0C. 38 In fact, there are reports of duplexes with mismatches that are more stable than their fully complementary counterparts. 41 This prompted us to scrutinize the fidelity of hybridization-based molecular recognition events on a more systematic level. Here we present the results of the initial phase of this project, the computer program \"ChipCheck\", which will be accessible free of charge on the Internet. The program calculates total hybridization equilibria for experiments with small DNA microarrays.", "cite_spans": [{"start": 322, "end": 325, "text": "38,", "ref_id": "BIBREF37"}, {"start": 326, "end": 328, "text": "39", "ref_id": "BIBREF38"}, {"start": 418, "end": 420, "text": "40", "ref_id": "BIBREF39"}, {"start": 651, "end": 653, "text": "38", "ref_id": "BIBREF37"}, {"start": 775, "end": 777, "text": "41", "ref_id": "BIBREF40"}], "ref_spans": []}, {"section": "MATERIALS AND METHODS", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "General.", "text": "The ChipCheck algorithm was implemented in the Perl scripting language that can be run on a variety of platforms. The program was developed and tested on personal computers running under Debian GNU/LINUX with Athlon AMD chipsets (1800+) and 512 MB RAM or under ", "cite_spans": [], "ref_spans": []}, {"section": "2154", "text": "SuSe Linux with an Intel PIII Processor and 256 MB RAM. Data for calculations can be submitted to ChipCheck via the Internet at the following URL http://chipcheck.chemie.unikarlsruhe.de/chipcheck/ or http://chip.chemie.uni-karlsruhe.de/chipcheck/. The Web page and output of the scripts was written in HTML 4.01 Transitional and was checked using the tool available at http:// validator.w3.org/. All thermodynamic data employed for calculations were extracted semiautomatically from HyTher at http:// ozone2.chem.wayne.edu/ using Module 1. Possible duplex formation between target strands in solution and intramolecular folding were not considered in the standard version of ChipCheck. A trial version of an extended program termed \"ChipCheck_Sol\" that does include binding equilibria for cross hybridization between target strands can be accessed via the ChipCheck homepages.", "cite_spans": [], "ref_spans": []}, {"section": "2154", "text": "Model Calculations. The sequences chosen for Example 1 are derived from those tested earlier experimentally in these laboratories. 38, 39 Mismatches were introduced at selected positions to test for cross hybridization, as described in the text (Vide infra). For the hybridization buffer, conditions close to those favored by us 40 were entered. A total number of 10 12 probe molecules of a given sequence was chosen, since, with the microarrays currently employed by us, 40 this number per spot was realistic, based on the probe density reported in other work with immobilized oligonucleotides, where high coverage and hybridization efficiencies had been achieved. 42 Numbers of probe strands that are typical for high-density microarrays (spot size approximately 50 \u00b5m) may, of course, also be entered when submitting data sets for calculations with ChipCheck. Experimental variables, like the concentration of monovalent ions and magnesium ions, do affect the thermodynamics of duplex formation and can be entered when generating thermodynamic parameters with HyTher.", "cite_spans": [{"start": 131, "end": 134, "text": "38,", "ref_id": "BIBREF37"}, {"start": 135, "end": 137, "text": "39", "ref_id": "BIBREF38"}, {"start": 329, "end": 331, "text": "40", "ref_id": "BIBREF39"}, {"start": 472, "end": 474, "text": "40", "ref_id": "BIBREF39"}, {"start": 666, "end": 668, "text": "42", "ref_id": "BIBREF41"}], "ref_spans": []}, {"section": "2154", "text": "For Example 2, sequences were provided by Drs. Pankratz and Bauer (Forschungszentrum Karlsruhe, http:// www.fzk.de/microarray) from a high-density chip set of 2 \u00d7 16 300 spots per chip for gene expression studies on zebrafish. Since the probe density on the surface has not been determined quantitatively, an immobilization of 20% of the strands spotted during the immobilization procedure (0.5 nL of 40 \u00b5M solutions) was assumed. In the simulation of the hybridization, only the regions of the target strands that are complementary to the probes were considered. The concentration of the target strands entered are based on the results of actual hybridization studies with the zebrafish chips. The concentrations were obtained by converting the mass values obtained from the analysis software of the collaborators (in ng cDNA) into molar concentrations using an average length of the cDNAs of 400 nt and an average mass of 308.8 Da per residue. The sequences of Example 3 were chosen to contain both variants of 5\u2032-TGGTTGAC-3\u2032 and a number of fully unrelated sequences. Conditions for the virtual hybridization were the same as those for Example 1.", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "In a hybridization experiment with an oligonucleotide microarray, target strands in the hybridization solution form duplexes with probe strands immobilized on the chip surface. The terms used in this work, together with some fundamental relationships, are shown graphically in Figure 2 . Throughout this work, the term \"probe\" is used for strands immobilized on a (virtual) chip surface, and the term \"target\" is used for strands introduced with the (virtual) solution to be analyzed. For calculating the total hybridization equilibria, the affinity of each target for each probe has to be known. The affinity is best expressed in the binding constant, which has a fundamental relationship with the free energy of binding. If standard entropy (\u2206S\u00b0) and standard enthalpy (\u2206H\u00b0) of duplex formation are known, then the binding constant can be calculated for any given temperature and hence the fraction of bound and single stranded probes and free target strands. The difficulty in computing the concentrations for a DNA chip experiment lies in the competition between the individual binding events. A mass distribution for the target strand has to be found that satisfies the constraints of all binding constants defined by the affinity for the probes on all spots and the total number of target molecules available.", "cite_spans": [], "ref_spans": [{"start": 277, "end": 285, "text": "Figure 2", "ref_id": "FIGREF1"}]}, {"section": "RESULTS", "text": "As shown in Figure 2 , the process of hybridization is described by the equilibrium with an equilibrium constant K ij , and employing the law of P i + T j / P i T j mass action, one obtains Fortunately, standard entropy, standard enthalpy, and standard free enthalpy of binding for any given sequence combination can be calculated with programs such as HyTher, 36, 37 which is accessible free of charge on the Internet at http://ozone2.chem.wayne.edu/, both for the solution case and with a linear correction for microchip setups. On the basis of observed linear correlations between the thermodynamic parameters of hybridization in solution and on a chip, it is possible to adapt the estimated thermodynamic parameters to the situation on the chip and obtain estimates of the binding constants K ij . With these, a solution to the matrix of equations resulting from the competing binding equilibria had to be found.", "cite_spans": [{"start": 361, "end": 364, "text": "36,", "ref_id": "BIBREF35"}, {"start": 365, "end": 367, "text": "37", "ref_id": "BIBREF36"}], "ref_spans": [{"start": 12, "end": 20, "text": "Figure 2", "ref_id": "FIGREF1"}]}, {"section": "RESULTS", "text": "If n i , c 0,j , K ij , and the volume (V) are given, a solution for x ij , x i , and c i , i.e., (N p + N p \u00d7 N T + N T ) variables total, can be developed based on the following equations:", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "obtained by rearranging eq 1 representing the mass balance for probe P i , and representing the mass balance for target T j . Altogether the number of equations matches the number of variables and a unique solution can be obtained, in general. The x i may be eliminated by combining eqs 1\u2032 and 2:", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "Substituting (4) in eq 1\u2032 yields while rearrangement of eq 3 gives An iterative procedure cycling through eqs 5 and 6 to determine the correct x ij and c j was initially considered straightforward. It turned out, however, that this procedure is not convergent if V is so small that the c j become much smaller than the c 0,j , i.e., if depletion effects of the sample solution become significant. Therefore, a mathematically more robust strategy had to be implemented to solve the equations in the general case. To this end, eq 5 for the x ij was substituted into eq 3 to yield c j N T coupled equations of the form", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "The main computational challenge was to develop a rugged iteration algorithm that would produce satisfactory, single solutions to the matrix of equations for all binding equilibria. Different iteration approaches were tested, and several sources of unsuccessful calculations were identified. When algorithms proceeding in increasingly small steps toward the solution were employed, the convergence criterion could be met, simply because the steps became too small to cause a noticeable change in the total result (the calculation would \"fall asleep\"). This problem was best solved by combining a few steps of conventional iteration with subsequent steps with the multidimensional Newton algorithm or using an optimized Newton algorithm exclusively. Another problem encountered was the generation of results that contained negative concentrations for target strands. In some instances, seemingly satisfactory solutions were obtained for all but a few strand concentrations, which were negative. This made too little difference to the total result to force the algorithm out of the negative concentration range for this very strand. To prevent negative concentrations, which are physically not meaningful, the program was modified to set all negative concentration values encountered to a specific fraction of the value of the last iteration.", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "Finally, a serious problem was encountered when longer DNA sequences were tested, such as those of Example 2, discussed below. The melting points of these sequences, more then 40 nucleotides in length, are approximately 90\u00b0C in standard buffers, and hybridization temperatures more than 40\u00b0C below this temperature lead to binding constants >10 40 M -1 in HyTher calculations. Accordingly, since one mole of probe strands is 6.022 \u00d7 10 23 strands, and a small fraction of 1 L is typically used as the hybridization solution, not a single target molecule would remain in solution to fulfill the binding constant, if less than one full equivalent of the target strand was present in the experiment. Calculations trying to find the theoretical tiny fraction of a single molecule remaining unbound are inherently difficult to set up with reasonable convergence criteria and lead to results that are physically not meaningful. The overly large constants cause the numeric derivation of the functions, needed for the Newton method, to fail due to rounding. The small variations made to some of the smaller binding constants were lost by rounding during the calculations, causing the derivative to become zero and producing nonmeaningful results or no result at all. This problem was addressed by determining and coding the analytical derivative of the functions used to calculate the equilibrium.", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "Ideally, calculations (and experiments) with duplexes of such high stability should not be performed at temperatures too far away from the melting point. Instead they should be performed at a temperature where reasonable binding energies are found (<10 20 M -1", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "), even for long duplexes. It should be noted, in this context, that the \u2206G values are not independent of temperature and have to be recalculated (in", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "x ij x i c j (1)", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "a trivial calculation) from the respective \u2206H and \u2206S values at every new temperature.", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "Three model calculations performed with ChipCheck will be discussed here briefly. The full list of free enthalpies of binding for the model calculation, as obtained from HyTher, are available as Supporting Information and may also be obtained from the ChipCheck homepage. The first model calculation (Example 1) involved DNA octamers derived from 5\u2032-TGGTTGAC-3\u2032 as the parent sequence immobilized on the virtual chip. These are very short sequences, where single mismatches can be expected to cause a more significant change in duplex stability than in longer sequences. To generate a demanding situation for binding selectivity, neighboring sequences on the virtual chip were chosen to differ by no more than a single base from each other. The strands offered in the virtual solution contained all eight complementary octamers.", "cite_spans": [], "ref_spans": []}, {"section": "RESULTS", "text": "ChipCheck offers four output options after a data set has been entered. The first two display the matrices of \u2206G values and binding constants for each probe/target pair. The next two show the results from total hybridization calculations, either on the level of each individual hybridization or on the level of total signals for a given spot. Figure 3 shows an excerpt from a screenshot taken from the third of the four output options for the octamer case outlined above and equimolar concentrations of all target strands. Every row represents the binding to one spot, drawn out horizontally into the contributions from the individual target strands. The extent to which a given target covers the probe strands on the surface is displayed both numerically and via a color code where yellow codes for the fully covered spot and black for the absence of hybridization. It can be discerned that even at this, the most favorable case in terms of the relative concentration of the target strands, a measurable level of cross hybridization is observed for most combinations. Cross hybridization between mismatched strands is particularly strong when the mismatches are at or near the terminus (upper left-hand corner of the matrix). Figure 4a shows the result of the simulation for the octamer case with equimolar concentrations of all target strands in a more condensed form, where all signals from strands other than the most tightly binding one are added and presented in the rightmost column of the table. Figure  4b shows the results of a simulation for the same probe/ target combination where the concentration of the strands complementary to the fourth and fifth probe was dropped by 3 orders of magnitude. It can be discerned that now the hybridization of strands other than the fully complementary one dominates the distribution of sequences bound to these spots. To visually highlight this fact, the sequence of these strongest binding mismatched strands are displayed in red, rather than the green reserved for the case where fully complementary strands dominate the binding at an individual spot.", "cite_spans": [], "ref_spans": [{"start": 343, "end": 351, "text": "Figure 3", "ref_id": "FIGREF2"}, {"start": 1227, "end": 1236, "text": "Figure 4a", "ref_id": "FIGREF3"}, {"start": 1504, "end": 1514, "text": "Figure  4b", "ref_id": "FIGREF3"}]}, {"section": "RESULTS", "text": "A model calculation involving 20 longer probe strands (65mers) and 15 target strands of the same length was also performed (Example 2). The target strands all have fully complementary partners on the virtual chip, but five of the probes (spots 1-5) do not have fully complementary target strands in the virtual solution. The hybridization temperature was set to 75\u00b0C, i.e., well under the average melting point of the fully complementary duplexes. Also, the concentrations of target strands were chosen based on the results of an actual chip hybridization experiment performed by Drs. Pankratz and M. Bauer, our collaborators, with a high-density chip. The condensed form of the results from the ChipCheck simulation is shown in Figure 5 . In all cases, the hybridization is dominated by one sequence in solution. For spots 2-6, these are mismatched sequences, since the solution is devoid of complementary targets. Spots 2-4 bear sequences similar to that of spot 1, except that one, two, or three mismatches were introduced. Spots 5 and 6 are repeats of tetramers AGCT and ACTG, respectively, and show hybridization of the nonsequence-related target strands present on a very low level (<0.01% coverage of immobilized strands).", "cite_spans": [], "ref_spans": [{"start": 729, "end": 737, "text": "Figure 5", "ref_id": "FIGREF4"}]}, {"section": "RESULTS", "text": "To test the performance of ChipCheck on a larger data set, a simulation was then run on 100 virtual spots and 42 target strands. Again, octamers were used, with part of the sequences being derived from 5\u2032-TGGTTGAC-3\u2032. The run time for this example (4200 binding equilibria) on a personal computer with an AMD chipset (1800+) with 512 MB RAM was 3.5 s, and results for the individual hybridization matrix were obtained in under 10 s as a remote user, including the loading of the html page. The result of the simulation is shown graphically in Figure 6 . The numerical information was left out to improve the visibility but may be obtained on the HyTher homepage. Even at the limited information level of this condensed form of the output, it can be discerned that noticeable false positive results are found in the lower half of the matrix, where no pairs of complementary probes/ targets are found. Once these hot spots for false positives are identified, they may be eliminated by using other probes or, where appropriate, through chemical modifications. 40 As a very first example of a simulation of experimental hybridization results, we have performed a ChipCheck calculation for the microarray data presented in Figure 2 of ref 40 . For this, HyTher thermodynamic values with linear correction for microchips were used for the unmodified strands, and the \u2206\u2206H and \u2206\u2206S values for the chl modification reported in Table 4 of ref 38 added to the \u2206H and \u2206S values of the unmodified, perfectly matched duplex to obtain values for the modified probe. Further, a density of 3.6 \u00d7 10 11 molecules/cm 2 was assumed, based on literature values for aldehyde-bearing glass slides and amino-terminal DNA. 43, 44 A hybridization temperature of 60\u00b0C was entered to compensate for the heating during the sonication step in the experimental procedure. Figure 7 shows a comparison of the experimental results (total fluorescence intensity integrals for each spot pair) and the results obtained by simulation. It can be discerned that the ChipCheck calculation slightly under- estimates the extent of cross hybridization observed for the probe strand with a single mismatch (MM).", "cite_spans": [{"start": 1057, "end": 1059, "text": "40", "ref_id": "BIBREF39"}, {"start": 1234, "end": 1236, "text": "40", "ref_id": "BIBREF39"}, {"start": 1697, "end": 1700, "text": "43,", "ref_id": "BIBREF42"}, {"start": 1701, "end": 1703, "text": "44", "ref_id": "BIBREF43"}], "ref_spans": [{"start": 1218, "end": 1226, "text": "Figure 2", "ref_id": "FIGREF1"}, {"start": 1840, "end": 1848, "text": "Figure 7", "ref_id": "FIGREF5"}]}, {"section": "RESULTS", "text": "As an outlook, the following provides a brief discussion of the possibility of reaching a further goal, i.e., assigning gene expression levels and specific probe-gene binding constants from the signal data obtained from an actual chip experiment (analysis instead of simulation). We assume that the signal intensities S i from the probes i have been normalized such that they represent the total hybridization of all targets to a particular probe i.", "cite_spans": [], "ref_spans": []}, {"section": "Eliminating x ij via eq 5 yields", "text": "For each chip experiment, expressions 7 and 9 represent a total of N T + N P equations.", "cite_spans": [], "ref_spans": []}, {"section": "Eliminating x ij via eq 5 yields", "text": "If the binding constants K ij are known, 2N T equations are needed to determine all the c j and c 0,j . If N P > N T , the data from one chip yield sufficient information to solve the problem and the redundancy in information can be used to check for the statistical significance of the parameter values.", "cite_spans": [], "ref_spans": []}, {"section": "Eliminating x ij via eq 5 yields", "text": "If the binding constants K ij are unknown, one would need 2N T + N T N P equations to determine the c j , c 0,j , and all K ij . However, only N T + N P equations are available with the data from one chip. If some variation in the relative concentrations of the genes in the sample can be achieved, e.g. by changing the conditions of gene expression, additional information is gained. With N C as the number of chips used to evaluate N C different samples, i.e., samples that differ systematically in the c o,j of the genes and are not just replicates of the same experiment, the number of parameters {c 0,j ,c j } 1 N c , K ij increases to 2N T N C + N T N P . However, the total information from the probe signals increases faster. With N C different chip experiments on N C different samples, the number of equations becomes N C (N T + N P ). Hence for Figure 6 . Screenshot of the ChipCheck output of a total hybridization calculation on Example 3 featuring 100 probe spots and 42 target strands. To improve the readability, the numerical information representing the extent of spot coverage was omitted. The full data set, with better readability, can be created on the ChipCheck Internet page using the Example 3 file. ", "cite_spans": [], "ref_spans": []}, {"section": "Eliminating x ij via eq 5 yields", "text": "the number of equations exceeds the number of unknown parameters. If we consider the typical practical situation in which sets of N S (j20) probes are selected to match single genes and if we neglect cross hybridization of the probes in one set to other genes, then each set of probes represents an isolated problem of N S probes and N T ) 1 targets. In this case it follows from eq 10 that as few as N C g 2 different chip experiments are sufficient to determine all the desired parameters.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "In its current form, ChipCheck can be employed to evaluate the performance to be expected theoretically of oligonucleotide arrays in hybridization experiments of moderate complexity. Thus, it may assist the design of new microarrays. This may be particularly important for the design of arrays with a high demand on fidelity, such as chips for diagnosis, SNP genotyping, and sequencing by hybridization. For these applications, resolving a single nucleotide with good signal-to-noise is often critical. The simulations will provide information on the fidelity to be expected in a given hybridization and allow optimizations by eliminating probes that can be expected to give high levels of false positive or false negative results.", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "A lack of reproducibility is a very serious concern in the DNA chip community. 45, 46 The difficulties in obtaining reliable, reproducible results from microarray hybridization experiments have led to some disenchantment. 47 Due to the complexity of the DNA chip hybridization experiments, it is difficult to test all factors (including strand concentration, probe density and integrity, counterions, salt concentration, temperature) affecting absolute and relative signal intensities experimentally. ChipCheck may be employed to study these effects in silico, allowing for more efficient use of the experimental resources and time. Most DNA chips currently employed are larger than what has been tested with ChipCheck thus far. However, it is often the custom designed, focused chips of smaller spot numbers that are employed when fidelity is particularly important. The examples tested demonstrate that ChipCheck can function properly for such examples.", "cite_spans": [{"start": 79, "end": 82, "text": "45,", "ref_id": "BIBREF44"}, {"start": 83, "end": 85, "text": "46", "ref_id": "BIBREF45"}, {"start": 222, "end": 224, "text": "47", "ref_id": "BIBREF46"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "The results of the model calculations presented above (Examples 1 and 2) already provide some insight. In the more demanding case, the hybridization where single mismatches have to be resolved (Example 1), the ChipCheck results demonstrate how severe the problem caused by false positives can be. If equimolar concentrations of all strands complementary to the probes on the surface are present, up to 38% of the strands bound to a given spot are from mishybridizations, even at equimolar concentrations of all target strands. If two target strands are present in much lower copy numbers, their signal is swamped out by the competing mismatch-bearing strands present in higher concentrations, leading to incorrectly high signals. In the case of the 65mers (Example 2), the fidelity is excellent for the strands without sequence homology, but spots with 1-3 mismatches again show strong signals (0.2-84.4% of probes bound, spots 2-4).", "cite_spans": [], "ref_spans": []}, {"section": "DISCUSSION", "text": "Currently, one possible weakness of the approach presented here may lie in the limited accuracy of thermodynamic data for DNA duplexes. While nearest neighbor calculations themselves necessarily involve a number of approximations, it has also been noted that the van't Hoff assumption of a stable \u2206H over a range of temperatures may be violated for hybridization experiments performed far from the melting point. 48 Next, the size of the data sets (number of spot and target sequences per hybridization experiment) employed in simulations thus far has been small. Data sets closer to typical high density DNA chips will necessarily lead to increased run times and greater challenges for successful iterations. Since MELTING, 49 a program providing similar capabilities as HyTher, is freely available on the Internet (http:// bioweb.pasteur.fr/seqanal/interfaces/melting.html), future versions of ChipCheck may contain a module for generating the thermodynamic parameters of duplexes itself, avoiding a bottleneck due to semiautomatic downloading of values from HyTher. In this upgraded version of ChipCheck, sequences and hybridization conditions would be the only data to submit to get a total hybridization result.", "cite_spans": [{"start": 413, "end": 415, "text": "48", "ref_id": "BIBREF47"}, {"start": 725, "end": 727, "text": "49", "ref_id": "BIBREF48"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "Equation 1 is actually the equivalent of the Langmuir adsorption isotherm and one should be aware of the high degree of idealization involved in this model. More realistic adsorption models, such as the Sips model have been suggested, 50 and may be easily implemented. However, the reduction in the binding constants resulting from the immobilization of probes in spots should be similar for all spots, so that the relative hybridization efficiencies determined are useful for practical considerations. The absolute values for the coverage of spots at any given temperature should be treated with great caution and confirmed experimentally.", "cite_spans": [{"start": 235, "end": 237, "text": "50", "ref_id": "BIBREF49"}], "ref_spans": []}, {"section": "DISCUSSION", "text": "As mentioned above, ChipCheck may be extended to include the capability to analyze rather than simulate the outcome of hybridizations on microarrays. Currently, the expression level of rarely expressed genes is often lost during the correction of chip results for background \"noise\". 51 For optimized chips, where many of the spots are used as internal controls, a dynamic range for linear detection of approximately 500-fold has been reported in \"routine use\" mode. 52 Data analysis involving total hybridization calculations for all matched duplexes and those formed through cross hybridization can be expected to yield more reliable results and higher sensitivity, not to mention more rigorous tests for statistical significance. With nearest neighbor parameters recursively optimized via tightly controlled experimental chip results, analyzed via the total hybridization approach, simulations and experiments should converge to high accuracy. Clearly, the very limited tests performed here provide little more than an approach to treating total hybridization equilibria. With further refined algorithms, most of the \"noise\" in DNA chip experiments should be removable via filtering. 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Cartoon of a hybridization on a DNA chip producing both correct and false signals.", "type": "figure"}, "FIGREF1": {"text": "Figure 2. Compilation of terms and equations employed in this work.", "type": "figure"}, "FIGREF2": {"text": "Figure 3. Screenshot of a ChipCheck output of a calculation on Example 1 showing the matrix of individual hybridizations between target and probe strands.", "type": "figure"}, "FIGREF3": {"text": "Figure 4. Screenshots of ChipCheck outputs of calculations on Example 1 showing total hybridizations per spot (a) with equimolar amounts of the target strands and (b) with target strands 4 and 5 depleted by 3 orders of magnitude.", "type": "figure"}, "FIGREF4": {"text": "Figure 5. Screenshot of an output of a total hybridization calculation performed on Example 2. Total hybridizations per spot are shown with low level binding by cross-hybridizing strands highlighted in red. Mismatched nucleotides in probe sequences were entered as lower case letters, solely to highlight their position.", "type": "figure"}, "FIGREF5": {"text": "Figure 7. Comparison of experimental (a) and simulated (b) hybridization results with the sequences 5\u2032-TAGTTGACTGCGAT-3\u2032 (MM), 5\u2032-chl-TGGTTGACTGCGAT-3\u2032 (chl-PM), and 5\u2032-TG-GTTGACTGCGAT-3\u2032 (PM) as immobilized probes and 5\u2032-Cy3-ATCGCAGTCAACCA-3\u2032 as target. The integration area of the fluorescence values reported in Figure 2 of ref 40 are plotted in (a), whereas (b) shows the relative fluorescence intensities expected based on the ChipCheck simulation. See ref 40 for experimental details.", "type": "figure"}}}
{"paper_id": "17435677", "_pdf_hash": "161e323674f5ac7bd1d6bbb5005270edca0204e9", "abstract": [], "body_text": [{"section": "", "text": "those proposed by the ChaLearn Looking at People series of workshops. 1 We would like to thank the authors of the 57 submissions we received, and above all the outstanding and timely work performed by the reviewers. All the 57 submissions followed a rigorous TPAMI review process, where at least three external reviewers provided reviews to each paper. We would also like to thank the Editor-In-Chief (EIC), David Forsyth, for making this special issue possible. We are also grateful to the editorial staff for managing the submission process and providing us with assistance.", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "The set of 16 accepted papers can be split into three main categories within M2HuPBA: (i) human pose recovery and tracking; (ii) action and gesture recognition; and (iii) datasets. We describe these next.", "cite_spans": [], "ref_spans": []}, {"section": "HUMAN POSE RECOVERY AND TRACKING", "text": "The first group of 6 papers are centered on multimodal human pose analysis.", "cite_spans": [], "ref_spans": []}, {"section": "HUMAN POSE RECOVERY AND TRACKING", "text": "The paper \"Spatio-Temporal Matching for Human Pose Estimation in Video\" by F. Zhou and F. de la Torre formulates the problem of human detection in videos as spatiotemporal matching (STM) between a 3D motion capture model and trajectories in videos. The algorithm estimates the camera view and selects a subset of tracked trajectories that matches the motion of the 3D model. The STM is efficiently solved with linear programming, and it is robust to tracking mismatches, occlusions and outliers.", "cite_spans": [], "ref_spans": []}, {"section": "HUMAN POSE RECOVERY AND TRACKING", "text": "The work \"3D Reconstruction of Human Motion from Monocular Image Sequences\" by B. Wandt, H. Ackermann, and B. Rosenhahn, estimates non-rigid human 3D shape and motion from image sequences taken by uncalibrated cameras. Authors factorize 2D observations in camera parameters, base poses and mixing coefficients. The method is based on previously trained base poses. Strong periodic assumptions on the coefficients can be used to define an efficient and accurate algorithm for estimating periodic motion, and non-periodic motion is estimated by including a regularization term based on temporal bone length constancy.", "cite_spans": [], "ref_spans": []}, {"section": "HUMAN POSE RECOVERY AND TRACKING", "text": "The paper entitled \"Real-Time Simultaneous Pose and Shape Estimation for Articulated Objects using a Single Depth Camera\" by M. Ye, Y. Shen, C. Du, Z. Pan, and R. Yang presents a real-time algorithm for simultaneous pose and shape estimation of articulated objects, such as human beings and animals. The key to the pose estimation component is to embed the articulated deformation model with exponential-maps-based parametrization into a Gaussian mixture model. A shape adaptation algorithm based on this probabilistic model automatically captures the shape of the subjects during the dynamic pose estimation process. The paper by G. Pons-Moll, T. von Marcard, and B. Rosenhahn entitled \"Human Pose Estimation from Video and IMUs\" presents an approach to fuse video with sparse orientation data obtained from inertial sensors to improve and stabilize full-body human motion capture. The authors propose a hybrid tracker that combines video with a small number of inertial units to compensate for the drawbacks of each sensor type.", "cite_spans": [], "ref_spans": []}, {"section": "HUMAN POSE RECOVERY AND TRACKING", "text": "The work \"Survey on RGB, 3D, Thermal, and Multimodal Approaches for Facial Expression Recognition: History, Trends, and Affect-Related Applications\" by C. Corneanu, M. Oliu, J. Cohn, and S. Escalera presents an up to date survey on facial expression analysis by considering different visual modalities, defining a new taxonomy encompassing all steps from face detection to facial expression recognition. Important datasets and future lines of research in the field are also discussed.", "cite_spans": [], "ref_spans": []}, {"section": "HUMAN POSE RECOVERY AND TRACKING", "text": "Finally, the work \"Full-Body Pose Tracking-the Top View Reprojection Approach\" by M. Sigalas, M. Pateraki, and P. Trahanias presents a model-based approach for markerless articulated full body pose extraction and tracking in RGB-D sequences. A cylinder-based model is employed to represent the human body. For each body part a set of hypotheses is generated and tracked over time using a particle filter. To evaluate each hypothesis, authors employ a novel metric that considers the reprojected top view of the corresponding body part. The latter, in conjunction with depth information, effectively copes with difficult and ambiguous cases, such as severe occlusions.", "cite_spans": [], "ref_spans": []}, {"section": "ACTION AND GESTURE RECOGNITION", "text": "The second group of nine papers in this special issue are focused on multimodal action and gesture recognition.", "cite_spans": [], "ref_spans": []}, {"section": "ACTION AND GESTURE RECOGNITION", "text": "The paper \"Deep Dynamic Neural Networks for Multimodal Gesture Segmentation and Recognition\" by D. Wu, L. Pigou, P. J. Kindermans, N. Le, L. Shao, J. Dambre, and J. M. Odobez uses deep neural networks for multimodal gesture recognition. A semi-supervised hierarchical dynamic framework based on a hidden Markov model (HMM) is proposed for simultaneous gesture segmentation and recognition where skeleton joint information, depth and RGB images, are the multimodal input observations. The system learns highlevel spatio-temporal representations using deep neural networks: a Gaussian-Bernouilli deep belief network to handle skeletal dynamics, and a 3D convolutional neural network to manage and fuse batches of depth and RGB images. This is achieved through the modeling and learning of the emission probabilities of the HMM required to infer the gesture sequence.", "cite_spans": [], "ref_spans": []}, {"section": "ACTION AND GESTURE RECOGNITION", "text": "The paper \"Semantic Event Fusion of Different Visual Modality Concepts for Activity Recognition\" by C. CrispimJunior, K. Avgerinakis, V. Buso, G. Meditskos, A. Briassouli, J. Benois-Pineau, Y. Kompatsiaris, and F. Bremond proposes a hybrid framework between knowledge-driven and probabilistic-driven methods for event representation and recognition. It introduces an algorithm for sensor alignment that uses semantic data similarity as a surrogate for the inaccurate temporal information of real life scenarios. It also proposes the combined use of an ontology language and a probabilistic interpretation for ontological models. The system is evaluated in multimodal scenarios considering different visual sources, such as RGB and depth maps.", "cite_spans": [], "ref_spans": []}, {"section": "ACTION AND GESTURE RECOGNITION", "text": "The work \"Nonparametric Feature Matching Based Conditional Random Fields for Gesture Recognition from Multimodal Video\" by J. Y. Chang presents a gesture recognition method based on a conditional random field (CRF) using multiple feature matching. The approach determines gesture categories and their temporal ranges at the same time. A generative probabilistic model is formalized and probability densities are non-parametrically estimated by matching input features with a training dataset. Frame-wise recognition results can then be obtained by applying an efficient dynamic programming technique. To estimate the parameters of the proposed CRF model, the structured support vector machine (SSVM) framework is incorporated.", "cite_spans": [], "ref_spans": []}, {"section": "ACTION AND GESTURE RECOGNITION", "text": "The paper \"Explore Efficient Local Features from RGB-D Data for One-Shot Learning Gesture Recognition\" by J. Wan, G. Guodong Guo, and S. Li proposes a spatio-temporal feature extracted from RGB-D data, namely Mixed Features around Sparse Keypoints (MFSK). The proposed MFSK feature is robust and invariant to scale, rotation and partial occlusions. It shows high categorization capability in both one-shot and classic gesture recognition problems.", "cite_spans": [], "ref_spans": []}, {"section": "ACTION AND GESTURE RECOGNITION", "text": "In the paper \"Labeled Graph Kernel for Behavior Analysis\" by A. Martinez and R. Zhao, it is proposed to model behavior using a labeled graph, where the nodes define behavioral features and the edges are labels specifying their order. In this approach, classification reduces to a simple labeled graph matching. Graph kernel is derived to quickly and accurately compute graph similarity.", "cite_spans": [], "ref_spans": []}, {"section": "ACTION AND GESTURE RECOGNITION", "text": "The work \"Structure-Preserving Binary Representations for RGB-D Action Recognition\" by L. Shao, M. Yu, and L. Liu proposes a binary local representation for RGB-D video data fusion with a structure-preserving projection (SPP). The authors convert the problem to describing the gradient fields of RGB and depth information of video sequences. With the local fluxes of the gradient fields, which include the orientation and the magnitude of the neighborhood of each point, a new kind of continuous local descriptor called Local Flux Feature (LFF) is obtained. The LFFs from RGB and depth channels are fused into a Hamming space via the Structure Preserving Projection, and a bipartite graph structure of data is taken into consideration as a high level connection between samples and classes.", "cite_spans": [], "ref_spans": []}, {"section": "ACTION AND GESTURE RECOGNITION", "text": "The work \"Robust Correlated and Individual Component Analysis\" by Y. Panagakis, M. Nicolaou, S. Zafeiriou, and M. Pantic addresses (i) the presence of gross nonGaussian noise, and (ii) temporally misaligned data. The authors propose a method for the Robust Correlated and Individual Component Analysis (RCICA) of data and two suitable optimization problems are solved. The generality of the proposed methods is demonstrated by applying them onto 4 applications, namely (i) heterogeneous face recognition and (ii) audio-visual feature fusion for prediction of interest and conflict, (iii) face clustering, and (iv) the temporal alignment of facial expressions.", "cite_spans": [], "ref_spans": []}, {"section": "I E E E P r o o f", "text": "The paper \"Probabilistic Social Behavior Analysis by Exploring Body Motion-Based Patterns\" by K. Khoshhal, U. Nunes, and J. Dias explores interrelations between body part motions in scenarios with people doing a conversation. The authors analyze body motion-based features in frequency domain to estimate different human social patterns: interpersonal behaviors and a social role. To analyze the dynamics and interrelations of people's body motions, a human movement descriptor is used to extract discriminative features, and a multi-layer dynamic Bayesian network technique is proposed to model the existent dependencies.", "cite_spans": [], "ref_spans": []}, {"section": "I E E E P r o o f", "text": "Lastly, the work \"Moddrop: Adaptive Multimodal Gesture Recognition\" by N. Neverova, C. Wolf, G. Taylor, and F. Nebout presents a method for gesture detection and localization based on multi-scale and multimodal deep learning. The training strategy performs gradual fusion involving random dropping of separate channels (dubbed ModDrop) for learning cross-modality correlations while preserving uniqueness of each modality-specific representation. The proposed training technique ensures robustness of the classifier to missing signals in one or several channels to produce meaningful predictions from any number of available modalities.", "cite_spans": [], "ref_spans": []}, {"section": "NEW DATASETS", "text": "The final paper in this special issue describes a new dataset.", "cite_spans": [], "ref_spans": []}, {"section": "NEW DATASETS", "text": "The work \"SALSA: A Novel Dataset for Multimodal Group Behaviour Analysis\" by X. Alameda-Pineda, J. Staiano, R. Subramanian, L. Batrinca, E. Ricci, B. Lepri, O. Lanz, and N. Sebe presents a dataset facilitating multimodal and Synergetic sociAL Scene Analysis. SALSA records social interactions among 18 participants in a natural, indoor environment for over 60 minutes. Challenges in the data include low-resolution images, lighting variations, numerous occlusions, reverberations and interfering sound sources. The authors also facilitate multimodal analysis by recording the social interplay using four static surveillance cameras and sociometric badges worn by each participant, comprising the microphone, accelerometer, bluetooth and infrared sensors. Additional annotations are also provided: individuals' personality, position, head, body orientation and F-formation information over the entire event duration.", "cite_spans": [], "ref_spans": []}, {"section": "RESEARCH OUTLOOK", "text": "This special issue summarizes the state of the art in the field of M2HuPBA, and presents interesting work that push the state of the art in the field, opening new lines of research and areas of applications. But we foresee many novel contributions still needed in order to solve some of the current requirements related to the generalization of human pose recovery and behavior analysis to uncontrolled environments and in the presence of arbitrary artifacts. We expect that new non-conventional modalities and fusion strategies with the support of new datasets for their evaluation will be important for further such advances. \" For more information on this or any other computing topic, please visit our Digital Library at www.computer.org/publications/dlib.", "cite_spans": [], "ref_spans": []}], "bib_entries": {}, "ref_entries": {"TABREF0": {"text": "S. Escalera is with the Mathematics and Informatics Department, Univer- sity of Barcelona, and the Computer Vision Center, Catalonia, Spain (http://www.sergioescalera.com). E-mail: sergio@maia.ub.es. J. Gonz alez is with the Universitat Aut onoma de Barcelona and the Com- puter Vision Center, Catalonia, Spain. E-mail: jordi.gonzalez@cvc.uab.es. X. Bar o is with the Universitat Oberta de Catalunya and the Computer Vision Center, Catalonia, Spain. E-mail: xbaro@uoc.edu. J. Shotton is with Microsoft Research, Cambridge, United Kingdom. E-mail: Jamie.Shotton@microsoft.com. For information on obtaining reprints of this article, please send e-mail to: reprints@ieee.org, and reference the Digital Object Identifier below.", "type": "table"}, "TABREF1": {"text": "Sergio Escalera received the PhD degree in multi-class learning from the Computer Vision Center, UAB. He received the 2008 best Thesis award. He leads the Human Pose Recovery and Behavior Analysis Group at UB, CVC, and BGSMath. He is an associate professor at the Mathematics and Informatics Department, UB. He is a partial time professor at UOC. He is a member of the Visual and Computational Learn- ing consolidated research group of Catalonia. He is member of the CVC. He is the Editor-in-Chief and editorial member of more than five journals. He is the director of ChaLearn. He is the co-founder of PhysicalTech and Care Respite companies. He is a member of BGSCMath, AERFAI, ACIA, and the vice-chair of IAPR TC-12: Multimedia and visual information systems. He has different patents and registered models. He has published more than 150 research papers and organized scientific events, includ- ing CCIA2004, CCIA2014, ICCV2011, and workshops at ICCV2011, ICMI2013, ECCV2014, CVPR2015, ICCV2015, CVPR2016. He has been the guest editor at IJCV, Neural Computing, TPAMI, JMLR. He has been AC of WACV2016 and NIPS2016. Jordi Gonz alez received the PhD degree in com- puter engineering from University Autnoma de Barcelona (UAB) in 2004. He is an associate pro- fessor in computer science at the Computer Sci- ence Department, UAB. He is also a research fellow at the Computer Vision Center, where he has co-founded three spin-offs and the Image Sequence Evaluation (ISE Lab) research group. His research interests include machine learning techniques for the computational interpretation of human behaviors in social images, or visual her- meneutics. He is a member of the Editorial Board of the journals Com- puter Vision and Image Understanding and IET Computer Vision. Xavier Bar o received the PhD degree in com- puter engineering from the Universitat Autnoma de Barcelona in 2009. He is currently a lecturer and researcher at the IT, Multimedia and Telecommunications Department at Universitat Oberta de Catalunya (UOC). He is the co-founder of the Scene Understanding and Artificial Intelli- gence group of the UOC, and collaborates with the Computer Vision Center of the UAB, as a member of the Human Pose Recovery and Behavior Analysis Group. His research interests include machine learning, evolutionary computation, and statistical pat- tern recognition, specially their applications to generic object recognition over huge cardinality image databases. Jamie Shotton studied computer science at the University of Cambridge. He leads the Machine Intelligence & Perception Group at Microsoft Research Cambridge. He joined Microsoft Research in 2008 where he is currently a Princi- pal Researcher. His research interests include the intersection of computer vision, AI, machine learning, and graphics, with particular emphasis on systems that allow people to interact naturally with computers. He has received multiple Best Paper and Best Demo awards at top academic conferences. His work on machine learning for body part recognition for Kinect was awarded the Royal Academy of Engineering's gold medal MacRobert Award 2011, and he shares Microsoft's Outstanding Techni- cal Achievement Award for 2012 with the Kinect engineering team. In 2014, he received the PAMI Young Researcher Award, and in 2015 the MIT Technology Review Innovator Under 35 Award.", "type": "table"}}}
{"paper_id": "17435830", "_pdf_hash": "d2fe28eb88c8a148362e2dbce77c7f6c09b35d7a", "abstract": [{"section": "Abstract", "text": "Crit Care Med 2014 \u2022 Volume 42 \u2022 12 (Suppl.) of the resuscitation effort, lesser post-resuscitation myocardial dysfunction, and improved survival. We investigated the effects of EPO on hemodynamic and myocardial function along with subsequent survival in a swine model of ventricular fibrillation (VF) and closed-chest resuscitation. Methods: VF was electrically induced in 16 male immature domestic pigs (35 to 41 kg) and left untreated for 8 minutes. Chest compression was delivered using a LUCAS device and defibrillation attempted 10 minutes later. Resuscitated pigs were observed for 120 minutes. Pigs were then recovered from anesthesia and observed for a maximum of 72 hours. Pigs were randomized 1:1 to receive 1,200 U/kg of EPO or vehicle control into the right atrium before starting chest compression. Results: LUCAS delivered CPR was highly effective hemodynamically yielding an aortic diastolic pressure of approximately 45 mmHg in both groups and a comparable resuscitation rate. Post-resuscitation there was comparable early hemodynamic and myocardial function as well as comparable organ blood flow but more control pigs died after resuscitation with only 2 of 8 control pigs and 6 of 8 EPO pigs surviving 72 hours (p = 0.048 by log-rank test). Demise -documented during the monitored period -was characterized by progressive hemodynamic deterioration. Conclusions: The present study is consistent with an emerging body of preclinical work and a single non-randomized, open-label, clinical study supporting a potential role of EPO for resuscitation for cardiac arrest. The present study failed to demonstrate effects during CPR or the early post-resuscitation phase but indicated an effect mitigating post-resuscitation myocardial and hemodynamic dysfunction that resulted in improved survival from cardiac arrest. A wide variability of use in ICUs has been identified with subsequent speculation that provider practice patterns as opposed to patient factors, including acuity, influence their use. A further understanding of CVC utilization by fellowshiptrained intensivists in a group practice would assist in risk-benefit analysis and facilitate consensus opinion on appropriate usage. Hypothesis: There would not be a significant difference in CVC use in ICUs managed by Pittsburgh Critical Care Associates (PCCA). Methods: A retrospective observational study utilizing data derived from an APACHE II B database that included three community hospital ICUs managed by PCCA, from January 1, 2013 to December 31 2013. Multivariate regression models were used to estimate the association between the presence and duration of a CVC at anytime during the ICU stay and APACHE II score on admission to the ICU, ICU length of stay, presence of an endotracheal tube (ET), presence of an arterial catheter (AC), and hyperalimentation (HAL). Results: 2,736 patients were admitted to the three ICU's in 2013, of which 423 received a CVC. The incidence was similar at ICU1 (9.6%) and ICU2 (12.7%), but higher at ICU3 (32.3%). ICU3 had higher acuity (mean APACHE II score 23.4 ICU3 vs. 18.8 ICU1 vs. 19.3 ICU2), longer ICU stays, and higher incidence of ET, AC, and HAL compared with ICU1 or ICU2. In a logistic regression model adjusting for APACHE II, ET, AC, HAL, and ICU days, the odds of CVC were 46.4% lower at ICU1 compared with ICU3 (OR 0.54; 95%CI 0.40-0.71) and 26.7% lower at ICU2 compared with ICU3 (OR 0.73; 95%CI 0.54-1.0). In contrast, a linear regression employing the same variables among those with CVC found that CVC duration was 0.52 days longer at ICU1 (95%CI -0.06 -1.1) and 0.64 days longer at ICU2 (95%CI 0.09-1.19). Conclusions: Significant variations in incidence and duration of CVCs in ICUs managed by the same intensivist group exist and are not fully explained by patient acuity. Learning Objectives: Continuous intravenous sedation is used frequently in the ICU to promote comfort and reduce anxiety associated with therapeutic modalities, such as mechanical ventilation. Nutrition support is also important to minimize metabolic demands. The contribution of sedation/analgesia, often with multiple pharmacologic agents, to resting energy expenditure (REE) is not well-described in the literature. The aim of this project was to examine the impact of these agents on REE by comparing predicted with measured REE obtained by indirect calorimetry (IC). Methods: This retrospective, correlational design used a convenience sample of adult ICU patients. Data from ICU patients during the period from October 2009 to present are summarized. Variables of interest include actual body weight, BMI, age, gender, respiratory quotient (RQ), VO2, VCO2, measured REE (MREE), predicted REE (PREE), use of sedatives/analgesics and dose classified as high or low, hospital day, and ventilator day. Results: 269 IC reports with sedative/analgesic data were available for review. Sample demographics are: mean age 60.5 (17.5) yrs, 62% male, 80% Caucasian, BMI 30.2, 71% receiving sedation/analgesia, mean hospital and ventilator days were 11.5 and 6.3, respectively. Mean (m) MREE 1792 + 585 kcals/d, mPREE 1585 + 329 kcals/d, mVO2 .260 (.08) L, mVCO2 .204 (.07) L, and mRQ .79 (.09). Hypermetabolic patients (V02 > .250 L; n=119) were younger (60.5 y) with a significantly greater MREE 2291 + 510 kcals/d than other ICU patients (n=147) who were older (70 y) with MREE 1389 + 215 kcals/d; p < .001. Amount of sedation/analgesia was correlated with MREE; high dose agents compared with no agents had higher MREE; mean difference of +355.9, SE 104.2; p=.002; this contradicts the assumption that higher levels of sedation/analgesia lower the REE. Conclusions: Both SCCM and ASPEN guidelines recommend the use of IC for critically ill patients. Energy needs are often unpredictable and hypermetabolism may not be reduced by sedative agents, even at higher doses. Further research into choice of sedative/analgesic agents and impact on REE is needed. Mayo Clinic (CCM), Rochester, MN Learning Objectives: Atrial fibrillation (AF) is the most common arrhythmia in the critically ill. However, data in the medical intensive care unit (MICU) is scare. This study was conducted to determine epidemiology and outcomes of newonset atrial fibrillation (NOAF) in non-cardiac and non-surgical ICU patients. Methods: Single center, retrospective cohort study of patients admitted to the MICU at Mayo Clinic, Rochester from 2008 to 2013. Patients were grouped into AF and no AF identified using ICD-9 diagnosis code 427.3x. AF cohort was further divided into NOAF and pre-existing AF. Demographics, comorbidities, CHADS2, and APACHE III scores were abstracted from the medical record along with outcomes such as vasopressor use, renal replacement therapy (RRT), mechanical ventilation (MV), length of stay (LOS) and mortality. Logistic regression analysis was used to compare outcomes of patients with NOAF, pre-existing AF, and no AF. Effects of age, CHADS2, and APACHE were adjusted for in regression models. Results: A total of 10,836 MICU patients were included in the study, of which 582 (5%) had NOAF, 2368 (22%) pre-existing AF, and 7886 (73%) no AF. Baseline characteristics were significantly different between groups (p<0.001) with AF patients being older (73.5 vs 78.6 vs 59.8). Hypertension was the most common comorbidity (68% vs 81% vs 53%). APACHE scores higher in the NOAF group (57 vs 54 vs 42). Outcomes significantly different (p<0.001) between cohorts with higher vasopressor use (33% vs 18% vs 12%); RRT (11% vs 9% vs 5%); MV (39% vs 22% vs 24%); MICU mortality (11% vs 8% vs 5%); and hospital mortality (20% vs 16% vs 8%) in the NOAF group. Logistic regression models comparing NOAF with no AF showed increased need for vasopressors (OR 2.45); RRT (OR 2.15); MV (OR 1.69); MICU and hospital mortality (OR 1.40; 1.63). Conclusions: NOAF was noted in 5% of MICU admissions. Our study suggests that even after adjusting for age, CHADS2 and APACHE III, NOAF patients exhibited poorer outcomes and higher resource utilization with increased need for vasopressors, RRT and MV along with higher MICU and hospital LOS and mortality. Learning Objectives: Readmissions occur in nearly 10% ICU discharges. Since readmissions are costly and often associated with high mortality, many tools have been devised and validated to prevent this from occurring. One such clinical tool is the Stability and Workload Index for Transfer (SWIFT) score which has been validated in several ICU centers worldwide. No study has of yet validated this tool in Asian population. Methods: We reviewed the records of all patients admitted/discharged from the medical ICU of a large university Hospital in Asia from January to June of 2008. The SWIFT score for each patient was calculated from their electronic medical records. The SWIFT score was then compared with the readmission rates to determine if it can be a valuable predictor for readmission in an Asian population. Results: 409 patients were admitted over the set time period. 59 patients were excluded from the study due to incomplete data [necessary for SWIFT score calculation]. 80 patients died before initial ICU discharge.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "VARIATION OF CENTRAL VENOUS CATHETER USAGE IN THREE ICUS MANAGED BY THE SAME INTENSIVIST GROUP", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "USING INDIRECT CALORIMETRY DATA TO ASSESS THE IMPACT OF SEDATIVES ON REE IN THE ICU", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "EPIDEMIOLOGY AND OUTCOMES OF NEW-ONSET ATRIAL FIBRILLATION IN THE ICU: A 6-YEAR RETROSPECTIVE STUDY", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "VALIDATION OF THE SWIFT SCORE FOR INTENSIVE CARE UNIT (ICU) READMISSIONS IN AN ASIAN POPULATION", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "", "text": "of the resuscitation effort, lesser post-resuscitation myocardial dysfunction, and improved survival. We investigated the effects of EPO on hemodynamic and myocardial function along with subsequent survival in a swine model of ventricular fibrillation (VF) and closed-chest resuscitation. Methods: VF was electrically induced in 16 male immature domestic pigs (35 to 41 kg) and left untreated for 8 minutes. Chest compression was delivered using a LUCAS device and defibrillation attempted 10 minutes later. Resuscitated pigs were observed for 120 minutes. Pigs were then recovered from anesthesia and observed for a maximum of 72 hours. Pigs were randomized 1:1 to receive 1,200 U/kg of EPO or vehicle control into the right atrium before starting chest compression. Results: LUCAS delivered CPR was highly effective hemodynamically yielding an aortic diastolic pressure of approximately 45 mmHg in both groups and a comparable resuscitation rate. Post-resuscitation there was comparable early hemodynamic and myocardial function as well as comparable organ blood flow but more control pigs died after resuscitation with only 2 of 8 control pigs and 6 of 8 EPO pigs surviving 72 hours (p = 0.048 by log-rank test). Demise -documented during the monitored period -was characterized by progressive hemodynamic deterioration. Conclusions: The present study is consistent with an emerging body of preclinical work and a single non-randomized, open-label, clinical study supporting a potential role of EPO for resuscitation for cardiac arrest. The present study failed to demonstrate effects during CPR or the early post-resuscitation phase but indicated an effect mitigating post-resuscitation myocardial and hemodynamic dysfunction that resulted in improved survival from cardiac arrest. A wide variability of use in ICUs has been identified with subsequent speculation that provider practice patterns as opposed to patient factors, including acuity, influence their use. A further understanding of CVC utilization by fellowshiptrained intensivists in a group practice would assist in risk-benefit analysis and facilitate consensus opinion on appropriate usage. Hypothesis: There would not be a significant difference in CVC use in ICUs managed by Pittsburgh Critical Care Associates (PCCA). Methods: A retrospective observational study utilizing data derived from an APACHE II B database that included three community hospital ICUs managed by PCCA, from January 1, 2013 to December 31 2013. Multivariate regression models were used to estimate the association between the presence and duration of a CVC at anytime during the ICU stay and APACHE II score on admission to the ICU, ICU length of stay, presence of an endotracheal tube (ET), presence of an arterial catheter (AC), and hyperalimentation (HAL). Results: 2,736 patients were admitted to the three ICU's in 2013, of which 423 received a CVC. The incidence was similar at ICU1 (9.6%) and ICU2 (12.7%), but higher at ICU3 (32.3%). ICU3 had higher acuity (mean APACHE II score 23.4 ICU3 vs. 18.8 ICU1 vs. 19.3 ICU2) , longer ICU stays, and higher incidence of ET, AC, and HAL compared with ICU1 or ICU2. In a logistic regression model adjusting for APACHE II, ET, AC, HAL, and ICU days, the odds of CVC were 46.4% lower at ICU1 compared with ICU3 (OR 0.54; 95%CI 0.40-0.71) and 26.7% lower at ICU2 compared with ICU3 (OR 0.73; 95%CI 0.54-1.0). In contrast, a linear regression employing the same variables among those with CVC found that CVC duration was 0.52 days longer at ICU1 (95%CI -0.06 -1.1) and 0.64 days longer at ICU2 (95%CI 0.09-1.19). Conclusions: Significant variations in incidence and duration of CVCs in ICUs managed by the same intensivist group exist and are not fully explained by patient acuity. Learning Objectives: Continuous intravenous sedation is used frequently in the ICU to promote comfort and reduce anxiety associated with therapeutic modalities, such as mechanical ventilation. Nutrition support is also important to minimize metabolic demands. The contribution of sedation/analgesia, often with multiple pharmacologic agents, to resting energy expenditure (REE) is not well-described in the literature. The aim of this project was to examine the impact of these agents on REE by comparing predicted with measured REE obtained by indirect calorimetry (IC). Methods: This retrospective, correlational design used a convenience sample of adult ICU patients. Data from ICU patients during the period from October 2009 to present are summarized. Variables of interest include actual body weight, BMI, age, gender, respiratory quotient (RQ), VO2, VCO2, measured REE (MREE), predicted REE (PREE), use of sedatives/analgesics and dose classified as high or low, hospital day, and ventilator day. Results: 269 IC reports with sedative/analgesic data were available for review. Sample demographics are: mean age 60.5 (17.5) yrs, 62% male, 80% Caucasian, BMI 30.2, 71% receiving sedation/analgesia, mean hospital and ventilator days were 11.5 and 6.3, respectively. Mean (m) MREE 1792 + 585 kcals/d, mPREE 1585 + 329 kcals/d, mVO2 .260 (.08) L, mVCO2 .204 (.07) L, and mRQ .79 (.09). Hypermetabolic patients (V02 > .250 L; n=119) were younger (60.5 y) with a significantly greater MREE 2291 + 510 kcals/d than other ICU patients (n=147) who were older (70 y) with MREE 1389 + 215 kcals/d; p < .001. Amount of sedation/analgesia was correlated with MREE; high dose agents compared with no agents had higher MREE; mean difference of +355.9, SE 104.2; p=.002; this contradicts the assumption that higher levels of sedation/analgesia lower the REE. Conclusions: Both SCCM and ASPEN guidelines recommend the use of IC for critically ill patients. Energy needs are often unpredictable and hypermetabolism may not be reduced by sedative agents, even at higher doses. Further research into choice of sedative/analgesic agents and impact on REE is needed. Mayo Clinic (CCM), Rochester, MN Learning Objectives: Atrial fibrillation (AF) is the most common arrhythmia in the critically ill. However, data in the medical intensive care unit (MICU) is scare. This study was conducted to determine epidemiology and outcomes of newonset atrial fibrillation (NOAF) in non-cardiac and non-surgical ICU patients. Methods: Single center, retrospective cohort study of patients admitted to the MICU at Mayo Clinic, Rochester from 2008 to 2013. Patients were grouped into AF and no AF identified using ICD-9 diagnosis code 427.3x. AF cohort was further divided into NOAF and pre-existing AF. Demographics, comorbidities, CHADS2, and APACHE III scores were abstracted from the medical record along with outcomes such as vasopressor use, renal replacement therapy (RRT), mechanical ventilation (MV), length of stay (LOS) and mortality. Logistic regression analysis was used to compare outcomes of patients with NOAF, pre-existing AF, and no AF. Effects of age, CHADS2, and APACHE were adjusted for in regression models. Results: A total of 10,836 MICU patients were included in the study, of which 582 (5%) had NOAF, 2368 (22%) pre-existing AF, and 7886 (73%) no AF. Baseline characteristics were significantly different between groups (p<0.001) with AF patients being older (73.5 vs 78.6 vs 59.8). Hypertension was the most common comorbidity (68% vs 81% vs 53%). APACHE scores higher in the NOAF group (57 vs 54 vs 42). Outcomes significantly different (p<0.001) between cohorts with higher vasopressor use (33% vs 18% vs 12%); RRT (11% vs 9% vs 5%); MV (39% vs 22% vs 24%); MICU mortality (11% vs 8% vs 5%); and hospital mortality (20% vs 16% vs 8%) in the NOAF group. Logistic regression models comparing NOAF with no AF showed increased need for vasopressors (OR 2.45); RRT (OR 2.15); MV (OR 1.69); MICU and hospital mortality (OR 1.40; 1.63). Conclusions: NOAF was noted in 5% of MICU admissions. Our study suggests that even after adjusting for age, CHADS2 and APACHE III, NOAF patients exhibited poorer outcomes and higher resource utilization with increased need for vasopressors, RRT and MV along with higher MICU and hospital LOS and mortality. Learning Objectives: Readmissions occur in nearly 10% ICU discharges. Since readmissions are costly and often associated with high mortality, many tools have been devised and validated to prevent this from occurring. One such clinical tool is the Stability and Workload Index for Transfer (SWIFT) score which has been validated in several ICU centers worldwide. No study has of yet validated this tool in Asian population. Methods: We reviewed the records of all patients admitted/discharged from the medical ICU of a large university Hospital in Asia from January to June of 2008. The SWIFT score for each patient was calculated from their electronic medical records. The SWIFT score was then compared with the readmission rates to determine if it can be a valuable predictor for readmission in an Asian population. Results: 409 patients were admitted over the set time period. 59 patients were excluded from the study due to incomplete data [necessary for SWIFT score calculation]. 80 patients died before initial ICU discharge.", "cite_spans": [], "ref_spans": []}, {"section": "VARIATION OF CENTRAL VENOUS CATHETER USAGE IN THREE ICUS MANAGED BY THE SAME INTENSIVIST GROUP", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "USING INDIRECT CALORIMETRY DATA TO ASSESS THE IMPACT OF SEDATIVES ON REE IN THE ICU", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "EPIDEMIOLOGY AND OUTCOMES OF NEW-ONSET ATRIAL FIBRILLATION IN THE ICU: A 6-YEAR RETROSPECTIVE STUDY", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "VALIDATION OF THE SWIFT SCORE FOR INTENSIVE CARE UNIT (ICU) READMISSIONS IN AN ASIAN POPULATION", "text": "", "cite_spans": [], "ref_spans": []}], "bib_entries": {}, "ref_entries": {"TABREF0": {"text": "Learning Objectives: The complications and costs associated with central venous catheters (CVC) have led to much interest in their incidence and epidemiology.", "type": "table"}}}
{"paper_id": "17435941", "_pdf_hash": "bac0448adc2b715601cf691aa2397230ebf59e81", "abstract": [{"section": "Abstract", "text": "ABSTRACT. We introduce a new invariant S (M ) for type III factors M with no almost-periodic weights. We compute this invariant for certain free Araki-Woods factors. We show that Connes' invariant \u03c4 cannot distinguish all isomorphism classes of free Araki-Woods factors. We show that there exists a continuum of mutually non-isomorphic free Araki-Woods factors, each without almostperiodic weights.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION.", "text": "The necessity to find effective invariants to distinguish full type III factors comes from the problem of classifying type III factors naturally occurring in free probability theory of Voiculescu [22] . These factors arise as free products of finite-dimensional or hyperfinite von Neumann algebras [1, 14, 13, 6] and more generally from a second-quantization procedure involving the free Gaussian functor (the so-called free Araki-Woods factors, [15] ). The classification results so far all relied on Connes' S and Sd invariants [3, 4] , and worked well for factors having almost periodic weights (for example, in [15] a complete classification of free Araki-Woods factors for which the free quasi-free state is almost-periodic was given). However, not all free Araki-Woods factors have almost periodic weights [17] , and the question of their complete classification remains open.", "cite_spans": [{"start": 298, "end": 301, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 306, "end": 309, "text": "13,", "ref_id": "BIBREF9"}, {"start": 310, "end": 312, "text": "6]", "ref_id": "BIBREF2"}, {"start": 446, "end": 450, "text": "[15]", "ref_id": "BIBREF10"}, {"start": 615, "end": 619, "text": "[15]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "INTRODUCTION.", "text": "This paper is devoted to the exploration of free Araki-Woods factors, having no almost-periodic states or weights. The most refined existing invariant for such factors is Connes' \u03c4 invariant [3, 4] , which measures the \"degree of continuity\" of the states on M.", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION.", "text": "We introduce a new invariant for a factor M, given by the intersection over the set of all normal faithful states (or weights) \u03c6 on M of the collections of measures, absolutely continuous with respect to the spectral measure of the modular operator of \u03c6. This invariant is in spirit related to the Connes' Sd invariant, where the intersection is taken over all almost-periodic weights on M. Amazingly, it turns out that our invariant can be computed for certain free Araki-Woods classes.", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION.", "text": "Using this invariant we are able to produce a pair of non-isomorphic free Araki-Woods factors, which cannot be distinguished by their \u03c4 invariant.", "cite_spans": [], "ref_spans": []}, {"section": "Spectral measures of group representations.", "text": "Let \u00b5 be a measure on a measure space X. Denote by C \u00b5 the collection of measures on X C \u00b5 = {\u03bd : \u00b5(Y ) = 0 \u21d2 \u03bd(Y ) = 0 for all measurable Y \u2282 X}.", "cite_spans": [], "ref_spans": []}, {"section": "Spectral measures of group representations.", "text": "In other words, C \u00b5 is the collection of all measures, which are absolutely continuous with respect to \u00b5. We shall abuse notation and write C T if T is a self-adjoint operator. By this we mean the collection of all measures, absolutely continuous with respect to the spectral measure of T on R.", "cite_spans": [], "ref_spans": []}, {"section": "Spectral measures of group representations.", "text": "It should be mentioned that, following an idea of Mackey, C \u00b5 can be viewed as a kind of replacement for the notion of the support of \u00b5. Indeed, any \u03bd \u2208 C \u00b5 can be written as f \u00b7 \u00b5 for some function f , which is completely determined except on a set of \u00b5-measure zero. One can form intersections of two families C \u00b5 and C \u03bd ; this operation is to remind us of the notion of intersection of sets. Similarly, inclusion of C \u00b5 and C \u03bd can be thought of as the inclusion of the support of \u00b5 into that of \u03bd. We shall say that a collection of measures C is supported on a set Y if for all \u03bd \u2208 C , the complement of Y has measure zero. Note also that if \u00b5 is atomic, then the knowledge of C \u00b5 is exactly equivalent to the knowledge of the set of atoms of \u00b5.", "cite_spans": [], "ref_spans": []}, {"section": "Spectral measures of group representations.", "text": "We now recall some basic facts about representations and duality of locally compact abelian groups (see e.g. [10] ). Let \u03c3 : G \u2192 U(H) be a * -strongly continuous representation of G on a Hilbert space H. Associated to \u03c3 it is spectral measure class C \u03c3 on the dual group\u011c. The class C \u03c3 can be defined as the smallest collection of measures, so that (1) if \u00b5 \u2208 C \u03c3 and \u00b5 \u2032 is a.c. with respect to \u00b5, then \u00b5 \u2032 \u2208 C \u03c3 and (2) for each \u03be \u2208 H, the measure obtained as the Fourier transform of the positive-definite function g \u2192 \u03be, \u03c3(g)\u03be belongs to C \u03c3 . If H is separable, there is a measure \u00b5 in C \u03c3 , with the property that it generates C \u03c3 (i.e., C \u03c3 is the smallest collection of measures satisfying (1) and containing \u00b5). We sometimes refer to this \u00b5 as \"the\" spectral measure of \u03c3. In particular, H can be decomposed as H = \u03c7\u2208\u011c H \u03c7 d\u00b5(\u03c7), so that \u03c3 = \u03c7\u2208\u011c \u03c3 \u03c7 , where", "cite_spans": [{"start": 109, "end": 113, "text": "[10]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Spectral measures of group representations.", "text": "If the group G contains R as a dense subgroup, the representation \u03c3 can be restricted to R \u2282 G. In fact, all representations \u03c3 of G arise as extensions of representations of R, which are continuous not just in the topology on R, but also in the restriction of the topology \u03c4 G on G to R \u2282 G. The measure class C \u03c3 and the spectral measure \u00b5 of \u03c3, when interpreted as objects on R \u2283\u011c become exactly the measure class and the spectral measure of the restriction of \u03c3 to R, viewed as a representation of R (this is evident from the direct integral decomposition formula stated above). In particular, a representation \u03c0 of R extends to a representation of G iff its spectral measure C \u03c0 is supported on\u011c \u2282 R.", "cite_spans": [], "ref_spans": []}, {"section": "Spectral measures of group representations.", "text": "It is customary to choose a particular spectral measure of a representation of R on H, by finding on H a non-negative operator A, for which \u03c0(t) = A it , and letting \u00b5 be the spectral measure of A (composed with some faithful state on B(H)). In particular, denoting by \u03c3 the extension of \u03c0 to G, we have C \u03c3 = C \u03c0 = C \u2206 .", "cite_spans": [], "ref_spans": []}, {"section": "Topologies induced by unitary or orthogonal representations of R.", "text": "Let \u00b5 be a measure on the real line, so that \u00b5(\u2212X) = \u00b5(X). Denote by \u03c0 the associated (real or complex) representation of R on L 2 (R, \u00b5) given by the map", "cite_spans": [], "ref_spans": []}, {"section": "Topologies induced by unitary or orthogonal representations of R.", "text": "where M g denotes the operator of multiplication by g. Write \u03c4 (\u00b5) for the weakest topology making the map t \u2192 \u03c0(t) \u2208 U(L 2 (R, \u00b5)) continuous with respect to the strong operator topology on the unitary group of L 2 (R, \u00b5). If \u00b5 is not supported on a cyclic subgroup of R, \u03c0 is injective and \u03c4 (\u00b5) is a Hausdorff topology. Proposition 2.1. The completion of R with respect to the topology \u03c4 (\u00b5) is a locally compact group iff either \u03c4 (\u00b5) is the usual topology on R, or \u00b5 is atomic (in which case the completion is compact).", "cite_spans": [], "ref_spans": []}, {"section": "Topologies induced by unitary or orthogonal representations of R.", "text": "Proof. Denote by (G, \u03c4 ) the completion of (R, \u03c4 (\u00b5)). Then R \u2282 G is an inclusion of locally compact abelian groups; by Pontrjagin duality, this inclusion is dual to the injective dense inclusion G \u2282 R.", "cite_spans": [], "ref_spans": []}, {"section": "Topologies induced by unitary or orthogonal representations of R.", "text": "By the structure theory for locally compact abelian groups [10] , the connected component of identity of\u011c must have the form R \u00d7 H, with R \u223c = R n and H compact and connected. First note that H = {e}. Indeed, the image of H in R must be a connected compact subgroup of R, hence must be the trivial group.", "cite_spans": [{"start": 59, "end": 63, "text": "[10]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Topologies induced by unitary or orthogonal representations of R.", "text": "Since there are no continuous injective maps from R n into R for n > 1, either n = 1 or n = 0. If n = 1, all continuous injective group homomorphisms from R to itself are surjective (their image must be a path-connected subgroup of R). Hence injectivity of\u011c \u2282 R requires that\u011c = R in this case, the inclusion be a homeomorphism onto R and hence \u03c4 (\u00b5) be the usual topology on R.", "cite_spans": [], "ref_spans": []}, {"section": "Topologies induced by unitary or orthogonal representations of R.", "text": "If n = 0,\u011c must be discrete. This corresponds to the completion G being compact. Moreover, it is not hard to see that \u00b5 must be supported on\u011c \u2282 R, since the representation \u03c0 with spectral measure \u00b5 must extend (by the definition of \u03c4 (\u00b5)) to the completion G. Hence \u00b5 is atomic. Proof. Let \u03c0 be a representation of R associated to \u00b5 as above, and let \u03be \u2208 L 2 (R, \u00b5) be the constant function 1. Then\u03bc", "cite_spans": [], "ref_spans": []}, {"section": "Topologies induced by unitary or orthogonal representations of R.", "text": "By definition, t n \u2192 0 in \u03c4 (\u00b5) iff \u03c0(t n ) \u2192 1 strongly. The vector state \u03c6(T ) = T \u03be, \u03be defines a faithful normal state on the commutative von Neumann algebra \u03c0(R) \u2032\u2032 \u2282 B(L 2 (R, \u00b5)). Hence strong convergence of \u03c0(t n ) to 1 is equivalent to", "cite_spans": [], "ref_spans": []}, {"section": "Topologies induced by unitary or orthogonal representations of R.", "text": "In other words, \u03c0(t n ) \u2192 1 strongly iff", "cite_spans": [], "ref_spans": []}, {"section": "Topologies induced by unitary or orthogonal representations of R.", "text": "Theorem 2.3. There exists a continuum of non-atomic measures \u00b5 \u03bb , \u03bb \u2208 I so that the topologies \u03c4 (\u00b5 \u03bb ) are mutually non-equivalent.", "cite_spans": [], "ref_spans": []}, {"section": "Topologies induced by unitary or orthogonal representations of R.", "text": "Proof. Let {c n : n = 1, 2, . . . } be a sequence of real numbers, so that c n \u2265 0, and c 2 k < +\u221e. Denote by \u00b5 n the n-fold convolution of delta-measures", "cite_spans": [], "ref_spans": []}, {"section": "Topologies induced by unitary or orthogonal representations of R.", "text": "Each \u00b5 n is a symmetric probability measure; and the Fourier transform of \u00b5 n is given b\u0177", "cite_spans": [], "ref_spans": []}, {"section": "Topologies induced by unitary or orthogonal representations of R.", "text": "The Fourier transform of the weak limit \u00b5 of \u00b5 n is given by the pointwise limit of this expression; the measure \u00b5 is non-atomic (see e.g. [8] ).", "cite_spans": [{"start": 139, "end": 142, "text": "[8]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Topologies induced by unitary or orthogonal representations of R.", "text": "There exists \u03c9 > 0 so that for 0 \u2264 x \u2264 \u03c9, cos(2\u03c0x", "cite_spans": [], "ref_spans": []}, {"section": "Topologies induced by unitary or orthogonal representations of R.", "text": "as long as k > n and n is such that", "cite_spans": [], "ref_spans": []}, {"section": "Topologies induced by unitary or orthogonal representations of R.", "text": "uniformly, and the function p \u2192 (1 \u2212 49a p ) p is increasing for any a < 1, given 1 > \u03b4 > 0, there exists a p = p(\u03b4) < +\u221e, so that", "cite_spans": [], "ref_spans": []}, {"section": "Topologies induced by unitary or orthogonal representations of R.", "text": "for all a \u2208 [0, 1/2]. Hence letting a = 1 6 , we get that for any n so that k! \u2212 n! \u2265 n \u00b7 n! > p,", "cite_spans": [], "ref_spans": []}, {"section": "Topologies induced by unitary or orthogonal representations of R.", "text": "Since log(1 \u2212 \u03b4) < 0, and", "cite_spans": [], "ref_spans": []}, {"section": "Topologies induced by unitary or orthogonal representations of R.", "text": "we get that", "cite_spans": [], "ref_spans": []}, {"section": "Topologies induced by unitary or orthogonal representations of R.", "text": "e for any n so that (1) 3 \u2212n\u00b7n! < \u03c9 and (2) n \u00b7 n! > p(\u03b4). It follows that\u03bc(t n ) \u2192 1 as n \u2192 \u221e. Now fix 0 < \u03bb < 1 and set", "cite_spans": [], "ref_spans": []}, {"section": "Topologies induced by unitary or orthogonal representations of R.", "text": "for any Borel set X \u2282 R. Then\u03bc \u03bb (t) =\u03bc(t/\u03bb). It follows that for any 0 < \u03bd \u2264 \u03bb, the sequence \u03bd3 n! is convergent to 0 in \u03c4 (\u00b5 \u03bb ) iff \u03bd = \u03bb. It follows that {\u03c4 (\u00b5 \u03bb ) : 0 < \u03bb \u2264 1} are pairwise non-equivalent.", "cite_spans": [], "ref_spans": []}, {"section": "Topologies induced by unitary or orthogonal representations of R.", "text": "The author is indebted to U. Haagerup for communicating to him the following example: Proof. Let \u00b5 be as in the proof of Theorem 2.3, with c n = 3 \u2212n . Then", "cite_spans": [], "ref_spans": []}, {"section": "Topologies induced by unitary or orthogonal representations of R.", "text": "We first claim that \u03c4 (\u00b5) is the usual topology on the real line. Assume that", "cite_spans": [], "ref_spans": []}, {"section": "Topologies induced by unitary or orthogonal representations of R.", "text": "It is not hard to see that f (c) is strictly less than 1 on the interval 1 < c \u2264 3. It follows that \u00b5(t) < 1 whenever t > 9. Contradiction. All convolution powers of \u00b5 are singular with respect to Lebesgue measure (see the discussion of Taylor-Johnson measures [8] for examples of similar measures \u00b5 but satisfying even stronger properties than what we need here).", "cite_spans": [{"start": 261, "end": 264, "text": "[8]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "Topologies induced by unitary or orthogonal representations of R.", "text": "2.3. Bimodule decompositions of crossed products. Let (M, \u03c6) be a von Neumann algebra, \u03c6 a faithful normal state, and let G be a locally compact abelian group. Assume that \u03b1 is an action of G on M, which leaves \u03c6 invariant. Then the crossed product von Neumann algebra", "cite_spans": [], "ref_spans": []}, {"section": "Topologies induced by unitary or orthogonal representations of R.", "text": "; moreover, the weight \u03c6 gives rise to a normal faithful conditional expectation E : C \u2192 A. Let\u03c8 be a normal faithful weight on A, and let \u03c8 =\u03c8 \u2022 E. This is a normal faithful weight on C. Moreover,", "cite_spans": [], "ref_spans": []}, {"section": "Topologies induced by unitary or orthogonal representations of R.", "text": "Denote by \u2113 2 the Hilbert space with basis e 1 , e 2 , . . . and by \u2113 n \u2282 \u2113 2 the subspaces spanned by e 1 , . . . , e n . Given a measure \u03b7 on X \u00d7 X whose projections onto the the coordinate directions on X \u00d7X are both equivalent to \u03bd G , and a multiplicity function n :", "cite_spans": [], "ref_spans": []}, {"section": "Topologies induced by unitary or orthogonal representations of R.", "text": "be the space of square-integrable functions from X \u00d7 X \u2192 \u2113 2 , so that f (x, y) \u2208 \u2113 n(x,y) for all x, y \u2208 X (where for convenience we set \u2113 \u221e = \u2113 2 ). Endow H(\u03b7, n) with an A,A-bimodule structure by letting", "cite_spans": [], "ref_spans": []}, {"section": "Topologies induced by unitary or orthogonal representations of R.", "text": "In fact [2, 11, 5] any bimodule over A can be represented in this way. It is easily seen that if \u03b7 \u2032 is another measure on X \u00d7 X, projecting onto \u00b5, and \u03b7 \u2032 is mutually absolutely continuous with \u03b7,", "cite_spans": [{"start": 8, "end": 11, "text": "[2,", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Topologies induced by unitary or orthogonal representations of R.", "text": ", a measure \u00b5 on\u011c and a multiplicity function n :\u011c \u2192 N, so that:", "cite_spans": [], "ref_spans": []}, {"section": "Topologies induced by unitary or orthogonal representations of R.", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "Topologies induced by unitary or orthogonal representations of R.", "text": "be a measure and a multiplicity function on\u011c \u00d7\u011c, and let H = H(\u03b7, n) (note that the projections of \u03b7 onto the coordinate directions are precisely", "cite_spans": [], "ref_spans": []}, {"section": "Topologies induced by unitary or orthogonal representations of R.", "text": "To see this, one can verify that the map", "cite_spans": [], "ref_spans": []}, {"section": "Topologies induced by unitary or orthogonal representations of R.", "text": "Note that the measure \u00b5 (which is the \"spectral measure\" of the representation of G on L 2 (M)) is uniquely determined up to absolute continuity by the L(G), L(G)-bimodule structure of L 2 (C, \u03c8).", "cite_spans": [], "ref_spans": []}, {"section": "FULL TYPE III FACTORS.", "text": "Assume that M is a full factor, so that its group of inner automorphisms Inn(M) is a closed subgroup of the group of all automorphisms Aut(M), endowed with the u-topology [9, 4] . Let Out(M) = Aut(M)/ Inn(M), with the quotient topology. Denote by \u03c0 the quotient map from Aut(M) to Out(M), and by \u03b4 the composition \u03c0 \u2022 \u03c3 \u03c6 t (which is independent of t by Connes' Radon-Nikodym type theorem [3] ).", "cite_spans": [{"start": 171, "end": 174, "text": "[9,", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "FULL TYPE III FACTORS.", "text": "Assume that the action of R on M by t \u2192 \u03c3 \u03c6 t extends, for some \u03c6, to an action of a locally compact completion G of R (by Proposition 2.1 above, this means that either G is just R, or G is compact, and \u03c6 is almost-periodic). In this case, call \u03c6 a G-state (or weight) on M. Call the crossed product", "cite_spans": [], "ref_spans": []}, {"section": "FULL TYPE III FACTORS.", "text": "It is known [3, 4] that the G-core of M is independent of the choice of the G-the state \u03c6 (having the property that its modular group extends to G). Denote by \u03c4 \u03c6 the weakest topology on R making the modular group \u03c3 \u03c6 t of a normal faithful semifinite weight \u03c6 on M continuous in the u-topology on Aut(M). Then define \u03c4 (M) to be the weakest topology among all \u03c4 \u03c6 . In other words, t n \u2192 t in \u03c4 (M) iff \u03c3 \u03c6 tn\u2212t \u2192 id for some normal faithful semifinite weight \u03c6 on M; (c) The S invariant to be the intersection", "cite_spans": [], "ref_spans": []}, {"section": "FULL TYPE III FACTORS.", "text": "We similarly define", "cite_spans": [], "ref_spans": []}, {"section": "FULL TYPE III FACTORS.", "text": "Part (c) of the definition is equivalent to the Sd invariant of Connes [4] if the intersection were to be taken over all faithful normal almost-periodic weights.", "cite_spans": [], "ref_spans": []}, {"section": "FULL TYPE III FACTORS.", "text": "Note that since we are dealing only with states in the definition of S (M), the delta measure at 1 is always in S (M).", "cite_spans": [], "ref_spans": []}, {"section": "FULL TYPE III FACTORS.", "text": "Note that \u03c4 (M) is not weaker than \u03c4 (M). ", "cite_spans": [], "ref_spans": []}, {"section": "FULL TYPE III FACTORS.", "text": "Then the spectral measure class \u2206 \u03c6 \u2297 d is the Lebesgue measure \u03bb on R, since the left regular representation of R is absorbing for tensor products. Hence W (M) can be no bigger than the class of the Lebesgue measure.", "cite_spans": [], "ref_spans": []}, {"section": "FULL TYPE III FACTORS.", "text": "Assume that the G-core of M is a factor. Note that since the G-core has a semifinite normal trace, it is a full iff its compression by a finite projection is non-\u0393. In particular, if the G core is a factor and is full, it has no non-trivial central sequences. ", "cite_spans": [], "ref_spans": []}, {"section": "FULL TYPE III FACTORS.", "text": "Hence m n is an asymptotically central sequence in C. Since C is assumed to be a full factor, and is of type II \u221e , we have arrived at a contradiction.", "cite_spans": [], "ref_spans": []}, {"section": "FULL TYPE III FACTORS.", "text": "Theorem 3.4. Assume that for some G-state \u03c6 on M, the G-core of M is a full factor. Then if for some H not necessarily locally compact containing R as a dense subgroup, there is an H-weight \u03c8 on M, one must have that H \u2282 G.", "cite_spans": [], "ref_spans": []}, {"section": "FULL TYPE III FACTORS.", "text": "Proof. Let C = M \u22ca \u03c3 \u03c6 G. Let L(G) \u2282 C be the canonical copy of the group algebra of G; for g \u2208 G, denote by w g \u2208 L(G) the implementing unitary. We write E L(G) for the canonical conditional expectation from C onto L(G).", "cite_spans": [], "ref_spans": []}, {"section": "FULL TYPE III FACTORS.", "text": "Assume that H \u2282 G, so that the topology defined by the inclusion R \u2282 H is not stronger than the topology defined by the inclusion R \u2282 G. Hence there exists a sequence t n \u2208 R, so that \u03c3", "cite_spans": [], "ref_spans": []}, {"section": "FULL TYPE III FACTORS.", "text": "Ad utwt | C = \u03c3 \u03c8 t . In particular, [u tn w tn , x] \u2192 0 * -strongly for all x \u2208 M \u2282 C. Note moreover that u t w t commutes with u s w s (since they form a one-parameter subgroup of U(C)). Hence for s fixed, [u tn w tn , u s w s ] = 0, and since u tn w tn asymptotically commutes with M \u2282 C, it follows that also [u tn w tn , w s ] \u2192 0 * -strongly. It follows that u tn w tn is a central sequence in M. Hence, by the assumption that C is a full factor, and by the fact that C is type II \u221e , we find that \u03bb n u tn w tn \u2192 1 * -strongly for some scalars \u03bb n \u2208 T. But then E L(G) (\u03bb n u tn w tn ) \u2192 1 * -strongly. Since u tn \u2208 M \u2282 C, E L(G) (u tn ) \u2208 C, so that \u03bb \u2032 n w tn \u2192 1 * -strongly for some sequence \u03bb \u2032 n \u2208 C, |\u03bb| \u2264 1. Hence \u03bb \u2032 n \u03c0(t n ) \u2192 1 * -strongly, where \u03c0 is the left regular representation of G (since the representation of G on L 2 (C, Tr) is a multiple of its left regular representation). Choose now \u03c6 a function on G, supported in a compact neighborhood of identity and so that", "cite_spans": [], "ref_spans": []}, {"section": "FULL TYPE III FACTORS.", "text": "In particular, it means that the support X of \u03c6 and its translate X + t n cannot be disjoint once n is sufficiently large. It follows that t n \u2208 X \u2212 X for sufficiently large n. It follows that t n \u2192 0 in G. Contradiction.", "cite_spans": [], "ref_spans": []}, {"section": "Corollary 3.5. If the G-core of M is full, then \u03c4 (M) = \u03c4 G , the weakest topology making the inclusion R \u2282 G continuous.", "text": "We also have:", "cite_spans": [], "ref_spans": []}, {"section": "Proposition 3.6. If M has a G-state and G \u2282 H is a proper inclusion of locally compact abelian groups, then the H-core of M is not a full factor.", "text": "Proof. Let \u03c6 be a G-state on M, and denote by C the H-core M \u22ca \u03c3 \u03c6 H. Assume that C is a factor. By assumption, there exists a sequence t n \u2208 R, t n \u2192 0 in the topology of G, but t n not convergent in H. Denote by w h \u2208 C, h \u2208 H, the implementing unitaries for the H action on M. Then Ad wt n (x) \u2192 x * -strongly for all x \u2208 M \u2282 C; moreover, Ad wt n (w) = w for all w \u2208 W * (w h : h \u2208 H) = L(H). Hence w tn form a central sequence. Arguing exactly as in the last paragraph of the proof of Theorem 3.4 we find that for no sequence of scalars \u03bb n \u2208 T does \u03bb n w tn \u2192 1 * -strongly in the group algebra L(H). Hence w tn is a non-trivial central sequence in M.", "cite_spans": [], "ref_spans": []}, {"section": "Proposition 3.6. If M has a G-state and G \u2282 H is a proper inclusion of locally compact abelian groups, then the H-core of M is not a full factor.", "text": "Choose p \u2208 L(H) \u2282 C a projection of finite trace. Then [p, w tn ] = 0 and hence pw tn p is a central sequence in pCp, which has a finite trace. Thus pCp has property \u0393. Hence by Connes' results [4], pCp and hence C is not full.", "cite_spans": [], "ref_spans": []}, {"section": "CROSSED PRODUCTS, FREE ENTROPY DIMENSION AND THE S INVARIANT.", "text": "The main result of this section is a computation of the W and S invariants of some type III factors M, for which the core has a sequence of generators with large free entropy dimension. We first recall some preliminaries.", "cite_spans": [], "ref_spans": []}, {"section": "Free entropy dimension for infinite families of generators. It is useful for us to consider", "text": "Voiculescu's free entropy dimension in the context of an infinite family of generators x 1 , x 2 , . . . in a von Neumann algebra M. We point out the necessary modifications of Voiculescu's approach ([20, 21]; see also [18] , where a similar modification was necessary). We freely use the notations of [19, 20, 21] .", "cite_spans": [{"start": 302, "end": 306, "text": "[19,", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "Free entropy dimension for infinite families of generators. It is useful for us to consider", "text": "Let x i , 1 \u2264 i < +\u221e and y i , 1 \u2264 i < +\u221e be in M. Fix a free ultrafilter \u03c9 and an element \u03ba in the Stone-Chech compactification of (0, 1], not lying in this interval. Define", "cite_spans": [], "ref_spans": []}, {"section": "Free entropy dimension for infinite families of generators. It is useful for us to consider", "text": "(note that the lim inf is actually a limit in this definition). Define \u03c7 \u03c9 (x 1 , . . . , x p : y 1 , y 2 , . . . ) in exactly the same way as in [20] , but using \u03c7 defined above. One still has the property", "cite_spans": [], "ref_spans": []}, {"section": "Free entropy dimension for infinite families of generators. It is useful for us to consider", "text": "where S 1 , . . . , S p are a free semicircular family, free from {x i } i \u222a {y j } j . Now define", "cite_spans": [], "ref_spans": []}, {"section": "Free entropy dimension for infinite families of generators. It is useful for us to consider", "text": "For a finite family x 1 , . . . , x n this is exactly Voiculescu's definition of free entropy dimension. In general, \u03b4( (x 1 , . . . x p , y 1 , . . . , y p : y 1 , y 2 ", "cite_spans": [], "ref_spans": [{"start": 120, "end": 168, "text": "(x 1 , . . . x p , y 1 , . . . , y p : y 1 , y 2", "ref_id": "FIGREF2"}]}, {"section": "Free entropy dimension for infinite families of generators. It is useful for us to consider", "text": "Definition 4.1. Let M be a II 1 von Neumann algebra. Denote by", "cite_spans": [], "ref_spans": []}, {"section": "Free entropy dimension for infinite families of generators. It is useful for us to consider", "text": "where the supremum is taken over all self-adjoint families (finite or infinite) x 1 , x 2 , . . . of generators of M. If N is type II \u221e , we write \u03b4(N) for the supremum over all finite-trace projections p \u2208 N of \u03b4(pNp).", "cite_spans": [], "ref_spans": []}, {"section": "Remark 4.2. It is quite likely that \u03b4(M)", "text": "While \u03b4(M) is clearly an invariant of M, our inability to prove that the number \u03b4(x 1 , x 2 , . . . ) is independent of the choice of generators x 1 , x 2 , . . . [19, 20, 21] results in the inability to compute the exact value of \u03b4 for infinite-dimensional von Neumann algebras. However, as we pointed out above, if M = L(F n ) * N, with N \u2282 R \u03c9 and n = 1, 2, . . . or +\u221e, we have \u03b4(M) \u2265 n and \u03b4(M \u2297 B(H)) \u2265 n (in fact, = +\u221e by [7] ). Furthermore, as Voiculescu proved in [20], \u03b4(R) = 1 if R is the hyperfinite II 1 (or II \u221e ) factor; more generally, \u03b4(M) \u2264 1 if M has property \u0393 or has a Cartan subalgebra (since these properties are inherited by compressions of a von Neumann algebra, these statements are valid for M type II 1 or type II \u221e ).", "cite_spans": [{"start": 163, "end": 167, "text": "[19,", "ref_id": "BIBREF11"}, {"start": 429, "end": 432, "text": "[7]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Remark 4.2. It is quite likely that \u03b4(M)", "text": "The following theorem essentially follows from the results of [20]; we sketch the necessary modifications of the proof coming from the fact that we may be dealing with infinite families of generators.", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 4.3. Let M be a II", "text": "as an A, A bimodule, and identify it with H(\u03b7, n) for some measure \u03b7 on X \u00d7 X. Assume that \u03b7 is disjoint from \u00b5 \u00d7 \u00b5, i.e.,", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 4.3. Let M be a II", "text": "Proof. (Sketch). We first reduce to the case that M is type II 1 . Given t \u2208 (0, +\u221e), let p \u2208 A be a finite projection, corresponding to the characteristic function of some set Y \u2282 X, \u00b5(Y ) < +\u221e. Then view pMp as a bimodule over pAp. It is not hard to see that pMp can be identified with H(\u03b7 \u2032 , n \u2032 ), with \u03b7 \u2032 absolutely continuous with respect to", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 4.3. Let M be a II", "text": "If the statement of the theorem can be proved for pMp and pAp \u2282 pMp, we would have that \u03b4(qMq) \u2264 1 for all q \u2208 M of finite trace (since qMq depends up to isomorphism only on the trace of q). Hence by definition we get that \u03b4(M) \u2264 1. Let x 1 , x 2 , . . . \u2208 M be a sequence of generators of M; by rescaling (which does not affect \u03b4(x 1 , x 2 , . . . )), assume that x j = 1. By the hypothesis, given \u03c9, \u03b4 > 0 and a measure \u03b7 \u2032 in the absolute continuity class of \u03b7, there exists an N = N(\u03b7 \u2032 , \u03c9, \u03b4) and a finite family of N disjoint measurable subsets X i , i \u2208 I of X, each of measure 1/N, a subset K \u2282 I \u00d7 I, so that X = X i and \u03b7", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 4.3. Let M be a II", "text": "It follows that for each fixed T , \u03b4 and \u03c9, there are projections p 1 , . . . , p N \u2208 A of trace 1/N (corresponding to the characteristic functions of X 1 , . . . , X N in the identification A \u223c = L \u221e (X, \u00b5)), so that:", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 4.3. Let M be a II", "text": ". . ), we get the estimate", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 4.3. Let M be a II", "text": "where C is a constant, independent of \u03c9, \u03b5 and \u03b4. Letting \u03c9 \u2192 0 first, we conclude that", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 4.3. Let M be a II", "text": "Since the sequence of generators {x j } was arbitrary, we get that \u03b4(M) \u2264 1.", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 4.3. Let M be a II", "text": "In a similar way one sees that \u03b4(M) > 1 implies that M is a non-\u0393 factor.", "cite_spans": [], "ref_spans": []}, {"section": "4.2.", "text": "Free entropy dimension and crossed products. Using Voiculescu's estimates from [20], stated above in Theorem 4.3, we record the following theorem (due to Voiculescu, but formulated by him under the additional hypothesis that M be finitely generated):", "cite_spans": [], "ref_spans": []}, {"section": "4.2.", "text": "Theorem 4.4. Let (M, \u03c6) be a von Neumann algebra. Let \u03b1 be an action of a locally compact nondiscrete abelian group G on M. Assume that \u03b1 preserves the state \u03c6 on M. Denote by U g :", "cite_spans": [], "ref_spans": []}, {"section": "4.2.", "text": "Then if C satisfies \u03b4(C) > 1, C \u00b5 must contain the Haar measure of G.", "cite_spans": [], "ref_spans": []}, {"section": "4.2.", "text": "Proof. View C as a bimodule over the abelian subalgebra", "cite_spans": [], "ref_spans": []}, {"section": "4.2.", "text": "This bimodule can be identified with H(\u03b7, n) for some measure \u03b7 on\u011c \u00d7\u011c and some multiplicity function n (see \u00a72.3).", "cite_spans": [], "ref_spans": []}, {"section": "4.2.", "text": "By Theorem 4.3, \u03b7 cannot be disjoint from the product measure \u03bd\u011c \u00d7 \u03bd\u011c on\u011c \u00d7\u011c. It follows that \u00b5 cannot be disjoint from the Haar measure \u03bd\u011c. We may assume that \u00b5 is symmetric. We claim that \u03bd\u011c is absolutely continuous with respect to \u00b5 \u2032 = n\u22651 1 2 n \u00b5 * n , which is the spectral measure of g \u2192 n U \u2297n g . We must show that if \u00b5 \u2032 (X) = 0, then also \u03bd\u011c(X) = 0 for all Borel subsets X \u2282\u011c. Assume to the contrary that \u03bd\u011c(X) > 0 but \u00b5 \u2032 (X) = 0. Then \u00b5 * n (X) = 0 for all n. Since \u00b5 is not disjoint from \u03bd G , there exists a subset Y of\u011c, for which \u03bd\u011c| Y = f \u00b7 \u00b5| Y . By modifying \u00b5 and Y , we may assume that f = 1 and \u00b5(Y ) = \u03bd\u011c(Y ) = 1. Then \u03bd\u011c = f n \u00b7 \u00b5 * n on nY = Y + Y + . . . + Y (n times). Moreover, since \u00b5 and \u03bd\u011c are symmetric, we may assume that Y = \u2212Y . Hence we find that \u03bd\u011c = f \u00b7 \u00b5 \u2032 on the subgroup of\u011c generated by Y . Clearly, X (modulo a set of \u03bd G -measure zero) is contained in the complement of H, and \u03bd G (H) = 0. Since \u03bd G is \u03c3-finite, there exists a countable sequence x n \u2208\u011c, so that (after possibly making X smaller by a set of \u03bd G -measure zero), X \u2282 n (x n + H).", "cite_spans": [], "ref_spans": []}, {"section": "4.2.", "text": "Let x \u2208\u011c. Then for any measure \u03c3 on\u011c of finite total mass,", "cite_spans": [], "ref_spans": []}, {"section": "4.2.", "text": "It follows that if there are finite measures \u03c3 n , absolutely continuous with respect to \u00b5 \u2032 and so that", "cite_spans": [], "ref_spans": []}, {"section": "4.2.", "text": "give X a nonzero measure (which would be a contradiction). Hence \u00b5 \u2032 (x n + H) = 0 for some n. Let p \u2208 L \u221e (\u011c) be the projection corresponding to the characteristic function of H, and let q \u2208 L \u221e (\u011c) be the projection corresponding to the characteristic function of", "cite_spans": [], "ref_spans": []}, {"section": "4.2.", "text": ", where \u03b7 and n are as in \u00a72.3. But this implies that pCq = 0, so that p and q are not equivalent in C. Hence C is not a factor. Hence \u03b4(C) \u2264 1.", "cite_spans": [], "ref_spans": []}, {"section": "Contradiction.", "text": "A similar statement holds also for actions preserving a normal faithful semifinite weight on M. ", "cite_spans": [], "ref_spans": []}, {"section": "Contradiction.", "text": "Proof. This is immediate from C = M \u22ca \u03c3 \u03c6 G and Theorem 4.4. Proof. By Corollary 4.5, we get that", "cite_spans": [], "ref_spans": []}, {"section": "Contradiction.", "text": "The proof of the second part of the statement proceeds exactly as the proof above, with the exception that we now know that \u03c8 can be chosen to be a state, and hence S (M) \u2282 C \u03bb+\u03b4 1 .", "cite_spans": [], "ref_spans": []}, {"section": "APPLICATIONS TO FREE ARAKI-WOODS FACTORS.", "text": "5.1. G-core for certain free Araki-Woods factors. Let\u011c \u2282 R, and denote by \u03c3 its Haar measure.", "cite_spans": [], "ref_spans": []}, {"section": "APPLICATIONS TO FREE ARAKI-WOODS FACTORS.", "text": "Let \u03bd be a measure on\u011c, which is symmetric, \u03bd(X) = \u03bd(\u2212X). Extending \u03bd to all of R by \u03bd(X) = \u03bd(X \u2229\u011c) gives us a measure on the real line.", "cite_spans": [], "ref_spans": []}, {"section": "APPLICATIONS TO FREE ARAKI-WOODS FACTORS.", "text": "Let", "cite_spans": [], "ref_spans": []}, {"section": "APPLICATIONS TO FREE ARAKI-WOODS FACTORS.", "text": "Denote by H R the subspace of H consisting of functions with the property that f (x) = f (\u2212x). Then H R is a real subspace of H, and the restriction of the inner product on H to H R is real-valued. Moreover, the one-parameter group of unitary operators", "cite_spans": [], "ref_spans": []}, {"section": "APPLICATIONS TO FREE ARAKI-WOODS FACTORS.", "text": "of multiplication operators acting on H leaves H R invariant and hence defines an action of R on this real Hilbert space.", "cite_spans": [], "ref_spans": []}, {"section": "APPLICATIONS TO FREE ARAKI-WOODS FACTORS.", "text": "Note that if we consider the dual inclusion R \u2282 G, then the map", "cite_spans": [], "ref_spans": []}, {"section": "APPLICATIONS TO FREE ARAKI-WOODS FACTORS.", "text": "extends to the map", "cite_spans": [], "ref_spans": []}, {"section": "APPLICATIONS TO FREE ARAKI-WOODS FACTORS.", "text": "where g, \u00b7 denotes the function g, \u00b7 (\u03c7) = \u03c7(g), g \u2208 G, \u03c7 \u2208\u011c. Hence U t extends to an action U g of G on H; it is not hard to see that once again H R is invariant under U g , g \u2208 G, and hence G acts on the real Hilbert space H R as well. Note that U g is isomorphic to the left regular representation of G. In particular, the spectral measure of the infinitesimal generator of t \u2192 U t is \u03bd. Let \u0393(H R , U t ) \u2032\u2032 be the free Araki-Woods factor [15] associated to the action U t of R on H R , and let \u03c6 denote the free quasi-free state on \u0393(H R , U t )", "cite_spans": [{"start": 443, "end": 447, "text": "[15]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "APPLICATIONS TO FREE ARAKI-WOODS FACTORS.", "text": "\u2032\u2032 . For convenience we shall write \u0393(\u00b5) for this von Neumann algebra. ", "cite_spans": [], "ref_spans": []}, {"section": "APPLICATIONS TO FREE ARAKI-WOODS FACTORS.", "text": "Proof. We first note that in the case that G is compact, the G-core is the so-called discrete core of M, and the claimed isomorphism was already proved by Dykema ([6] ; see [15] for the argument reducing the case of a general Araki-Woods factor to the form which can utilize Dykema's results). Therefore, we proceed under the assumption that G is not compact and hence G = R, \u03bd\u011c is the Lebesgue measure. In particular, \u03bd\u011c is non-atomic.", "cite_spans": [{"start": 173, "end": 177, "text": "[15]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "APPLICATIONS TO FREE ARAKI-WOODS FACTORS.", "text": "Let C denote the core. Let \u03be \u2208 H R be a cyclic vector for U g , g \u2208 G (one can take, for example, any function f (x) = f (\u2212x), which is nowhere zero on\u011c, and which lies in L 2 (\u011c, \u03c3)). Let \u03c6 be the positive-definite function on G associated to \u03be, \u03c6(g) = \u03be, U g \u03be . Let \u00b5 be the Fourier transform of \u03c6 (viewed as a measure on\u011c). By [16] and [17] ,", "cite_spans": [], "ref_spans": []}, {"section": "APPLICATIONS TO FREE ARAKI-WOODS FACTORS.", "text": "where \u03b7 is a completely positive map from", "cite_spans": [], "ref_spans": []}, {"section": "APPLICATIONS TO FREE ARAKI-WOODS FACTORS.", "text": "h \u2192 h * \u00b5, * denoting the convolution on measures on\u011c. Notice that the measure \u00b5 is just the measure resulting from applying the state \u03be, \u00b7\u03be to the spectral measure of the infinitesimal generator of U g . Hence \u00b5 is absolutely continuous with respect to the Haar measure \u03c3 on\u011c.", "cite_spans": [], "ref_spans": []}, {"section": "APPLICATIONS TO FREE ARAKI-WOODS FACTORS.", "text": "The L(G), L(G) bimodule associated to this completely positive map is L 2 (\u011c \u00d7\u011c,\u03bc),", "cite_spans": [], "ref_spans": []}, {"section": "APPLICATIONS TO FREE ARAKI-WOODS FACTORS.", "text": "The real Jordan sub-bimodule of this bimodule (cf.", "cite_spans": [], "ref_spans": []}, {"section": "APPLICATIONS TO FREE ARAKI-WOODS FACTORS.", "text": "[17]) is generated by the constant function 1.", "cite_spans": [], "ref_spans": []}, {"section": "APPLICATIONS TO FREE ARAKI-WOODS FACTORS.", "text": "By arguing exactly as in [16] , it follows that", "cite_spans": [], "ref_spans": []}, {"section": "APPLICATIONS TO FREE ARAKI-WOODS FACTORS.", "text": "as claimed.", "cite_spans": [], "ref_spans": []}, {"section": "APPLICATIONS TO FREE ARAKI-WOODS FACTORS.", "text": "The same proof works to show that ", "cite_spans": [], "ref_spans": []}, {"section": "APPLICATIONS TO FREE ARAKI-WOODS FACTORS.", "text": "the last isomorphism by [12] (see also [7] ). Since by assumption N \u22ca \u03c3 G is embeddable in R \u03c9 , we get that \u03b4(C) = +\u221e.", "cite_spans": [{"start": 24, "end": 28, "text": "[12]", "ref_id": "BIBREF8"}, {"start": 39, "end": 42, "text": "[7]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Theorem 5.4. There exists a continuum of mutually non-isomorphic free Araki-Woods factors, each having no almost-periodic weights.", "text": "Proof. It was shown in [17] that for each topology \u03c4 (\u00b5) as discussed above, there exists a free Araki-Woods factor whose \u03c4 invariant is exactly \u03c4 (\u00b5). Moreover, a factor M has an almostperiodic weight iff the completion of R with respect to \u03c4 (\u00b5) is compact in that topology (hence \u00b5 is atomic, as then \u00b5 is supported on the Pontrjagin dual \u0393 \u2282 R, where R \u2282\u0393 is the inclusion of R into its completion with respect to \u03c4 ). By Theorem 2.3, there exists a continuum of mutually non-equivalent topologies \u03c4 (\u00b5 \u03bb ), with \u00b5 \u03bb non-atomic.", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 5.4. There exists a continuum of mutually non-isomorphic free Araki-Woods factors, each having no almost-periodic weights.", "text": "Theorem 5.5. There exist two non-isomorphic free Araki-Woods factors, which cannot be distinguished by their \u03c4 invariant.", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 5.4. There exists a continuum of mutually non-isomorphic free Araki-Woods factors, each having no almost-periodic weights.", "text": "Proof. Let M 1 be the free Araki-Woods factor associated to the representation of R with spectral measure \u03b4 1 + \u03b4 \u22121 + \u03bb, where \u03bb denotes the Lebesgue measure on the additive group R. Then by Theorem 5.1 and by Corollary 4.5,", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 5.4. There exists a continuum of mutually non-isomorphic free Araki-Woods factors, each having no almost-periodic weights.", "text": "Moreover, we have that \u03c4 (M 1 ) = \u03c4 (\u03b4 1 + \u03b4 \u22121 + \u03bb) is the usual topology on R [17].", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 5.4. There exists a continuum of mutually non-isomorphic free Araki-Woods factors, each having no almost-periodic weights.", "text": "Let M 2 be the free Araki-Woods factor associated to the representation of R with spectral measure \u00b5 + \u03b4 \u22121 + \u03b4 1 , where \u00b5 is as in Theorem 2.4. Then again \u03c4 (M 2 ) = \u03c4 (\u00b5 + \u03b4 \u22121 + \u03b4 1 ) = \u03c4 (\u00b5) is the usual topology on R. Thus \u03c4 (M 1 ) = \u03c4 (M 2 ). However,", "cite_spans": [], "ref_spans": []}, {"section": "Theorem 5.4. There exists a continuum of mutually non-isomorphic free Araki-Woods factors, each having no almost-periodic weights.", "text": "and so M 1 and M 2 are not isomorphic. In fact, going through the proof of Theorem 4.4, we see that the cores of M 1 and M 2 are not isomorphic (one has \u03b4(M 1 ) > 1, \u03b4(M 2 ) \u2264 1). ", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Free products of von Neumann algebras of type III", "authors": [{"first": "L", "middle": [], "last": "Barnett", "suffix": ""}], "year": 1995, "venue": "Proc. Amer. Math. Soc", "link": null}, "BIBREF1": {"title": "Almost periodic states and factors of type III 1", "authors": [{"first": "A", "middle": [], "last": "Connes", "suffix": ""}], "year": 1973, "venue": "Noncommutative geometry", "link": "121037775"}, "BIBREF2": {"title": "Free products of finite dimensional and other von Neumann algebras with respect to non-tracial states", "authors": [{"first": "K", "middle": [], "last": "Dykema", "suffix": ""}], "year": 1997, "venue": "Fields Institute Communications", "link": "7962906"}, "BIBREF3": {"title": "Compressions of free products of von Neumann algebras", "authors": [{"first": "K", "middle": [], "last": "Dykema", "suffix": ""}, {"first": "F", "middle": [], "last": "R\u0203dulescu", "suffix": ""}], "year": 2000, "venue": "Math. Ann", "link": "9894710"}, "BIBREF4": {"title": "Essays in commutative harmonic analysis", "authors": [{"first": "C", "middle": ["C"], "last": "Graham", "suffix": ""}, {"first": "O", "middle": ["C"], "last": "Mcgehee", "suffix": ""}], "year": 1979, "venue": "", "link": "117126457"}, "BIBREF5": {"title": "The standard form of von Neumann algebras", "authors": [{"first": "U", "middle": [], "last": "Haagerup", "suffix": ""}], "year": 1975, "venue": "Math. Scand", "link": "120206130"}, "BIBREF6": {"title": "Abstract harmonic analysis", "authors": [{"first": "E", "middle": [], "last": "Hewitt", "suffix": ""}, {"first": "K", "middle": ["A"], "last": "Ross", "suffix": ""}], "year": 1979, "venue": "Structure of topological groups", "link": "124016233"}, "BIBREF8": {"title": "Universal properties of L(F \u221e ) in subfactor theory", "authors": [{"first": "S", "middle": [], "last": "Popa", "suffix": ""}, {"first": "D", "middle": [], "last": "Shlyakhtenko", "suffix": ""}], "year": 2000, "venue": "", "link": "116979351"}, "BIBREF9": {"title": "A type III \u03bb factor with core isomorphic to the von Neumann algebra of a free group, tensor B(H), Recent advances in operator algebras", "authors": [{"first": "F", "middle": [], "last": "R\u0203dulescu", "suffix": ""}], "year": 1992, "venue": "A one parameter group of automorphisms of L(F \u221e ) \u2297 B(H ) scaling the trace", "link": null}, "BIBREF10": {"title": "Some applications of freeness with amalgamation", "authors": [{"first": "D", "middle": [], "last": "Shlyakhtenko", "suffix": ""}], "year": 1997, "venue": "J. reine angew. Math", "link": "121211061"}, "BIBREF11": {"title": "The analogues of entropy and of Fisher's information measure in free probability theory II", "authors": [{"first": "D.-V", "middle": [], "last": "Voiculescu", "suffix": ""}], "year": 1994, "venue": "III, Geometric and Functional Analysis", "link": "189829729"}}, "ref_entries": {"FIGREF0": {"text": "Lemma 2.2. A sequence {t n } \u221e n=1 converges to zero in \u03c4 (\u00b5) iff\u03bc(t n ) \u2192 1, where\u03bc is the Fourier transform of \u00b5.", "type": "figure"}, "FIGREF1": {"text": "There exists a measure \u00b5, so that \u00b5 as well as its arbitrary convolution powers \u00b5 * \u00b7 \u00b7 \u00b7 * \u00b5 (any number of times) are singular with respect to Lebesgue measure, but \u03c4 (\u00b5) is the usual topology on the additive group of real numbers.", "type": "figure"}, "FIGREF2": {"text": "Let M be full. Then define: (a) \u03c4 (M) to be the weakest topology on R making the map \u03b4 : R \u2192 Out(M) continuous (this invariant was introduced by Connes in [4]). Thus t n \u2192 0 in \u03c4 (M) iff there exists a sequence of faithful normal semifinite weights \u03c6 n on M, for which \u03c3 \u03c6n tn \u2192 id in the u-topology. (b)", "type": "figure"}, "FIGREF3": {"text": "W (M) is contained in C \u03bb , the class of the Haar measure on R + = R. Proof. Let \u03c6 be any G-weight on M. Denote by \u00b5 the spectral measure of infinitesimal generator \u2206 \u03c6 of the unitary group \u03c3 \u03c6 t acting on (M, \u03c6). Denote by d the function x \u2192 x on R + . On B(L 2 (R)), consider the normal faithful weight \u03c8 = Tr(d\u00b7). Then the modular group of \u03c8 is given by conjugation with d it , and hence \u03c8 is a weight on B(L 2 ( R)). In particular, the modular group of \u03c8, acting on L 2 ( R), is the left regular representation of R. Consider the normal faithful weight \u03b8", "type": "figure"}, "FIGREF4": {"text": "Assume that for some G-state \u03c6 on a factor M the G-core is a full factor. Then M is full. Proof. Let C = M \u22ca \u03c3 G be the G-core of M. Assume for contradiction that M is not full. Then by [4, Corollary 3.6, Proposition 2.8] there exists a sequence of unitaries m n \u2208 M, \u03c6(m n ) = 0, and so that [m n , m] \u2192 0 * -strongly for all m \u2208 M and [m n , \u03c6] \u2192 0 in norm on M * for any \u03c6 \u2208 M * . View m n \u2208 C \u2283 M. We claim that {m n } is a non-trivial central sequence in C. Let E : C \u2192 L(G) \u2282 C be the canonical conditional expectation. Then E(m n ) = \u03c6(m n ) = 0, so that m n is not asymptotically scalar. For any m \u2208 M, [m n , m] \u2192 0 * -strongly. Denote by U g \u2208 L(G) \u2282 C, g \u2208 G, the implementing unitaries. Then by Connes' results [4", "type": "figure"}, "FIGREF5": {"text": "Consequences for the S invariant. Corollary 4.5. Assume that for some normal faithful G state \u03c6 on M, the G-core C of M satisfies \u03b4(C) > 1. Then for any other n.f.s. weight \u03c8 on M, the Haar measure on\u011c is contained in the spectral measure of the action of", "type": "figure"}, "FIGREF6": {"text": "Assume that the core C of M satisfies \u03b4(C) > 1. Then W (M) = C \u03bb , where \u03bb is Lebesgue measure on the multiplicative group R + . If in addition there exists a state \u03c6 on M, for which the spectral measure of the modular group is \u03bb + \u03b4 1 , then S (M) = C \u03bb+\u03b4 1 .", "type": "figure"}, "FIGREF7": {"text": "Let \u03c3 be the Haar measure on G. Then the G-core of", "type": "figure"}, "FIGREF8": {"text": "Let M = \u0393(\u03c3) as before and \u03c6 be the free quasi-free state on M. Then the G core of the n-fold free product (M, \u03c6) * n , for any n \u2265 1 or n = +\u221e, is L(F \u221e ) \u2297 B(H). Proposition 5.3. Let (N, \u03b8) be a full factor with a G-state \u03b8. Assume that the G core of N can be embedded into R \u03c9 . Denote by C the G-core of (N, \u03b8) * (\u0393(\u03bd\u011c), \u03c6). Then \u03b4(C) = +\u221e. In particular, C is full. Proof. Fix p \u2208 N \u22ca \u03c3 G a projection of trace 1. By [17],", "type": "figure"}, "TABREF0": {"text": "x 2 , . . . ) can be embedded into R \u03c9 , the ultrapower of the hyperfinite II 1 factor. If x 1 , . . . , x p are free form x p+1 , x p+2 , . . ., then \u03b4In particular, if the families {x 1 }, . . . , {x p }, . . . , {y 1 , y 2 , . . . } are free, and {y 1 , y 2 , . . . } \u2032\u2032 is em- beddable, we get by [21] that \u03b4(x 1 , y 1 , x 2 , y 2 , . . . ) = lim", "type": "table"}, "TABREF1": {"text": "A strengthened asymptotic freeness result for random matrices with applications to free entropy, IMRN 1 (1998), 41 -64. 22. D.-V. Voiculescu, K. Dykema, and A. Nica, Free random variables, CRM monograph series, vol. 1, American Mathematical Society, 1992. DEPARTMENT OF MATHEMATICS, UCLA, LOS ANGELES, CA 90095, USA E-mail address: shlyakht@math.ucla.edu", "type": "table"}}}
{"paper_id": "17436199", "_pdf_hash": "bef674097dedf03f9634570aa242ca77acba936e", "abstract": [{"section": "Abstract", "text": "Proof schemata are a variant of LK-proofs able to simulate various induction schemes in first-order logic by adding so called proof links to the standard first-order LK-calculus. Proof links allow proofs to reference proofs thus giving proof schemata a recursive structure. Unfortunately, applying reductive cutelimination is non-trivial in the presence of proof links. Borrowing the concept of lazy instantiation from functional programming, we evaluate proof links locally allowing reductive cut-elimination to proceed past them. Though, this method cannot be used to obtain cut-free proof schemata, we nonetheless obtain important results concerning the schematic CERES method, that is a method of cut-elimination for proof schemata based on resolution. In \"Towards a clausal analysis of cut-elimination\", it was shown that reductive cut-elimination transforms a given LK-proof in such a way that a subsumption relation holds between the pre-and post-transformation characteristic clause sets, i.e. the clause set representing the cut-structure of an LK-proof. Let CLp\u03d5 1 q be the characteristic clause set of a normal form \u03d5 1 of an LK-proof \u03d5 that is reached by performing reductive cut-elimination on \u03d5 without atomic cut elimination. Then CLp\u03d5 1 q is subsumed by all characteristic clause sets extractable from any application of reductive cut-elimination to \u03d5. Such a normal form is referred to as an ACNF top and plays an essential role in methods of cut-elimination by resolution. These results can be extended to proof schemata through our \"lazy instantiation\" of proof links, and provides an essential step toward a complete cut-elimination method for proof schemata.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "The schematic CERES (Cut Elimination by RESolution) method of cut-elimination was developed for a primitive recursively defined first-order sequent calculus, the LKS-calculus [13] . Note that LKS-proofs have a free parameter, which when instantiated results in an LK-proof. The method is based on CERES which is an alternative to the reductive cut-elimination method of Gentzen [14] . It relies on the extraction of a characteristic clause set C from a sequent calculus proof \u03d5, where C represents the global cut structure of \u03d5. C is always unsatisfiable and thus, refutable using resolution. A refutation R of C can be used to construct a proof \u03d5 of R and adding the necessary contractions results in \u03d5 1 . Benefits of the CERES method are its non-elementary speed-up over the Gentzen method [7] and its \"global\" approach to the elimination of cuts. A global approach is essential for analysis of proofs with an inductive argument.", "cite_spans": [{"start": 175, "end": 179, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 378, "end": 382, "text": "[14]", "ref_id": "BIBREF13"}, {"start": 704, "end": 705, "text": "1", "ref_id": "BIBREF0"}, {"start": 793, "end": 796, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Introduction", "text": "The LKS-calculus is based on propositional schemata introduced by Aravantinos et al. [1, 2] . Propositional schemata have been used in the field of inductive theorem proving [3] to define more expressive classes of inductive formula whose satisfiability is decidable. The proofs of the LKS-calculus are used to construct proof schemata which are denoted using a finite ordered list of proof schema components. The components consist of a proof symbol, an LKS-proof and an LKE-proof. The LKE-calculus is essentially the LK-calculus with a rudimentary equational rule for dealing with recursively defined functions and predicates. In addition, LKSproofs are allowed to \"call\" other proofs through proof links. To maintain well foundedness, a constraint was added to proof schemata that an LKS-proof can only contain proof links to proof schema components lower in the ordering. Also, no \"free\" proof links are allowed, i.e. proofs links must point to proofs within its proof schema. It was shown that proof schemata, under these constraints, can be used to express certain inductive arguments [13] . One way to think about proof schemata is as a countable set of LK-proofs. Thus, cut-elimination would be the elimination of cuts from a countable set of proofs simultaneously. One can imagine why such a problem would benefit from a global approach.", "cite_spans": [{"start": 85, "end": 88, "text": "[1,", "ref_id": "BIBREF0"}, {"start": 89, "end": 91, "text": "2]", "ref_id": "BIBREF1"}, {"start": 174, "end": 177, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 1091, "end": 1095, "text": "[13]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Introduction", "text": "Induction has been a stumbling block for classical cut-elimination methods, i.e. reductive cut-elimination\u00e0 la Gentzen, because passing cuts over the inference rule for induction can be unsound. Note that this is still an issue for the more exotic (non-reductive) methods such as CERES because the cut ancestor relation is not well defined [13] . Though, there have been systems developed to get around the issue, such as the work of Mcdowell and Miller [17] , and Brotherston and Simpson [8] . These systems manage to eliminate cuts but without some of the benefits of cut-elimination like the subformula property, i.e. every formula occurring in the derivation is a subformula of some formula in the end sequent. This property admits the construction of Herbrand sequents and other objects which are essential in proof analysis. Proof schemata preserve the ancestor relation by representing an inductive argument through recursion indexed by a free parameter. Though, not completely satisfactory for reductive methods, i.e. pushing cuts through proof links is non-trivial, the preservation of the ancestor relation benefits a more global approach to the problem. The schematic CERES method [13] takes advantage of this property and results in a \"proof\" with the subformula property, though for a smaller class of inductive arguments than other methods. Problematically, the application of the method to proof schemata is not trivial.", "cite_spans": [{"start": 340, "end": 344, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 454, "end": 458, "text": "[17]", "ref_id": "BIBREF16"}, {"start": 489, "end": 492, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 1192, "end": 1196, "text": "[13]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Introduction", "text": "A method for the algorithmic extraction of the characteristic clause set from proof schemata exists, but like the proof schemata it is primitive recursively defined. As shown in [10] refuting such a clause set is non-trivial even for a simple mathematically meaningful statement. This analysis was performed with the aid of automated theorem provers. Part of the issue is that the refutation must also be recursive. To simplify the construction of a recursive refutation, the substitutions are separated from the resolution rule and are given their own recursive definition. Essentially, we define the structure separately from the term instantiations. Thus, the result of the method is a substitution schema and a resolution refutation schema, both having a free parameter, which when instantiated can be combined to construct an LK-derivation. An LK-proof is not constructed being that schematic proof projections are not extracted. Nonetheless, the resulting LK-derivation contains enough information to allow extraction of a Herbrand system [13] , that is a schematic version of a Herbrand sequent. Though, this separation simplifies the definitions and construction it requires a mapping to exists between the two schemata, thus, more complex refutations/term instantiation become difficult to represent using the method. This issue was highlighted in [9] . Thus, finding a canonical structure [20] for resolution refutations of proof schemata would remove the problem of mapping the substitutions to the refutation structure.", "cite_spans": [{"start": 178, "end": 182, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 1045, "end": 1049, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 1357, "end": 1360, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 1399, "end": 1403, "text": "[20]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "Introduction", "text": "It has been shown that characteristic clause sets extracted from LK-proofs are of a specific shape [6, 7, 20] , thus resulting in interesting clausal subsumption properties. If we consider an alternative reductive cut-elimination method, which does not eliminate atomic cuts, it is possible to prove the existence of a subsumption relation between the characteristic clause sets extracted at different steps during the application of reductive cut-elimination to an LK-proof [6, 7] . The characteristic clause set of the final proof, all atomic cuts as high as possible in the proof structure, is subsumed by all the extracted clauses sets from previous steps [6, 7] . Essentially, there is a canonical clause set associated with the CERES method [20] . What is most important about this canonical clause set is that there is only one way to refute it. The structure of this refutation is recursive and fits perfectly into the current language for representing schematic resolution refutations [11] . Problematically, we do not know if the subsumption properties hold for schematic characteristic clause sets. In the case of propositional proof schema, a weakening rule was added to the resolution calculus allowing the construction of the so called Top Atomic Cut Normal Form (ACNF top ) [11, 20] . Note that resolution for propositional logic does not require substitutions and thus this provides a decidable and complete method for propositional proof schemata. While it seems intuitive that the result would carry over, the original clausal analysis of first-order sequent calculus proofs used the Gentzen method [14] to construct the subsumption relation between clause sets. As we have already pointed out, reductive cutelimination and proof links do not get along.", "cite_spans": [{"start": 99, "end": 102, "text": "[6,", "ref_id": "BIBREF5"}, {"start": 103, "end": 105, "text": "7,", "ref_id": "BIBREF6"}, {"start": 106, "end": 109, "text": "20]", "ref_id": "BIBREF19"}, {"start": 475, "end": 478, "text": "[6,", "ref_id": "BIBREF5"}, {"start": 479, "end": 481, "text": "7]", "ref_id": "BIBREF6"}, {"start": 660, "end": 663, "text": "[6,", "ref_id": "BIBREF5"}, {"start": 664, "end": 666, "text": "7]", "ref_id": "BIBREF6"}, {"start": 747, "end": 751, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 994, "end": 998, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 1289, "end": 1293, "text": "[11,", "ref_id": "BIBREF10"}, {"start": 1294, "end": 1297, "text": "20]", "ref_id": "BIBREF19"}, {"start": 1617, "end": 1621, "text": "[14]", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Introduction", "text": "In this paper we develop a proof schema transformation which allows one to \"unroll\" a proof link without instantiating the free parameter. The transformation preserves syntactic equivalence insomuch as for every instantiation of the resulting proof schema there is an instantiation of the original proof schema which results in an identical LK-proof. This transformation allows us to perform the Gentzen method on proof schemata because every time we get to a proof link we apply the transformation. Though, this does not result in a method which leads to cut-free proofs, it allows us to extend the clausal analysis results of [6, 7] to proof schemata and allows us to use the clause set of the Top Atomic Cut Normal Form (ACNF top ). This implies that we can use the schematic resolution refutation structure discussed in [11] for every schematic characteristic clause set.", "cite_spans": [{"start": 628, "end": 631, "text": "[6,", "ref_id": "BIBREF5"}, {"start": 632, "end": 634, "text": "7]", "ref_id": "BIBREF6"}, {"start": 824, "end": 828, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Introduction", "text": "This work is part of a research program into computational proof analysis, which, so far, has lead to the analysis of F\u00fcrstenberg's proof concerning the infinitude of primes [4] . The proof includes an inductive argument and as mentioned earlier the standard CERES method cannot be applied. A recursive formalization of the proof was constructed allowing for a informal clausal proof analysis and the discovery of a relationship between Euclid's proof and F\u00fcrstenberg's proof. Though, the theory of proof schemata is not yet sufficiently developed to handle such a complex proof formally, the results of this paper greatly advances the state of the art in the field. Though, investigations of proof schemata have so far been driven by the above research program, the applications are not limited to this particular type of proof analysis. They also serve as a compact way to store a formal proof whilst allowing analysis and transformations to take place. We plan to investigate alternative uses of the formalism in future work.", "cite_spans": [{"start": 174, "end": 177, "text": "[4]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Introduction", "text": "The rest of this paper is as follows: In Section 2 we discuss the necessary background knowledge needed for the results. In Section 3 we introduce the concept of lazy instantiation. In Section 4 we use lazy instantiation to perform clause analysis of proof schema and show that every schematic clause set can be subsumed by a sequence of clause sets in top form corresponding to the instantiations of the schematic clause set. In Section 5, we conclude the paper and discuss future work and open problems.", "cite_spans": [], "ref_spans": []}, {"section": "Preliminaries", "text": "Due to the maturity of Gentzen's reductive cut-elimination and the sequent calculus we refrain from giving an introduction to the material. Unconventional uses of the method and/or calculus will be addressed when necessary to understanding. For more details, there exists numerous publications addressing his results ( [7, 14, 19] to name a few) as well as the basics of the sequent calculus. One point we would like to address concerning reductive cut-elimination as considered in this paper is that we will use the generalized rewrite system introduced in [6] allowing application of the rewrite rules to any cut in the proof, not just to the upper-most cut. This generalized rewrite rule system R will be referred to as reductive cut-elimination. When an application of reductive cut-elimination must be made explicit, we write \u03c8 \u00d1 R \u03c7 where \u00d1 R is a binary relation on LK-derivations and \u03c8 and \u03c7 are LK-derivations. The meaning of \u03c8 \u00d1 R \u03c7 is \u03c8 can be transformed into \u03c7 using the rewrite rule system R. By \u00d1R, we mean the reflexive and transitive closure of \u00d1 R .", "cite_spans": [{"start": 319, "end": 322, "text": "[7,", "ref_id": "BIBREF6"}, {"start": 323, "end": 326, "text": "14,", "ref_id": "BIBREF13"}, {"start": 327, "end": 330, "text": "19]", "ref_id": "BIBREF18"}, {"start": 558, "end": 561, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "The Atomic Cut Normal Form (top) (ACNF", "text": "ptopq )", "cite_spans": [], "ref_spans": []}, {"section": "The Atomic Cut Normal Form (top) (ACNF", "text": "The Atomic Cut Normal Form of an LK-calculus proof was introduced in [5] as the result of the CERES method. A proof transformed to ACNF still has cuts, but only rank reduction has to be applied to the proof to get a truly cut-free proof, i.e. all cuts are atomic. Rank reduction operations are the cheapest reduction rules of R which may be applied to an LK-proof, thus, a proof in ACNF can be thought of as essentially cut-free. In this work, we consider a special ACNF, the ACNF top . An ACNF top is an ACNF where all cuts are shifted to the top of the proof. An easy way to transform a given proof \u03d5 into ACNF top is to apply generalized reductive cut-elimination without the following transformation rules", "cite_spans": [{"start": 69, "end": 72, "text": "[5]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "The Atomic Cut Normal Form (top) (ACNF", "text": "being applied to \u03d5. A full explanation can be found in [6, 20] .", "cite_spans": [{"start": 55, "end": 58, "text": "[6,", "ref_id": "BIBREF5"}, {"start": 59, "end": 62, "text": "20]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "Proof Schemata: Language, Calculus, and Interpretation", "text": "To give a formal construction of proof schemata we extend the classical first-order term language. Following the syntax of a to be published paper concerning proof schemata [16] , we partition the set of function symbols P into two categories, uninterpreted function symbols P u and defined function symbols P d . Together with a countable set of schematic variable symbols these symbols are used to construct the \u03b9 sort of the term language. We will denote defined function symbol using\u02c6in order to distinguish them from uninterpreted function symbols. Defined function symbols are added to the language to allow the definition of primitive recursive functions within the object language. Analogously, we allow uninterpreted predicate symbols and defined predicate symbols.", "cite_spans": [{"start": 173, "end": 177, "text": "[16]", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "Proof Schemata: Language, Calculus, and Interpretation", "text": "In addition to the \u03b9 sort, we add an \u03c9 sort where every term normalizes to numerals (hence, the only uninterpreted function symbols are 0 and sp\u00a8q). We will denote numerals by lowercase Greek letters, i.e. \u03b1, \u03b2, \u03b3, etc. There is also a countable set N of parameter symbols of type \u03c9. For this work, we will only need a single parameter which in most cases we denote by n. We use k, k 1 to represent \u03c9-terms containing the parameter. This parameter symbol, referred to as the free parameter, is used to index LKS-derivations. The set of all \u03c9-terms will be denoted by \u2126 \u2126 \u2126 \u2126. Schematic variables are of type \u03c9 \u00d1 \u03b9, i.e. when the schematic variable x is instantiated by a numeral \u03b1, xp\u03b1q, it is to be interpreted as a first-order variable of type \u03b9. Hence, schematic variable symbols describe infinite sequences of distinct variables.", "cite_spans": [], "ref_spans": []}, {"section": "Proof Schemata: Language, Calculus, and Interpretation", "text": "Formula schemata (a generalization of formulas including defined functions and predicates) are defined as usual by induction starting with a countable set of uninterpreted predicate symbols and defined predicate symbols. To deal with defined functions and predicates, we add to our interpretation a set of convergent rewrite rules, E, of the formf ptq \u00d1 E, wheret contains no defined symbols, and eitherf is a function symbol of range \u03b9 and E is a term or f is a predicate symbol and E is a formula. We extend the LK-calculus with an inference rule applying this set of rewrite rules as an equational theory. This extended calculus is referred to as LKE.", "cite_spans": [], "ref_spans": []}, {"section": "Definition 1 (LKE)", "text": ". Let E be a given equational theory. LKE is an extension of LK with the E inference rule", "cite_spans": [], "ref_spans": []}, {"section": "Definition 1 (LKE)", "text": "where the term t in the sequent S is replaced by a term t 1 for E |\u00f9 t \" t 1 .", "cite_spans": [], "ref_spans": []}, {"section": "Definition 1 (LKE)", "text": "Example 1. We can add iterated _ and^( the defined predicates are abbreviated as \u017d and \u0179 ) to the term language using the following rewrite rules:", "cite_spans": [], "ref_spans": []}, {"section": "Definition 1 (LKE)", "text": "Formula schemata are used to build schematic sequents \u2206 $ \u0393, where \u2206 and \u0393 are multi-sets of formula schemata. Schematic sequents are to be interpreted in the standard way. Note that the size of \u2206 and \u0393 cannot depend on the free parameter n.", "cite_spans": [], "ref_spans": []}, {"section": "Definition 1 (LKE)", "text": "Schematic proofs are a finite ordered list of proof schema components that can interact with each other. This interaction is defined using so-called proof links, a 0-ary inference rule we add to LKE-calculus: Let Spk,xq be a sequent wherex is a vector of schematic variables. By Spk,tq we denote Spk,xq wherex is replaced byt respectively, wheret is a vector of terms of appropriate type. Furthermore, we assume a countably infinite set of proof symbols B denoted by \u03d5, \u03c8, \u03d5 i , \u03c8 j . The expression p\u03d5, k,tq Spk,tq is called a proof link with the intended meaning that there is a proof called \u03d5 with the end-sequent Spk,xq. For k P \u2126 \u2126 \u2126 \u2126, let Vpkq be the set of parameters in k. We refer to a proof link as an E-proof link if Vpkq \u010e E. Note that in this work E \" tnu or E \" H.", "cite_spans": [], "ref_spans": []}, {"section": "Definition 2 (LKS).", "text": "LKS is an extension of LKE, where proof links may appear at the leaves of a proof.", "cite_spans": [], "ref_spans": []}, {"section": "Definition 2 (LKS).", "text": "The class of all LKS-proofs will be denoted by (read little yus). For two LKS-proofs (LKE-proof) \u03d5 and \u03c8, we say that \u03d5 \" syn \u03c8 if they are syntactically the same. We will denote a subLKS-proof (LKE-proof) \u03bd of an LKS-proof (LKE-proof) proof \u03d5 by \u03d5.\u03bd. If the subLKS-proof \u03d5.\u03bd is a tnu-proof link p\u03c8, k, xq then we define Pp\u03d5.\u03bdq \" \u03c8 and Ip\u03d5.\u03bdq \" k. If \u03d5.\u03bd is not a proof link Pp\u03d5.\u03bdq and Ip\u03d5.\u03bdq do nothing. The set of proof links in an LKS-proof \u03d5 is PLp\u03d5q. We also define substitution of subproofs, that is let \u03d5, \u03c8 be LKS-proof and \u03d5.\u03bd a subLKS-proof such that esp\u03c8q \" esp\u03d5.\u03bdq, then we can construct a new LKS-proof \u03d5 r\u03c8s \u03bd where \u03d5.\u03bd is replaced by \u03c8. We also allow term substitutions for the parameters of an LKS-proof. Definition 3. Let \u03bd P be an LKS-proof. A parameter substitution is a term substitution \u03c3 : N \u00d1 \u2126 \u2126 \u2126 \u2126, such that \u03bd\u03c3 is a new LKS-proof with the substitutions applied to every \u03c9-term containing a parameter.", "cite_spans": [], "ref_spans": []}, {"section": "Definition 2 (LKS).", "text": "Definition 4 (Proof Schema Component). Let \u03c8 P B and n P N . A proof schema component C is a triple p\u03c8, \u03c0, \u03bdpkqq where \u03c0 is an LKS-proof only containing H-proof links and \u03bdpkq is an LKS-proof containing tnu-proof links. The end-sequents of the proofs are Sp0,xq and Spk,xq, respectively. Given a proof schema component C \" p\u03c8, \u03c0, \u03bdpkqq we define C.1 \" \u03c8, C.2 \" \u03c0, and C.3 \" \u03bdpkq.", "cite_spans": [], "ref_spans": []}, {"section": "Definition 2 (LKS).", "text": "If \u03bdpkq of a proof schema component p\u03c8, \u03c0, \u03bdpkqq contains a proof link to \u03c8 it will be referred to as cyclic, otherwise it is acyclic.", "cite_spans": [], "ref_spans": []}, {"section": "Definition 2 (LKS).", "text": "Definition 5 (Proof Schema [13] ). Let C 1 ,\u00a8\u00a8\u00a8, C m be proof schema components such that C i .1 is distinct for 1 \u010f i \u010f m and n P N . Let the end sequents of C 1 be Sp0,xq and Spk,xq. We define \u03a8 \" xC 1 ,\u00a8\u00a8\u00a8, C m y as a proof schema if C i .3 only contains tnu-proof links to C i .1 or C j .1 for 1 \u010f i \u0103 j \u010f m. The tnu-proof links are of the following form:", "cite_spans": [{"start": 27, "end": 31, "text": "[13]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Definition 2 (LKS).", "text": "\u2126 \u2126 \u2126 such that Vptq P tnu, k 1 is a sub-term of k, and\u0101 andb are vectors of terms from the appropriate sort. S 1 pk 1 ,\u0101q and S 2 pt,bq are the end sequents of components C i and C j respectively. We call Spk,xq the end sequent of \u03a8 and assume an identification between the formula occurrences in the end sequents of the proof schema components so that we can speak of occurrences in the end sequent of \u03a8. The class of all proof schemata will be denoted by (read big yus).", "cite_spans": [], "ref_spans": []}, {"section": "Definition 2 (LKS).", "text": "For any proof schema \u03a6 P , such that \u03a6 \" xC 1 ,\u00a8\u00a8\u00a8, C m y we define |\u03a6| \" m and \u03a6.i \" C i for 1 \u010f i \u010f m. Note that instead of using proof schema pair [13, 16] to define proof schemata we use proof schema components. The only difference is that proof schema components make the name explicit. All results concerning proof schemata built from proof schema pairs carry over for our above definition.", "cite_spans": [{"start": 150, "end": 154, "text": "[13,", "ref_id": "BIBREF12"}, {"start": 155, "end": 158, "text": "16]", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "Definition 2 (LKS).", "text": "Definition 6. Let \u03a6 P such that \u03a6 contains p\u03c7, \u03c0, \u03bdpkqq. Let \u03bd.\u03b3 P P Lp\u03bdpkqq. We call \u03bd.\u03b3 an incoming link if Pp\u03bdpkq.\u03b3q \" \u03c7, otherwise, we call it an outgoing link. Example 2. Let us consider the proof schema \u03a6 \" xp\u03d5, \u03c0, \u03bdpkqqy. The proof schema uses one defined function symbol\u015cp\u00a8q which is used to convert terms of the \u03c9 sort to the \u03b9 sort, i.e. E \" !\u015c pk`1q \" sp\u015cpkqq ;\u015cp0q \" 0 ; k`splq \" spk`lq ) . The proofs \u03c0 and \u03bdpkq are as follows:", "cite_spans": [], "ref_spans": []}, {"section": "Definition 2 (LKS).", "text": "\u03c0 \" P p\u03b1`0q $ P p\u03b1`0q w : l P p\u03b1`0q, @x.P pxq \u00d1 P pspxqq $ P p\u03b1`0q E P p\u03b1`0q, @x.P pxq \u00d1 P pspxqq $ P p\u03b1`\u015cp0qq \u03bdpkq \" p\u03d5, n, \u03b1q P p\u03b1`0q, @x.P pxq \u00d1 P pspxqq $ P p\u03b1`\u015cpnqq P psp\u03b1`\u015cpnqqq $ P psp\u03b1`\u015cpnqqq \u00d1 : l P p\u03b1`0q, @x.P pxq \u00d1 P pspxqq, P p\u03b1`\u015cpnqq \u00d1 P psp\u03b1`\u015cpnqqq $ P psp\u03b1`\u015cpnqqq @ : l P p\u03b1`0q, @x.P pxq \u00d1 P pspxqq, @x.P pxq \u00d1 P pspxqq $ P psp\u03b1`\u015cpnqqq E P p\u03b1`0q, @x.P pxq \u00d1 P pspxqq, @x.P pxq \u00d1 P pspxqq $ P p\u03b1`sp\u015cpnqqq E P p\u03b1`0q, @x.P pxq \u00d1 P pspxqq, @x.P pxq \u00d1 P pspxqq $ P p\u03b1`\u015cpn`1qq c : l P p\u03b1`0q, @x.P pxq \u00d1 P pspxqq $ P p\u03b1`\u015cpn`1qq", "cite_spans": [], "ref_spans": []}, {"section": "Definition 2 (LKS).", "text": "Note that \u03c0 contains no proof links, while \u03bdpkq contains tnu-proof links.", "cite_spans": [], "ref_spans": []}, {"section": "Definition 2 (LKS).", "text": "For our clausal analysis, we need to consider a specific type of proof schema which we will refer to as an accumulating proof schema. For a given proof schema we can easily construct the corresponding accumulating proof schema by adding a new proof component to the beginning of the proof schema. The additional component allows incremental unfolding of the proof schema (see Section 3). Definition 7. Let \u03a6 \" xC 1 ,\u00a8\u00a8\u00a8, C m y P . We define the accumulating proof schema of \u03a6, as \u03a6 a \" xA, C 1 ,\u00a8\u00a8\u00a8, C m y, where A \" p\u03c7, \u03c0, \u03bdpkqq, \u03c7 is a distinct proof symbol from those of \u03a6, \u03c0 \" C 1 .2, and \u03bdpkq is defined as follows:", "cite_spans": [], "ref_spans": []}, {"section": "Definition 2 (LKS).", "text": "where Spk,tq is the end sequent of C 1 .3.", "cite_spans": [], "ref_spans": []}, {"section": "Definition 2 (LKS).", "text": "Definition 8 (Evaluation of proof schema [13] ). We define the rewrite rules for proof links p\u03d5, 0,tq \u00f1 \u03c0 Sp0,tq p\u03d5, k,tq \u00f1 \u03bdpkq Spk,tq for all proof schema components C \" p\u03d5, \u03c0, \u03bdpkqq. We define C \u00d3 \u03b1 as a normal form of p\u03d5, \u03b1,tq Sp\u03b1,tq where \u03b1 P N, under the rewrite system just given extended with rewrite rules for defined function and predicate symbols. Further, we define \u03a6 \u00d3 \u03b1 \" C 1 \u00d3 \u03b1 for a proof schema \u03a6 \" xC 1 , . . . , C m y.", "cite_spans": [{"start": 41, "end": 45, "text": "[13]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Definition 2 (LKS).", "text": "Example 3. Let \u03a6 be the proof schema of example 2 and \u03a6 a be the corresponding accumulating proof schema. For 1 P N we can write down \u03a6 a \u00d3 1 :", "cite_spans": [], "ref_spans": []}, {"section": "Definition 2 (LKS).", "text": "P psp\u03b1`Sp0qqq $ P psp\u03b1`Sp0qqq P p\u03b1`0q $ P p\u03b1`0q w : l P p\u03b1`0q, @x.P pxq \u00d1 P pspxqq $ P p\u03b1`0q E P p\u03b1`0q, @x.P pxq \u00d1 P pspxqq $ P p\u03b1`Sp0qq \u00d1 : l P p\u03b1`0q, @x.P pxq \u00d1 P pspxqq, P p\u03b1`Sp0qq \u00d1 P psp\u03b1`Sp0qqq $ P psp\u03b1`Sp0qqq @ : l P p\u03b1`0q, @x.P pxq \u00d1 P pspxqq, @x.P pxq \u00d1 P pspxqq $ P psp\u03b1`Sp0qqq E P p\u03b1`0q, @x.P pxq \u00d1 P pspxqq, @x.P pxq \u00d1 P pspxqq $ P p\u03b1`spSp0qqq E P p\u03b1`0q, @x.P pxq \u00d1 P pspxqq, @x.P pxq \u00d1 P pspxqq $ P p\u03b1`Sp0`1qq c : l P p\u03b1`0q, @x.P pxq \u00d1 P pspxqq $ P p\u03b1`Sp0`1qq E P p\u03b1`0q, @x.P pxq \u00d1 P pspxqq $ P p\u03b1`Sp1qq", "cite_spans": [], "ref_spans": []}, {"section": "Definition 2 (LKS).", "text": "Proposition 1 (Soundness of proof schemata [13] ). Let \u03a6 \" xC 1 , . . . , C m y be a proof schema, and let \u03b1 P N. Then there exists a LK-proof of C 1 \u00d3 \u03b1 .", "cite_spans": [{"start": 43, "end": 47, "text": "[13]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Definition 2 (LKS).", "text": "If Spk,tq is the end sequent of \u03a6 then Proposition 1 essentially states that C 1 \u00d3 \u03b1 is an LK-proof of Sp\u03b1,tq \u00d3 where by \u00d3 we refer to normalization of the defined symbols in Sp\u03b1,tq.", "cite_spans": [], "ref_spans": []}, {"section": "The Characteristic Clause Set", "text": "The characteristic clause set of an LK-proof \u03d5 is extracted by inductively following the formula occurrences of cut ancestors up the proof tree to the leaves. The cut ancestors are sub-formulas of any cut in the given proof. However, in the case of proof schemata, the concept of ancestors and formula occurrence is more complex. A formula occurrence might be an ancestor of a cut formula in one recursive call and in another it might not. Additional machinery is necessary to extract the characteristic clause set from proof schemata. A set \u2126 of formula occurrences from the end-sequent of an LKS-proof \u03c8 is called a configuration for \u03c8. A configuration \u2126 for \u03c8 is called relevant w.r.t. a proof schema \u03a8 if \u03c8 is a proof in \u03a8 and there is a \u03b3 P N such that \u03c8 induces a subproof \u03c0 \u00d3 \u03b3 of \u03a8 \u00d3 \u03b3 such that the occurrences in \u2126 correspond to cut-ancestors below \u03c0 \u00d3 \u03b3 [12] . By \u03c0 \u00d3 \u03b3 , we mean substitute the free parameter of \u03c0 with \u03b3 P N and unroll the proof schema to an LKE-proof. We note that the set of relevant cut-configurations can be computed given a proof schema \u03a8. To represent a proof symbol \u03d5 and configuration \u2126 pairing in a clause set we assign a clause set symbol cl \u03d5,\u2126 pk,xq to them, where k P \u2126 \u2126 \u2126 \u2126.", "cite_spans": [{"start": 865, "end": 869, "text": "[12]", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "The Characteristic Clause Set", "text": "Definition 9 (Characteristic clause term [13] ). Let \u03c0 be an LKS-proof and \u2126 a configuration. In the following, by \u0393 \u2126 , \u2206 \u2126 and \u0393 C , \u2206 C we will denote multisets of formulas of \u2126-and cut-ancestors respectively. Let r be an inference in \u03c0. We define the clause-set term \u0398 \u03c0,\u2126 r inductively:", "cite_spans": [{"start": 41, "end": 45, "text": "[13]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "The Characteristic Clause Set", "text": "\u2022 if r is an axiom of the form \u2022 if r is a binary rule with immediate predecessor r 1 , r 2 , then -if the auxiliary formulas of r are \u2126-or cut-ancestors, then \u0398", "cite_spans": [], "ref_spans": []}, {"section": "The Characteristic Clause Set", "text": ", where r 0 is the last inference of \u03c0, and \u0398 \u03c0 \" \u0398 \u03c0,H . \u0398 \u03c0 is called the characteristic term of \u03c0.", "cite_spans": [], "ref_spans": []}, {"section": "The Characteristic Clause Set", "text": "Note that considering an empty configuration and ignoring the rule for proof links results in the definition of clause set term for LK-proofs [5] . Clause terms can be evaluate to sets of clauses using", "cite_spans": [{"start": 142, "end": 145, "text": "[5]", "ref_id": "BIBREF4"}], "ref_spans": []}, {"section": "The Characteristic Clause Set", "text": "where C\u02ddD is the sequent whose antecedent is the union of the antecedents of C and D and analogously whose succedent is the union of the succedents of C and D.", "cite_spans": [], "ref_spans": []}, {"section": "The Characteristic Clause Set", "text": "The characteristic clause term is extracted for each proof symbol in a given proof schema \u03a8, and together they make the characteristic clause set schema for \u03a8, CLp\u03a8q.", "cite_spans": [], "ref_spans": []}, {"section": "The Characteristic Clause Set", "text": "Definition 10 (Characteristic Term Schema [13] ). Let \u03a8 \" xC 1 ,\u00a8\u00a8\u00a8, C m y be a proof schema. We define the rewrite rules for clause-set symbols for all proof schema components C i and configurations \u2126 as cl Ci,\u2126 p0, uq \u00d1 \u0398 \u03c0i,\u2126 and cl Ci,\u2126 pk, uq \u00d1 \u0398 \u03bdi,\u2126 where 1 \u010f i \u010f m. Next, let \u03b3 P N and cl Ci,\u2126 \u00d3 \u03b3 be the normal form of cl Ci,\u2126 p\u03b3, uq under the rewrite system just given extended by rewrite rules for defined function and predicate symbols. Then define \u0398 Ci,\u2126 \" cl", "cite_spans": [{"start": 42, "end": 46, "text": "[13]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "The Characteristic Clause Set", "text": "and \u0398 \u03a8,\u2126 \" cl C1,\u2126 and finally the characteristic term schema", "cite_spans": [], "ref_spans": []}, {"section": "The Characteristic Clause Set", "text": "Note that, concerning the characteristic clause schema of a proof schema \u03a6 the following essential proposition holds.", "cite_spans": [], "ref_spans": []}, {"section": "Proposition 2 ([13, 16]). Let", "text": "Example 4. The following characteristic term schema is taken from the proof analysis of [10] where \u0398 \u03a6 \" cl \u03c8,H pn`1q and \u2126pnq \" Dx@y pppx \u010f yq \u00d1 n`1 \" f pyqq _ f pyq \u0103 n`1q :", "cite_spans": [{"start": 88, "end": 92, "text": "[10]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Proposition 2 ([13, 16]). Let", "text": "\u2126pn`1q pn`1q'pt$f p\u03b1q\u0103n`1ubt$n`1\"f p\u03b1qubt0\u010f\u03b2$uq cl \u03d5,\u2126p0q p0q\" tf p\u03b1q\u01030$u'tf pgp\u03b1qq\u01030$u't$\u03b1\u010f\u03b1u't$\u03b1\u010fgp\u03b1qu't0\"f p\u03b1q,0\"f pgp\u03b1qq$u cl \u03d5,\u2126pn`1q pn`1q\" cl \u03d5,\u2126pnq pnq'tn`1\"f p\u03b1q,n`1\"f pgp\u03b1qq$u't$\u03b1\u010f\u03b1u't\u03b1\u010fgp\u03b1qu'tn`1\"f p\u03b2q$n`1\"f p\u03b2qu' t\u03b1\u010f\u03b2$\u03b1\u010f\u03b2u'tf p\u03b2q\u0103n`1$f p\u03b2q\u0103n`1u'tf p\u03b1q\u0103n`1,\u03b1\u010f\u03b2$n\"f p\u03b2q,f p\u03b2q\u0103nu", "cite_spans": [], "ref_spans": []}, {"section": "Proposition 2 ([13, 16]). Let", "text": "The following clause set is \u0398 \u03a6 \u00d3 1 . Equivalence can be checked by referring to the formal proof of [10] .", "cite_spans": [{"start": 101, "end": 105, "text": "[10]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Top Clause Set", "text": "Let us consider the characteristic clause set of an ACNF top \u03d5, that is CLp\u03d5q. The smallest unsatisfiable subset of CLp\u03d5q has a special structure pointed out be S. Wolfsteiner in [20] (Definition 6.1.6) which he called a TANCF. Such a clause set term is generated from the product of atomic clause sets tA $, $ Au where A is an atom. Later this structure was used for constructing clause sets from a set of propositional symbols by A. Condoluci [11] , the so called top clause set.", "cite_spans": [{"start": 179, "end": 183, "text": "[20]", "ref_id": "BIBREF19"}, {"start": 445, "end": 449, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Definition 11 ([11]", "text": "). Let A be an atom whose predicate symbol is P P P u , and A, A 1 be multisets of atoms. We define the operator CL t p\u00a8q which maps a set of atoms to a clause set:", "cite_spans": [], "ref_spans": []}, {"section": "Definition 11 ([11]", "text": "We refer to CL t pAq as the top clause set with respect to the set of atoms A.", "cite_spans": [], "ref_spans": []}, {"section": "Definition 11 ([11]", "text": "As was shown in both [11, 20] , such a clause set is always unsatisfiable, even in the first-order case. We use this concept later to further extend the results presented in Section 4.", "cite_spans": [{"start": 21, "end": 25, "text": "[11,", "ref_id": "BIBREF10"}, {"start": 26, "end": 29, "text": "20]", "ref_id": "BIBREF19"}], "ref_spans": []}, {"section": "Clausal Subsumption: Theory and Results", "text": "Let Apxq be a formula with the free variablesx \" px 1 , . . . , x n q for n P N. A substitution \u03b8 \" rxzts is an instantiation of the free variables x 1 , . . . , x n within a formula A with the terms t \" pt 1 , . . . , t n q such that t i do not contain x i for 1 \u010f i \u010f n as a subterm, i.e. Apxq\u03b8 \" Aptq\u03b8.", "cite_spans": [], "ref_spans": []}, {"section": "Clausal Subsumption: Theory and Results", "text": "We call a sequent containing only atomic formulas a clause. Moreover, we define the subset relation \u010e on clauses, i.e. a clause C is a subset of a clause D (C \u010e D) if the atoms in the succedent of C are a subset of the atoms in the succedent of D and analogously the atoms in the antecedent of C are a subset of the atoms in the antecedent of D. Now we are able to define the subsumption relation of clauses (see [7] ).", "cite_spans": [{"start": 413, "end": 416, "text": "[7]", "ref_id": "BIBREF6"}], "ref_spans": []}, {"section": "Clausal Subsumption: Theory and Results", "text": "Definition 12 (Subsumption). Let C and D be clauses. Then C subsumes D (C \u010f ss D) if there exists a substitution \u03b8 s.t. C\u03b8 \u010e D. Since we define \u010e with sets we do not have to consider permutation. We say that a set of clauses C subsumes a set of clauses", "cite_spans": [], "ref_spans": []}, {"section": "Clausal Subsumption: Theory and Results", "text": "The concept of clausal subsumption was used in [6] derive the theorems that the following two corollaries are based on.", "cite_spans": [{"start": 47, "end": 50, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Clausal Subsumption: Theory and Results", "text": "Corollary 1 (Direct corollary of Theorem 6.1 [6] ). Let \u03d5 be an LK-proof and \u03c8 be the ACNF top of \u03d5 as described in Section 2.1. Then \u0398p\u03d5q \u010f ss \u0398p\u03c8q.", "cite_spans": [{"start": 45, "end": 48, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Clausal Subsumption: Theory and Results", "text": "Corollary 2 (Direct corollary of Theorem 6.2 [6] ). Let \u03d5 be an LK-proof and \u03c8 be an ACNF top of \u03d5 as described in Section 2.1. Then there exists a resolution refutation \u03b3 of CLp\u03d5q s.t. \u03b3 \u010f ss RESp\u03c8q where RESp\u03c8q is the resolution proof corresponding to \u03c8.", "cite_spans": [{"start": 45, "end": 48, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Lazy Instantiation of Proof Schema", "text": "In this section we define a transformation which allows for a kind of lazy evaluation [15] of proof schemata, that is lazy instantiation. A similar concept was used by C. Sprenger and M. Dam [18] to transform global induction into local induction for a variant of the \u00b5-calculus. Lazy instantiation allows us to apply reductive cut-elimination to proof schemata by moving the cyclic structure (proof links) whenever it impedes the cut-elimination procedure, i.e. auxiliary sequents introduced by proof links do not have a reductive cut-elimination rule. Though one can never eliminate the cuts through lazy instantiation we can get a better understanding of the relationship between proof schemata in there instantiated and uninstantiated forms. Essentially, we extend the clausal analysis of [6] to proof schemata. The lazy instantiation relation is defined as \u00d1 L : \u00d1 . We first provide an example transformation before providing a formal definition of the transformation.", "cite_spans": [{"start": 86, "end": 90, "text": "[15]", "ref_id": "BIBREF14"}, {"start": 191, "end": 195, "text": "[18]", "ref_id": "BIBREF17"}, {"start": 793, "end": 796, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Lazy Instantiation of Proof Schema", "text": "Example 5. Consider the following proof schema \u03a6 \" xC 1 y where C 1 \" p\u03c8, \u03c0, \u03bdpkqq (note that by we represent the empty tuple of terms),", "cite_spans": [], "ref_spans": []}, {"section": "Lazy Instantiation of Proof Schema", "text": "where \u03d5 pn`1q is an LK-proof of P pn`1q \u00d1 Qpn`1q $ P pn`1q _ Qpn`1q.", "cite_spans": [], "ref_spans": []}, {"section": "Lazy Instantiation of Proof Schema", "text": "\u03c0 \"", "cite_spans": [], "ref_spans": []}, {"section": "Lazy Instantiation of Proof Schema", "text": "We can lazily evaluate the accumulating proof schema", "cite_spans": [], "ref_spans": []}, {"section": "Lazy Instantiation of Proof Schema", "text": "1 q, and C 2 \" p\u03c7, \u03c0, \u03bdpkq 2 q. Let \u03bdpkq.\u00b5 \" p\u03c8, n, q. We define \u03bdpkq 1 \" \u03bdpkq\u03c3 r\u03bdpkq 2 s \u00b5 , where \u03c3 \" tn \u00d0 n`1u. The LKS-proof \u03bdpkq 2 is the same as \u03bdpkq except \u03bdpkq 2 .\u00b5 \" p\u03c7, n, q. The important parts of \u03bdpkq 1 can be sketched as follows:", "cite_spans": [], "ref_spans": []}, {"section": "Lazy Instantiation of Proof Schema", "text": "p\u03c7, n, q", "cite_spans": [], "ref_spans": []}, {"section": "Lazy Instantiation of Proof Schema", "text": "For the formal definition we use \u03bdpkq 1 and \u03bdpkq 2 as in example 5 even though \u03bdpkq is not directly discussed.", "cite_spans": [], "ref_spans": []}, {"section": "Lazy Instantiation of Proof Schema", "text": "Definition 13. Let \u03a6, \u03a8 P , such that PLp\u03a6.1q does not have incoming links. We say that \u03a6 lazily instantiates to \u03a8, \u03a6 \u00d1 L \u03a8, if", "cite_spans": [], "ref_spans": []}, {"section": "Lazy Instantiation of Proof Schema", "text": "where \u03bdpkq 1 is constructed from \u03a6.1.3 as follows: First construct \u03bdpkq 2 \" \u03a6.1.3\u03c3 where \u03c3 \" tn \u00d0 n`1u is a parameter substitution. Then we construct \u03bdpkq 1 from \u03bdpkq 2 by replacing every proof link p\u03c7, k 1 ,tq P PLp\u03bdpkq 2 q at position \u03b3 with the appropriate LKS-proof, that is if \u03a6.i \" p\u03c7, \u03c0 i , \u03bd i pkqq then we substitute \u03bdpkq 2 r\u03bd i pkqpk 1 qs \u03b3 and \u03bdpkq 2 r\u03c0 i s \u03b3 if k 1 \" 0.", "cite_spans": [], "ref_spans": []}, {"section": "Remark 1. Note that if \u03a6 is accumulating then PLp\u03a6.1q does not have incoming link.", "text": "In general it will be necessary to lazily instantiate a proof schema several times. In fact, we will consider all proof schemata that are producible by lazy instantiations. Definition 14. Let \u03a6, \u03a8 P . We define the set of lazily reachable proof schemata from a proof schema \u03a6, lr p\u03a6q by the following inductive construction:", "cite_spans": [], "ref_spans": []}, {"section": "Remark 1. Note that if \u03a6 is accumulating then PLp\u03a6.1q does not have incoming link.", "text": "\u2022 \u03a6 P lr p\u03a6q \u2022 if \u03a8 P lr p\u03a6q and \u03a8 \u00d1 L \u0393, then \u0393 P lr p\u03a6q Definition 15. Let \u03a6, \u03a8 P . We define the set of reductively reachable proof schemata from a proof schemata \u03a6, rr p\u03a6q by the following inductive construction (\u00d1 R is define at the beginning of Section 2) :", "cite_spans": [], "ref_spans": []}, {"section": "Remark 1. Note that if \u03a6 is accumulating then PLp\u03a6.1q does not have incoming link.", "text": "\u2022 \u03a6 P rr p\u03a6q \u2022 if \u03a8 P rr p\u03a6q and \u03a8 \u00d1 R \u0393, then \u0393 P rr p\u03a6q Definition 16. Let \u03a6, \u03a8 P . We define the lr-chain length |\u03a8| \u03a6 lr (respectively the rr-chain length |\u03a8| \u03a6 rr ) inductively as follows:", "cite_spans": [], "ref_spans": []}, {"section": "Remark 1. Note that if \u03a6 is accumulating then PLp\u03a6.1q does not have incoming link.", "text": "An important property of this transformation is that, when applied to accumulating proof schemata \u03a6, for every proof schema in \u03a8 P lr p\u03a6q, there are only finitely many evaluations of \u03a6 that are not equivalent to an evaluation of \u03a8. In Example 5 there is no evaluation of \u03a8 equivalent to \u03a6 \u00d3 1 . Lemma 1. Let \u03a6 P be accumulating and \u03a8 P lr p\u03a6q. Then for all \u03b1 P N there exists \u03b2 P N such that \u03a8 \u00d3 \u03b1 \" syn \u03a6 \u00d3 \u03b2 .", "cite_spans": [], "ref_spans": []}, {"section": "Remark 1. Note that if \u03a6 is accumulating then PLp\u03a6.1q does not have incoming link.", "text": "Proof. By induction on |\u03a8| \u03a6 lr . Lemma 1 tells us that we can use lazy instantiation to change the structure of a given proof schema \u03a6 into a proof schema \u03a8 without completely losing the logical meaning, that is equivalence is only lost for finitely many LK-proofs. More specifically, every evaluation of \u03a8 is equivalent, syntactically, to an evaluation of \u03a6.", "cite_spans": [], "ref_spans": []}, {"section": "Remark 1. Note that if \u03a6 is accumulating then PLp\u03a6.1q does not have incoming link.", "text": "Definition 17. Let \u03a6, \u03a8 P such that \u03a8 P lr p\u03a6q and \u03a6 is accumulating. We define a numeral pair p\u03b1, \u03b2q as a pair of natural numbers such that \u03a8 \u00d3 \u03b1 \" syn \u03a6 \u00d3 \u03b2 . The set of all numeral pairs for \u03a8 and \u03a6 is npp\u03a8, \u03a6q.", "cite_spans": [], "ref_spans": []}, {"section": "Remark 1. Note that if \u03a6 is accumulating then PLp\u03a6.1q does not have incoming link.", "text": "The next lemma is a direct result of Lemma 1.", "cite_spans": [], "ref_spans": []}, {"section": "Remark 1. Note that if \u03a6 is accumulating then PLp\u03a6.1q does not have incoming link.", "text": "Lemma 2. Let \u03a6 P be an accumulating proof schema and \u03a8, \u03a8 1 P be proof schemata. Furthermore, let \u03a8 P lr p\u03a6q be lazily reachable from \u03a6, \u03a8 1 P rr p\u03a8q be reductively reachable from \u03a8, and p\u03b1, \u03b2q P npp\u03a8, \u03a6q be a numeral pair of \u03a8 and \u03a6. Then there exists an LK-proof \u03c7 such that \u03c7 P rr p\u03a6 \u00d3 \u03b2 q and \u03a8 1 \u00d3 \u03b1 \" syn \u03c7.", "cite_spans": [], "ref_spans": []}, {"section": "Remark 1. Note that if \u03a6 is accumulating then PLp\u03a6.1q does not have incoming link.", "text": "Proof. Consider application of reductive cut-elimination rules which only reduce the cuts of \u03a8. ", "cite_spans": [], "ref_spans": []}, {"section": "Clausal Analysis of Proof Schemata", "text": "Before we discuss the relationship between the various concepts and results, as shown in Figure 1 , we introduce a concept closely related to the ACNF top , that is the atom set schema and its clause set [11] . Intuitively, an atom set schema of a clause set is just a list of the atoms found in a clause set schema. Though, not exactly the same as the clause set extracted from an ACNF top , the clause set of an atom set schema, when instantiated, is subsumed by the clause set of the corresponding ACNF top .", "cite_spans": [{"start": 204, "end": 208, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": [{"start": 89, "end": 97, "text": "Figure 1", "ref_id": "FIGREF2"}]}, {"section": "Atom Set Schema", "text": "This concept was introduced by A. Condoluci in his master thesis concerning schematic propositional logic [11] . We extend his definition to first-order logic by considering the predicate symbols modulo tuples of terms rather than just an arithmetic term. Note that, these terms form a schema which is easily extractable from a proof schema or characteristic clause set schema. We refer to this schema as a predicate term schema. In some cases the predicate term schema may be describable by a case distinction, i.e. the terms do not contain the free parameter.", "cite_spans": [{"start": 106, "end": 110, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Atom Set Schema", "text": "Definition 18 (Predicate Term Schema ). Let P P P u be an \u03b1-ary predicate symbol. Then the predicate term schema of P is a mapping t P : N \u00d1 \u03b9 \u03b1 from numerals to \u03b1-tuples of terms such that for \u03b2 P N, P pt P p\u03b2qq is a well-formed atom. we assume that, if the \u03b1-tuple contains a defined function symbol it will be evaluated and normalized.", "cite_spans": [], "ref_spans": []}, {"section": "Atom Set Schema", "text": "Definition 19 (Extension of Definition 78 [11] ). An atom set schema A is a finite set of 3-tuples", "cite_spans": [{"start": 42, "end": 46, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Atom Set Schema", "text": "where", "cite_spans": [], "ref_spans": []}, {"section": "Atom Set Schema", "text": "Pi is a predicate term schema of P i for 1 \u010f j \u010f \u03b1 i , and a j i is an arithmetic term.", "cite_spans": [], "ref_spans": []}, {"section": "Atom Set Schema", "text": "Example 6. The atom set schema !A P, \u03bbr.p\u03b1`\u015cprqq, n`1 E) was extracted from Example 2.", "cite_spans": [], "ref_spans": []}, {"section": "Atom Set Schema", "text": "Definition 20 (Extension of Definition 79 [11] ). For every \u03b1 P N, we define the evaluation of an atom set schema, where xP, t P , ay \u00d3 \u03b1 \" tP pt P p0qq, P pt P p1qq,\u00a8\u00a8\u00a8, P pt P pa rnz\u03b1sqqu, as:", "cite_spans": [{"start": 42, "end": 46, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Atom Set Schema", "text": "Example 7. Using the atom set schema of Example 6, we can derive the following evaluation:", "cite_spans": [], "ref_spans": []}, {"section": "Atom Set Schema", "text": "An atom set schema can always be extracted from a clause set term schema.", "cite_spans": [], "ref_spans": []}, {"section": "Atom Set Schema", "text": "Lemma 3 (Completeness for atom set schemata [11] ). For every clause set term schema T, there exists an atom set schema for T.", "cite_spans": [{"start": 44, "end": 48, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Atom Set Schema", "text": "Though, this lemma was proven for schematic propositional logic, it can easily be extended by constructing the corresponding predicate term schema for each use of a given predicate symbol. We introduced the concept of lazy instantiation to deal with precisely the following problem faced during application of reductive cut elimination to proof schemata. Note that this may result in additional predicate and term pairings which do not exists in the proof schema, but more importantly, the extraction method presented in [11] guarantees that no pairings, of which are presented in the given proof schema, are missing. This property allows us to further extend our subsumption results, as can be seen in Figure 1 point (x).", "cite_spans": [{"start": 521, "end": 525, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": [{"start": 703, "end": 711, "text": "Figure 1", "ref_id": "FIGREF2"}]}, {"section": "Atom Set Schema", "text": "Definition 21 (Top clause set schemata [11] ). Let A be an atom set schema. We denote the corresponding top clause set schema by CL t pAq.", "cite_spans": [{"start": 39, "end": 43, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Atom Set Schema", "text": "Definition 22 (Semantics of top clause set schemata [11] ). For \u03b1 P N, CL t pAq \u00d3 \u03b1 \" CL t pA \u00d3 \u03b1 q.", "cite_spans": [{"start": 52, "end": 56, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Atom Set Schema", "text": "In [11] , it was shown that a propositional top clause set schemata can be refutated schematically (Lemma 10). Problematically, in the first-order case, a substitution schema must also be defined [13] . If a substitution schema exists for a given first-order top clause set schema a schematic refutation can be defined. Though, the specification of such a substitution schema remains an open problem. In Figure 1 , construction of the substitution schema and construction of the refutation (see [11] ) are point (xii).", "cite_spans": [{"start": 3, "end": 7, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 196, "end": 200, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 495, "end": 499, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": [{"start": 404, "end": 412, "text": "Figure 1", "ref_id": "FIGREF2"}]}, {"section": "Clausal Analysis", "text": "The main result of this paper is as follows:", "cite_spans": [], "ref_spans": []}, {"section": "Clausal Analysis", "text": "be an accumulating proof schema, \u03a6 P lrp\u03a8q be lazily reachable from \u03a8, and \u039e P rrp\u03a6q reductively reachable from \u03a6. Then for all \u03b1 P N there exists a numeral \u03b2 P N and an ACNF top \u03c7, such that \u0398p\u03c8q \u010f ss \u0398p\u03c7q for all \u03c8 P rrp\u03a8 \u00d3 \u03b2 q, and \u0398 \u039e \u00d3 \u03b1 \u010f ss \u0398p\u03c7q \u010f ss q \u00d3 \u03b1 is a result of Lemma 3 and the extraction method of [11] .", "cite_spans": [{"start": 316, "end": 320, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Clausal Analysis", "text": "In Figure 1 , we present the entire process concerning how one goes from a proof schema \u03a6 to a refutation. Note, as we mention before, the existence of a refutation for a first-order top clause set schema is dependent on the existence of a substitution schema [13] , of which the construction is still an open problem, that is whether a substitution schema exists for every first-order top clause set. We leave this question to future work. The first step in Figure 1 , (i), constructs an accumulating proof schema \u03a6 A from \u03a6. This adds an additional component which \"accumulates\" the lazily instantiated proof links. After the construction of an accumulating proof schema \u03a6 A , we can either instantiate it (iii) or apply lazy instantiation (ii) and construct a proof schema \u03a6 1 . The point of lazy instantiation is to get around situation like the following:", "cite_spans": [{"start": 260, "end": 264, "text": "[13]", "ref_id": "BIBREF12"}], "ref_spans": [{"start": 3, "end": 11, "text": "Figure 1", "ref_id": "FIGREF2"}, {"start": 459, "end": 467, "text": "Figure 1", "ref_id": "FIGREF2"}]}, {"section": "Clausal Analysis", "text": "in which Gentzen rules cannot be applied unless we evaluate the proof links. Note that by Lemma 1, we can instantiate \u03a6 A and \u03a6 1 such that they are equivalent. The heart of our result is that lazy instantiation allows us to apply reductive cut elimination to an arbitrarily large but finite portion of \u03a6 A . This results in a proof schema \u03a8. In turn, we can apply the same reductive cut elimination steps \u03a6 A \u00d3 \u03b1 resulting in an LK-proof \u03c8 whose clause set subsumes the evaluation of the clause set schema of \u03a8 at \u03b2. Furthermore, by extending the results of [6] , we are able to show subsumption properties between the clause set schema of \u03a8 and the clause set of \u03c8, as well as between both clause sets and the clause set of the ACNF top of \u03c8. ", "cite_spans": [{"start": 559, "end": 562, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Conclusion", "text": "In this work we extend results concerning the clausal analysis of LK-proofs to first-order proof schemata [6] . The results of [6] are based on clause set subsumption properties between an LK-proof \u03d5 and an LK-proof \u03c8 which is the result of applying reductive cut-elimination to \u03d5, without atomic cut elimination. These results are not easily extendable to proof schemata because cuts cannot be easily passed through proofs links. We define lazy instantiation allowing proof links to unfold and allowing reductive cut-elimination to continue. Thus, we were able to derive clause set subsumption results for arbitrary applications of reductive cut-elimination to proof schemata. Furthermore, using the structural results of [11, 20] , we were able to strengthen these results and reduce the problem of constructing an ACNF schema (see [13] ) to find a substitution schema [13] . As discussed in [9, 10] , defining the structure of the resolution refutation is the hardest part of the proof analysis using schematic CERES [13] . For future work, we plan to investigate how the introduced concepts can be applied to other issues concerning proof schemata. Also, we plan to investigate ways one can simplify the construction of substitution schemata, possibly through the use of automated theorem proving methods [10] .", "cite_spans": [{"start": 106, "end": 109, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 127, "end": 130, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 723, "end": 727, "text": "[11,", "ref_id": "BIBREF10"}, {"start": 728, "end": 731, "text": "20]", "ref_id": "BIBREF19"}, {"start": 834, "end": 838, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 871, "end": 875, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 894, "end": 897, "text": "[9,", "ref_id": "BIBREF8"}, {"start": 898, "end": 901, "text": "10]", "ref_id": "BIBREF9"}, {"start": 1020, "end": 1024, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 1309, "end": 1313, "text": "[10]", "ref_id": "BIBREF9"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "A schemata calculus for propositional logic", "authors": [{"first": "Ricardo", "middle": [], "last": "Vincent Aravantinos", "suffix": ""}, {"first": "Nicolas", "middle": [], "last": "Caferra", "suffix": ""}, {"first": "", "middle": [], "last": "Peltier", "suffix": ""}], "year": 2009, "venue": "Automated Reasoning with Analytic Tableaux and Related Methods", "link": "15189993"}, "BIBREF1": {"title": "Decidability and undecidability results for propositional schemata", "authors": [{"first": "Ricardo", "middle": [], "last": "Vincent Aravantinos", "suffix": ""}, {"first": "Nicolas", "middle": [], "last": "Caferra", "suffix": ""}, {"first": "", "middle": [], "last": "Peltier", "suffix": ""}], "year": 2011, "venue": "Journal of Artificial Intelligence Research", "link": "1333814"}, "BIBREF2": {"title": "A resolution calculus for first-order schemata", "authors": [{"first": "Mnacho", "middle": [], "last": "Vincent Aravantinos", "suffix": ""}, {"first": "Nicolas", "middle": [], "last": "Echenim", "suffix": ""}, {"first": "", "middle": [], "last": "Peltier", "suffix": ""}], "year": 2013, "venue": "Fundam. 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"Daniel", "middle": [], "last": "Weller", "suffix": ""}], "year": 2017, "venue": "Journal of Logic and Computation", "link": "9443856"}, "BIBREF16": {"title": "Cut-elimination for a logic with definitions and induction", "authors": [{"first": "Raymond", "middle": [], "last": "Mcdowell", "suffix": ""}, {"first": "Dale", "middle": [], "last": "Miller", "suffix": ""}], "year": 1997, "venue": "Theoretical Computer Science", "link": "7600116"}, "BIBREF17": {"title": "On the Structure of Inductive Reasoning: Circular and TreeShaped Proofs in the \u00b5Calculus", "authors": [{"first": "Christoph", "middle": [], "last": "Sprenger", "suffix": ""}, {"first": "Mads", "middle": [], "last": "Dam", "suffix": ""}], "year": 2003, "venue": "", "link": "28388732"}, "BIBREF18": {"title": "Proof Theory, volume 81 of Studies in logic and the foundations of mathematics", "authors": [{"first": "Gaisi", "middle": [], "last": "Takeuti", "suffix": ""}], "year": 1975, "venue": "", "link": null}, "BIBREF19": {"title": "Structural analysis of cut-elimination", "authors": [{"first": "Simon", "middle": [], "last": "Wolfsteiner", "suffix": ""}], "year": 2015, "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "then define \u2126 1 as the set of formula occurrences from \u0393 \u2126 , \u0393 C $ \u2206 \u2126 , \u2206 C and \u0398", "type": "figure"}, "FIGREF1": {"text": "This means if a rule would require passing a cut through a proof link of \u03a8.1.3 it cannot be applied. Being that \u03a8 and \u03a6 are equivalent when instantiated by pn,mq and by definition \u03a8.1 is acyclic, application of rules transforming \u03a8.1.3 can be repeated in \u03a6 without influencing unwanted parts of the proof. The rest of the proof is an induction on |\u03a8 1 | \u03a8 rr .", "type": "figure"}, "FIGREF2": {"text": "Figure 1: Clause set subsumption relationships for proof schemata. (i):Def. 7, (ii):Def. 13, (iii): Def. 8, (iv):Lem. 1, (v): Reductive cut-elimination, (vi): Def. 10, (vii): Corollary 1, (viii): Proposition 2 (ix): Theorem 1 and transitivity of \u010f ss , (x): Lemma 3, (xi): Definition 21, (xii) When there exists a substitution schema for CL t pA \u03a8 q. Note that dashed arrows represent our results and solid arrows existing results.", "type": "figure"}, "TABREF0": {"text": "where A \u0398 \u039e is an atom set schema. Proof. The statement \u0398 \u039e \u00d3 \u03b1 \u010f ss \u0398p\u03c7q is a consequence of Lemma 2 and Corollary 1. The statement \u0398p\u03c7q \u010f ss CL t pA", "type": "table"}}}
{"paper_id": "17436382", "_pdf_hash": "470d92e570b279a156ae95b5d7f0b7ca5ca6f881", "abstract": [{"section": "Abstract", "text": "A survey of recent results in elementary number theory is presented in this paper. Special attention is given to structure and asymptotic properties of certain families of positive integers. In particular, a conjecture on complete sequences of Burr, Erd\u0151s, Graham and Wen-Ching Li is amended.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "The aim of this paper is to survey some topics in elementary number theory. The contents are based on the talk given in Parma at the occasion of the Second Italian Meeting of Number Theory in november 2003. All these topics are of arithmetical nature and, as is often the case, no special knowledge is required. Still today improvements and new developments are possible, so this makes this paper suitable for students who wish to begin or to continue their studies in elementary number theory.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Each section contains a problem involving a suitable sequence of family of sequences with a short literature, open problems, and some new results.", "cite_spans": [], "ref_spans": []}, {"section": "Introduction", "text": "Section 2 is consacrated to practical numbers, i.e., those numbers m such that the set of all distinct positive divisors sums contains all positive integers not exceeding m. Section 3 concerns sum-free sequences, i.e., increasing sequences of positive integers such that each term is never a sum of distint preceding terms. Section 4 presents some results on density of certain sets whose elements are sums of distinct powers of positive integers. We provide a counterexample to a conjecture of Burr, Erd\u0151s, Graham and Wen-Ching Li [2] , so showing the necessity of an amended version. Section 5 deals with certain families of positive integer sequences whose digital expansion of elements is suitably related to the digital expansion of their powers.", "cite_spans": [{"start": 532, "end": 535, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Practical numbers", "text": "A positive integer m is a practical number if every positive integer n < m is a sum of distinct positive divisors of m.", "cite_spans": [], "ref_spans": []}, {"section": "Practical numbers", "text": "Let P (x) be the counting function of practical numbers and let P 2 (x) be the function that counts practical numbers m \u2264 x such that m+ 2 is also a practical number. Stewart [19] proved that a positive integer m \u2265 2, m = q", "cite_spans": [{"start": 175, "end": 179, "text": "[19]", "ref_id": "BIBREF18"}], "ref_spans": []}, {"section": "Practical numbers", "text": "with primes q 1 < q 2 < \u00b7 \u00b7 \u00b7 < q k and integers \u03b1 i \u2265 1, is practical if and only if q 1 = 2 and, for i = 2, 3, . . . , k,", "cite_spans": [], "ref_spans": []}, {"section": "Practical numbers", "text": "where \u03c3(n) denotes the sum of the positive divisors of n. A wide survey of results and conjectures on practical numbers is given by Margenstern [10] .", "cite_spans": [{"start": 144, "end": 148, "text": "[10]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "Practical numbers", "text": "Practical numbers appear to be a prime-like sequence. Saias [16] , using suitable sieve methods introduced by Tenenbaum provided a good estimate in terms of a Chebishev-type theorem:", "cite_spans": [{"start": 60, "end": 64, "text": "[16]", "ref_id": "BIBREF15"}], "ref_spans": []}, {"section": "Practical numbers", "text": "Theorem 1 For suitable constants c 1 and c 2 ,", "cite_spans": [], "ref_spans": []}, {"section": "Practical numbers", "text": "The author [11] solved the Golbach problem by proving that every even positive integer is a sum of two practical numbers. The proof used an auxiliary increasing sequence m n of practical numbers such that for every n, m n +2 is also a practical number and m n+1 /m n bounded by an absolute constant, and a corollary of Stewart's theorem, namely if m is a practical number and n \u2264 2m, then mn is a pratical number too. Every pair of twin practical numbers yields a suitable interval of even numbers expressible as a sum of two practical numbers and intervals overlap. A local property which does not appear in primes holds for practical numbers: there exist infinitely many practical numbers m such that both m \u2212 2 and m + 2 as one can check by taking m = 2 \u00b7 3", "cite_spans": [{"start": 11, "end": 15, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Practical numbers", "text": "Further, infinitely many 5-tuples of practical numbers of the form m \u2212 6, m \u2212 2, m, m + 2, m + 6 exist under a suitable but still unproved hypothesis [14] .", "cite_spans": [{"start": 150, "end": 154, "text": "[14]", "ref_id": "BIBREF13"}], "ref_spans": []}, {"section": "Practical numbers", "text": "Twenty years ago Margenstern conjectured that for suitable \u03bb 1 and", "cite_spans": [], "ref_spans": []}, {"section": "Practical numbers", "text": "He empirically proposed \u03bb 1 \u2243 1.341 and \u03bb 2 \u2243 1.436. Such conjectures appear far to be proved. However it should be interesting to prove that lim x\u2192\u221e P (2x)/P (x) = 2, a somewhat weaker result conjectured by Erd\u0151s [5] .", "cite_spans": [], "ref_spans": []}, {"section": "Practical numbers", "text": "Concerning the counting function of twin practical numbers a recent result of the author [13] is the following Theorem 2 Let k > 2 + log(3/2). For sufficiently large x,", "cite_spans": [{"start": 89, "end": 93, "text": "[13]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "Practical numbers", "text": "In particular this implies that for every \u03b1 < 1, P 2 (x) \u226b x \u03b1 . The proof uses the fact that if m 1 and m 2 are two practical numbers, with 0.5 < m 1 /m 2 < 2, and with gcd{m 1 , m 2 } = 2, there exist r and s, not exceeding respectively 2m 1 and 2m 2 , such that m 1 r and m 2 s are a pair of twin practical numbers. It is possible to build m 1 and m 2 by pick primes of their factorization in suitable intervals in order to control their mutual size. One has to count all possible pairs and divide by the maximal number of repetitions.", "cite_spans": [], "ref_spans": []}, {"section": "Practical numbers", "text": "Many other open probems on practical numbers and related questions have been raised by Erd\u0151s in [6] .", "cite_spans": [{"start": 96, "end": 99, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "Practical numbers", "text": "3 Sum-free sequences An increasing sequence of positive integers {n 1 , n 2 , . . . } is called a sum-free sequence if each term is never a sum of distinct smaller terms. This definition is due to Erd\u0151s [4] who proved certain related results and raised several problems. In his paper he proved that if {n k } is a sum-free sequence then it has zero asymptotic density. In other words, for every \u03b5 > 0, and for sufficiently large k, n k > k 1+\u03b5 . By the same argument he proved that for every \u03b2 < ( \u221a 5 + 1)/2, for infinitely many k, n k > k \u03b2 . Until 1996, all known sum-free sequences had a gap, namely lim sup", "cite_spans": [{"start": 203, "end": 206, "text": "[4]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "Practical numbers", "text": "In [3] , Deshouillers, Erd\u0151s and the author gave some examples of infinite sumfree sequences with no gap. They also proved that for every positive \u03b4, there exists a sum-free sequence {n k } such that n k \u223c k 3+\u03b4 . The best extremal result concerning sum-free sequences is due to Luczak and Schoen [9] . They proved that for every positive \u03b4, there exists a sum-free sequence {n k } such that n k \u223c k 2+\u03b4 and that the exponent 2 is the best possible. However an interesting problem remains open. Erd\u0151s proved that for any sum-free sequence {n k } one has", "cite_spans": [{"start": 3, "end": 6, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 297, "end": 300, "text": "[9]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "Practical numbers", "text": "It is natural to define", "cite_spans": [], "ref_spans": []}, {"section": "Practical numbers", "text": "The best known lower bound is due to Abbott [1] who proved that R > 2.064. Levine and O'Sullivan [8] proved the actual best known upper bound R < 4.", "cite_spans": [{"start": 44, "end": 47, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 97, "end": 100, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "Sums of distinct powers", "text": "A sequence S = {s 1 , s 2 , . . . } of positive integers is a complete sequence, if", "cite_spans": [], "ref_spans": []}, {"section": "Sums of distinct powers", "text": "contains all sufficiently large integers. In this section we deal with sequences S whose elements are powers of positive integers. Let s \u2265 1 and A be a (finite or infinite) set of integers greater than 1. Let Pow(A; s) be the nondecreasing sequence of positive integers of the form a k with a \u2208 A and k \u2265 s. Burr, Erd\u0151s, Graham and Wen-Ching Li [2] proved several results providing sufficient conditions in order that Pow(A; s) is complete. They also conjectured that for any s \u2265 1, Pow(A; s) is complete if and only if", "cite_spans": [{"start": 345, "end": 348, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "Sums of distinct powers", "text": "As Graham noted [7] , A must be intended as finite, even if from the text of the conjecture this is not explicitely said. In fact the following proposition disproves the conjecture in the case of infiniteness is allowed. We provide counterexamples using suitable infinite sets A. However, we point out that for finite sets the problem is open.", "cite_spans": [], "ref_spans": []}, {"section": "Sums of distinct powers", "text": "Proposition 1 Let \u03b5 \u2265 0. There exists a set A of integers \u2265 2 such that:", "cite_spans": [], "ref_spans": []}, {"section": "Sums of distinct powers", "text": "Proof. Let p \u2265 3 be a prime, and let R p := {n 2 p, n \u2208 N}. We have that Pow(R p ; s) \u2287 {n 2s p s , n \u2208 N}. Since every sufficiently large integer is a sum of distinct 2s-th powers of positive integers [18] , there exists r 2s such that (Q p ; s) ). Since \u03a3(Pow(R p ; s)) contains all sufficiently large multiple of p s , in order that Pow(R p \u222a Q p ; s) is complete, it suffices to provide a set Q p such that \u03a3(Pow(Q p ; s)) contains at least one element for each congruence class modulo p s . Let Q p = {p + 1}. It is clear that Pow(Q p ; s) contains infinitely many elements \u2261 1 mod p s , so \u03a3(Pow(Q p ; s)) contains at least one element for each congruence class modulo p s . By the above arguments this implies that for A := R p \u222a Q p , Pow(A; s) is complete. Note that elements of A do not depend on s, and that for sufficiently large p,", "cite_spans": [{"start": 202, "end": 206, "text": "[18]", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "2", "text": "A related open question is the following one. Consider the sequence {n k } of positive integers that are a sum of distinct powers of 3 and of 4. Erd\u0151s asked for a proof that n k \u226a k. The best known result is n k \u226a k 1.0353 as shown in [12] . More generally we propose the following conjecture. (A; s) ) has positive lower asymptotic density.", "cite_spans": [{"start": 235, "end": 239, "text": "[12]", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "Conjecture 1 Let", "text": "Note that if we replace the condition 'for every a 1 , a 2 \u2208 A, gcd{a 1 , a 2 } = 1' by 'gcd{a \u2208 A} = 1' the statement is not true. For the set A = {3, 9, 81, 104}, we have gcd{a \u2208 A} = 1, and \u03a3(Pow (A; s) ) has zero lower asymptotic density [12] .", "cite_spans": [{"start": 242, "end": 246, "text": "[12]", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "Simultaneous binary expansions", "text": "Let B(n) be the sum of digits of the positive integer n written on base 2. A natural question of some interest is to describe the sequence of positive integers n such that B(n) = B(n 2 ). Other related questions can be easily raised. For example it can be of interest to study the sequence the positive integers n such that 2B(n) = B(n 2 ), i.e., those n such that n and n 2 have the same 'density' of ones in their binary expansion. The above sequences respectively represent the (2, 1, 2)-numbers and the (2, 2, 2)-numbers.", "cite_spans": [], "ref_spans": []}, {"section": "Simultaneous binary expansions", "text": "The simplest case is (k, l, m) = (2, 1, 2), which corresponds to the positive integers n for which the numbers of ones in their binary expansion is equal to the number of ones in n 2 . The list of (2, 1, 2)-numbers as well as the list of (2, 2, 2)-numbers shows several interesting facts. The distribution is not regular. A huge amount of questions, most of which of elementary nature, can be raised.", "cite_spans": [], "ref_spans": []}, {"section": "Simultaneous binary expansions", "text": "In spite of their elementary definition, as far as we know these sequences do not appear in literature. Several questions, concerning both the structure properties and asymptotic behaviour, can be raised. Is there a necessary and sufficient condition to assure that a number is of type (2,1,2)? of type (2,2,2)? What is the asymptotic behaviour of the counting function of (2,1,2)-numbers? of (2,2,2)-numbers?", "cite_spans": [], "ref_spans": []}, {"section": "Simultaneous binary expansions", "text": "The irregularity of distribution does not suggest a clear answer to these questions.", "cite_spans": [], "ref_spans": []}, {"section": "Simultaneous binary expansions", "text": "Let p (k,l,m) (n) be the number of (k, l, m)-numbers which do not exceed n. By elementary arguments one can prove the following.", "cite_spans": [], "ref_spans": []}, {"section": "Simultaneous binary expansions", "text": "Theorem 3 Let p (2,1,2) (n) be the counting function of the (2, 1, 2)-numbers. We have p (2,1,2) (n) \u226b n 0.025 .", "cite_spans": [], "ref_spans": []}, {"section": "Simultaneous binary expansions", "text": "The proof uses the fact the for every n it is possible to construct a set of n distinct (2,1,2)-numbers not exceeding An 40 . To do this, one uses the fact that for every n < 2 \u03bd , B(n(2 \u03bd \u2212 1)) = \u03bd. The construction uses an arbitrary number not exceeding n and by adding in their binary expansion a suitable finite sequence of zeros and ones, with a special attention for the control of the function B for simultaneously the new number and its square, one obtains a (2, 1, 2)-number not exceeding An 40 . Further details can be found on [15] . By an analogous procedure it is possible to prove the following theorem.", "cite_spans": [{"start": 538, "end": 542, "text": "[15]", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "Simultaneous binary expansions", "text": "Theorem 4 Let p (2,2,2) (n) be the counting function of the (2, 2, 2)-numbers. We have p (2,2,2) (n) \u226b n 0.909 .", "cite_spans": [], "ref_spans": []}, {"section": "Simultaneous binary expansions", "text": "Concerning upper bounds for counting functions, recently S\u00e1ndor [17] announced that p (2,1,2) (n) \u226a n 0.9183 .", "cite_spans": [], "ref_spans": []}, {"section": "Simultaneous binary expansions", "text": "Some conjectures on counting functions can be proposed. Apart from small intervals centered in powers of 2, B(n) and B(n 2 ) appear as a random sequence of zeros and ones. Using this appearence and considering B(n) and B(n 2 ) as indipendent random variables where zeros and ones are equally probable, an eurisitc approach suggests the following conjectures.", "cite_spans": [], "ref_spans": []}, {"section": "Conjecture 2", "text": "p (2,1,2) (n) = n \u03b1+o (1) where \u03b1 = log 1.6875/ log 2 \u2243 0.7548875.", "cite_spans": [{"start": 22, "end": 25, "text": "(1)", "ref_id": "BIBREF0"}], "ref_spans": []}, {"section": "Conjecture 3 For each k one has:", "text": "p (2,k,k) (n) = n (log n) 1/2 G k + R(n), where G k = 2 log 2 \u03c0(k 2 +k) and R(n) = o(n/(log n) 1/2 ).", "cite_spans": [], "ref_spans": []}, {"section": "Conjecture 3 For each k one has:", "text": "A detailed discussion of the above conjecture can be found on [15] . Computations show that the above conjectures describe quite well the behaviour of counting functions for n < 10 8 .", "cite_spans": [{"start": 62, "end": 66, "text": "[15]", "ref_id": "BIBREF14"}], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "On sum-free sequences", "authors": [{"first": "H", "middle": ["L"], "last": "Abbott", "suffix": ""}], "year": 1987, "venue": "Acta Arith", "link": "117844291"}, "BIBREF1": {"title": "Complete sequences of sets of integer powers", "authors": [{"first": "S", "middle": ["A"], "last": "Burr", "suffix": ""}, {"first": "P", "middle": [], "last": "Erd\u0151s", "suffix": ""}, {"first": "R", "middle": [], "last": "Graham", "suffix": ""}, {"first": "Wen-Ching", "middle": [], "last": "Li", "suffix": ""}, {"first": "W", "middle": [], "last": "", "suffix": ""}], "year": 1996, "venue": "Acta Arith", "link": "13967275"}, "BIBREF2": {"title": "On a question about sum-free sequences", "authors": [{"first": "J-M", "middle": [], "last": "Deshouillers", "suffix": ""}, {"first": "P", "middle": [], "last": "Erd\u0151s", "suffix": ""}, {"first": "G", "middle": [], "last": "Melfi", "suffix": ""}], "year": 1999, "venue": "Discrete Mathematics", "link": "32516772"}, "BIBREF3": {"title": "Some remarks on number theory", "authors": [{"first": "P", "middle": [], "last": "Erd\u0151s", "suffix": ""}], "year": 1962, "venue": "Mat. 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We say that a positive integer n is a (k, l, m)-number if the sum of digits of n m in its expansion in base k is l times the sum of the digits of the expansion in base k of n.", "type": "figure"}}}
{"paper_id": "17436406", "_pdf_hash": "73891b488d85f4b2556b86adb67b5d51d2dc2629", "abstract": [{"section": "Abstract", "text": "Abstract-An appropriate adaption of the decision boundaries of the well-known signal space detector (SSD) yields a detector that whitens the input noise in the detector forward path. This new detector, called a whitening signal space detector (WSSD), offers higher reliability without increasing the dimensionality of the signal space. A WSSD can be designed by applying a transformation into the ordinary SSD case. We use the new concept to design a WSSD based on three-dimensional 110 equalization and demonstrate its feasibility and performance. The detector can be implemented with a small increase of hardware and offers a significant improvement in terms of bit error rate, especially at low to moderate channel densities.", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": "Index Terms-Colored noise, magnetic recording, signal space.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Signal Space Detection in Colored Noise", "text": "Guido Stromberg, Student Member, IEEE, Martin Hassner, Member, IEEE, and Uwe Schwiegelshohn, Member, IEEE Abstract-An appropriate adaption of the decision boundaries of the well-known signal space detector (SSD) yields a detector that whitens the input noise in the detector forward path. This new detector, called a whitening signal space detector (WSSD), offers higher reliability without increasing the dimensionality of the signal space. A WSSD can be designed by applying a transformation into the ordinary SSD case. We use the new concept to design a WSSD based on three-dimensional 110 equalization and demonstrate its feasibility and performance. The detector can be implemented with a small increase of hardware and offers a significant improvement in terms of bit error rate, especially at low to moderate channel densities.", "cite_spans": [], "ref_spans": []}, {"section": "Signal Space Detection in Colored Noise", "text": "Index Terms-Colored noise, magnetic recording, signal space.", "cite_spans": [], "ref_spans": []}, {"section": "I. INTRODUCTION", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "S", "text": "IGNAL space detection is based on the geometric interpretation of the detection process on a discrete-time channel. A constant number of subsequent samples at the detector input forms a signal vector in the -dimensional signal space. The signal space is divided into regions, which are associated with a certain detector output. The region in which a particular input signal point is located thus determines the current decision of the signal space detector (SSD).", "cite_spans": [], "ref_spans": []}, {"section": "S", "text": "After passing through the noiseless discrete-time channel, each possible information sequence corresponds to one particular signal point in the signal space. In the presence of noise, the actual received signal point will differ from the ideal position by some noise component. Thus we can assign to each point in the signal space a certain probability of occurrence, which depends both on the recorded information sequence and on the characteristics of the underlying channel noise model. Similar to the fixed delay tree search (FDTS) detector [1] , we choose the noiseless vector that is \"closest\" to the received vector using an appropriate metric [2] . The detector output is then , i.e., the first bit of the corresponding information sequence. This detection rule can be applied in a bit-serial fashion after subtracting the intersymbol interference (ISI) tail of the last detected bit. It should be noted that in the same manner, more than one bit can be detected at a time [3] , [4] .", "cite_spans": [{"start": 545, "end": 548, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 651, "end": 654, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 981, "end": 984, "text": "[3]", "ref_id": "BIBREF2"}, {"start": 987, "end": 990, "text": "[4]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "S", "text": "As pointed out above, a particular implementation of this detection procedure is called signal space detection. The detection problem can be solved by distinguishing points corresponding to sequences with from those with . This is done by partitioning the signal space into regions that determine Publisher Item Identifier S 0018-9464(00)03900-5. the detector output (see Fig. 1 ). The regions are labeled by the corresponding class attributes or , respectively.", "cite_spans": [], "ref_spans": [{"start": 372, "end": 378, "text": "Fig. 1", "ref_id": "FIGREF0"}]}, {"section": "S", "text": "In Section III, we show that the region boundaries consist of hyperplanes if the channel noise is independent of the information sequence. This leads to the following SSD architecture [5] , [6] : the region boundaries are implemented by a set of finite impulse response (FIR) filters, whose outputs are qualified by slicers. A Boolean function maps the slicer outputs on the detector output. Additionally, a feedback loop is used to subtract the ISI tail of the current decision from the detector input. An example for an SSD is illustrated in Fig. 5 . Signal space detection can thus be viewed as a special implementation of the fixed delay tree search with decision feedback (FDTS/DF) detection algorithm [6] - [8] .", "cite_spans": [{"start": 184, "end": 187, "text": "[5]", "ref_id": "BIBREF4"}, {"start": 190, "end": 193, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 707, "end": 710, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 713, "end": 716, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": [{"start": 544, "end": 550, "text": "Fig. 5", "ref_id": "FIGREF5"}]}, {"section": "S", "text": "The problem of finding an appropriate set of decision boundaries has been addressed in a number of previous publications; see [4] , [6] , and [8] - [11] . For channels subject to stationary white input noise, the complete set of decision boundaries is determined by the Voronoi regions [8] . In this case, the Euclidean distance measure yields an appropriate metric. As mentioned above, the optimum decision boundaries are hyperplanes.", "cite_spans": [{"start": 126, "end": 129, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 132, "end": 135, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 142, "end": 145, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 148, "end": 152, "text": "[11]", "ref_id": "BIBREF10"}, {"start": 286, "end": 289, "text": "[8]", "ref_id": "BIBREF7"}], "ref_spans": []}, {"section": "S", "text": "Due to the use of an equalization scheme, which is common practice to reduce the dimensionality of the signal space, the coefficients of the noiseless sampling points are restricted to small integer values. Therefore, the FIR filter coefficients that describe the Voronoi decision boundaries are also small integers. This may be advantageous with respect to an implementation.", "cite_spans": [], "ref_spans": []}, {"section": "S", "text": "0018-9464/00$10.00 \u00a9 2000 IEEE However, the complete set of Voronoi boundaries is usually too complex for an implementation in a high-dimensional signal space. Therefore, heuristics are used to simplify the detector structure. This is feasible since error events are dominated by the points that are relatively close to a separating hyperplane. In practice, it suffices to guarantee a particular minimum distance of the region boundaries to each possible signal point. Therefore, a certain number of Voronoi decision boundaries can be ignored. Different heuristics have been proposed for this purpose; see [4] and [6] . These methods yield a reduced number of decision boundaries, which can be implemented by FIR filters with small integer coefficients.", "cite_spans": [{"start": 606, "end": 609, "text": "[4]", "ref_id": "BIBREF3"}, {"start": 614, "end": 617, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "S", "text": "We already explained that the predominant criterion of detector performance is the minimum distance of the decision region boundaries to the enclosed signal points. Therefore, the set of decision boundaries can also be chosen regardless of the Voronoi region boundaries. Although this type of heuristic for boundary selection may be more difficult to develop, in some cases the additional degree of freedom leads to a smaller set of FIR filters [8] , [10] , [12] .", "cite_spans": [{"start": 445, "end": 448, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 451, "end": 455, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 458, "end": 462, "text": "[12]", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "S", "text": "Kim and Moon proposed an algorithm that provides a minimal set of hyperplanes [12] . Unfortunately, the application of this algorithm soon becomes infeasible as the number of observed samples is increased. On the other hand, practical SSD implementations with a performance close to the maximumlikelihood bound can be found by using one of the algorithms mentioned above.", "cite_spans": [{"start": 78, "end": 82, "text": "[12]", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "S", "text": "Therefore, detector performance is directly related to the signal constellation. The signal constellation depends both on the equalization scheme and on the modulation code. It has been demonstrated that the noise correlation, which is to a certain extent imposed by the equalizer, also has a relevant impact on the detector performance [10] , [11] .", "cite_spans": [{"start": 337, "end": 341, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 344, "end": 348, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "S", "text": "For this reason, equalization schemes that avoid heavy noise correlation at the input of the decision device have been proposed in the context of signal space detectors. Like in FDTS detectors, the minimum phase channel response has been used as the desired target [10] , which completely avoids coloring of the noise.", "cite_spans": [{"start": 265, "end": 269, "text": "[10]", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "S", "text": "Usually, however, symmetries in the signal space are desired to ease the detector implementation. This requires constraining the first samples of the equalized channel response [6] . To reduce the noise correlation, relaxed equalization schemes have been proposed. They constrain only a few samples of the equalized channel response and let the other samples take their natural values [11] .", "cite_spans": [{"start": 177, "end": 180, "text": "[6]", "ref_id": "BIBREF5"}, {"start": 385, "end": 389, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "S", "text": "As an alternative, the use of a simple noise predictor has been proposed in [11] . This method does not avoid the noise correlation but counteracts the performance degradation by reducing the variance of the noise observed by the detector.", "cite_spans": [{"start": 76, "end": 80, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "S", "text": "In this paper, we propose another approach to enhance the SSD performance. We discuss the adaption of the decision boundaries with respect to the noise correlation, and we show that the resulting boundaries are the optimum maximum-likelihood sequence estimator (MLSE) boundaries for the particular signal constellation. We thus apply signal space detection to channels that are subject to stationary, correlated input noise. This model is appropriate for all detection schemes that employ an input filter to constrain the ISI of the channel response. However, we assume that the noise characteristic is independent of the information sequence. Our particular discrete-time channel model is described in Section II.", "cite_spans": [], "ref_spans": []}, {"section": "S", "text": "In Section III, we discuss the necessary modifications of the SSD to address the noise correlation during the detection process. This emphasizes the need for construction methods that are appropriate for the new detector, which we dub the noise whitening signal space detector (WSSD). We show in Section III that the design process of a WSSD can be transformed into an SSD design, so that known algorithms for SSD construction can also be applied to the colored noise case.", "cite_spans": [], "ref_spans": []}, {"section": "S", "text": "We conclude this paper with an example to prove the feasibility of the new detection concept. To this end, we apply the whitening approach to the well-known three-dimensional 110 (3D-110) detector [6] in Section IV. Since the equalizer used in the 3D-110 detector imposes heavy noise correlation at moderate channel densities ( ), the WSSD provides an improvement of 1-1.8 dB over the SSD solution with a comparable hardware complexity.", "cite_spans": [{"start": 197, "end": 200, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "II. CHANNEL MODEL", "text": "The discrete-time channel model we use for this study is shown in Fig. 2 . The model comprises the magnetic channel itself as well as the equalizer, which is usually part of the detector. This is useful since we consider the signal-processing front end to be invariant during the following discussion of detection algorithms. Now assume a particular binary nonreturn-to-zero (NRZ) data sequence being recorded on the disk. Let the corresponding NRZI sequence be causal, i.e., for each time instance , the corresponding data symbol constantly equals 1 or 1.", "cite_spans": [], "ref_spans": [{"start": 66, "end": 72, "text": "Fig. 2", "ref_id": "FIGREF1"}]}, {"section": "II. CHANNEL MODEL", "text": "During the read-back process, a continuous-time signal is generated by the magnetic channel. We assume that the magnetic channel is linear and denote its causal continuous-time step response by . We further assume that the bits are equally spaced by the bit interval . Formally, the noiseless continuous-time channel output is determined by the convolution of and the recorded data sequence . The read-back signal is subject to media and electronics noise . Although our investigations are valid for any type of stationary noise, for convenience we will restrict the discussion of the example in Section IV on the special case that is a zero-mean white Gaussian random variable.", "cite_spans": [], "ref_spans": []}, {"section": "II. CHANNEL MODEL", "text": "The magnetic channel typically suffers from heavy ISI. To ease detector implementation, linear equalizers are commonly used to counteract this phenomenon. Other filters, e.g., an antialiasing low-pass filter, are also included in the signal path. Let the overall filter impulse response be denoted by . Then the continuous-time channel output corresponding to the recorded data sequence is given by (1) where denotes the equalized channel response. Finally, the discrete-time channel output is derived by sampling the output of the continuous-time channel with the bit rate 1 (2) Note that the sequences , , and are sampled versions of , , and , respectively. The equalizer is designed such that equals the desired target sequence. The output noise sequence is a stationary, autocorrelated discrete random variable.", "cite_spans": [{"start": 399, "end": 402, "text": "(1)", "ref_id": "BIBREF0"}, {"start": 576, "end": 579, "text": "(2)", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "III. WSSD DESIGN", "text": "As discussed above, the published methods for SSD boundary construction neglect the correlation of the input noise. In colored noise, additional measures must be taken to asymptotically achieve the maximum-likelihood performance bound with signal space detection.", "cite_spans": [], "ref_spans": []}, {"section": "III. WSSD DESIGN", "text": "The straight-forward solution is to use a noise whitening filter at the detector input. Let the discrete impulse response of the noise whitening filter be . Then the coordinates of the noiseless sampling point are given by (3) Since the noise is uncorrelated at the detector input, the algorithms referred to in the previous section can be applied to these altered signal points without further modification. This approach asymptotically guarantees MLSE performance.", "cite_spans": [{"start": 223, "end": 226, "text": "(3)", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "III. WSSD DESIGN", "text": "However, the noise whitening prefilter smears the pulse, i.e., the signal energy is dispersed on more adjacent samples than without the prefilter. Consequently, a broader pulse requires more detector look ahead to achieve the MLSE performance. Increasing the dimensionality of the signal space inherently increases the detector complexity.", "cite_spans": [], "ref_spans": []}, {"section": "III. WSSD DESIGN", "text": "In this section, we propose an alternative method that incorporates the noise correlation into the detector design by an appropriate adaption of the decision boundaries. Thus no additional prefilter is required, which enables us to keep the detector look-ahead constant while preserving the total signal energy.", "cite_spans": [], "ref_spans": []}, {"section": "III. WSSD DESIGN", "text": "First we show that such a detector exists and that it asymptotically ( ) yields MLSE performance in the presence of stationary colored noise.", "cite_spans": [], "ref_spans": []}, {"section": "III. WSSD DESIGN", "text": "Proposition 1: The optimum decision boundaries can be found in the -dimensional signal space. They are hyperplanes, i.e., they can be implemented by linear FIR filter and slicer combinations.", "cite_spans": [], "ref_spans": []}, {"section": "III. WSSD DESIGN", "text": "Proof: For MLSE, each decision region is assigned to a noiseless signal point such that every point inside is closer to than to any other noiseless signal point . Let denote the region for which all points are closer to than to . Then, is the intersection of all these , and the decision boundaries of comprise a subset of the decision boundaries of all . To prove Proposition 1, it suffices to restrict the discussion to a particular region . Thus, without loss of generality, assume one pair of sampling points in the -dimensional signal space . Denote the points by and , as shown in Fig. 3 . They correspond to the sequences and with and , respectively. Both sampling points are subject to stationary, zero-mean additive Gaussian noise whose covariance matrix is denoted by . The covariance matrix is determined either by measurements or by an appropriate channel model.", "cite_spans": [], "ref_spans": [{"start": 587, "end": 593, "text": "Fig. 3", "ref_id": "FIGREF2"}]}, {"section": "III. WSSD DESIGN", "text": "Under the hypothesis that has been recorded, the probability density function of the detector input is given by (4) The optimum decision boundary that separates the decision regions and can be found by classical hypothesis testing [13] . More specifically, the Bayes solution of the detection problem can be applied to minimize the overall error probability if we are given the a priori probabilities of the hypotheses. Since the a priori probabilities of the two data sequences are equal, by computing the likelihood ratio we obtain the decision boundary (5) Equation (5) imposes a single linear constraint on the points of in the -dimensional signal space. Consequently, the optimum decision boundary consists of a linear hyperplane. Hence, the SSD architecture can perform optimum detection in the presence of colored noise. Moreover, we observe that an optimum solution to this detection problem can be found without increasing the dimensionality of the signal space.", "cite_spans": [{"start": 112, "end": 115, "text": "(4)", "ref_id": "BIBREF3"}, {"start": 231, "end": 235, "text": "[13]", "ref_id": "BIBREF12"}], "ref_spans": []}, {"section": "III. WSSD DESIGN", "text": "To construct the SSD with an arbitrary number of signal points, it is possible to compute the set of optimum decision boundaries of all relevant pairs of points by (5) . For instance, Barbosa proposed an appropriate metric for detector construction [2] . However, this method is computationally very intensive. Furthermore, it lacks any immediate geometric interpretation of detector performance, so that efficient heuristics to reduce the detector complexity are hard to develop. Thus, it makes sense to look for a better way of detector construction.", "cite_spans": [{"start": 164, "end": 167, "text": "(5)", "ref_id": "BIBREF4"}, {"start": 249, "end": 252, "text": "[2]", "ref_id": "BIBREF1"}], "ref_spans": []}, {"section": "III. WSSD DESIGN", "text": "We propose to transform the problem of WSSD construction to the white noise case (see Fig. 3 ). In the white noise domain , known algorithms yield a feasible set of decision planes. From this solution, the final decision boundaries in the colored noise domain can be found by inverse mapping. Proposition 2: The WSSD design problem in colored noise can be mapped on a design problem in white noise by a linear transformation. The solution for the WSSD can be directly derived from the solution in the white noise domain.", "cite_spans": [], "ref_spans": [{"start": 86, "end": 92, "text": "Fig. 3", "ref_id": "FIGREF2"}]}, {"section": "III. WSSD DESIGN", "text": "Proof: Let us first consider a single pair of signal points. The two classes of signal points are and . The transforms of the signal points are denoted by and , respectively (see Fig. 3 ).", "cite_spans": [], "ref_spans": [{"start": 179, "end": 185, "text": "Fig. 3", "ref_id": "FIGREF2"}]}, {"section": "III. WSSD DESIGN", "text": "From Proposition 1 follows that the optimum decision boundary that separates the two signal points in is a hyperplane. As its transform is the Voronoi boundary of and , is also a linear boundary. Thus, there is a mapping from to with (6) where is an -dimensional square matrix and is an -dimensional vector. In general, this corresponds to a coordinate transformation of and given by (7) and (7a)", "cite_spans": [{"start": 234, "end": 237, "text": "(6)", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "III. WSSD DESIGN", "text": "The parameters of and must be chosen such that the detector input , after being passed through the transformation according to (7a), appears as an uncorrelated random variable. Additionally, we can require the noise to have unit variance. These properties yield the following probability density function of the detector input after transformation into the white noise domain :", "cite_spans": [], "ref_spans": []}, {"section": "III. WSSD DESIGN", "text": "(8) is related to the probability density function of the actual detector input [] (9) Comparing (8) and (9) reveals that the transformation must satisfy (10) and (11) From (11), we identify (12) and (13) where is the identity matrix. Since the vector does not affect the noise correlation, it can be chosen arbitrarily. For convenience, in the following we assume . Thus, the transform of the signal constellation is given by (14) This result corresponds to the signal space transformation given by (7a) for . The choice of the transformation matrix is now constrained by (13) and (10) .", "cite_spans": [{"start": 105, "end": 108, "text": "(9)", "ref_id": "BIBREF8"}, {"start": 154, "end": 158, "text": "(10)", "ref_id": "BIBREF9"}, {"start": 427, "end": 431, "text": "(14)", "ref_id": "BIBREF13"}, {"start": 573, "end": 577, "text": "(13)", "ref_id": "BIBREF12"}, {"start": 582, "end": 586, "text": "(10)", "ref_id": "BIBREF9"}], "ref_spans": []}, {"section": "III. WSSD DESIGN", "text": "The solution of (13) is given by diag (15) where is a square matrix whose columns are the normed eigenvectors of and is the eigenvalue corresponding to . The solution follows directly from the spectral theorem for symmetric matrices diag (", "cite_spans": [{"start": 38, "end": 42, "text": "(15)", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "III. WSSD DESIGN", "text": "Finally, we need to check that (15) satisfies (10)", "cite_spans": [], "ref_spans": []}, {"section": "III. WSSD DESIGN", "text": "Thus, a valid transformation is given by", "cite_spans": [], "ref_spans": []}, {"section": "III. WSSD DESIGN", "text": "and (18a) if the transformation matrix is chosen according to (15) . Note that only depends on the given covariance matrix and is invariant to the particular signal constellation. Therefore, it was sufficient to show that the design problem can be solved for a single pair of signal points and generalize the result to an arbitrary number of points. Thus, by applying (18a) to all signal points, we find the new signal constellation in the white noise domain.", "cite_spans": [{"start": 62, "end": 66, "text": "(15)", "ref_id": "BIBREF14"}], "ref_spans": []}, {"section": "III. WSSD DESIGN", "text": "The decision regions and in the colored noise domain are defined by the decision boundary , which is the inverse transform of . Note that the probability density function satisfies", "cite_spans": [], "ref_spans": []}, {"section": "III. WSSD DESIGN", "text": "i.e., the transform of the decision boundary preserves the error probability of the altered signal constellation in the white noise domain. This feature eases development and application of heuristics for detector construction. Summarizing, we propose the following method for WSSD construction.", "cite_spans": [], "ref_spans": []}, {"section": "III. WSSD DESIGN", "text": "1) Calculate the new signal constellation according to (18a).", "cite_spans": [], "ref_spans": []}, {"section": "III. WSSD DESIGN", "text": "2) Calculate a set of decision boundaries for the signal constellation in the white noise domain by applying some heuristic. The detector performance of the final WSSD is equal to the one obtained for the transformed detector in white noise. ", "cite_spans": [], "ref_spans": []}, {"section": "IV. EXAMPLE", "text": "The method of constructing the WSSD as proposed in Section III is applicable to any discrete-time channel. In this section, we improve the performance of the 3D-110 detector by using the new design algorithm. First, we sketch the original 3D-110 detector concept as proposed by Brickner and Moon [6] .", "cite_spans": [{"start": 296, "end": 299, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "IV. EXAMPLE", "text": "The 3D-110 detector uses a forward equalizer that constrains the first three samples of the channel step response to . A maximum transition run (MTR) modulation code [14] , which prevents the occurrence of three consecutive transitions, is used to eliminate pairs of signal points with a distance less than . The convolution of the 3-bit NRZ data sequences with yields the signal constellation shown in Fig. 4 . An SSD is used to detect the current bit . The detector operates in an -dimensional signal space, requiring three linear boundaries to separate the two classes of signal points. Within the detector, an internal feedback is used to cancel the ISI due to the previous bit . Note that the bit does not impose any ISI since . The signal constellation depends on the previous direction of medium magnetization , even after subtracting the ISI term due to this bit. The reason is that the MTR code prevents different NRZ data symbols depending on . Thus, the SSD has to be designed for two cases, which in general slightly increases its complexity.", "cite_spans": [{"start": 166, "end": 170, "text": "[14]", "ref_id": "BIBREF13"}], "ref_spans": [{"start": 403, "end": 409, "text": "Fig. 4", "ref_id": "FIGREF4"}]}, {"section": "IV. EXAMPLE", "text": "The current decision of the SSD is used to cancel the ISI tail of the forward equalizer target. For this purpose, an additional feedback equalizer filter is used outside the SSD. The (1, 1, 0) target of the forward equalizer is a close approximation of the minimum phase step response of the Lorentzian channel at channel densities above . For lower channel densities, this equalization scheme leads to heavy noise correlation at the SSD input, which significantly degrades its performance [11] .", "cite_spans": [{"start": 490, "end": 494, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "IV. EXAMPLE", "text": "We can thus replace the SSD by an appropriate WSSD, keeping the analog front end of the detector fixed. As an example of detector construction, we assume a channel density of . At this channel density, the 3D-110 performs about 2 dB worse than the FDTS detector with the same look-ahead [11] .", "cite_spans": [{"start": 287, "end": 291, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "A. Signal Space Transformation", "text": "According to the procedure described in Section III, we first transform the signal space to the white noise domain. In Fig. 4 , the three-dimensional signal space is shown for both the white and the colored noise domain for . Choosing results in a similar signal constellation. Note that the equalizer and the parameters of the magnetic channel contribute to the signal constellation in the white noise domain. Thus, the calculations conducted in this step depend on the correlation of the input noise.", "cite_spans": [], "ref_spans": [{"start": 116, "end": 125, "text": "In Fig. 4", "ref_id": "FIGREF4"}]}, {"section": "B. SSD Design", "text": "We now design an SSD in the white noise domain. Since the new signal constellation does not have any obvious symmetries that allow the detector to be constructed simply from the geometric view, a different technique must be chosen. As explained in Section I, several heuristics have been proposed for this purpose. The algorithm we use in this study consists of two phases. In the first phase, a set of required decision boundaries is selected from the total set of Voronoi boundaries such that a certain minimum distance 2 for each signal point to the separating hyperplanes is guaranteed. Let denote the noiseless signal points in the white noise domain and the corresponding NRZ data sequences. In lines 1-4, a list of all pairs of signal points that belong to different classes is generated and sorted in ascending order of their Euclidean distance . The minimum distance is denoted by . During the following steps of the algorithm (lines 6-19), a separating hyperplane is assigned to each of the pairs of signal points. Note further that is the number of signal pairs of set . The are chosen from a set of hyperplanes, which is derived from the Voronoi boundaries such that separates the maximum number of signal pairs. The set comprises the projections of the particular Voronoi hyperplane on all combinations of dimensions. The first phase usually generates a set of boundaries that is small enough to be implemented. Moreover, a certain minimum distance is guaranteed.", "cite_spans": [], "ref_spans": []}, {"section": "B. SSD Design", "text": "To improve the detector performance without increasing hardware complexity, a second phase is introduced to enhance the mean distance between the sampling points and their separating hyperplanes (lines 20-23). Considering only the set of boundaries that have been used in the first phase, we reselect the boundary of each ( ) in order to maximize the minimum distance to each of the two signal points.", "cite_spans": [], "ref_spans": []}, {"section": "B. SSD Design", "text": "The Boolean equation that finally determines the decision regions of one of the two classes, say, , can be computed from the list of signal pairs that have now been assigned the particular boundaries. For a particular signal point , the decision region is the area that jointly satisfies all boundary equations of for which . A decision must be taken in favor of class if one of these signal points is detected. These two rules result in a min term for the overall Boolean equation.", "cite_spans": [], "ref_spans": []}, {"section": "B. SSD Design", "text": "Note that in the white noise case, this algorithm yields exactly the 3D-110 detector parameters of [6] .", "cite_spans": [{"start": 99, "end": 102, "text": "[6]", "ref_id": "BIBREF5"}], "ref_spans": []}, {"section": "C. WSSD Design", "text": "Finally, the parameters of the decision boundaries of the WSSD are computed by using the transformation of (20). Although we have taken care to reduce the dimensionality of the boundaries in the previous step, this property gets lost during the transformation. Moreover, the boundary coefficients are real-valued.", "cite_spans": [], "ref_spans": []}, {"section": "C. WSSD Design", "text": "Usually, however, our proposed SSD design algorithm reveals some symmetries in the signal constellation. Symmetries lead to parallel decision boundaries, so that hardware can be shared except for the slicers. The detector implementation can be further simplified by dividing each boundary equation by one of the coefficients. This way, at least one of the coefficients can be set to one.", "cite_spans": [], "ref_spans": []}, {"section": "C. WSSD Design", "text": "We conduct these steps for both signal constellations according to and , respectively. The final boundary equations differ only in the sign of some of the thresholds. In our example, we obtain for sign sign sign (21) Note that the left-hand sides of the boundary equations and are all equal. Thus, three multipliers suffice to implement all five boundaries. Note that the change of the sign of the thresholds can be easily implemented by multiplying the left-hand side of the equation by 1, such that the logical value is generated. This can be compensated by accordingly adapting the Boolean equation that is used to generate the current decision from the Boolean variables or ( ), respectively (see Fig. 5 ).", "cite_spans": [], "ref_spans": [{"start": 701, "end": 707, "text": "Fig. 5", "ref_id": "FIGREF5"}]}, {"section": "D. Detector Performance", "text": "Computer simulations as well as a theoretical analysis have been used to estimate the bit error rate (BER) of the detectors at different channel densities . The magnetic channel is assumed to be linear with Lorentzian impulse response. We further assume additive white Gaussian noise. The signal-to-noise ratio (SNR) is defined as the ratio of the signal energy of the Lorentzian impulse response to the integrated noise power within the Nyquist band. Taking the energy of the forward equalizer into account, the effective noise variance at the detector input is determined by SNR", "cite_spans": [], "ref_spans": []}, {"section": "D. Detector Performance", "text": "Since according to (19) the error probability in the colored noise domain and in the white noise domain are equal, the theoretical study can be solely based on the evaluation of the signal space in the white noise domain. Here, the error probability is completely determined by the Euclidean distance of the signal points. Note that the signal constellation for different SNR in the white noise domain is simply scaled by 1 . Thus, instead of computing the signal space for each desired SNR, we first assume a standardized Gaussian noise process and finally scale the distances of the signal points as appropriate.", "cite_spans": [], "ref_spans": []}, {"section": "D. Detector Performance", "text": "Neglecting error propagation, we provide upper and lower bounds of the BER similar to [9] . Assume that two signal points and are differentiated by a hyperplane . Let denote the Euclidean distance of a point to ", "cite_spans": [{"start": 86, "end": 89, "text": "[9]", "ref_id": "BIBREF8"}], "ref_spans": []}, {"section": "D. Detector Performance", "text": "where denotes the opposite class of and equals the probability that the particular signal point has been transmitted.", "cite_spans": [], "ref_spans": []}, {"section": "D. Detector Performance", "text": "Equation (23) is an approximation of since it has been neglected that not every point in the signal space beyond is assigned to the particular signal point . However, the decision regions are determined by more than one decision boundary, so that certain regions are considered multiple times. Thus, (23) imposes an upper bound on .", "cite_spans": [], "ref_spans": []}, {"section": "D. Detector Performance", "text": "Similarly, a lower bound can be derived from (23) by neglecting all signal points but the closest to erfc (", "cite_spans": [], "ref_spans": []}, {"section": "D. Detector Performance", "text": "with Min", "cite_spans": [], "ref_spans": []}, {"section": "D. Detector Performance", "text": "Note that all data sequences have been assumed to be equally likely, i.e., . The upper and the lower bound on the error events have been calculated first based on the signal space, using the complete Voronoi set of decision regions, and second based on the particular WSSD. As explained above, the complete set of Voronoi decision regions is equivalent to the MLSE. The detector only uses a subset of the MLSE decision boundaries.", "cite_spans": [], "ref_spans": []}, {"section": "D. Detector Performance", "text": "In Fig. 6 , the SNR required to achieve a BER of 10 is plotted for different channel densities. Since the upper and lower bound on the error event probability are close within 0.3 dB, the theoretical analysis provides a meaningful estimate of the WSSD performance. We also recognize that the performance gap between the MLSE detector and the WSSD is small. Thus removing certain boundaries of the MLSE detector does not impose a significant performance loss. This result emphasizes the concept of signal space detection.", "cite_spans": [], "ref_spans": [{"start": 3, "end": 9, "text": "Fig. 6", "ref_id": "FIGREF6"}]}, {"section": "D. Detector Performance", "text": "Also, both the 3D-110 SSD and the 3D-110 WSSD have been simulated. Obviously, for both detector types the forward and feedback equalizer were identical, and just the SSD was substituted by the WSSD version. The equalizers, which were long enough to avoid degradation, have been optimized using a minimum mean square error criterion.", "cite_spans": [], "ref_spans": []}, {"section": "D. Detector Performance", "text": "The simulation results, also shown in Fig. 6 , demonstrate a significant improvement of the WSSD over the conventional SSD at low to moderate channel densities. At high channel densities, the constrained equalization target closely matches the minimum phase channel step response, so that no significant noise correlation is imposed by the forward equalizer. This is the main reason for the closing performance gap between the SSD and the WSSD.", "cite_spans": [], "ref_spans": [{"start": 38, "end": 44, "text": "Fig. 6", "ref_id": "FIGREF6"}]}, {"section": "D. Detector Performance", "text": "Error propagation is the reason for the performance gap between the theoretical estimates and the WSSD simulation results at high channel densities. Simulations employing the correct feedback values have also been conducted (see Fig. 6 ). They demonstrate consistence of the simulations and the bounds expressed in (23) and (24).", "cite_spans": [], "ref_spans": [{"start": 229, "end": 235, "text": "Fig. 6", "ref_id": "FIGREF6"}]}, {"section": "D. Detector Performance", "text": "Noise prediction as presented in [11] provides a less significant performance gain compared to the WSSD we proposed. Note, however, that noise prediction can well be combined with the WSSD approach, further improving the detector performance at a considerable hardware overhead. This hybrid approach is left for further studies.", "cite_spans": [{"start": 33, "end": 37, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "V. CONCLUSION", "text": "A generic method for incorporating the noise correlation into the design of the signal space detector decision boundaries has been presented. The method introduces an additional intermediate step in the usual SSD design process. Thus it does not offer an alternative, but a valuable extension to existing design algorithms. Since the filter front end of the detector is left unchanged, the resulting noise whitening signal space detectors operate with the same look-ahead as the original SSD. Thus the hardware complexity of both detectors is comparable.", "cite_spans": [], "ref_spans": []}, {"section": "V. CONCLUSION", "text": "As an application, we presented a three-dimensional WSSD, which operates on a constrained 110-equalized, MTR coded channel. This example proves the feasibility of the concept. The new detector offers a performance gain of 1.8 dB at over the conventional SSD. 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Magn", "link": "15838599"}, "BIBREF14": {"title": "An Introduction the Theory of Random Signals and Noise", "authors": [{"first": "W", "middle": ["L"], "last": "Root", "suffix": ""}, {"first": "W", "middle": ["B"], "last": "Davenport", "suffix": ""}], "year": 1987, "venue": "", "link": null}}, "ref_entries": {"FIGREF0": {"text": "Fig. 1. Concept of signal detection ( = 2). Decision planes (dashed) form the decision regions (bold).", "type": "figure"}, "FIGREF1": {"text": "Fig. 2. Discrete-time model of the magnetic channel.", "type": "figure"}, "FIGREF2": {"text": "Fig. 3. Signal points subject to (a) colored noise are transformed into (b) the white noise domain, where the decision boundary E is computed. Its transform E may differ significantly from the Voronoi boundary (dashed).", "type": "figure"}, "FIGREF3": {"text": "Implement the decision boundaries for the colored noise domain in the detector. They are given by (20)", "type": "figure"}, "FIGREF4": {"text": "Fig. 4. Signal space of the 3D-110 detector for s = 1 in (a) the colored noise domain and (b) its transform for P W =T = 2. The WSSD decision boundaries, which are adapted to the correlation of the input noise, are also shown.", "type": "figure"}, "FIGREF5": {"text": "Fig. 5. WSSD implementation for the 3D-110 equalized Lorentzian readback channel at P W =T = 2. The feedback loop cancels the remaining ISI of the data bit s in the x sample.", "type": "figure"}, "FIGREF6": {"text": "Fig. 6. Comparison of the 3D-110 SSD against the 3D-110 WSSD for a Lorentzain channel with additive white Gaussian noise.", "type": "figure"}, "TABREF0": {"text": "Manuscript received June 1, 1999; revised December 2, 1999. This work was supported by the Deutsche Forschungsgemeinschaft. G. Stromberg and U. Schwiegelshohn are with the Computer Engineering Institute, University of Dortmund, Dortmund 44221 Germany (e-mail: stromberg@ieee.org; uwe@ds.e-technik.uni-dortmund.de). M. Hassner is with the IBM Almaden Research Center, San Jose, CA 95120-6099 USA (e-mail: hassner@almaden.ibm.com).", "type": "table"}}}
{"paper_id": "17436476", "_pdf_hash": "ce19e79a6fec1b3b446785855896a6fbaddd362d", "abstract": [{"section": "Abstract", "text": "With modem simulation packages, the modeler can choose almost any standard statistical distribution for generating input random variables. The question arises as to how sensitive are output performance measures to the particular type of distributions selected for modeling the input. We investigate the sensitivity of two output performance measures (average queue wait and the 95 percentile value of the queue wait distribution) for a G/G/I queue, simulated using GPSS/H.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "INTRODUCTION", "text": "The major question we attempt to answer in this study is just how important is it to expend resources (time and money) in determining the input distributions (interarrival and service times, for example) for a queueing simulation model? That is, how sensitive are the output measures of performance such as queue sizes and waiting times to the particular choice of input distributions? Note that we are not concerned here with how well the input distributions chosen fit, in a statistical sense, the data we may be using to determine distribution choice, but how sensitive the output performance measures are to the distribution choice. In other words, we want to fmd out if it suffices to choose distributions with roughly the same density shape and first two moments matched to the data at hand. Or is it necessary to collect large amounts of data and spend great effort in precisely choosing input distributions, and, if so, which procedures are best?", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "There is some evidence that, perhaps, matching only the first two moments might suffice. For M/G/l, the Pollaczek-Khintchine (P-K) formula tells us we need only the mean (I/h) of the interarrival time distribution (this is also the standard deviation) and the mean (l/p) and standard deviation (a,) of the service time distribution to calculate expected value measures of performance (MOP). The expected queue size, for example, is given in Equation (1) is given by Equation (2), which is also the heavy trafftc approximation, and depends only on the first two moments of the interarrival and service time distributions (I//z, 02, I/p , a\",).", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "There is a great deal of material in the statistical literature concerning fitting known statistical distributions to data. However, we are not particularly interested in how well a distribution fits the data with respect to classical statistical measures, but how sensitive the MOPS are to distribution choice.", "cite_spans": [], "ref_spans": []}, {"section": "INTRODUCTION", "text": "In this study, we conduct a series of experiments using a G/G/l simulation model written in GPSSIH. The two MOPS we consider are the mean queue wait, W,, and the 95th percentile of the queue wait distribution which we denote as W, (.95) ; that is, letting T, represent the random variable, wait in queue, then Pr{T, > W&.95)} = .05. Twenty replications of 20,000 customers with a warm-up period of 2,000 were used in all cases considered and confidence interval estimates were produced for the MOPS. The simulation model was validated for cases where known theoretical steady-state results existed (e.g., M/M/l for both MOPS and M/G/l for W,>, and simulation error for mean values was generally within 5%, with the confidence bound range, for most cases, being f 5%, with a worst case of*l3%.", "cite_spans": [], "ref_spans": []}, {"section": "FIRST EXPERIMENT", "text": "This experiment was performed to determine whether the first two moments of interarrival and service time distributions are sufficient in estimating the MOPS. The F/F/l (F = Gamma distribution) was selected as a base case model and compared to LN/LN/I (LN = lognotmal), Sensitivity of Output Measures to Input Distributions in Queueing Simulation Modeling 297 W/W/l (W = Weibull) and P5/P5/1 (P5 = Pearson, type 5) models. Traffic intensities (p) of 0.2, 0.5, and 0.8 were considered along with coefficients of variation of interarrival and service time distributions (CVat and CVst respectively) of 0.5, 1.0 and 2.0, making a total of 108 cases in all (each with 20 replications of 20,000 customers and a 2,000 customer warm-up period). Table 1 presents some sample results showing that there can be significant sensitivity in the output MOPS, and that, in general, matching only the first two moments is not sufficient. We see that for higher p values (.8), the percentage differences are, for the most part, modest. But for p = .5, percentage differences are sizable, and for p = .2, some turned out to be very large, although the absolute values of the MOPS were near zero, which partially accounts for large percentage differences. Even so, there is ample evidence that it is not always sufftcient to match only the first two moments. Twenty-eight of the 108 cases run had percent differences for W, greater than 20%, twelve of these being cases with p values of .5 or .8. These were either P5 models, or W and LN models with CV& =2. Further, some of the P5 cases of the original 108 cases had to be eliminated from consideration due to slow convergence of the second moment in the generated variates. One curious result was that in many cases, the percentage differences seemed to be somewhat less for W,(.95) than for W, -there were only 21 cases where percentage differences for W,(.95) were greater than 20%, nine of these for p values of .5 or .8, with conditions similar to those 12 for W, ", "cite_spans": [], "ref_spans": [{"start": 738, "end": 745, "text": "Table 1", "ref_id": "TABREF1"}]}, {"section": "cases (MOPS = 0)", "text": "For thirty six of the 108 cases run, analytical solutions exist for W, , i.e., those cases for which CVti = 1, the F/ F /I and W/W/l reduce to M/G/l models. Further, when CVti is also 1, the M/G/l models further reduce to M/M/l models and analytical results are available for both W, and W,(.95). Tables 2 and 3 show these results. Table 2 shows the M/M/l results and we see both the simulated F (=GM) and W (=WB) models are very close to the theoretical values, again validating the simulation. We can also see the \"heavy traffic\" effect in that the large percent differences of the LN and PT models diminish as 0 increases. But there is sizable differences in these models, again indicating that matching the first two moments only is, in general, not sufficient. Table 3 shows similar effects for the M/G/l cases.", "cite_spans": [], "ref_spans": [{"start": 297, "end": 311, "text": "Tables 2 and 3", "ref_id": "TABREF3"}, {"start": 332, "end": 339, "text": "Table 2", "ref_id": "TABREF3"}, {"start": 766, "end": 773, "text": "Table 3", "ref_id": "TABREF4"}]}, {"section": "SECOND EXPERIMENT", "text": "This experiment investigated selecting two-parameter distributions by matching the first and third quartiles of the base case f/F /l to W/W/l, LN/LN/l and PS/P5/1. The same 108 cases were attempted, although many of these resulted in infeasible tits, or feasible fits with 0 11. For the feasible cases, the percent deviations from the base case were much larger, and we concluded from this experiment that matching the first and third quartile is considerably poorer than matching the first two moments.", "cite_spans": [], "ref_spans": []}, {"section": "THIRD EXPERIMENT", "text": "In this experiment, we compared Maximum Likelihood estimation (MLE) to MOM for fitting two-parameter distributions. The experimental design had p =.5, CV.,t = 1, CV,, = .5,1,2. Data were generated for sample sizes of 20,50,100,200,500,1000 for the above three cases for F / l? 11 and LN/LN/l models. F and LN parameters were estimated for each of the sample sizes by both MOM and MLE. The empirical distribution, MOM and MLE cases were simulated for the various sample sizes and compared to the actual F / r /l and LN/LN/l base case simulations. The conclusions drawn from this experiment were (i) as sample size increases, the empirical model converges to actual, (ii) MOM appears somewhat \"better\" than MLE for small sample sizes, but both yield similar results for large sample sizes, and (iii) percent differences from actual are still quite large in many cases, especially for small sample sizes.", "cite_spans": [], "ref_spans": []}, {"section": "THIRD EXPERIMENT", "text": "The general conclusion from experiments 1,2 and 3 is that two parameter distributions are not sufftcient in general. It appears that, although the first two moments are important, that it is necessary, in many cases, to capture higher-order moments. To attempt to determine just how many may be necessary, we did a final experiment using a discrete point distribution. While there are families of distributions that have more than two parameters (e.g., Johnson translation distributions, phase-type distributions, Coxian distributions, generalized hyper exponential distributions), fitting can be a formidable task (see, for example, Johnson and Taffe, 1991 , Johnson, 1993 , and Harris and Marchal, 1997 . We chose discrete point distributions, which were very easy to fit by MOM and allowed us to see what happened as we increased the number of moments matched. The experimental design for this final experiment had p =.5, CV,, =l, and CV,, =.5,1,2. Data were generated for sample sizes (n) of 20,50, 100,200,500, 1000 for above three cases for r / I-/l and LN/LN/l models (same as the third experiment). For each sample size and each G/G/l model, a discrete k-point distribution was fit by nonlinear programming, matching two up to five moments respectively. The nonlinear programming problem to be solved is given by (3) below. @j cases (CV, =.5 and 2). It is interesting to note that using the discrete distribution with a five mom&t match is almost as good as using the entire empirical distribution and for large n, they both are fairly close to the actual simulated MOPS. Output measures of performance can, indeed, be sensitive to the particular \"shape\" of the input distribution. Using standard two-parameter distributions for which only the first two moments are captured in many cases is not sufficient, unless the system is in heavy traffic (probably p > .9). Results here indicate that it may be necessary to capture at least five moments, even though the lower order moments dominate in importance. Sample sizes when determining input distributions should be at least 200 and preferably closer to 1000 which should provide good results when using empirical distributions from which to generate inputs. Using a discrete k-point distribution for which the first five moments are matched to the data is almost as good. These are easy to determine by non-linear programming and easily generate sample data for simulation. The actual, empirical and the four discrete k-point fits were simulated, and W, and W&.95) compared. Figure 1 shows, for the CV,, =l case, the percent differences in W, and W, (.95) from the gamma and lognormal simulated cases with simulations using the empirical distribution, and discrete distributions with two, three and four moments matched for sample data generated from gamma and lognormal distributions for sample sizes of 50, 200 and 1000 observations. Results are similar for the other two This research shows that attention must be paid to proper input modeling, and that it is not a trivial task. Some general papers in this area include Fox (1981) , Kelton (1984) , Cheng (1993) , Cheng, et al (1996) , Leemis (1995 Leemis ( , 1996 and Nelson et al (1995) . Three rather \"nonclassical\" classes of distributions which appear to have potential in input modeling are the Johnson translation distributions (see Storer et al, 1988) , Phase-type distributions (see Johnson and Taaffe, 1991) , and Bezier distributions (see In a master level discrete-event simulation course at The George Washington University, a student team did a project involving a local bank. A G/G/c queue r as simulated. The interarrival time and teller service t me data were run through the UNIFIT II data fitting package and Table A . 1 shows the moment comparison given by UNIFIT II for the actual data and the best five theoretical distributions it suggests. For c = 7 (giving a c 1 = .63), two sets of simulations were run. Using the empirical distribution (EM) for service times, G/EM/7 runs were made for G = EM , the first five theoretical distributions given by UNIFIT and the four discrete k-point distributions matching two, three, four and five moments to the data. A similar set of runs were made using EM for interarrival times (EMG/7) and G= EM, the first five distributions given by UNIFIT and the four k-point distributions. Percent differences of the G/EM/7 and EM/G/7 models from the EM/EM/7 model are given in Table A .2. Note the anomaly when G is Pearson 6. The moments vary considerably from the data, yet the percent differences in output measures are modest. Except for this, \"generally\" the percent differences are smallest when the percent differences in moments are smallest. 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{"paper_id": "17437745", "_pdf_hash": "6ddb34d44ff6d9382191d674074f221240cb5c9d", "abstract": [], "body_text": [], "bib_entries": {"BIBREF1": {"title": "Problems and Tentative Solutions in InternetCAR Testing with IPv6", "authors": [{"first": "K", "middle": [], "last": "Uehara", "suffix": ""}, {"first": "H", "middle": [], "last": "Sunahara", "suffix": ""}, {"first": "J", "middle": [], "last": "Murai", "suffix": ""}], "year": 2003, "venue": "SAINT2003 IPv6 Workshop", "link": "16556978"}, "BIBREF2": {"title": "Experimentation of Networked Vehicle with Multihomed Mobile Router", "authors": [{"first": "R", "middle": [], "last": "Wakikawa", "suffix": ""}, {"first": "T", "middle": [], "last": "Yokota", "suffix": ""}, {"first": "K", "middle": [], "last": "Tasaka", "suffix": ""}, {"first": "H", "middle": [], "last": "Horiuchi", "suffix": ""}, {"first": "K", "middle": [], "last": "Uehara", "suffix": ""}, {"first": "J", "middle": [], "last": "Murai", "suffix": ""}], "year": 2005, "venue": "IEEE VTC'Fall 05", "link": "29354493"}, "BIBREF3": {"title": "The InternetCAR network architecture: Connect vehicles to the Internet using IPv6", "authors": [{"first": "K", "middle": [], "last": "Uehara", "suffix": ""}, {"first": "H", "middle": [], "last": "Sunahara", "suffix": ""}, {"first": "J", "middle": [], "last": "Murai", "suffix": ""}], "year": 2005, "venue": "ITST'2005", "link": null}, "BIBREF4": {"title": "Route Optimization in Nested Mobile Networks (NEMO) using OLSR", "authors": [{"first": "E", "middle": [], "last": "Baccelli", "suffix": ""}, {"first": "T", "middle": [], "last": "Clausen", "suffix": ""}, {"first": "R", "middle": [], "last": "Wakikawa", "suffix": ""}], "year": 2005, "venue": "IASTED International Conference on Networks and Communication Systems (NCS)", "link": null}, "BIBREF5": {"title": "WIDE Project -SHISA Implementation for NEMO Basic Support", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF6": {"title": "WIDE/USAGI and Nautilus6 projects / GO-Core Team -NEMO Platform for Linux", "authors": [], "year": "", "venue": "", "link": null}, "BIBREF7": {"title": "RFC 3626 : Optimized Link State Routing Protocol", "authors": [{"first": "T", "middle": [], "last": "Clausen", "suffix": ""}, {"first": "P", "middle": [], "last": "Jacquet", "suffix": ""}], "year": 2003, "venue": "", "link": null}}, "ref_entries": {}}
{"paper_id": "17438079", "_pdf_hash": "d389e62265b09b1d888a33d74d4809b2c1f36617", "abstract": [], "body_text": [{"section": "", "text": "1 / 2 heterozygous Cx43 mice connexin43 has been shown that passes through gap junctions. The model described in to be the main conductor of intercellular current in the the study of Yasui et al. may become a useful tool to ventricle [3] . The gap junctions are mainly localized at the identify apoptosis associated signals exchanged between intercalated discs of the cardiomyocytes [4] . cells which either promote or inhibit apoptosis in adjacent Although all these details on structure and function of cells. single gap junctions are known, their importance for heart", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "The findings of Yasui et al. [30] may be surprising, since function is a matter of ongoing investigations. Best studied in other cell types an enhancement of cell-cell coupling is their role in synchronization of electrical activation and through gap junctions has usually been found to increase 21 contraction of cardiac myocytes [5] . Gap junctional uncouthe number of apoptotic cells, e.g., after Ca -overload, pling is associated with electrical instability and appearoxidative stress or metabolic inhibition [10] . However, ance of arrhythmias [6] . On the other hand gap junctional when comparing the results two specific aspects of the communication seems to play a role in the development of study of Yasui et al. [30] should be considered: first, in this manifest myocardial cell injury. It has recently been shown study no single, defined stimulus for apoptosis induction that gap junctional uncoupling can limit infarct size in the was added to the cells. Second, the authors are looking at a heart [7] . If gap junctions are also involved in apoptotic process that takes several days until apoptosis appears, cardiac cell death has remained an open question. The whereas in other studies apoptosis was induced within 24 study of Yasui et al. [30] In various cardiac diseases uncoupling of carnecrosis. As we learn from the work of Yasui et al. [30] , diomyocytes is found, e.g., in remodeling myocardium gap junctions can mediate protection against apoptosis [17], in cardiomyopathic [18] or ischemic hearts [19] .", "cite_spans": [{"start": 29, "end": 33, "text": "[30]", "ref_id": "BIBREF11"}, {"start": 722, "end": 726, "text": "[30]", "ref_id": "BIBREF11"}, {"start": 1254, "end": 1258, "text": "[30]", "ref_id": "BIBREF11"}, {"start": 1356, "end": 1360, "text": "[30]", "ref_id": "BIBREF11"}, {"start": 1520, "end": 1524, "text": "[19]", "ref_id": "BIBREF3"}], "ref_spans": []}, {"section": "", "text": "induction in cardiomyocyte cultures. How this protective During myocardial infarction Cx43 expression is downeffect relates to heart diseases implying apoptotic myocarregulated [20] . Factors that emerge in the acute phase of dial cell death remains to be investigated. myocardial infarction, like lysophosphatidylcholine (LPC), high cytosolic calcium, intracellular acidosis or ATP depletion are known inhibitors of gap junctional communiReferences cation [15, [21] [22] [23] . In isolated papillary muscle these factors are believed to contribute to a rapid electrical fibrillation [25] . This is a potentially important beneficial band necrosis [7] . It was also shown in isolated pairs of agate from cell to cell by a mechanism communicated via ute to acceleration of apoptotic cell death in this situation.", "cite_spans": [{"start": 177, "end": 181, "text": "[20]", "ref_id": "BIBREF5"}, {"start": 462, "end": 466, "text": "[21]", "ref_id": "BIBREF6"}, {"start": 467, "end": 471, "text": "[22]", "ref_id": "BIBREF7"}, {"start": 584, "end": 588, "text": "[25]", "ref_id": "BIBREF2"}], "ref_spans": []}, {"section": "", "text": "[12] Communal C, Singh K, Pimentel DR, Colucci WS. Norepinephrine", "cite_spans": [], "ref_spans": []}, {"section": "", "text": "In contrast to the situation of reperfusion during the stimulates apoptosis in adult rat ventricular myocytes by activation of the beta-adrenergic pathway. In conclusion, gap junctions seem to confer both benefi- [16] De-Mello WC. Atrial natriuretic factor reduces cell coupling in the cial and detrimental effects on the heart: in ischemia failing heart, an effect mediated by cyclic GMP. J Cardiovasc reduction of coupling makes the heart more prone to Pharmacol 1998;32(1):75-79.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "in the epicardial border zone of healing canine infarcts that isolated, arterially perfused rabbit papillary muscle", "authors": [], "year": 1987, "venue": "Circ Res cause ventricular tachycardia. 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Effects of ing agents in isolated cardiomyocytes [13,29].", "type": "table"}}}
{"paper_id": "17438686", "_pdf_hash": "c63cd90e876953e327ffa2663ecf4cade9b792db", "abstract": [{"section": "Abstract", "text": "Aim: Diabetic nephropathy is one of the major complications of diabetes and the major cause of end-stage renal disease. In this study we investigated the insulin deficiency (ID) induced changes in renal mesangial cells (MCs) and in the kidney of STZ-induced diabetic rats. Methods: Cultured rat renal MCs were incubated in ID media. Cell proliferation was analyzed using BrdU incorporation assay. The expression of insulin receptor (IR), insulin-like growth factor-1 receptor (IGF-1R), phosphorylated IGF-1R, fibronectin, and collagen IV was determined with Western blot analysis. STZ-induced diabetic rats were treated with an IGF-1R antagonist picropodophyllin (PPP, 20 mg\u00b7kg -1 \u00b7d -1", "cite_spans": [], "ref_spans": []}, {"section": "Abstract", "text": ", po) for 8 weeks. After the rats were euthanized, plasma and kidneys were collected. IGF-1 levels in renal cortex were measured with RT-PCR or ELISA. The morphological changes in the kidneys were also examined. Results: Incubation in ID media significantly increased cell proliferation, the synthesis of fibronectin and collagen IV, and the expression of IGF-1 and IGF-1R and phosphorylated IGF-1R in renal MCs. Pretreatment of the cells with PPP (50 nmol/L) blocked ID-induced increases in cell proliferation and the synthesis of fibronectin and collagen IV; knockdown of IGF-1R showed a similar effect as PPP did. In contrast, treatment of the cells with IGF-1 (50 ng/mL) exacerbated ID-induced increases in cell proliferation. In the kidneys of diabetic rats, the expression of IGF-1, IGF-1R and phosphorylated IGF-1R were significantly elevated. Treatment of diabetic rats with PPP did not lower the blood glucose levels, but significantly suppressed the expression of TGF-\u03b2, fibronectin and collagen IV in the kidneys, the plasma levels of urinary nitrogen and creatinine, and the urinary protein excretion. Conclusion: Insulin deficiency increases the expression of IGF-1 and IGF-1R in renal MCs and the kidney of diabetic rats, which contributes to the development of diabetic nephropathy.", "cite_spans": [], "ref_spans": []}], "body_text": [{"section": "Introduction", "text": "Diabetes (diabetes mellitus, DM) is a group of metabolic diseases in which blood glucose levels are higher than normal for prolonged periods of time. Diabetic nephropathy (DN) is one of the major complications of DM and is the major cause of end-stage renal disease (ESRD) [1] . In the early stage of DN, the kidneys are enlarged. These changes are followed by the overproduction and accumulation of extracellular matrixes (ECM), thickness in the glomerular basal membrane, and final development of glomerular sclerosis and interstitial fibrosis [2] . The glomerulus is an important target for DN. Glomerular hypertrophy is one of the main pathological features of early DN. Mesangial cells (MCs) are inherent mesenchymal cells among the glomerular capillary loops. MC proliferation is commonly observed in a variety of pathological changes in glomerular injury. It has been demonstrated that MC dysfunction, including overproliferation and an increase in ECM production [3, 4] , is implicated in the development of DN [5, 6] . Hyperglycemia has been well documented as an independent risk factor for DM-induced complications. Many previous studies, including the observations in our lab, explored the role of hyperglycemia in DN and the related mechanisms [7] [8] [9] [10] [11] . Moreover, many other factors, such as the overactivation of the renin-angiotensin system, oxidative stress, and an elevation in advanced glycation end products, are all reported to be involved in diabetes-induced renal injury.", "cite_spans": [{"start": 273, "end": 276, "text": "[1]", "ref_id": "BIBREF0"}, {"start": 546, "end": 549, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 971, "end": 974, "text": "[3,", "ref_id": "BIBREF2"}, {"start": 975, "end": 977, "text": "4]", "ref_id": "BIBREF3"}, {"start": 1019, "end": 1022, "text": "[5,", "ref_id": "BIBREF4"}, {"start": 1023, "end": 1025, "text": "6]", "ref_id": "BIBREF5"}, {"start": 1257, "end": 1260, "text": "[7]", "ref_id": "BIBREF6"}, {"start": 1261, "end": 1264, "text": "[8]", "ref_id": "BIBREF7"}, {"start": 1265, "end": 1268, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 1269, "end": 1273, "text": "[10]", "ref_id": "BIBREF9"}, {"start": 1274, "end": 1278, "text": "[11]", "ref_id": "BIBREF10"}], "ref_spans": []}, {"section": "Introduction", "text": "The fundamental basis of diabetes is functionally insuffi-cient insulin, which can be due to either the \u03b2-cells in the pancreas islet not producing enough insulin or an inability of cells in the body to correctly respond to the secreted insulin. In addition to its blood glucose-regulating effect, insulin confers multiple physiological effects by binding to its receptors and interacting with its homologue IGF-1. However, few studies have explored the functional role of a deficiency of insulin in the development and progression of DN. The aim of this study was to identify the role of insulin deficiency (ID) in DN and its underlying mechanism in cultured renal MCs and in STZ-induced DM rats.", "cite_spans": [], "ref_spans": []}, {"section": "Materials and methods", "text": "", "cite_spans": [], "ref_spans": []}, {"section": "Materials and reagents", "text": "Normal-glucose Dulbecco's modified Eagle's medium (DMEM) and STZ were purchased from Sigma-Aldrich (St Louis, MO, USA). Steroid hormone-free fetal bovine serum (FBS) was purchased from Sijiqing Biological Engineering Materials Co (Hangzhou, China). Insulin was from Eli-Lilly (Indianapolis City, IN, USA). The recombinant murine IGF-1 was from Peprotech (Rocky Hill, NJ, USA). Picropodophyllin (PPP) was from Millipore (Billerica, MA, USA) and MedChemExpress (Monmouth Junction, NJ, USA). The BCA Protein Assay Kit was from Shenergy Biocolor BioScience and Technology (Shanghai, China). The RNA extraction kit was from Sangon Co (Shanghai, China). The ReverTra AceqPCR RT kit and the SYBR Green reaction mix were from Toyobo Co (Dojima Hama, Osaka, Japan). The BrdU assay kit was purchased from Roche (Mannheim, Germany). The enhanced chemiluminescence (ECL) detection kit was from Pierce Biotechnology (Rockford, IL, USA). The rabbit anti-IR antibody and the rabbit anti-IGF-1R antibody were obtained from Santa Cruz Biotechnology, Inc (Dallas, TX, USA). The phospho-IGF-1 receptor (Tyr1135/1136) was obtained from Cell Signaling Technology (Beverly, MA, USA). The anti-fibronectin antibody was obtained from Sigma-Aldrich (St Louis, MO, USA), the anti-collagen IV antibody was from Abcam (Cambridge, MA, USA), the rabbit anti-rat TGF-\u03b2 (Y369) antibody was obtained from Bioworld Technology, Inc (Nanjing, China), and the alpha-tubulin monoclonal antibody was from Proteintech (Chicago, IL, USA). All of the other chemicals and reagents used in the experiment were of analytical grade.", "cite_spans": [], "ref_spans": []}, {"section": "Cell culture", "text": "The rat renal mesangial cell line (HBZY-1) was purchased from the China Center for Type Culture Collection (Wuhan, China) and cultured in normal DMEM media containing 10% FBS and 100 \u03bcU insulin under an atmosphere of 5% CO 2 at 37\u00b0C. Before the experiment, the cells were starved in a medium containing 0.5% FBS and 100 \u03bcU insulin for 12 h to obtain quiescent cells. The ID media was made by supplementing the normal DMEM media without insulin. When necessary, the cells were pretreated with a diluent (DMSO) or PPP at different concentrations for 60 min before ID application. Each experiment was repeated at least three times.", "cite_spans": [], "ref_spans": []}, {"section": "Animal model", "text": "Age-matched 4-month-old male SD rats weighing 180-210 g were provided by the Shanghai SLAC Laboratory Animal Center. All of the experimental procedures followed the Criteria of the Medical Laboratory Animal Administrative Committee of Shanghai and the Guide for Care and Use of Laboratory Animals of Fudan University, and were approved by the Ethics Committee for Experimental Research, Shanghai Medical College, Fudan University. The animals were acclimatized for 7 days before the study and had free access to water and standard rat chow throughout the experiment. Diabetes was induced by a single intraperitoneal injection of STZ (60 mg/kg) dissolved in 0.1 mol/L sodium citrate buffer (pH 4.0). Seventy-two hours later, the diabetic state was confirmed by measuring blood glucose from the rat tail, using a blood glucose meter (Abbott, Chicago, IL, USA) and One Touch strips (range=0-27.8 mmol/L). Only those rats with plasma glucose concentrations >16.7 mmol/L were recruited in the study. After 4 weeks of cultivation, the rats were randomly divided into four groups (n=10 for each group): (1) control rats (Con), injected with vehicle (0.1 mol/L sodium citrate buffer, pH 4.0); (2) diabetic rats (DM); (3) diabetic rats with IGF-1R blockade PPP (DM+PPP) (20 mg\u00b7kg -1 \u00b7d -1 , po); and (4) diabetic rats with insulin (DM+insulin) (10 U, twice/day, hypodermic injection). The drugs were administered to the rats for 8 weeks. Twelve weeks after the STZ injection, the rats were killed, and the plasma and kidneys were removed and kept at -80\u00b0C until used.", "cite_spans": [], "ref_spans": []}, {"section": "Animal model", "text": "Cell proliferation assay A total of 1\u00d710 3 cells per well were cultured in 96-well plates. When the cells reached 50% confluence, they were serum starved for 12 h and then treated with the ID media, IGF-1 or PPP. After 48 h, cell proliferation was assessed by BrdU incorporation assay as previously described [12] . Briefly, 10 \u03bcmol/L BrdU labeling solution was added to the medium, which was incubated at 37\u00b0C for 4 h. Then, the cells were fixed, denatured and incubated in an anti-BrdU-POD (peroxidase) antibody for 90 min at room temperature. At the end of incubation, the cells were rinsed with phosphate-buffered solution (PBS) at pH 7.0 three times to remove any excess antibody, and then 100 \u03bcL of the substrate solution was added to each well. After a 30 min incubation at room temperature, the absorbance of the samples was measured on a TECAN Infinite M200 microplate reader (Salzburg Umgebung, Salzburg, Austria) at 370 nm, while the absorbance obtained at 492 nm served as a reference value.", "cite_spans": [{"start": 309, "end": 313, "text": "[12]", "ref_id": "BIBREF11"}], "ref_spans": []}, {"section": "Western blotting", "text": "Renal cortex or cultured renal MCs were lysed in 1\u00d7sodium dodecyl sulfate (SDS) supplemented with proteinase inhibitor at a dilution of 1:25. Protein concentrations were determined with the BCA Protein Assay Kit according to the manufacturer's instruction. Approximately 50 \u03bcg of protein was loaded in each well and separated on a 10% sodium dodecyl sulfate-polyacrylamide gel and then electrophoretically transferred to polyvinylidene difluoride membranes at 270 mA for 120 min. The membranes were blocked with 5% skim milk in Tris-buffered saline (TBS) and 0.1% Tween (TBS/Tween) for one hour at room temperature with gentle rocking. The membranes were incubated in primary antibody overnight at 4\u00b0C (anti-collagen IV antibody, 1:1000; anti-fibronectin antibody, 1:10000; anti-IR antibody, 1:1000; anti-IGF-1R antibody, 1:1000; antirat TGF-\u03b2 antibody, 1:1000; anti-phospho-IGF-1 receptor antibody, 1:1000; anti-tubulin antibody, 1:10000). The membranes were incubated with a secondary anti-rabbit/mouse antibody (1:1000) for 2 h at room temperature after three washes with TBS/Tween. The hybridization signals were developed using the ECL detection kit according to the manufacturer's instructions and then detected and quantified using the ImageQuant LAS4000 mini system (GE Healthcare, UK). Alpha-tubulin was used as an internal standard to normalize the protein amounts. The relative intensity of the bands exposed on the films was quantified using Smart Viewer software (Furi Technology Co, Shanghai, China). The average relative protein level in the control group was defined as 1.0.", "cite_spans": [], "ref_spans": []}, {"section": "Western blotting", "text": "RNA extraction, cDNA synthesis and quantitative real-time PCR Total RNA from renal MCs was isolated with TRIzol reagent, and the RNA concentration was measured at the specific absorbance at 260 nm. Two micrograms of total RNA was used for cDNA synthesis in a 20-\u03bcL reaction mixture with the ReverTra Ace qPCR RT Kit. SYBR Green qRT-PCR was used to quantify the relative abundance of IGF-1 mRNA. The PCR primers are: forward primer 5'-TAGGTGGTTGAT-GAATGGT-3', reverse primer 5'-GAAAGGGCAGGGCTAAT -3' for IGF-1; and forward primer 5'-CCCTTCATTGACCT-CAACTACATG-3', reverse primer 5'-CTTCTCCATGGTGGT-GAAGAC-3' for GAPDH, which was used as an endogenous control to normalize the amount of RNA. The PCR procedures were as follows: pre-denaturing at 95 \u00b0C for 5 min followed by 40 cycles of amplifications by denaturing at 95 \u00b0C for 15 s; annealing for 30 s at 64 \u00b0C (for IGF-1) or 60 \u00b0C (for GAPDH); and extension at 72 \u00b0C for 30 s. After a final extension at 72 \u00b0C for 10 min, the amplified products were subjected to a stepwise increase in temperature from 55 \u00b0C to 95 \u00b0C to construct dissociation curves. The average relative mRNA in the control group was defined as 1.0.", "cite_spans": [], "ref_spans": []}, {"section": "Western blotting", "text": "SiRNA transfection IGF-1R siRNA was synthesized by Biotend Company (Shanghai, China), with a sequence of 5'-GCCGACACUACUACUA-CAATT-3'. A nonsilencing siRNA oligonucleotide that does not recognize any known homolog of mammalian genes (Biotend, Shanghai, China) was used as a negative control. MCs were transfected with IGF-1R siRNA (50 nmol/L) or control siRNA (50 nmol/L) facilitated by Lipofectamine 2000 transfection reagent (Invitrogen, Carlsbad, CA, USA) according to the manufacturer's instructions. In brief, before transfection, the Lipofectamine 2000 reagent was incubated in OPTI-MEM medium (Gibco, Carlsbad, CA, USA) for 5 min at room temperature. At the same time, siRNA was diluted into OPTI-MEM medium for 5 min at room temperature. Next, the diluted Lipofectamine 2000 transfection reagent and diluted siRNA were gently mixed and incubated for 20 min at room temperature to form siRNA/Lipofectamine 2000 Transfection Agent transfection complexes. IGF-1R protein and cell proliferation were analyzed 48 h after transfection.", "cite_spans": [], "ref_spans": []}, {"section": "Western blotting", "text": "Plasma creatinine, blood urea nitrogen (BUN), urinary protein and glucosuria Glucosuria was detected using the oxidase method by employing a glucosuria detection kit (Applygen, Beijing, China). Plasma creatinine, BUN and urinary protein were detected with a creatinine detection kit, BUN detection kit and urinary protein detection kit, respectively (Nanjing Jiancheng Bioengineering Institute, Nanjing, China). All of the kits were used in accordance with the manufacturer's instructions.", "cite_spans": [], "ref_spans": []}, {"section": "Western blotting", "text": "Quantification of IGF-1 in renal cortex homogenates by ELISA At the end of the experiment (12 weeks of diabetes), the rats were euthanized, and the renal cortex was harvested and stored at -80 \u00b0C until they were used for the IGF-1 assay by ELISA, which was performed according to the manufacturer's instructions (R&D Systems, Minneapolis, MN, USA). Briefly, the renal cortex homogenates were diluted 5-fold and then transferred to microplates coated with a monoclonal anti-IGF-1. After a 2 h incubation at room temperature on a horizontal orbital microplate shaker, the wells were aspirated and washed 5 times with wash buffer. This was followed by incubation with the HRP conjugated anti-IGF-1 antibody for another 2 h, and then, the substrate for HRP was added to each well, with subsequent incubation for 30 min at room temperature on the benchtop, protected from light. Finally, the chromogenic reaction was halted with a stop solution, the plate was gently tapped to ensure thorough mixing, and the absorbance at 540 nm was measured using a TECAN Infinite M200 microplate reader.", "cite_spans": [], "ref_spans": []}, {"section": "Western blotting", "text": "Renal histology and electron microscopy At the end of the experiment, the kidneys were collected and fixed in 10% neutral buffered formalin and then embedded in paraffin. The paraffin sections (3 \u03bcm) were prepared and stained with HE, PAS and Masson's trichrome. Histological changes, such as the degree of glomerular injury and renal fibrosis, were observed under 400\u00d7 optical magnification. Part of the right kidney was fixed in 2.5% glutaraldehyde for electron microscopy. The ultrastructure (glomerulus basement membrane and podocyte processes) of the kidney was observed at magnifications of \u00d71500 and \u00d74000, respectively.", "cite_spans": [], "ref_spans": []}, {"section": "Statistical analysis", "text": "The data are expressed as the mean\u00b1SEM. The statistical analyses were performed using SPSS Statistics 17.0 software (SPSS, Inc, Chicago, IL, USA). The results of three or more groups were analyzed by one-way ANOVA. The differences between two groups were compared by independent samples ", "cite_spans": [], "ref_spans": []}, {"section": "Results", "text": "Effects of ID on mesangial cell proliferation and ECM synthesis MCs were cultured in a medium containing different concentrations of insulin (300-0 \u03bcU). A BrdU incorporation assay was used to evaluate cell proliferation. A decrease in insulin concentration induced an increase in cell proliferation ( Figure  1A) . After depriving the cells of insulin for 48 h, the Western blot results showed that ECM protein levels, including fibronectin ( Figure 1B ) and collagen IV ( Figure 1C ), were significantly increased.", "cite_spans": [], "ref_spans": [{"start": 301, "end": 312, "text": "Figure  1A)", "ref_id": "FIGREF0"}, {"start": 443, "end": 452, "text": "Figure 1B", "ref_id": "FIGREF0"}, {"start": 473, "end": 482, "text": "Figure 1C", "ref_id": "FIGREF0"}]}, {"section": "Results", "text": "Effects of ID on insulin receptor (IR), IGF-1R and IGF-1 expression in renal MCs After insulin deprivation for 48 h, the Western blot results showed that the expression of both IR ( Figure 2A ) and IGF-1R ( Figure 2B ) was significantly increased in MCs; the RT-PCR results showed that the IGF-1 mRNA level was also significantly increased ( Figure 2C ).", "cite_spans": [], "ref_spans": [{"start": 182, "end": 191, "text": "Figure 2A", "ref_id": "FIGREF1"}, {"start": 207, "end": 216, "text": "Figure 2B", "ref_id": "FIGREF1"}, {"start": 342, "end": 351, "text": "Figure 2C", "ref_id": "FIGREF1"}]}, {"section": "Results", "text": "The IGF-1R antagonist PPP inhibited ID-induced cell proliferation and increase in ECM synthesis in renal MCs To examine whether the change in the IGF-1 and IGF-1R pathway was involved in ID-induced MCs proliferation and ECM synthesis, PPP (an IGF-1R antagonist) was utilized in the experiment. The Western blot showed that the phosphorylation of IGF-1R was significantly increased in the insulindeprived MCs. PPP reversed the ID-induced up-regulation in IGF-1R phosphorylation ( Figure 3A and Figure 3B ). The BrdU incorporation assay showed that the blockade IGF-1R with PPP reduced ID-induced MC proliferation ( Figure 3C ). Similarly, the increase in fibronectin ( Figure 3D ) and collagen IV ( Figure 3E ) synthesis in the ID MCs was also inhibited by PPP treatment.", "cite_spans": [], "ref_spans": [{"start": 479, "end": 488, "text": "Figure 3A", "ref_id": "FIGREF2"}, {"start": 493, "end": 502, "text": "Figure 3B", "ref_id": "FIGREF2"}, {"start": 614, "end": 623, "text": "Figure 3C", "ref_id": "FIGREF2"}, {"start": 668, "end": 677, "text": "Figure 3D", "ref_id": "FIGREF2"}, {"start": 698, "end": 707, "text": "Figure 3E", "ref_id": "FIGREF2"}]}, {"section": "Results", "text": "Effects of IGF-1R knock-down on ID-induced cell proliferation in renal MCs IGF-1R siRNA (50 nmol/L) transfection (48 h) significantly knocked down the expression of IGF-1R, while the transfection of the negative control (NC) siRNA (50 nmol/L) did not have an obvious effect ( Figure 4A ). ID elevated MC proliferation. IGF-1R siRNA (50 nmol/L) transfection significantly inhibited the elevation of MC proliferation induced by ID ( Figure 4B ).", "cite_spans": [], "ref_spans": [{"start": 276, "end": 285, "text": "Figure 4A", "ref_id": "FIGREF4"}, {"start": 431, "end": 440, "text": "Figure 4B", "ref_id": "FIGREF4"}]}, {"section": "Exogenous IGF-1 increased MC proliferation", "text": "The BrdU incorporation assay showed that compared with the control group, the ID group induced an increase in MC proliferation, and cells treated with IGF-1 (50 ng/mL) showed increased MC proliferation. In the insulin-deprived cells, the application of IGF-1 induced an even higher increase in cell proliferation ( Figure 4C ).", "cite_spans": [], "ref_spans": [{"start": 315, "end": 324, "text": "Figure 4C", "ref_id": "FIGREF4"}]}, {"section": "Effects of IGF-1R blockade on physiological parameters in diabetic rats", "text": "As illustrated in Figure 5 , the body weights of the DM, npg DM+PPP and DM+insulin groups were significantly lower than in the control animals ( Figure 5A ), while the urine volumes were significantly increased ( Figure 5B ). The ratio of kidney weight to body weight was significantly higher in the DM animals than in the control rats, while the DM rats treated with PPP or insulin showed a decreased ratio of kidney weight to body weight but it was still significantly higher than in the control rats ( Figure 5C ). Blood glucose was significantly elevated in the DM rats ( Figure 5D ). A decrease in blood glucose was observed in the insulin-supplemented DM rats at 4 h after insulin injection but not at 12 h ( Figure 5E ). Urinary glucose was not detected in the control rats. DM rats treated with PPP or insulin tended to show a decrease in urinary glucose output, but obvious urinary glucose was still detected in both the DM+PPP and DM+insulin groups ( Figure 5F ).", "cite_spans": [], "ref_spans": [{"start": 18, "end": 26, "text": "Figure 5", "ref_id": "FIGREF5"}, {"start": 145, "end": 154, "text": "Figure 5A", "ref_id": "FIGREF5"}, {"start": 213, "end": 222, "text": "Figure 5B", "ref_id": "FIGREF5"}, {"start": 505, "end": 514, "text": "Figure 5C", "ref_id": "FIGREF5"}, {"start": 576, "end": 585, "text": "Figure 5D", "ref_id": "FIGREF5"}, {"start": 715, "end": 724, "text": "Figure 5E", "ref_id": "FIGREF5"}, {"start": 961, "end": 970, "text": "Figure 5F", "ref_id": "FIGREF5"}]}, {"section": "Effects of IGF-1R blockade on physiological parameters in diabetic rats", "text": "Changes in the IGF-1 and IGF-1R protein and phosphorylation levels in the kidney tissues of diabetic rats Western blot analysis showed that IGF-1R protein ( Figure 6A ) and phosphorylated IGF-1R ( Figure 6B ) were significantly increased in DM rats when compared to normal rats. Either administration of the IGF-1R blocker PPP or insulin supplementation significantly reduced IGF-1R expression and its phosphorylation. The ELISA results also showed that the IGF-1 level ( Figure 6C ) was significantly increased in the DM rats. Treatment of the diabetic rats with either PPP or insulin significantly reduced the IGF-1 level in the DM rats.", "cite_spans": [], "ref_spans": [{"start": 157, "end": 166, "text": "Figure 6A", "ref_id": "FIGREF6"}, {"start": 197, "end": 206, "text": "Figure 6B", "ref_id": "FIGREF6"}, {"start": 472, "end": 481, "text": "Figure 6C", "ref_id": "FIGREF6"}]}, {"section": "IGF-1R blockade on renal function in diabetic rats", "text": "The 24 h urinary protein ( Figure 7A ), plasma BUN ( Figure 7B ) and plasma creatinine ( Figure 7C ) were significantly increased in the DM group at the end of the experiment (12 weeks after the STZ injection). Significant reductions in the 24 h urinary protein, plasma BUN and plasma creatinine were observed in the DM rats treated with the IGF-1R blockade PPP or insulin.", "cite_spans": [], "ref_spans": [{"start": 27, "end": 36, "text": "Figure 7A", "ref_id": "FIGREF8"}, {"start": 53, "end": 62, "text": "Figure 7B", "ref_id": "FIGREF8"}, {"start": 89, "end": 98, "text": "Figure 7C", "ref_id": "FIGREF8"}]}, {"section": "IGF-1R blockade on renal function in diabetic rats", "text": "Blocking IGF-1R alleviated the renal fibrotic response and reduced TGF-\u03b2 protein levels in the kidney The Western blot results showed that the expression of fibronectin ( Figure 8A ), collagen IV ( Figure 8B ) and TGF-\u03b2 ( Figure  8C ) were significantly increased in the DM rats compared to the normal group. Significant reductions in the expression of fibronectin, collagen IV, and TGF-\u03b2 were observed in the DM rats treated with the IGF-1R blockade PPP or insulin.", "cite_spans": [], "ref_spans": [{"start": 171, "end": 180, "text": "Figure 8A", "ref_id": "FIGREF9"}, {"start": 198, "end": 207, "text": "Figure 8B", "ref_id": "FIGREF9"}, {"start": 222, "end": 232, "text": "Figure  8C", "ref_id": "FIGREF9"}]}, {"section": "IGF-1R blockade on renal function in diabetic rats", "text": "Effects of IGF-1R blockade on renal morphology in normal and diabetic rats HE staining ( Figure 9A ) showed that there was mild expansion in the glomerular mesangial area and mesangial cell proliferation, and basement membrane thickening in the DM rats. The PAS stain showed that there were sporadic KimmelstielWilson nodules, and few instances glomerular basement membrane thickening, mesangial matrix accumulation and plasma protein extravasation in the DM group ( Figure 9B ). The Masson staining ( Figure 9C) showed that there was a slight increase in ECM deposition in the DM rats. The electron microscopy ( Figure 9D ) results showed that there was local thickness in the glomerular basement membrane and partial epithelial foot processes fusion in the DM rats. The pathological morphology showed some improvement in the DM+PPP and the DM+insulin groups. With the changes in people's lifestyles, the prevalence of DM is continuously increasing. DM has become a growing public health problem of global concern [13] . As one of the most common complications of diabetes, DN is a leading cause of endstage renal disease. The initial phase of DN is characterized by enlargement in the kidneys. At the early stage of DN, basic pathological changes in the glomeruli include thickening of the basement membrane, ECM accumulation and microcirculation disorder. All of the changes will lead to glomerular sclerosis and ultimately contribute to renal functional regression [2] . MCs are inherent mesenchymal cells among the glomerular capillary loops. The activation and proliferation of the MCs is involved in a variety of factor-induced pathological changes in glomerular injury. Abnormalities in the MCs cause increases in ECM expression and cytokine secretion, which play an important role in glomerular sclerosis [14] . Therefore, MCs were utilized as a target cell in the in vitro studies.", "cite_spans": [{"start": 1015, "end": 1019, "text": "[13]", "ref_id": "BIBREF12"}, {"start": 1469, "end": 1472, "text": "[2]", "ref_id": "BIBREF1"}, {"start": 1814, "end": 1818, "text": "[14]", "ref_id": "BIBREF13"}], "ref_spans": [{"start": 89, "end": 98, "text": "Figure 9A", "ref_id": "FIGREF10"}, {"start": 467, "end": 476, "text": "Figure 9B", "ref_id": "FIGREF10"}, {"start": 502, "end": 512, "text": "Figure 9C)", "ref_id": "FIGREF10"}, {"start": 613, "end": 622, "text": "Figure 9D", "ref_id": "FIGREF10"}]}, {"section": "IGF-1R blockade on renal function in diabetic rats", "text": "Over the past few decades, numerous studies have explored the pathophysiological mechanism of DN. Multi-factors, such as hyperglycemia [10, 15] , excessive activation of the RAS system [9] , increased oxidative stress [16] and accumulation of advanced glycation end-products (AGEs) [17, 18] are all reported to contribute to the development of DN.", "cite_spans": [{"start": 135, "end": 139, "text": "[10,", "ref_id": "BIBREF9"}, {"start": 140, "end": 143, "text": "15]", "ref_id": "BIBREF14"}, {"start": 185, "end": 188, "text": "[9]", "ref_id": "BIBREF8"}, {"start": 218, "end": 222, "text": "[16]", "ref_id": "BIBREF15"}, {"start": 282, "end": 286, "text": "[17,", "ref_id": "BIBREF16"}, {"start": 287, "end": 290, "text": "18]", "ref_id": "BIBREF17"}], "ref_spans": []}, {"section": "IGF-1R blockade on renal function in diabetic rats", "text": "Radically, diabetes is a far-reaching pathophysiologic effect of ID [19, [21] [22] [23] [24] , which may be caused by \u03b2-cells in the pancreas islet that do not produce enough insulin or cells of the body that do not correctly respond to secreted insulin [2, 19, 20] . In addition to the hypoglycemic effect, insulin has multiple effects on metabolism and cell growth. Currently, few studies have investigated the role of ID in the development and progression of DN. The normal physiological insulin concentration is approximately 5-15 \u03bcU/mL, and it increases five- to ten-fold after eating a meal. To determine the direct role of ID, we cultured MCs in an insulin-deprived condition. In the study, we observed that insulin deprivation induced increased MC proliferation and collagen IV and fibronectin synthesis, which are the major components of the ECM. These results suggested that ID can directly lead to the overproliferation of mesangial cells and ECM overproduction and is one of the direct reasons for cellular functional changes. IGF-1 is the homolog of insulin, and it plays an important role in regulating the cell cycle and growth [25] . IGF-1R also has a structure similar to IR. They all belong to the kinase receptor family [26] . IGF-1R activation affects the cell cycle and promotes cell division, differentiation and proliferation. In recent years, many studies have confirmed that the alteration and functional changes of the IGF-1R pathways, by activating the MAPK and PI3K pathways, are closely related to tumor development. IGF-1R overexpression is observed in breast cancer, colon cancer, lung cancer, prostate cancer and pancreatic tumors. As a result, inhibition of the IGF-1R pathway has become one of therapeutic targets for the treatment of cancer, and there are studies showing that inhibition of IGF-1R can effectively alleviate the occurrence and development of tumors [26] [27] [28] [29] [30] [31] [32] [33] . Abnormal proliferation in MCs and ECM accumulation are the main pathological changes of DN. Previous studies have found [29] . Therefore, we speculate that the IGF-1 and IGF-1R pathways might be involved in regulating the function of MCs. The present study showed that ID increased the expression of IR, IGF-1 and IGF-1R, and the phosphorylation of IGF-1R was also increased. Pretreatment with PPP, a blocker of IGF-1R, antagonized the ID-induced increase in IGF-1R phosphorylation and reversed the ID-induced MC proliferation and fibrosis-related gene expression. These results suggested that the activation of the IGF-1 and IGF-1R pathways is related to ID-induced abnormalities in MC proliferation and increase in ECM synthesis. Knockdown of IGF-1R expression by siRNA showed a similar effect to the application of PPP. Furthermore, in the current study, exogenous IGF-1 significantly promoted MC proliferation. These results confirmed that the activation of IGF-1R stimulates proliferation and ECM synthesis in renal MCs.", "cite_spans": [{"start": 68, "end": 72, "text": "[19,", "ref_id": "BIBREF18"}, {"start": 73, "end": 77, "text": "[21]", "ref_id": "BIBREF20"}, {"start": 78, "end": 82, "text": "[22]", "ref_id": "BIBREF21"}, {"start": 83, "end": 87, "text": "[23]", "ref_id": "BIBREF22"}, {"start": 88, "end": 92, "text": "[24]", "ref_id": "BIBREF23"}, {"start": 254, "end": 257, "text": "[2,", "ref_id": "BIBREF1"}, {"start": 258, "end": 261, "text": "19,", "ref_id": "BIBREF18"}, {"start": 262, "end": 265, "text": "20]", "ref_id": "BIBREF19"}, {"start": 1143, "end": 1147, "text": "[25]", "ref_id": "BIBREF24"}, {"start": 1239, "end": 1243, "text": "[26]", "ref_id": "BIBREF25"}, {"start": 1900, "end": 1904, "text": "[26]", "ref_id": "BIBREF25"}, {"start": 1905, "end": 1909, "text": "[27]", "ref_id": "BIBREF26"}, {"start": 1910, "end": 1914, "text": "[28]", "ref_id": "BIBREF27"}, {"start": 1915, "end": 1919, "text": "[29]", "ref_id": "BIBREF28"}, {"start": 1920, "end": 1924, "text": "[30]", "ref_id": "BIBREF29"}, {"start": 1925, "end": 1929, "text": "[31]", "ref_id": "BIBREF30"}, {"start": 1930, "end": 1934, "text": "[32]", "ref_id": "BIBREF31"}, {"start": 1935, "end": 1939, "text": "[33]", "ref_id": "BIBREF32"}, {"start": 2062, "end": 2066, "text": "[29]", "ref_id": "BIBREF28"}], "ref_spans": []}, {"section": "IGF-1R blockade on renal function in diabetic rats", "text": "To further verify the role of IGF-1 and IGF-1R pathway in ID-induced renal injury, an STZ-induced diabetic rat, which is a classic animal model of ID, was utilized in this study. STZ specifically destroys the \u03b2 cells in the islets of the pancreas, which results in an absolute lack of insulin and leads to the occurrence of diabetes [34] . In the present study, blood glucose, urine volume, urinary glucose and kidney weight in the STZinjected rats were significantly higher than in the control group. Similar to the observations from the in vitro study, the expression of IR, IGF-1 and IGF-1R was significantly elevated in the diabetic rats. The administration of the IGF-1R blocker PPP significantly reduced kidney weight, which is a sign of early stage DN, while no obvious changes were observed for body weight, blood glucose levels, urine volume and urinary glucose. Moreover, the increased urinary protein output, BUN and plasma creatinine, as well as the ECM expression and TGF-\u03b2 synthesis, were significantly attenuated. These results suggested that blockade of IGF-1R does not affect blood glucose in diabetic rats, but slows down the development of DN.", "cite_spans": [{"start": 333, "end": 337, "text": "[34]", "ref_id": "BIBREF33"}], "ref_spans": []}, {"section": "IGF-1R blockade on renal function in diabetic rats", "text": "Supplementation of exogenous insulin in the diabetic rat also showed a similar protective effect. However, treatment of the animal with either insulin or IGF-1R blocker did not completely retard the occurrence of DN. The reason for the IGF-1R blockade results might be that it did not eliminate the effect of high blood glucose. The reason for the insulin supplementation results, we would speculate, is due to a failure to stably control blood glucose. In the clinic, a major obstacle in the treatment of diabetes is that exogenous supplementation cannot restore the blood glucose level to the endogenous secretion level [35] . In this experiment, we noticed that a decrease in the blood glucose was observed 4 h after the insulin injection but not at 12 h. Urinary glucose was detected, and the urine volume and kidney weight were only partially decreased in the DM+insulin group.", "cite_spans": [{"start": 622, "end": 626, "text": "[35]", "ref_id": "BIBREF34"}], "ref_spans": []}, {"section": "IGF-1R blockade on renal function in diabetic rats", "text": "In this experiment, the renal morphological observations showed that there was little MC proliferation, a slight mesangial matrix increase, glomerular basement membrane thickening, mesangial matrix accumulation, plasma protein extravasation and partial epithelial foot processes fusion in the DM group, and all of these features are principle pathological changes in DN. The morphological changes were improved slightly in the DM+PPP and the DM+insulin groups. Overall, the subjected animals were still in the early stages of DN, and the morphological differences among the groups were not obvious. To confirm the morphological effects, studies exploring prolonged treatment are required.", "cite_spans": [], "ref_spans": []}, {"section": "IGF-1R blockade on renal function in diabetic rats", "text": "In summary, the renal IGF-1/ IGF-1R pathway is upregulated and activated under an insulin-deficient condition. The activation of the IGF-1/IGF-1R pathway contributes to the development of DN. The stimulation of renal MC proliferation and ECM production is involved in the IGF-1/IGF-1R pathway activation-induced renal damage. Blockade of the IGF-1/IGF-1R pathway activation might be a potential target in manipulating DN, and an early application of insulin might be recommended in the clinic to prevent the overactivation of the IGF-1/IGF-1R pathway.", "cite_spans": [], "ref_spans": []}], "bib_entries": {"BIBREF0": {"title": "Diabetic nephropathy and extracellular matrix", "authors": [{"first": "S", "middle": ["O"], "last": "Kolset", "suffix": ""}, {"first": "F", "middle": ["P"], "last": "Reinholt", "suffix": ""}, {"first": "T", "middle": [], "last": "Jenssen", "suffix": ""}], "year": 2012, "venue": "J Histochem Cytochem", "link": "29502959"}, "BIBREF1": {"title": "Diabetic nephropathy: mechanisms of renal disease progression", "authors": [{"first": "Y", "middle": ["S"], "last": "Kanwar", "suffix": ""}, {"first": "J", "middle": [], "last": "Wada", "suffix": ""}, {"first": "L", "middle": [], "last": "Sun", "suffix": ""}, {"first": "P", "middle": [], "last": "Xie", "suffix": ""}, {"first": "E", "middle": ["I"], 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Effects of insulin deficiency (ID) on cell proliferation and ECM synthesis in cultured renal MCs. (A)Cell proliferation was measured by BrdU incorporation assay. The cells were cultured in different concentrations of insulin (300-0 \u03bcU) for 48 h. The data are expressed as the mean\u00b1SEM of 8 experiments. b P<0.05, c P<0.01 vs insulin 300 \u03bcU. The relative protein levels of fibronectin (B) and collagen IV (C) were analyzed by Western blot. The data are expressed as the mean\u00b1SEM of 3 experiments. c P<0.01 vs the control [insulin (100 \u03bcU)].", "type": "figure"}, "FIGREF1": {"text": "Figure 2. Effects of insulin deficiency (ID) on insulin receptor (IR), IGF-1R and IGF-1 expression in renal MCs. The cells were deprived of insulin for 48 h. The relative protein levels of IR (A) and IGF-1R (B) were analyzed by a Western blot assay. (C) The IGF-1 mRNA levels were analyzed by realtime PCR. The data are expressed as the mean\u00b1SEM of 3 experiments. b P<0.05, c P<0.01 vs the control [insulin (100 \u03bcU)].", "type": "figure"}, "FIGREF2": {"text": "Figure 3. IGF-1R antagonist PPP inhibited insulin deficiency (ID)-induced cell proliferation and increase in ECM synthesis in renal MCs. (A) The cells were treated with ID for 0-120 min. Phospho-IGF-1R (Tyr1135/1136) was analyzed by a Western blot assay. The data are expressed as the mean\u00b1SEM of 4 experiments. b P<0.05, c P<0.01 vs the control [ID (0 min)]. (B) The phosphorylation of IGF-1R was observed by a Western blot assay after the cells were pretreated with PPP 50 nmol/L or a diluent for 60 min and deprived of insulin for 5 min. (C) Cell proliferation was measured by a BrdU incorporation assay after the cells were pretreated with PPP 50 nmol/L or a diluent for 60 min and deprived of insulin for 48 h. The relative protein levels of fibronectin (D) and collagen IV (E) were analyzed by Western blot assay. The data are expressed as the mean\u00b1SEM of 8 experiments (C) and 4 experiments (D and E).", "type": "figure"}, "FIGREF3": {"text": "P<0.01 vs the control [ID (-) and PPP (-)].", "type": "figure"}, "FIGREF4": {"text": "Figure 4. Effect of IGF-1R siRNA transfection on insulin deficiency (ID)-induced cell proliferation and the effect of exogenous IGF-1 on the proliferation of renal MCs. (A) The protein level of IGF-1R was detected by a Western blot assay after the MCs were transfected with an IGF-1R siRNA (50 nmol/L) or a control siRNA (50 nmol/L) for 48 h. (B) The effect of the IGF-1R siRNA on ID-induced proliferation in renal MCs. Cell proliferation was measured by a BrdU incorporation assay after siRNA transfection for 48 h. (C) The effect of exogenous IGF-1 on the proliferation of renal MCs. Cell proliferation was measured by a BrdU incorporation assay after the MCs were treated with ID or IGF-1 (50 nmol/L) for 48 h. The data are expressed as the mean\u00b1SEM of 3 experiments (A) and 8 experiments (B and C). b P<0.05, c P<0.01 vs the control. e P<0.05, f P<0.01 vs ID [ID and NC siRNA)].", "type": "figure"}, "FIGREF5": {"text": "Figure 5. Effects of IGF-1R blockade on the physiological parameters in the diabetic rats. (A) Body weight and (B) urine volume were measured every two weeks after the STZ injection. (C) Twelve weeks after the STZ injection, the rats were euthanized, the kidneys were collected, weighed and the ratio of kidney weight to body weight was calculated. (D) Blood glucose was measured one week before the STZ injection and every two weeks after the STZ injection. (E) Six weeks after the STZ injection, the blood glucose level was measured after insulin administration for 4 h and 12 h. (F) Glucosuria was detected by a glucosuria detection kit before the STZ injection and 6 and 12 weeks after the STZ injection. The data are expressed as the mean\u00b1SEM of 7 experiments (B and F) and 10 (A, C, D and E) experiments. c P<0.01 vs Con. f P<0.01 vs DM.", "type": "figure"}, "FIGREF6": {"text": "Figure 6. Changes in IGF-1 and IGF-1R protein and IGF-1R phosphorylation levels in diabetic rat kidney tissues. At the end of the study (12 weeks after the STZ injection), the protein levels of IGF-1R (A) and p-IGF-1R (B) were analyzed by a Western blot assay. (C) IGF-1 protein levels were analyzed by ELISA. The data are expressed as the mean\u00b1SEM of 6 experiments. c P<0.01 vs Con.", "type": "figure"}, "FIGREF7": {"text": ".01 vs DM.", "type": "figure"}, "FIGREF8": {"text": "Figure 7. Effects of IGF-1R blockade on renal function in diabetic rats. (A) The urinary protein was detected by a urinary protein detection kit every two weeks after the STZ injection. At the end of the study (12 weeks after STZ injection), plasma creatinine (B), and plasma BUN (C) were detected, respectively. The data are expressed as the mean\u00b1SEM of 6 experiments (A) and 10 experiments (B and C).", "type": "figure"}, "FIGREF9": {"text": "Figure 8. Effects of IGF-1R blockade on ECM synthesis and TGF-\u03b2 protein levels in diabetic rats. At the end of the study (12 weeks after the STZ injection), a Western blot revealed the protein levels of fibronectin (A), collagen IV (B) and TGF-\u03b2 (C). The data are expressed as the mean\u00b1SEM of 6 experiments. c P<0.01 vs Con. f P<0.01 vs DM.", "type": "figure"}, "FIGREF10": {"text": "Figure 9. Effects of IGF-1R blockade on renal morphology in normal and diabetic rats. At the end of the study (12 weeks after STZ injection), kidney histology was examined by HE (A), PAS (B) and Masson's trichrome staining (C). Original magnifications \u00d7400. (D) Part of the right kidney was fixed in 2.5% glutaraldehyde for electron microscopy, and the ultrastructure (glomerulus basement membrane and podocyte processes) of the kidney was observed at magnifications of \u00d71500 and \u00d74000, respectively.", "type": "figure"}, "TABREF0": {"text": "www.nature.com/aps Kong YL et al Acta Pharmacologica Sinica npg t-test. All of the group data were tested for normal distribu- tions before statistical comparisons. P<0.05 was considered a statistically significant difference between groups.", "type": "table"}, "TABREF2": {"text": "www.nature.com/aps Kong YL et al Acta Pharmacologica Sinica npg that there is IGF-1R expression in the kidney", "type": "table"}}}